the oslo study of untreated syphilis *t commentaryfor the purposes of the present re-study, 574...

Brit. J. vener. Dis. (1956), 32. 70.

THE OSLO STUDY OF UNTREATED SYPHILIS *tREVIEW AND COMMENTARY

BY

L. W. HARRISONLondon

Some books are to be tasted, others to be swallowed, andsome few to be chewed and digested, that is ... some fewto be read wholly, and with diligence and attention.

F. BACON

This is eminently a work which should be readwholly, and with diligence and attention by allvenereologists, whether they are only readers orboth readers and authors: readers, so that theymay learn-if they have not done so already-toread critically, not confining themselves to "Con-clusions"; and authors that they may bestrengthened in avoiding the pitfalls of drawinglarge inferences from small data and of quotingwith approval " Conclusions" which they have notsatisfied themselves are justified by the evidence.The material on which this work is based is

unique and for its re-study not only venereologistsbut colleagues in other branches of medicineshould be grateful to those mentioned below, andtheir assistants, who have brought it about.

Since the Editor of the British Journal of VenerealDiseases, realizing the importance of this work, hasallotted enough space to permit of a review which isnot merely a glorified account of its contents but acritical commentary, and since many readers of thisJournal may not be acquainted with events in thesyphilological world as far back as a quarter of acentury ago, it seems appropriate to give here ashort history of the events which led to the presentstudy.From 1891 to 1910, Caesar Boeck, Professor of

Dermatology in the University of Oslo, practicallyforbade the use of mercury in the treatment of thesyphilitic cases in his wards, believing that mercurygenerally interfered with the patient's own defence

* Invited review, received for publication April 10, 1956.t " An Epidemiological Investigation of the Natural Course of

the Syphilitic Infection based upon a Re-study of the Boeck-Bruusgaard Material " by Trygve Gjestland (1955). Acta derm.-venereol. (Stockh.), 35, Suppl. 34 ; pp. 368 with 83 Tables and 12Figs, plus Appendix of 56 pp. with 30 Tables and 2 Figs.

mechanism, which he thought was better than themetal. In the period mentioned, approximately2,000 cases of early syphilis were dealt with onthese lines in his wards and a number of years later(1925-27) his successor, E. Bruusgaard, carried outan investigation to discover how Boeck's cases hadfared. As a result, Bruusgaard (1929) published anarticle of which a free translation of the title is" The Fate of Syphilitics who have received noSpecific Treatment ".

His article excited a great deal of attention, evenleaders in some medical periodicals, and here Imay perhaps be pardoned for introducing a personalnote. At that time I was reviewing articles for theBulletin of Hygiene, and in due course I received aslip which was an invitation to review Bruusgaard'spaper. I read the paper and returned the slipmarked " Not worth review " because I thoughtthe results recorded by Bruusgaard were notstatistically sound and could be misleading; thiswas no reflection on Bruusgaard, who, for the mostpart, enjoined caution in the inferences to bedrawn from his material. My rejection of the paperwas a mistake as I soon discovered in the, to mymind, unwarranted inferences being drawn fromBruusgaard's data by different authors. About 2years later a paper by a distinguished dermatologist,in which some quite illogical inferences weredrawn from the Bruusgaard report, provided mewith an excuse for reviewing the Bruusgaard papertogether with that of the dermatologist. In myreview (Harrison, 1932, 1939, 1941) 1 tried to showthat, for purposes of prognosis of untreated syphilis,the Bruusgaard statistics were useless. My criticismswere repeated in various papers by myself and incorrespondence with American and other colleagues-they are freely quoted in the study under presentreview-but the Bruusgaard percentages of ultimateresults continued to be quoted in various articles

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and text-books, sometimes with and sometimes with-out acknowledgment. Then W. T. Sowder (1940) ofthe Johns Hopkins School of Medicine published inthe American Journal of Syphilis a re-study of theBruusgaard paper and showed that the materialanalysed by Bruusgaard was not a fair randomsample but highly selected.

Perhaps from all this may have sprung the idea ofre-examining as many of Boeck's cases as could betraced and the records of the remainder, and onecan readily endorse the gratitude expressed byTrygve Gjestland, the author of the study underreview, in his preface, to those who brought itabout. These, mentioned in the author's order,are: Prof. N. Danbolt, Chief of the UniversityDermatological Clinic, Oslo; Dr. T. Guthe, Chiefof the Venereal Diseases and TreponematosisDivision of WHO; Dr. Joseph Earle Moore, JohnsHopkins Hospital, who, with Dr. J. R. Heller, atthat time Chief of the Venereal Diseases Division ofthe United States Public Health Department, usedhis great influence in obtaining funds from theU.S.P.H. without which the re-study could not havebeen carried out; Surg.-Gen. Karl Evang, Chief ofthe Norwegian Public Health Service; and Dr. E.Gurney Clark, Professor of Epidemiology, Univer-sity of Columbia, in whose department the newfigures obtained from the Oslo records were analysedby the author. To Prof. Clark and his staff Gjestlandmakes special acknowledgment for constructivecriticism and guidance, and he was helped byDr. Fertig, Professor of Biostatistics, and Dr.Kingsley Davis, Director of the Bureau of AppliedSocial Research. Altogether this is an imposing listof collaborators which gives a clue to the manyangles from which Gjestland examined the Boeckmaterial.

