Treatment practices and follow-up examinations

0. IDS0E, T. GUTHE, & R. R. WILLCOX TREATMENT PRACTICES AND FOLLOW-UP EXAMINATIONS DOSE/TIME REQUIREMENTS AND PENICILLIN PREPARATIONS As indicated previously a dose/time relationship aimed at maintaining a penicillinaemia of not less than 0.03 IU per ml of serum over a period of time is essential for the successful outcome of therapy in early syphilis. To ensure an adequate safety margin, the period of penicillinaemia is in practice often extended to at least 15-20 days (Mach & Breitfellner, 1968). Such a penicillinaemia can be obtained from most penicillin G preparations if used judiciously; this entails spacing the injections in accordance with the defined but different penicillin levels in the blood characterizing the different preparations used. Any penicillin preparation and treatment schedule that fulfils the dose/time relationship requirements is acceptable from a theoretical viewpoint. But it is obvious, as noted on page 10, that in practice the long-acting penicillin preparations-PAM, DBED, or BOM-are to be preferred, since treponemicidal penicillinaemia of adequate duration can be achieved with a limited number of injections. To a large extent DBED has replaced PAM in clinical and hospital practice in recent years. TREATMENT SCHBEULES Table 12 shows generally accepted treatment schedules for various penicillin preparations in different stages of syphilis (Olansky & Norins, 1966; US Department of Health, Education and Welfare, 1968; Brown, 1968). These treatment schedules can be modified in accordance with the practical circum- stances of the patient and the physician, with due consideration of the dose/time relationship require- ments (WHO Expert Committee on Venereal Infec- tions and Treponematoses, 1953). Some venereo- logists, syphilologists, dermatologists and other experienced doctors prefer somewhat higher total doses, e.g., in some cases of neurosyphilis (Regnier, 1955), than indicated in Table 12. However, it should again be emphasized that a high total dose or large individual doses as such do not represent " strong" treatment unless adjusted in accordance with the time/dose relationship characteristics of the peni- cillin preparation used. FOLLOW-ULP EXAMINATION After intensive penicillin treatment, as noted earlier, the duration of follow-up care is related to the immunological response in different stages of syphilis. In cases of inadequately treated early syphilis, it was pointed out that treponemes remain- ing in the host may remultiply and a new cycle of the syphilitic infection develop. Depending on the immunological state at the beginning of treatment, the reappearance of clinical and serological symp- toms will vary. In the great majority of cases, relapsing manifestations occur within one year, and for all practical purposes within two years (Thomas, 1949). Primary and secondary syphilis should there- fore be followed by clinical inspection and quantita- tive serological tests monthly for 6 months after the end of treatment and then at 3-monthly intervals for one year (Danbolt, 1960; Willcox, 1964a; Skog, 1966; US Department of Health, Education and Welfare, 1968). If possible, half-yearly examinations during the next year should also be made, including spinal fluid examination some time between one and 2 years after treatment (WHO Expert Committee on Venereal Diseases and Treponematoses, 1953a). Clinical relapse, serological relapse or marked increase of titre require immediate retreatment with the same or an intensified treatment regimen. Some investigators, for example Jefferiss (1963) and Fernando (1969), have considered the result of treatment of early syphilis with penicillin to be so satisfactory as to render lumbar puncture unnecessary, although this view is not universally accepted. Following the treatment of late latent syphilis, quantitative serological reactions should be under- taken at about 3-monthly intervals for the first year, at 6-monthly intervals for the second year and then possibly annually for at least 3 more years (US Department of Health, Education and Welfare, 1968). Spinal fluid examinations should be perform- ed before a diagnosis of latent syphilis is established. Again it is stressed that the persistence of reactive serological tests is not unequivocally an indication for retreatment (US Department of Health, Educa- tion and Welfare, 1968; Thomas, 1949). There has been recent confirmation (Perdrup, 1964) of Dattner's view (1951) that the response to 38 39PENICILLIN IN THE TREATMENT OF SYPHILIS 0 > 0 > 0 0 0 0 0 C Cr cm, CO0a 0 00 C CC 22; C 0 2 0 > -0 o -~~~~~~~~~~~~~oC00L E. CD C-4 ~~~0 0L 0 0 ~~ ~ ~ ~ ~ ~ ~ .. 0 2co ..- N 0 000~~~~~~C f.- C < 0 0 . E~a "..o .0 C< >. * 0 C - C0 CC0) E CL0~ CD 0 ~ 0 '. 0m 0C w(0A .0- C 0C~~~~~~~~ ~~L 0E..: 0, 0 0 0. .0 CCt o 0' co e E~~~~~,.0 0 0 0 00 o) o o070 0 -.~~~~~. C .20 0 CC0 C t o3C.0C0EOC 0 -~~~~~2 ~ 0C. *-. 