1268

to community survey work (i.e., undertaking tuber-culin testing as well as radiography of selected groupsor in selected areas) within a year the informationobtained would display the tuberculosis problem ofthe country in sharp outline. There are, of course,difficulties. More than one public authority is involved;agreement concerning the best method of tuberculintesting has still to be reached (a research committeeof the British Tuberculosis Association is investigatingthis) ; nurses trained in reading results are required ;and the means of bringing - particularly the youngadult into the survey demands forethought. But the

opportunity for such reconnaissance work, investedwith an intriguing detective quality, should stimulate,interest.

1. Idsoe. O., Guthe. T., Christiansen, S., Krag, P., Cutler, J. C.Bull. Wld Hlth Org. 1954, 10, 507.

2. Tech. Rep. Wld Hlth Org. 1952, no. 56.

Treatment of SyphilisIT is now more than ten years since penicillin was

first shown to be effective in the treatment of syphilis-a discovery which opened the way to an intensivecontrolled investigation which is perhaps without

parallel in the history of medicine. The World HealthOrganisation has chosen this as a suitable time toreview the results and to summarise modernideas.1 .

Experience has shown that Treponema pallidum,though very sensitive indeed to penicillin, must beexposed to the drug longer than is necessary withmost other micro-organisms ; and during treatmentthe blood-penicillin content should not be allowed tofall below an effective level long enough to allowrecuperation or fresh multiplication of the treponemes.The reproductive cycle in vivo has been computed totake about thirty hours, and it has been thoughtinadvisable to allow the blood-penicillin level to fallbelow 0-03 unit per ml. for more than twenty-fourhours during the period of active treatment. In the

very early stages of syphilis four days of continuousexposure of the tissues to penicillin may suffice forcure ; but with so variable a disease a margin ofsafety is desirable, and commonly treatment of earlyseronegative syphilis is continued for not less thanfive to seven days and of early seropositive syphilisfor not less than two weeks. (There is no evidencethat treatment of longer duration or with higherpenicillin levels will produce better results ; nor,

apparently, is advantage derived from intermittenthigh levels of the drug in the serum or tissues.) Theintroduction of repository preparations of penicillinhas made possible the application to outpatients oftreatment on these lines ; and the preparation whichhas been most widely used in recent years is a suspen-sion of procaine penicillin in oil containing 2%aluminium monostearate (P.A.M.). The marketing ofsome inferior brands of r.A.M. led W.H.O. to fixcertain standard requirements,2 by which a " test dose ’’of 300,000 units injected intramuscularly into 10

healthy adults doing normal ambulant work wouldcause in the majority a penicillin level of not less than0-03 unit per ml. of serum for at least seventy-twohours.

Benzyl amine salts of penicillin in waterysuspension have since been shown to have an evenmore distinct repository effect than P.A.M.; and pre-

liminary evidence suggests that the administrationof a single dose of 2,500,000 units of one of thesepreparations-benzathine penicillin G-is effective

against early syphilis in more than 90% of cases.3 Inthe early stages of the disease the treponemes multiplyrapidly, and the quantity of penicillin required forcure is related to the number of organisms present inthe host. In the seronegative stage very small dosesmay cure, but later larger doses are needed.ALEXANDER et a1.4 found that in patients with sero-positive early syphilis the proportion of relapses fellfrom 12-8% after 1,200,000 units of P.A.M. was givento 6.5% after 2,400,000, and 2-5% after 4,800,000,units were given. In early syphilis, which includesprimary, secondary, and early latent infection (thatis, symptomless seropositive syphilis within the firsttwo years) results are not improved by higher dosesthan 4,800,000-6,000,000 units of P.A.M.; and

apparently dosage of this order is used for all stagesof early syphilis in nearly 80% of 277 clinics through-out the world which provided information in replyto a questionary from W.H.O. Commonly 600,000units of P.A.M. is administered intramuscularly everyday or every second day until the required total hasbeen reached. Daily injections of this kind causean accumulation of penicillin in the blood rising to1 unit per ml. of serum after ten days, and giving aneffective level for seven to ten days after treatmenthas been completed. If the drug is given every secondday the accumulation is slower, reaching 0-5 unit perml. of serum after ten injections (that is, on thetwentieth day), and an effective level persists forsix to eight days thereafter. By another scheme oftreatment, which has proved particularly valuable inunder-developed countries, a large single dose of1,200,000 or 2,400,000 units of P.A.M. is given intra-muscularly in two or four " depots." This ensures a.

