·Die Tuberculose der Leber ist in Il'iderspruch zu den bisher gebrauchlichen Angaben eine der lufigsten secumdaren Tuberculosen nicht unter des kindlichen, sonduru ist gleicher IV'erse auch dus eru achsenen Alters Nichr gur selten sind alle oder einzelne Tiiberkel nur roskopisch sichtbar Die Sympionie der Lebertuberkein terden so lange unbekannt sein, als die Diagnose der Leberkrankheten berhaupt noch so schu serig ist Ivie bisher E WAGNER (1861)

·TUBERCULOSIS
AND
ASPIRATION LIVER BIOPSY
ITS CLINICAL SIGNIFICANCE IN DIAGNOSIS AND THERAPY
BY
AJ CH HAFX MD
Head of the departs ent of Ga truer ter ! gy
Rjk miers te Leiden
AND
CORNELIA VAN BEEK
Instrutor Iath I sy
Ryksu neric Leiden
HAARLEM
DE ER VENT BOHN N V
1955

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·IN MEMORY Or PROFESSOR HA KUENEN MD

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·FOREWORD Aspiration liver biopsy can be considered as a justifiable procedure in patients suspected of liver disease assuming that the right indications are present and the clotting mechanisni has been thoroughly examined--but cvery proposal to extend the indications for biopsy has to be judged critically on its merits and on the value in diagnosis and treatment in cach individual case in which one wants to apply thic method The skill and the caution of the person who has to perform the biopsy counts in the assessment too It us fortunate therefore that my colleague Dr A J Cu Baex who is the originator of the problem that led to the publication of this monograph possesses both these qualities The results of the investigations described in this monograph are so great that one may consider the biopsy wholly justified in the many difficult cases of tuberculosis where this so important diagnosis is in doubt provided that the patho logical technique lad down by Miss C JAN Brek is followed For every older clinician who has had in the past some difficulty in imagining tlic node of origin of haematogenous cuberculosis of organs in general this monograph will be a res clation Besides thus we are shown clearly that an early and accurate diagnosis of doubtful tuberculosis of the lungs or any other organ as well as of the classic muliary tuberculosis has become readily attunable so that antibiotic treatment can be instituted as carly as possible Thirt this is for the benefit of many patients who have had to do without this treatment in a decisive stage of their illness because of the difficults of earli diagnosis Lues without saying J MULDER

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·ACKNOWLEDGMENT With reference to the well-known fact that in sarcoidosis thcic are lesions in numerous organs (eyes, salivary glands, lungs, kidneys, bones) we set out in 1940, with the help of aspiration Irver biopsy, to find out whether this disease causes such changes in the liver also The tubercles which we found in nearly 100% of our cases greatly resembled those found in tuberculosis and we tried to ascertain whether there were any histological differences between the tubercles of tuberculosis and those of sarcoidosis, for this we performed aspiration liver biopsy 112 patients with tuberculosis We owc a grcat debt to the late Prof KUENEN University Hospital, Leiden, for the fact that he agreed to do these investigations in his clinic at a time when the clinical development of the liver biopsy had hardly begun During the war the investigations had to be discontinued, but after the war – I'rof KUENEN having retired in thc mcanu lulc - they were resumed with the full co-operation of luis successor, Prof Mulder For las co-operation we wish to express our thanks to him here Thanks to the scrupulous care with which our techniczın, Miss A Suit made the serial sections, it was possible for us to do serial camination in all our cases Without these it would have been difficult not to say impossible, to find the smaller lesions of types III and IV and the diagnosis of tuberculosis would have been russed many times for the devotion with which slic pertorned her share in our work wc want to render thanks to Miss SuIT

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·ACKNOWLEDGMENT With reference to the well-known fact that in sarcoidosis there are lesions in numerous organs (eyes, salivary glands, lungs, kidneys, bones) we set out in 1940, with the help of aspiration liver biopsy, to find out whether this discase causes such changes in the liver also The tubercles which we found in nearly 100% of our cases greatly resembled thosc found in tuberculosis and we tried to ascertain whether there were any histological differences between the tubercles of tuberculosis and those of sarcoidosis, for this wc perfornied aspiration liver biopsy ui patients with tuberculosis We oue a great debt to the late Prof KveNEN, University Hospital, Leiden for the fact that he wgreed to do these investigations in his clunc at a time when the clinical development of the liver biopsy had hardly begun During the war the investigations had to be discontinued but after the war - Prof Kuenen having retired in the meanwhile -- they werc resumed with the full co-operation of his successor, Prof MULDER For his co-operation we wish to cxpress our thanks to him here Thanks to the scrupulous care with which our technician, Miss A SMIt made the serial sections, it was possible for us to do serial crimination in all our cases Without these it would have been difficult not to say impossible to find the smaller lesions of types III and IV and the diagnosis of tuberculosis would have been missed many times For the devotion with which she performed her share in our work we want to render thanks to Muss SMIT ·For the financial help we express our thanks to the Board of the 'Jan Dekker Fonds' We owe gratitude to Mr P A BOUTER who made the photomucrographs In conclusion we want to express our thanks to Dr BERNARD LENNOX of the Postgraduate Medical School of London for his assistance with the translation of this monograph ·CONTENTS 1 11 20 Foreword Acknowledgment reface I Technique and contra-indications S II Introduction III Pruinary infection 16 IV Typhobacillosis of LANDOUZY V Erythema nodosum and crythema induratum (Bazin's disease) 261 VI Miliary tuberculosis 32 VII Tuberculous meningitis 38 VIII Tuberculous pleurisy 47 IX Tuberculous peritonitis and abdominal tuberculosis so X Tuberculous pericarditis S3 XI Pulmonarı tuberculosis S6 XII Tuberculosis of the ly niplı nodes 60 XIII Tuberculosis of the kidncy OS XIV Tuberculosis of the adrenals 6S XV Bonc and joint tuberculosis 70 XVI Tuberculosis of the cic 74 XVII The significance of subtubercles of cypes III and IV 77 XVIII Sonic general observations 84 References Tables Photomicrographs 97 101

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·PREFACE In spite of the multiplication of modem niethods of clical invcstigation in liver disease, especially the numerous liver function tests, we are forced to adnut that in many cases diagnosis is still by no means casy During the past fifty years, therefore, the need has been increasingly felt for a simple, harmless, and reliable aspiration biopsy method Exploratori liver puncture has been performed for more than a century (particularly in tropical countries) in order to make a diagnosis in cases of abscess and cyst the carliest report we have been able to find was that of STANLEY in 1833 For histopathological examination of the liver, however recourse was nearly always made to laparotomy with formal surgical removal of a ucdge brops from the liver margi For the patient such an operation entails both discomfort and some degree of risk from the pathologists point of view it suffers also the disadvantage that the margin of the liver with its c\ccss of commective tissuç is often a musicadıg sample ! The size of the liver and its position m the right hypochondruum render it casily accessible to nccdle bops Morcover in most cases in wluch we are likely to be interested the layer lesion 15 n ditluse one or if it consists of discrete foc such foci arc ditlusch distributed, so that 1 small biopsy cspecially when it 15 cvamined in scnal section mas very often suffice to giç a completels adequate picture of the state of the cntirc liver It is only in the presence of focal morbid conditions such as for mistance localized tumours that needlc biopss is not suitable in shut we are more or less dependent on chance for obtaining an adequate sample in such cases The first mcntis aspiration liver biopsy was that of von Fre- RICES whose assistant l'AUL ETIRLICH uscd thus technique to study che glicogen content ot the later in diabetes mellitus (1884) ·2 PREFACE Good results were obtained by SCHUPFER (1907), BINGEL (1923) and OLIVET (1926), but owing to the risks attached to their technique it failed to acquire any general popularity Thanks to the work of IVERSEN and ROHOLM (1939) we have now a satisfactory and safe method, one which we ourselves have used on approximately 2000 occasions without a single serious complication Some pathologists are rather sceptical of the diagnostic possibilities of a small column of liver tissue, i} to 3 cm long, and I to 1, mm in diameter In our opinion, however, these possibilities are very great, exceeding those of marginal biopsy in laparotomy, and, paradoxical as it may seem, have advantages even over the larger pieces of tissue obtained at autopsy On account of the small size of an aspiration biopsy all the details may be examined with a minuteness seldom possible in studying the larger pieces examined at autopsy When moreover the little column of aspirated tissue is examined in_serial_section, one learns to know the normal and the pathological patterns of the liver in a manner impossible in autopsy tissues, unless the needle technique is applted in them also, for serial examination of a relatively large portion of the liver, such as is ordinarily used for postmortem histology, is so exacting that one loses one's pattern Apart from the diagnostic (and therefore therapeutic) possibilities of the method in studying liver diseases, the aspiration biopsy offers similar advantages in other diseases (Hodgkin's disease, sarcoidosis, tuberculosis, berylliosis, etc) From a more general standpoint the aspiration liver biopsy is also very valuvable At autopsy one learns to know only the final stages of disease, biopsy, on the other hand, gives a dynamic character to histopathology, so that the pathogenesis of many diseases is illuminated It should also be remembered that postmorteni histology is considerably disturbed by the autolytic changes to which the liver is so liable Needle biopsy of the liver only serves a useful purpose of full cooperation on the part of the pathologist can be assured. way in the liver ·PREFACE لیا The physician nuse have a perfect knowledge of the technique the indications and the contra-indications but the pathologist must also be an arc of the high demands that will be made upon lun He must be cxpert in the pathology of the liver and he must be prepared for the laborious examination of serial sections which greatly increases the value of the method and is in some cases indispensablc Finally one must also be able to rely on the meticulous assistance of a skillcd tcclinician In this monograph we are concerned with the use of the aspiration liver biopss in the carly diagnosis the therapy and the prognosis of the different fornis of tuberculosis It is especially in tliesc cases that serial sections are important and as their çuamination may take up a great deal of timc one might bu inclined to question the economics of the method in the anrlogous situation of the examination of bronchial sccrctions for tumour cells WOOLNER and McDONALD describe a workable procedure The slides are examined systematically by trained technicians and the suspicious arcas marked for verification by the pathologist The sind working method may be followed in the detection of tubercles in luser biopsies Necdle biopsy is only justifiable if the abovcmentioned con ditions are adequately fulfilled but when that is so the results ure so spectacular that the little group of workers concerned count all their pains will spent

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·CHAPTER I TECHNIQUE AND CONTRA-INDICATIONS Before discussing the diagnostic value of aspiration Iner biopsy in the various forms of tuberculosis, we think it proper to give a summary of our nicthod and to discuss the contra-indications which we consider inportant TECIINIQUE (AFTER IVERSEN AND ROHOLM) Aspiration biopsy of the liver is performed with a dry sterilized needle of V2A stcel, 18.cnulong and with a diamicter of 1.4-16 wm with sharp serrations at the end, and provided with a trocar and a dry-sterilized 10 ml syringe with a stopcock The exact site for the liver biopsy is carefully cstablished For anatomical reasons, puncturc is performied in the postenor aullary line (personally we prefer a slightly morc dorsal location) a little below the margin of the diaphragmı and the lung, and TIemer below the 9th intercostal space In e\ceptional cases puncture of very large livers may be performed at a slightly lower point but this should be done for very special reasons only if the puncture is made in the 8th or oth intercostal space and slightly dorsal to the posterior axıllar; linc, there will be no risk of fatal injury to vital parts and in this respect there could be no better place for the operation Puncture is pertormed with the patient situng or lying, in the latter case preferably with the paticut lying on lus icft side We prefer die sitting position, others (VIRSEN and ROHOLM) the lateral recumbent position on the left side It is desirable to hasc an X-ray of the thorax and the lopatic region prior (odlic operation as it has become cudent that subnormal conlevt of the diphragm may be responsible for failure of tlic 2 ·6 TECHNIQUE AND CONTRA-INDICATIONS puncture Interposition of an intestinal loop which has not been identified may have most unpleasant consequences but we never saw any complications of this type after accurate percussion At the slightest sign of tympanism in the hepatic region we make an X-ray examination, which is often extended to the colon When the exact site has been located, the skin is thoroughly cleared, first with alcohol and then with iodine The skin and underlying tissues are then anaesthetized, after thus the needle track (up to and including the diaphragm and peritoneum) is anaesthetized, particularly during deep expiration With adequate practice, the anaesthesis can be made efficient enough to eliminate pain almost completely from the operation The crucial point is the diaphragmatic pleura If a thick trocar is used, incomplete anaesthesia of this structure may give to violent pains in the epigastrium, often radiating to the shoulders, which may cause shock A2 per cent novocaine solution is used as an anaesthetic We have discontinued the combination of novocaine and adrenalin, as this sometimes resulted in a slight collapse Such a collapse, though not serious in itself, necessitated postponement of the biopsy Part of the novocaine may enter the blood stream, and also cause a minor collapse When the anaesthetic has been injected, the patient must be trained to make a deep expiration and then refrain from breathing focabout 10 seconds. At the previously determined spot the skin and fasciae are pierced by a vaccination stylet, and the liver needle with trocar in place is then inserted If then it is found that the local anaesthetic is adequate, the liver needle now penctrates through the pleural sinus into the diaphragm, tlus can easily be observed, as the trocar follows the respiratory movements The patient is now requested to stop breathing for 10 seconds, and fix lus chest in the position of deep expiration, in which, for obvious reasons, liver biopsy is most casily performed Next the needle pierces the diaphragm, the trocar is withdrawn and the 10 ml syringe with stopcock is attached to the needle A vacuum is then produced by withdrawing the piston of the syringe as far as possible The needle is now introduced into the ·* TECHNIQUE AND CONTRA INDICATIONS 7 liver for a few centmetres a rotary movement found its long axis beng given to it as it advances This action punches out a small piece of liver tissue The needle is then quickly withdrawn from the liver care being taken that the syringe remains firml coinccted as otherwise the operation will definitely fail Atmospheric pressure now pushes the piece of liver tissitc into the vacuunt of the syringe Sometimes the fragment of tissue lodges in the needle this should be born in mind if a failure is suspected As a rule the liver tissue is fixed in a 4 per cent solution of formaldehyde and processed like other biopsy material GILLMAN and GILLMAN have des cloped a promising technquc the needle and the syringe arc permanently attached to each other the trocar in tlic nccdlc is fixed to the piston which therefore withdraws the trocar along with it when a vacuum is produ ccd This naterially reduces the time needed for the operation At cach puncture we should consider the necd for a culture of pathogens (B coli tubercle baallı etc) from the liver tissue and for a smear to be stained by GIFMSA S method which may be used together with the blood smear React ons We must now consider the possiblc reactions which nay follos puncture These are generally slight some patients do not feel any clunc at allIf necessary wc even perform puncture on out patients who return home after a few hours rest l'ossible reactions are i Epigastric pain with possible radiation to the shoulders (usually the neht) originating from the diaphragmic pleura This pain usually subsides rapidly After biopsy sonic patients have pain on brcathing for some hours after the effect of the anacsthesia has ccased in such cases 16 15 adussable to gue a subcutaneous injection of mo mg of pantopon 3 Sonctimes there is a slight risc of temperature for a short period If this should last it may indicate a complication resultint c. 5 from a non-sterile needle or a luser infection Wcharc seen one such case only in our own series (aver infection) wel sphy Mix and CAINI !! ) + ·6 TECHNIQUE AND CONTRA-INDICATIONS puncture Interposition of an intestinal loop which has not been identified may have most unpleasant consequences but we never saw any complications of this type after accurate percussion At the slightest sign of tympanism in the hepatic region we make an X-ray examination, which is often extended to the colon When the exact site has been located, the skin is thoroughly cleared, first with alcohol and then with 1odine The skin and underlying tissues are then anaesthetized, after this the needle track_(up to and including the diaphragm_and peritoneum) is anaesthetized, particularly during deep expiration With adequate practice, the anaesthesis can be made efficient enough to eliminate pain almost completely from the operation The crucial point is the diaphragmatic pleura If a thick trocar is used, incomplete anaesthesia of this structure may give rise to violent pains in the epigastrium, often radiating to the shoulders, which may cause shock A 2 per cent novocaine solution is used as an anaesthetic We have discontinued the combination of norocare and adrenalin, as this sometimes resulted in a slight collapse Such a collapse, though not serious in itself, necessitated postponement of the biopsy Part of the novocaine may enter the blood stream, and also cause a minor collapse When the anaesthetic has been injected, the patient must be trained to make a deep expiration and then refrain from breathing for about 10 seconds At the previously determined spot the skin and fasciae are pierced by a vaccination stylet, and the liver needle with trocar in place is then inserted if then it is found that the local anaesthetic is adequate, the liver needle now penetrates through the pleural sinus into the diaphragm, this can easily be observed, as the trocar follows the respiratory movements The patient is now requested to stop breathing for 10 seconds, and fix his chest in the position of deep expiration, 111 which, for obvious reasons, liver biopsy is most easily performed Next the needle pierces the diaphragm, the trocar is withdrawn and the 10 ml syringe with stopcock is attached to the needle A vacuum is then produced by withdrawing the piston of the syringe as far as possible The needle is now introduced into the ·7 TECHNIQUE AND CONTRA-INDICATIONS liver for a few centimetres, a rotary movenient round its long axis being gncn to it as it advances Tlus action punches out a small piece of livet tissue Thc needle is then quckly withdrawn from the liver, care being taken that the syringe remains firmlı connected, as otherwise the operation will definitely fail Atmospheric pressure now pushes the piece of liver tissuc into the vacuum of the syrmige Somctimes the fragment of tissuc lodges in the needle, this should be born in mind if a failure is suspected As a rule the liver tissue is fiasd in a 4 per cent solution of formaldehyde and processed like other biopsy material GILLMAN and Gillman have developed a promising technique, the needle and the syringe are permanently attached to each other, the crocar in the necdle is fixed to the piston, which therefore withdranıs the trocar along with it when a vacuum is producd This matenally reduces the time needed for the operation At cach puncture we should consider the necd for a culture of pachogens (B coli, tubercle bacıllı etc) from the liver tissue, and for a smear to be stained by GIEMSA's method, which mas be used together with the blood smear Reactions We must now consider the possible reactions which may follou puncture These are generally slight, sonc patients do not feel anything at all If necessary sc even perform puncture on out-patients who return home after a few hours' test Possible reaccions are 1 Epigastric pain, with possible radiation to the shoulders, (usually the right) onginating from the diaphraginic pleura This pain usually subsides rapidly . After biopsy some patients have pain on breathing for some hours after the effect of the anaesthesia has ceased in such cases It is advisable to give a subcutançous injection of 20 mg of pantopon Sometimes there is a slight rise of temperature for a short period If this should last it may indicate a complication, resulung og from a non-sterile needle or a liver infection We have seen one such case only in our own series (hver infection) * (sec bibhography GALLMAN and COZMAN HAEX) * ·8 TECHNIQUE AND CONTRA-INDICATIONS 4 Occasionally we have observed slight shock of short duration, never severe shock necessitating a blood or plasma transfusion s Very rarely we have seen a temporary paralytıc ileus We have not established the cause of this, but we believe it arises from irritation of the peritoneum or perhaps a slight haemorrhage in the abdomen 6 Thrice we observed a slight pneumothorax which did not affect the patient at all Complications Is there any risk attached to liver biopsy? This question must be answered in the affirmative injudicious use of the needle or an incorrect indication may cause serious com plications, which may even be fatal These complications may be I Haemorrhage, which may be prevented in most cases. We have never seen a severe haemorrhage On one occasion we observed at laparotomy some blood in the abdominal cavity of a patient who had been punctured some days before the operation, but had not shown any severe reaction In order to prevent unexpected copious haemorrhages it is essential to examine the clotting mechanism in every patient, as discussed below under contra-indications 2 False route (technical failure) Not real 3 Infection (incorrect indication or nonsterile needle) complications Failure of the operation may be due to i Insufficient convexity of the diaphragm 2 Imperfect or non-airtight attachment of the syringe to the needle 3 Right pleural effusion or ascites 4 Poor condition of instruments (leakıg syringe, blunt needle) 5 Patient s collapse following anaesthesia CONTRAINDICATIONS Aspiration biopsy of the liver, if practised without sufficient knowledge of contra-indications, constitutes a serious threat to the ·TECHNIQUE AND CONTRA-INDICATIONS patient s life The following is a summary of these contraindicagons 1 Humorrhagic tenduscy In order to establish the condition of the patient s clotting mechanism it is necessary to determine the bleeding cloting and prothrombin cimes of the blood Our routine preliminari cxammauon includes also determination of clot retraction and thrombocy to count Persistent deviations from normal in any of the above figures contra-indicatc biopsy This restriction often prevents biopsy in a case in which it appears to be indispensable to establish a diagnosis Nevertheless the temptation to attempt puncture under these circumstances should be resisted In case of doubt it is better to postpone the operation and make a final decision lacer In any cient jaundiced paticiits should be given vitamin K two or three days before the operation On no account should it be performed until the prothrombin truc has become normal 2 Cholangitis Biopsy is dangerous in cases of jaundice with fever accompanied by the presence of B coli or other pathogens in the duodenal Aud (when as a matter of fact gallstones are usually presene) Exen a slight haemorrhage caused by puncture may carry infected matter (blood or bıle) from the liver into the abdomual cavity and cause serious peritoneal reactios a subphrenic abscess or even diffuso peritonitis In such cases therefore cxammation of the duodenal Aud is necessary in order to identifi a possible inflammation of the intrahepatic bilary ducts (cholangiolitis) It will often be necessary to forego histological examination of the liver for this reason in cases where it would have been very valuable The liver of a patient suffering from obstructive jaundice due to carcinoma may be infected couisequently great caution should be exercised in performing biopsy on such patients 3 Laser puncture is inadvisable when the patient is suffering from an intercurrit o ficho: An existing bacteriaenua might infect the haematoma of the puncture chus causing a subplurenic abscess 4 An astle uc lud necessitates greater caution among other ·IO TECHNIQUE AND CONTRA-INDICATIONS rersons because puncture is made more difficult by the visceroptosis which is so often found with this type of physique s Like IVERSEN and ROHOLM, we consider right-sided pleurisy a contra-indication - a matter which needs no further anatomical argument 6 Puncture should not be performed on patients suffering from a local skin infection (risk of infection) 7 As some patients are prone to increased haemorrhage during nitenstruation, puncture should not be performed during the periods 8 A possible anomalous position of viscera (situs inversus) should be taken into account Particular attention should be paid to interposition of the colon, which may be ascertained by careful percussion or X-ray examination before the operation 9 With children it is, of course, generally inadvisable to attenipt puncture they cannot hold their breath Exceptions might be made for very large livers (see bibliography van Beek and Haex) 10 It goes without saying that a puncture is inadvisable when the patient is suffering from a coronary arterosclerosis Puncture should not be performed on patients suffering from amyloidosis, 12 That lack of cooperation on the part of the patient is a contra-indication goes without saying The general rule is No puncture should be performed on any patient on whom a laparotony 11 ould be deemed madvisable!!

