Journal of Neuro-Ophthalmology, March 1987, Volume 7, Issue 1

Syphilis in 1986.

Symptoms of syphilis have evolved over the ages. In the 16th century, they were essentially cutaneomucous ones. While the intensity of the symptoms decreased localization of the infection in the various organs--mainly those of the cardiovascular and nervous system--gradually appeared. Over a period of years following the introduction of penicillin therapy, the cutaneous and visceral stages became less common. Reminder of the chief serological reactions and of some aspects of the experimental syphilis in the rabbit, similar to certain forms of human syphilis--a strong but late penicillin therapy has been proven ineffective in humans as well as in animals. It is to be regretted that numerous methods of using penicillin (all over the world), had been, from the beginning--except in a few cases--of a purely empirical nature. The authors emphasize--with proof to support their opinion--the failure of antibiotic therapy, which can explain the recent reappearance of hepatic and nervous localizations that had disappeared for 30 years. Despite views to the contrary the authors conclude that penicillin has in no way resolved all the problems raised by the treatment of syphilis.

Tournai of Clinicnl Neuro-ophthalmology 7(1): 11-16, 1987. Syphilis in 1986 M. Poitevin, P. Collart, and Marc Bolgert* Symptoms of syphilis have evolved over the ages. In the 16th century, they were essentially cutaneomucous ones. While the intensity of the symptoms decreased lo­calization of the infection in the various organs-mainly those of the cardiovascular and nervous system-grad­ually appeared. Over a period of years following the in­troduction of penicillin therapy, the cutaneous and vis­ceral stages became less common. Reminder of the chief serological reactions and of some aspects of the experi­mental syphilis in the rabbit, similar to certain forms of human syphilis-a strong but late penicillin therapy has been proven ineffective in humans as well as in animals. It is to be regretted that numerous methods of using penicillin (all over the world), had been, from the begin­ning- except in a few cases-of a purely empirical na­ture. The authors emphasize-with proof to support their opinion-the failure of antibiotic therapy, which can explain the recent reappearance of hepatic and nervous localizations that had disappeared for 30 years. Despite views to the contrary the authors conclude that penicillin has in no way resolved all the problems raised by the treatment of syphilis. Key Words: Syphilis-Treponema pallidum-Penicillin re­sistance. From the Laboratoire de Recherches en Syphilis Experimen­tale, Institut Alfred Fournier, 25 Boulevard Saint-Jacques, F. 75680 Paris Cedex 14, France. Address correspondence and reprint requests to M. Poitevin, Institut Alfred Fournier, 25 Boulevard Saint-Jacques, F. 75680 Paris Cedex 14, France. *Member of the Academie Nationale de Medicine. 11 © 1987 Raven Press, New York For a considerable number of dermatologists, there is nothing more to be said about syphilis. They believe that everything is known about its symptoms, serology, and methods of treatment as well as about the fundamental facts regarding the causative agent's physiology. We question the truth of this. THE EVOLUTION OF CLINICAL ASPECTS As has happened with many infectious dis­eases, the symptoms of syphilis have evolved. Ini­tially described under various names, such as "French disease" by the Italians and "Neapolitan disease" by the French, the great pandemic at the end of the 15th century was characterized by a particularly widespread crop of mucocutaneous eruptions, which, according to Fracastor (1), were often associated with agonizing bone pains. In the COUrse of time, however, these cutaneous charac­teristics lost their intensity and were progressively replaced by visceral lesions. In the latter part of the 19th century, A. Four­nier (2), using purely clinical arguments, identified tabes and general paralysis with the disease, while Professor A. Sezary (3,4) ascribed the increase in syphilis of the nerVOUS system to the ageing of the infecting agent in Europe as opposed to in Africa and Asia where syphilis was still characterized by cutaneous eruptions. In the early part of the 20th century, Milian's classic papers (5) continued to testify to the fre­quency of mucocutaneous lesions consisting of genital and nongenital chancres differing widely in appearance, as well as numerOUS forms of sec­ondary and tertiary syphilis skin disorders (6). At the early stage, adenitis and splenomegaly would appear. Various visceral disorders, how­ever, were observed mOre and mOre frequently. Fervent discussion arOse over the parts played by Treponema and the arsenical treatment used in causing the early Or late appearance of secondary jaundice{7--10r ImpaitmentoLthenervous system was characterized by either declared or la­tent meningitis, i.e., as identified by lumbar punc­ture{ LP) or sometimes by the sudden onset of paraplegia from the secondary stage onward. In addition to the cutaneous lesions {tuberculary syphilis papules, gummata){6) the tettiary stage was characterized by sclerogummatousliver and polymorphic kidney impairment (II); Syphilitic aortitis (with osteal coronary arteritis) occurred frequently. Sezary's work (4) showed the wide-ranging and polymorphic nature of central nervous system lesions, diffuse or limited late meningitis, cerebral arteritis, and paraplegia; Thirty years later (1975-76) (12,13) the course of syphilis underwent further modification,. some­times in the wake of penicillin therapy.• The time of incubation of genital or anal chancres increased beyond the classic 21days, and they appear under various aspects, sometimes herpetiform, often ul"' cerous and inflamed,. rarely multiple, at least in Europe. Associated adenitis was sometimes in­flammatory with an aseptic puriform content.Sec­ondary roseola, often classic in form,couldeither be discrete or, on rare occasions, localized. Among secondary syphilitic symptoms, the papulousand squamo-papulous forms {often palmoplantar) were the most common. These were occasionally pruritic. Hypertrophic· mucous patches. in the genito-anal· region. were common, while those in the buccal mucous area were rarer. Classic patchy alopecia was often replaced by more generalalo­pecia of the commonplace infectious type in the parietal region. Adenitis in •postjugular and. epi"' trochleaiareas retained its diagnostic value.• Sec~ ondary hepatorenallesions were no longer seen; secondary meningitis. became. unusual, and •• sys"' tematic LPsonly revealed discrete and easily re~ ducible anomalies. Finally, aortitis, tabes, and general paralysis became rarer and rarer,at least in the region around Paris.• [Elsewhere they are still to be seen (14,15).r--However, emphasis must. be placed on the ever-increasing incidence verified on numerous occasions by one of our col­leagues (12) .........ofpurely serological syphilis. This had been described long ago by Bizard,at St.• La~ zare Hospital and later (1932)confirmed by Schul­mann. (11,12,16,17). Patients defined as having serologiealsyphilis are those with no known syphilitic history, who are free fromalldinicalsigns, and who have normalLPs but exhibit fully positive serological re­actions {including Nelson's test). Whereas Sezary (1934--1938) showed in a statistical study (4) that the mean frequency of incidence was estimated at ! C"l I'll ·.·NCllrl1-'Oll!tthafmol, .·Vf)1,7,··No.l ,J987 3.4% in men and9.2%jnwomen; between 1952 and 1960 one of us found nearly five times that frequency in men and three. times that frequency in women. (13) Interpretation of these statistics was based on various hypotheses: the part played bysysternatic blood sampling,. the eradication of lesions by anti~ biotics adIriinistered for other purposes, failure to notice symptoms •(very common among homo­sexuals), and poor quality ofinoculum. It seemS, however, that syphilis can be contratted without causing noticeable ••symptoms:•• one of •us has •ob­served positive serological reaction in 73 practising prostitutes, all of whom were regularly.examined and were free of any symptom. The widespread endemicity of •syphilis in 1945~46was followed by a rapid decrease (with regional oscillations) (14,15) to the point where ill. 1955 some WHO and U.S.A. assessors of the inci"' denceofsyphilisbelieved that it had definitely been eradicated. From 1960 onward, however, it has been inexorably. increasing.