relatively high proportion of cures even if patientsdefault from further treatment. Replies to theW.H.O. questionary made it clear that the tide ofworld opinion is flowing strongly towards the con-clusion that penicillin alone suffices for the treatmentof early syphilis and that the older remedies now haveno place. Of those who replied, 65% used penicillinalone and 29% used it in combination with other

drugs ’. In this respect Europe has been slow to change;all clinics in North America used penicillin alone,but in Europe only 52% of clinics relied on it

entirely.Changes in methods of treatment have led to

changes in the clinical manifestations of relapse andreinfection. Whereas with older remedies sub-curative doses were given over long periods, nowadayscurative doses of penicillin are administered in a veryshort period. Accordingly the development of trueimmunity is often prevented, and reinfection may,like the first infection, cause early lesions. Whenreinfection followed treatment with arsenic andbismuth early lesions were extremely rare, because ofimmunity and therefore non-reactivity of the tissues,and presumably sometimes because reinfection tookplace during the protracted treatment. Relapsesafter treatment with penicillin generally occur early-within four to nine months. There is still great3. Shafer, J. K., Smith, C. A. Bull. Wld Hlth Org. 1954, 10, 619.4. Alexander, L. J., Schoch, A. G., Mantooth, W. B. Amer. J.

Syph. 1950, 34, 420.

1269

difficulty in distinguishing between infectious relapseand reinfection. From the points of view of treatmentand prognosis this distinction is not really important ;but it is important to detect reinfection, so thatsources of infection and contacts may be sought.The indications for re-treatment, in addition to clinicalevidence of relapse or reinfection, are serologicalrelapse or persistence of positive serological tests aftersix to twelve months. Follow-up after treatmentmust include frequent reliable quantitative serologicaltests ; the trends of rise or fall in titre are even moreimportant than positivity or negativity.Latent syphilis in the later stages is usually treated

by 6,000,000 units of P.A.M. divided into doses of600,000 units daily or every second or third day. Theultimate outcome in such cases has not yet beendetermined; but there is some evidence to showthat patients have no signs of neurosyphilis or cardio-vascular syphilis after observation for six or more

years,5 and that serological tests tend to show a slowfall in titre. There is no evidence that in such cases

persistence of positive serological tests after treatmentimplies greater risk of subsequent progression ofinfection and late complications than if the tests hadbecome negative. The same dosage and method ofadministration are satisfactory for the treatment ofgummata of the skin, mucous membranes, bones, andinternal organs. Herxheimer reactions have beenrare in the treatment of these cases, and most

physicians have no qualms about using penicillin atonce ; but such patients may have lesions of vitalorgans without symptoms or signs, and preliminarytreatment with bismuth may prevent occasional

catastrophes. Similarly, the dysfunction of internalorgans that may result from rapid healing of gummataafter intensive treatment—what is sometimes called

"therapeutic paradox "—has led some investigatorsto recommend preliminary administration of bismuth.Gummatous lesions do not, of course, heal at onceafter treatment with penicillin : healing takes one totwo months or even longer. Penicillin has also beenaccepted as the remedy of choice in the treatment ofsyphilitic disease of the cardiovascular system ; herethe prognosis depends on the extent of damage beforetreatment is begun, the cardiac reserve, and the ageand occupation of the patient. Commonly 6,000,000-9,000,000 units of P.A.M. is given in divided doses of600,000 units over a period of two to five weeks. TheAmerican view, which W.H.O. evidently endorses, isthat Herxheimer reactions are unusual in such casesand not to be feared unless the patient has neuro-syphilis. But whether any benefit from speed justifieseven a very slight risk of a reaction is questionable,and many workers in this country have continued togive bismuth before starting intensive treatment. Inthese and other cases the Herxheimer reaction cannotbe prevented or diminished by starting with smalldoses of penicillin. The reaction is of the " all ornone " type.

