Journal of Neuro-Ophthalmology, March 1991, Volume 11, Issue 1

Late-onset congenital syphilis. A retrospective look at University of Iowa Hospital admissions.

A retrospective review of 766,742 hospital admissions was performed between 1966 and 1986 at the University of Iowa Hospital for the diagnosis of congenital syphilis. Although 88 individuals were identified with this diagnosis, adequate treatment was documented in only 33 (38%). Thirty-nine of the 88 individuals identified were initially seen for visual complaints by the ophthalmology department. We recommend that all physicians increase their index of suspicion for this disease, and institute appropriate therapy and follow-up if late congenital syphilis is diagnosed.

! ounral of Clinical Ncuro- ol'hthalmology 11( 1). 1- 6, 1991. Late- Onset Congenital Syphilis A Retrospective Look at University of Iowa Hospital Admissions Kathleen B. Digre, M. D., George L. White, Jr., Ph. D., Steven A. Cremer, B. S., and R. Michael Massanari, M. D. ( 9 1991 Raven Press, ltd., New York A retrospective review of 766,742 hospital admissions was performed between 1966 and 1986 at the University of Iowa Hospital for the diagnosis of congenital syphilis, Although 88 individuals were identified with this diag­nosis, adequate treatment was documented in only 33 ( 38%). Thirty- nine of the 88 individuals identified were initially seen for visual complaints by the ophthalmology department. We recommend that all physicians increase their index of suspicion for this disease, and institute appropriate therapy and follow- up if late congenital syphilis is diagnosed, Key Words: Late- onset congenital syphilis- Index of suspicion- Hutchinson's triad. From the Departments of Ophthalmology ( K. B. D., G. L. W:) and Neurology ( K. B. D.), University of Utah School of MedI­cine, Salt Lake City, Utah; and the Department of Ophthalmol­ogy ( S. A. C.), and the Departments of Internal and Preventive Medicine ( R. M. M.), University of Iowa School of MedICine, Iowa City, Iowa, U. S. A. Presented at the 37th Annual Meeting of the American Acad­emy of Neurology, April 11, 1987, New York, New York. Address correspondence and repnnt requests to Dr. Kath­leen B. Digre at Department of Ophthalmology, 50 North Med­ical Drive, Salt Lake City, UT 84132, U. S. A. 1 Syphilis has fascinated writers, historians, poli­ticians, and physicians since the 15th century. Consequently, few diseases have a history that is better chronicled. Congenital syphilis has been recognized since 1530, when Parcelsus suggested the disease was an inherited condition. Curtis clas­sified the clinical findings of congenital syphilis as early, late, and stigmata ( 1). Early congenital syph­ilis is acquired in utero, and may be manifested at birth by signs such as snuffles and hepatospleno­megaly. If untreated, it may present with " late manifestations." Late- onset congenital syphilis is found in subjects in whom early congenital syph­ilis was untreated and unrecognized until after the subject was two years of age. The signs of this stage may include stigmata or late manifestations ( interstitial keratitis, sensory neural hearing loss) of congenital syphilis. Stigmata of congenital syph­ilis are remnants of earlier disease ( Table 1). In 1858, Sir Jonathan Hutchinson identified pathog­nomonic stigmata, now known as " Hutchinson's triad": notched incisors, interstitial keratitis, and sensory neural hearing loss. After centuries, the challenge to control and eradicate syphilis continues. In fact, the incidence of congenital syphilis is increasing ( 2,3), despite nationwide prenatal screening programs. Iowa has traditionally had one of the lowest rates of congen­ital syphilis in the United States ( 4). Prompted by the clinical work- up of a man with the stigmata of congenital syphilis, we discovered that little has been written on the diagnosis and treatment of late