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Neurosyphilis (NS) is a clinical condition caused by infection of the central nervous system (CNS) by Treponema pallidum (Tp) that can lead to asymptomatic meningitis and more serious neurological diseases, such as dementia and blindness. However, current studies on the pathogenesis of NS are limited. Here, through the integration analysis of proteomics and single-cell transcriptomics, Toll-like/NF-κB signaling is identified as the key pathway involved in CNS damage caused by Tp. Moreover, monocyte-derived macrophages are key cells involved in the inflammatory response to Tp in the CNS of NS patients. In addition, it is found that inflammatory cells in peripheral blood may cause neurological damage through disruption of the blood‒brain barrier (BBB) in individuals with NS. Notably, activation of the Toll-like/NF-κB signaling pathway, as well as dysregulation of neural function, is likewise validated in an in vitro NS brain organoid model. In conclusion, the results revealed the mechanisms of inflammation-mediated brain injury in Tp-induced NS and provided new ideas for the clinical treatment of Tp infection., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Objectives: Invasive lumbar puncture is the conventional method for diagnosing neurosyphilis (NS). We investigated a non-invasive alternative method to detect serum Treponema pallidum-specific antibodies against highly immunogenic antigens TP0171 (TP15), TP0435 (TP17), and TP0574 (TP47) by using luciferase immunosorbent assay., Methods: A total of 816 HIV-negative patients suspected of NS from the Beijing and Guangzhou cohorts were retrospectively selected and tested for serum anti-TP15, TP17, and TP47 IgG antibodies. Two diagnostic prediction models were developed using stepwise logistic regression in the Beijing cohort, and evaluated in the Guangzhou cohort for external validation., Results: Serum antibodies against TP15, TP17, and TP47 showed moderate capability for NS diagnosis in the Beijing cohort and the corresponding area under the receiver operating characteristic curves (AUCs) were 0.722 [95% confidence interval (CI): 0.680-0.762)], 0.780 (95% CI: 0.741-0.817), and 0.774 (95% CI: 0.734-0.811), respectively. An expanded NS prediction model integrated with anti-TP17 and anti-TP47 antibodies showed better performance than the base NS diagnostic model without anti-TP17 and anti-TP47 antibodies with the AUC of 0.874 (95% CI: 0.841-0.906) vs. 0.845 (95% CI: 0.809-0.881) (p = 0.007) in the development cohort, and 0.934 (95% CI: 0.909-0.960) vs. 0.877 (95% CI: 0.840-0.914) (p < 0.001) in validation cohort, respectively. Decision curve analysis revealed that the net benefit of the expanded model exceeded that of the base model when the threshold probability was between 0.10 and 0.95 in both the development and external validation cohorts., Discussion: Serum antibodies against TP17 and TP47 exhibited promising diagnostic capability for NS and significantly enhanced the predictive accuracy of model for NS diagnosis. Our study highlights the potential of serum treponemal antibody detection as a non-invasive method for NS diagnosis to substitute invasive lumbar puncture in NS diagnosis., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Evidence from epidemiological, clinical, and biological research resulted in the immune hypothesis: the hypothesis that immune system dysfunction is involved in the pathophysiology of schizophrenia spectrum disorders (SSD). The promising implication of this hypothesis is the potential to use existing immunomodulatory treatment for innovative interventions for SSD. Here, we provide a selective historical review of important discoveries that have shaped our understanding of immune dysfunction in SSD. We first explain the basic principles of immune dysfunction, after which we travel more than a century back in time. Starting our journey with neurosyphilis-associated psychosis in the nineteenth century, we continue by evaluating the role of infections and autoimmunity in SSD and findings from assessment of immune function using new techniques, such as cytokine levels, microglia density, neuroimaging, and gene expression. Drawing from these findings, we discuss anti-inflammatory interventions for SSD, and we conclude with a look into the future.

Background: Considering the unknown prevalence of neurosyphilis in West China, and the confusing diagnosis of neurosyphilis, the role of CSF&#95;CXCL13 and syphilis serology was studied to provide a more accurate reference for the clinical detection and diagnosis of neurosyphilis., Methods: A retrospective data set I was used to investigate the prevalence of neurosyphilis, as well as the laboratory characteristics of 244 patients. Besides, to explore the diagnostic value of CSF&#95;CXCL13 and syphilis serology for neurosyphilis, another 116 CSF&#95;serum paired samples (data set II) were collected from 44 neurosyphilis and 72 non-neurosyphilis/syphilis patients., Results: About 6.25% (156 out of 2494) syphilis was neurosyphilis. When Treponema pallidum infection occurs, syphilis serology (sero&#95;TRUST ≥1:16 and sero&#95;TPPA titre ≥1:10240) can be good predictors of neurosyphilis, as well as syphilis CSF serology (CSF&#95;TPPA ≥1:320, CSF&#95;TRUST and venereal disease research laboratory). The sensitivity of serology in neurosyphilis can be complemented by CSF&#95;CXCL13, which could be the therapy monitor of neurosyphilis., Conclusion: Due to the lack of ideal biomarkers for neurosyphilis, the importance of syphilis serology cannot be ignored, and their combination with CSF&#95;CXCL13 or other biomarkers should be further investigated., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cytokines play multiple roles during neuro-inflammatory processes and several cytokines have been studied in the context of specific diseases. This study provides a comprehensive picture of cerebrospinal fluid (CSF) changes during neuro-inflammation by analyzing multiple cytokines in combination with immune cell subsets and standard CSF parameters., Methods: Using multiplex assays, we simultaneously measured 36 cytokines (CCL1-3, CCL7, CCL8, CCL11, CCL13, CCL19, CCL20, CCL22-27, CXCL1, CXCL2, CXCL5, CXCL6, CXCL8, CXCL9, CXCL11-13, CXCL16, CX3CL1, IL2, IL4, IL6, IL10, IL16, GM-CSF, IFNγ, MIF, TNFα, and MIB1β) in the CSF and serum of 75 subjects. Diagnoses included clinically isolated syndrome and relapsing-remitting multiple sclerosis (MS, n = 18), secondary progressive MS (n = 8), neuro-syphilis (n = 6), Lyme neuro-borreliosis (n = 13), bacterial and viral meningitis (n = 20), and patients with non-inflammatory neurological diseases (NIND, n = 10). Cytokine concentrations were correlated with CSF standard parameters and CSF immune cell subsets (CD4 and CD8 T cells, B cells, plasmablasts, monocytes, and NK cells) quantified by flow cytometry., Results: We observed increased levels of multiple cytokines (26/36) in patients with neuro-inflammatory diseases when compared to NIND that consistently correlated with CSF cell count and Q Albumin . Most CSF cytokine concentrations correlated with each other, but correlations between CSF and serum values were scarce (3/36). Within the CSF compartment, CXCL13 showed a strong association with B cells when analyzing all patients, as well as patients with an intact blood-brain barrier (BBB). NK cells positively correlated with CSF concentrations of multiple cytokines (22/36) when analyzing all patients. These correlations were maintained when looking at patients with a disrupted BBB but not detectable in patients with an intact BBB., Conclusions: Under conditions of neuro-inflammation, multiple CSF cytokines are regulated in parallel and most likely produced locally. A combined increase of CSF CXCL13 levels and B cells occurs under conditions of an intact BBB. Under conditions of a disrupted BBB, CSF NK cells show significantly increased values and seem to have a major contribution to overall inflammatory processes, reflected by a strong correlation with multiple cytokines. Future studies are necessary to address the exact kinetics of these cytokines during neuro-inflammation and their relation to specific diseases phenotypes.

