SEMINARS I N NEUROLOGY-VOLUME

12, NO. 1 MARCH 1992

Syphilis and Human Immunodeficiency Virus Infection

In 1987 Berry and coworkers1 and Johns and coworkers2 published case reports that suggested that patients infected with both human immunodeficiency virus (HIV) and syphilis were more likely to develop neurosyphilis. Since then, accumulating data (mostly in the form of case reports) further support the contention that the clinical course of syphilis is altered in HIV-infected patients. These reports describe increased frequency of syphilitic ocular and neurologic disease, increased rate of treatment failure for early syphilis, and aberrant responses in serologic tests for syphilis. In this review, the clinical course of syphilis in HIV-infected patients will be compared to that described in the preantibiotic era in immunologically normal individuals, and recommendations will be made for diagnosis and treatment of neurosyphilis in patients infected with HIV.

lidum could be isolated from CSF in 10 to 15% of patients with early syphilis.' These findings were recently confirmed and expanded upon by Lukehart and coworker^,^ who showed that 16 (41%) of 39 patients with untreated primary and secondary syphilis had CSF pleocytosis (defined as more than 5 white blood cells [WBC] per p1) and 8 (24%) of 33 patients with secondary but none of seven patients with primary syphilis had reactive CSFVDRL tests. In this study, T. pallidum was recovered from 12 (30%) of 40 CSF samples, one third of which were otherwise normal. CSF abnormalities in early syphilis resolve in the majority of cases, even without therapy? However, about one fourth of untreated patients have persistent CSF abnormalities many years after initial infection, and about 20% of these develop symptomatic neurosyphilis.1° The prognostic value of CSF abnormalities in syphilis was demonstrated by Moore and Hopkins," who followed 123 individuals with CSF abnormalities due to syphilis for CENTRAL NERVOUS SYSTEM INVASION an average of 7 years; 55 patients had early syphilis and 68 had late syphilis. Nineteen patients (seven THE ZMMUNOCOMPETENT HOST with early and 12 with late) developed clinically defInvasion of the central nervous system (CNS) inite neurosyphilis. Those patients with the most abby Treponema pallidum, the bacterium responsi- normal CSF were the most likely to develop sympble for syphilis, occurs early in the course of in- tomatic disease. Similarly, Hahn and coworkers"' fection. Several studies from the first half of this demonstrated that the likelihood of progression to century showed that cerebrospinal fluid (CSF) ab- symptomatic neurosyphilis in individuals with CSF normalities such as pleocytosis, elevated protein, abnormalities was five times greater in those in and reactive CSF Wassermann tests (similar to non- whom CSF was unchanged or worse on repeat extreponemal tests such as the VDRL test used today) amination, compared with those in whom CSF bewere seen in 10 to 20% of patients with pri- came normal or improved. mary"-4and 30 to 70% with secondary syphilis.4-" Conversely, a normal CSF examination in CSF abnormalities were more common in seropos- early syphilis suggests that symptomatic neuroitive primary than in seronegative primary syphilis, syphilis will not develop. Moore and Kempl2 and and reactive CSF nontreponemal tests were more HopkinsIs showed that development of clinically common with increasing duration of i n f e ~ t i o n . ~definite CNS syphilis was uncommon in individuEven in the absence of CSF abnormalities, T. pal- als who had normal CSF parameters in early syph-

Acting Instructor, Neurology, University of Washington, Seattle, Washington Address correspondence to: Dr. Marra, Department of Neurology, Harborview Medical Center, ZA95, 325 9th Avenue, Seattle, WA 98104-2499 Copyright O 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.

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Christina M. Marra, M.D.

SEMINARS IN NEUROLOGY

THE HUMAN IMMUNODEFICIENCY VIRUS-INFECTED HOST CNS invasion by T. pallidum does not appear to be significantly more common in HIV-infected patients than in those not infected with HIV. In the study by Lukehart and coworker^,^ reactive CSFVDRL, elevated CSF protein concentration, and isolation of T. pallidum from CSF occurred with equal likelihood in 15 HIV-infected and 25 HIVuninfected patients with untreated primary and secondary syphilis. CSF WBC count greater than 5Ip1 was seen in 10 (67%) of the HIV-infected, and in only 6 (25%, p = 0.02) of the HIV-uninfected patients. Mild CSF pleocytosis has been described in asymptomatic HIV-infected individuals without syphilis and is probably due to CNS infection with ~1v.l~