congenital syphilis since a report issued in 1960 by the U. s. Public Health service ( 5). The retrospective study reported here was un­dertaken in order to determine ( a) the frequency of the diagnosis of congenital syphilis among admis- 2 K. B. DIGRE ET AL. RESULTS TABLE 2. Criteria for congenital syphilis diagnosis in our study Serology consisted of VORL, FTA, Kolmer, and Wasser­man. Signs consisted of interstitial keratitis, Hutchinson's teeth, and/ or sensory neural hearing loss. NA, not available. " Only 4 had negative FTA tests, all others were nonspecific reag In tests. Eighty- eight patients were classified as having congenital syphilis. Nine of these 88 were infants who had been initially diagnosed as early congen­ital syphilitics; the remaining 79 patients were con­sidered late congenital syphilitics from the time of diagnosis. Twenty- four cases were classified as definite congenital syphilis, 44 as probable, and 20 as possible congenital syphilis cases ( Table 2). The majority of cases in this study were Caucasian women ( see Table 3), similar to other studies re­ported in the literature ( 9). However, this finding may be an artifact because the women were rou­tinely screened for syphilis during pregnancy. A family history of syphilis ( i. e., mother was diagnosed with syphilis during pregnancy) was re- + + + + + ++ NA + + + Family Signs history Diagnosis (# cases) Serology Definite ( 24) Infants ( 9) + All others ( 15) + Probable ( 44) ( 41) + ( 3) + Possible ( 20) ( 2) + ( 3)" ( 9)" ( 2) NA ( 4) NA of infants or two clinical signs of the disease ( in­terstitial keratitis, Hutchinson's teeth, sensory neural hearing loss). Probable late- onset congenital syphilis: No family history, but a positive serology and at least two clinical signs. Possible late- onset congenital syphilis: A positive se­rology or at least one clinical sign which could not be explained in any other way. All charts were screened for the patient's age at presentation, the department to which each pre­sented, chief complaint at time of presentation, family history of syphilis, clinical signs of congen­ital syphilis, extent of evaluation, and treatment history. TABLE 1. Signs of congenital syphilis Early ( classic) manifestations snuffles marasmus pot belly withered skin bone defects old man's face hepatosplenomegaly meningitis periostitis Late manifestations" interstitial keratitis sensory- neural deafness neurosyphilis Stigmatab saddle nose frontal bossing short maxilla saber shin scaphoid scapulae rhagades Hutchinson's teeth mulberry molars Higoumenakis's clavicle Glutton's joint MATERIALS AND METHODS A computer- assisted retrospective search of 766,742 hospital charts ( of patients admitted be­tween 1966 and 1986 at the University of Iowa Hos­pitals) was performed for inpatients with the diag­nosis of congenital syphilis. Twelve other patients with documented congenital syphilis seen on an outpatient basis ( only in Ophthalmology) were not included in this review. Although only patients admitted during this 20- year period were included in our report, many patients' records included clin­ical information on this disease from as early as 1916. Although there are criteria for the diagnosis of early congenital syphilis ( 6,7), there are no criteria for the diagnosis of late congenital syphilis in those over 2 years of age. Although some say a definitive diagnosis cannot be made ( 8), all of the patients in our study were diagnosed by a physician as having congenital syphilis. We reviewed patient charts and used the following criteria to substantiate the diagnosis: Late- on; cl ""' s'cnifal syphilis: A family history of syphilis a rId either a positive serology in the case sions to the University of Iowa Hospitals, ( b) the method of diagnosis, and ( c) the type of treatment instituted. We also discuss current guidelines for evaluation and treatment. " Findings at age 2 years or more- a sign of ongoing dis­ease or inflammation. b Sequelae due to earlier infection. I II No. 1. 