It was at first believed that penicillin did not passfrom the blood into the cerebrospinal fluid ; but it isnow known that in the presence of meningeal inflam-mation penicillin injected intramuscularly does passinto the cerebrospinal fluid, and intrathecal injections,which are potentially harmful and even dangerous,

5. Chester, B. J., Cutler, J. C., Price, E. V. Ibid, 1954, 38, 7.

are unnecessary. The most satisfactory time to treatpatients with neurosyphilis is before the clinicalmanifestations have appeared ; involvement of thecentral nervous system is usually manifested bychanges in the cerebrospinal fluid early in the courseof the disease-perhaps years before symptoms andsigns develop. Accordingly the cerebrospinal fluidshould always be tested during the initial investi-

gation of all cases of late syphilis and as part of thetests of cure after treatment of early syphilis. Neuro-

syphilis is commonly treated by administering about9,000,000 units of P.A.M. divided into doses of 600,000units given every second day ; further similar coursesare needed in some cases. Here again some prefer tostart with bismuth, while others accept the risk of aHerxheimer reaction and use penicillin at once. In

general paralysis bismuth will not prevent a Herx-heimer reaction, and the risk has to be taken. Another

special problem is syphilitic primary optic atrophy-a condition which, despite all treatment, often pro-gresses to blindness. Because of the rapidity withwhich progression may occur, many take the viewthat preliminary treatment with bismuth is a waste oftime ; and there are still some who prefer to followintensive treatment with penicillin by malarial

therapy, which is also effective. The prognosis is alwaysuncertain, but where the decline in vision has beenarrested for twelve months there is reasonable groundfor hoping that further deterioration will not occur.The need for further treatment of neurosyphilis canseldom be decided by clinical examination alone.After treatment the neurological signs are more likelyto reflect residual changes than an active process.Progress must be estimated mainly by tests of thecerebrospinal fluid, which should be repeated everythird or fourth month in the first year after treatmentand then once yearly for some years. As the resultof successful treatment the cell-count and then thequantity of protein return rapidly to normal, butchanges in the colloidal and complement-fixation orprecipitation reactions are likely to be delayed.DATTNER et a,.1. put forward the view, now widelyaccepted, that the cerebrospinal fluid may be regardedas

" inactive " if the cell-count is normal, even whenthe other tests do not show full response. In suchcases after treatment with penicillin the syphiliticprocess may be deemed to be arrested, and furthertreatment is unnecessary regardless of the clinicalfindings. On the other hand, persistently high cell-counts or increase in cells following normal findingsindicate activity of the syphilitic process and thenecessity for further treatment.

Penicillin has proved particularly effective in theprevention of congenital syphilis ; good results areusually obtained even if treatment is given as late asthe last week of pregnancy. A common dosage is

4,800,000-6,000,000 units of P.A.M., of which 600,000units is given every second or third day ; but late in

pregnancy it may be necessary to intensify treatment.Whether when penicillin has been given very earlyin pregnancy a further course should be given late inpregnancy, and whether syphilitic women so treatedshould again be treated in subsequent pregnancies,are questions that can be answered only in relation toparticular patients and particular circumstances.

6. Dattner, B., Thomas, E. W., De Mello, L. Amer. J. Med.1951, 10, 463.

1270

There is no evidence that neglect of either precautioninvolves risk to the foetus, provided that the initialtreatment has been adequate, the patient has beenproperly observed and tested, and infected sexualpartners have been traced and adequately treated.If a child is born with clinical signs of syphilis, treat-ment should be instituted at once irrespective of theresults of serological tests—which are sometimes

negative. Total dosage of P.A.M. may be in the neigh-bourhood of 250,000 units per kg. of body-weight,divided into ten doses given every day or every secondday. Clinical examination and serological tests arerepeated monthly in the first year, six-monthly in thenext two years, and then at increasing intervalsthroughout childhood and adolescence. If the childof a treated syphilitic mother is born without clinicalsigns of syphilis but the serological tests are positiveat birth it is by no means certain that the child hassyphilis, for " reagin " can be transferred from motherto foetus through the placental circulation. In such acase the titre of the quantitative test may be expectedto be lower in the child than in the mother, and thepositive test in the child will become less stronglypositive and then negative within two months ofdelivery. The diagnosis of congenital syphilis shouldbe based on clinical findings, radiographic changes inthe long bones, and the behaviour of the serologicaltests ; and only exceptionally is it justifiable to giveantisyphilitic treatment before the diagnosis has beenfirmly established. Where the child of a treated