In his Introduction the author gives a shorthistory of Bruusgaard's Study-the details ofBruusgaard's findings are shown in six Tables inthe Appendix to the present study-and criticizesthe findings on grounds which need not be givenhere.The author quotes Bruusgaard as having himself

warned that the acceptance of his data should bemade " with the reservations the nature of thematerial necessitates ". He also quotes a number ofextracts from books and articles by various syphilo-logists of repute who attached much more import-ance to the Bruusgaard figures than has the presentreviewer. In this section Gjestland shows quiteclearly that there were strong grounds for there-examination of the Boeck-Bruusgaard materialif this was to be of any value either academically orpractically.

In his second chapter Gjestland discusses otherinvestigations on the outcome of untreated syphilis,notably the Alabama group " left untreated forinvestigative purposes in comparing the effects onhealth and longevity of an untreated syphiliticpopulation with one non-infected (Vonderlehr,Clark, Wenger, and Heller, 1936; Heller andBruyere, 1946; Deibert and Bruyere, 1946;Pesare, Bauer, and Gleeson, 1950) ", and to this headds the autopsy studies by Rosahn (1937).Throughout the work under review Gjestlandfrequently quotes the Alabama and the Rosahnfigures for comparison with those obtained byhimself from the Boeck cases.

In his third chapter he quotes the views of CaesarBoeck in defence of his practical non-use of mercuryand discusses carefully, with the thoroughnesswhich characterizes this study, the reasons for hishaving found only 1,978 cases in this basic materialas contrasted with the 2,181 said to have been thebasis of the Bruusgaard investigation.For the purposes of the present re-study, 574

non-Norwegians and non-residents of Oslo wereexcluded, reducing the basic material to 1,404cases; the author shows in great detail that thisexclusion left the 1,404 cases fully representative ofthe original 1,978.The limitation of the re-study to residents (or

potential residents) reduced the percentage of malesfrom 36-5 in the original 1,978, to 318 in the1,404. The proportion of 1 male to 2-1 females inthis material was the exact reverse of the sex ratioof the patients reported for syphilis to the Oslo CityHealth Department during the Boeck reign, thereason being that Boeck's female ward was twicethe size of the male ward. The different mani-festations observed in the original study group arerelated to the respective sexes and their ages onfirst admission to Boeck's wards. The occupationalstatus and the districts in which the patients residedin Oslo are also noted, and from this it is clear thatmost of Boeck's cases were what are commohlycalled under-privileged and came from the slumdistrict of Oslo. From a Table showing the distri-bution of the patients by sex and stage of syphilison final diagnosis the percentages of the 446 malesand the 958 females respectively appeared asfollows:

Primary, 0-9 males and 0 3 females;Primary and secondary, 42-6 and 205;Secondary, 52-2 and 73-6;Clinical secondary relapse, 4-3 and 5-6.

Some pages later, Gjestland discusses the validityof these diagnoses made at a time when no help was

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BRITISH JOURNAL OF VENEREAL DISEASES

available from the microscope or the test-tube. Onthe strength of the diagnostic acumen of Boeck andhis staff and the fact of the patients being underobservation for an average of several weeks, hesees no reason to doubt the original diagnoses.Personally, as one of those who questioned thevalidity of the original diagnoses when the Bruus-gaard report was under discussion, as one who hasseen the very elect mistaken when reliance hadperforce to be placed only on clinical signs and hasseen syphilis imitated by various skin diseases, Iretain some scepticism but do not think mistakes indiagnosis made any very material difference to theresults recorded in the present study.

Whilst under Boeck, approximately 40 per cent.of the patients were treated with potassium iodideand 3-6 per cent. with mercury in some form.Thus mercury cannot have had any influence on theoutcome, and the author having dismissed the ideaof potassium iodide having had any specific effect,leaves open the question of its having had anyinfluence on the immune processes. In this con-nexion, however, it may be of interest to recall thatBrown and Pearce (1923) saw in animals effects ofpotassium iodide that suggested a significant powerof increasing the resistance to syphilis.

Patients were kept in hospital as long as theyshowed any sign of syphilis, the figures being:primary and secondary syphilis, males, 93-3 days;females, 132-2 days; secondary, males 64-3 days andfemales 104-1 days. Taking the figures for primaryand secondary syphilis as a guide, the authorthinks they indicate that the average duration ofearly syphilis when untreated is 4-6 months infemales and 3-2 months in males. An objection tothis estimate seems to lie in the fact that there is noinformation as to duration of the disease on firstadmission. Every syphilologist knows that theprimary sore may still be present some monthsafter its first appearance and when the patient is faradvanced in the secondary stage. One would judgethat the conditions favoured concealment sincegrape-vine intelligence would inform the districtfrom which these patients came that admission tothe syphilis wards in the Rikshospital would meanincarceration there for months and months. Onecan well imagine that, in such circumstances,application for admission would usually be regardedas a desperate last resort. Whatever may be one'sjudgment on such points, the longer duration ofsigns in females, on which the author comments,seems to be incontestable, especially when one canwell imagine that the females were admitted longafter the primary sore had developed and thatin many cases the primary sore would be discovered

for the first time after admission, a different casefrom that in males.