0*;CO. 0 . . C .C E- . CO.-> COC0 c o *-N .2 bc 0C0 NC oE.JC E'C M.0 -*11 t.00 a0 CO0 C E o C CE ,. C E.. 0 0 C .0~~~~~~~C44 .0 ...a~~~~~~~~~~~ Co> 0> C 0 700 0 00 C0 >5.co0- .0 000 ( A m - 0 Ce 0.. .- O5,CE 0 0 0 .C~ ~~~0CO. 0.0 ~~~~~~')O. 0 000 .0.0a O~~~~>.O.0- :5 C C.4 _ 0C0>.~~~~~~~~~~O O~~~~ ~ ~ ~ 0~~C0L 0o 0 5 .0C/) C o0 CD.~- O0 0 -a ~>jC4 C0E N~~~~0 oC>. oC J0-.0 Cl. o00> j ~ 0 OcrE 0 40 0. IDS0E, T. GUTHE, & R. R. WILLCOX penicillin treatment in neurosyphilis could be syste- matically measured by laboratory examinations of the spinal fluid. Thus, in asymptomatic neuro- syphilis the follow-up control should comprise quantitative serology and spinal fluid examinations at 3-monthly intervals in the first year, and at 6-monthly intervals in the second year. The cell count and total serum protein in the spinal fluid should return to normal within the observation period, as a measure of the arrest of the syphilitic process. Following treatment, the spinal fluid reagin (and treponemal antibody) tests may remain reactive for several years at a low titre without indication of active syphilis (Perdrup, 1968). There is evidence that the IgM levels in the spinal fluid decrease more rapidly than the IgG levels and that therefore quantitative flocculation tests, which are more reac- tive to IgM immunoglobulins than the complement fixation test, would be of particular value in assessing the results of therapy (Oxelius et al., 1969). In cardiovascular syphilis and other late compli- cations, the serological,follow-up care after treat- ment will be similar to that in late latent syphilis. The clinical results and the functioning of the cardio- vascular system will depend on the damage already present when treatment begins (Perdrup, 1964). Follow-up control for many years will obviously be necessary. Supporting therapy, including surgery and medical care, may be required. After treatment of early syphilis in pregnancy, quantitative serological tests should be carried out monthly until delivery. Newborn babies of ade- quately treated mothers should be followed with quantitative serological tests monthly for 3 months and a final test after 6 months. Particular attention should be paid to the possibility of passive trans- placental transfer of reagins and treponemal anti- bodies, should the initial tests prove to be positive without clinical or radiological signs of the disease. In such circumstances the reagin titre should be checked at more frequent intervals. If it increases, syphilis is likely; if it decreases, passive transfer is the cause (special consideration being given to the results of the quantitative flocculation tests because of their particular affinity to the IgM immuno- globulins). Alternatively the modified FTA test may be used if available to demonstrate IgM immuno- globulins in the infant (see page 32). In late con- genital syphilis the spinal fluid should be examined before treatment. Otherwise, the follow-up prin- ciples are the same as for late latent and late syphilis in adults. ADVERSE REACTIONS TO PENICILLIN WITH PARTICULAR REFERENCE TO TREATMENT OF SYPHILIS TOXIC REACTIONS Among the antitreponemal antibiotics penicillin stands out because of its very low toxicity (Stewart, 1964). Toxic reactions occur almost exclusively when penicillin is given in excessive doses to patients with reduced renal function hampering its excretion (McGovern et al., 1970; Kurtzman et al., 1970). The toxic effect in such cases is associated with the pharmacological properties of the penicillin prepara- tion used, and almost entirely with the cations of the potassium or sodium salts (Stewart, 1965; McGovern et al., 1970). In particular, neurotoxic reactions have been observed (Smith et al., 1967; Cohill et al., 1967; Kurtzman et al., 1970), especially if brain tissue has been weakened by cerebral disease (Deisenhammer, 1969). When administered intrathecally, a procedure now rarely used, even very low doses ofpenicillin may cause neurotoxicphenomena (Kurtzman et al., 1970). Other rare complications may result from the physical nature of the penicillin preparation used, e.g., pain and other local reactions at the injection site, and Hoigne's syndrome (sensory phenomena, elevated blood pressure) (Hoigne & Schoch, 1959; Hoign6, 1962), which may end fatally (Kieswetter & Ernst, 1968). There is evidence that reactions of this type are due to emboli caused by large penicillin crystals (20-100 IU or more) in the pre- paration used (Batchelor et al., 1951), and that therefore only microcrystalline or micro-particle size penicillin preparations should be employed (WHO Scientific Group on Treponematoses Re- search, 1970). Embolic toxic reactions arising from accidental intravenous injection of procaine peni- cillin, suggesting the procaine element as the major factor (Reuter, 1970), are also rare (Popper, 1964; Freedman, 1965).