1991 /----------....... LATE- ONSET CONGENITAL SYPHILIS 3 TABLE 3. Demographic data on patients with congenital syphilis TABLE 5. Clinical presentation of patients with late- onset congenital syphilis TABLE 4. Serology findings in 88 patients Age Finding Infant 1- 20 21- 40 41- 60 61- 80 Total VDRL (+), FTA (+). 8 6 5 11 31 VDRL (-), FTA (+) 0 0 9 9 7 25 VDRL only ( + ) 0 0 1 0 2 3 FTA only (+) 0 0 0 1 1 2 Wasserman ( + ) 1 4 0 0 0 5 Kolmer- Kahn (+) 0 3 0 0 4 VDRL (-), FTA (-) 0 0 1 0 2 3 VDRL only ( - ) 0 0 1 1 4 7b FTAonly(-) 0 0 0 0 1 1 Kolmer- Kahn (-) 0 0 1 0 0 1 No serology 0 1 2 0 3 6 • Includes 8 weakly positive VDRL. b Includes one patient of unknown age. ported in 32 patients in our study group. Blood serology ( VORL, FTA, Kahn, Kline, Wasserman) was positive for 70 of 88 patients. Twelve had neg­ative serology despite clinical manifestations of disease. Serology was either not recorded in charts or was never performed on six patients despite clinical manifestations of disease ( see Table 4). The 20- year prevalence of congenital syphilis for the University of Iowa Hospital was 1.5 per 10,000 admissions. The majority of patients ( 46 of 88 pa­tients [ 52%]) were over age 20 years at diagnosis. Average age at diagnosis was 30.2 years, ranging from birth to 77 years. These patients presented most commonly to Ophthalmology with visual complaints [ 39 of 88 patients ( 44%)] and to other departments less fre­quently ( see Table 5). Although many patients pre- • Includes 9 infant patients. b Includes Surgery, Dermatology, Obstetrics, etc. ( 44%) ( 16%) ( 6%) ( 7%) ( 27%) 39 ( 44%) 16 ( 18%) 10 ( 11%) 6( 7%) 5( 6%) 12 ( 14%) Department patient admitted to: Ophthalmology Pediatrics · ENT Internal Medicine Neurology Otherb Reason for referral: Visual complaint Positive serology Hearing impairment Neurologic problems Other unrelated problems sented with problems related to congenital syphi­lis, 30 of 88 patients ( 34%) presented to the hospi­tal with unrelated problems. Examination of these records for clinical signs and stigmata of late- onset congenital syphilis re­vealed that the most common manifestation was interstitial keratitis ( seen in 61 of 73 patients exam­ined. Other eye manifestations included " ghost vessels" ( 35 of 50 patients examined); and evi­dence of old chorioretinitis ( salt and pepper fun­dus) was seen in 17 of 37 patients examined. Ghost vessels were defined as nonperfused stromal ves­sels indicative of earlier interstitial keratitis. A large number of patients had hearing loss ( 44 of 63). Fewer ( 15 of 43) had abnormal teeth ( Hutchin­son's teeth) and saddle nose deformity ( 15 of 45). Other manifestations were uncommon. These signs and stigmata were not looked for or recorded uniformly by the examining physicians; therefore, all 88 cases are not always represented in the above data. Neurologic examinations were recorded in only about two- thirds of the patients. Neurologic in­volvement included mental retardation ( seen in 13 patients), seizures ( 3), chorea ( 3), tabes dorsalis in 2 patients aged 15- 16 and another aged 58 whose mother was syphilitic ( 3), Argyll- Robertson pupils ( 3), optic atrophy ( 4), schizophrenia ( 2), and cere­bral palsy ( 1). Cerebrospinal fluid ( CSF) was examined in only 53 patients in our study group ( Table 6). A positive CSF serology ( VORL) was found in one infant and four late- onset patients. Of the four late- onset pa­tients with positive serology in the CSF, 2 were aged 16 years old, and 2 were 25 and 36 years old, respectively ( Table 7). Fifteen of the patients with late- onset congenital syphilis had protein greater than 45 mg/ dl and 2 had more than 4 WBC ( see Table 6). 