In his own words, the author aimed:(1) To trace as many patients as possible to anend point ", defined as the last observation whether

living or dead.(2) To collect a maximum amount of clinical data

(including data on treatment) on each patient from thedate of his original discharge from Boeck's depart-ment, all through the interim period and up to the" end points ".

(3) To determine the cause of death through studyof post-mortem examinations, hospitalizations, deathcertificates, etc. with the maximum amount of accuracy.

(4) To examine at the Rikshospital as many livingpatients as possible and to employ as completeexaminations as circumstances will permit, and tohave examined elsewhere, according to the sameprinciples, those patients who, for one reason orother, could not be brought to the Rikshospital.In the next twelve pages are described the careful

procedures to trace and identify the original patients.According to the author's Table 21, the number ofliving males at the time of the study was 72 of theoriginal 446, and the number of females was 187of the original 958. Of these 259 living patients, 216were personally examined during or shortly beforethe present investigation (1949-51) either at theRikshospital or elsewhere, apparently by the authoror under his direction (p. xlvi of Appendix). Forthe remainder of the 1,404 cases, living and dead,reliance had to be placed on records, the accuracyof which in respect of physical states may well havevaried considerably. From his study of the stepsdescribed in this report, the reader must concludethat the utmost available information has beenextracted from the records, and any limitations arecertainly not due to any lack of diligence in thoseconcerned in this inquiry.

In the results of the follow-up the patients wereprimarily classified as " Known ", " PartiallyKnown ", and " Unknown ". The " Known"were those who were alive at the time of the re-study(72 males and 187 females or about one-sixth of thebasic material), and those who were dead but aboutwhom there was sufficient information (259 malesand 435 females). The " Partially Known" werethose about whom one or more observations wereavailable since discharge from Boeck's department,but about whom the end result was unknown (43males and 151 females). The " Unknown " werethose about whom no information was availablesince discharge from Boeck's department (72 malesand 185 females). As far as could be ascertained,83-4 per cent. of the study group had had notreatment, and of the remainder less than one halfhad had what could be regarded as adequate treat-

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ment since leaving Boeck's department. On thisquestion of what may be regarded as having beenadequate and what " highly inadequate " treatment,there may be room for difference of opinion-thispoint will be discussed later in connexion withcardiovascular syphilis-but here the author con-cludes that treatment subsequent to discharge fromBoeck's wards " can only to a relatively small degreehave interfered with the natural course of theinfection in the present series".

In an important chapter on secondary clinicalrelapse, the author discusses the views of differentworkers as to its aetiology, the chief schools beingthose who believe, like Meirowsky and Pinkus (1923),that syphilis pursues a rhythmic course, activemanifestations alternating with latency, regardlessof treatment, and those who believe that inadequatetreatment provokes relapse. He quotes a number ofsets of results obtained by different workers withvarying amounts of arsphenamine-type remediesand heavy metal in the Salvarsan era and withpenicillin after this. This is preliminary to thereport of what occurred in the case of Boeck'spatients. In this connexion, we are reminded of thegreat length of time the patients were in hospitalafter first admission. Of 335 males of all ages attime of first infection, 22-7 per cent. developedsecondary relapse, and of 700 females, 24-0 percent. Of 278 males aged 15 to 39 on first admission,23-4 per cent. relapsed in this way, and of 612females in this category, 24-3 per cent. Of the 244who relapsed, 189 did so once only; 46, twice only;eight, three times; and one, four times. In acomprehensive Table showing the sites of thesesecondary relapses, it is seen that 84-8 percent.were in the mouth and/or ano-rectal region. Theimportance of this from the point of view of spreadof the infection is stressed by the author. In regardto the period which had elapsed between dischargefrom hospital and first relapse, it is shown that88-2 per cent. occurred within the first year.

In an instructive discussion of these results, theauthor thinks they show that secondary clinicalrelapse cannot be regarded as a product of in-adequate treatment and he adheres to the views ofMeirowsky and Pinkus already mentioned.

After pointing out the difficulties of comparingthe results in the Boeck series with those reportedby other workers, a number of which the authorquotes. he thinks that probably the nearest com-parison is one with the two series quoted by Lomholt(1931) since these were studied in Denmark and,thanks to the fact that there all syphilitic serum testsare carried out in one institute, follow-up is probablymore efficient than in any other country. This is the

