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Abstract: We conducted a systematic literature review and meta-analysis to assess the efficacy of alternative treatments for neurosyphilis. We searched MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Embase, Cochrane, Scopus, and Web of Science from database inception to September 2023, for studies in neurosyphilis that compared penicillin monotherapy with other treatments. We focused on the impact of these therapies on treatment response, but also assessed data regarding reinfection and adverse drug events. Random-effect models were used to obtain pooled mean differences. Of 3415 screened studies, 6 met the inclusion criteria for the systematic literature review. Three studies provided quantitative data that allowed for inclusion in the meta-analysis. Our analysis revealed that the efficacy of intravenous (IV) ceftriaxone 2 g daily for 10 days (51 patients) did not appear statistically different compared with IV penicillin G 18 to 24 million units daily for 10 days (185 patients) for neurosyphilis (pooled odds ratio, 2.85; 95% confidence interval, 0.41-19.56; I 2 = 49%). No statistical difference between ceftriaxone and penicillin was identified in people living with human immunodeficiency virus (HIV) (pooled odds ratio, 4.51; 95% confidence interval, 0.50-40.49; I 2 = 34%). We concluded that alternative therapy with IV ceftriaxone appears similar to penicillin, potentially expanding treatment options for neurosyphilis. Other treatment options including doxycycline warrant further study., Competing Interests: Conflicts of Interest: None declared., (Copyright © 2024 American Sexually Transmitted Diseases Association. All rights reserved.)

Competing Interests: Conflicts of Interest: H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. The other authors report no conflicts of interest related to this work.

Background: Syphilis diagnosis relies on serological tests, which may be falsely nonreactive or may be reactive but not reflect current syphilis., Methods: Polymerase chain reaction for detection of T. pallidum DNA was performed on 123 oropharyngeal swabs, 120 whole bloods, and 46 lesion exudate swabs from 123 untreated individuals with syphilis (cases); oropharyngeal swabs from 148 at-risk controls without syphilis; and 73 oropharyngeal swabs and 36 whole bloods from 73 individuals recently treated for syphilis., Results: Most (90.2%) cases had early syphilis. T. pallidum DNA was detected in 33 (26.8%) of 123 oropharyngeal swabs, 32 (26.7%) of 120 bloods, and 30 (65.2%) of 46 lesion exudate swabs. T. pallidum DNA was detected in 49 (40.8%) of 120 individuals in whom both oropharyngeal swabs and blood were tested. T. pallidum was more likely to be amplified from oropharyngeal swabs when it was amplified from blood than when it was not (15 of 32 [46.9%] vs. 17 of 88 [19.3%], P = 0.003). For each 2-fold increase in serum rapid plasma reagin titer, the odds of detection of T. pallidum DNA in oropharyngeal swabs increased by 1.44 (95% confidence interval, 1.14-1.82, P = 0.003). T. pallidum DNA was not detected in oropharyngeal samples from controls, but it was detected in 3 (8.3%) of 36 bloods from individuals recently treated for syphilis: 2 at 1 day and 1 at 5 days after initiation of syphilis treatment., Conclusions: Nucleic amplification tests can identify recent T. pallidum infection and may be particularly useful for diagnosis of very early or asymptomatic syphilis., Competing Interests: Conflict of Interest and Sources of Funding: The authors have no conflict of interest relevant to this work. This work was supported by grants from the National Institutes of Health (NS34235 and NS082120) to C.M.M., (Copyright © 2021 American Sexually Transmitted Diseases Association. All rights reserved.)

Background: At least 3 syphilis typing systems are proposed. Recent work suggests that multilocus sequence typing (MLST) may be superior to enhanced Centers for Disease Control and Prevention typing (ECDCT) by yielding a higher discriminatory power. The goal of this study was to compare the 2 systems and identify associations between neurosyphilis and strain types., Methods: Multilocus sequence typing for tp0136, tp0548, and tp0705 was determined for DNA from 78 Treponema pallidum subspecies pallidum isolates propagated in rabbits, 10 oral and 10 genital or non-genital lesion swabs, and 10 blood samples from patients with syphilis. These samples were chosen because they were completely typeable by ECDCT. Using both systems, association between strain types and neurosyphilis, defined as a reactive cerebrospinal fluid Venereal Disease Research Laboratory test, was determined. Partial and complete ECDCT types were also determined for samples from different anatomical sites in 35 patients, and from blood and blood isolates (rabbit propagated) from 13 patients., Results: The MLST type could be fully determined for 100 (92.6%) of 108 samples. Although MLST subdivided 3 common ECDCT types, it failed to distinguish among others. Neurosyphilis was more common in individuals infected with type 1.1.2 and tp0705 type 2 using MLST, and tp0548 type f using ECDCT. Enhanced Centers for Disease Control and Prevention typing was stable among anatomical sites and between patient-derived and rabbit propagated organisms., Conclusions: Compared with ECDCT, MLST was not uniformly more discriminating. Both typing systems demonstrate that specific types may be more neurotropic than others., Competing Interests: Conflict of Interest and Sources of Funding: None declared., (Copyright © 2021 American Sexually Transmitted Diseases Association. All rights reserved.)