·CHAPTER II INTRODUCTION We propose to discuss first the valuc of aspiration bropsy of th liver with regard to the diagnosis the therapy and thc prognosis uf tuberculosis before going on to sketch the valuc of aspiration In er biopsy in relation to the pathogenesis of tuberculosis The fragment of liver tissuc obtainable by veedle bropsy minutc though it is is sufficicut to influence fundamentally the clinical practice of tuberculosis in the course of ame pathology has gradually developed from a static science based on the jutopsy into a more dynamic branch of medicine By means of biopsies we are now learning the listopathological substrate of various chirucal pictures in all their stages Aspiration liver biopsy an particular has proved to be a most valuable and in the diagnosis of numerous diseases we słuall cramphfy this in the case of tuberculosis by means of extensive investigations The starting-point as an observation made in 1941 thao in practically all cases of sarcoidosis tubercles and small epithelord cell granulomala could be found in the liver brops; Thus made examination of serial sections indispensable In order to find out whether there were any histological differences berwen the cubercles of sarcoidosis and those of tuberculosis wc perforsed laser biopsies in 1946 on fifteen patients in whom the diagnosis of tuberculosis had been established bacteriologically - almost all bemg cases of pulmonary tuberculosis and none having clinical ulary tuberculosis On curang senial sections of the liver fragments from these is cases we found tubercles in fourteen In addition to the well-known caseating and epitheloid-cell tubercles and conglomerate subercles in the portal ·12 tures except, that INTRODUCTION spaces, we observed, just as in sarcoidosis, minute epithelioid-cell granulomata in the parenchyma In early 1947 the serial-section examination of forty liver biopsies in sarcoidosis and forty biopsies in tuberculosis showed that it was impossible to establish clear histopathological differences between the two clinical pic- 15, for caseation, wluch we never observed in sarcoidosis (there are, however, a few reports in the literature of necrosis in this disease) These investigations led us to enlist the liver biopsy as an ad in the early diagnosis of tuberculosis When streptomycin and P.A S made their appearance the whole picture of the therapy and prognosis of the disease was altered To the diagnostic indication for liver biopsy now the therapeutic-prognostic one was added, for modifications in the clinical picture due to modern antibiotic and tuberculostatic treatment could be elucidated when liver bropsies were performed every two or three months Since 1947 some results have been published It has seemed to us desirable to classify the tubercles that were found more carefully than is usually done Without the examination of serial sections it is impossible to acquire a full picture of the exact location, the size, the presence or absence of caseacion or fibrinous exudation, the type of cellular exudation, the presence and the type of the giant cells, and the age of the lesion The number of foci and their localization size, character, and age are ascertained not only for scientific reasons, but also for practical clinical purposes All this is set out in what we have called the tuberculogram of the liver (see table III) Over one hundred sections of each liver biopsy were examuned Among the advantages of thus method of examination was the frequent demonstration that tubercles which seemed to lie in the parenchyma could be proved several sections later to be attached to 3 portal space Caseation was only occasionallı observed, unless the case was one of miliary tuberculosis When cascation was present, it was nearly always possible (though sometinies only after a prolonged search in many sections) to demonstrate some acid-fast rods, sometimes in the caseous mate- ·INTRODUCTION rial, but more often phagocytosed by the giant cells outside it. As we found that staining according to HALLBERG }icided beercr results than the ZIEHL-NELLSEN technique, we used only the former method On only a few occasions as it possible to demonstrate acid-fast rods in non-casearing epicheliosd-cell tubercles With regard to the grant cells, too, serial cronunaton proved very instructie in 1868 LANCHANS called attention to che peripheral distribution of the nuclei, wluich arc found someumes in the form of a circle, but sometimes in polar groups Serial examination showed us the grant cells in three dimensions, which sometimes yielded surprising results At present we will only say that the gasit cell type afterwards called after Langitans, with the nucles in the form of a circle or a horseshoc, is by no ineans always present or predommant Wc often came across grant cells (also described by LANGKANS un cuberculosis) of the oreign body type and the bcnign giant-cell tumour type The } toplasm is often large and vacuolated, dozcts of nucle bang seen together We observed neither mitotic figures in the giant cells, nor SCHAUMANN'S corpuscles On one occasion à grant cell was seen to contain a so-called astcroid body" Our insestigations did not yield any suggespons regarding the origin of the grant cells we are unable to say whether they result from repeated mucosis without cell division or from fusion of many cpithelioid cells As for the cells of the connective tissue, no fresh pomts of view emerge According to the age of the lesion cpithelioid cells (occasionally dividing), fibroblasts, young and old fibrocytes, and finally scar aissue wich or without hvalınusation were seen We gamed the impression that it is especially the cascous tubercle wluch becomes transformed into the so-called hy alime ball Special attention was devoted to the cellular exudate Young cubercles, bult up of epithelard cells contain lymphocytes, side by side with neutrophils and or cosinophuls, and sometimes plasma cells Older tubercles contan only lymphocytes The age of the tubercle can be esaimated from the elements of the ·14 INTRODUCTION connective tissue, the presence of mitoses, and the type of the cellular exudate present Finally we wish to call attention to several points which the serial sections taught us regarding the size of the tubercles First of all we must point out that the word "miliary" is often used in a wrong sense It really means "the size of a nullet seed' (1 e 2-3 mm), and therefore a miliary tubercle must be easily visible to the naked eye Microscopically, such lesions mostly prove to be conglomerate tubercles Autopsy experience shows that true miliary tubercles are not often seen in the liver, submiliary tubercles, on the other hand occur very frequently As the standard liver biopsy has a diameter of about 15 mm, it is clear that only part of any miliary tubercle could be present in the biopsy, never a complete lesion So far we have not seen a single example We must, of course, allow for the possibility that the needle slips past a lesion of this size As most tubercles in the liver are of submıllary size it is this type that is found in the liver biopsy We have subdivided these tubercles into five types, viz 0,1, II III, and IV this classification is based on the greatest diameter observed in the series (see Table 1 and photonucrographs) The largest are macroscopically almost the size of a pin's head, and as they are extremely rarely seen in the liver biopsy we have ranged them under the type o Microscopically they are mostly, but not always conglomerate tubercles They are situated in the portal spaces, and may have caseous centres Of the submiliary tubercles of types O, I and II type I and especially type II are the ones which occur most frequently in the liver in cases of tuberculosis, irrespective of the location of this disease in the body They are nearly always found in the portal spaces The skilled observer can just obserse them with the naked eye as minute grayish-white points They often contain giant cells and are sometimes caseous Like type Othey form scars and may become hyalıne balls When such a hy alıne ball is examined in serial sections a giant cell may suddenly emerge and also a solitary lymphocyte The smaller types III and IV are only visible under the micro- ·INTRODUCTION 15 scope They occur in the parenchyma as clearly outlmcd epitic loid cell granulomata of round to oval shape they very rarel contain a giant cell Most often they are situated near the centre of the liver lobulc occasionally attached to the wall of the central cih more often to a hyperaemic capılları They never cascate The cpithelioid cells do not become ordinary fibrocytes their nucleus which is at first vesicular and palcstuning beconies in They will be considered in greater detail in Chapter XVIII Meanu lule Table / summarizes the character of the five types of rubercles Lesions of types III and IV differ in several aspects besides their small size from classical tubercles and we propose mi what follows to refer to thein as subtubercles using the word mberck 352 general ccrm for the whole series and submiliar) Abercle to refer especially to lesions of types o I and II We introduce tlus nos term subrubercle with considerablc trepidation but it scems to us a great advantage to mark in tus way their difference from the generally recogruzcd larger lesions Although ncarly a century ago several pathologists (WAGNER 1861 VIRCHOW 1863 ORTII 1876 ARNOLD 1880 SINIMONDS 1880) examined microscopically the organs of persons who had died of generalized miliary tuberculosis or cavitating tuberculosis of the luss and recorded the fact that submiliary tubercles occurred frequently in the lever until a short time ago tuberculosis of the liver was looked upon as being cluically of no importance (B FISCHER GRUBER and BOYD) Since 1946 this vicu 1125 been abandoned in our department We shall now pass to a systcniatic discussion of the indications for aspiration Irver biopsy in the various forins of tuberculosis This will be followed by a discussion of the results of our in Seagations after which thus monograph ends with able of the tuberculograms made from the liver biopsies which have been discussed and a series of photomcrographs ·~ ·PRIMARY INFECTION 17 conjunctivitis which howcycf, soon disappeared After rather more than a scar recovery was complete and non, 4 years later she is in good health Cue II Miss v d E, aged zo, had been 1.1 for a fortnight tkr family physician scported that the tuberculin tests were negative Ten days later the cost of iov PIRQUET proved to be strongly positive The physical crainination ded not seveal any abnormalities The tulperature was subfebnic The erythrocyte scduncntacion rate was 32 mm clucing the first hour, and 64 mm duong the second hour The blood picture revealed shght toxic altcrations The roentgenogram of the chest showed in the nght middle zone a sound indistinctly bordered shadow and an enlarged night hilus of sections) 68 sections were stained with lucmatory lin-cosin 70 sections were stared according to HALLBERG but no acid-fast rods were found Among the sections stained with hacmatorylın-cosm 30 foci m tocal were observed of wluch 28 lay in the parenchyma and 2 in the portal traces 21 foc belonged to type 11 7 to rspc 111 and 2 to type IV All were young cpithclord-ceillestoas with marked cellular hyperplasia Several foc were very vaguely outlined against the parenchymi In total 3 grant cells ucrc sien There was no necrosis or fibrinous exudate There were no ncutropluis but besides lymphocytos several cosinophil lcucocytes were observed Condusion Extensive recent hacmatogenous disseinination In consequence of these findings the patent was advesed to undergo a strict rest-cure in a sanatorium Before going there she was subjected to a careful cxamination of the chest on wluch occasion a slight improvement was found She appeared to recover completely after a strict rest-curc of three years duration but 2'/, ycars later a new pulmonary lesena developed Surgery is at present being considered What is the indication for liver biopsy in this type of tuberculosis In the first place the cause of the irregularity observed on the X-ray picture of the chest may be ascertained with great promptitude in some cases at least At present we have nor sufficient cxperience on this subject but wc are of the opinion that there are adequate grounds to expect that this particular ·18 without saying PRIMARY INFECTION form of tuberculosis will not be an exception to the rule that every active tuberculous focus is prone to produce a haematogenous dissenunation, and that this may be detected by means of aspiration biopsy of the liver if the aspirated material is cut in serial section For theoretical reasons also one might expect a haematogenous dissemination of tubercle bacteria from a primary infection this will be especially clear from the fact that in these cases there is no question as yet of any immunity, so that the tubercle bacteria can develop freely It goes that immunity factors play an important (if not decisive) part during the first contact with the tubercle bacıllı Both cases examined in this group have been positive, and though they number only two this would seem to give a substantial amount of support to the above views We need hardly say that in these patients the indications for aspiration liver biopsy do not often arise unless the scientific inquiry is regarded as the main object In spite of this, however, there may be occasions when time presses and it is not possible to await the results of the culture of the sputum or the stomach washings From the nature of things this form of tuberculosis is mostly observed in children, and therefore for accurate diagnosis of an infiltration in the lungs one often has to rely entirely on the clinical and roentgenological findings Generally speaking we consider it unwise to perform aspiration liver biopsy by the IVERSEN and ROHOLM technique in children * This objection does not hold good in the case of adults, it is especially case that this diagnostic method will be often resorted to, as the differential diagnosis of an infiltration in the lung sometinies causes great difficulties Further, it is possible in these cases to establish the presence of a haematogenous dissemination objectively by means of aspiration Iner biopsy This is of paramount in their *We have as yet no personal experience with the GALLMAN BRYDEN needle in children. The GILLMAN brothers (personal communication 1954) have performed many hver biopsies in children w th this needle (constructed for them by BRYDEN) without a sngle mishap (cc Fage 7) ·PRIMARY INFECTION 15, importance, for it is the fresh dessenuinations that are especir sensitive to modern therapeutic agents Later on we shall rex to this in greater detail As in many forms of tuberculosis it is possible in thesc ca to imagine that sınali foci, similar to those in the liver tiss may be found else where in the body, for instance in thc mening It however, m practice impossible to perform lunibar per ture regularly in all these patients Later on we shall ment: the considerations which Inye led us to introducc repea examination of the CSF in a select group of patients LANDOUZY's typlobacillosis and muliary tuberculosis) In the third place, aspiration liver biopsy enables us to obsci the degree of the activity of the process, and it is clear ti generally speaking fresh cubercles are found in these cases would point out once more however that our range of cx] Tience is as yet inadequate to give a final opinion on the actr of these forms of tuberculosis The question of any alterati which may occur in the histological appearances in liver broj at the time of conversion of the tuberculin reaction from neg 1e to positive, and the effect of inoculation with BCG, fascinating subjects for future studies ·22 TYPHOBACILLOSIS OF LANDOUZY we subjected these patients to a number of successive punctures - TL 1 IS CASE HISTORIES Case III Mr W.912/1948, aged 18, had been ill for about six months with periods of high fever On physical examination no irregulanties were found, apart from a doubtfully palpable spleen The crythrocyte sedimentation rate was 36 mm during the first hous, and 85 mm during the second - malities for typh tuberculin test (von PIRQUET) was positive Gradually a fairly distinct shadow became visible on the X-ray of the chest It lay next to the hilar vessels, rendenng the diagnosis of tuberculosis of the hılar lymph glands probable To settle the matter the patient was transferred to our clinic for an aspiration liver biopsy The pathological report on the liver tissue read as follows * The biopsy measured 28 cm long, and was examined in serial sections (108 sections) 66 sections were stained with hacmatorylincosin, and 42 were stained according to HALLBERG No acid-fast rods were observed In the 66 sections stained in the usual fashion 76 tubercls wer found Only 4 of them are portal, the other 72 being situated in the parenchyma Two focs are of type I, 9 of type II 36 of type III, and 29 of type IV Out of the 76 foci 39 are recent, 28 of the intermediate type, and 9 must be called old This leads us to suspect the occurrence of several episodes of dissemination The two tubercles of type I (situated in the portal tracts) contain grant cells and a trace of fibrin Necrosis is nowhere to be observed Several neutrophul lcucocytes and only one cosinophul leucocytc were found in the fresh tubercles Conclusion multiple partly recent, partly older submary tubercles and cpithehoid-cell subtubercles, practically all of them localized in the parenchyma It is most probable that haematogenous disserunanon took place on several scparate occasions The patient was treated with streptomycin and promin combined with good nutrition and strict bed-rest Some time after the liver biopsy was performed the stomach washings proved to contain tubercle baalla on culture One weck after the commencement of anti-bacterial treatment the temperature had fallun to normal valuss the disease subsided graduallı and this was confirmed by a second and a third biopsy, 'done respectively about the middle and at the end of the streptomycin treatment ·TYPHOBACILLOSIS OF LANDOUZY 23 The pathological report on the second liver biopsy, which was performed nearly two months after the first onc, read as follows *The biopsy measured 1 2 cm long, and was cramuned in serial section (108 sections) In total 34 foci were found, 33 of them being in the parenchyma, and one portal Four foc arc of type II, 19 of type III, and I of type IV. Out of the 34 there are 4 of a recent type, 18 of an intermediate type, and 12 are old (the latter include 3 scars) No necrosis or fibrinous exudation was observed There are no guant cells Eosinophil leucocytes are not observed, but an occasional neutrophil lcucocyte is seen A sporadıc fatty vacuole can be seen in the parenchyma Conclusion multiple, submiliary foa in the parenchynia, showing a shift towards an older type as compared with the previous biopsy." The pathological report on the third biopsy, wluch was performed cho months after the second, and four months after the first, read as follows. "The biopsy measured 18 cm long, and was cxanuncd in scrial section (122 sections) 29 subtubercles were found, 28 of them being in the parenchyma, and one in a portal tract Out of these, 13 arc of type III, and 16 of type IV Four of them are scars, viz one of type iv, and threc of type III 13 foc are relatively recent Apart from an occasional fatty vacuole and a trace of periportal nuclear glycogen we observed no abnormalities Conclusion Multiple subtubercles in the parenchyma, showing a shift towards a somewhat older type, as compared with the two previous biopsics However, the hacmatogenous dissemination has not yet come to a standstill" After the streptomycin treatment had been completed the patient was discharged in a good condition At home he had to continue the rest cure, combined with good nutrition and extra vitamins The most recent followup cxamination (s years after discharge from hospital) revealed notlung of note from a clinscal point of view He is an excellent condition and has resumed work Case IV' Mr K, 1372/1948, aged 17, became acurcly all three weeks before his admission (temperature 38 4° C, shuvcring, malaise) He also complained of nught sweats and hcadache On admission he had a high fever On physical examination we did not find anything of notc exccpt palpable lymph nodes at the angles of the jaws and in the neck, and a palpable spleen The erythrocyte sedimentation rate was s2 mm during the first hour, and 82 mm dunng the second hour The blood picture showed a slight anaemia (Hb 70%) and slight toxic changes in the leucocytes No ·TYPHOBACILLOSIS OF LANDOUZY abnormalities were found in the urine The tuberculin test (von PIRQUET) was positive The X-ray picture of the lungs showed an cnlargement of the left hilus on tomographic examination, hou ever, it was not possible to demonstrate a definite glandular swelling After the exclusion of other causes that might have been responsible for the chnical picture (the agglutination reactions to typhoid, parityphoid, and bruccilosis werç negative, the urine was sterile and the blood culture was also sterilc), we decided in order to establish the diagnosis to performs an aspiration liver biopsy The pathological report on the liver tissue read “The biopsy mncasured 3 4 cm long, and was examined in serial section (120 scctions) 108 sections were stained with hacmatorylincolin, 12 sections by HALLBERG's method There is a striking hyperacma In total 12 foci were observeril, all of them being of a recent type 15 follows lymphocytes and many neutropluls, besides one acıd-fast rod Out of the other i foci s are of type III and 6 of type IV Scicral portal tracts contain nctitrophtls and eosinophils The parenchyma contains a normal quantity of glycogen Conclumun acute hacmtatogenous tuberculosis Now that the diagnosis of tuberculosis had been cstablished it was decided to treat the patient with streptomycin and pronun Afics seien days his temperature and alrcady fallen considerably Acid-fast rods had incanwhile been found in the patient s sputum but cultures for tubercle bacıllı proved negative Tubercle bacill were never demonstrated by means of any culture technique in this case After the months the temperature was still subfebrile, and it was decided to perform a second liyer biopsy The pathological report of the tissuc read as follows *The biopsy measured 3 1 cm long and was examined in serial section (112 seccions) There are now no fewer than 64 foci of a rather young farge-cellular type but distinctly older than right weeks ago No Necrosis or fibrin is seen any here and there arC DO Sosinophil leucocytes and only occasional neutrophi leucocytes There are a few giant cells of the LANGHANS TYPC Out of the 6t foci 21 are localzedł in the portal spaces and 43 in the parenchyma 13 belong to type II, 34 to type III and 17 to cype IV Conclusion extensive hacmatogenous dissemination Therapy with streptomycin promin, and PAS wuch was added after Sie udeks was therefore continued After three monthus the temperature 91 ·TYY 1 + TYPHOBACILLOSIS OF LANDOUZY 25 was still subfebrile but the crythrocyte sedimentation rate had fallun to gmn during the first hour and 24 mm during the second hour Streptomycin trcatnient was then stopped, and therapy continued with PAS and promin A third biopsy was performed two months after the second The pathological report on the liver tissuc read as follows "The biopsy measured 27 cm long and was cxaminced in serial section (130 sections) In total 41 foci acre observed 2 of which were portal, 39 being situfted in the parenchyma Out of these there ubtubercles II >> portal type II, it is neither an ordinary tubercle nor a scar, but belongs to an mtermediate type Conclusion ft subtubercles predo antly of type IV, and relatively recent The last biopsy showed that the process was saill active, though both the ESR and the temperature had become normal Consequently the print was advised to continue bed-rest and PAS treatment at home His at present in cxcllent health In view of the positive findings in the liver tisslic of the above patients, who were seriously ill and had high temperatures, a strong casc could be made out for regular examination of the CSF, lest the carliest stages of meningitis be missed That this was not done in our patients was due to the fact that at that time our insight into the pathogenesis of the different forms of tuberculosis was not yet sufficiently adequate At present our views have so far been modificd that we believe that the necessity of a regular examination of the CSF depends in most cascs on cal symptomatology, but that in miliary tuberculosis (1c when a miliary picture is visible on the roentgenogram) examination of the CSF should be done at regular intervals independently of the patient's general clinical condition ·CHAPTER V ERYTHEMA NODOSŮM AND ERYTHEMA INDURATUM (BAZIN'S DISEASE) ERYTHEMA NODOSUM Erythema nodosum is a more or less transient “allergic" reaction in which the skin responds to tous present in the blood stream These toxins may be derived from a bacterium or a virus or from some chemical substance of exogenous origin Thus is a non-specific syndrome, whose pathogenesis is at present anything but certain There is no doubt that in medical literature too much stress has been laid on the attempt to find a definite aetiology for every case of erythema nodosum, but we are safe in saying thar the origin of these lestons cannot always be traced to tuberculous infection, although (in Europe at least) this aspect requires especial attention in the myjority of cases In the first place we wish to lay stress on the use of aspiration liver biopsy in any individual case of erythema nodosum in which a tuberculous origin is suspected From clinical statistics it has long been known that erythema nodosum of this type must be ascribed to a haematogenous dissemination of tubercle bacıllı This fact stimulated us to perform liver biopsy in such cases, as we believe that tubercles will be found in the liver in practically all cases of haematogenous tuberculosis In 14 out of 20 cases of erythema nodosum in which we have performed aspiration liver biopsy tubercles were demonstrated in the liver tissue, so that the diagnosis of granulomatous disease could be arrived at with a degree of probability bordering on certainty (Table II) 9 out of the 14 patients with positive biopsy showed enlarged hılar nodes on chest X-ray examination No such changes were ·27 ERYTHIEMA NODOSUM found in X-rays of the 6 patients with negative biopsies 12 of these 14 cases with positive liver biopsies were on clinical grounds diagnosed as tuberculosis, 2 as sarcoidosis In one of the two cases which on clinical grounds were diagnosed as rclapsing acute rhcumatic fever and in one also of two cascs similarly diagnosed as chronic theumatoid arthritis one subtubercle of type IV was found, but we have not yet enough experience to interpret this observation In two cases in which the liver biopsy was negative it proved impossible to arrive at a diagnosis on clinical grounds In the second place, since in cases with a positive biopsy we have irrefutable evidence of blood-spread tuberculous infection, and since we believe that haematogenous dissemination is the principal indication for antibiotic and chemotherapcutic trcatment in tuberculosis, it would appear to be logically necessary to institute such therapy in these cases also Up to the present, however, we have avoided the rigid view that every patient with this clinical picture should be subjected to streptomycin treatnient, if necessary combined with chemotherapeutics, such as PAS, isoniazid or few years ago) sulphetrone or promu, remembering not only that it is possible for streptomycin to cause serious toxic symptoms, but that there is also the possibility of the tubercle bacill becoming resistant, so that such agents could no longer be used in the treatment of later more serious recurrence of the infection It appeared, however, that the use of a combination of agents reduces the chance of development of drug-resistance by the tubcrclc bacıllı The view that every patient with erythema nodosum of tuberculous origin should be treated actively with streptomyan and other drugs is, however, supported by statistics drawn up by MASCHER, who reported that 25 of his patients later developed active pulnonary tuberculosis and a further 28, developed active tuberculosis elsewhere For the present, we believe that therapy should be decided after full clinical assessment of the individual case, considering especially such factors as fever, the general state of nutrition, ·28 ERYTHEMA NODOSUM general synıptoms and age This position may be modified by the discovery of safer and more active remedies against tuberculosis in the future The following case illustrates our views CASE HISTORY Case Miss DS 1177/1948 aged 13 was admitted to hospital acutely ill with a high temperature and erythema nodosum on the extensor aspect of the arms and legs Apart from the extensive skin lesions on the extremities nothing signi ficant could be found on examination The erythrocyte sedimentation rate was 87 mm during the first hour and 1 3 mm during the second lour The differential leucocyte count showed slight toxic changes No abnor mality could be found in the urine The tuberculin tcst (vow PARQUET) was strongly positive Chest X ray showed a left hılar shadow which on tomographic examination proved to be due to cnlarged hular glands Repeated examination of stomach washings failed to yield tubercle bacıllı Aspiration liver biopsy was performed in order to confirın the probabl diagnosis of tuberculosis The pathological report read as follows The biopsy measured 4 cm long and was examuned in serial section (+00 sections) In total 16 tubercles were found s of them being situated in portal tracts and 11 in the parenchyma Of these i belongs to type I 12 to type II - to type III and i to type IV They are all epithelioid without any necrosis or fibrinous exudate and without giant cells Among the epithelioid cells there are lymphocytes ncutrophuls and cosinophils Conclusion multiple young submiliary epithelioid-cell tubercles and subtubercles without necrosis or giant cells cxtensive hacmatogenous dissemination The clinical picture of a seriously ill patient combined with the positric liver biopsy decided us in favour of streptomycin trcatment wc hoped to eliminate the active foci as soon as possible and to prevent new dissemi nations Two weeks after the beginning of the streptomycin therapy (1 c a little over six weeks after admussion) a second biopsy was performed The pathological report read as follows The biopsy (one sixth the size of the previous fraterial) was examined in serral section (100 sections) There is slight fatty infiltration in the perportal parenchyma An occasional cosinoplul leucocyte is ob ·29 ERYTHEMA NODOSUM scrued in the capillanes We found one submiliary tubercle of type 1, without necrosis or fibrin, and without giant cells it lay in a portal tract The young fibroblasts, of a slightly older type than previously, arc surrounded by lymphocytes and occasional cosinophils in addition a munute round cpithelod-cell focus with an cosinophil leucocytc, and a small ill-defined type III focus consisting of young fibroblasts, lymphocytes and cosinophul leucocytes were seen in the parenchyma Conclusion haematogenous dissemination of a slightly older typu than the first biopsy As it happened fever had rcmitted partly just before therapy was commenced, but during therapy the patient's general condition unproved rapidly, her weight increased and the temperature remained subfebrile Erghe uccks after the commencement of the streptomycin therapy a thurd biopsy was performed the pathological report read as follows "The biopsy measured 2 cm long and was cramined in serial section (104 sections) Only s small foci of type IV were found These foci may be a later stage of development of the subtubercles seen in the former biopsies There is slight fatry infiltration and a tract of periportal nuclear glycogen Conclusion five minute subtubercles in the parenchyma Slight fatty infileration Before the patient was discharged at the end of the streptomycin therapy a fourth topsy was performed Three and a half months had elapsed since the first biopsy The pathological report read as follows * The biopsy measured 38 cm long and was crammed in serial section (108 sections) There is slight to moderate farty infiltration (slightly more than in the two previous biopsics) Som nuclear glycogen is found in the persportal arcas Fourteen foci are observed cight of which are portal Among them there are five portal scar balls (1 of type I 3 of type II and I of type III) two of which are already hyalınızed There are also in the same site a small tuburcle of type III consisting of older connective tissue and two relatively young tubercles of type II in which there are som cosmophil leucocitos In the parenchyma three older and two younger subtubercles of types III and IV and a small young focus of type IV were observed Conclusion muluple relatively young tubercles apart from the older and the completely cicatrized tubercles which are partly hvalınızed There is some fatty infiltration The patient was advised to continue the rese-cure at home combined with good nutrition and cxtra vitamins After the months she was again admitted for a follow-up examination Her condition was excellent No abnormalities were found Thu er throcyte sedimentation rate was 13 min ·30 ERYTHEMA INDURATUM during the first hour, and 32 mm during the second hour Chest X-ray still revealed enlargement of the hilar nodes on the left, but the shadox ivas betrer defined A fifth ker biopsy was performed in order to determine objectively whether the process had really subsided since the first biopsy seien months had now clapsed The pathological report read as follows "The biopsy measured : 1 cm long, and was examined in serial section (111 sections) There is no trace of fresh dissenunation As could be expected, there are scars of previous lesions in the parenchy ma four foci of type III and IV, of medium age, and three portal hyaline scars were found Although not of practical importance, it is worth mentioning that we observed hyperaemia, a trace of lipofuscin (pericentrally) and a trace of nuclear glycogen (per portally) The fatty infiltration, scen during and shortly after the streptomycin therapy, has disappeared again Only a very rare fates vacuole could be observed. Conclusion some remains of older lesions, but no fresh dessenunitione The process was therefore proved to have come to a standsall The patient was allowed to return very gradually to full activity Rather more than a car after leaving hospital the chest X-ray showed an infiltration in the left middle zone and she was treated with bed-rest and PAS per os for about a year At the moment of writing about 3*): years after lier complete recovery, she is well We would further refer the reader to our preliminary report elsewhere concerning liver changes in cases of erythema nodosum (sec bibliography) ERYTHEMA INDURATUM (BAZIN'S DISEASE) We have examined liver biopsies in four cases of this discase All were positive The following will serve as an example CASE HISTORY C15l’I Miss v M 538/1949 aged 23, came to our outpatient department companing of a red induraced area on the legs belon she looks The dermatologist diagnosed crythema indurarum The young lady's fiance was knoun to suffer from tuberculosis Apart from obesity nothing signticant could be found on general cramunition The cothrocyte sedimencation rate was 8 mm dunng the first hour, and 41 mm duning the second hour The differential leucocite count revealed nothing of note The tuberculin rest (vov PIRQUET) was positisc ·ERYTHIEMA INDURATUM 31 In order to determine the cause of the condition it was decided to perform an aspiration liver biopsy The pathological report read as follows ** The biopsy measured 2 cm long, and was cramined in scrial section (130 ccctions) 25 foci were seen They are all still young 3 beng situated in the portal areas, and 22 in the parenchyma One of them is of type I, 3 arc of type II, s of type III, and 16 of type IV There 15 10 necrosis In two foci there is a ccrtam amount of fibrin Theru are some giant cells, neutrophuls, and lymphocytes No cosmophils can be found There is a fatty infiltration of the liver parenchyma Conclusion cxtensic haematogenous dissemination, which is in an early stage Accordmgly the patient was treated with streptomycin