Jersild system of nameless notification started in1920 and sufficiently described in the report underreview.The first series quoted by Lomholt included 446

secondary cases treated in two hospitals in Copen-hagen between 1910 and 1914 with two to threeSalvarsan injections and thirty to fifty mercurialinunctions; 25- 1 per cent. of them showed aclinical recurrence. In the second series, treated inthe same hospitals between 1920 and 1927, with sixto seven Salvarsan injections and more mercury orbismuth than in the first series, were 1,241 secondarycases and the clinical relapses traced in this groupwere 4 1 per cent. The author expresses doubtwhether the results referred to by Lomholt can beaccepted at their face value, especially those in thesecond series, having regard to the low relapse ratecompared with that in other series " where con-siderably more adequate treatment has beenemployed ". Here one wonders by what standardthe author gauges the adequacy of the treatmentgiven to the Danish cases. He quotes resultsreported by the American Cooperative ClinicalGroup and if the standard is that of the treatmentsshown in this series, one would, with respect, objectthat the two systems are not comparable as theywere based on different principles. In the Danishsystem the arsenical remedies were given concur-rently with the heavy metal, and in the Americanseries, one gathers, the treatment was mostly onthe Almkvist system of alternating continuoustreatment, courses of arsphenamine alternating withcourses of heavy metal. At the risk of starting apolemical discussion in this Journal, I would saythat there is abundant evidence to show that theconcurrent administration of both types of remedyis more efficient than giving them during differentperiods; in other words 2+2 on the concurrentsystem makes more than 4 and the same on thealternating continuous system makes less than 4.At this stage one may perhaps be allowed to antici-pate- by saying that in respect of neuro-recurrences(expressed in the form of cranial nerve disturbances)the purely alternating continuous system has shownworse results in the American Cooperative ClinicalGroup series than befell the untreated Boeck cases.Another point in this argument of incomparabilityis the size of the individual dose. It is not enough tosay that so many injections should be given; whatshould be mentioned is the size of each dose andthe intervals between doses. In regard to individualdoses of the arsenical remedy, one would judgethat, according to the principles of the late Prof.Rasch, those in the Danish cases were high. Myown impression of clinical relapses after the course

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of treatment given to British soldiers in the war of1914-18 makes me a little surprised that those inthe second series quoted by Lomholt (1931) wereas high as 41 per cent. Our " war course " was animitation of that which had been reported as success-ful by Gennerich (1914), a naval surgeon workingat Kiel-he had reported no clinical relapse withina period of at least a year in 92 primary and 81secondary cases-and it seems to have been ratherweaker than that described by Lomholt. I amsure that if our " war course " had been followed byeven 1 per cent. of clinical relapses-and warconditions encourage reporting sick-I should soonhave heard of it, considering the tens of thousandsof early cases treated on this scheme every year ofthe war.On the other hand, it seems rather a pity that the

author of the work under review had not seen theresults of treatment in a well-observed series ofcases of early syphilis treated with mercury withoutany other aid than perhaps some potassium iodide.Such a series was reported by Gibbard andHarrison (1914) to the International MedicalCongress which was held in London in 1913.

It may be of interest here as a sort of bridgebetween the untreated cases of Boeck and thosetreated with arsenicals and heavy metal, and alsobecause the percentage of clinical relapses in thisseries was far higher than in the Boeck series. Forthe correctness of the figures given below I canvouch as I collected them. The aim of the collectionwas to see how much time was lost by a soldierunder treatment by mercury, on a scheme drawnup by a War Office committee after careful inquiryinto existing practice, as compared with that lostunder treatment by Salvarsan and mercury as thenpractised. For the purpose the syphilis case recordsof men of the Brigade of Guards which had beenreturned to the War Office from 1906 to 1912werescrutinized and the relapses in the first year oftreatment were extracted, as well as the days spentin hospital, in all cases in which the treatment,(chiefly in.jections of mercurial cream) had been givenwith perfect regularity. The fact of relapse had beendetermined by the weekly medical inspectionwhich all soldiers on the syphilis register had toundergo, and for any clinical relapse the soldierwas admitted to hospital. In this way, 371 caserecords were examined and it was found thatthe percentage of cases that had relapsed at leastonce was 83-8 (315 cases). Of the total, 151 hadrelapsed once only; 115, twice; and 49, three ormore times.The reasons for this far higher incidence of

clinical relapses in these soldiers treated with

perfect regularity with mercury on what was thenthought to be the best lines, than in the untreatedcases of Boeck seem worth discussion. Were thesewell-fed and reasonably well-housed guardsmen,picked for their superior physique, naturally moreprone to relapse than the down-and-outs whoformed the material of the Oslo study ? Or was thesystem of inspection practised in the British armymore likely to discover relapses than the more orless voluntary civilian system, which depended onthe patient seeking advice and treatment for somerecurrence which in a good proportion of caseswould not be very uncomfortable ? It seems to mequite possible that a patient who int the first instancehad lain in hospital for several weeks under notreatment that would impress him as an activeattack on his disease would not be very willing toreturn there, and, by wishful thinking, he mightwell persuade himself that the slight discomfort inhis mouth was not due to any relapse of his syphilisor at any rate could be cured with a few bottles ofsome " blood mixture ".