Background: The diagnosis of neurosyphilis relies in large part on the cerebrospinal fluid (CSF) Venereal Disease Research Laboratory (VDRL) test, which is diagnostically specific but not sensitive., Methods: We determined the sensitivity and specificity of 3 CSF tests in addition to the CSF-VDRL in participants with syphilis enrolled in a research study: detection of Treponema pallidum ribosomal RNA, T. pallidum particle agglutination titer, and chemokine (C-X-C motif) ligand 13 (CXCL13) concentration. Neurosyphilis was defined as asymptomatic or symptomatic meningitis: CSF white blood cells >10/μL without or with neurological symptoms, including new vision or hearing loss., Results: Cerebrospinal fluid-VDRL, CSF T. pallidum ribosomal RNA detection, and CSF T. pallidum particle agglutination titer ≥1:640 were specific (89%-96%) but not sensitive (12%-48%). In contrast, diagnostic sensitivity of CSF-CXCL13 thresholds established from receiver operating characteristic curves using the Youden index was 78% to 83% and specificity was 76% to 81%. In individuals with nonreactive CSF-VDRL, neurosyphilis diagnosis could be confirmed by CSF-CXCL13 concentration in 69% to 75%., Conclusions: Further studies of CSF-CXCL13 should include CSF samples from multiple cohorts and countries and should use standard neurosyphilis definitions to establish uniform thresholds for diagnosis., Competing Interests: Conflict of Interest and Sources of Funding: NIH/NINDS grant NS34235 to CMM., (Copyright © 2021 American Sexually Transmitted Diseases Association. All rights reserved.)

Background: The diagnosis of neurosyphilis relies on cerebrospinal fluid (CSF) abnormalities (pleocytosis, elevated protein) and CSF-Venereal Disease Research Laboratory (VDRL) test. In resource-limited settings, the CSF-VDRL test may not be widely available., Methods: We optimized a commercial immunochromatographic strip test, the DPP Chembio syphilis assay, for performance with CSF and tested centrifuged CSF samples of 71 patients with syphilis (35 with neurosyphilis and 36 without neurosyphilis). A CSF dilution of 1:4 was chosen based on agreement with CSF pools with documented results from the CSF-VDRL test and fluorescent treponemal antibody absorption test on CSF. Using an electronic reader, we obtained unit values of treponemal and nontreponemal antibodies for all study samples and generated a receiver operating characteristic curve; using the Youden index, we established diagnostic cutoffs with optimal sensitivity and specificity., Results: Diagnostic sensitivity of the nontreponemal test was 80% (95% confidence interval, 63%-92%) and specificity was 97% (95% confidence interval, 85%-100%) for neurosyphilis diagnosis using a reactive CSF-VDRL that improved after neurosyphilis therapy as a criterion standard., Conclusions: In this small study, the DPP Chembio test showed promising results for neurosyphilis diagnosis. Further studies are needed to assess its performance in resource-limited settings., Competing Interests: Conflict of Interest and Sources of Funding: H.G. has received a grant from an AIDS Clinical Trials Group Minority HIV Mentoring Program award. I.J.K. has served on an advisory board for Medimmune and received royalties from UpToDate for chapters on HIV and progressive multifocal leukoencephalopathy. G.D.H. has received institutional research grants from Gilead, Janssen, Proteus, Viiv, and BMS and has served on an advisory board for Gilead, Viiv, Janssen, and Theratechnologies. C.M.M. has received royalties from Wolters Kluwer and grants from the National Institutes of Health. L.C.T. and Z.O. have no conflicts of interest to disclose., (Copyright © 2021 American Sexually Transmitted Diseases Association. All rights reserved.)