3 39 32 59 8 76 4 9 33 12 14 13 2 5 28 60 Sex Men Women Race Black White Other/ unknown Date of birth 1896-- 1900 1901- 1920 1921- 1940 1941- 1960 1961- 1980 Age at diagnosis Infant Age 1- 18 years Age 19- 30 years Age 31- 50 years Age 51- 70 years Age > 70 years Age unknown JClin Neuro- ophthalmol, Vol. 11, No. 1, 1991 K. B. DIGRE ET AL. 8 pr ,- AS and cells <. 5. b pr > 45 or cells > 5. N, number of patients: CSF. cerebrospinal fluid. Note: Not all patients had CSF values and serology. TABLE 6. CSF Findings VORL Normal Abnormal CSF" CSFb (- ) (+) Infants ( N = 7) 0 6 6 Late- onset ( N = 53) 23 15 20 0 Wasserman (-) (+) o 0 13 4 TABLE 8. Treatment of congenital syphilis 1. Antiquated therapy alone: 6 patients . 2. Antiquated therapy plus meeting or exceeding CDC recommendations of PCN: 10 patients unknown PCN dose/ unknown time: 6 patients 3. Penicillin therapy alone . A. Meets or exceeds CDC requirement: 16 patients B Falls below CDC requirements: 1 patient C: Unknown PCN dose or duration: 8 patients D. Tetracycline therapy ( PCN allergic): 1 patient 4. Infants treated: 7/ 9 adequate (> 50,000 u x 10 days) 1 unknown 1 antiquated therapy 5. None recorded: 31 patients Five patients underwent needle aspiration of the anterior chamber of the eye. Spirochetes were found on dark- field examination in a neonate and in a 51- year- old man with optic atrophy. Twenty- three of the 88 patients received one or more forms of now- antiquated therapy ( i. e., bis­muth, mercury, arsenic, and fever therapy); 10 of the 16 patients who were later treated with peni­cillin ( PON) received a more than a 3- week course of penicillin. Thirty- two other patients received penicillin treatment on diagnosis. Twenty- three patients received the dosage recommended by the Centers for Disease Control ( CDC), or a greater dosage. Thirty- one patients had no record of treat­ment, despite the diagnosis of congenital syphilis. See Table 8 for treatment received. DISCUSSION Prior to 1943, the treatment of syphilis consisted of the administration of mercury, arsenic, and bis­muth preparations. A combination of arsenic and bismuth became the most accepted " heavy metal treatment." Fever therapy, which consisted of in­oculating patients with the Plasmodium vivax ma­larial parasite that subsequently induced high fe­vers, was also a widely used treatment after the mid- 1920s. The induced malaria was then con- TABLE 7. Patients with late congenital syphilis with positive cerebrospinal fluid serology Date of Age at birth diagnosis Sex Clinical findings 1932 15 years F Argyll Robertson pupil, meningovascular 1923 16 years F Mental retardation, chorea. juvenile tabes 1932 25 years M No known CNS manifestations, asymptomatic 1927 36 years F Argyll Robertson pupil, meningovascular CNS, central nervous system. PCN, penicillin; CDC, Centers for Disease Control. trolled with quinine treatment. Julius von Wag­ner- Jauregg received the Nobel Prize in medicine for fever therapy in 1927 ( 10). Although they were welcomed advances in syphilis therapy at that time, these initial treat­ment regimens were poorly tolerated, very time consuming, and often ineffective. Consequently, many patients over 45 years of age who had been treated with these forms of therapy years ago may remain infected today, In his book Congenital Syphilis, Nabarro ( 11) stated, " As regards the incidence of congenital syphilis in older children and adults, my expertise leads to the belief that the incidence is underesti­mated even more than in the infantile form of the disease." Judging from our review of University of Iowa Hospitals admissions from a state with a rel­atively low incidence of syphilis, this appears to be the case. By surveying only hospital admissions, the frequency of late congenital syphilis was prob­ably underestimated. This is a methodologic prob­lem associated with retrospective studies, which in this case emphasizes the intrinsic value of our find­ings. Late congenital syphilis is still present and more