It might well be argued that the Boeck cases werelonger in hospital in the first instance than wereour guardsmen, who were there for an average of6 weeks. It might further be argued that there weremore primary cases in the soldiers. As to this Ihave no direct information, but the ratio of primaryto secondary cases in the British Army at home inthose days was approximately as 1 to 1 or aboutthe same as in the Boeck series.With all regard for the limitations of comparisons

between results reported in different nations, onecannot escape the suspicion that, assuming themercury neither provoked nor prevented clinicalrelapses, the guardsmen figures were nearer thetruth in regard to the chances of secondary relapsethan were the Oslo figures.On page 137, the author says that when primary

syphilis is allowed to go untreated it " usuallyresults in close to 100 per cent. secondary syphilis ".But he does not know how many primary casesnever sought treatment and, on the other hand,anyone who has worked in a syphilis clinic for evena short time must have noted in the later cases quitea significant number who have no recollection ofhaving seen any earlier manifestation of the disease.This is particularly noticeable in cases discoveredby routine blood tests-in one series of 200 suchcases taken seriatim, which I had questioned, morethan half had no history whatever of anythingwhich might in any way suggest syphilis-and it isnotorious that in neurosyphilis and other lateeffects of this disease it is very common to find ablank history in this respect.

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The criticisms contained in the paragraphs abovein no way mitigate my high opinion of the value ofthis study; they are intended only to supplement it.An interesting feature in the section dealing with

secondary clinical relapse is that no significantdifference was found between males and femalesin this respect, so that whatever factor may beresponsible for the generally believed milderoutcome in females, it does not operate in the earlierstages of the disease. It is possible, of course, thateconomic factors may have been to some extentresponsible for a greater proportion of house-keepers than of breadwinners seeking treatment,with all its consequences in the shape of internment,loss of wages, and so forth.The author comments on the fact of only one

neuro-recurrence having been found in thesesecondary relapses. He says: " Neuro-recurrencemay constitute a form of relapse that is practicallyalways related to irregular or inadequate treatment".This does not say enough. It is well known thatneuro-recurrence of the kind meant here, commonlyexpressed by paralysis of one or more cranialnerves, became a prominent feature in the earlydays of the Salvarsan era, and it has been provedbeyond any reasonable doubt that the cause of theincrease was arsphenamine treatment, using rela-tiveljy high doses, without concomitant heavy metal.Neuro-recurrence, in fact, is a form of relapsecommonly related to inadequate treatment of acertain kind.

After, rightly, emphasizing the caution whichmust be exercised in comparing the results shown inthis study with those in treated syphilis, the authorsays: " As far as the comparisons go, indicationis that even inadequate treatment protects againstclinical secondary relapse ". The results in casestreated solely, but with perfect regularity, withmercury which have been cited above suggest thatthis is applicable only to a combined arsphenamineand heavy metal treatment or to one employing oneor more reliable antibiotics, with or perhaps withoutheavy metal.

In his chapter on " Benign Tertiary Syphilis ",which includes gummata of the skin and mucousmembranes and skeletal structures, the authorreviews the literature, and one is struck by thediversity of experience in respect of incidence andof views on the question whether such outbreaksprotect against more serious manifestations in thecardiovascular and/or the central nervous system.

In regard to causes of benign tertiary syphilis theauthor speaks of " upset in the parasite-hostrelationship resulting from re-activation of re-

maining treponemes in a sensitized host ", but not aword, as far as I have been able to see, is said aboutthe factor of trauma. It is difficult to believe that asyphilologist could practise his specialty for longbefore being impressed by the overwhelmingimportance of trauma in the precipitation oftertiary, or even secondary, relapse. This is trans-ferring the weight to the other pan of the scale.The difficulty of comparing the results in the

Boeck cases with those reported by others, somequoted, is again emphasized. For the series understudy the author used the "Known" and the" Partly Known", viz. 374 males and 773 females,as denominator. Of this number the author foundthat 15 8 per cent. developed some form of benigntertiary syphilis; he gives reasons for supposingthe percentage to be a minimum. He does not,however, seem to think many of the Boeck caseswho had remained in Oslo escaped registration byseeing private practitioners because that would betoo expensive for most of the patients comprisingthe Boeck series. He does not mention the possi-bility of self-treatment by blood mixtures (whichmay contain potassium iodide) or even such homelyremedies as poultices (which I have known usedwith good effect), as an alternative to reporting tothe Indigents' authorities and possible internment.The fear of being infectious, or of being consideredinfectious, remains with a high proportion ofsyphilitics throughout life.The views of Grin (1953) that in areas of endemic

syphilis " super-infection plays a major role in thedevelopment of benign tertiary syphilis " are discussedand the author seems inclined to agree. If therelatively small doses of infectious material whichmust be concerned in contamination of one personby another in an endemic area are sufficient toprovoke tertiary lesions, one wonders why Fingerand Landsteiner (1906) had to use such largeamounts of live syphilitic material, inserted more-over into pockets under the epidermis, to producetertiary-like lesions.The chapter on neurosyphilis, which occupies 68

pages, is a very valuable addition to the literatureon the subject but cannot with justice be summarizedhere.