FORMS OF NEUROSYPHILIS THE ZMMUNOCOMPETENT HOST

Neurosyphilis has been traditionally categorized into discrete syndromes, each occurring at a typical time after primary infection. These include asymptomatic neurosyphilis, meningitis, meningovasculitis, tabes dorsalis, and general paresis (Table 1). In reality, the various manifestations of neurosyphilis can occur at any time after primary infection, although meningeal and meningovascular disease tend to occur months to years after infection (early neurosyphilis), and paresis and tabes tend to occur after decades (late neurosyphilis). Thus, neurosyphilis cannot be simply classified as a manifestation of tertiary syphilis as is generally assumed, but includes syndromes that span all stages of syphilis (Fig. 1).

Table 1. Classification Scheme for Neurosyphilis

44

Meningeal Asymptomatic Symptomatic Meningitis Cranial neuritis Gumma Meningovasculitis Meningeal and parenchymal General paresis Tabes dorsalis

MARCH 1992

Asymptomatic Neurosyphilis Syphilis patients without clinical signs or symptoms of neurologic involvement but with abnormal CSF have asymptomatic neurosyphilis. As discussed earlier, CSF abnormalities can be seen at any time after infection. With increasing time after infection, the proportion of patients with asymptomatic neurosyphilis declines as these patients progress to develop symptomatic neurosyphilis (Fig. 2).

Meningeal and Meningovascular Syphilis Meningeal syphilis may be symptomatic, with headache, confusion, nausea and vomiting, and stiff neck. It may involve cranial nerves (especially 11, VII, and VIII), or, rarely, spinal roots. Meningitis may be associated with arteritis of small, medium, or large vessels, producing ischemia or infarction of brain or spinal cord; the combination is termed meningovascular syphilis. Focal meningeal inflammation may lead to formation of hypertrophic meningitis or to gummata. Seizures may occur as a result of cortical irritation by meningitis, stroke, or gumma. The largest series of cases of symptomatic meningitis was reported by Merritt and Moore15 and the largest series of meningovascular syphilis by Merritt and coworkers.16 These authors found that syphilitic meningitis and meningovasculitis were uncommon, occurring in 0.5 and 3% of all syphilis patients, respectively. Most cases of symptomatic meningitis occurred within a year after primary infection, and in 7.5% the secondary rash was still present. Meningovascular disease occurred an average of 7 years after primary infection.

General Paresis Paretic neurosyphilis, also called general paresis of the insane or dementia paralytica, is a chronic, progressive, dementing illness that is said to mimic "every type of mental disorder."16 This neurologic manifestation was estimated by Merritt et a1 to develop in 5% of cases of untreated syphilis, and most commonly occurred 10 to 30 years after primary infection.

Tabes Dorsalis The most common symptoms of tabes dorsalis, or locomotor ataxia, are lancinating pains,

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ilis and occurred only in patients who had evidence of relapse or reinfection. Thus, identification of individuals with CSF abnormalities in early syphilis also identifies the population at risk for development of symptomatic neurosyphilis.

VOLUME 12, NUMBER I

SYPHILIS AND HIV INFECTION-MARRA

/

-

- ! + - - - - -

Secondary

-----

Meningitis Meningovascular Syphilis General Paresis Tabes Dorsalis

t 0

1

2

3 4 Months

1

5

5

10 15 2 0 2 5 + Years

Figure 1. Time course of clinical manifestations of syphilis. The various manifestations of neurosyphilis can occur at any time after primary infection. Meningeal and meningovascular disease tend to occur early in the course of disease and may be seen in patients with symptomatic primary and secondary syphilis. Paresis and tabes tend to occur later after infection. Modified from Hook EW Ill, Marra CM. Acquired syphilis in adults. N Engl J Med 1992: 326(16). Reproduced with permission.

As noted, paresis and tabes dorsalis were the most commonly observed forms of neurosyphilis in the prepenicillin era, and meningitis and meningovasculitis were less common. Several authors noted that the early forms of neurosyphilis were more often seen in patients who had been inadequately treated for primary or secondary syphilis than in untreated patients.6.15.17 Similarly, syphilitic uveitis was twice as common in individuals inadequately treated for secondary syphilis as in those

sensory changes, progressive ataxia, and bowel and bladder dysfunction. Pupillary abnormalities are the rule and optic atrophy is common. Tabes, the most common form of neurosyphilis described in the preantibiotic era, was seen in 9% of patients with syphilis evaluated by Merritt and coworkers.16 This form of neurosyphilis has the longest latent period between primary infection and onset of symptoms, ranging from 3 to 47 years, with an average of 2 1 years.