Introduction: During syphilis a compelling fight is engaged between the host's humoral and cellular immune responses that work to eliminate the infection and Treponema pallidum (T. pallidum) that manages to evade eradication and cause chronic infection. Different mechanisms are utilized by treponemes to overcome immunological response. Although penicillin (BPG) proved to be effective in quelling the early manifestations of the disease and consequently its contagiousness, questions remain about its ability to prevent the late complications and to provide a microbiological eradication in vivo. In fact, both serological and microbiological failures have been reported following conventional treatment., Evidence Acquisition: We reviewed some biologic properties of T. pallidum in order to establish a relationship with the persistence of the infection and the alleged treatment resistance., Evidence Synthesis: The host humoral response, sometimes, may not protect completely against T. pallidum and accounts for the persistent infection and tertiary damages. In fact, the cell mediated response during infection may be downregulate in response to pathogen-derived molecules, or indirectly by generating Treg cells. It is also possible that there are strain types of T. pallidum with higher ability of evasion determining neurosyphilis. In addition, apart the impressive results that BPG has made on the syphilis cutaneous lesions, concerns still remain on its efficacy in preventing late complications., Conclusions: Understanding the biology of the T. pallidum may help researchers in this field to develop future target therapies in order to prevent persistent infection and progression of the disease.

Neuromyelitis optica spectrum disorder (NMOSD) is a common neuroinflammatory demyelinating disease associated with aquaporin-4 (AQP4) antibody in the central nervous system. Neurosyphilis is a neurological disease caused by Treponema pallidum infection. NMOSD commonly occurs concurrently with autoimmune diseases. However, they have rarely been associated with infectious diseases. In this report we describe a rare case of concurrent AQP4-positive NMOSD and neurosyphilis. A 60-year-old man was admitted to our hospital with a complaint of progressive weakness in his legs for one month. T2-weighted magnetic resonance images of the spinal cord showed longitudinal extensive lesions at C7-T7. The rapid plasma reagin test and T. pallidum particle agglutination assay performed using patient serum and cerebrospinal fluid (CSF) were positive. Additionally, the AQP4-immunoglobulin (Ig) G was detected in the serum and CSF. The patient's symptom gradually improved after penicillin and methylprednisolone treatment. This case report highlights the possibility of the presence of an infectious disease in patients with NMOSD., (Copyright © 2019. Published by Elsevier B.V.)

Background: Syphilis is a re-emerging sexually-transmitted infection, caused by the spirochete Treponema pallidum, that may penetrate early into the central nervous system. The venereal disease research laboratory test (VDRL) on the cerebrospinal fluid (CSF) is the most widely used for neurosyphilis diagnosis. We evaluated the performance of two other nontreponemal tests (rapid plasma reagin [RPR] and unheated serum reagin [USR] tests) in comparison with the VDRL in CSF., Methods: We analyzed CSF samples from 120 individuals based on VDRL reactivity in the CSF and the clinical picture of neurosyphilis., Results: High inter-rater reliability was found among all three tests, with equivalent sensitivity and specificity. Intraclass correlation coefficient for absolute agreement was 1 for VDRL versus USR, 0.99 for VDRL versus RPR, and 0.99 for RPR versus USR., Conclusions: Rapid plasma reagin and unheated serum reagin tests were identified as excellent alternatives for neurosyphilis diagnosis.