common than anticipated in Iowa. Although many of these patients came to Uni­versity of Iowa Hospital for problems directly re­lated to their disease ( interstitial keratitis, hearing loss, or positive serology), about one- third pre­sented with presumably unrelated illnesses. If un­treated and inadequately treated people can be found in Iowa, it seems reasonable to speculate that similar conditions exist in other states. Con­sequently, physicians should be aware that pa­tients with congenital syphilis may present in their clinics with related and/ or unrelated problems. Both VORL and FTA laboratory tests were used to detect evidence of syphilis. VORL identified 34 patients, and FTA identified 58 patients. There were 12 seronegative patients diagnosed by clinical /---------..... LATE- ONSET CONGENITAL SYPHILIS 5 manifestations. This has been previously reported ( 12). It seems clear from reports in the literature that an FTA on patients with suspected late con­genital syphilis gives the highest yield ( 13- 16). What do you do once the diagnosis of late con­genital syphilis is made? Should the work- up be extended, and, in particular, do you perform a CSF examination? The literature recommends spinal fluid examina­tion for every infant with suspected or proven con­genital syphilis ( 6,17). In 1985, Mascola presented data that one half of asymptomatic infants had a positive VORL in the CSF ( 6). Budell found 72% of infants to have abnormal spinal fluid ( 17). There are very few studies of CSF in late congenital syph­ilis ( Table 9). Yet, 7- 36% of the spinal fluid exam­inations performed in three studies demonstrated positive serologies in late congenital syphilitics ( 9,18,19). Furthermore, many CSF exams are not normal since there may be an increased protein or cell count. Furthermore, most authors conclude that many late- onset congenital syphilitics have neurologic involvement ( 5,9,20- 22). In 1964 Curtis stated that neurosyphilis is the second most common mani­festation of late congenital syphilis ( 1). Platou, in 1948, found that of the 39 children aged 2- 13 years who had abnormal spinal fluid examination, 15 ( 38%) had an abnormal neurologic examination ( 18). Because of the previously mentioned concerns, it would seem reasonable that anyone with the signs of congenital syphilis who has not been treated for the illness undergo a neurologic history and examination. A CSF examination should be performed, provided there are no contraindica­tions to the use of the CSF procedure ( 23). Treat­ment can then be tailored to the results ( i. e., if there are increased cells, protein, or a positive VORL, a neurosyphilis regimen should be used; if the CSF is normal, treatment using CDC guide­lines for latent syphilis can be employed). Treatment for congenital syphilis diagnosed in TABLE 9. Cerebrospinal fluid findings in late congenital syphilis Report nl + ( ref. #) N CSF Serology Age Platou ( 18) 109 62" 39 ( 36%) 2- 13 years Laird ( 9) 38 32" 6 ( 16%) 3- 75 years Stechel berg ( 19) 15 13" 1 ( 7%) 12- 54 years This series 53 23b 4 ( 10%) 15- 80 years N, number; nICSF, normal cerebrospinal fluid. " Normal by author's report. b Protein < 45 mg/ dl and < 4 cells. infancy has been defined by the ( CDC) ( 2). The efficacy of treatment of the late disease is less cer­tain ( 24). The only study of efficacy of treatment in late congenital syphilis was done by Platou in 1948 ( 18). He treated 109 children aged 2- 13 years with penicillin in doses ranging from 20,000 to 100,000 units per kg. Twenty children had clinical neuro­syphilis. In follow- up six months later, 14 had sta­ble or decreasing serology. Six had elevated or fluctuating serology titers. Clinical symptoms ei­ther improved or did not change in 18 children; two progressed despite treatment ( 18). Another reason to treat late congenital syphilis is to prevent so- called " third- generation syphilis" ( women