PAS, and strict bed-rest After some months the crythema had completely disappeared Six months after the first biopsy we performed a second onc The pathological report on the liver tissue read as follows "The biopsy measured 1 9 cm long, and was examined in scrial section (108 sections) Nosubmiliary tubercles werc observed In the parenchym there are a total of 11 subtubercles, some young, some less young and some mtermediate Three of them belong to type III cight to type IV There is also a slight fatty infiltrauion Conclusion partly young partly older lesions of types III and IV m the parenchyma Comparison with the previous biopsy suggested some improvement" As a result of these findings the patient was advised to contiue the rest curs, in combination with PAS At the last follow-up examination she was in cxcellent condition Biopsies in these four cases were done in the first place as a matter of pure scientific inqury, but they have taught us that this remarkablc skin affection, so different from erythema nodosum, may also be an expression of the haematogenous dissemination of tubercle bacılls We do not however yet regard ourselves as being on firm cnough ground to make detailed suggestions for the treatment of this disease ·30 ERYTHEMA INDURATUM during the first hour, and 32 mm during the second hour Chest X-ray still revealed enlargement of the hular nodes on the left, but the shadow was better defined A fifth liver biopsy was performed in order to determine objectncly whether the process had really subsided Since the first biopsy seven months had now clapsed The pathological report read as follows "The biopsy measured 2 1 cm long, and was examined in serial section (111 sections) There is no trace of fresh dissemination As could be expected there are scars of previous lesions in the parenchyma four foci of type III and IV, of medium age, and three portal hyaline scars were found Although nor of practical importance, it is worth mentioning that we observed hyperacmia, a trace of lipofuscin (pericentrally) and a trace of nuclear glycogen (periportally) The fatty infiltration, scen during and shortly after the streptomycin therapy, has disappeared again Only a very rare fatty vacuole could be observed Conclusion some remains of older lesions, but no fresh dissemination The process was therefore proved to have come to a standseill The patient was allowed to return very gradually to full activity Rather more than a year after leaving hospital the chest X-ray showed an infiltration in the left middle zone and she was treated with bed-rest and PAS per os for about a year At the moment of writing about 24/2 years after her complete 1) recovery, she is well We would further refer the reader to our preliminary report elsen here concerning liver changes in cases of crythema nodosum (see bibliography) ERYTHEMA INDURATUM (BAZIN'S DISEASE) We have examined liver biopsies in four cases of this disease All were positive The following will serve as an example CASE HISTORY Case II Miss v M 538/1949 aged 23 came to our outpatient departinent complaming of a red indurated arca on the legs below the knees The dermatologist diagnosed crythema induratum The young lady's fiance was known to suffer from tuberculosis Apart from obesity nothing signsficant could be found on general examination The crythrocyte sedimenrition rate 11 as 8 mm during the first hour and 41 mm dunng the second hout The differential leucocyte count revealed nothing of nore The tuberculin test (vov PIRQUET) was positive ·10 ERYTIEMA INDURATUM 31 In order to determine the cause of the condition it was decided to performn an aspiration liver biopsy The pathological report road as follows * The biopsy measured 2 cm long, and was examined in serial section (130 sections) 25 foci were seen They are all still young, 3 being situated in the portal areas, and 22 in the parenchyma One of them is of type I, 3 are of type II, s of type 111, and 16 of type IV There is no necrosis In two foci there is a certain amount of fibrin There are some giant cells, ncutrophils, and lymphocyte No cosinophils can be found There is a fátty infiltration of the liver parenchyma Conclusion extensive haematogenous dissemination, whuch is in an early stage Accordingly the patient was treated with streptomycin, PAS, and strict bed-rest After some months the crythema had completely disappeared Six months after the first bropsy we performed a second one The pathological report on the liver tissue read as follows "The biopsy measured I 9 cm. long, and was examined in scrial section (103 sections) Nosubmiliary tubercles were obscrved in the parenchyma there are a total of 11 subtubercles, some young some less young, and some intermediate Three of them belong to type III, cight to type IV There is also a slight fatty infiltration Conclusion partly young partly older lesions of types Ill and IV in the parenchyma Comparison with the previous biopsy suggested some improvement As a result of these findings the patient was advised to continue the restcure, in combination with PAS At the last follow-up examination shu was in excellent condition Biopsies in these four cases were done in the first place as a matter of pure scientific inquiry, but they have caught us that this remarkable skin affection, so different from crythema nodosum, may also be an expression of the haematogenous dissemination of tubercle bacıllı We do not howcver yet regard ourselves as being on firm enough ground to make detailed suggestions for the treatment of this disease ·30 ERYTHEMA INDURATUM during the first hour, and 32 mm during the second hour Chest X-ray still resealed enlargement of the hilar nodes on the left, bur the shadow was better defined A fifth liver bropsy was performed in order to deternilne objectively whether the process had really subsided Since the first biops; seven months had now elapsed The pathological report read as follows *The biopsy measured 2 1 cm long, and was examined in serial section (111 sections) There is no trace of fresh dissemination As could be expected there are scars of previous lesions In the parenchy ma four foci of type III and IV, of medium age and three portal hyalıne scars were found Although not of practical importance, 1 is worth mentioning that we observed hyperaema, a trace of lipofuscin (pericentrally) and a trace of nuclear glycogen (per portally) The fatty infiltration, scen during and shortly after the streptomycin therapy, has disappeared again Only a very rare fatty vacuole could be observed Conclusion some remains of older lesions, but no fresh dissemination' The process was therefore proved to have come to a standstill The patient was allowed to return very gradually to full activity Rather more than a year after leaving hospital the chest X-ray showed an infiltration in the left middle zone and she was treated with bed-rest and PAS per os for about a year At the moment of writing about 24/2 years after her complete recovery, she is well We would further refer the reader to our preliminary report elsewhere concerning liver changes in cases of erythema nodosum (see bibliography) ERYTHEMA INDURATUM (BAZIN'S DISEASE) We have examined liver biopsies in four cases of this disease All were positive The following will serve as an example CASE HISTORY Case I'I Miss v M, 38/1919, aged 23 came to our outpatient department complaring of a red indurated area on the legs below the knees The dermatologist diagnosed erythema induratum The young lady's fiance was known to suffer from tuberculosis Apart from obesity nothing signeficant could be found on general cxamunation The erythrocyte sedimentation rate was 8 mm during the first hour, and 41 mm dunng the second hour The differential leucocyte count revealed nothing of note The tuberculin text (VON PIRQUET) was positive ·33 MILIARY TUBERCULOSIS 1 urocytes being 8 000 per c mm The urine was normal The tuberculın reaction (VON PIRQUEI) was negative though according to the patient it had been positive on an carlser occasion On examming the cerebrospinal Hurd the pressure proved to be 31 mm the number of cells was 308 mm almost charcly lymphocytes The Nonne and PANDY reactions were positive The glucose content was 40 mg . No tubercle bacıllı were found on microscopical examination Chest X-ray revealed the picture of muliary tuberculosis Tubercles were observed also in the optic fundus In order to confirm this diagnosis and as a control for a second biopsy planned to follow treatment, it was decided to perform an aspiration liver biopsy The pathological report read as follows * The biopsy measured i 3 cm long and was examined in serial section (114 sections) 78 sections were stained with hematoxylın-cosin and 36 according to HALLBERG In total 80 focs were observed 3 of type I 16 of type II s of type III and 56 of type IV These tubercles arc predominantly young though some belong to an intermediate type 17 are located in the portal spaces and 63 in the parenchyma There is some fibrın and a trace of cascation in the larger tubercles There are many guant cells of vanous types lymphocytes and neutrophils Tuiclve aad-tast rods arc secn sıx of them ingested by giant cells Conclusion subacute hacmatogenous tuberculosis Follow mg thus positive result streptomyom was administered both intramuscularly and intrathccally in combination with promin A considerable improvement resulted the crythrocyte sedimentation rate remamed normal and after three weeks the tu mperature was subfebrile The tubercles in the optic fundi sere seen to be becoming fibrotic A second biopsy was performed nearly two months after the first Tix pathological report read as follows The biopsy measured 2 4 cm long and was cramined in serial section (120 sections) In total 66 foci were found 13 of them in the portal spaces and s3 in the parenchyma Types and I are lacking 19 foci belong to type Il 10 to typu III and 41 to type IV Those that belonged to typu I in the first biopsy have shrunku down into type II in the second Necrosis or fibrin art nou lure to be observed There are a few guant cells neutrophuls and cosinophuls besides lymphocytes The foct of type IV are often young Among the larger tubercles the intermediate type prevails Conclusion there is still an extensive haematogenous dissemination but fewer foci and there is a shift to 1 somewhat older rype as compared with the previous biopsy * ·CHAPTER VI MILIARY TUBERCULOSIS picture and Aspiration liver biopsy has been performed in sixteen cases of miliary tuberculosis In each of these cases the cluucal the chest X-ray, taken together, had been enough to establish beforehand the probable diagnosis of multary tuberculosis In every case tubercles (of types I to IV inclusive) were found in the liver in twelve there was caseation In such cases of frank miliary tuberculosis the degree of haematogenous dissenunation is so great that tubercles can nearly always be found in the biops | without having resort to serial sections HALLBERG staining was done in ten cases and acid-fast rods found in nine of these (in necrotic material sometimes but more often in near-bu giant cells) Previous streptomycin treatment accounted for the one negatie case and in the patient concerned tubercle bacıllı were later grown from genito-urinary lesions of the nine cases in which the bacıllı were demonstrated in the liver biopsy seven also vielded bacıllı in cultures from the sputum stomach washings or cerebrospinal fluid (three times before the liver biopsy and four times after it) In two cases the liver biopsy was the only material in which bacıllı were found We gne details of two of our cases CASE HISTORIES Cuill Miss US 1/1949 aged 17 complained of violent headach tor a fortnight on the day of her admission she became sick and somited Sic the onse stie had had fever (about 38 9° C) Physical examination vided the chnical picture of tuberculosis Percussion res caled an enlarged spleen Thre was neck rigidity The erythrocyte sedimentation rate was 10 mm firing the first hour and mm during the second hour Thu differential li crunt revealed slight touc changes the total number of ·35 tissus MILIARY TUBERCULOSIS The patient s sputum was found to contain acid fast rods In view of the swelling of the ankle a synovial biopsy was done The pathological report read as follows The capsular tissue was examined in serial section of the 132 sections 80 were stained with haematorylın-cosin and s2 according to Hall- BERG The material proves to be subchronic tuberculous granulation ve relatively young vascular connective tissue with many lymphocytes and plasma cells a few neutrophils and with many mulury and submuliary tubercles with guint cells (of both osteoclastoma and LANGIIANS types) and occasionally a trace of necrobiosis necrosis On staining with night blue 9 acid fast rods were observed 22 of which were located in giant cells Cordion subchronic tuberculous granulation tissue Gunea pig moculation with a portion of the capsular tissue confirmed the presence of tuberculosis The patient was treated with streptomycin promun and PAS After two months of treatment evidence of meningitis appeared The CSF pressure was 24 cm the glucose content was 21 mg . NONNE s test was negative and PANDY S positive The number of cells was 248 per c mm chicfly lymphocytes in view of these findings additional streptomycm was administered intrathecally Cultures of CSF were negative Eighteen days after meningitis fuad been diagnosed a second aspiration liver bropsy was performed the pathological report read as follows The biopsy mcasured 1 scm long and was examined in serial section (110 sections) In total 43 foci were observed 9 of them portal and 34 in the parenchyma Three of them are of type I 4 of type II u of type III and .s of type IV The tubercles of types I and II arc cicatrızıng Their centres are still active sometimes containing a giant cell of the LANGHANS or osteoclastoma tvpe but they are completely or partially encapsulated the capsule being sometimes incomplete Fibrin and necrosis are absent Eosinophul leucocytes are not seen but a few neutrophuls are present The foc of types III and IV att predominantly of the large-cellular type Conclusion haematogenous dissemination considerably less dense than in the first biopsy The larger tubercles are cicatrizing This indicated clearly that the process outside the central nervous system had receded to a considerable extent Meanwhile the muliary shadows on the chest X ray had disappeared Because of the meningitic symptoms at was decided to continue the intrathecal streptomycm treatment in combi nation with PAS and promin for a considerable period Three years after the onset of the illness the pacient was considered as completely ·34 MILIARY TUBERCULOSIS The patient's condition continued to improve The CSF continued to shou a few lymphocytes this persistent slight pleocytosis may well have been caused by the intrathecal administration of the streptomycin four months after admission the miliary shadows on the chest X-ray had disappeared In view of the positive liver biopsies, the clinical picture, and the fact that in the meantime positie cultures had been obtained from the CSF and the liver, it was decided to proceed to a very long period of intrathecal administration of streptomycin About three years after the onset of the illness the patient was considered as completely recovered and now, tuo years afterwards, she is in an excellent health. Duong 14 months she had becn treated with streptomycin, administered intrathecally, and during two years she had received PAS per os Case VIII Miss B 291/1949, aged 26, was admitted at the request of a consultant physician because diffuse milary shadows had been found in her chest X-rays She had developed a painful swelling of the nght ankle after injury, and the chest condicion had come to light during investigation of this There were no other complaints On physical examination there were fine crepitant rales scattered through both lungs Apart from a swollen ankic there were no further abnormalities There were no symptoms of meningitis The crythrocyte sedimentation rate was 3 mm during the first hour, and 7 mm during the second hour The differential cell count was normal The urine did not reveal anything of note The tuberculn reaction (von PIRQUET) was positive On admission there was a subfebrile temperature In order to confirm the diagnosis of miliary tuberculosis and to determine the extent of the process, if possiblc, it was decided to perform an aspiration liver biopsy The pathological report read as follows "The biopsy measured 16 cm long and was examined in serial section (110 sections) 60 sections were stained with haematory In-cosin, and so according to HALLBERG In the oo sections stained with hacmatory Incosin there are 146 foci, 1 of which are of type I, 6 of type II, 39 of type III and 90 of type IV All the tubercles of type I are cascaong and lie in the portal spaces There are many grant cells of the osteoclastoma type and the foreign body type The 6 tubercles of type II are also portal and they are partly cascating The lesions of types III and IV have epitheloid cells and are situated in the parenchyma The cell type suggests a fairly recent dissemination Neutrophils arc observed in addition to the lymphocytes in the so sections that were stained according to HALLBERG 9 acid-fast rods (6 in gunt cells, and 3 in necrotic tissue) were found Conclusion extensive partly caseating haematogenous tuberculosis of fairly recent ongin ·37 MILIARY TUBERCULOSIS or sarcoidosis Although negaase findings do not completely exclude these dascases we are justified by the clinical and pathological data in believing that the entite picture was due to mural stenosis As a second point in considering the value of hver biopsy in these cases, the histological structure of the tubercles may give us some idea of the activity of the process We are often misled in this matter by the clinical symptoms, the erythrocytc sedimentation rate the blood picture, the temperature chart, etc In the third place it is possible that the tuberculogram we mentioned in Chapter II may supply us with an objcctive picture in assessing the value of modern therapeutic agents in this it is of especial value to be able to compare the histological picture of a first biopsy with that of the subsequent specimen or specimens In the fourth place it is possible to examine the liver tissue bacteriologically We shall revert to the importance of this later In the fifth place one may find indications for the carrying out of a lumbar puncture The presence in the liver biopsy of submiliary tubercles and subtubercles in such numbers that they can be found at once without serial sections must raise a strong suspicion that many submiliary and perhaps also miliary foci (possibly latent) are present not only in the liver and the lungs but elsew here in the body as well in other words they may also be already established in the cerebral cortex and the meninges which are so difficult to reach by antibiotic therapy In view of these considerations and after we had scen a tuberculous meningitis develop in two patients during treatment with streptomyan we nowadays perform lumbar puncture regularly (once a month) in all patients suffering from miliary tuberculosis At the slightest suspicious sign (increase of lymphocytes and reduction of glucose in the CSF) they are treated as cases of tuberculous meningitis So far this has taken place three times We look upon the neurologists fear that tuberculous meningitis may be lit up by lumbar puncture as obsolete Finally we would point out that with the aid of modern therapeutic agents the miliary shadows on the chest X-rays disappear as a rule in two to five months ·36 MILIARY TUBERCULOSIS recovered At the moment of writing, two further y cars later, she is in an excellent health During 13 months she had been treated with streptomycin administered intrathecally and during 15 months she had received PAS pet os What is the clinical value of the aspiration liver biopsy in these cases? In the first place, it is possible to make an carly diagnosis without having to wait for the culture of tubercle bacıllı (which sometimes takes up so much time), even though direct microscopic examination of the sputum, urine, pus or other material for tubercle bacıllı is negative, Further it is clear chat this technique may be of especial value in the differential diagnosis of muiltary shadows in the lungs where several conditions (pulnionary carcinomatosis, cardiac insufficiency, pneumocontosis, syplulis) may prove indistinguishable from muhary tuberculosis The absence of tubercles from the liver in such cases is, in our opinion, strong evidence against the diagnosis of miliary tuberculosis The following case may serve as an example CASE HISTORY Case IX Mr T, aged 23, complained originally of haemoptysis He recovered after a rest-curc He had never been seriously ill, and had no history of acute rheumatism On physical examination clcar evidence of mitral stenosis was found There were no cnlarged lymph glands The spleen and liver were enlarged and casily felt There were no other abnormalities The blood pressure was normal The urine was normal The erythrocyte scdımcntation rate was 41 mm during the first hour The WASSERMANN reaction was negative The von PIRQUET and MANTOUX reactions were negative Fluoroscopic examination of the chest revcalcd lular enlargement and fincly granular lung fields If the heart shadow had not shown to a slight degree the shape peculiar to mitral stenosis, the whole picture would have socmed wholly typical of tuberculosis or sarcoidosis At the health centre the diagnosis of tuberculosis or sarcordosis was seriously considered The palpable spleen might have pointed to cither of these diseases, or to mitra! stenosis (probably Theumatic in ongın) The patient was admitted for an aspiration liver biopsy in the biopsy material (scrally sectioned) we were able to find a distinct stasis but there was no centrilobular fibrosis There were no traces of tuberculosts ·MILIARY TUBERCULOSIS 37 or sarcoidosis Although negative findings do not completely excludi these discases, we are justified by the clinical and pathological data in beleving that the entire picture was due to mitral stenosis As a second point in considering the value of liver biopsy in these cases, the histological structure of the tubercles may give us some idea of the activity of the process We are often musled in this matter by the clinical symptoms, the erythrocyte sedimentation rate the blood picture, the temperature chart, etc In the third place, it is possible that the tuberculogram we imentioned in Chapter II may supply us with an objective picture in assessing the value of modern therapeutic agents in thus it is of especial value to be able to compare the histological picture of a first biopsy with that of the subsequent specimen or specimens In the fourth place it is possible to examine the liver tissue bacteriologically We shall revert to the importance of thus later In the fifth place, one may find indications for the carrying out of a lumbar puncture The presence in the liver biopsy ot submiliary tubercles and subtubercles in such numbers that they can be found at once without serial sections must rarse a strong suspicion that many submiliary and perhaps also miliary foci (possibly latent) are present not only in the liver and the lungs, but elsewhere in the body as well, in other words they may also be already established in the cerebral cortex and the meninges which are so difficult to reach by antibiotic therapy In view of these considerations, and after we had seen a tuberculous meningitis develop in two patients during treatment with streptomycin, we nowadays perform lumbar puncture regularly (once a month) in all patients suffering from muliary tuberculosis At the slightest suspicious sign (increase of lymphocytes and reduction of glucose in the CSF) they are treated as cases of tuberculous meningitis So far this has taken place three ames We look upon the neurologists fear that tuberculous meningitis may be lit up by lumbar puncture as obsolete Finally we would point out that with the aid of modern therapeutic agents the miliary shadows on the chest X-rays disappear as a rule in two to five months ·CHAPTER VI TUBERCULOUS MENINGITIS 3s Aspiration liver biopsy was performed in fourteen cases of tuberculous meningitis In thirteen of them we observed tubercles in the liver tissue The only negative case was that of a patient from another town, whose liver biopsy was sent to us for examınation The chest X-ray was clear in this case, but later tubercle bacıllı ucre cultured from the cerebrospinal fluid on one occasion only After the conclusion of streptomycin treatment a relapse occurred causing the patient's death five months after the onset of his disease Autopsy was not possible, and unfortunately no liver biopsy was done postmortem In eight of the positive cases there was also generalized blood-spread mıkary tuberculosis with its characteristic chest X-ray The clinical importance of the aspiration liver biopsy in meningitis may briefly be summed up follows The prospect of the major therapeutic procedures which must follow the diagnosis of cuberculous meningitis especially the prolonged intrathecal administration of streptomycin compels us to sech a positive diagnosis at the earliest moment It is not always easy to arrive at this diagnosis with certainty by examination of the cerebrospinal fud alone Lymphocytosis for instance is not by any means an objective proof of the presence of tuberculous meningits in this respect benugn lymphocytic meningitis (virus-meningits or chorio-menuingias) caused by the ARMSTRONG virus or the herpes zoster virus is particularly important especally is its waal stages when differential diagnosis may be very difficult Personal experience has taught us that the CSF glucose can be equally unreliable Culture of the bacılh is still too often too slow it takes at least six weeks (at any rate in ·TUBERCULOUS MENINGITIS 39 early cases) before a definite result is attained Irreparable damage may be caused by delaying the therapy while waiting for a certain diagnosis On the other hand, it is possible to camouflage the true nature of the case by proceeding too quickly to intrathecal streptomyan treatment, thus, for instance, a spontaneous improvement may be wrongly ascribed to the streptomycin that has been administered Moreover, later repetron of the bactenological examination for cuberculosis which may prove necessary may be rendered impossible Besides, intrachecal streptomycin treatment leads to an increase of the number of lymphocytes in the spinal fluid, so that this standard for measuring the activity of the disease is obscured It goes without saying that these objections do not arise when acid-East rods are demonstrated by microscopical examination in the vell-like clot formed in the spinal Aud But in other cases it may certainly be looked upon as a gain when liver biopsy supplies either support or a definite resulo With regard to the pathogenesis of tuberculous meningitis we would like to draw atcention to the following macter The grave cluical picture, with its (failing intrathecal streptomyan) big chance to a fatal outcome (LORBER) derives principally from the repeated infection of the meninges by one or more tuberculous foa (mulary or larger) in the brain substance (Rich and MCCOR- DOCK MACGREGOR and GREEN) At postmortem it has appeared that this localisation in the brain is usually secondary to a localızed often relatively inacave lesson elsewhere in the body, under which heading an important part is played by the hular and the mediastınal lymph nodes from which haematogenous dissemination so often starts (Chap XII) From experience we know that such partly caseous partly hyalınızed lymph nodes may escape attention in the rocntgenogram When meningitis has an origin of this type streptomycin can only affect the tubercle baallı uy the meninges and in the spinal flud wlule those in the cerebrał focus remain uncouched Thus recurrence of tuberculous meningitis is easily understandable in these cases the low activity of the focus of dissemi- ·TUBERCULOUS MENINGITIS activity Did nation accounts for our observation that (except of course in those cases in which the meningitis is merely one mamfestation of an overt generalized miliary tuberculosis) the liver biopsy contains only scanty tubercles of the larger sizes (cicatrizing or otherwise) even when types III and IV are common A difficulty might be thought to arise in cases in which lesions of type IV only are present Simular structures can be found in virus meningitis, and it might appear that the liver biopsy will fail to provide the diagnosis in such cases in practice, however, wc have found that the trained eye can differentiate the two liver lessons It is clear that even repeated liver biopsies do not give us a full insight into the course of the process. The extra-cerebral disease may subside and this will be mirrored by the lives, but meanwhile the cerebral focı may continue their baleful not investigacions by BAGGENSTOSS, FELDMAN HINsiiat and HEILMAN Show conclusively that streptomyain does not penctrace ruco the brain tissue while it is present an adequate concentration in the spinal fluid? One can only hope that a spontaneous cure (possibly with calcification) will take place in the cerebral foc under the influence of bed-rest and good nutrition -- in other words the old conservative therapy? Systematic intrathecal administranon of strepromycin ss partly based on the expectation that the cubercle bacilh already present in the spinal flud will be rapidly atrached, but at the same time it is hoped to deal at once with fresh meningeal disseminations We will finally submit some general remarks about the streptomycin creatment of tuberculous meningias It is of the grcatest importance to inject the mtrathecal streptomycin elccedingly slowly (10 to Is munutes per injection) Rivoire and COLLEAU drew attention to this mode of injection which prevents blochage of the subarachnoid space It is very important to be aware of this as conanuation of the therapy depends entirely on it A second pout to which we would like to dran atiention is the necessitt of continuing intrathecal streptomycin treatment for a considerable period of time Experience with a patient who suffered from tuberculous meningitis for more than a ·TUBERCULOUS MENINGITIS 41 year has taught us this it is not yet clear why the long continuation of the intrathecal streptomycin treatment is so necessary to success An explanation may perhaps be found in the fact that the cerebral focus which is difficult of access to streptomycin continually discharges streptomycin-sensitive tubercle bacilli into the CSF but the bacıllı are again and again rendered harmless by the streptomycin injected intrathecally Our own experience would suggest that when these two conditions are fulfilled the prognosis of tuberculous meningitis is considerably more tavourable than is generally stated in medical literature Out of 12 patients treated with streptomycin and PAS four died and cight are doing splendidly Thc intra venous administration of PAS-stabilise of Debar and of INH improved the prognosis of tuberculous meningitis enormously (it would take us too far to discuss the significance of ACTH tuberculın hyaluronidasc and streptokinase 22. this connection) We may look upon aspiration liver biopsy as a distinct diagnostic gain in these cases for it is especially in the cases with an early diagnosis that it is possible to obtain a permanent cure provided the above-mentioned conditions are met CASE HISTORIES Case Miss V 125811948 aged 27 was admitere to tic clinic as a case of meningitis Sıx weeks previously she had had a miscarnage losing a large quancicy of blood Against her doctor s ordess she made a mnp on a motorcycle after tlus miscarriage on thus trip she was said to have con tracted pncumonia and was confined to bed for three wecks Her temperaturc was said never to have been above 37° C Two days before her admis sion she lead had a violent headache attended with vomiting The family doctor diagnosed meningios and advised admission to a hospital On admission there was a slight stiffness of the neck BRUDZINSKY S signs 1 and 11 lowever were both negative Thc left pupil was decidedly larger than the right and the right pupil was not exactly round On palpa cion small swollen lymph nodes were found in the neck, axıllac and groins, The heart was of normal sizc thc heart sounds loud but clear Neither iver nor spleen was enlarged. There were no further physıcal findings On the roentgenogram of the thorax a diffuse and cyen distribution of small focal shadows was obscrved the radiologist believed he had to ·TUBERCULOUS MENINGITIS do with miliary tuberculosis or with sarcoidosis The temperature was intermittent in character and fluctuated between 37° C and 39 ° C The red cell sedimentation rate was 60 mm during the first hour, and 83 mm during the second hour The differential cell count showed neutroplul leucocytosis with primitive forms and couc granulation, eosinophel leucocytes were lacking in the unne there was a trace of albumin but there were no reducing substances in the sediment tuo or three leucocytes per visual field were found The von PIRQUET was negative, the MANTOUX positive at 1 1000 The luetic reactions were very decidedly positive On the day of admission thc patient had an epileptic attack in the hospital The neurologist who was called into consultation after considering the results of the examination of the spinal fluid and the chest X-ray thought he had to do with tuberculous meningitis with a nghe sided cerebral focus Examination of the spinal fluid yielded the following facts The number of cells was 48 cells per c mm predominantly lymphocytes The protein content was increased The colloidal gold reaction was abnormal (012332211) The glucose content was o0osNo bacteria were found in the Gram specimen and the web of fibrin did not yield any tubercle bacilli A guinea-pig test afterwards proved to be negative As a result of this diagnosis even though it was not confirmed bacteriologically it was decided to commence intensive streptomycin treatment The drug was injected intrathecally (o i gm a day) and intramuscularly (24gm a day) After twelve days the intrathccal admurustration of streptomycin was discontinued after which an improvement was noted in the temperature curve After four weeks the intramuscular administration was discontinued for a period of nineteen days because the patient vomited continually intoxication) As the diagnosis had not been confirmed bactenologically, it was decided ten days after admission to perform a liver biopsy The pathological report read as follows The biopsy measured 16 cm long and was examined in serial section (150 sections) In total 13 tubercles were found ii of which were portal and no parenchymal One belongs to type 1 i to type II and i to type IV In onc tubercle we noted the commencement of cascation and ewo showed a trace of fibrin There are many guant cells of vanous types Besides lymphocytes we observed some ncutrophils and an occasional eosinophil 42 sections were stuned according to HALLBERG and cxo acid fast rods found in them No spirochetes were demonstrated in LEVADITI-stained materia! Conclusion subacute non-eascating submulary tuberculosis Guncapig test inoculation with a portion of the biopsy material afterwards proved positive 2 ·TUBERCULOUS MENINGITIS 43 During treatment with streptomycin there developed a neurological proture with papillocdema, which was explained by the neurologist as a consequence of persistent basal meningitis with arachnoiditis optica Because of the high pressure of the spinal Aud he thought also of the possibility of internal hydrocephalus As the papillac seemed to be becoming atrophic, It was decided to dehydrate with MgSO,, in order to reduce the cerebrospinal pressure This treatment failed, and trephining, which was at first rejected, was considered necessary as a last resort The patient was therefore semoved to the department of neurosurgery in Utrecht At that inoment she had undergone streptonsycin treatment for a period of four months Dr VexBitst performed ventriculography, and found a displacement of the ventricular system to the left The line of the septum vcntriculorum was somewhat concave towards the right Dr VERBIEST could only decide with certainty on an ocdema of the night hemisphers, and he thercrore resolved to perform a subtemporal decompression only The examination of the fluid obrained at that time yıclded the following