Asymptomatic Neurosyphilis ..

Paresis

0

1

2

3

Months

4

5

1

5

10 15 Years

2025+

Figure 2. Time course of development of neurosyphilis. Cerebrospinal fluid (CSF) abnormalities are common in early syphilis. Although the CSF becomes normal in most patients, about 25% have persistent asymptomatic neurosyphilis. A proportion of these patients subsequently develop symptomatic neurosyphilis. Patients with asymptomatic neurosyphilis should be treated to prevent this progression.

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Primary

SEMINARS I N NEUROLOGY

who were not treated and was more likely to be associated with meningitis.ls These authors postulated that partial therapy cleared most organisms from peripheral sites of infection and that the normal immune response was thereby attenuated. However, this therapy was not sufficient to eradicate organisms sequestered in the eye and the CNS. In the absence of an effective immune response, organisms were then free to multiply and cause ocular and neurologic disease.

common than late neurosyphilis in patients with HIV infection, and concomitant ocular disease is a frequent manifestation. Moreover, even though the incidence of clinically evident CNS involvement cannot be calculated without knowing the number of all HIV-infected patients with syphilis, the frequency of these cases makes it likely that early neurosyphilis is more common in the presence of HIV infection.

THE HUMAN IMMUNODEFICIENCY VIRUS-INFECTED HOST

NEUROSYPHILIS AFTER PENICILLIN THERAPY FOR EARLY SYPHILIS

Table 2.

Neurosyphilis in 40 HIV-Infected Patients*

Asymptomatic neurosyphilis Acute syphilitic meningitis Presenting as meningitis Presenting with cranial nerve dysfunction Presenting with polyradiculopathy Meningovascular syphilis General paresis 'Modified from Musher et allg with permission.

5

9 13 1 11 1

THE IMMUNOCOMPETENT HOST

Since its introduction in the 1940s, penicillin has been the mainstay of treatment for all forms of syphilis. Currently recommended therapy for early syphilis, intramuscular benzathine penicillin G,2' fails to achieve consistently treponemicidal penicillin levels in the CSF,*%nd persistence of viable T. pallidum in CSF following treatment has been deHowever, despite these limitations, the use of benzathine penicillin G therapy for early In the presyphilis has been 95% succes~ful.*~ AIDS era, serologic relapse, not neurologic or ocular relapse, was the most common manifestation of treatment failure. The success of intramuscular benzathine penicillin G therapy for early syphilis has likely been due to the combination of modestly effective therapy and an intact immune system that act together to clear and control organisms in the CNS and eye as well as from less immunologically privileged sites of infection. THE HUMAN IMMUNODEFICIENCY VIRUS-INFECTED HOST

Intramuscular benzathine penicillin G therapy for early syphilis appears to fail more frequently in HIV-infected patients than in those without HIV infection. In the series of 40 patients compiled by Musher and coworkers,l"6 HIV-infected individuals had been treated for syphilis prior to diagnosis of neurosyphilis; five of these developed neurosyphilis within 6 months after therapy. Similarly, three of the nine cases described by McLeish and coworkers2" received intramuscular benzathine penicillin G prior to development of neurologic or ocular syphilis, as did three of the 12 patients described by Katz and Berger.*' These case reports support not only the contention that HIV-infected patients are more likely to develop syphilitic meningitis and meningovasculitis, often with concomitant ocular disease, but also the contention that the rate of treatment failure is increased in HIV-infected persons with early syphilis. Data from animal models of primary

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In the past decade, several case reports have suggested that the clinical course of syphilis and response to antibiotic therapy are altered in patients also infected with HIV. The largest number of these reports describe development of early neurosyphilis (asymptomatic or symptomatic meningitis and vasculitis) and ocular syphilis, previously uncommon manifestations of syphilis. Several of these patients had been previously treated with recommended antibiotic regimens for early syphilis. Musher and coworkerslg summarized 40 reported cases of neurosyphilis in persons also infected with HIV (Table 2). Thirty-nine patients had early neurosyphilis (34 symptomatic meningitis or meningovasculitis and five asymptomatic neurosyphilis) and one patient had late neurosyphilis (tabes). McLeish and coworkers2" described nine cases of syphilitic eye disease in patients with HIV infection, most commonly uveitis and optic neuritis or retinitis, and combined their data with similar case reports to find that 79% of HIV-infected persons with ocular syphilis also had syphilitic meningitis. Katz and Berger" retrospectively identified 12 patients with neurosyphilis and AIDS; five (42%) had concomitant ocular involvement. It is difficult to draw conclusions from these case reports. Bias toward reporting unusual manifestations of syphilis in patients with HIV infection cannot be excluded and, because denominator data are not available, the rate of development of unusual manifestations of syphilis in HIV-infected patients is not known. Nonetheless, these case reports are in striking contrast to historical data in two respects. Early neurosyphilis is much more