with congenital syphilis giving birth to infants with congenital syphilis). Also there is al­ways the problem of the mother being reinfected ( 25). Curtis concluded that third- generation syph­ilis probably can occur ( 1). Laird suggested such women and their children should be examined and treated, if necessary ( 9). Penicillin remains the drug of choice 45 years after it was first recognized as an effective syphilis treatment by John Friend Maheney. The CDC has guidelines for treating neurosyphilis: aqueous crystalline penicillin ( 2.4 x 106 units intravenously every four hours for 10 days), followed by benza­thine penicillin ( 2.4 x 106 units intramuscularly ( 1M) weekly for three weeks) or aqueous procaine penicillin ( 2.4 x 106 units i. m.) plus probenecid 500 mg administered orally four times per day for 10 days, followed by benzathine penicillin G ( 2.4 x 106 units i. m. weekly) for three doses. The blood penicillin level required to kill the treponemes is 0.018 mcg/ mL ( 26). Cerebrospinal fluid levels of this magnitude are reached by a regimen of peni­cillin and probenecid. In patients with late latent syphilis without neurologic involvement and with normal CSF, the CDC has recommended benza­thine penicillin ( 2.4 x 106 units i. m. every week for three successive weeks). The efficacy of these treatment regimens is uncertain. There are reports of patients who were treated with adequate doses of penicillin who still had treponemes in their ce­rebrospinal fluid or had aqueous fluid in the eye ( 12). No treatment was reported for one- third of the patients in this retrospective review. We doubt that this is peculiar to the University of Iowa Hos­pitals. The reasons for this lack of treatment could be ( a) late congenital syphilis was perceived to be a benign disorder; ( b) physicians overlooked the di­agnosis; or, ( c) the patient was treated, but treat­ment was not documented by record, or the pa­tient did not know that he or she had been treated I Clin Neuro- ophthalmo/' Vol. 11, No. 1, 1991 6 K. B. DIGRE ET AL. earlier. Until there is evidence to suggest that peo­ple with late congenital syphilis do not require treatment, the most conservative approach will be to treat. Documentation of treatment is important because there are many reports of " overtreatment" of some cases ( 6,17,27). Late- onset congenital syphilis continues to be a public health threat in this country despite strin­gent prenatal guidelines concerning the disease. This may be due to several factors, including ( a) poor adherence to prenatal guidelines, ( b) medi­cally unsupervised pregnancies and births, ( c) in many states relaxation of laws requiring perinatal screening for this disease. The human immunodeficiency virus ( HIV) crisis further emphasizes the need to recognize and ad­equately treat individuals with late- onset congen­ital syphilis. There is strong evidence that genital ulcer diseases such as syphilis increases the effi­ciency of sexual transmission of HIV ( 28- 31). The rise in syphilis and HIV infections may also con­tribute to a rise in congenital syphilis. Conse­quently, all neonatal HIV- infected patients should be suspected of having congenital syphilis until proven otherwise, and the converse is also true. The public health service has long recognized that syphilis control is dependent on a combina­tion of factors, including a high index of suspicion, clinical acumen, appropriate serological screening tests, diagnosis, treatment, case reporting, and ep­idemiology. The identification of 88 cases where 62% received either no treatment, inadequate treatment, or unrecorded treatment confirms the need for strict adherence to the established guide­lines for syphilis control. Acknowledgment: This report was supported in part by an unrestricted grant to the Department of Ophthal­mology at the University of Utah School of Medicine from Research to Prevent Blindness, Inc., New York. The authors thank Steven M. Thiese for his assistance and advice in the preparation of this report. REFERENCES 1. Curtis AC, Philpott OS. Prenatal syphilis. Med Clin N Am 1964; 48: 707- 19. 