In the 953 " Known " cases in the study groupconsidered by sexes the author found the followingpercentages of the respective forms of neuro-syphilis: meningo-vascular plus vascular, males,3.3, females, 17; general paresis, 3 0 and 1-7,tabes, 2 6 and 15; gumma of brain, 0 3 and 0-2.The author compares the figures in his study

series with those found by Nielsen (1950), who had

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followed up 467 male patients who during theperiod 1913-20 had received two to three injectionsof Salvarsan and fifty inunctions of mercury. Thecases had been followed for 29 to 36 years and thepercentages were: general paresis, 4-3; meningo-vascular, 3-2: tabes, 1 1. In addition there wereseven with eye manifestations and one with an earailment.Comparing his results in the Boeck series with

those found by Bruusgaard in the same material,the author found a gross similarity but in respectof sex and type of neurosyphilis such dissimilaritiesas made the two not comparable, though both werederived from Boeck's cases. That should make onethink !

In cardiovascular syphilis, which occupies 75pages, the author follows much the same lines as inother sections, giving a critical review of the moreimportant papers on the subject as a preliminaryto the results of his own investigation. In thereview the author discusses the reliability of thediagnosis of " uncomplicated aortitis " made antemortem and seems sceptical. In regard to compli-cated aortitis, under which he lists aneurysm, ostialstenosis, and aortic regurgitation, he agrees that thedifficulties are less, but I could not find any dis-cussion of the diagnosis of aortic incompetencecaused by syphilis from that due to other causessuch as rheumatism and atheroma. This seems tobe an important defect since the diagnosis seems tohave been made chiefly by clinical examinationante mortem of a material derived from a classwhose social circumstances would make its indivi-duals more prone than the average to contractacute rheumatism. He discusses the reasons for thegreater proportional incidence of cardiovascularsyphilis in males than in females, with apparentlyan open verdict. The author again emphasizes thedifficulty of comparing the results in one serieswith those in another, particularly when an authorgroups all cardiovascular syphilis together andincludes in it uncomplicated aortitis diagnosedante mortem. Later in this review I shall hope toshow the fallacy of grouping together all cardio-vascular syphilis with the inclusion of aortic regurgi-tation.

He, rightly I think, devotes much attention to theNielsen series, already mentioned, because of thesuperiority of the follow-up that is possible inDenmark thanks to the Jersild system. He describesthe treatment given in the first instance as " highlyinadequate ", but reference to the paper by Nielsenshows that it comprised 1 to 3 g. old Salvarsan plusfifty inunctions of mercury, which would make the

treatment spread over about 8 weeks, ending, Ishould guess, with a good dose of " 606 ". Forreasons already given, whatever its defects inpreventing late neurosyphilis, I should describe thiscourse as " nearly adequate ", the elimination of thelast small vestiges of infection in remote corners ofthe body requiring far more treatment than sufficesto prevent cardiovascular syphilis. In regard toNielsen's cases the author poses the followingquestions:

(1) Can it be assumed with reasonable certaintythat all or the majority of the patients who developedsymptoms and signs of aortic insufficiency or aneurysmhave at one time or another sought medical adviceand thus submitted themselves to examination ?

(2) If examined, what proportion was hospitalizedand where, and what proportion was seen by prac-titioners ?

(3) To what extent were serologic tests for syphilisemployed by the hospitals and the practitionersrespectively during the period of time through whichthe patients in question lived ?

(4) How many patients died of other causes withthese syphilitic complications undiagnosed ?

(5) If any of these patients came to autopsy, werethe findings of syphilis recorded also ?For reasons given, Gjestland thinks the results in

the Nielsen series must be regarded as a minimum.Nielsen found a total of 3-6 per cent. cardiovascularsyphilis, including 2-8 per cent. uncomplicatedaortic aortitis and only 0-8 per cent. aortic in-sufficiency and aneurysm. The author seemssurprised by the lowness of these figures, but Ithink I can lend some support to the Danish resultsfrom another angle. The evidence is not so preciseas it is given in a follow-up study, such as the oneunder review, but it is worth consideration if onlyto show what a treatment not much, if any, morestrenuous than that given to the Danish cases musthave done to prevent cardiovascular syphilis inBritish males who contracted syphilis during thewar of 1914-18.A number of years ago, when preparing a paper

on the prognosis of syphilis for the AssuranceMedical Society (Harrison, 1940), I thought it wouldbe interesting to see if the great increase in syphilis-which we know, without having any precise figuresto prove its degree, must have occurred in ournationals during the war of 1914-18 and immediatelyafter-would be reflected in an increase of mortalityfrom those late effects of syphilis on which treatmentafter their detection did not seem to have had anystriking effect. For this reason I excluded neuro-syphilis and concentrated on aneurysm and aorticincompetence. The Table shows deaths and crudedeath rates in England and Wales from aneurysm(1911-39) and from aortic valve disease (1921-39).