46

VOLUME 12. N U M B E R 1 MARCH 1992

syphilis demonstrate the importance of intact cel- microhemagglutination test for T. pallidum (MHAlular immunity in controlling syphilis infection. TP), and the T. pallidum hemagglutination assay Immunosuppression of rabbits with cortisone de- (TPHA) remain reactive and are therefore reliable creases local cellular infiltration and significantly indicators of past infection with T. p a l l i d ~ m . ~ ' delays T. pallidum clearance from skin le~ions,'~ However, recent data suggest that after therapy for and HIV-infected rabbits show larger and more primary syphilis the FTA-ABS test may revert to prolonged cutaneous syphilitic lesions.27 Unusual negative in 24% and the MHA-TP in 13% of pae apply only to treated indior more severe cutaneous manifestations of sec- t i e n t ~ . : ~ q h e sfigures ondary syphilis as well as delayed healing of skin viduals; there are no data suggesting that these lesions after therapy have been occasionally de- tests revert to negative in untreated disease. scribed in HIV-infected humans,28-"' supporting the idea that, as in the animal models, clearance of Cerebrospinal Fluid T. pallidum from cutaneous sites is impaired. Similarly, the alterations in cell-mediated immunity Mild CSF mononuclear pleocytosis, usually in caused by HIV are likely to impair the ability of the host to control CNS or ocular infection. Given the the range of 10 to 400 cellslpl, is characteristic of failure of intramuscular benzathine penicillin G to neurosyphilis; higher cell counts are seen in the achieve treponemicidal penicillin levels in the CSF, early forms. Mild elevations in CSF protein, rangpatients treated with this regimen may potentially ing between 45 and 200 mgll are also common, have persistent T. pallidum in the CNS and the again with higher values in early compared with eye. Patients infected with both T. pallidum and late neurosyphilis. Depending on the diagnostic HIV can be compared to patients in the preanti- criteria chosen, the CSF-VDRL may be reactive in biotic era who received inadequate therapy for 0 to 100% of individuals with neurosyphilis; the early syphilis. Because of impaired immune func- generally accepted sensitivity is 30 to 7096." The tion, both groups are less able to control organisms CSF-VDRL test is very specific; false-positive resequestered in the CNS and in the eye than are sults may be obtained when the CSF is visibly those who are adequately treated or HIV-unin- blood-tinged,94," or, very rarely, in the absence of fected and are therefore at increased risk for ocu- blood ~ o n t a m i n a t i o n . ~ ~ V h uas ,reactive CSFVDRL confirms neurosyphilis, but a nonreactive lar and neurologic disease. Data from the prospective study by Lukehart test does not exclude it. Although some inv.estigaand coworkers8 support the contention that HIV- tors have shown that quantitative measures of aninfected individuals are less able to clear or control titreponemal antibody content in the CSF (for exT. pallidum in the CNS. Seven patients with T. pal- ample, the TPHA index) can be used to diagnose the use of this and other treponelidum isolated from CSF before therapy for sec- neur~syphilis,"~ ma1 serologic tests on CSF is not uniformly ondary syphilis had repeat CSF examinations after completion of therapy. Four of the seven patients accepted. received a single dose of 2.4 million units of benTHE HUMAN IMMUNODEFICIENCY zathine penicillin. Three of the four required reVZRUS-INFECTED HOST treatment for neurosyphilis because of persistence of T. pallidum in CSF of two, and worsening of There have been a few reports of HIV-inCSF parameters in one. T h e one patient cured by fected patients with well-documented secondary or a single dose of benzathine penicillin was the only ocular syphilis but negative serum nontreponemal one of the four who was not infected with HIV. tests, treponemal tests, or b ~ t h . ~ ~ ' . ' ~ . ~ ~ " .of "Wost these patients had advanced HIV-related illness. Two studies have shown that treponemal tests are more likely to revert to nonreactive after syphilis DIAGNOSIS OF NEUROSYPHILIS therapy in patients with AIDS.40.41Conversely, a THE ZMMUNOCOMPETENT HOST study of 341 patients with syphilis found that those with HIV and secondary syphilis had higher serum rapid plasma reagin (RPR) titers than those without HIV;42these individuals had relatively early Serum HIV-related disease (Hook EW 111: personal comIt is commonly taught that although the se- munication). These differing observations are rum VDRL test may be negative in up to 25% of likely explained by the underlying immune status patients with late syphilis and neurosyphilis, spe- of the host. Studies in HIV-infected individuals cific treponemal tests such as the fluorescent trep- document impaired antibody responses to new or onemal antibody-absorbed (FTA-ABS) test, the to previously encountered antigens such as 47