The number of cases of syphilis has increased in the United States and in many high-income nations. Otosyphilis is a less recognized complication of syphilis that can lead to irreversible sensorineural hearing loss. Different pathophysiological mechanisms have been proposed to explain hearing loss in otosyphilis. We review the literature on otosyphilis in adults and propose the need for future work in this field to identify better ways to diagnose, treat, and manage this disease. Patients with syphilis should be screened routinely for hearing loss, and all patients with new, sudden, or fluctuating sensorineural hearing loss should be evaluated for syphilis.

Despite over a century of clinical experience in diagnosing and managing patients with syphilis, many thorny clinical questions remain unanswered. We focus on several areas of uncertainty for the clinician: the role of serologic tests in diagnosing syphilis and assessing syphilis treatment responses, and the risk of neurosyphilis and ocular syphilis in patients with syphilis. We also address whether clinical approaches should differ in patients who are, and are not, infected with HIV. The current increases in syphilis rates in the United States and elsewhere underscore our urgent need to definitively address these issues.

Background: High rates of 23S rDNA mutations implicated in macrolide resistance have been identified in Treponema pallidum samples from syphilis patients in many countries. Nonetheless, some clinicians have been reluctant to abandon azithromycin as a treatment for syphilis, citing the lack of a causal association between these mutations and clinical evidence of drug resistance. Although azithromycin resistance has been demonstrated in vivo for the historical Street 14 strain, no recent T. pallidum isolates have been tested. We used the well-established rabbit model of syphilis to determine the in vivo efficacy of azithromycin against 23S rDNA mutant strains collected in 2004 to 2005 from patients with syphilis in Seattle, Wash., Methods: Groups of 9 rabbits were each infected with a strain containing 23S rDNA mutation A2058G (strains UW074B, UW189B, UW391B) or A2059G (strains UW228B, UW254B, and UW330B), or with 1 wild type strain (Chicago, Bal 3, and Mexico A). After documentation of infection, 3 animals per strain were treated with azithromycin, 3 were treated with benzathine penicillin G, and 3 served as untreated control groups. Treatment efficacy was documented by darkfield microscopic evidence of T. pallidum, serological response, and rabbit infectivity test., Results: Azithromycin uniformly failed to cure rabbits infected with strains harboring either 23S rDNA mutation, although benzathine penicillin G was effective. Infections caused by wild type strains were successfully treated by either azithromycin or benzathine penicillin G., Conclusions: A macrolide resistant phenotype was demonstrated for all strains harboring a 23S rDNA mutation, demonstrating that either A2058G or A2059G mutation confers in vivo drug resistance.

Background: Syphilis can have many clinical manifestations, including eye involvement, or "ocular syphilis." In 2015, an increase in reported cases of ocular syphilis and potential case clusters raised concern for an oculotropic strain of Treponema pallidum, the infectious agent of syphilis. Molecular typing was used to examine strains found in cases of ocular syphilis in the United States., Methods: In 2015, after a clinical advisory issued by the Centers for Disease Control and Prevention, pretreatment clinical specimens from US patients with ocular syphilis were sent to a research laboratory for molecular analysis of T. pallidum DNA. Molecular typing was conducted on these specimens, and results were compared with samples collected from Seattle patients diagnosed with syphilis, but without ocular symptoms., Results: Samples were typed from 18 patients with ocular syphilis and from 45 patients with syphilis, but without ocular symptoms. Clinical data were available for 14 ocular syphilis patients: most were men, human immunodeficiency virus-infected, and had early syphilis. At least 5 distinct strain types of Treponema pallidum were identified in these patients, and 9 types were identified in the Seattle nonocular patients. 14d/g was the most common type in both groups. An unusual strain type was detected in a small cluster of ocular syphilis patients in Seattle., Conclusions: Ocular syphilis is a serious sequela of syphilis. In this preliminary study, clear evidence of a predominant oculotropic strain causing ocular syphilis was not detected. Identification of cases and prompt treatment is critical in the management of ocular syphilis., Competing Interests: The authors report no conflict of interest

We reviewed 68 cases of possible neurosyphilis among 573 syphilis cases in King County, WA, from 3rd January 2012 to 30th September 2013; 7.9% (95% confidence interval, 5.8%-10.5%) had vision or hearing changes, and 3.5% (95% confidence interval, 2.2%-5.4%) had both symptoms and objective confirmation of complicated syphilis with either abnormal cerebrospinal fluid or an abnormal ophthalmologic examination.