• Whereas this in~ crease has. been variously •• attributed •to prostitu~ tion, to the laxity in morals, and to the increase in homosexuality (18,19), it could also be explained bya fairly general .lacko! knowledge. about. syphilis among the younger medical practitioners. It is remark.. able that the increase in syphilis since 1970 has been accompanied by the reappearance of hepatic lesions. (combined. or not with nephrotic syn.. drome) (7,20~28)and neurological incidents such as meningitis, hemiplegia, •• paraplegia, •tabes,an~ general paralysis,. whose frequency since 1971 been stressed by Basset and associates (29),.by Ra.. verdyandassociates(30), and by Delapotteand associates (25); In 1983, Buge and associates (31) wrote a paper about the foregoing. PROBLEMS IN SEROLOGY (32,33) In practice,. TrepOnema pallidum{TP) can only be detected in chancres.and secondary-stage lesions; hence the importance of serological reactions. The oldest and. best..knowntests operate either by complement. fixation (Bordet-'-'Wasserman) or by floculation (Kline, VORL, etc.), butthese are sub­ject toa great variety of techniques. The only specific and sensitive reactions are those in which the antigens are spirochetes, as in the •• immunofluorescenceot fluorescent trep~" nemal antibody (PTA) (Deacon) and Treponema Pill; lidumimmobilization .(TPI) •tests. All. theseteac­tionsbecomeprogressivelypositive •during the primary. stage,. led by those FTA and Treponelrftl pallidum hemagglutination assay (TPHA) tests<ana followed by first the classic reactions and then those to the TPI test the moment at which serolog~ icalchangedivides this stage into a preserologic period (51- ) and a serological period (51 +). During the secondary Or 52 stage all reactions are positive. Even since 1958, Bolgert and associates (34) have. been saying that, contrary to generally ac­cepted practice, the titer of antibody present ex­presses neither the intensity of the syphilis nor the time during which it has been present, whereas it does depend upon individual patient reaction. Although the exact physiological significance of such reactions is unknown, it is true to say that, whereas complete and long~lasting test negativity gives hope that full bacteriological sterilization has been achieved, this is not the case if doubtful or dissociative results continue to be obtained. In this respect, TPHA test results regrettably remain in~ definitely positive for certain. correctly· treated pa­tients for whom all other reactions are negative (35). CERTAIN ASPECTS OF EXPERIMENTAL SYPHILIS IN RABBITS (23) Despite. the. fact that the •• discovery •• of TP by 5chaudinnand.Hoffman occurred 80 years ago no one has ever succeeded in cultivating this spiro­chete, in spite of innumerable attempts hence it has only been possible to. study its physical and biological characteristics by experimentation on animals. It should be stressed,. however, that in spite of the importance of the knowledge gained by such research, an absolute criterion of bacterio­logical sterilization still does not exist; •as a conse­quence, allexisting •therapeutic methods. are still entirely empiric in character. In 1903, Metchnikov and Roux succeeded in proving that TP could be induced in chimpanzees, but it was Bertarelli who, in 1906, demonstrated the susceptibility of the rabbit to Treponema infec­tion. Indeed, if a suspension of Treponema pallidum is injected into a rabbit's testicle, this will resultin an orchitis (always accompanied by a concomitant satellite adenitis), which will evolve toward spon~ taneousregression with the infection remaining in the orgartism of the inoculated animal without vis­ible signs of its presence (exclusive of positivese­rological reaction and the persistence of TP in the tissues). Only in exceptional cases do delayedcu­taneous or osseous symptoms appear. If treated with adequate doses before the 100th day fol­lowing inoculation, the lesions shrink rapidly, the spirochetes leave the tissues. (ganglions, cerebro- IN 1986 spinal fluid, or aqueous humors) and serological test results become negativeagain.