Objectives: People living with HIV (PLWH) are at increased risk of asymptomatic neurosyphilis; thus, it has been common practice to perform a lumbar puncture (LP) in all PLWH presenting with syphilis regardless of stage, signs or symptoms. However, this practice varies widely among clinicians. Our objective was to elucidate the number of LPs required to diagnose a single case of asymptomatic neurosyphilis., Methods: We performed an electronic health record (EHR) review of PLWH who were diagnosed with syphilis of any stage over a 10-year period. EHRs were reviewed to determine the number of subjects who had an LP performed, what proportion had neurological signs or symptoms, and whether a diagnosis of neurosyphilis was made at presentation or follow-up., Results: In 261 separate episodes of syphilis in 230 subjects, we found the major risk factors for asymptomatic neurosyphilis to be low CD4 T-cell count (P = 0.0007), high rapid plasma reagin (RPR) titre (P = 0.019) and lack of HIV virological suppression (P = 0.003). The majority of our subjects (78%) with neurosyphilis presented with central nervous system (CNS) symptoms. We estimate, if standard practice is to perform LP in all patients, that the number needed to test (NNTT) = 38., Conclusions: This large number of potentially unnecessary LPs, along with heterogeneity of presentation, and the never-nil risk of asymptomatic neurosyphilis should be incorporated into clinical decision-making. The majority of PLWH presenting with a serological diagnosis of syphilis, but no neurological signs or symptoms, do not necessarily require an LP for an evaluation of asymptomatic neurosyphilis., (© 2018 British HIV Association.)

To develop predictive model of damage of nervous system on the basis of definition of concentration of interleukins-23, 12p40 and also a glial fibrillar acid protein (GFAP) in liquor of patients with various forms of syphilis. Comprehensive laboratory examination of patients with neurosyphilis and syphilis without specific damage of nervous system who were observed in venereologic office of BOUZAS of OO «Clinical Dermatovenerologic Clinic» of Omsk is conducted. To all patients were carried out: a serological blood analysis, serological and clinical trial of liquor, and also immunological research of liquor (interleukins - 23, 12p40, and also GFAP). On the basis of the research IL-23, SILT-12p40, GFAP, the level of protein and a pleocytosis in liquor the predictive model of development of neurosyphilis in patients with syphilis without specific damage of nervous system is offered. The analysis of immunological changes in liquor of patients showed that the research of a number of cytokines and markers of damage of nervous tissue to liquor as the most specific and reliable, especially in the absence of clinical symptomatology from central nervous system can be an integral part of diagnostics of neurosyphilis also., Competing Interests: The authors declare no conflict of interest.

The surveillance of neurosyphilis, an uncommon but severe consequence of syphilis, is complex; surveillance classification of neurosyphilis requires a lumbar puncture and cerebrospinal fluid analysis. We examined the prevalence of reported neurosyphilis among primary, secondary, and early latent syphilis cases reported in the United States from 2009 to 2015. Overall, the prevalence of reported neurosyphilis from 2009 to 2015 was low (0.84%); however, this is likely an underestimate of the true burden in the United States.

Background: The diagnostic criteria for active infectious syphilis in the clinic are important matter of controversy and debate. So far, clinicians habitually do use the negative results of the nontreponemal and/or the specific antitreponemal IgM as the evidences of disease-free or active infection-free status., Method: We present a case study involving a patient who was admitted to Zhongshan Hospital because of cerebral infarct. Clinical examination indicated he had a history of latent syphilis with negative nontreponemal and specific antitreponemal IgM tests. The cerebrospinal fluid sample from the patient was inoculated into seronegative New Zealand rabbit., Results: Motile Treponema pallidum was detected by a rabbit infectivity test in the patient's cerebrospinal fluid. This syphilis strain was confirmed by DNA subtyping form of "centers for disease control subtype/tp0548 sequence type", and the strain type was 14d/f. Treatment with benzathine penicillin provided no apparent benefit, but treatment with aqueous crystalline penicillin G, especially recommended for neurosyphilis, led to disease regression. No evidence of cerebral infarct was observed during a 2-year follow-up period., Conclusion: The definitive differential diagnosis of active infectious syphilis should be reconsidered. Moreover, selecting the appropriate penicillin preparation is important because T pallidum can reside in sequestered sites. It is necessary to treat a patient with known invasion of the central nervous system with aqueous crystalline penicillin G, if previous treatment for syphilis failed and patients had some clinical neurological presentation that is otherwise unexplained, but that could represent neurosyphilis. Additional studies are needed to confirm the results in other syphilis patients.

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.

The detection of serodiscordant syphilis test results raises several important clinical and public health questions. Based on our retrospective review, the probability of neurosyphilis in persons with serodiscordant serologies is low. The probability of ophthalmic syphilis may be higher, but we lack objective measures for that diagnosis.

The ratio of patients with RPR constant positive more than 2 years despite receiving standard syphilis treatment has been reported to be 11.54%~31.3%. The current interpretations on this phenomenon are cellular immune function restrained and the existence of neurosyphilis or asymptomatic neurosyphilis. We conducted this study to detect the treponemal antibody in cerebrospinal fluid (CSF) and lymphocyte subsets in peripheral blood of syphilis patients with persisting RPR positive more than 2 years without neurologic signs, and then explore their relationship. In this study, Treponemal antibody in CSF of 46 syphilitic with HIV negative were measured by syphilis serum test and compared with that of 5 neurosyphilis. Lymphocyte subsets were measured by flow cytometry (FCM) and compared with that of 30 healthy controls. We observed that treponemal antibody in CSF was detected not only in 12 cases (25.21%) of 46 treated patients, but also in 5 neurosyphilis. The ratio of lymphocyte subsets revealed that CD3+, CD4+ T cells and natural killer (NK) cells showed no significant differences between the patient and healthy controls (P>0.05), while CD8+ T cells in patients were significant higher than that in healthy controls (P<0.001). Lymphocyte subsets showed no significant differences between the patients with treponemal antibody positive and negative in CSF (P>0.05). In conclusion, the treponemal antibody in CSF of treated patients suggests that part of them were asymptomatic neurosyphilis and with cellular immunodifeciency. And there is no significant relationship between asymptomatic neurosyphilis and cellular immunodeficiency in peripheral blood.