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SYPHILIS AND HIV INFECTION-MARRA

SEMINARS IN NEURO1,OGY

liminary data show a 25% failure rate of this ceftriaxone regimen for asymptomatic neurosyphilis."'None of the nonpenicillin regimens has been sufficiently studied to recommend its routine use. Until more data are available on nonpenicillin regimens, all patients with neurosyphilis should be treated with penicillin; individuals with a history of penicillin allergy should be skin tested and desensitized if necessary. MONITORING TREATMENT RESPONSE

Serum

The serum VDRL titer should fall after therapy, but may not reflect activity of neurosyphilis; worsening of CSF parameters may occur despite stable or decreasing serum nontreponemal tit e r ~ . ~ The , " rate of serum nontreponekal titer deTHERAPY cline after treatment for neurosv~hilis has not ,n been investigated. Romanowski and coworkers32 Patients with all forms of CNS syphilis should be treated with a regimen adequate for neurosyph- examined the serologic response to currently recilis. Patients with CSF abnormalities alone (asymp- ommended therapy for first-episode early syphilis. tomatic neurosyphilis) compose the population at These workers showed that successful treatment risk for symptomatic disease and should be treated for primary and secondary syphilis resulted in a fourfold decline in serum RPR titer at 6 months to prevent its development. and an eightfold decline by 12 months after therapy and that a fourfold decline in titer at 12 and ANTIBIOTIC REGIMENS 24 months was seen in patients successfully treated The Centers for Disease Control recommend for early latent syphilis. In all groups, titers fell intravenous aqueous penicillin G, 2 to 4 million U more slowly in individuals with previous syphilis. A every 4 hours for 10 to 14 days, or daily intramus- recent study has demonstrated that HIV-infected cular procaine penicillin, 2.4 million U with pro- patients treated for primary and secondary syphilis benecid, 500 mg by mouth four times daily, both may also show slower declines in serum RPR titers with HIV-uninfected patients, even af~ for 10 to 14 days, for treatment of n e ~ r o s y p h i l i s . ~compared In contrast to previous reports, a recent study sug- ter controlling for previous syphili~.~' By analogy, neurosyphilis patients with early gests that the latter therapy may not reliably disease, those without previous syphilis, and those achieve treponemicidal penicillin levels within the who are HIV-uninfected should show a more rapid CSF.45However, well-documented instances of faildecline in serum nontreponemal titers than those ure of the intramuscular procaine penicillin with with late neurosyphilis. However, an expected rate oral probenecid regimen have not been reported. of decline is not known. As is recommended for The efficacy of current therapy for neuroHIV-infected patients without neurosyphilis, HIVsyphilis has not been systematically investigated. In infected patients with neurosyphilis should have the late 1940s through the early 1960s, various serum nontreponemal titers followed monthly for forms of intramuscular penicillin, most ranging in 3 months after therapy and every 3 to 6 the first dosage from 2 to 9 million Ulday, were evaluated months thereafter until the CSF is normal. in patients with symptomatic and asymptomatic neurosyphilis. Based on clinical and laboratory criteria, 10 to 20% of patients failed therapy, and, Cerebrospinal Fluid over the ensuing years, progressively higher doses of penicillin were deemed "adequate" for therapy No data are available on the rate of CSF nor. ~ ~recent years several nonpenof n e u r ~ s y p h i l i s In icillin therapies for neurosyphilis have been sug- malization after currently accepted therapy for gested, including 6 gm of oral amoxicillin with pro- neurosyphilis. After treatment with lower-dose inbenecid daily,47400 mg of oral doxycycline daily,48 tramuscular regimens, CSF WBC count usually reor 1.0 gm intramuscular ceftriaxone daily.4Y,50 Pre- turned to normal quickly, whereas CSF-VDRL and