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TABLEANEURYSM AND AORTIC VALVE DISEASE IN ENGLAND

AND WALESAnnual Deaths and Crude Death Rates per Million Living

Aneurysm Aortic Valve Disease

Year Males Females Males Females

No. Rate No. Rate No. Rate No. Rate

1911 935 53 225 121914 902 50 229 12 Not available1917 770 51 225 1 11921 787 44 205 10 1,917 106 850 431926 777 42 245 12 2,076 111 956 471931 989 52 325 16 2,359 123 1,167 561934 984 51 431 20 2,118 109 11044 501935 982 50 459 22 2,144 110 1:048 501936 1,030 53 490 23 2,051 105 1,014 481937 1,001 51 528 25 1,919 97 969 451938 1,024 52 551 26 1,789 90 892 421939 1 ,010 51 554 26 1,822 93 916 42

The Table shows that, whereas from 1914 to1939 there was no significant increase in mortalityof males from aneurysm, that of females had morethan doubled, the increase having started in 1931.The explanation offered is that syphilis increasedgreatly in females as well as in males during thewar of 1914-18, but that whereas males, beingmostly in the fighting services, were treated, females,the civilian V.D. Service being then in its infancy,were mostly untreated. On the other hand, thefigures relating to aortic valve disease show no suchchange as those relating to aneurysm, and I suggestthat the syphilitic element in them is buried in thenumbers of deaths from aortic valve disease due toother causes. It may be argued that the figures havebeen taken too early after the probable dates ofinfection and I have studied the figures after 1939with this objection in mind. They are not very easyto follow owing to changes in classification of thedifferent causes of death and it would burden thiscommentary too much to explain them here, butthey certainly do not show any increase in mortalityfrom either aneurysm or aortic incompetence after1939.

In the patients of the Boeck series aged less than15 years at the time of infection, no case of cardio-vascular syphilis was later discovered; this was incontrast to a finding of 12 3 per cent. in the 73whose syphilitic infection was discovered at agesover 40 years and of 10 4 per cent. in all over 15years at the time of first infection. The greaterincidence of cardiovascular disease in syphiliticmales is illustrated by the overall percentage of 13-6as compared with 7-6.

In all this one may justifiably wonder how muchcardiovascular syphilis was missed by the observersof these cases, whether clinically or in the post-mortem room, and when, on the other hand, onethinks of the fallacy of including all aortic incom-petence under the heading of cardiovascular syphilis,

there does seem to be room for some scepticism asto the prognostic value of these figures.

In the Boeck cases aged over 15 years at infection,the duration of the disease at the time of recognitionof the cardiovascular complication was 30-1 yearsin males and 29-8 in females. As another exampleof the difficulty of comparing series in differentcountries with each other, Gjestland quotes thefindings of Frazier and Li (1948) in white patientsat the Johns Hopkins Hospital. Their figures were18-1 years for males and 14 1 years for females,and these were arrived at by deducting from themean ages of the cardiovascular patients undertheir study the mean ages of the males and femalesarriving at their clinic with fresh infections at thetime of their study. These mean ages were 30 and26 years respectively and the author quotes thefollowing comment by Frazier and Li: ". . . for,contrary to the commonly held opinion, syphilis isnot a disease of youth but rather one of sexualmaturity ". In this connexion it may be of interestto quote here the ages at first infection of the caseswhose records, collected from five nations, wereanalysed for the Expert Committee of the Leagueof Nations by Prof. H. Martenstein (1935) fromapproximately the end of 1929 to 1935. The sexeswere not differentiated and the ages were given in5-year periods, which showed for every nation anoutstanding preponderance of infections in the21-25 year age group. The mean ages by nationswere: Denmark, 2,308 cases, 24-8 years; Germany,2,873 cases, 25-1 years; Great Britain, 3,123 cases,27-7 years; United States, 3,741 cases, 26-1 years.Thus the mean age of the American cases did notdiffer materially from that found in the Boeck cases.The author stresses the far higher proportion of

males than of females with cardiovascular syphiliswho died of it, 61-0 per cent. as compared with47-6. He shows that there is no point on whichthe results of this re-study can be compared withthose of Bruusgaard in respect of cardiovascularsyphilis. In the next chapter the author discussesthe prognostic import of secondary relapses. Hefound no significant difference, in respect of lateeffects, between those who had suffered secondaryrelapse and those who had not. He could find noevidence, in these cases, that benign tertiary syphilisprotected against more serious forms.The causes of the excess mortality, apart from

that due to syphilis, which afflicts syphilitics arealways interesting, and the author, as a preliminaryto his report on what happened in this respect toBoeck's cases, quotes the two conflicting views, thus:

(1) Syphilis is a disease that practically always isassociated with socio-economic status, or rather with

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various disturbances of the socio-economic equili-brium. Therefore, whenever we choose a relativelylarge population-group of syphilitics for study, weinvariably end up with patients who by and largecome from the lower socio-economic strata of society.These same patients, in addition to the risk imposedon them by the syphilitic infection per se, are naturallyalso exposed to the risk of a whole series of otherdiseases more commonly encountered in such popula-tion-groups, and naturally they would be expectedto show a greater mortality from all causes than non-syphilitics do. Syphilis, therefore, can only be partlyresponsible for the excess mortality usually found.

(2) Syphilis is a generalized systemic disease affectingto a variable degree most of the organ-systems of thebody, True enough, in a certain proportion of thoseinfected the disease causes death primarily, but itmay also, withcut causing death directly, producechanges in the host, presumably non-specific incharacter, that increase the morbidity and thereby themortality from many illnesses other than syphilis.The author thinks that the Alabama study in

which the syphilitics showed a greater mortalityfrom other diseases than did the controls lendssupport to the second of these views. He alsoquotes the experiments of Rosahn (1952) on mice,which showed that " syphilitic infection in mice,even though it produces no lesions of syphilis, inand of itself causes a reduction in longevity ".