Background: Treponema pallidum infection evokes vigorous immune responses, resulting in tissue damage. Several studies have demonstrated that IL-17 may be involved in the pathogenesis of syphilis. However, the role of Th17 response in neurosyphilis remains unclear., Methodology/principal Findings: In this study, Th17 in peripheral blood from 103 neurosyphilis patients, 69 syphilis patients without neurological involvement, and 70 healthy donors were analyzed by flow cytometry. The level of IL-17 in cerebrospinal fluid (CSF) was quantified by ELISA. One-year follow up for 44 neurosyphilis patients was further monitored to investigate the role of Th17/IL-17 in neurosyphilis. We found that the frequency of Th17 cells was significantly increased in peripheral blood of patients with neurosyphilis, in comparison to healthy donors. IL-17 in CSF were detected from 55.3% neurosyphilis patients (in average of 2.29 (0-59.83) pg/ml), especially in those with symptomatic neurosyphilis (61.9%). CSF IL-17 was predominantly derived from Th17 cells in neurosyphilis patients. Levels of IL-17 in CSF of neurosyphilis patients were positively associated with total CSF protein levels and CSF VDRL (Venereal Disease Research Laboratory) titers. Notably, neurosyphilis patients with undetectable CSF IL-17 were more likely to confer to CSF VDRL negative after treatment., Conclusions: These findings indicate that Th17 response may be involved in central nervous system damage and associated with clinical symptoms in neurosyphilis patients. Th17/IL-17 may be used as an alternative surrogate marker for assessing the efficacy of clinical treatment of neurosyphilis patients.

Dural granuloma is extremely rare. To our knowledge, there has no case reported solitary spinal dural syphilis granuloma worldwide so far. Here we report our findings in a 49-year-old woman, who presented with 10-year progressive left lower-limb numbness and two weeks of right lower-limb numbness. Magnetic resonance imaging (MRI) suggested a homogeneous enhanced spindle-shaped lesion, 2.9 × 1.5 cm in size, occupying the spinal intradural extramedullary space, at the level of Thoracic (T)-2/3, which mimicked the appearance of spinal meningioma. The Treponema pallidum particle agglutination (TPPA) test titer of 1:8, and the venereal diseases research laboratory of cerebral spinal fluid (VDRL-CSF) was reactive, so confirmed neurosyphilis was considered. After formal anti-syphilis treatment, posterior laminectomy surgery was performed, and the lesion was completely separated and extirpated. Final histopathologic diagnosis of the lesion was confirmed as chronic granulomatous inflammation, combined with the neurosyphilis history, spinal dural syphilis granuloma was finally diagnosed. Postoperatively, the patient recovered without any further treatment.

Background: The origin of cerebrospinal fluid (CSF) syphilis antibodies (intrathecal or blood-derived) is in doubt. Little is known about CSF test behavior under the condition of physiological or disturbed functioning of blood-CSF barrier (BCB) and intrathecal immunoglobulin (Ig) production., Methods: We collected 126 serum/CSF pairs from patients with serological evidence of syphilis. We explored the relationships between the established facts of intrathecal Ig synthesis and/or BCB dysfunction and the results of CSF diagnostic tests: the Treponema pallidum hemagglutination (TPHA) test, the fluorescent treponemal antibody absorption (FTA-Abs) test, the Venereal Disease Research Laboratory (VDRL) test, and white blood cell counts. We checked the criteria used either to support or refute the diagnosis of neurosyphilis., Results: Reactive CSF-VDRL tests, elevated CSF-white blood cell counts, and elevated CSF-TPHA titers/indices were associated with the signs of intrathecal Ig synthesis, whereas nonreactive CSF-fluorescent treponemal antibody absorption, nonreactive CSF-TPHA tests, and CSF-TPHA titers from 1:4 to 1:160 were associated with cases where the intrathecal synthesis was not detected. There were some peculiarities of the tests toward BCB dysfunction.Most of reactive CSF-VDRL test samples and CSF samples with pleocytosis were also meeting at least 1 of the CSF-TPHA titer/indices-based criteria. T. pallidum hemagglutination indices were in no better conformity with the facts of intrathecal immune response than CSF-TPHA titers., Conclusions: Our findings have shown that all the examined criteria for the diagnosis of neurosyphilis in CSF are different assessment tools of intrathecal humoral immune activity and support the hypothesis that high CSF treponemal-specific antibody titers are a consequence of inflammatory pathology of the central nervous system.

Background: Syphilis, a sexually transmitted disease caused by spirochetal bacterium Treponema pallidum, can progress to affect the central nervous system, causing neurosyphilis. Accumulating evidence suggest that regulatory T cells (Tregs) may play an important role in the pathogenesis of syphilis. However, little is known about Treg response in neurosyphilis., Methodology/principal Findings: We analyzed Treg frequencies and Transforming Growth Factor-β (TGF-β) levels in the blood and CSF of 431 syphilis patients without neurological involvement, 100 neurosyphilis patients and 100 healthy donors. Suppressive function of Tregs in peripheral blood was also assessed. Among syphilis patients without neurological involvement, we found that secondary and serofast patients had increased Treg percentages, suppressive function and TGF-β levels in peripheral blood compared to healthy donors. Serum Rapid Plasma Reagin (RPR) titers were positively correlated with Treg numbers in these patients. Compared to these syphilis patients without neurological involvement, neurosyphilis patients had higher Treg frequency in peripheral blood. In the central nervous system, neurosyphilis patients had higher numbers of leukocytes in CSF compared to syphilis patients without neurological involvement. CD4(+) T cells were the predominant cell type in the inflammatory infiltrates in CSF of neurosyphilis patients. Interestingly, among these neurosyphilis patients, a significant decrease in CSF CD4(+) CD25(high) Treg percentage and number was observed in symptomatic neurosyphilis patients compared to those of asymptomatic neurosyphilis patients, which may be associated with low CSF TGF-β levels., Conclusions: Our findings suggest that Tregs might play an important role in both bacterial persistence and neurologic compromise in the pathogenesis of syphilis.