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influenza4:' and p o l i o ~ i r u svaccines; ~~ the most impaired responses are seen in patients with advanced HIV-related illness. Thus, diagnosis of neurosyphilis in patients with significant HIV-related immunosuppression may be especially difficult. These individuals may fail to develop appropriate serologic responses to infection. Treponemal serologic tests, commonly used to identify patients at risk for neurosyphilis (because nontreponemal tests may be nonreactive in late disease), also may not be reliable indicators of previous syphilis infection. Similarly, HIV-infected patients without syphilis infection may have CSF pleocytosis, elevated CSF protein, and high CSF gamma globulin levels that may be impossible to distinguish from changes due to neurosyphilis.

VOLUME 12, NUMBER 1 MARCH 1992

SYPHILIS AND H I V INFECTION-MARRA

elevated protein could take years to become normal." A reasonable rule is that failure of the CSF WBC count to become normal by 6 months after therapy is an indication for retreatment. Since CSF protein and VDRL titer may decline much more slowly, therapy cannot be considered inadequate unless these parameters unequivocally increase. CSF examinations should be repeated at 6-month intervals after therapy until the formula is normal.

rosyphilis and even an appropriate decline in serum nontreponemal titer does not exclude the possibility of neurosyphilis. Those individuals with CSF pleocytosis or a reactive CSF-VDRL are assumed to have asymptomatic neurosyphilis and should be treated with a penicillin regimen recommended for neurosyphilis to prevent development of symptomatic disease. HIV-infected patients with syphilis but normal CSF can be treated with the appropriate dose of intramuscular benzathine penicillin G.

CONCLUSIONS AND RECOMMENDATIONS

REFERENCES Berry CD, Hooton T M , Collier AC, Lukehart SA. Neurologic relapse after benzathine penicillin therapy fbr secondary syphilis in a patient with H I V infection. N Engl .J Med 1987;316: 1587-9 Johns DR, Tierney M, Felsenstein D. Alteration in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus. N Engl J Med 3987;316:1569-72 Wile UJ, Hasley CK. Involvement of nervous system d u r ing primary stage of syphilis. Continued study. JAMA 1921;76:8-9 Mills CH. Routine examination of the cerebrospinal fluid in syphilis: its value in regard to more accurate knowledge, prognosis and treatment. Br Med J 1927;2: 527-32 Ravaut P. Le liquide cephalo-rachidien des syphilitiques eri periode secondaire. Ann Dermatol Syphiligr 1903; 4:537-54 Wile U J , Stokes J H . A study of the spinal fluid < ~ t hreference to involvement o f t h e nervous system in secondary syphilis. J Cutan Dis 1914;32:607-23 Chesney AM, Kemp JE. Incidence of Spirochaela pallida in cerebrospinal fluid during early stage of s'yphilis. JAMA 1924;83: 1725-28 ~ u k e h a r SA, t Hook EW 111, Baker-Zander SA, et al. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis a n d therapy. Ann Intern Med 1988; 109:855-62 Stokes J H , Beerman H, lngraham NR. Modern clinical syphilology. Diagnosis, treatment, case study. Philadelphia: WB Saunders, 1944:971 Hahn RD, Clark EG, Felsovanyi A, et al. Asymptomatic neurosyphilis: prognosis. Am J Syph Gonorrhea Vener Dis 1946;30:513-48 Moore J E , Hopkins H H . Asymptomatic neurosyphilis V1. T h e prognosis of early and late asymptomatic neurosyphilis. JAMA 1930;95: 1637-41 Moore JE, Kemp JE. T h e treatment of early syphilis 11. Clinical results in 402 patients. Bull J o h n Hopkins Hosp 1926;39: 16-35 Hopkins H H . Prognostic import of a negative spinal fluid in early a n d in latent syphilis. Arch Derm Syphilol 193 1;24:404-8 Appleman ME, Marshall DW, Brey RL, et al. Cerebrospinal fluid abnormalities in patients without AIDS who are seropositive for the human immunodeficiency virus. J Infect Dis 1988; 158: 193-9 Merritt H H , Moore M. Acute syphilitic meningitis. Medicine (Baltimore) 1935: 14: 119-83 Merritt H H , Adams RD, Solomon HC. Neurosyphilis. New York: Oxford, 1946 Moore JE. Studies in asymptomatic neurosyphilis 11. T h e classification, treatment, a n d prognosis of early asymp-