In regard to the Boeck cases, a study of themortality in Oslo by regions showed that in theregion providing these cases the " average excessmortality in East Oslo (all ages) ranged between16 and 27 per cent. in males and between 25 and38 per cent. in females ". The excess mortality inthe Boeck cases as compared with that in theregion from which they came was 53 per cent. inmales and 63 per cent. in females (all ages). In thediscussion following the relating of these facts, theauthor finally inclines to the view that the excessmortality was due to the socio-economic status ofthe syphilitics of East Oslo being lower than thatof the non-syphilitics of the same region (lowthough this might be). Finally, he agrees withSchamberg (1945), who said that syphilis killsonly through the lethal effects of its serious latemanifestations.

There we must leave it to the reader, but onecannot escape the strong suspicion that muchsyphilis in this Boeck material must inevitably haveescaped the notice of the scrutineers. Apart fromthe fact that an important part of the evidence isdocumentary with reliance on reports by personswho might not be very syphilis-conscious, withoutmicroscopic examination autopsy evidence may lackinformation respecting those insidious round-celledinfiltrates on which Warthin (1914-29) reported sofully and which may bedevil the functions ofimportant organs.

On the question of spontaneous cure, aboutwhich so much nonsense has been written on thebasis of Bruusgaard's figures, nonsense for whichBruusgaard was in no way responsible, the authorconcludes that the Bruusgaard figures afford noanswer and he thinks that the re-examination underreview has not brought us any nearer to it.The grand conclusion is that " somewhere

between sixty and seventy, and probably closer tosixty than seventy, out of every one hundreduntreated syphilitics went through life with little orno inconvenience as a result of the disease ".The cynical student might ask what value that

knowledge may be in the clinic or the consultingroom, seeing that nobody in his senses is to-daygoing to repeat Caesar Boeck's experiment. But thatdoes not detract from the value of this study;apart from the great mass of information which theauthor has gathered so skilfully into this mono-graph, it is a model which every venereologistshould have before him when he is tempted to playwith figures relating to results of infection or oftreatment, or when he reads some other person'sefforts in that direction.

REFERENCESBrown, W. H., and Pearce, L. (1923). Proc. Soc. exp. Biol. (N. Y.),

20, 476.Bruusgaard, E. (1929). Arch. Derm. Syph. (Wien), 157, 309.Deibert, A. V., and Bruyere, M. C. (1946). Vener. Dis. Inform.,

27, 301.Finger, E., and Landsteiner, K. (1906). S.B. Akad. Wiss. Wien,

Abt. 3, 115, 179.Frazier, C. N., and Li, Hung Chiung (1948). " Racial Variations in

Immunity to Syphilis." Univ. Chicago Press.Gennerich, -. (1914). Munch. med. Wschr., 61, 513.Gibbard, T. W., and Harrison, L. W. (1914). J. roy. Army med.

Cps, 22, 247.Gjestland, T. (1955). " The Oslo Study of Untreated Syphilis

Acta derm.-venereol. (Stockh.), 35, Suppl. 34.Grin, E. (1953). " Epidemiology and Control of Endemic Syphilis.

Report of a Mass Campaign in Bosnia." W.H.O. MonographSeries, No. I1. W.H.O., Geneva.

Harrison, L. W. (1932). Bull. Hyg. (Lond.), 7, 223.(1939). Ibid., 14, 482.

- (1940). British Journal of Venereal Diseases, 16, 1.- (1941). Bull. Hyg. (Lond.), 16, 458.Heller, J. R., and Bruyere, P. T. (1946). Vener. Dis. Inform., 27, 34.Lomholt, E. (1931). Hospitalstid., 74, 1175.Martenstein, H. (1935). Quart. Bull. Hlth Org. L.o.N., 4, 129.Meirowsky, E., and Pinkus, F. (1923). " Die Syphilis." Springer,

Berlin.Nielsen, J. P. (1950). Acta derm.-venereol. (Stockh.), 30, 507.Pesare, P. J., Bauer, T. J., and Gleeson, G. A. (1950). Amer. J.

Syph., 34, 201.Rosahn, P. D. (1937). Amer. J. med. Sci., 193, 534.

(1952). Arch. Derm. Syph. (Chicago), 66, 547.Schamberg, I. L. (1945). Amer. J. Syphl., 29, 529.Sowder, W. T. (1940). Ibid. 24, 684.Vonderlehr, R. A., Clark, T., Wenger, 0. C., and Heller, J. R.

(1936). Vener. Dis. Inform., 17, 260.Warthin, A. S. (1914). Amer. J. med. Sci., 147, 667.

(1916). J. infect. Dis., 19, 138.(1918). Amer. J. Syph., 2, 425.

- (1922). J. infect. Dis., 30, 569.- (1926). Amer. J. Syph., 10, 1.

(1928). Ibid., 12, 301.(1929). Brit. med. J., 2, 236.

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the oslo study of untreated syphilis *t commentaryfor the purposes of the present re-study, 574...

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