Background: The laboratory diagnosis of neurosyphilis rests upon identifying cerebrospinal fluid (CSF) abnormalities, including CSF-Venereal Disease Research Laboratory (VDRL) reactivity. The CSF-VDRL may not be available in the parts of the world where neurosyphilis is most common. Treponemal immunochromatographic strip tests (ICSTs) have been developed as point-of-care tests on blood for syphilis diagnosis in resource-limited settings., Methods: We optimized 3 commercial ICSTs for performance on CSF and tested CSF samples from 217 patients with syphilis. The Syphicheck-WB test (Qualpro Diagnostics, Goa, India; "Syphicheck") was chosen for further study based on agreement with CSF-VDRL test results. We determined CSF-Syphicheck titers for 152 samples. We modified the CSF-Syphicheck for point-of-care testing in a US sexually transmitted diseases clinic and compared results on 102 paired centrifuged and uncentrifuged CSF samples obtained in the laboratory to the results obtained at point of care; results of samples diluted 1:4 were compared in a subset., Results: The diagnostic sensitivity of a reactive CSF-Syphicheck (62%-64%) and the diagnostic specificity of a CSF-Syphicheck titer at or above 1:4 (79%-81%) were equivalent to the CSF-VDRL (54%-69% sensitivity, 73%-75% specificity) for laboratory and clinical neurosyphilis diagnoses. The CSF-Syphicheck normalized after neurosyphilis therapy similarly to the CSF-VDRL. The modified CSF-Syphicheck performed well at the point of care, albeit with better performance on cell-free compared with uncentrifuged CSF., Conclusions: Cerebrospinal fluid treponemal ICSTs hold promise for point-of-care neurosyphilis diagnosis in regions where the CSF-VDRL is not available. Further study should address the performance of CSF ICSTs in resource-limited settings.

Background: Single-nucleotide polymorphisms (SNPs) in toll-like receptors (TLR) 1, 2, and 6 impair cell signaling in response to spirochetal lipoproteins. We investigated whether common SNPs in TLR1, TLR2, or TLR6 were associated with laboratory- or clinically-defined neurosyphilis., Methods: Polymorphisms in the genes for TLR1 (a T→G mutation at position 1805), TLR2 (a G→A mutation at position 2258), and TLR6 (a C→T mutation at position 745) were sought in 456 white patients with syphilis. Laboratory-defined neurosyphilis included a reactive cerebrospinal fluid (CSF)-Venereal Disease Research Laboratory (VDRL) test. Clinically-defined neurosyphilis included new vision or hearing loss. Controls had CSF white blood cells of 5/μL or less, nonreactive CSF-Venereal Disease Research Laboratory, and no vision or hearing loss., Results: Overall, 26.2% of patients had laboratory-defined and 36.2% had clinically-defined neurosyphilis. Compared with controls, patients with any of the 3 SNPs were more likely to have laboratory-defined neurosyphilis. Those with TLR2 or TLR6 SNPs were more likely to have clinically-defined neurosyphilis. These associations were independent of serum rapid plasma reagin titer., Conclusions: A common TLR1 polymorphism is associated with an increased risk of laboratory-defined neurosyphilis, and common TLR2 and TLR6 polymorphisms are associated with an increased risk of both laboratory- and clinically-defined neurosyphilis. These data suggest that host factors impact the natural history of syphilis.

Background: Although azithromycin promised to be a safe and effective single-dose oral treatment of early syphilis, azithromycin treatment failure has been documented and is associated with mutations in the 23S rDNA of corresponding Treponema pallidum strains. The prevalence of strains harboring these mutations varies throughout the United States and the world. We examined T. pallidum strains circulating in Seattle, Washington, from 2001 to 2010 to determine the prevalence of 2 mutations associated with macrolide resistance and to determine whether these mutations were associated with certain T. pallidum strain types., Methods: Subjects were enrolled in a separate ongoing study of cerebrospinal fluid abnormalities in patients with syphilis. T. pallidum DNA purified from blood and T. pallidum strains isolated from blood or cerebrospinal fluid were analyzed for two 23S rDNA mutations and for the molecular targets used in an enhanced molecular stain typing system., Results: Nine molecular strain types of T. pallidum were identified in Seattle from 2001 to 2010. Both macrolide resistance mutations were identified in Seattle strains, and the prevalence of resistant T. pallidum exceeded 80% in 2005 and increased through 2010. Resistance mutations were associated with discrete molecular strain types of T. pallidum., Conclusions: Macrolide-resistant T. pallidum strains are highly prevalent in Seattle, and each mutation is associated with discrete strain types. Macrolides should not be considered for treatment of syphilis in regions where prevalence of the mutations is high. Combining the resistance mutations with molecular strain typing permits a finer analysis of the epidemiology of syphilis in a community.