Background: The mechanisms underlying the process of Treponema pallidum clearance from the central nervous system have not yet been established. Considering that neurosyphilis is associated with mild cerebrospinal fluid (CSF) pleocytosis with a lymphocytic predominance, it has been suggested that cells involved in the adaptive immune response may play a role in this process. In the current study, we assessed the cytokine production profile of T-helper cells in the serum and CSF of patients with early syphilis, with and without CSF abnormalities., Methods: Cerebrospinal fluid and blood samples were collected from 33 patients with secondary and early latent syphilis. Five patients (15%) had a reactive CSF Venereal Disease Research Laboratory test without any accompanying neurological symptoms. According to the Centers of Disease Control and Prevention classification, they were diagnosed with asymptomatic neurosyphilis. Serum and CSF levels of interferon-γ (IFN-γ; Th1-type cytokine), interleukin-4 (IL-4; Th2-type cytokine), and interleukin-17A (IL-17A; Th17-type cytokine) were determined by enzyme-linked immunosorbent assay., Results: Patients with asymptomatic neurosyphilis had significantly higher levels of IL-17A (8-fold) and IFN-γ (7.8-fold) in the CSF compared with patients in the no-neurosyphilis group. Six individuals had CSF pleocytosis but a negative CSF Venereal Disease Research Laboratory test result (presumptive neurosyphilis group). In this group, CSF IFN-γ and CSF IL-17A levels were also significantly elevated when compared with no-neurosyphilis group. There was no correlation between serum and CSF concentrations of IL-17A. However, CSF pleocytosis correlated positively with both CSF IL-17A (r = 0.4, P = 0.01) and IFN-γ (r = 0.42, P = 0.01)., Conclusions: Increased CSF levels of IFN-γ and IL-17A in syphilitic patients with CSF abnormalities suggest that cells of adaptive immunity (probably T-helper cells producing IFN-γ and IL-17) may contribute to the inflammatory response associated with neurosyphilis. In addition, the lack of correlation between serum and CSF IL-17A levels suggests intrathecal production of this cytokine. Further studies are needed to establish the exact nature of the immune response accompanying neurosyphilis and its clinical significance.

It is unclear how Treponema pallidum affects the immune response among various lymphocyte subsets in neurosyphilis patients with different clinical stages. In order to determine the immune response by T. pallidum infection, we detected the peripheral blood lymphocyte subsets among 14 asymptomatic neurosyphilis patients, 19 early neurosyphilis patients, 9 late neurosyphilis patients, and 50 healthy persons. The result indicated that the number of CD3+CD8+ lymphocytes was significantly higher in neurosyphilis patients than in the control group (χ(2) = 4.427, P = 0.035). The number of CD3+CD8+ lymphocytes was significantly higher in the asymptomatic neurosyphilis group than in the early neurosyphilis group, late neurosyphilis group, and control group (F = 4.644, P = 0.005). The number of NK cells was significantly lower in neurosyphilis patients than in the control group (χ(2) = 13.226, P = 0.000). The number of NK cells in neurosyphilis patients with different clinical stages was also lower than in the control group (F = 4.402, P = 0.006). The number of CD3+ lymphocytes, CD3+CD4+ lymphocytes, and B lymphocytes had no difference among the 4 groups. The results indicated that the progression of neurosyphilis may be related to the continued reduction in the number of NK cells and to the continued increase in CD3+CD8+ lymphocytes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The clinical spectrum of neurosyphilis (NS) has changed over time., Objective: To describe the clinical spectrum and characteristics of NS in HIV-negative patients., Methods: A retrospective chart review was performed for 149 in patients with NS., Result: All patients were >25 years old, including 16.8% asymptomatic for NS, 15.4% with syphilitic meningitis, 24.2% with meningovascular NS, 38.9% with general paresis, 4.0% with tabes dorsalis and 0.7% with gummatous NS. The original misdiagnosis rate was 84.6%. All 149 patients had positive serum Treponema pallidum particle agglutination (TPPA) and rapid plasma reagin (RPR). The overall positive rates of cerebrospinal fluid RPR (CSF-RPR) and CSF-TPPA were 57.0 and 89.9%, respectively. CSF pleocytosis and elevated CSF protein were found in 40.3% of patients. Nonspecific abnormal brain magnetic resonance imaging and electroencephalography findings were present in 60.4 and 54.8% of NS patients, respectively., Conclusions: NS has various clinical manifestations, laboratory findings and magnetic resonance imaging and electroencephalography findings, but all studies lack specificity. Every patient with neurological or psychiatric symptoms that are without unambiguous causes should have blood tests for syphilis. When serology proves positive, patients should undergo CSF examination., (Copyright © 2013 S. Karger AG, Basel.)

Background: No single laboratory test is both sensitive and specific to diagnose neurosyphilis. Several major clinical guidelines suggest that negative cerebrospinal fluid (CSF) treponemal-specific antibody tests rule out the diagnosis of neurosyphilis. Our aim was to systematically review the literature and describe the performance of treponemal-specific CSF antibody tests when diagnosing neurosyphilis., Methods: Two reviewers independently assessed studies published in electronic databases, trial registries, and bibliographies for content and quality. Entry criteria included the assessment of treponemal-specific CSF tests currently used in clinical practice, and the use of standard criteria for both diagnosis and exclusion of neurosyphilis. The primary outcomes were sensitivity, specificity, and negative predictive values of treponemal-specific CSF antibody tests., Results: Of 141 unique citations, 18 studies were included in the systematic review. Due to significant heterogeneity among studies, we were unable to generate pooled summary statistics. Seven different treponemal-specific tests were assessed. Of those, 13 studies evaluated the CSF FTA-ABS (fluorescent treponemal antibody-absorbed) and 9 evaluated the CSF fluorescent treponemal antibody. The performance estimates of these tests were highly variable and depended on the choice of negative and positive controls. No single test had perfect sensitivity, thus the negative predictive value was dependant on the specificity of the test and the prevalence (i.e., pretest probability) of neurosyphilis: the higher the prevalence, the lower the negative predictive value. Few studies included HIV-infected persons., Conclusions: A negative CSF-treponemal-specific antibody test may not exclude the diagnosis of neurosyphilis when the clinical suspicion for neurosyphilis is high.