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T. pallidum invades the CNS early in the course of infection but neurologic and ocular syphilis do not commonly develop in immunocompetent patients. However, available data indicate that even though CNS invasion is not more likely, patients infected with both syphilis and HIV more often develop syphilitic meningitis, meningovasculitis, and ocular syphilis, even after therapy with intramuscular benzathine penicillin G for early syphilis. HIV-infected patients may be at increased risk for neurologic and ocular disease because the immunologic defects caused by HIV impair their ability to clear or control T. pallidum from the CNS and the eye. Ideally, these patients should be identified and treated before they develop symptomatic disease. A dilemma arises in choosing the criteria for this treatment. Serum nontreponemal tests may be nonreactive in up to 25% of individuals with late or neurosyphilis; this may be more common in patients with advanced HIV-related illness and AIDS. Similarly, serum treponemal tests may become nonreactive after treatment for early syphilis in immunocompetent individuals but more commonly in patients infected with HIV, especially those with AIDS. However, it is not known whether this is the case in untreated or active syphilis. Finally, CSF abnormalities such as pleocytosis, elevated total protein, and immunoglobulin G concentrations are seen in patients with neurosyphilis and in HIV-infected patients without syphilis. Thus, the questions arise: how should we screen and whom should we treat? All HIV-infected patients should have serum nontreponemal and treponemal tests performed as early in the course of HIV infection as possible to minimize the chance of a falsely negative result. All HIV-infected patients with current syphilis should undergo CSF examination. Additionally, HIV-infected patients who were treated for early or late syphilis but did not have a CSF evaluation prior to therapy should be considered for CSF evaluation, since these individuals are at higher risk for neu-

18. 19.

20.

21. 22. 23. 24. 25. 26.

27.

28. 29.

30.

31. 32. 33. 34. 35. 36.

tomatic neurosyphilis. Bull Johns Hopkins Hosp 1922; 33:23 1-46 Moore JE. Syphilitic iritis. A study of 249 patients. Am J Ophthalmol 193 1; 14: 1 10-26 Musher DM, Hamill RJ, Baughn RE. Effect of human immunodeficiency virus (HIV) infection o n the course of syphilis a n d o n the response to treatment. Ann Intern Med 1990; 1 13:872-8 1 McLeish WM, Pulido JS, Holland S, et al. T h e ocular manifestations of syphilis in the human immunodeficiency virus type I-infected host. Ophthalomology 1990;97: 196-203 Katz DA, Berger JR. Neurosyphilis in acquired immunodeficiency syndrome. Arch Neurol 1989;45:895-8 Centers for Disease Control. Sexually transmitted diseases treatment guidelines. MMWR 1989;38: 1-13 Mohr JA, Griffiths W, Jackson R, et al. Neurosyphilis a n d penicillin levels in cerebrospinal fluid. JAMA 1976; 236:2208-9 Tramont EC. Persistence of Treponema pallidurn following penicillin G therapy. JAMA 1976;236:2206-7 Schroeter AL, Lucas JB, Price EV, Falcone VH. Treatment for early syphilis a n d reactivity of serologic tests. JAMA 1972;221:471-6 Lukehart SA, Baker-Zander SA, Lloyd RMC, Sell S. Effect of cortisone administration o n host-parasite relationshipsinearly experimentalsyphilis.J Immunol198 1; 127:1361-8 Tseng CK, Hughes MA, Hsu P-L, et al. Syphilis superinfection activates expression of human immunodeficiency virus 1 in latently infected rabbits. Am J Pathol 1991;138:1149-64 Gregory N, Sanchez M, Buchness MR. T h e spectrum of syphilis in patients with human immunodeficiency virus infection. J Am Acad Dermatol 1990;22:1061-7 Radolf JD, Kaplan RP. Unusual manifestations of secondary syphilis and abnormal humoral immune response to Treponema pallidurn antigens in a homosexual man with asymptomatic human immunodeficiency virus infection. J Am Acad Dermatol 1988;18:423-8 Frederick WR, Delapenha R, Barnes S, et al. Secondary syphilis a n d H I V infection. (Abstr.) Abstracts of the 28th lnterscience Conference Antimicrobial Agents Chemotherapy. Washington DC: American Society for Microbiology, 1988:320 Deacon WE, Lucas JB, Price EV. Fluorescent treponema1 antibody-absorption (FTA-ABS) test for syphilis. JAMA 1966; 198:624-8 Romanowski B, Sutherland R, Fick G H , et al. Serologic response to treatment of infectious syphilis. Ann Intern Med 1991;114:1005-9 H a r t G. Syphilis tests in diagnostic and therapeutic decision making. Ann Intern Med 1986;104:368-76 lzzat NN, Bartruff JK, Glicksman JM, et al. Validity of the VDRL test o n cerebrospinal fluid contaminated by blood. Br J Vener Dis 197 1;47: 162-4 Davis LE, Sperry S. T h e CSF-FTA test a n d the significance of blood contamination. Ann Neurol 1979;6: 68-9 Madiedo G, H o K-C, Walsh P. False-positive VDRL a n d FTA in cerebrospinal fluid. JAMA 1980;244:688-9