results The NONNE and PANDY reactions were negative, the flud containing only 7/3 cells per mm The colloidal gold curve was normal After a seventeen days' stay in the hospital in Utrecht the patient was sctumed to our clinic Physical examination now yielded litele, except for the operation scar The reactions of the pupil had become normal A detailed neurological examination did nor yield anything of note except a rapid nystagmus on looking towards both sides with a slight rotatory component, and a slight secondary atrophy in the optic papillac The she had been through, the patient was now in a very good condition In order to obtain an idea of the influence of the streptoniyain on the sulary tuberculosis, roentgenograms of the chest werc agam made, the radiologis was of the opinion that the muliary shadows in the lungs had become less well-defined The lungs gave an impression of decreased activity At the same time a second liver biopsy was performed, seven months after the firse Tlic pathological report read as follows • The biopsy measured 1 3 cm long 84 serial sections were examined, 60 of them stained with haematoxylın and cosin, 12 stained with VAN GIESON, and 12 according to HALLBERG Only 8 foci were observed, two of which were in a portal position, and 512 in the parenchyma One is of type I, 1 of type II, and 6 of type IV Necrosis, fibrın, grant cells and leucocytes are absent No acid-fast rods can be found One of the portal foci i wnusual, consisting of a central arca of ·44 TUBERCULOUS MENINGITIS lymphocytes and some fibrocytes enclosed by homogencous hyalını Conclusion cicatrizing submuliary tubercles and a few subtubercles In view of the concomutant lues the patient received penialın treat ment The result of this of course cannot ver be ascertained After this treatment the patient was discharged in very good condition and is at present in cxccllene health Case XI Mrid B 338/1948 aged 19 was adnutted complaining of headache present for about ten days and becoming worse His famul believed that they had noticed something strange in hus behaviour Three and a half weeks earlier the patient had had a cough. Physical examination showed a meningeal syndrome The left pupil was smaller than the nght There was ptosis of the left cyclad. The roene genogram of the chest did not reveal any irregulantics The erythrocyte sedimentation rate was 9 mm during the first hour and 30 mm during the second hour The white cell count shou cd leucocytosis and there were toxic changes of the segmented leucocytes Eosinophils were lacking The unne was normal The spinal fluid was clear and it contained almost cxclusi cly mononuclear leucocytes (980 cells per c mm) The Novve and PANDY reactions were positive in the GRAM stained specimen no bacteria were observed Tubercle bacallı were demonstrated in the web of fibrin The tuberculin test (vow PIRQUET) was positive The patient underwent intensivc creatment with streptomyan 17 gm a day was administered intramuscularly and or gm a day intrathecally Neurological examination showed that we were probably faced with medullar lesions with involvement of the night pontine opac centre After some time the ocologist noted that (possibly owing to the influence of streptomycin treatment) the sestibular apparatus on both sides no longer responded to calonc stimul which, however in viest of the patients serious condition did not justify us in discontinuing streptomycia treat ment -8 days after the commencement of the streptomycin therapy a liver biopsy was performed. It could for obvious clinical reasons not be done at first The pathological report read as follows The biopsy measured 1 1 cm long and was examined in serial section (108 sections) in total only four very small subtubercles of type were found We noted a dimunution in the amount of glycogen In spite of intensne streptomy an treatment the condition of the patient slowly deteriorated After the temperature had risen to 45° he died forv days after admussion to the clinic Immediately after his death iner brops was repeated The pathological examination of the liver tissue resulted in the following report It was a crumbly biopsy i cm of which was cut in serial sections IV ·TUBERCULOUS MENINGITIS (198 sections) Only one pectulist submaltary porta! cubesck, of cype I of a very unusual type was found Peuphurally it consisted of hyahne connective tissue centrally of lymphocytes and a single large giant cell whosc nucler were placed in the shape of an egg (thus remarkable fearure could only be recogmsed msenal sections) With HALLBERC S staming method no and fast rods were foun i m thus tubercle The liver parenchyma contained no glycogen its cells were dassociated and atrophed Pencentrally there was lipofuscin and hyperacmua Conclusiou a sclerorc portal tuberda The autopsy (Department of pathology M VAN Wijne) confirmed thic Clinical diagnosis of basal tuberculous meningstis No cascous focus was found in the bram The lymph nodes in the nghr kulus proved to be partly hyalıuzed partly cascated and liquefied in the lungs in the louer lobc on the nghe some tubercles were observed on microscopic examination they proved to be partly caseous and they were always enveloped by a thuck layer of lymphocytes in the macroscopically norinal liver and spleen many sclerosed tubercles were observed and in the former organ they were seen in the portal tracts Cose XII Mr B 1012/1949 aged 19 whosc behaviour during the last year had been peculiar (refused to say anything for four wecks listless unwilling highly cmosional) complained of concmual headache and loss of concentrauon when studying He also complained of bad eyesight Four weeks before admission he had a period of faver lasting two weeks The headache increased during this penod he was very restless and com plained of sleeplessness There was then a short relapse accompanied by rubcola like rash Three days before admission the temperature was again rassed with headache vomuang and uscreasing confusion Os physical examination no abnormalnes could be found apart fronu obvious neurological symptoms The case was at first thought by our neurologist to be one of encephalicts No improvement was however noticed after treatment with sodnom salicylate and absolure bedrese The consulting car nose and throat specialist could find no aural lesions 7 ophthalmologist reported signs of carly papıllocdema The neurologist Utreche (D VERBIESY) who was consulted il en suggested the possibih of a mesingoencephaluc process perhaps of cuberculoos ongi The cerebrospinal fluid containcă 704 cells per cmm mostly lymph cytes The glucose content was so mg, while the bloodsugar was mg . NONNE S reaction 13 as negative and PANDY S positive On muc scopical examination no tubercle bacıla could be demonstrated Cul was stenle The colloidal gold reaction was normal ·46 per day) TUBERCULOUS MENINGITIS The possibility of tuberculosis having been raised an aspiration liver biopsy was performed The pathological report rcad as follows The biopsy measured 2 6 cm long and was examined in serial section (100 sections) Only three rather young subrubercles of type IV were observed Conclusion Threc rather young subtubercles of type IV suspicious of tuberculosis On the above findings a diagnosis of probable tuberculosis was made It was then decided to begin treatment with streptomycin which was administered by the intramuscular (i gm per day) and intrathecal (100 mg routes combined with P AS 20 gm per day per os After seven weeks the intrathecal dose was reduced to so mg per day Sta wecks later the guinea pig inoculation of the spinal Aud was reported to be positive The patient is now --- five years after admission in very good condi tion The cerebrospinal fluid became normal and the above mentioned treatment was stopped after the completion of one year Case XIII Miss D 141/1948 aged 17 was admitted complaining of suc violent headache and vomiting On physical examination we found si of meningitis and definite herpes zoster on the left buttock In the cereb. spinal fluid we noted an increased number of lymphocytes the gluct content was normal The crythrocyte sedimentation rate was 35 mi during the first hour and 68 mm during the second hour The bloo picture showed slight toxic changes No changes were found in the urine The tuberculin tests (VON Pirquet and MANTOUX) were negative (which does not exclude tuberculous meningitis however) On a presumptive diagnosis of tuberculous meningitis we commenced mtrathecal streptomycin administration In order to confirm the diagnosis as soon as possible a liver biopsy was done Examination of the liver biopsy in serial sections did not reveal any tubercles so that the above diagnosis was not supported As the diagnosis of herpes zoster meningios was be coming more probable the streptomycin therapy was discontinued The patient made a perfect recovery which supported the latter diagnosis We have observed three other patients in whom we discontinued streptomyan treatment because of a negative liver biopsy These patients also recovered completely confirming our behef that this condition had been one of lymphocytic virus meningitis The value of the aspiration liver biopsy for the early diagnosis of tuberculous meningias is demonstrated especially obviously in the third case For further details the reader is referred to a paper published in 1950 ·CHAPTER VIII TUBERCULOUS PLEURISY Aspiration liver biopsy has been performed in fifteen cases of tuberculous pleurisy Here again we have been struck by the fact that a majority of the cases (14) yielded positive results We are therefore justified in looking upon aspiration liver biopsy as an important diagnostic and in such cases It so often occurs that the pleural effusion containing lymphocytes is found to be sterile and, without aspiration liver biopsy, a diagnosis could then be arrived at on general grounds only The arguments adduced by us in the case of previous groups hold good here also We are not yet in a position to pass a final judgment on the use of periodic lumbar puncture in these cases when the liver biopsy is strongly positive in a patient suffering from dry pleurisy or from pleurisy with effusion, the clinician may readily imagine himself justified in assuming the presence of a clinically latent focus in the brain also It is hardly necessary to point out, lowever, that periodic lumbat puncture in all cases has practical objections In the long run one must rely on the clinical assessment of the case as a whole for the indications for lumbar puncture That the latent focus may unexpectedly become active, even though the pleurisy is 'cured", is a clinical observation which every experienced medical man has made at some time or other The statistical investigations of NATHHORST on pleurisy with effusion in children support the view that antibacterial therapy may be called for From his investigations it is very clear that after pleurisy with effusion the change of subsequent tuberculosis extrapulmonary or pulmonary, is by no means negligible ·48 TUBERCULOUS PLEURISY CASE HISTORY Case XIV Miss v d M,641/1948, aged 18, was adnutted to hospital suffering from left-sided exudative pleurisy, accompanied by high fever On physical cxamination a doubtful dullness with impaired breath sounds was found in the left chest There was displacement of the heart to the right Fluid was demonstrated by exploratory pleural puncture Many lymphocytes were observed in this exudate, rendering the dugnosis of tuberculous pleurisy probable The erythrocyte sedimentation rate was os mm during the first hour and nro mm during the second hour The blood picture revcaled slight toxic changes The urine was normal The tuberculin reaction (VON PARQUET) was strongly positive Chest X-ray showed an opacity of the left half of the thorax, with considerable displacement of the heart to the night In view of this displacement paraccntcsis to the extent of half a litre was performed after some days' interval In order to support the probable diagnosis of tuberculous picuriss, and in order to obtain an idea of the activity of the process, an aspiration liver biopss was performed Thc pathological report read as follows *The biopsy measured 2 1 cm long and was exammed in serial section (116 sections), 80 sections being stained with hacmatorylin and cosin, and 36 by the HALLBERG techmquc Twelve foci were found, 10 located in the parenchyma, and in the portal space One belongs to type 1 (conglomerate tubercle), 2 are of type II, 4 of type III, and s of type IV These rubercles are of an unusual type, they are exudative to an exceprional degree, being hyperaemic with a serofibrinous and cellular (lymphocytic and leucocytic) exudatc, and a few young connective tissue cells There are sporadıc, somex hat atypical giant cells No necrosis is observed The smaller foci sometimes lic against the wall of a central vein No acid-fast rods were found Conclusion multiple young submilary tubercles of an cxudan c type" Although the temperature was already falling without any therapy, it was decided, in view of the presence of active haematogenous tuberculosis to proceed to intensive streptomycin treatment on the tu cnty-fifth day of this treatment there was a return of fever which did not, howcver exceed 39º In view of this relapse the streptomy an trcatment 112 combined usth pronun The temperature slowly fell agan to normal Micanwhil cultures for rubercle baalls of the fascing gastric contents and the pleural fiuud had proved positive After one month of streptomycin treatment dunng the second fever phase, hver biopsy was repeated The pathological report read as follows ·TUBERCULOUS PLEURISY 49 The biopsy masunng - + thu long was examined in serial section (120 sections) In total we observed 23 very small round foc consisung of young or slightly older epitheliod cells and lymphocytes -- of them are situated in the parenchyma and one lies in contact with the portal connective tissue of these 2. arc of type IV 1 ss of type III Judged by their nucler seven are young 14 intermediate and 2 old Necrosis fibrin guant cells or leucocytes were not observed Cone iston mulcplc any subrubercles in the parenchyma The find in the left pleural cavity slowly resorbed After an initial nise here was a fall in the crythrocyte sedimentation rate The patients clinical diaor improved and three months after the commencement of strepto my esa creatment a third liver biopsy was performed Thic pathological cport scad as follows The biops incasured 38 cm long and was examined in serial section (114 sections) We observed 21 focs 4 of which are of type II and portal The remaining 17 ars parenchymal subtubercles, 4 being of type III and 13 of type IV Out of the 21 foai 12 are old and 9 are of an intermediate type there are no recent foci Out of the 4 portal foci 2 concau fairly young connective cassue cells surrounded by lymphocytes and a sporadic rcutrophil leucocyte The other eno consist of lymphocytes among which there are some older connective tissuc nucle and apart from their somewhat oval shape they arc not ac all typical In nont of the foci do uc obscrve necrosis fibrin hyalınc or grant cells in contrast with the two previous biopsics there is now slight fatty infiltration Corci ose Remnants of earliet hacmatogchous disseminations Slight fatty infiltration Summing up we may say that the bacmatogenous dissemination (starting possibly from a primary infection) of which the pleurisy formed a part Eind probably subsided As the streptomycin therapy had come to an end after treatment of the patient consisted of strict bed rest good nutrition and extra vitamins She is at present in crcclient health ·CHAPTER IX TUBERCULOUS PERITONITIS AND ABDOMINAL TUBERCULOSIS We were able to determine the value of in thus form of tuberculosis in fourteen cases in all cases tubercles aspiranon liver biopsy were observed in the biopsies when we consider that the affected tissues be in the drainage area of the portal vein this is not surprising The diagnosis had been considered certain or probable on clisucal grounds before biopsy in five of these cases, and had been considered possible in seven in the other two cases the pre-biopsy clisucal diagnosis was carcinoma Up to the present as it happens, we have no experience of the contrary process of disproving a clirucal diagnosis of tuberculosis How often the diagnosis of tuberculous peritonids is missed! How often this diagnosis is needlessly dreaded' How depressing the consequences are in those cases where vague abdominal pains have been present for a long time, and where an X-ray examination has faled to establish its cause! What experienced clinician does not know of cases in such a "malignant tumour' found on palpation of the abdomen or on rectal or vaginal examinacion has proved at laparotomy or at autopsy, to have a ruberculous aetiology? > or similar cases in which on examnation a few months later these proves to be, not an extension bur a shrinkage of the palpable mass? Even before the days of modem specific therapy the consequences, medical social and psichological, of a musinterpretapon of such a clinical picture could be serious enough nowadays the need for exact diagnosis as a guide to treatment is niore than ever important ·TUBERCULOUS PERITONITIS SI CASE. ISTORIES Case XV Mass P , 882/1946, aged 13, was admyrred to hospital complamıng bed for some months On physical examinanon no abnormalines were found Nothing of note was revealed by an examination of the facres There was no rise in the temperature The erythrocyte sedimentation rate was normal The blood picture was normal The tuberculın test (von Pixquer) was positive Chest X-ray and straight X-ray of the abdomen did not reveal any changes Nor did we observe anything of note from a gynaecological point of view Suspeating tuberculous periconırıs, we performed an aspiracion lover biop L.- subchroruc portal tubercles belonging to type II, with some giant cells There was no trace of necrosis In the parenchyma there were Ewo young subcubercles of types III and IV No acid-Cast rods were observed in the specimens, which were stained according to HALLBERG Conclusiont non-caseating submiliary tubercles and subtubercles" This finding rendered the diagnosis of tuberculous pontonitis extremely probable The patient was advised scrice bed rest and good nutrition She returned at regular intervals for further examunaton At that time treatment with streptomycin was not possible Just over a year later the paticnt had a slight rise of temperature, and the region of the caecum was found to be a little painful on pressure Some local resistance was felt The gynaecologist arrived at the dugnosis of tuberculous salpingitis Some months later the panent was admitted once more (to the synaccological ward this time) because she had become much worse A guinca-pig inoculated with cervical secretion developed a positive tuberculin reaction and swelling of the lymph nodes two months later Tubercle bacills were cultured from the lymph nodes Case II M135 D aged 46, who had suffered from asthma for many jcars was admutted with vague abdominal pains On physical examination there were no sgnificant findings apart from L found The question arose whether they were in fact of a malignant ·52 TUBERCULOUS PERITONITIS character and in order to obtain some measure of certainty we decided to perform an aspiration liver biopsy The histopathological examination of the biopsy material revealed two non-cascating tubercles of type I together with a subtubercic of type III and onc of type IV In conjunction with the clinical findings the diagnosis of tuberculosis was now considered extremely probable Artificial sunlight treatment cured the abdominal discase The sceming metastases, therefore, were probably tuberculous lymph nodes On two occasions we have had the opportunity of examuning an aspiration liver biopsy in patients suffering from chronic intestinal obstruction In both cases an extensive intestinal resection was performed and several old stenoses were found Microscopical examination of the stenotic areas pointed to granulomatosis but the result of cxamination of the liver tissue by serial section was negative "The possibility of Crohn's disease in the two cases was seriously considered, although not proved In this latter disease we have had not enough opportunity of examining liver biopsies ·CHAPTER X TUBERCULOUS PERICARDITIS In one of several cases of constrictive pericarditis we have found aspiration liver biopsy very helpful The biopsy was performed in order to gain an idea of the vascular state of the liver We found not only the expected serious degree of venous congestion, but also extensive haematogenous tuberculosis CASE HISTORY Cn e XVII M L 8161949 aged 40 was admutted complaining of a fecling of persistent tiredness and listlessness and also of a painful sense of pressure in the region of the stomach About one month after the onset of symptoms the patient became short of breath on exertion This dyspnoea assumed such proportions that hus removal to hospital became necessary On physical examination thc heart beat could not be felt The heart was somewhat cnlarged towards thc nght at the cardiac apex and over the pulmonary artery the second sound was reduplicated on cxpiration We also found a greatly cnlarged fairly firm pulsating liver There was a very distinct pulsus paradoxus and ocdema of the legs There was no rise in temperature the crythrocyte sedimentation rate was i mm during the first hour and 2 mm during the second hour The blood picture revealed slight polycythaemia and there were no toxic changes in the leucocytes The urine showed only a distinctly positive urobilinogen rcaction The tuberculin test (von PIRQUET) was positive On fluoroscopic examination of the chest pulsation of the heart was seen to be strikingly deficient movement to the left was very slight The radiologist thought he was faced with a case of constrictive pericarditis The lungs were normal In order to establish the degree of stasis objectively an aspiration liver biopsy was performed We were very surprised by the histological findings The pathological report read as follows The biopsy measured 1 3 cm long and was examined in serial section 128 sections were stauned with hacmatorylın-cosin and 44 according to HALLBERG No acid fast rods were observed in total 14 tubercles ·5+ TUBERCULOUS PERICARDITIS were found, viz 4 belonging to type o, s to type I, 3 to type II, r - type III, and i to type IV The tubercles of types O and I were olde suith cascating centres Apart from them an occasional farly recen cascous tubercle was seen There was well-marked centrilobulas congestion with considerablc haemorrhage The wall of the central veins was not thickened ” In view of these findings it was decided to postpone operation on the constrictive pericarditis, in order to treat the patient first with streptomycin and PAS What does this case teach us? In the first place it is of paramount importance to establish as carefully as possible the cause of the constrictive pericarditis before proceeding to pericardiolysis There is no consensus of opinion with regard to the frequency of a tuberculous aetiology, and we believe it is necessary either to exclude or to establish that aetiology as accurately possible in every case In the above mentioned case the liver biopsy was of great help in this respect In the second place it is very important to determine the degree of activity of the process underlying the constrictive pericarditis It is instructive to note that in our patient ordinary criteria failed to yield a satisfactory picture of the activity the process and that liver biopsy revealed a very intensive dissemination Although ultimately the patient's general condiaon must remam the chief factor in assessing the need for pericardiolysis, yet knowledge of the activity of the process will influence the choice of the optimum time for operation; for the possibility of the surgeon cutting into areas of active tuberculosis with caseation is by no means negligible The possibility of consequent haematogenous dissemination, folloued by a fresh localization of the process (for example, in the meninges) may be avoided if sufficient attention is paid beforehand to the need for ascertaining the activity of the process Scrious mischuef may be avoided by means of streptomycin, combined with other drugs, admirustered prophylactically before and after the operation If the process is very active, and if an operation cannot be postponed by means for instance of dehydration as of ·TUBERCULOUS PERICARDITIS therapy one will certainly have recourse to it in order to nush the possibility of post-operative complications In the third place aspiration liver biopsy teaches us that culosis of the pencardium like that of the pleura and the neum may constitute part of a more general process in m tis we mostly have to do with one or more active foc cortex of the brain which unceasingly pour tubercl into the cerebrospinal fluid and must be considered re: for the symptoms of the diseasc It is quite possible that pathogenesis cxists in the tuberculosis of the pleura peritoneum and cven of the pericardium The case history we have just related exemplific that aspiration liver biopsy may be helpful in all the we have mentioned ·CHAPTER XI PULMONARY TUBERCULOSIS Aspiration liver biopsy was originally performed in Is cases of cavitating tuberculosis of the lungs, mainly for scientific reasons In fourteen cases we found the tubercles of the types I to IV mentioned at the beginning of this monograph This observation formed the starting point of a comprehensive general study of pulmonary tuberculosis, which has taught us that this disease (especially with regard to its carly diagnosis) is one of the principal indications for liver biopsy Apart from the primary complcx, which has already been discussed, we afterwards investsgated other forms of pulmonary tuberculosis with the aid of liver biopsy Out of 30 patients with infiltrations, ranging from very small to relatively large, scen in the chest X-ray, 28 proved to have tubercles in the liver In most cases serial sections of the liver biopsies proved indispensable, for it was especially in the cascs of so-called minimal tuberculosis that we sometimes observed young and small subtubercles of unacconipanied by larger lesions The patients were seenungly healthy soldiers, in whom a routine X-ray examination revealed one or more small areas of infiltration In several cases the temperature and the erythrocyte sedimentation rate were normal, and in some tubercle bacill were cultured afterwards from the stomach u ashings type IV CASE HISTORY Case XI III Mr H aged 20 was adnutted to a military hospital in March 1949 because slight changes had been found in his chest X-ray The temperature was normal The crythrocyte sedimentation rate was 14 mm ·57 PULMONARY TUBFRCULOSIS during the first hour The tuberculin reaction was positive in the sputum no tubercle bacilli could be found On April 14th 1949 a leer biopsy was performed the pathological report read as follows The biopsy measured 27 cm long and was cxainined in serial section (1°2 sections) Twelve relatively young lesions of type IV were observed in the parenchy ma Conclus on twelve young subtubercles of type IV si spicious of tuberculosis Follow up of this patient is essential Sıx months later u was leamed that guinea pig moculation with fasting gastnc contents was positive On the one hand the clinical and radiological pictures and the biopsy findings on the other did not always run parallel Sometimes the degree of dissemination scen in the liver proved to be much more serious than had been anticipated while at others only a few small subtubercles were to be seen It is obvious that pulmonary tuberculosis is no exception to the general rule that haematogenous dissemination to other parts of the body is frequent with all active local lesions but the factors that determine the occurrence and degree of this dissemination remain obscure Immunological considerations must be important but the nature of immunity in tuberculosis remains a dispured subject which lies outside the scope of this monograph We need hardly explain that aspiration liver biopsy will seldom be resorted to in cases of phthisis with cavitation when tubercle baallı can be demonstrated in the sputum Yer there may be circumstances which render this operation advisable as may be seen in the follow ing case CASE HISTORY Cuc I Mrs BD 645/1948 aged 9 was admutted because of a high temperature following delivery Her previous history included an attack of nght-sided pleurisy six years earlier and tuo y cars after that episode a three months rest-cure On physical examination the liver and the spleen were just palpable The enthrocyte sedimentation rate was 68 mm during the first hour and 107 mm during the second hour The blood picture showcd unmistakable touc changes the unne was normal Chest X ray showed bilateral ·58 PULMONARY TUBERCULOSIS tuberculosis of the lungs with a cavity near the left hilus The sputum contained many acid-fast rods which on culture were confirmed as tubercle bacıllt In order to acquire an idea of the extent and the activiy of the process an aspiration liver biopsy was performed The pachological report read as follows "The biopsy measured 2 I cin long anii was examined in serial section (112 scctions) We observed 77 munite tubercles, only 2 of which were of type II, 27 belonging to type Ill, and 48 to type IV Only 3 were attached to a portal tract, the remaining 74 being cntircly situated on the parenchyma Three foci arc of a very young largecellular type tivo arc old with long narrow nuclei the remaining 72 arc of a young type, though often an intermediate age 15 suggested by the nucles of the cpithelioid cells Guant cells are lacking Necrosis 15 nowhere to be seen, and in only one focus is there a trace of fibrın Eosinophil leucocytes are not observed in contrast to sicutrophils Conclus" very extensive hacmatogenous dissemination in the form of subtubercles in the parenchyma and a few submullary tubercles' As a result of this findmg, taken with the patient's scrious febrile conduion it was decided to treat her with streptomycin About six weeks after th commencement of this therapy another liver biopsy was performed The pathological report on the liver tissue read as follows • The brops measured 2 cm long and was cxamined in serial section (136 sections) The difference from the first biopsy is striking in total only 8 foci are observed 2 of which are of type II, 3 of type ??? and 3 of type IV Doch rype ļI rubercles are portal one of them rona)gnne cell of LANGKANS The 6 subsuburcles lie to the parenchyma in only ons are the epithelioid cell nuck young in tration The cavity in the lett lung together with the cnlarged lymph nodes in the Arne duastınum must be looked upon as the origin of the haematugenous dissonunation It gous without saying that treatment of thus focus was of first importance After the temperaturc had been normal for some necks Pneumothorax was decided on Apart from some cord-like adhessons in the apical region a complete collapse of the lung was cffected The cords tre severed by cautery according to the method of JACOBAEUS When antibacterial crestment had been given for three months a third braipse iv 35 performed before the patient was discharged The pathological report on the liver tissue ccad as follows ·PULMONARY TUBERCULOSIS 59 *Th biopsy measured 1 s cm long and was franzmed ın serial section (108 sections) Only six small foc were observed, all of them ináltration Conclusion remnants of an carlicr hacmatogenous dissemination m the parenchyma Moderate fatty change The parent went honie in good condition The pneumothorax vas manamed as an outpatient She is at present in cxelient health In addition to the local process in the lung, there was in this case an cytensive haematogenous dissemination accompanied by high fever By means of aspiranon liver biopsy the presence of one form of disscmnation (viz that to the liver) was objecttcly proved, and this observation in combination with the clinical symptoms led to the administration of streptomyan Successive luce biopsies then demonstrated that, from the collapse therapy and general rest streptomycin favourably influenced the course of the disease Aspiration liver bropsy is, however, comparatively rarely indicated in cases of cavitating tuberculosis of the lungs depending on a full review of the clincal symptoms and the X-rays of the chest apart ·CHAPTER XII TUBERCULOSIS OF THE LYMPH NODES that in Before considering the more important subject of mediastınal lymph node tuberculosis, we wish to discuss involvement of the superfically situated nodes We have performed aspiration liver biopsy in seven such cases, and in all these cases tubercles were found in the liver tissue It gacs without saying these cases liver biopsy is rarely necessary, for biopsy of a lymph node carries with it even less risk for the patient while it confirms or excludes the clirucally probable diagnosis equally if not more clearly, and with less trouble Nevertheless we have performed aspiration liver biopsy in such cases on a few occasions, at first only for scientific reasons Experience has taught us that at times this seemingly benign form of tuberculosis is in reality anything but innocent, and that in these cases the lymph nodes are not the only site of the tuberculous process, there be clinically silent but microscopically active foci clsewhere a the body When one knows this, it will be clear one should arm, 112 designing treatment at avoiding every trace of the conception chat these cases are comparativelv unimportant It is obvious that when tubercles in the liver are especially numerous or especially young in type, the treatment must be correspondingh thorough Personally we believe that every case of active tuberculosis carries a tendency to haemacogenous dissemmation, our findings with aspiration liver biopsy prove this irrefutably We therefore arrive at the conclusion that every case of active ruberculosis should be treated with meticulous care, irespective of the results of the pathological examunanon of the liver One may ask whether in such cases, apart from scientific interess, may ·TUBERCULOSIS OF THE LYMPH NODES 61 there is also a practical indication for liver biopsy This question inust be answered in the affirmative We are of the opinion that aspiration liver biopsy is indicated in those forms of tuberculosis of the superficial lymph nodes where ferer or a sub febrile temperature or a chrohuc sinus is present It need hardly be said that enlargement of the spleen reinforces this indication, for the clinician knows that the enlargement of the spleen may be an expression of haematogenous dissemination CASE HISTORY Case XX Mrs vd W-d R 499/1948 aged 57 was admitted for treatment of a colloid goitre She also complained of nervousness insomnu and a distended feeling in the abdomen On physical examination a large rounded firm go.trc was found in the neck the scars of several sinuscs could be seen There were enlarged lymph nodes in the right axılla and behind the left ear No further abuormalities were found The crychrocyte sedimentation rate was 13 mm dunng the first hour and 34 mm during the second hour The blood picture was normal The urinu was normal The tuberculin test (VON PIRQUET) was positive The temperature fluctuated between 37 s and 38 9° C The chest X ray revcalcd some fibrosis of the upper part of the night lung The cularged lynıph node in the nght axılla was punctund and cascous material was found. No actd fast bacılls were seen on microscopical cxamination Pus aspirated from the mass behind the left car was proved to contain tubercle bacılls of human type In vicw of the raised temperature and the tuberculosis of the lymph nodes haematogenous dissemination of the process was considered probable In order to confirm tlus suspicion and also in order to get an 1 fea of the extent of the process we perfornied aspiration liver biopsy The pathological report read as follows The biopsy consiste 1 of six portions measuring together - 4 cm long They were cxamined in serial section in toul 48 sections were stained with haematoxylin-cosin and 48 according to HALLBERG Twenty seven tubercles were found viz 3 of type 1 9 of type II 8 of type III and 7 of type IV They are recent with many neutropluls and a sporadic cosinophul No necrosis is seen in one tubercle there is a trace of fibrin Some giant cells of the foreign body osteoclastonia and LANGHANS types arc observed Fivc tubercles are certainly portal In spite of a meticulous search na aad fast rods were found. C