• But if penicillin therapy is. inadequate, even though the orchitis may have completely regressed, it can reappear in the following weeks. If, on the other hand, treat­ment is delayed for more than 100 days after inoc­ulation,. serological. test. results will remain posi~ tive, and it will always be possible to find TP in ganglion smears. Because. of the difficulty in re­producing the disease from tissue sources of this sort, there is cause for thinking that spirochetes con­tinue to survive in the tissues in a state of commensality (21); this in no way excludes the possibility that, in as yet undetermined biological conditions (espe­cially under the influence of cortisone), TP may be able to recover all or part of its virulence and to become pathogenic once more, at least for the host it infects.•• This would explain the late appearance of various functional disturbances of the viscera. Another point of view is that held by certain statisticians who,on an empiric basis, maintain that: (a) All TP divide every 30-33 h; (b) 0.03 J.L/ml of penicillin is enough to destroy all TP; (c) This dosage given 3 times for 33 h issuffic:ient to pro­duce bacteriological sterilization of all syphilitic infections nO matter at what stage, thereby achieving eradication of the disease; To believe in such a syllogism one must believe that: (a) all TP regularly divide every 30-33h(experimentation formally contradicts this), and (b) that the antibi­otic agent diffuses uniformly through all the tissues. Furthermore, in 1950, •• Eagle (26---- 28) showed that penicillin's maximum efficacy against TP was a function of its concentration in •• the blood,. and that regression of induced orchitis would only be achieved with. doses 50 times greater than the mean dose considered to be treponemicidic (0.03 J.L/ml). The above illustrate the empiric c:haracter of all the therapeutic methods so far proposed (36). PROBLEMS IN THERAPY Contrary to certairiopinioris, urtt.reatedsyphilis is not always benign in character. In a scientific study of considerable interest, despite doubts about its ethics two thirds of more than 1,000 vol­untarilyuntreated subjects with both 51 and 52 disease, were followed over a long period of time. (One~third of the subjects were not able to be fol­lowed). Gjestlandandassociates (37), Rockwell and associates (38), and Towpik (39) observed that half of the subjects persistently showed positive reactions despite being free of clinical attack, while J Gin Neuro~ophthalmol, Vol.?, No.1, 1987 14 M. POITEVIN ET AL. the other half had specific vascular or nervous le­sions. Therapeutic methods On the basis of research conducted by Bessmans and Derom, one of us, working with G. Levy in 1947, was the first person in France to treat pri­mary- secondary stage syphilis with 15 MU of G penicillin in aqueous solution* over a number of years (40). For a sample number of 370 patients, the following results were achieved: total failure 0.8%, durable clinical and serological cure 89.6%, uninterpretable results 9.6% (sexual promiscuity, persistent positive serology, etc.) (41-43). Many other systems of treatment have been proposed (19,24,44), as was borne out by Pro­fessor Pautrier's remark of "therapeutic anarchy" at the Congress of Brussels-Liege in 1949. It con­tinues to this day, for in 1954 the WHO counted 294 different methods of treatment. In point of fact, prescription over the last few years has been for 4.6 or 9 MU, of delayed-action penicillin (PAM, Extencilline) and more recently for 15 MU but this has been administered over widely different periods and at very variable rhythms of injection. It would seem that what the WHO. considers an "adequate" dose should vary upwards in accordance with the duration of the infection. (At present the WHO has failed to state what an "adequate" dose is.) However, one may well think that the 8,819 cases of late-stage syphilis (including the 78.3% that were of neuro­syphilis) discovered in 1975 by WHO experts could have progressed to late stage due to inade­quate treatment, thus confirming Sezary's opinion (4). Since the disappearance of Stovarsol (a.k.a. Acetarsone, Acetphenarsine, or 3-(acetylamino)-4­hydroxyphenyVarsonic acid) and the discontinua­~? n of m~laria therapy in the treatment of syph­IliS, Boudm and Arfouilloux (45) have successfully treated general paralysis with daily perfusions over 30 days o.f ~sotonic glucose serum containing 20 MU of SpeClllme G (benzylpenicillin sodium) in association with 100 mg of hemisuccinate of hy­drocortisone for 2 weeks and 50 mg of adrenocorti­cotropic hormone for a week. The treatment is, however, less effective with tabes. 