Two hundred and ninety-five patients who had been found to have Treponema pallidum antibodies detected by enzyme immunoassay were additionally studied by a Western blot test to confirm their presence. Every four cases were ascertained to be false-positive, false seropositivity being more frequent in the presence of IgM antibody against T. palladium. Spinal fluid analysis provided evidence for the course of neurosyphilis in 5 cases. The diagnosis of congenital syphilis was verified in 2 children who had p15, p17, p45, and 47. The findings demonstrate it necessary to extensively use a Western blot in the health care system.

Syphilis is a frequent coinfection with human immunodeficiency virus (HIV). Whereas systemic syphilis infection increases plasma HIV RNA levels (viral load; VL), effects of syphilis on cerebrospinal fluid (CSF) VL are unknown. We hypothesized that intrathecal immune activation in neurosyphilis would selectively increase CSF VL in coinfected patients. In this study, HIV-infected research subjects (N = 225) were categorized into three groups based on serum rapid plasma reagin (RPR), microhemaglutination for Treponema pallidum (MHA-TP) MHA-TP, and CSF VDRL: 23 with neurosyphilis (NS+; reactive serum RPR and MHA-TP and positive CSF VDRL); 42 with systemic syphilis but not neurosyphilis (Syph+; reactive serum RPR and MHA-TP; negative CSF VDRL), and 160 without syphilis (Syph-; nonreactive serum RPR). Plasma and CSF HIV VL were quantified by reverse transcriptase-ploymerase chain reaction (RT-PCR) (Amplicor, Roche) in log(10) copies/ml. To adjust for covariates previously shown to influence CSF HIV VL (i.e., plasma VL, CD4, pleocytosis, and highly active antiretroviral therapy [HAART]), multivariable linear regression was used. Lumbar punctures (LP) done for research purposes diagnosed 23 with neurosyphilis; most (83%) of these reported prior syphilis treatment. Among subjects with detectable plasma VL, CSF VL was highest in NS+, followed by Syph+ and Syph- (P =.006). This relationship was independent of the level of plasma VL or CSF pleocytosis. By contrast, among subjects with undetectable plasma HIV VL, CSF VLs were similar in the three syphilis subgroups (P = .50). Neurosyphilis may amplify intrathecal HIV replication, possibly through immune activation that persists even after syphilis treatment. Because elevated CSF VL is associated with subsequent neurocognitive decline, future studies should evaluate the impact of neurosyphilis on the course of central nervous system (CNS) HIV infection.

The patient initially presented with bilateral optic neuritis and periventricular cranial MRI abnormalities in the context of syphilis. Blood was positive but cerebrospinal fluid testing was negative for specific syphilis markers and he was oligoclonal cerebrospinal fluid (CSF) band negative. He initially responded well to penicillin and corticosteriod treatment, but went on to develop the clinical syndrome of neuromyelitis optica (NMO). Testing for the presence of the serum autoantibody for aquaporin-4 was negative. This patient appears to represent another case of post-infectious NMO. Possible pathogenesis of this post-syphilis NMO syndrome in the patient is discussed.

Background: Laboratory detection of intrathecal synthesis of specific antitreponemal antibodies remains a challenge. Traditional syphilis serology is unable to provide a satisfactory result; therefore, several other diagnostic procedures were used to demonstrate central nervous system (CNS) involvement in this disease. The introduction of molecular methods makes today's laboratory testing easier., Objective: Our study used a new commercially available test, the INNO-LIA Syphilis Score, intended for use on serum samples, to detect specific antitreponemal antibodies in the cerebrospinal fluid (CSF) of patients with the tertiary stage of syphilis., Patients and Methods: We tested 26 patients suspected of neurological complications of late syphilis with conventional immunological tests such as VDRL-RPR, TPHA, FTA-ABS IgG, FTA-ABS-IgM, and the molecular INNO-LI Syphilis Score test for the presence of nontreponemal and treponemal antibodies. All tests were performed simultaneously in serum and CSF. The test results were evaluated with descriptive statistics and the probability was tested with an ANOVA test., Results: All 26 samples of serum were LIA-S (line immune assay in serum) positive and presented anticardiolipin and antitreponemal antibodies in high titer. Seventeen samples of CSF were LIA-L (line immune assay in liquor) positive and nine were LIA-L negative. Anticardiolipin and antitreponemal antibodies were detected only in the group of LIA-L positive samples. Anticardiolipin antibodies were present in two cases, antitreponemal (TPHA) in five cases, specific IgG (FTA-ABS IgG) in six cases, and specific IgM (FTA-ABS IgM) in one case. Six patients with antitreponemal antibodies in CSF presented with pathologic albumin index, two with a milder form, and four with a severe form. Two had a pathological IgG index and four a pathological IgM index. Altogether, two of the patients had laboratory signs of neurosyphilis., Conclusions: Detecting anticardiolipin and antitreponemal antibodies in CSF in patients with a late form of syphilis is laborious. Using the new INNO-LIA Syphilis Score molecular test, we were able to identify patients with silent neurosyphilis together with patients with active intrathecal synthesis of IgG antibodies. The development of a new generation of tests for the detection of specific antitreponemal antibodies in CSF offers a valuable tool for discovering possible CNS involvement in syphilis.