nens on extensive recent haematogenous dissemination ·62 TUBERCULOSIS OF THE LYMPH NODES goes without It saying that thyroidectomy was postponed for the tim being, and the patient was advised to observc strict bed rest, with good nutrițion and extra vitimus We lost all trace of her We will now consider the chnical importance of aspiration liver biopsy in cases with enlarged lymph nodes m the long kul and the mediastinum First and foremost it has become clear that thus type of examination is a valuable contribution to the differential diagnosis in such cases Generally speaking, the differential diagnosis of hilar and mediastinal lymph node enlargement is a clinical one, but in many cases the clinician cannot distinguishi HODGKIN's disease, tuberculosis, sarcoidosis, lung tuniour, etc Although in some cases the chest X-ray is more or less characteristic of one of these diseases, this is by no means always true, and tomographic examination also often fails to supply the diagnosis Aspiration liver biopsy was performed in 74 cases of enlargement of lymph nodes in mediastinum and lung hilus, all of which were on clinical grounds possibly or probably cases of cuberculosis or sarcoidosis Haematogenous dissemination was in this way established in 71 of the cases We shall not discuss here the changes in the liver in sarcoidosis, and its place in the differential diagnosis of tuberculosis It is beyond doubt that a positive liver biopsy is extremely valuable in arriving at the diagnosis in these cases As yet it is impossible to say how important a negative serialsectioned liver biopsy is in these cases. We believe, however, that such a finding taken in conjunction with the clinical symptoms, always deserves close attention, and that it renders the diagnosis of tuberculosis or sarcoidosis less probable in onc patient with enlarged hilar glands, with the clinical diagnosis of probable tuberculosis, but with no tubercles in the liver biopsy, 14 was afterwards found that the true diagnosis was Hodgkin's disease In rarc cases the tubercles in the liver may occur simultaneously with some other pathologic process in the enlarged lymph nodes ·TUBERCULOSIS OF THE LYMPH NODES ans of lung hilus and mediastinum carcinoma for example or HODGKIN S discase We have not yet observed such examples of multiple pathology and we believe that they must be very unusual and they do not affect the results of this investigation Aspiration liver biopsy may also assist in cases where the differential diagnosis between tuberculosis and primary bronclual carcinonna causes difficulty The diagnosis of bronchial carcinoma was considered very probable in two cases in one of these the surgeon was about to perform an exploratory thoracotomy aspiration liver biopsy revealed tuberculosis just in time That the therapy based on this diagnosis was successful qocs without saying in the second case the shadows found in the chest X-ray were reported as metastases with the aid of an aspiration laver biopsy honever the diagnosis of tuberculosis was established with all its therapeutic and prognosac conse quences We do not propose in this monograph to enter into the value of sputum ctology in the diagnosis of prinary bronchial carcinoma for ut lias been well described by Woolner and MCDONALD Wc only wish to draw atfention to the great value of aspiration liver biopsy in some obscurc cases of tuberculosis In tlus connection it would seem uscful to consider some of the disadvantages from the clinical point of view of the available methods of bacteriological study of tuberculosis that is to say of course in cases where direct examination of smears does not give the answer at once in the first place (and certainly when a successful treatment depends on an carly diagnosis) the long duration of the examinanon (in most cases at least six weeks) is an almost insuperablc objection Moreover a negative result does not exclude tuberculosis in the two cases mentioned above which elsewhere were taken for bronchial circinoma thic bacteriologist was unable to demonstrate tubercle bacıllı Both patients then canze to our clinic and it was the aspiration luer biopsy which gave the right diagnosis In the cases of tuberculosis of the lymph nodes it is agam possible to see hou exceedingly frequent is lizeniacagerous ·patients with 65 TUBERCULOSIS OF THE KIDNEY become active Elsewhere in the body, too, (eg in the brain) these clinically latent foci may suddenly ftare up and give rise to a fresh manifestation of the process At tle end of this chapter we shall briefly describe a case where renal tuberculosis was found accidentally during microscopical examination of the kidney tissue, although there were no clinical symptoms Subsequent liver biopsy also revealed tubercles In thus case the tuberculosis was entirely latent It is therefore, of the greatest importance that so-called unilateral tuberculosis of the kidney (whether or no surgical intervention is necessary) should undergo prolonged treatment with the modern anti-tuberculous drugs, PAS, etc Treatment must be protracted because, generally speaking, it is a long time before a clinical improvement is followed by hustological inactivity This was brought home to us very convincingly in studying disease elsewhere On several occasions it was possible to speak of a clinical recovery, while serial examination of the liver tissue revealed new-formed tubercles We cannot point to actual cases of renal tuberculosis in which this has happened, but it is most unlikely that this site constitutes an exception Sometimes it is not easy to arrive at the diagnosis of tuberculosis of the kidney In such difficult cases the liver biopsy may be of assistance, and as a general rule we would limit the indication for the operation to such cases CASE HISTORIES Case XXII M R 366/1947 aged 23 was admitted complaining of continual pains in the left upper part of the abdomen On physical examination pothing was found The erythrocyte sedimentation rate however was constantly raised to a considerable degree viz nis mm during the first hour and 128 mm during the second hour The blood picture did not reveal anythung of note The tuberculin test (von PIRQUET) was positive Leucocytes were regularly seen in the urinary sediment On systematic radiological examination, intravenous pyelography of the left kidney revealed a constant defect Repeated bacteriological search for tubercle bacıllı in the urine was frutless As a tumour of the kidney was suspected ·TUBERCULOSIS OF THE KIDNEY 67 MC decided to perform an exploratory lapicotomy, it did not recal anything abnormal however tissue of both organs The lyer biopsy measured 13 cm long and the kidney biopsy 13 cm In total there were 96 sections which were serially examined in the liver paranchyma were found in total 3 small foc i of them belonging to type III and 2 to type IV The kidncy biopsy showed no lesions Conclusion three subtubercles in the liver parenchyma, which may very well be of tuberculous ongin" Hence the duagnosis of renal tuberculosis became more probable Bacteriological examination of the urine for tubercle bacıll, was resumed, onc of the cultures brcamc posiave after three months thus confirming the diagnosis of tuberculosis The patient was advised to undergo an operation under the protection of streptomyan and PAS Case XVIII Mrs M-C501/1949 aged 48 was admitted complaming of headaches from which she had suffered for a considerable timc She was also troubled by tinnitus dizziness and sceing stars Her troubles were mamly the effects of hypertension On physical ctamination a slight dilatation of the heart to the left was observed the blood pressure was 210/120 mm Hg Tliere sere no abrormalities in the urine The crythrocyte sedimentanion rate was 9 mm during the first hour and 28 mm during the second hour The blood picture showed no irregulantics The tuberculin test (NON PIRQUET) was positive It was decided to perform sympathectomy In the course of the operation biopsy of the left kidney was donc The pathological report by Dr W ET WINCFFL states that apart from the archiosclerosis and arteriolosclerosis a fairly recent non-cascaang conglomerate cubercle of type Olt was found un xpectedly in the cortex In order to obtain an impression of the extent and the activity of the process we performed an aspiration liver biops) The report read as follows The biopsy measured 2 4 cm long and was examined in serial scction (92 sections) in the parenchymia 73 iesions were found 12 of them belonging to type Mi and 61 to type IV This is a relaticly recent disse tination for apart from the lymphocytes a few neutrophuls are still observed between the cpithelioid cells Conclusion extensive relats els recent haematogenous dissemination' The patient was treated with sinct bed rest and PAS ·CHAPTER XIV TUBERCULOSIS OF THE ADRENALS Aspiration liver biopsy was performed in one case of Addison's disease As is well-known, this disease is generally speaking tuberculous but it is equally a well-known fact that primary adrenal atrophy, metastatic carcinoma pituitary disease or amyloidosis may also give rise to the same clinical syndrome (incidence of non-tuberculous ADDISON's discase WELLS J0%. GUTTMAN 20%) In this connection the report of RICKARDS and BARRETT acquires a special significance The authors describe an example of ADDISON’s disease which is characterized by the presence of noncaseating granulomata with giant cells Formerly such cases were regarded as examples of a glandular disease due to noncaseating tuberculosis, but study of these cases leaves little doubt that they represent examples of the disease granuloma", considered by these authors to be a specific clinicopathological entity In general the significance of aspiration liver biopsy in cases of ADDISON's disease is twofold In the first place the tuberculous genesis can be established, and in the second place it is possible in thus way to make a diagnosis of general haematogenous tuberculosis We need hardly explain that the view of the haematogenous origin of adrenal tuberculosis may be corroborated in this way It goes without saying that a patient suspected of this disease, has to be observed attentively after the puncture, in view of the greater liability to shock in these cases This can not be regarded, however, as an absolute contra-indication to aspiration liver biopsy "giant cell ·TUBERCULOSIS OF THE ADRENALS 69 CASE HISTORY Cası XYIL Me E 723/1949 aged 48 was admitted to the hospital complaming of extreme fatigue The patient had also observed that he had developed generalized bodily pigmentation At the age of eight he had suffered from pleursy with cffusion and when he was twenty five there was a slight relapse of this About the sanze time he had a cold abscess of the left buttock The present complaint led the local physician to a diagnosis of ADDISONS discase When the pati nt was admitted to hospital in Leyden for observation he was placed on DOCA intramuscularly daily These injections were contin icd in our clinic On physical examination nothing sign ficant was found apart from skin pigmentation There was no pigmentation of the buccal mucous membrane The blood pressure was 130/80 min Hg The crythrocyte sedimentation care was 11 min during the first hour and 24 mm during tl e second hour Haematological investigation showed only leukopenia The tuberculin test (von PIRQUET) was positive There was no fever The chest X ray revealed numerous small blurred shadows there was no question however of definite tuberculosis of the lungs In vi“ 61 1 1 of thic nspirati The biopsy measured - 6 cm long and was cxamined in serial section (110 sections) In total 49 tubercles were observed 3 of them of type I 12 of type II 6 of type III and 28 of type IV It is found that three different disseminations can be distinguished with certainty a fresh dissemination with mitoses and many cositopluls an older so-called large cell hyperplasia and a sall older one showing the commencement of scarring in some of the lesions of type III and several of type IV the cells have phagocytosed many black pigment particles These give a negative reaction for iron In one of the giant cells a so called asteroid body was found Conclusion extensive non-cascating chicfly large-coll epithelioid cell granulo natosis (tuberculosis) three separate dissenunations of different ages Anthracosis In vicw of the result of this examination it was advised that specific antibacterial therapy be added to the hormonal treatment About a year after his admission to hospital he died of a myocardial infarction at home ·CHAPTER XV BONE AND JOINT TUBERCULOSIS Aspiration liver biopsy was performed in seven cases of ruberculosis of the skeletal system and joints In sıx cases tubercles were observed in the liver Here again, it may be asked what are the indications for liver biopsy Every clinician knows only too well that even in the presence of radiological bone changes the diagnosis of tuberculosis may be uncertain Lesions of this type arc often inacccssible to ordinary biopsy (which is in any case not devoid of risk) The posuion is worse when the presence of a lesion is suspected on clinical grounds in the absence of X-ray changes This holds especially for carly tuberculous arthritis formerly a presumptive diagnosis on clinical grounds might have been adequate, but now the clinician requires a greater measure of certainty before deploying his full therapeutic armamentarium Correct and prompt treatment in the early stages may now completcly prevent irret crsible changes in the joints By the time X-ray changes are present the prognosis has become more doubtful, although even at this stage it is better than formerly Aspiration liver biopsy may assist considerably in arriving at an early diagnosis and may be the only available mcans of establishing it with certainty Here again the considerations which we mentioned in discussing miliary tuberculosis apply, with the exception perhaps of those related to lumbar puncture It is clear that it is - possible to examine regularly the spinal fluid of all the patients in whose laer tubercles have been observed, although on theoreacal grounds it would be easy to defend such a course Here, too the clinical status of the case must be the deciding factor ·BONE AND JOINT TUBERCULOSIS 71 It is a well-known fact that operative manipulation of a tuberculous joint may disseminate the bacıllı It is even probable that normal movement of the inflamed joint may cause dissemination, so that liver biopsy niay be expected to be positie in a large percentage of cases This operation may therefore prove a most welcome diagnostic method in affections of the skeletul system or the joints where the aetiology is obscure CASE HISTORIES Case XX1 Mr S R 476/1948 aged so had suffered from pun in the right knec for six years It was said to have commenced after injury For five ycars he had received various forms of physiotherapy In January 1948 at thc health centre for rheumatic discases the possibility of tuberculosis was raised Immobilization of the joint had no effect Finally an open biopsy of the capsule of thc knee joint was performed but no huscological cvidence of tuberculosis was found Subsequently a consultant physician trcated the patient with gold and amudopy nnc there was no improsement On clinical examination the circumference of the right knec was found to be 25 mm more than that of the left knee A flexion contracture was present the crythrocyte sedimentation rate was r2 mm during the first hour and 30 mm during the second hour The tuberculin tesc (vov PIRQULT) was positive The chest x-ray showcd nothing of note apart from some old upacities Yet tuberculosis was not ruled out especially in view of the X-ray appearances of the joint in the lower part of the femur there were some all-defined radiolucent arcas associated with distinct periostcal irregularities and thickchings Another synovial biopsy was done The diagnosis was focal cellular proliferative inflammation with tubercles and necrosis The pathologist (Dr G J VERDOVK) considered honescr that he could not altogether exclude the possibility of a rheumatic process After the bropsy the patient developed ferer An aspiration biopsy of the liver was then performed The pathological report read as follows The biopsy measured 3 cm long and was examined in serial scct1013 (108 sections) In total 47 tubercles were observed 3 of them of type II Il of type III and 33 of type IV In addition to limphocytes and polymorphs the tubercles of type Il also contain some cosinophuls and one contams son e fibrin and ; sunt culls Staining according to HALLEERC is negative all the focs are situated in the parenchymı and they are of a young type wonic Kupffer cells contain a grayish brost pigment such as Js seun in patients treated with gold ·73 BONE AND JOINT TUBERCULOSIS Conclusion many recent tubercles, onc of which contains giant cells Highly suspicious of tuberculosis" Meanwhile tubercle bacılkı had been cultured from the synovial fluid, thus establishing a diagnosis of tuberculous archricts with hacmatogenous dissemination Therapy consisted of surgical resection of the joint, combined with treatment with streptomycin and PAS Ar the operation three bone foci were found in the proximal part of the tibia Abscesses in the popliteal fossi were also observed After pathological examination of the resected Ince Dr. G I VERDONK reported that it showed extensive cascating tuberculosis Six months after resection, when the plaster of Paris was removed, the patient's condition was satisfactory, although the sedimentation rate was still high (23 mm during the first hour and 41 mm during the second hour) Case XXI'I Miss O. 946/1949, aged 23, was admitted with intense pan in the left hig, which lead appeared acutely and was attended with fever On physical examination the only finding was limitacion of all movements of the left hip joint The crythrocyte sedimentation rate it as 63 mm during the first hour, and 100 mm during the second hour The blood picture showed only slight leucocytosis The urinc was normal The chest X-ray revealed nothing of norc X-rays of the hup joints were normal The diagnosis of tuberculosis was however scriously considered partly owing to the fact that 2 years previously the patient had suffered from tuberculous pleurisy In order to confirm the diagnosis of tuberculosis an aspitaniou liver biopsy was performed Thc pathological report read as follows "The brapsy measured 2 7 cm long, and was examined in serial la foci wetc observed, one of which homiliary ing of fibroblasts, Lu. sich some scrous exudate of the four foci in truc par type III, and two of type IV Onc focus of type III is still young and contains a mitosis, the other foci are of intermediate age The parenchyma is normal Conclusion young submuliasy portal tubercic, and four subtubercles in the parenchyma Tuberculosis is very probable' onc The patient was treated with streptomy an and PAS combined with rest, good nutrition, and immobilization of the left hip joint Nineteen dars after the commencement of tłus therapy the sedimentation rate had droppeu ·BONE AND JOINT TUBERCULOSIS 73 to somn during the firschour, and 35 mm during the second hour Within one weck the temperature became normal, and remained so until the patient was discharged five and a half months after admission Before she was discharged a second aspiration liver biopsy was performed The report read as follous "The biopsy mcasured 2 cm long and was exanuned in scrial section (120 sections) Only & pericentral lesions of type IV were found, partly of a rather young type, and partly of an intermediate type No mitoses were observed Conclusion Eight subtubercles of type IV" The patient was advised to continue the rest cure at home, combined with PAS and cxtra vitamins Immobilization of the lup joint was continued Four months afterwards the paticnt was again admitted for a follow-up cxamination She was in a very good condition, the function of the hip joint was 100°, After discussion with the surgcon careful movement of the hip was begun She was advised to take inuch rest at home, and to conunuc the PAS therapy The patient is now in cxcellent condition on physical cxamination nothing significant can be found The crythrocyte sedimentation rate is normal She consulted her family physician in connection with sterility, bacteriological cxamination of the menstrual blood revealed the presence of tubercle bacıllı ·CHAPTER XVI TUBERCULOSIS OF THE EYE In fourteen cases of eye discase in wluch the aetiology was not clear (11 cases of iridocyclitis 2 cascs of keratius and I casc of retirutis) we had recourse to aspiration liver biopsy In each of these cases it was suspected that the disease of the eye mught be a manifestation of tuberculosis Experience has taught the oculise that such intra-ocular processes have often a tuberculous origin, and therapy must conform to these ideas The therapeutic consequences being far-reaching it is most desirable (as in most cases when considering therapy) to be as sure as possible of the aetiology In eleven out of the fourteen cases tubercles were observed in serial sections of the liver biopsy in eight of the cases they were cyclusively of the types III and IV CASE HISTORIES Casc \\ | Mr H 504/1950 aged 27 visited our outpatient department with general vague complaints and was found also to be suffering from a chronic iridocyclins in both eyes On physical examination there was notlung of note The X-ray of the chest showed a distinct sporty shadowing with enlarged hilar lymph nodes Thc tuberculin test (VON PIRQUET) was negative the Mantoux was positive at 1 10 000 The red cell sedimentation rate was omm during the first hour The diagnosis of sarcoidosis was considered but could not be established The chest X ray was very suggestive of this discase though the positive MANTOUX spoke against it A liver biopsy was performed ciscus here Apart from one subrubercle of type IV nothing abnormal could be found bur the biopsy was far too small for satisfactory study In view of the chronic indocyclins the patient was treated with tuberculin ·TUBERCULOSIS OF THE EYE 73 and PAS, treatment being continued elsewhers On onc occasion tubercle baalli scre cultured from the sputumn About 3 years later the patient returned to our department The iridocyclitis was now much worse To determine the activity of the process a second liver biopsy was performed The pathological report scad as follows **The biopsy measured 1,2 cm long and was examined in scrial section, TE tubercles of type and I wah sometimes sinall hyalmc bands Two of the 8 tubercles of type II were completcly scarred, but on exanınation in serial section one was found to contain a giant cell and a few cpitheliod cells Some of the remaining tubercles were rather young, a few cosinophil leucocytes were found in these Ten of the 28 subtubercles, all located in the parenchyma, belonged to type III, 18 to type IV Further there was found a slight farty infiltration Conclusion Many non-cascating partly young, partly older and partly sclerosed tubercles of all types The patient was treated with PAS streptomycin and INH Sıx months later a third biopsy was perforined The pathological report read as follows "The biopsy measured 1.5 cm long and was examined in scrual section (120 sections) In total 69 foci were observed 10 submuliary tubercles and 59 subtubercles, 38 of the latter belonged to type IV, i to type III Only a few were young Thc subruliary tubercles were located in the portalspices and were markedly older than those in the former biopsy There were 6 conglomerate tubercles I of type and s of type I built up of mjinly large-cellular foci surrounded sometimes by broad hy alınc bands One was somewhat younger the hyalıne band was narrower and surrounded by a rather broad zone of lymphocytes plasma cells and cosinoplul leucocytes further there was one solitary tubercle of type 1 with a large-cellular structure and a periphery consisting of old connective tissue wahout hy alınc One of thic 3 tubercles of type II was relatively young and surrounded by a zone of lymphocytos onc cicatrised with a centre of epithelioid cells and one a hualinc ball with a large cellular contre The parenchyma showed sotne cosinophilic degeneration and dissoxtation of the individual losct culls with slight fatty infiltration Conclusa Alany non-cascating older and cicatrising tubercles and conglomerate tubercles of types o 1 and 1 and many subtubercles of type IV' ·76 TUBERCULOSIS OF THE EYE Unfortunately afterwards the patient was observed and treated elsсu here and we have lost all trace of him picture was Case XXVIII Miss P, 5559/1948, aged 47, was referred to us by the ophthalmological outpatieni department for a general examination, as she was suffering from indocyclitis Physical examination showed nothing of significance except the indoczclits in the right cye Tuberculosis was frequent in the family The patient told us that from time to time she had small erythematous spots scattered all over her body The erythrocyte sedimentation rate was 14 mm during the first hour, and 30 mm during the second hour The blood normal The MANTOUX reaction was positive The chest X-ray was normal In order to establish the aetiology of the iridocyclatis it was decided to perform an aspiration liver bropsy The pathological report of the liver tissue read as follows "The biopsy measured 3 6 cm long and was examined in serial section (99 sections) Nine subtubercles were observed in the parenchymi, 2 of type III and 7 of type IV They are partly recent partly somewhat older Conclusion partly recent, partly somewhat older subtubercles of type. III and IV, which are suspicious of tuberculosis' The diagnosis of tuberculous iridocyclıtıs had now become probably The patient was advised rest, and PAS was prescribed ·CHAPTER XVII THE SIGNIFICANCE OF SUBTUBERCLES OF TYPES III AND IV We turn now to discuss a phenomenon which has been nicntioned many times in earlier chapters In the liver biopsies of patients known with certainty to be suffering from active tuberculosis we have regularly observed epithelioid-cell subtubercles of types III and IV The significance of these differs entirely from that of the better-known subnulary tubercles (usually portal) of types O, I, and II As a rule these epithelioid-cell subtubercles are situated in the parenchyma But sometimes they are located in the portal spaces and probably the majority of these have to be considered as preliminary stages of the submiliarv tubercles of types II, 1 or 0 Occasionally parenchymal lesions of type III may be observed which have irregular boundaries and produce atrophy of the surrounding liver cells shown by the intense staining of the latter with cosin These probably must be considered as preliminary stages of the type II tubercles sometimes to be found in the parenchyma We have never yet observed tubercles of types I and O with a parenchymal location However most of the parenchymal subrubercles of types III and IV are clearly outlined epithelioid-cell foci of round to oval shape They may be found in all sections of the lobule but preference to a pericentral location, which applics especially to the smallest type IV They are occasionally attached to the wall of the central vein more often to a hyperacmic capillary In young lesions mitoses neutrophils and or cosinophils with a few ly niphocytes may be found When older lesions contain any cells these consist exclusively of a fes lymphoc) tes These lesions never cascate they very rarely (in the case show 2 ·78 SUBTUBERCLES OF TYPES OIL AND IV of type III only) contain a giant cell Although the epithelioid cells do not develop into ordinary fibrocytes, their nucleus, which is at first vesicular and pale-staining, becomes in tim longer, drawn out and pyknotic Subtubercles of these types never develop into true tubercles, but disappear completely without leaving a trace This statement is based on the examınation in serul section of serial liver biopsies, 1 e repeated biopsies at intervals in each of a substantial number of cases These lesions in all probability arise from the KUPFFER cells In favour of this statement we should like to mention that the epithelioid cells of subtubercles of types III and IV occasionally contain some lipofuscın derived from destroyed liver cells What is the clinical significance of these small granulomata (which we observed first in sarcoidosis) when they are found alone in liver biopsies performed for diagnostic purposes in persons suspected of tuberculosis? Before we could answer this the examination of a large series of controls was necessary Between 1946 and 1950 practically all liver biopsies done for other indications (approximately 1s0 cases) were examined in serial section We can conclude from these that the presence of subtubercles of types III and IV is not pathognomonic, but is always suspicious of tuberculosis or sarcoidosis We observed such lessons four times in Hodgkin's disease once in infections 11100011cleosis, and once in malaria (The epitheltoid cells of the type III and IV lesions in the last mentioned case contained malaria pigment, which supports the view that they may arise from KUPFFER cells) We are not in a position to decide how far in these cases they were a response to the agent of the disease, or a consequence of simultaneous tuberculosis At the autopsy (by Dr STRAUB) on one of the patients suffering from Hodgkin's disease however, not a trace of tuberculosis was found We also had the opportunity of performing liver biopsy on a patient suffering from brucellosis, in which disease, on theoretical grounds we expected to find these lesions as well as the more classical tubercles observed by HOFFBAUER and Spink They were present in large number The same observation ·SUBTUBERCLES OF TYPES III AND IV 79 was made in the only case of beryllosis we have seen Unfortunately we have no experience of their occurrence in syphilis * and in histoplasmosis, coccidiomycosis, blastomycosis, torulosis, and various tropical diseases, in which we consider their appcarance as possible. In a few cases of mechons hepatitis pericentrally located lesions of type IV were found These were quite characteristic, for the cpithelioid cells (= KUPFER cells) are loaded with lipofuscin to a degree never seen in tuberculosis Since in more severe cases the virus of infectious liepatitis by preference destroys pericentrally located liver cells, a good deal of lipofuscin may be liberated This pigment is phagocytosed by KUPFFER cells and thus leads to the formation of solitary lipofuscin-containing cells or to the formation of small clusters of such cells which we should like to call "lupofuscin granulomata". Thrice we have had the opportunity to study the liver at autopsy in cases of typhoid fever, in two of thesc cascs by mcans of aspiration biopsy directly postmortem The common typhoid fever lesions differed from those scen in tuberculosis, sarcoidosis brucellosis, berylliosis and Hopgkin's discase in the presence of an abundance of neutrophils Moreover the nuclear lobes of these polymorphs had beconie separated, an observation wluch up to now we have made only in this disease In 10 cases, where the clinical symptoms were such that tuberculosis could not be excluded from the diagnosis, we found 1, 2 or as many as s subtubercles of type IV in view of the circumstances that from time to time tuberculosis is present and heals without being noticed, we do not look upon these cases as sperking against our view In a number of cases we made a diagnosis of "suspicious" or very suspicious of tuberculosts”, based exclusively on our finding of 1–20 fresh subtubercles of type III and/or IV, fogasher is the chascal symptoms Ibis * LAQLILR and EGELI des ribed miliary syphlonista ubuni na lever h psy without do cut me the d fferentul dugnos s from tukar ut ss In ur fout is ju te poss ble that these fhad a tuberculus sent we have had the trutunuty diseint this riper With one of the a thors (D) LA ILTL) Whatod wth our *25*3 ·80 SUBTUBERCLES OF TYPES III AND IV diagnosis was afterwards confirmed in 1cases by the findig of tubercle bacıllı in stomach washings, sputum, or urine Two of these cases have already been described in the sections dealing with renal tuberculosis, and pulmonary tuberculosis It is clear that the early therapy of such cases is very important In this connection we would recall the patient with post-partunı fever, mentioned in the section dealing with tuberculosis of the lymph nodes The clinical symptoms, together with the subtubercles III and IV seen in the liver biopsy, decided us in favour of early streptomycin therapy This appeared to exert a decisic effect in the patient's subsequent complete recovery In one case in which the presence of a mediastinal muss was the indication for liver biopsy we found a single subtubercle of type III in the otherwise normal liver Autopsy revealed mediastinal sarcoma, but there was also tuberculous pleurisy The clinical significance of these small foc should always be weighed in the light of the symptoms of the case under consideration It is certain that they may occur in abortive cases of tuberculosis These small foci could only be regarded as specific for tuberculosis if they occurred exclusively in this disease, which is not the case It is also to be expected, if these are specific lessons, that it should be possible to demonstrate the tubercle bacillus in cases showing only these lesions (i e in the absence of tubercles of types O, I and II) not only hustologically, but also on culture In the series reported in this monograph we have consistently failed to do this We have attempted to approach this problem experimentally As the investigations lie outside the scope of this monograph, we will only mention our observation that it is not difficult, by means of intravenous injection of tubercle bacıllı into the allantoic vessels of hen's eggs, to produce subtubercles of types III and IV as well as tubercles of types I and II, in the livers of chicks (technique of LEE and STAVITSKY) These subtubercles are loaded with acid-fast rods, and their appearances corroborate our view that they may be produced by tubercle bacill in the chick liver they are even more easily overlooked than in the human liver ·SUBTUBERCLES OF TYPES JIL AND IV 81 that special We have recently been able to prove thiar in man also these subtubercles may be caused by tubercle bacalle A baby bom prematurely of a tuberculous mother died on the twenty sixth day from excensive bilateral caseating tuberculous bronchoprcumoruz We expected on theoretical grounds that there would be subtubercles of types III and IV nich 101d-fast rods present in the liver and the spleen The conditions were most favourable a prematurely-born child practically without immunity dying from rapidly lethal tuberculosis of the lungs Our suspicions ricre confirmed and these lesions also proved so difficult to see - particularly in the splen c\perience proved necessary for their confident recognition in our opiuon le is quite possible that in less abnormal circumstances these subtubercles may be the response to the phagocytosis and disintegration of a very small number of tubercle bacalls by and in the Kupffer cells in this way failure to find any acid-fast rods becomes readily understandable * We beliesc it would be wrong to assume that a tuberculous origin must be regarded as improbable becausc of the negative bacteriological findings in the subtubercles {II and IV of our lucr biopsics It was repeatedly observed by us that in adı anced cases of tuberculosis with posicruc bacteriological findings in other material no tubercle bacılh could be demonstrated (ether microscopically or culrurally) ur liver tissue continung tubercles of a pes I to IV inclusive In thus connection tc nould point out that ur face tubercles of rupes I and II are also not specific for cuberculosis They also occur in other diseases ( g srcoidosis şıplıslis leprosy and other tropical discases brucellosis beni liosis Histoplasmosis and other fungus infections and tale granulomata) Even morphologicallı apicat acıd fast rods do not afford certainty Certimi i attamed only when these acid fast rods have been proved to be tubercle brcally by means of cultures or quinca-pig inoculadou Vesuba et op n n to our loc u ter EFF {xt of n con 1x โ# 35 and he made the appropriate unna in that are the les types ad IV # ha c to be cois Jercia ho best n fhuben? bau ·82 SUBTUBERCLES OF TYPES III AND IV It is the exception rather than the rule to be able to demonstrate acid-fast rods in liver tubercles even in cases of proved ruberculosis They are usually to be found in fresh