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MARCH 1992

37. Luger A, Schmidt BL, Steyrer, Schonwald E. Diagnosis of neurosyphilis by examination of the cerebrospinal fluid. Br J Vener Dis 1981;57:232-7 38. Hicks CB. Benson PM., Luoton GP. Tramont EC. Sero, negativ; secondary syphilis in a patient infected with the human immun~deficiencyvirus (HIV) with Kaposi sarcoma. A diagnostic dilemma. Ann l n t e r n ~ e d 1987; 107:492-5 39. Tikjob G, Russel M, Petersen CS, et al. Seronegative secondary syphilis in a patient with AIDS: identification of Treponema pallidurn in biopsy specimen. J Am Acad Dermatol 199 1;24:506-8 40. Haas JS, Bolan G, Larsen SA, et al. Sensitivity of treponemal tests for detecting prior treated syphilis during human immunodeficiency virus infection. J Infect Dis 1990; 162:862-6 4 1. Johnson PDR, Graves SR, Stewart L, et al. Specific syphilis serological tests may become negative in H I V infection. AIDS 1991;5:419-23 42. Hutchinson CM, Rompalo AM, Reichart CA, Hook EW 111. Characteristics of syphilis patients attending Baltimore STD Clinics: multiple high risk subgroups a n d interactions with human immunodeficiency virus infection. Arch lntern Med 1991; 151:5 11-6 43. Nelson KE, Clements ML, Miotti P, et al. T h e influence of human immunodeficiency virus (HIV) infection o n antibody responses to influenza vaccines. Ann l n t e r n Med 1988; 109:383-8 44. Vardinon N, Handsher R, Burke M, et al. Poliovirus vaccination responses in HIV-infected patients: correlation with T 4 cell counts. J Infect Dis 1990; 162:238-41 45. van d e r Valk PGM, Kraai EJ, van Voorst Vader PC, et al. Penicillin concentrations in cerebrospinal fluid (CSF) during repository treatment regimen for syphilis. Genitourin Med 1988;64:223-5 46. Rothenberg R. Treatment of neurosyphilis. J Am Vener Assoc 1976;3: 153-8 47. Morrison RE, Harison SM, Tramont EC. Oral amoxycillin, an alternative treatment for neurosyphilis. Genitourin Med 1985;61:359-62 48. Whiteside Yim C, Flynn NM, Fitzgerald FT. Penetration of oral doxycycline into the cerebrospinal fluid of patients with latent o r neurosyphilis. Antimicrob Agents Chemother 1985;28:347-8 49. Hook EW 111, Baker-Zander SA, Moskovitz BL, et al. Ceftriaxone therapy for asymptomatic neurosyphilis. Case report a n d Western blot analysis of serum a n d cerebrospinal fluid IgG response to therapy. Sex Transm Dis 1986; 13: 185-8 50. Dowell ME, Ross PG, Cate T R , et al. Ceftriaxone therapy for HIV-infected persons with late latent syphilis o r asymptomatic neurosyphilis. (Abstr.) Abstracts of the 1991 lnterscience Conference Antimicrobial Agents Chemotherapy. Washington DC: American Society for Microbiology, 1991: 148 51. Hahn RD, Cutler JC, Curtis AC, et al. Penicillin treatment of asymptomatic central nervous system syphilis. Arch Dermatol 1956;74:367-77 52. Telzak EE, Zweig Greenberg MS, et al. Syphilis treatment response in HIV-infected individuals. AIDS 1991;5: 591-5

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SEMINARS IN NEUROLOGY

Syphilis and human immunodeficiency virus infection.

SEMINARS I N NEUROLOGY-VOLUME 12, NO. 1 MARCH 1992 Syphilis and Human Immunodeficiency Virus Infection In 1987 Berry and coworkers1 and Johns and c...
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