'After one i.v. injection/day for 3 days of mercury cyanide (to aVOid the Jansh-Herxheimer reaction), the first l,()OO OOO/U of penicillin used to be given at progressively higher dos~ges for 3 days, and then, l,OaO,OOO/u/day, in 2 injections, for 14 days. I Cli" .\"t/I',H11,ltlhnfmof, Vol. 7. No. 1. 1987 Dogmas associated with penicillin therapy The following have contributed to obscuring as­sociated problems, as they have been invalidated by facts. Penicillin Always Cures Early Syphilis Infection This is simply not true (46). Apart from the 0.8% total failure already mentioned, numerous other statistics have been published. Additionally, peni­cillin has shown itself to be less effective in cases of syphilitic reinfection. In spite of obtaining nega­tive results in reagent-based reactions, TPI test re­sults remain positive in the majority of cases (13). The treponeme has acquired resistance to penicillin Although this thesis has never been demon­strated experimentally (22), certain observations tend to confirm it. In 1972, Hatos (47), obtained better results with early syphilis at doses of 6 MU than Jefferiss and Willcox had in 1963 (48) with 2.5 MU. One of our team, whose suspicions had al­ready been aroused by the progressive increase in periods during which patients had negative test results over the passing years, was able to confirm the fact. Two groups of syphilitics (with both SI and S2 disease), both treated identically, one in 1947-1950, the other in 1961-1967, were com­pared. In the SI + subgroup of the latter group, the mean length of time for negative test results had climbed from 1-4 months (p < 10-8) and for the S2 subgroup from 2-8 months (p < 10-9). Fur­ther, the number of serological failures is signifi­cantly higher for the latter group, whether at 6 months (X2 = 61.2 and p < 10-9) or at 2 years (X2 = 25.2 and p < 10-6) (13). The persistence of positive reactions after penicillin therapy is a "serological blemish" The term "serological blemish", too commonly used, has no biological significance. It claims to express the persistence of antibody formation after the treponemic antigen has disappeared. While not denying the feasibility of this process, which is an admitted fact in various infections, it is possible that the persistence of positive reactions may also be due to the persistence of seats of quiescent tre­ponema, as already described. CONCLUSION In 1.9~6., it is impo,~sible t? continue considering pemCllhn to be the therapIa sterilisans magna" of SYPHILIS IN 1986 /5 syphilis. Hence, we must revise our ideas about this antibiotic. During the early years of its use in adequate doses, obtaining total, rapid, and du­rable serum negativity was the rule in cases of early syphilis. Now, however, in spite of the fact that penicillin may result in eradicating clinical le­sions, a persistent and more or less complete sero­logical positivity should lead to a fear of the ap­pearance at a late stage of signs of attack. In spite of its specificity, an isolated, feebly positive IPI test result is less alarming, because it may end by clearing up spontaneously, due doubtless to the disappearance of residual seats of treponemic in­fection. REFERENCES 1. Fracastor. Le mal franc;ais ou syphilis. Extrail du livre de "contagionibus et contagiosis morbis" (1546) avec com­mentaires de A. Fournier (1869). 2. Fournier A. De I'ataxie locomotrice d'origine syphilitique (Tabes specifique). Paris: Masson Ed .. 1882. 3. Sezary A. La syphilis dll systeme ner!'eus. Paris: Masson et Cie, 1938. 4. Sezary A. Galmiche P. 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No.1, 1987 de 3 injections de cyanure de mercure. Recul maximum de 17 ans. Bull Acad Nat! Med (Paris) 1965;149:20-1;517-23. 44. Lortat-Jacob E. Negativation des reactions serologiques par Ie traitement d'attaque bismuthique au cours de la syphilis primo-secondaire. Statistique. Ann Derm et Syph 1946;5: 279-80. 45. Boudin G, Arfouilloux Je. Paralysie generale et manifesta­tions cerebrales de la syphilis, E.M.C., 17055 AlD, 6, 1970. 46. Moulin G, Magnin P, Monnet P, Thiers H. Echec de la penicillinotherapie dans la prevention d'une syphilis con­genitale. Bull Soc Fr Derm et Syph 1973;80:306-7. 47. Hatos G. Evaluation of 460 cases of treated syphilis. Med I Aust 1972;2:415-20. 48. Jefferiss FJ, Willcox BR. Treatment of early syphilis with penicillin alone. BlVD 1963;39:143-7.