caseating tubercles, but these are not often observed in the liver They are rare in old caseating tubercles (which are also of rare occurrence), and in the common epithelioid-cell tubercles This would tally with the fact that guinea-pig inoculation with liver tissue obtained by means of an aspiration biopsy rarely yields positive results After completing this work we found that the German pathologists ORTH (1887), W FISCHER (1907) and B FISCHER (1910), and the French clinician DIEULAHOY (1901) pointed out half a century ago that the liver is not a favourable soil for the tubercle bacillus It is probable that the high resistance of this organ results from the presence of the KUPFFER cells This in our opinion, is the reason why macroscopically visible tuberculosis of the liver, and especially tuberculomata of the liver, are rare (WAGNER, ORTH, MORRIS, ASHTON) On the microscopic scale, however, our investigations go to show that tuberculosis of the liver is exceedingly frequent This also we found had already been pointed out more than half a century ago at autopsy by German pathologists (WAGNER, 1861, VIRCHOW, 1863, ORTH 1876, ARNOLD, 1880), and the French clinician DIEULAFOY (1901) All thus had, hou ever, been largely forgotten in the course of time There seemed to be no descriptions of the common type III and IV subtubercles in medical literature Apparently they escaped the attention of all of us for all these years By careful examination we succeeded in finding these so-called subtubercles not only in liver biopsies but also at postmortem in the livers of patients dying of tuberculosis It may be wondered why they have been overlooked in autopsy material, but the explanation seems to be quite plain In the first place the portion of hver tissue removed at autopsy for microscopical investigation 15 relatively large and therefore one is more likely to be satisfied by the sight of one or more of the larger tubercles and the small foci escape attention But when a postmortem needle puncture is ·SUBTUBERCLES OF TYPES 111 AND IV 83 performed and the small column of liver tissue obtained is examined 11 serial section practically no detail escapes the attention of the investigator and so even tiny focs mas bu observed A second reason for overlooking the subtubercles i the liver at autopsy is found in agonal and postmortal changes With loss of glycogen the mosaic pattern of the liver cells as replaced by a trabecular design and owing to this the foc lose their romd or oval shape and become morc drawn out and irregular The venous congestion of the liver and dissociation of the parenchyma which occur as postmortem changes also interfere with recognition of these small lesions The only communication bearing on the subrubercles is one on liver puncture in miliary tuberculosis by JAVBOV et al in which a lesson of this type was illustrated. These workers express the opinion that it represents a prelummary stage of the common submhary tubercles Considering the cudence presented by our serial section clammation of iner biopsies in 189 cascs (151 25 of wluch the course of the disease wis studsca by serial biopsies) we cannot share this opinion Clear cut parenchymal foci of types III and IV do not der clop into ordinary tubercles but disappear without kung a trace Continued clinical pathological experimental and statistical word is required to iniprove our insight into the significance of these small losions ·86 SOME GENERAL OBSERVATIONS 2 and bactenology One is not in a position to evaluate the activity of a tuberculous process (especially in relation to the lesions scen in the liver in aspiration biopsies) when one has not 1 clear idea of the pathological background and the problems of immunity and bacteriology Although we cannot deny certain parallelism in the concept of "activity of the clinician and the pathologist, yer there is a distinct difference It is generall accepted that clinical activity always implies the presence of an active (in the pathologist's sense) tuberculous focus somewhere in the body, the reverse, however, is certauly not true Everı experienced medical man knows of cases with no clinical evidence of active tuberculosis in whom autopsy has shown (as a secondary finding) active cascous foci containing virulent tubercle bacıllı Many persons go much further still and hold, on good grounds, the view that every man with a positive tuberculin rcaction harbours such a focus, “using" this focus to keep bus iinmunity Sat the proper level Generally speaking we may say that the specific immunc state derived from contact with virulent tuberclc bacıllı tends to check the development of the bacıllus in the body A positive tuberculin test indicates that there arc immune bodics present Perhaps it is too bold to suggest that absence of tubercles in liver biopsies in persons with a positive VON PIRQUET or MANTOUX rcaction points to an cquilibrium of the active focus and the production of immune bodies When this equilibrium is disturbed (the production of immunc bodies decreasing, or the activity of the focus increasing) disserunation becomes possible In this way histological examination by means of serial sections of the aspiration liver biopsy might serve as a rough indicator of the degree of immunes (rubercilogram) Nevertheless it is well-established that in tuberculous meningitis the number of foci in the liver may be tnfling, but the gravity of the clinical picture is determined independently by the state of the cerebral focus which affects the cerebrospinal flud Hence local conditions may also decisively affect the course of the illness may therefore also be postulated that everyone who conies It ·SOME GENERAL OBSERVATIONS 8 into contact with tubercle baalls passes through a phase of disscnunation, equilibrium ss the great majont, of cases soon re-established in favour of the host and the tuberculin cest becomes positive from this point of view it niust be regarded as probable that every primary infecnon is attended with dissemination of tubercle bach which as a matter of fact we were able to demonstrate in the cases In short when one has noted the churcal facts it is possible to accept the vieu that Chaty actuc tuberculous process involves disseminunon That the liver can be made to serve as an indicator of the degree of this dissenunation is an important fact because we may be able to use it as a reliable measuring rod or standard Alstrate techngurs Theoretically the splu could also be used for this purpose The fact that the liver is more accessible and less vascular houerer renders it technically more suitablc for aspiration biopsy than the spleen Morcover aspiration splcem biopsy should in our opinion only be permutted under the control of the laparoscope (HAEX DE OUDSIIN and van Brex) To this must be added the fact that the above-mentioned tubercles (especially the smaller types) are more cisely obsessed 3g3nst the background of lover cells than against the more compucatcd splenic partem in a fess cases of miliary tubcrculosis SCHLEICHLR perfornicd shmal puncture Thc tiny bone marros particles were embedded in paraffin and examined 112 serial section In agreement with the mestigations at RANDERATH cubercles uerc found mall cases (Sec also the impor. Cant work of GERTRUD PEASE) Smce aspiration biopsy of the liver prouides us with a solid column ot Incr tissue ric beheve this method more satisfactors for diagnostic purposes It has more than once been mentioned m medical literature that consel biopsy (suggested as a diagnostic operation in sarcol dosis by SCHAUMANN) might also be valuable is the diagnosis of tuberculosis Without discussing this question in detail it Bay be said cluat in our opiruon a tonsil biopsy is of little imporrance en eksis respect This opinion is based on microscopical ·88 SOME GENERAL OBSERVATIONS examination at two levels of 64 pairs of tonsils removed » children suffering from pulmonary or hilar lymph node tuber culosis Thus i vestigation was carried out by one of us (v B) in co-operation with Dr WARNS, director of the sanatorum a1 Katwijk aan Zec In 23 cases a few submiliary tubercles and/or subtubercles were found These tubercles were not diffusely disseminated as in the liver but confined to one or two areas The result of a tonsil biopsy is hence more or less a matter of chance This opinion is reinforced by the fact that of the 23 positive cases quoted above 7 only had bilateral lesions while 111 56 only one tonsil was involved But we must of course stress that thesc tonsils were not cvatuned in serial section, but at tuo levels each only PATHOGENESIS OF TUBERCLES OF DIFFERENT TYPES Let us now look a httle more carefully into the pathogenesis and the histological picture of the vanous types of tubercles in the liver Wc conceive the liver as a filter We imagine that small particles in the blood (whether portal or hepatıc) arc held up as emboli in the sinusoids of the liver, the larger particles (conglomerates of tubercle bacill, or reticulo-endothelal elements from elsewhere which have phagocytosed tubercle bacıllı) in the portal tracts and at the periphery of the lobule, the smaller particles (solitary tuberclc bacıllı), on the other hand, more towards the lobulc centre Kurfrer cells are well known to phagocytose small particles One can therefore imagine that as far as the tubercle bacıllı arc concerned, once they have entered the vesscls of the liver they will be phagocytosed by thesc cells We were able to observe this directly in the case of one patient who died of exceptionally acute tuberculous infection It is an obvious step to assume that thesc KUPFFER cells, having ingested the tubercle bacıllı, thereafter act as starting points for small tubercles This vicw finds support in an observation made by us in a patient suffering from anthracosis and pulmonary tuberculosis We found carbon not only in the Kupffer cells but also in the subtubercles in the Iner parenchyma (types III ·SOME CINERAL OBSERVATIONS 89 and IV) We can only explain thus by assuming that the proleforated cells of these granulomata have phagocytic properties It is thcoretically possible that the stimulus to formation of the subtubercles in the liver is not the direct presence of bacıllı but the effect of toxins This view is not supported however by the strictly focal character of the lesios We would expect a more diffusc reaction of the reticuloendothelial system to toxins moreover circulating toxins have not yet been demonstrated in tuberculosis (Rici) It would lead us too far afield to discuss the question of the production of cubercles by the release of specific chemucal substances willen tubercle bacıllı disintegrate The phagocytic and detoxifying functions of the liver are well known and it is easy to believe that this organ is actic in rendering harmless both the bacıllı and the products of their destruction The presence of such an activity accords well with the listopathological findings for tubercles with cascation are rare in the liver cxcept in miliary tuberculosis – much rarer than in many other sites In non-caseous tubercles we may expect norc variations in structure now that antibionc and chemotherapeutic treatment is considered of great value in the battle against tuberculosis we try to make use of tliese variations in estimating the activity of the process Very important arc in this respect the presence of cpithelioid cells mitoses and polymorphonuclear leucocytes As we said earlier we imagine that solitari tubercle bacıllı arc caught within the Inter lobulc while conglomerates are held up as embol at the periphery of the lobule it small and within the portal tracts of large Because of the different huistological structure of the parenchyma and the portal tract the tubercles formed in them ditfer Within the lobulc there is no connective tissue between the liver cells The reticuloundothelial cells present there chiefs the KUPITER cells are the principal material for the subrubercles of types ill and IV formed there In the portal tracts the cells of the connective tissue also cooperate in the formation of these structures in this wa arc tormed the submilary tubercles of types () 1 and Il as well as the cons- ·90 SOME GENERAL OBSERVATIONS paratively rare miliary and larger conglomerate tubercles Not only has the examination of the liver tissue obtained by means of aspiration biopsy and studied in serial section assisted us in localising the different tubercles and establishing their various types, but it has also fortified our belief in the haematogenous dissemination of the process, which is still questioned by some workers We were able to make innumerablc obscrvations of subrubercles contiguous to a blood vessel We believe that the small epithelioid-cell lesions of types III and IV, which are situated in the parenchyma, disappear without leaving a scar It remains an open question whether the reticuloendotliclial cells are resorbed, or whether they revert to the lining of sinusoids The most probable ansuer is that both can occur The portal tubercles, on the other hand, must leave behind them older connective tissue, or scar-tissue, in the shape of hyalıne balls, when healing takes place These hyaline balls are scon especially after the healing of cascous tubercles We never directly observed organisation of the caseous centre Penetration of fibroblasts into fibrin was seen several tunes Serial sections have shown that the periphery of ageing tubercles often consists of a hyalıne zonc surrounding a centre of epithehoid cells in a few cases we have seen, in a preceding biopsy, cxclusively caseous tubercles and hence we presume that in these cascs there has been at first a cascous centre afterwards replaced by cpithelioid cells in this way the presence of an older hy alıne zonc surrounding a core of younger tissue becomes understandable Hyperacmic capillaries are sometimes found in the hyalınc zone Serial sections gac the impression that the hyaline substance comes from the blood and that the capillaries represent the pre-existing sinusords of the liver We find it extremely difficult to decide whether streptomycin mu accelerate this scarring process BAGGENSTOSS er al are of the opinion that under the influence of streptomicin young epithelioid-cell tubercles neither cascate nor encapsulate ·SOME GENERAL OBSERVATIONS 91 From what precedes it will be clear that generally speaking the 350 of a disseminated process may be better gleaned from the larger portal tubercles than from the smaller lesions in the parenchyma Generally speaking the latter can only point to a recent dissemination in the acute stage the sinali epithelioidcell subtabercks in the parenchyma consist of vesicular cells whose nuclei become pyknoticas they grow older In the beginning a few polymorphs may be present but later only lymphocytes are found Finally it is probable that the entire lesion is resorbed without leaving a scar behind All this is based on the observations made in the course of serial examinations of positive liver biopsies from 176 patients suffering from tuberculosis Although 11 is really superfluous we would once again mention the importance already stressed of the examination by serial section of biopsies of a large scries of control cascs These were provided by some 150 biopsies performed for other indications Unfortunatcly we have not yet furnished experimental proof of our views It would at cins stage lead us too far afield to discuss the experimental work in progress at the present moment in the attenipt to obtain thus essential confirmation of our ideas It is obvious however that we need data on thic occurrence of microscopicalls visible tuberclc bacıllı in the different foci For this purpose we have preferred the method of HallBLPC (using mught-blue) to that of ZienL NEELSEN We were especially struck by the fact that acid fast rods were not to be found even in recently cascating tubercles unless a large number of sections kere elamined We never succeeded in old cascous tubercles In non cascating tubercles ne sav 20d fast rods only rarek They were never observed in the small epithelioid-cell lesions of tipos III and IV which however docs not mean that they had not been present at an earlier stage of these keskus In all nc examined 4s cascs using this staining method acid tast rods being found 21 The results of guinea pig inoculation with a small portion of the inertissine are in a reciment with this in ali-o guinea pig ·92 SOME GENERAL OBSERVATIONS tests were done, of which only 4 were positive, and this only after on the average four months These observations would support the view that the liver is able to phagocytose and climinate the tubercle bacıllı Experiments have likewise very clearly demonstrated the destructive action of the liver towards tubercle bacıllı (LURIE, WESSELS) In this connection the work of WOODRUFF et al is interesting Tubercle bacıllı were cultured from the spleen, the liver and the kidneys of patients who died of pulmonary tuberculosis Often tubercle bacıllı were cultured from the liver (especially when there was also abdominal tuberculosis), but better results were obtained from the spleen Positive cultures were obtained most often when cascous cubercles were present According to Rich and Follis tuberculosis of the liver is especially infrequent in cases of pulmonary tuberculosis because of the lowered oxygen tension Experiments on rabbits and guinea-pigs demonstrated thus influence of low oxygen tension It would exceed the scope of this nionograph to discuss the problem of immunity against tuberculosis It is reasonable to suppose that factors such as malnutrition, conditioned deficiency, intercurrent infections, pregnancy, lactation, and psychic difficulties may cause a disturbance of the equlibrium between the active disseminating focus and the production of immune bodies That the consequence of this may be overt tuberculosis, in whatever shape is a fact that is confirmed again and again by experience JENSEN's investigations demonstrate very clearly that there are rubercle bacıllı of different degrees of virulence it goes without saying that this factor must also play a part in the course of the infection (as JENSEN could prove in his experiments) How far the above-mentioned influences are to be explained immunologically is still an open question We may say that in six cases we observed serious haematogenous tuberculosis after pregnancy This would confirm the old clinical view that the period of lactation is especially perilous in this respect ·SOME GENERAL OBSERVATIONS 93 THERAPY Finally we will go a little more decply into the therapeutic conscquences of our observations In the first place it is imperatie to realise that an early diagnosis of tuberculosis is of the greatest importance for therapy * One must remember that as a matter of course the greatest therapeutic successes are obtained when the tuberculous process is confined to relatively smiall lesions 110 matter which organ of the body is involved, whereas the larger foci hold out less prospect or nonc at all, of improvenient It may therefore be supposed that an effective concentration of anti-tuberculous drugs penctrates into the comparatively small tubercles (types 1-IV) we have described, but this happens to a much lesser extent in the presence of cascation, so that the tubercle bacıllı then are in a position to multiply When one keeps this in mind it will be fully realised that the early diagnosis of tuberculosis may be decisive with regard both to the success of therapy and to the ultimatu prognosis As we described in detail above every active tuberculous focus disseminates but this does not necessarly imply that the mctastases in their tum will become actic foc The possibilırs exists, however that one or more of them may become the scar of active organic tuberculosis That this possibility is small however, appears from the circumstances that the greater part of the population (viz those who have a positivo tuberculin test) may be presunied to have a niore or less active focus somewhere in the body, yet they do not develop clinically active tuberculosis It miay be presumed that some ot us (It is impossible to ac an estimate) occasionally pass through an cpisode of temporan * Wolf and FLOREY destbed n **** uge man wh had suffered sruseks tha Pyrexu of unknown on The ! I was yrossly enlarıed An seal ratory laparctomy disclosed only large lymph mas the mercutcry Thril at chuards the patient de and the cl mcal dugn siswa Flory. Jiseax At autofse av abd inal tubercu dors * bn Jary dem na respeculls in the ki er séu J Screta! weeks later it reported that tuberk te I had been bloured the bkx and unne for us tha ak would have bera an nd at n for pra on Icon bly dutint lasatene ry) as w the case of AH 045 ·SOME GENERAL OBSERVATIO faring-up of the process, attended by haematogenous dissemination, without its resulting in overt tuberculosis It is not impossible that this group includes those patients in whom the serial sections of the liver tissue reveal only a few type IV subtubercles The patient overcomes this kind of haematogenous dissemination by virtue of his immunity It would therefore be wrong to treat all such persons with streptomycin, PAS INH or a combination of these drugs In which cases, then, must we proceed with specific therapy? It is very difficult to lay down definite rules for all cases The clinical condition of the patient must always be decisive, and the interpretation of clinical symptoms is a very individual matter in doubtful cases In many clinical forms one will have to depend on the result of statistical investigations of the course of the disease What danger does premature administration of antituberculous drugs involve? Those major bugbears of streptomycin treatment, drugresistance and intoxication, are considerably diminished now we have at our disposal several other drugs Nevertheless the development of resistance of the tubercle bacıllı to whatever drugs are used remains possible The use of a combination of scveral drugs has reduced this danger considerably As a rule we make use of the combination of PAS (PASstabilise for intravenous application) and INH Streptomycin is reserved for a possible aggravation of the discase or for preparfor operation It is obvious that as onc has at onc's disposal more potent drugs so one will use them also in the so-called minor forms of tuberculosis (erythema nodosum primary infection etc ) Yet nowadays the value of antibiotic and chemotherapeutic therapy in these cases is disputed by many in the second place we must reckon with the risk of intoucation The dosage schemes however are now adays such that we can neglect this risk in practice The reader will forgive our inability to give an accurate answer to many of the questions arising in the course of these investigations Most probably he will himself realise that ation ·SOME GENERAL OBSERVATIONS 95 systematic comparative investigations extending over long periods are required before anyone is in a position to pass a wellfounded opinion on the desirability or the necessity of trcatnient with antituberculous drugs under varying circumstances Aspiration liver biopsy has assisted us in many difficult cascs in arnving at a decision whether to apply thus therapy or not It goes without saying however that in the majority of cascs we allowed oursches to be guded mainly by the clinical simptonis What danger does belated admunistration of streptoman involve? This question also is difficult to answer satisfactorily for the simple reason that tise of the term belated may be vers clastic An example may make this clear When a patient with serious caudative pleurisy does not respond to conservatore theraps, and develops a tuberculous empyema we believe that subsequent drug therapy will be belated This view still too often stubbornly defended that the antituberculous drugs must be reserved until a decided visceral manifestation or tuberculous empyema has developed is wrong for at this stage we can no longer look for quick success with this chcrap Some other forms of tuberculosis fall under this heading we believe that for instance, in typhobacillosis of Landouzy and in erythema nodosum attended with grave clinical symptoms it is desirable to begin specific drug therapy early We are perfectly aware that there are all kinds of transitional stages betucen premature and bclared and that there are still mans defects in our evaluation of the clumcal symptoms with regard to the indication tor drug treatment This difficult but rewarding task still lies betore the clinician and the pathologist in our opinion the aspiration fiver biopsi is an important aid Conclusion We would like to point out that it has not been our intention to gnc detailed referencus to medical literature as that would exceed the scope of this monograph In placing our experiences of liver biops before the reader 116 hasc aimed at contributing to a better insight into the ·SOME GENERAL OBSERVATIONS 96 pathogenesis, diagnosis, therapy, and prognosis of haeniatogenous tuberculosis We will conclude this monograph by expressing the hope that the day may not be far distant when we shall have at our disposal preparations yet more effective, but less liable to cause complications, than streptomycin, PAS,INH and similar drugs, and that we soon shall have at our disposal a simple, quick and reliable method for the early diagnosis of tuberculosis, which makes the resource to aspiration liver biopsy superfluous ·REFERENCES ARVOD) Be rage zur A ato e des I re Tuberkei Ueber Leber ube culo e V rco s Arch f pa! Anat 8 377 1880 A rov N A ca c of nul plet berlo 13 of the l or JualadB 35 95 1986 BAGCENSTO AH FOLD IN WH ad Hv 40 HCS repo mlary berculoss A Rev T be S5 S4 1947 Buk CAN 2 dHAEX A J CI De be cle is idle cop nct c b P VO de phys ol ge en de za hologc Ned il Til v 61 cch s 878 194 BEEK C VAN 2 HSEX AJ C Le crpu te b opse by o on loc nfec o a en bj le z ekte a BE N ER BOLA SCAL 4 der! Tu s hr Gc cesk 87 1 64 943 BLEX C VAN 3 HAEX AC A pro bops oth ! nu leosis fact osa 2 d BE NER Bo ck SC AL 4 dac A Md Scand 13 19 1943 Brex C VAN and HatX AJC Spell f d! d rs aa crytle a od Nederl Tdh v 6 cesh 9 47 94 Berk C VANa d IAX AIC Sprt aler h r nodo u the pes esh 93 BECK C VAN and HAEX AJC De day o k ulc ubora lo c Nederl Tid h 70 942 BLEK C VAN 3 dHAIX AJO Ара с тър Mas d sche v Knde gecek 7 1 249 BETA C VAN and Haex AIC De le erb p al hl dalbada nose val vergro e kl crc n del gh1 h Neuil T dslr Ceneesh 93 346 949 Brix C VAV ani HEX A Ci Ара 1 ca s het Largest of th h la ad eda all ! pross BEEK C vva Hacx A CH Debe k dar br 3 le Is er voor d dag ck terube ut ALIIdh Che cosk 94 137 1950 Bitx C VAN ani !! EX AC Hc b dle Model Td hr G cesk 94 $0 90 BCEK C VAY and Illex AC De as a br s hulp J! 1 bs de vroeg-dag k de ub 8 SI 190 2 a duas le ulga ·98 REFERENCES BECK, C VAN and Haex, A ICH Aspiration liver biopsy as an aid in the early diagnosis of tuberculous meningitis, in the press BEEK C va and Hex, A ) Cu Een geval van chronische berylliosis, mer als diagnostisch hulpmuddel de aspiratie-les erbiopsie, Neder) Tijdschr 1 Geneesk. 98 563, 1934 Brger, A Z'ber die Parenchympunktion der Leber, Verhandi d deutsch Gesellsch finn Med 35 Kongress 210, 1923 Boyd, W The pathology of internal diseases, Lea and Fibiger, Philadelphia 4th edition, page 327, 1917 and Henty Kunpton, London, sth edition page 335. 1930 DIEULAIOY, G Manuel de Pathologie Interne, 13e Edition, Masson Paris, 1901 FISCHFR, B Die Bedeutung der Darminfektion fur die Lungentuberkulose und ihre Verlauf, Frankfurt Ztschr Paths 395, 1910 FISCHER, W Uber groszknotige tumorahnliche Tuberkulose der Leber, wahsschemlch Lomblusert mit Syphilis Virchows Arch f path Anat 188 21, 1907 FRERICHS FR Tu vov Uber deu Diabetes, August Hirschwald, Berlin 1884 GULIWAN, Tu and GALLMAN, ) A modabod leser aspiration hiopsy apparatus and technique with special reference to us clinical applications as assessed by soo biopsies S Afr ] Med so lo 53, 1915 GRUBER, G B Henke-Lubarsch Handb d spez pith Anat u Hist Bd V, Teil 1, Seite 559 1930 GUTTNAN, P H ADDISONS disease, a statistical analysis of five hundred and s}xry-sex cases and a study of the pathology, Arch Path 10 743, 1930 HAEX, AI Cu De Llumsche betekenis van de aspiratie-les erbiopsie, Duss Leiden, 1945 HAEX A J Cl and BEEK C VAN De aspiratie lesetbiopsie als hulpnuddel bij het vaststellen der haematogene tuberculose, Nederl Tijdschr v Ge- 902 1947 (lecture) HAEX A ICH JONG, JAC ) DF and BEEX,C VAN Leverpunctie als hulpnuddel bij de clumsche duagnostiek, Nederl Tijdschr Geneesh 87 923, 1943 HqEX, A ) Cm, OUDSTEN, S A DIY and Bex, C YAv Deaspiratie-bropse van de muilt met de dikke troicart onder laparoscopische controle Neder) Tydschr Gencesk 93 388.4. 1949 HAEX, ACs Aspirasteleverbiopsie en tuberculose, Aanwinstets op Dugnostisch en Therapeutisch Gebied VI 73, Elsevier's Publishing Company, Amsterdam- Brussel - Londen - Houston, 1951 HREX A ) Cr Aspiratie-acrbiopsie met de apparatuur solgens GILLAAN BRYDEN, Nederl Tijdschr v Geneesk 98 1561, 1954 HALLBERG. V A ness method for staining tubercle bacıllı, Acta Med Scandiav 108 12, 1941 neesk 01 ·REFERENCES 92 YINLBERG V A ne nalad for sau g tubercle bac !! appicabl al oro he n00-o ganisn of lepros} a { o her aç d fue gera Acta Mied Scan dansa supp 1&O 194 Ifor SAUER Wand SP WW Rpy of I cr pach bucell s descrip of heps cles ons } Lab & Cin Med.) 047 IERS fout and RO OLM KAJ O ap 3 bop 3 of the is sdag o sw.nf ance Acta Med Scand uy 10 139 JINSON M Caza P an! BERTRAND L La poc on b opse du fo ed il tube cul es m lua res p csse M 1 57 854 9.49 JEV IN KA Sudes the vlet ce and gee na ut perce age of ube? Acta Tube Sca da o 46 946 KORTENE R All goudmi bethulo e fra f rt 2.fsels Pah) narls on ba uspu I re Tulo LANC INST U ber Rezelier nd and go benci The Kb udde fb c Fo cd's Tube kel ho Al fpah A 4 382 7868 LAQUEUR WILL ES Mae Sph lo d Leber Belen AD mbor och bei Shez Zsi fla! 301 249 LEE, HF d STA ITSKY A 3 In 1 en 22 fle * 1ub 1b 11 An R LORER b 49 MBA he Iyal ha ges and to lic 3 Turabb Tra & f! Nak ITub Bo Ale 93 M COR GOR AR and CREENCATI rul hc en alt 3 n ret + 6) 03 MACIER W N be L th is por ubrii d A Tubt Scan չէ իր +3 VRR E Tub A R Tubet & 030 Nar X Hier de A a Tube 1 X1 ܐܐܐ 7 ܬ 7 out us 1 پر لی تو C. sal Ib Ortix I А X ORTL bu h} ( A rt TO เk y Alcd 3 } Leber Vrlo Alfa 10 pa lah lgsel Anao 356 & bu! aos ons Ci lab 2107 195 cDer! SS cm o ·98 REFERENGES Beek, C VAN and HAEX, A ) CAspiration liver bropsy as an aid in the early dugnosis of tuberculous ineningitis in the press BEEK, C VAN and HEX, A J Cu Een geval van chronische berylliosis niet als diagnostisch hulpmiddel de aspiratie-les crbiopsie, Nederl Tydschr Geneesk 98 sós, 1954 BINGEI, A Lber die Parenchympunktion der Leber, Verhandl d deursch Gesellsch finn Med. 35 kongress 210 1923 Boyd, W The pathology of internal diseases, Lea and Fibiger, Philadelphia 4th edition page 327, 1947 and Henry Kupton, Londort, sch edition pagc 335. 1930 DIEULAFOY, G Manuel de Pathologie Interne 130 Edition Masson, Paris, 1901 FISCHER, B Die Bedeutung der Darminfektion fur die Lungentuberkulose und ihre Verlauf, Frunkfurt Zuscht Paths 395, 1910 FISCHER, W Uber groszknotige tumorabnliche Tuberkulosc der Leber, wahrscheinlich kombiniert mit Syphilis, Virchows Arch f path Anat 188 21, 1907 Frericus, Fr Tu VON Uber den Diabetes, August Hirschwald, Berlin, 1884 GILLMAN, TI and GILMAN, I A modified laer aspiration biopsy apparatus and technique, with special reference to its cluzcal applications as assessed by 500 biopsics S Afr ! Med Sa 10 S3, 1945 GRUBER, G B Henke-Lubarsch Handb d spez path Anat u Hesr Bd V. Teu I, Scite 359 1930 GUTTMAN, P H ADDISOV S disease, a statistical analysis of five hundred and sixty-six cases and study of the pathology, Arch Path 10 74: 1930 HAEX, A J Cu De klinische betchenis van de aspiratic-leverbiopsic, Duss Lerden, 1945 HACX, A ICH and Beck, C VAN De aspiratie-leverbiopsie als hulpmiddel bij het vaststellen der haenutogene tuberculose, Nederl Tijdschr y Geneesk 91 902, 1947 (lecture) HAEX A ICH Jovo, JAC ) DF and Beek, C van Leserpunctie als hulpmiddel by de chinische diagnostiek Nederl Tijdschr v Gencesk 87 923, 1943 H4EX A ] Cu OUDSTEN SA DEN and Beek, C van De aspiratie-biopsie 120 de milt met de dikke trojcart onder laparoscopische controle, Nederl Tijdschr Geneesk 93 3884, 1949 HAEX A ICH Aspirabeleverbiopsie en tuberculose, Aanwinsten op Diasnostisch en Therapeutisch Gebied VI 73, Elsevier's Publishmg Company, Amsterdam- Brussel - Londen - Houston, 1951 HAEX A J CH Aspiratie-les erbiopsie met de apparatuur volgens GWLAN- BRYDEN Nederl Tijdschr Geneesk 98 1561, 1954 HALLBERG V A new method for staining tubercle bacill, Acta Med Scandiny 108 12, 1941 ·99 REFERENCES WALLBERG V A ne 1 tl od for staning tubercle bacil appl abl al o to the m cro-organis of leprosy a d other ac i fast gerns Acra Med Scan dina supp 180 1946 HOTTALER FW and SPINK W W B opsy of I ser un pat ents h act brucello is description of hepat e less ns J Lab & Clin Med. 3 3 S 194 I ERSEN POLL and Ro Sory Kaj On asp rat on b psy of the leruich re Turks on its davno tc sgni ca ce Acta Afed Scand nas 10 193) JANBOX M Cazut la d BERTRAND [ La ponct o b opse duf c da sles tuberculoses m lua res Prese Med 57 854 1949 JEN EN KA Stud es on the rule ce and ger atu g percci tage ftuber 1 ba ! in spu unt Acta Tuberc Scandu av O 46 1946 KORTEWEG R Allerg c nd Mlar uberkuls Frankfurt Zrschr lah ) 1 19 3 LANGI AVS Tur Ueber Resenzellcı t and ta d get Kernen Tub tkci ind de fbrose Foren des T berke! Vrchos Arch f pa h A at 4 39 1888 LAQLEUR W and ECELIES Melare Syph! cder Leber Befu den der Asp rat on b ops e eth bei Schw z Zirt Pa! Bik 300 19.42 LEE H F and STA TSAY AB + on ott br I tubercle bac ! A R 917 LORBER J is uaz 1 ad t 1149 1954 LRF MBA correlat n be heh Tala gosadh ti the Iving bacall of tuber? rabb Tra mth annual n eet ng the Na IT berul А 3 3 ACCR GOR A Rand (RUR ( А тыг u tlcc yste h spec al retorc tuber ul 5 5 4 32 45 613 1937 MASCHER W Das Eryl Indu be Er allt der tuberkul sem Prnarnek I beru all Aarber Sca dan suppo MORRS E Tuber ot lol c A 1 bar 1930 NATOR T 11 The 14 pl h) tren Ata Tuber Sand na upp OLI ET) D Jun s! Leter puikt dan 1440 12 en Tubs Lu ele nga r r ORTI) Ucber inal Tub Isdrlber Virch Arht path Aut 66 3 Ortu į Lehrb h 17 poln! I lishe A Ber! ISS PALL 58 is conna n loc marro arrat ons A ns ·100 REFERENCES RANDERATIT, E Pathologisch-anatomische Vatersuchungen uber die Tuberlulose des Knochensystents, Bestr z Klu Tuberk 79 201, 193: * RICH, A R The pathogenesis of tuberculosis, Charles C Thomas, Spingfield, Humous, First edition, second printus, 1946 RICH, A R and FOLLI, R H, }r The effect of low on gen tension upon the developmeat of experimental tuberculosis, Bull Johns Hopkins Hosg 71 345.894 RICH, A R and McCORDOCK, H A The pathogenesis of tuberculous mcningits, Bull Johns Hopkins Hosp 52 S. 1933 RICKARDS, A G and BARRETT, G M Non-tuberculous Addison's disease and ses relationship to 'gan-cell granuloma' and mulciple glandular disease, Quart J Med 23 403. 1954 RIVOIRE, R and COLLEAU, A Le traitement des ménmgites tuberculeuses par la streptomycine, Presse Mid 57 632, 1949 SCICAPMANY, ) On the nature of certain peculiar corpuscles present in the Cissue of lymphogrinuloniatosus berugna, Acta Med Scandal 100 239. 1941 SCHAUMANN, ) Lymphogranulomatosis benigna m the light of prolonged clinical observations and autopsy findings, Brit J Dermat 48 399, 1936 SCHLEICHER, E M Mduary tuberculosis of the bone marron, Am Re Tubere $3 195, 1946 SCHUNTER, F De la posssbilité de faire „tra vitam" un diagnostic histopathologique precis des maladies du foie et de la rate, Semaine Med 27 229, 1907 SINIMONDS, M Beirräge zur Statistik und Anatome der Tuberculose, Deutsches Arch fklu Med 27 448, 1880 STANLEY Abscess of the liver, with hydatids-operanon Lancet I 189. 1833 VRCHOW, R Die krankhaften Geschwiste, Hirschwald Verlag, Berlin, 1863 WACNER, E Die Tuberculose der Leber, Archd Heilk · 33, 1867 WELL, H G ADDISON's disease with selective destruction of the suprarena! cortex 'suprarenal corter atrophy'), Arch Path so 499, 1930 WESSELS, CC Tuberculosis in the rat, Am Rev Tuberc 43 459, 1941 WOLF, G A and FLOREY, C M Mitrary tuberculosis of the liver, An Rey Tuberc 51 553, 1945 WOODAUFT, CE, KELLY, RG and LEAMING, MA The culturng of tubercle bacull from the human spleen, lance and kidney, An Rev Tuberc 48 76, 1943 WOOLNER L B and McDONALD, J R Bronchogenic carcinonra diagnosis by mucroscopic examination of spirum and bronchal secretions, preliminuary reporr, Proc Staff Meet , Mayo Clin 22 369, 1947 WOOLNER, L B and McDONALD, J R Caraconia cells all sputum and bronchial secretions Surg, Gyniec & Obst 88 273, 1949