Objective: Paired serum and cerebrospinal fluid (CSF) specimens were investigated for Chlamydia pneumoniae-specific oligoclonal bands (OCBs) to determine band specificity in multiple sclerosis (MS)., Material and Methods: Serum and CSF samples were collected from patients with relapsing-remitting MS (n = 56), other inflammatory (n = 18) or non-inflammatory (n = 15) neurologic diseases, and from 10 healthy controls. OCBs were determined with affinity immunoblotting of C. pneumoniae-specific IgG onto antigen-coated nitrocellulose paper after protein separation with agarose isoelectric focusing., Results: Chlamydia pneumoniae-specific OCBs were present in 5 of 56 patients with MS, and in 3 of 18 patients with other inflammatory neurologic diseases., Conclusions: The intrathecal production of C. pneumoniae-specific oligoclonal IgG occurs in a minority of patients with MS. This intrathecal anti-C. pneumoniae reactivity is likely part of a polyspecific humoral immune response in MS.

Neurosyphilis can develop during any stage of syphilis. It has recently been reported that cerebrospinal fluid (CSF) data from patients with parenchymal or meningovascular neurosyphilis all show the absence of IgA synthesis and occasionally a concomitant IgM synthesis. In this context, it has been stated that intrathecal IgA synthesis contradicts the diagnosis of neurosyphilis. In our CSF analysis of four patients with definite neurosyphilis we observed an intrathecal synthesis of IgA, IgG and IgM in two patients. Our data are consistent with data of other studies suggesting that about 50% of patients with neurosyphilis show intrathecal synthesis of IgA. Therefore, intrathecal synthesis of IgA does not necessarily contradict the diagnosis of neurosyphilis. We hypothesize that intrathecal synthesis of IgA does not necessarily serve as a discriminating feature between neurosyphilis and other inflammatory central nervous system (CNS) disorders and that other laboratory parameters and the clinical picture have to be taken into account as well.

Objective: To define clinical and laboratory features that identify patients with neurosyphilis., Methods: Subjects (n=326) with syphilis but no previous neurosyphilis who met 1993 Centers for Disease Control and Prevention criteria for lumbar puncture underwent standardized history, neurological examination, venipuncture, and lumbar puncture. Neurosyphilis was defined as a cerebrospinal fluid (CSF) white blood cell count >20 cells/ microL or reactive CSF Venereal Disease Research Laboratory (VDRL) test result., Results: Sixty-five subjects (20.1%) had neurosyphilis. Early syphilis increased the odds of neurosyphilis in univariate but not multivariate analyses. In multivariate analyses, serum rapid plasma reagin (RPR) titer > or =1 : 32 increased the odds of neurosyphilis 10.85-fold in human immunodeficiency virus (HIV)-uninfected subjects and 5.98-fold in HIV-infected subjects. A peripheral blood CD4+ T cell count < or =350 cells/ microL conferred 3.10-fold increased odds of neurosyphilis in HIV-infected subjects. Similar results were obtained when neurosyphilis was more stringently defined as a reactive CSF VDRL test result., Conclusion: Serum RPR titer helps predict the likelihood of neurosyphilis. HIV-induced immune impairment may increase the risk of neurosyphilis.

Background: Neurosyphilis (NS) is nowadays a less frequent disease. Its incidence and clinical spectrum have changed over time., Objective: To estimate the incidence of NS and describe the clinical spectrum of NS in immunocompetent patients in the last decade., Methods: Demographic and clinical features, cerebrospinal fluid (CSF) changes, neuroimaging findings and outcome were retrospectively analyzed., Results: Forty-three patients met NS criteria. The yearly incidence was 0.2- 2.1 cases per 100,000 inhabitants. The mean age was 48.1 years, males being more frequently involved. The most frequent clinical patterns were meningovascular (30.2%), meningeal (25.6%) and general paresis (25.6%). Compared to prepenicillin series, we observed a decrease in late forms, mainly tabes dorsalis. CSF titers studied by the Venereal Disease Research Laboratory were higher in early NS. Neuroimaging findings were nonspecific. Outcome was better for early forms., Conclusions: Compared to the preantibiotic era, a lower frequency of late NS was observed, similar to that reported in other modern series which include patients with HIV infection. Therefore, this trend seems to be due to the impact of antibiotics rather than to HIV infection., (Copyright 2004 S. Karger AG, Basel)

In the past neurosyphilis and tuberculosis of the nervous system were the basic clinical problems in neurology. The decrease of the incidence rate has changed the situation. However, in the last few years, especially in connection with HIV infection, the incidence has even started to increase. In Poland the epidemiological situation is not alarming, but there exists some concern connected with the epidemic of syphilis and tuberculosis in countries near the Polish eastern border. In the laboratory diagnosis of syphilis the highest specificity and sensitivity has the TPHA test. In the therapy till now the best results are obtained with megadoses of penicillin. Early diagnosis of tuberculous meningitis, what is the decisive factor for positive results of the treatment can be obtained by PCR technique for detection of DNA genome of mycobacterium. In the treatment the method of choice is the concomitant use of four antimycobacterial drugs. However, there exists the serious problem of often observed drug resistance of mycobacterium.