2. Centers for Disease Control. Continuing increase in infec­tious syphilis in the United States. MMWR 1988; 37: 35- 8. 3. Centers for Disease Control. Syphilis and congenital syph­ilis- United States 198>- 1988. lAMA 1988; 260( 11): 1533- 4. 4. Centers for Disease Control. Congenital syphilis. MMWR 1986; 34: 945- 955. 5. U. S. Public Health Service. Syphilis: modern diagnosis and treatment. Washington: U. S. Government Printing Office, 1960: 37~. hil' 6. Mascola L, Pelosi R, Blount JH, et al. Congenital syp IS revisited. Am I Dis Child 1985; 139: L575- 80. . 7. Centers for Disease Control. Guidelines for the prevention and control of congenital syphilis. MMWR 1988; 37( suppl S- I). 8. Zoeller M, Wilson WR, Nadol JB. Treatment of syphilitic hearing loss. Combined penicillin and steroid therapy in 29 patients. Ann Otol Rhinol LaryngoI1979; 88: 160- 5.. 9. Laird SM. Late congenital syphilis. An analySIS of 115 cases. Br I Vener Dis 1950; 26: 143- 5. 10. Dennie Cc. A History of syphilis. Springfield, lIlinois: Charles C. Thomas, 1962: 106-- 26. 11. Nabarro D. Congenital syphilis. London: Edward Arnold Ltd., 1954: 40. 12. Smith JL. Spirochetes in late seronegative syphilis, penicillin not­withstanding. Springfield: Charles C. Thomas, 1969: 252~ 0. 13. Hart G. Syphilis tests in diagnostic and therapeutic decision making. Ann lnt Med 1986; 104: 368-- 76. 14. Hughes GB, Rutherford I. Predictive value of serologic tests for syphilis in otology. Ann Otol Rhinol lAryngol 1986; 95: 250- 9. 15. Jaffe HW. The laboratory diagnosis of syphilis. New con­cepts. Ann Int Med 1975; 83:~ 50. 16. Sparling PF. Diagnosis and treatment of syphilis. N Engl I Med 1971; 284: 642- 51. 17. Budell JW. Treatment of congenital syphilis. I Am VD Assn 1976; 3: 168-- 71. 18. Platou RV, Kometani JT. Penicillin therapy of late congen­ital syphiliS. Pediatrics 1948; 1: 606-- 16. 19. Steckelberg JM, McDonald D. Otologic involvement in late syphilis. lAryngoscope 1984; 94: 753- 7. 20. Dennie CC, Pakula SF. Congenital syphilis. Philadelphia: Lea and Febiger, 1940: 426-- 9. 21. Dennie Cc. Congenital neurosyphilis. In Moulton FR, ed. Syphilis. Lancaster: The Science Press, 1938; 111- 7. 22. Robinson RCV. Congenital syphilis. Arch Derm 1969; 99: 599~ 1O. 23. Jaffe HW, Kabins SA. Examination of cerebrospinal fluid in patients with syphilis. Rev Infect Dis 1982; 4: 5842- 5847. 24. Clark EG, Danbolt N. The Oslo study of the natural history of unrelated syphilis: an epidemiologic investigation based on a restudy of the Boeck- Bruusgaard material. I Chronic Dis 1955; 2: 311- 44. 25. Fiumara NJ. Acquired syphilis in three patients with con­genital syphilis. N Engl I Med 1974; 290: 1119-- 20. 26. Dunlop EMC, A1- Egaily 55, Houang ET. Penicillin levels of blood and CSF achieved by treatment of syphilis. lAMA 1979; 241 : 2538- 40. 27. Brown Wj, Moore MB. Congenital syphiliS in the United States. Clin Pediatr 1963; 2: 220- 2. 28. Cameron DW, D'Costa LJ, Ndinya- Achola JO, et aI. Inci­dence and risk factors for female to male transmission of HIV [ Abstract}. IV International Conference on AIDS, Book 1. Stockholm, June 12- 16, 1988: 275. 29. Plummer F, Cameron W, Simonsen N, et al. Cofactors in male- female transmission of HIV ( Abstract). IV International Conference on AIDS, Book 2. Stockholm, June 12- 16, 1988: 200. 30. Simonsen IN, Cameron W, Gakinya MN, et aJ. Human immunodeficiency virus infection among men with sexu­ally transmitted diseases: experience from a center in Af­rica. N Engl I Med 1988; 319: 274- 278. 31. Holmber& SD, Stewart JA~ Gerber AR, et aI. Prior herpes sunples VlfUS type 2 mfection as a risk factor for HIV infec­tion. lAMA 1988; 259: 1048- 50. /--------....--.....