·TABLES
1
TUBERCLES TOUND I LIVER BIOPSIES IN CASES OF
TUBERCULOSIS
II
ASPIRATION LIVER
NODOSUM
BIOPSY IN CASES OF ERYTHEMA
III
103
TUBERCULOGRAMS OF THE CASES REPORTED IN THE TEXT
104
106

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·Frequency of Ourenc TABLET TUBERCLES FOUNI IN LIVER BIOPSIES IN CASES OF TUBERCULOSIS Size Pype) Tyre Site Extremely rare Almuest a Cascation Time Guant Cells licad Aicrage o 7 mitt Usually a conglomerate tuberc Juris frequent Portal tract l'ossibic Iurel Minute pray white punt Aserce Omni Usually present Conglomerate or sistary tuberilc Portal frequenze tract Possible ery minute brayish wlute point Ancrage 0 25 mm Solitar tubercle Often present ers frequent Usually porcal Persible tract Grussly insuble Average o tom Often present Epitheinud cell subrubcrsic Ispe IV Abrent Very frequent Usually parencluyma cpecially pencentrally Grussly ans piblic Erreptional ASCISCO OS farmi [pichlid cell rudtuberide Parenchyma, especially pericentrally Absent Abxnt

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·TYIE O Te A conglomerate tubercle of type o The ksen subml arv cp thel od-cell cuber les o cof the contau ng as ant call a c surrounded by hyal ne bandt and lymphocytes. Hacn atoxyl YANCESOS TOO Tranh tite tas korpe wahrerat axt272+2 MG MIT Dyiha tulek won the site of about 140 ·TYPE O Fig 1 A solitary non-cascating tubercle of type O x 100 Fig 4 A sobtary non-ascating tubercle of type in the middle a grant cell. X 140