syphilitic mother is born without clinical signs ofsyphilis and the serological tests are negative at birth,this means that the child is well unless infection hasoccurred very late in pregnancy or insufficient prenataltreatment has prolonged the time taken for serologicaltests to become positive. In such cases it is importantto keep the child under observation and to do repeatedtests. How long this observation should be continuedis not agreed. Most consider that six months issufficient, but others would continue it for one to twoyears. When the diagnosis is made late in the courseof congenital syphilis the serological tests no longerindicate reliably the efficacy of treatment, and thedosage of penicillin must be decided by analogy withlate acquired syphilis in the adult, by the results oftests of the cerebrospinal fluid, and by long-continuedobservation. The dosage is based on body-weight,as in the earlier stages of congenital syphilis ; butwith older children there is a tendency to increase thetotal dose of P.A.M. to 4,800,000-6,000,000 units. The

special problem of interstitial keratitis (which is notcertainly the direct result of treponemal activity) hasbeen largely solved by local application of cortisone,which has improved the prognosis of this serious

complication.The introduction of penicillin in the treatment of

syphilis has proved one of the most remarkable

therapeutic advances of recent times ; it is the fittingclimax of many years of achievement in the study ofthe disease which began with the discovery of Tre-ponema pallidum in 1905. But the ease and apparentsafety with which it can be given are deceptive. Aswith most other remedies its effectiveness and safetydepend greatly on the care and discretion of thosewho prescribe it. Moreover the venereal diseases,despite advances in treatment, still strike terror in thehearts of many patients, and fear and uncertainty

about infection are often more catastrophic thaninfection itself. " Diagnosis before treatment " is asafe rule.

1. Meyer, P. C., Reah, T. G. Brit. J. Cancer, 1953, 7, 438.2. Lesse, S., Netsky, M. G. Arch. Neurol. Psychiat. 1954, 72,

133.3. Willis, R. A. Pathology of Tumours. London, 1952 ; p. 178.4. Krasting, K. Z. Krebsforsch. 1906, 4, 315.5. Rau, W. Ibid, 1922, 18, 141.

Necropsy StatisticsNECROPSY records very rarely indicate the absolute

frequency of any particular finding : too many factorsof selection are involved, and, particularly where

negative findings are being recorded, too much dependson the thoroughness with which the necropsy hasbeen done. When the pathologist is recording datawith a plan in mind, these are likely to be reliable;but when, he is merely accumulating facts for thefuture it is hard for him to achieve reasonable accuracywithout being swamped in detail. Reported necropsystudies of the frequency with which various neoplasmsgive rise to secondary tumours in the brain illustratethe effect of selection. The series of MEYER andRBAH, from the London Hospital, gives the lung asthe source of well over half the cerebral. secondariesfound, mammary and gastric growths following withabout a tenth each. LESSE and NETSKY 2 and WILLIS,3on the other hand, put mammary tumours at the headof the list. This difference probably reflects differencesin admission policy. But there are surprising differ-ences in the total frequency of cerebral metastasis:in 500 cancer cases, WiLLis found only 29 with intra-cranial deposits ; whereas in 595 cases, LESSE found207. Thus in WrLLis’s cases, which were recorded

mainly in Australia, cerebral secondaries were morethan six times less common than in LEssE’s cases,which were recorded in New York. If this discrepancyis not due to selection, it is due to a very remarkablegeographical difference in the behaviour of malignantdisease. Older figures show more easily explicabledifferences ; neither KRASTING 4 nor RAU 5 had to dealwith carcinoma of the lung, and they found an incidenceof intracranial metastasis even lower than thatrecorded by WiLLis.The main lesson is surely clear: the common

mammary and pulmonary growths are often associatedwith cerebral secondaries, and neoplasms of breastand lung should be looked for whenever an apparentlyprimary intracranial tumour is found. It is doubtfulwhether much more can be learnt now by elaboratestatistical handling of bulked figures to give over-allage or sex distribution, irrespective of the type ofneoplasm. Despite the current liking for figures andthe easy way they lend themselves to tabulation,detailed study of individual cases of one given type ofdisease is likely to contribute more to knowledge.This is not a popular view : the eye of readers is stilldrawn to the large series, and it is far easier to collectmany superficial figures than to follow the tangledbehaviour of a growth in the infinite variety of thesingle patient. Fresh ideas and fresh techniques ofstudy are more likely than additional figures to

explain why pulmonary growths favour the brain,or why one patient gets thousands of secondaries, andanother but one.