Background: The cerebrospinal fluid (CSF) Venereal Disease Research Laboratory (VDRL) test is a mainstay for neurosyphilis diagnosis, but it lacks diagnostic sensitivity and is logistically complicated. The rapid plasma reagin (RPR) test is easier to perform, but its appropriateness for use on CSF is controversial., Methods: RPR reactivity was determined for CSF from 149 individuals with syphilis using 2 methods. The CSF-RPR was performed according to the method for serum. The CSF-RPR-V was performed using the method recommended for the CSF-VDRL. Laboratory-defined neurosyphilis included reactive CSF-fluorescent treponemal antibody absorption test and CSF white blood cells >20/uL. Symptomatic neurosyphilis was defined as vision loss or hearing loss., Results: CSF-VDRL was reactive in 45 (30.2%) patients. Of these, 29 (64.4%) were CSF-RPR reactive and 37 (82.2%) were CSF-RPR-V reactive. There were no instances where the CSF-VDRL was nonreactive but the CSF-RPR or CSF-RPR-V was reactive. Among the 28 samples that were reactive in all 3 tests, CSF-VDRL titers (median [IQR], 1:4 [1:4-1:16]) were significantly higher than CSF-RPR (1:2 [1:1-1:4], P = 0.0002) and CSF-RPR-V titers (1:4 [1:2-1:8], P = 0.01). The CSF RPR and the CSF-RPR-V tests had lower sensitivities than the CSF-VDRL: 56.4% and 59.0% versus 71.8% for laboratory-diagnosed neurosyphilis and 51.5% and 57.6% versus 66.7% for symptomatic neurosyphilis., Conclusions: Compared with the CSF-VDRL, the CSF-RPR has a high false-negative rate, thus not improving upon this known limitation of the CSF-VDRL for neurosyphilis diagnosis. Adapting the RPR procedure to mimic the CSF-VDRL decreased, but did not eliminate, the number of false negatives and did not avoid all the logistical complications of the CSF-VDRL.

With the rising incidence and prevalence of syphilis, meningovascular syphilis and other forms of neurosyphilis have reappeared, particularly among persons infected with human immunodeficiency virus. We present a patient with meningovascular syphilis leading to stroke after treatment with penicillin and antiretroviral therapy.

Background: Asymptomatic neurosyphilis is more difficult to diagnose in human immunodeficiency virus (HIV)-infected patients because HIV itself can cause cerebrospinal fluid (CSF) pleocytosis. The proportion of CSF lymphocytes that are B cells is elevated in neurosyphilis, suggesting that the CSF concentration of the B cell chemoattractant, chemokine (C-X-C motif) ligand 13 (CXCL13) concentration may also be elevated., Methods: CSF and blood were collected from 199 HIV-infected patients with syphilis and neurosyphilis. Serum and CSF CXCL13 concentrations were determined., Results: Patients with neurosyphilis had higher CSF and serum CXCL13 concentrations compared to patients with syphilis but not neurosyphilis. The odds of having symptomatic neurosyphilis were increased by 2.23-fold for every log increase in CSF CXCL13 concentration and were independent of CSF white blood cell and plasma HIV RNA concentrations, peripheral blood CD4+ T cell count and use of antiretroviral medications. A cut-off of 10 pg/mL CSF CXCL13 had high sensitivity and a cut-off of 250 pg/mL or evidence of intrathecal synthesis of CXCL13 had high specificity for diagnosis of both symptomatic and asymptomatic neurosyphilis. CSF concentrations of CXCL13 declined after treatment for neurosyphilis., Conclusions: CSF CXCL13 concentration may be particularly useful for diagnosis of neurosyphilis in HIV-infected patients because it is independent of CSF pleocytosis and markers of HIV disease.

Background and Objectives: It is difficult to distinguish between relapse and reinfection in patients who develop a second episode of syphilis after treatment., Goal: The goal of this study was to use molecular methods to distinguish between relapse and reinfection in a patient with recurrent secondary syphilis., Study Design: Treponema pallidum tprK sequences were amplified from cerebrospinal fluid (CSF), skin, and blood from the initial presentation and from blood from the second presentation. Neighbor-joining clustering analysis was performed for deduced tprK sequences from the case patient and for sequences derived from blood and CSF of a different patient with secondary syphilis., Results: The case patient's tprK sequences from both episodes of syphilis clustered together with a high degree of similarity., Conclusion: Our patient likely relapsed despite treatment.