·fes A young mural pachel de tuberck of tyf
.60
Is INR Nalep cheb sellest le filtraf! in the
nam
at the Kft hand ule.MK 1X1 Kyn 110

·TYPE 1 Fig? A portal tuberck of type I with central cascasion 140 A portal tubercle of type I with peripheral hyalinization and Large-cebulat hyperplasia ud ka mohacices in the enere in the has aliruang margin tua capillariet are 12sible 260

·roo A pral tu her 1 of type 1 apparently up clv hy al nosze!
(sele 10)
The unxe tubet I as inft* futher Tunty hl. Jer thane
feminthe site of the bylin
ti OK
ie

·TYPE I
F& 1 C catrzation of a portal tubercle of type I w th a giant cell x 280
rg 14 The scat of a portal tubercle of type 1 290

·In A purtaltuhetele of type II a butts yg in anterlobular sein 140 (we in 14 1x The 4 x tubenk as of Huber sur large beperstare 450 ·TYPE Fic 15 A subacute portal tubercle of type 11 x 240 110 A later portal tubercle of type II The nucles of the fibrotes arek ng and thin To the right hand side belon a bile duct is seen 400

·1
The sat fa un real tule k fire II
450

·TYPE III
Fig 18 An epitheloid-cell subtubescle of type III in the neighbourhood of a central vein
400 (see fig 19)
Tig 1y The same lesion as u fc 18 800

·TYPE III
.ܝ
re? AL
ly young ep 1 dclub whers of rell hapi di mud from the
nd
nahna sho
w Tuct key ritme 1 wly ck! et

·TYPE III
F 22 A later epithel od-cell subrubercle of type III vaguely delined front the surround
parenchyma 560
Fig 23 A more advanced epithel odcell subtubercle of type III almost hadden in the paren
chyma > 560

·1 1111
In An old or helewdall suhuber de care all
It Ada pun mukavall thank firii.ro
tona pasand na
(

·TYPE IV XOAN Fig 20 A young epithelioid-cell subtubercle of type IV x 560 Fig 27 A young cpitheliodell subtuber«ie of type IV hidden in the parenchyma Besides lymphocytes a polymorphonuclear leucocyte 15 v35ible "కరం

·TYICI
15 An older spiccbon-cell subeubeuk of type Il conta ning numerously phocytes
and al 10 lym roh leat cyfco
1 An 11 !!**ell sutsulet k tre !

·TYPE IV Fig 30 A rather young minuto epithebod-cell subrubercle

·run fritheb Jalt hereketh a mit
sho (sec fic 32)
Ihr unterbo * ! The Shafthr unrur
11

·Fig 33 The same tubercle again one section further Besides a glant cell part of a second mitos s has appeared so (sec s 34) F# The same tubercle agaur one se tion further The giant cell is still partly nes bic and another segment of the matosis froin FL 31 18 seen sro ·In Anny barely wbk young cr hal n-cells bukur ktha duster M I MAL 400 ·Fig 36 A des cloping epitheliod cell subrubercle with a descer putosis. X 640 Fl 37 As espation Lives biopsy of a patient with pulmonary tuberculosis and anthracosis The protoplasm of the Kuyffer cells forming this type III lesion (suruated in the neighbourhood of the central vein) is loaded with coal dust particles x 100 ·& The I er of a pa eit who ded of hypera vte tubercul us nfe tun A shagocytosed au ffrir con in the fait pu noah PR c!! (TSIDER t ) im net n enlarne ent Tu An 14hdysgues Take the k. Tke på kaffi Armas Jak dat hulle nou as are begynte vix efTussu Wir den

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