Our objective is to assess the specificity and sensitivity, and thus elaborate the relevance, of different laboratory findings for the diagnosis of neurosyphilis. One hundred and fourteen HIV-negative pairs of serum and cerebrospinal fluid (CSF) samples were examined by the Venereal Disease Research Laboratory (VDRL) test, a fluorescent treponemal antibody-absorption (FTA-ABS) test, microhaemagglutination assay with Treponema pallidum antigen (MHA-TP) test (serum) and Treponema pallidum haemagglutination assay (TPHA) test (CSF); further, albumin, total protein, and total IgG were determined and, in the CSF, cell count was performed. The donors were 60 patients with active neurosyphilis and 54 healthy persons with a former history of syphilis and with persisting positive results in the T. pallidum haemagglutination tests (serum: MHA-TP, CSF: TPHA), who supplied specimens for control. Albumin quotient, IgG index, TPHA index, modified TPHA index, Intrathecally produced T. pallidum Antigen (ITpA) index, its 2 modifications and, in 12 samples, the adenovirus group antibody (AVGA)/TPHA index were ascertained. The specificity and sensitivity of the TPHA index were 100% and 98.3%, of the modified TPHA index 50.0% and 96.7%, of the ITpA index 42.6% and 90.0%, of the modified ITpA indices 51.8% and 68.3% (first modification) and 53.7% and 63.3% (second modification). The AVGA/TPHA index yielded a specificity of 91.7% (11/12). The CSF VDRL test was positive in 55/60 (91.7%) of samples from patients with neurosyphilis and in none of the controls (0/54). A CSF-TPHA titre greater than 1:320 was observed in 59/60 (98.3%) of the neurosyphilis specimens and in none of the controls (0/54). A TPHA index above an outcome of 70, a positive CSF-TPHA test at a titre greater than 1:320 and, with lower sensitivity, the criteria of the Centers for Disease Control (CDC) guidelines yield the most reliable results for laboratory support to a diagnosis of neurosyphilis. The modified TPHA index, the ITpA index, and its 2 modifications produce results of minor sensitivity and poor specificity. Observations on the AVGA/THPA index are too limited yet for judgement. The diagnostic significance of a CSF-TPHA titre above 320 needs further confirmation on a greater number of observations made by different laboratories.

Introduction: Neurosyphilis (NS) is an entity which still frequently presents to our Neurology Department. The prozone phenomenon occurs in approximately 2% of all cases of late primary syphilis or secondary syphilis; we have found no cases described of prozone and neurosyphilis occurring together., Clinical Case: We present the unusual case of a 44 year old patient with NS and dementia PGP (progressive general paralysis). Initially serum VDRL was negative, but in CSF reacted at dilutions of 1:32. When serum VDRL was repeated using dilutions, it was reactive 1:128 and serum FTA was also reactive. The patient was treated with i.v. crystalline penicillin, after which his condition improved., Conclusions: We wish to draw attention to the possibility that patients with a dementia syndrome and negative serum VDRL may have the prozone phenomenon, and the laboratory should therefore be asked to do serial dilutions.

Objectives: To establish a model of CNS invasion by Treponema pallidum and to use it to investigate the immune mechanisms responsible for clearance., Methods: Four macaques were intrathecally inoculated with 0.6 to 2.1 x 10(8) T. pallidum and underwent clinical examinations and blood and CSF collections every 1 to 2 weeks for 12 to 13 weeks. The following were determined: serum Venereal Disease Research Laboratory (VDRL) and microhemagglutination-T. pallidum reactivities, CSF-VDRL, CSF white blood cell (WBC) count, and the presence of viable T. pallidum in CSF by the rabbit infectivity test (all animals), as well as the presence of T. pallidum in CSF by reverse transcriptase (RT)-PCR, WBC phenotype by fluorescence-activated cell sorter, WBC cytokine production by RT-PCR, and brain MRI at 10 weeks (two animals)., Results: All animals became systemically infected and developed CSF pleocytosis that resolved after 8 weeks. CSF T. pallidum was detected from 2 to 8 weeks. CSF T lymphocytes were predominantly CD4+. Interferon-gamma (IFN-gamma) mRNA was consistently detected in CSF WBCs, but interleukin (IL)-4 and IL-5 were not. All animals remained clinically well. MRIs were normal., Conclusions: In this model, T. pallidum is cleared from the CNS just as in most humans with early syphilis. Local production of IFN-gamma likely participates in this process. This model could be used to clarify the effect of retrovirus-induced immunodeficiency on clearance of T. pallidum from the CNS and on the local CNS immune response.

The intrathecal synthesis of borrelial-specific IgM- and IgG-antibodies was studied in 67 patients with neuroborreliosis and in 14 patients with neurosyphilis (controls). Antibody concentrations in serum and in the cerebrospinal fluid were determined by an enzyme immunoassay (EIA) using, as antigens, a sonicate of Borrelia burgdorferi, the recombinant 14 kDa flagellin fragment, the outer surface protein C (22 kDa), and the high molecular mass protein p83 (83 kDa). In the sonicate EIA, IgG- and/or IgM-antibodies to Borrelia burgdorferi in serum were detected in all patients with neuroborreliosis and in 71% of patients with neurosyphilis. Intrathecal synthesis of borrelial-specific IgG- and/or IgM-antibodies was demonstrated in 82% of patients with neuroborreliosis and in 71% of patients with neurosyphilis. Immunoglobulin G- and/or IgM-antibodies in serum against any of the recombinant antigens were detected in 92% of patients with neuroborreliosis and in none of those with neurosyphilis. Intrathecal synthesis of IgG- and/or IgM-antibodies to individual recombinant antigens was demonstrated in 67% of patients with neuroborreliosis and in none of those with neurosyphilis. The sensitivity of the recombinant antigens in serum was almost equal to that of the sonicate EIA, whereas the recombinant antigens were clearly less sensitive in the estimation of the intrathecal specific immune response. It was concluded that in suspected cases of neuroborreliosis, the estimation of high specific antibodies in the recombinant EIA will be helpful in confirming the diagnosis.

A 33-year-old male HIV-positive patient developed pure right motor hemiplegia due to meningovascular neurosyphilis. 12 years ago he was successfully treated for early syphilis with a single dose of 2.4 million units penicillin G benzathine without subsequent evidence of new infection or disease progression. Repeated HIV tests remained negative until 1993 when the HIV infection was diagnosed. It is well known that Treponema pallidum, the etiologic agent of syphilis, may be detected in the cerebrospinal fluid during early infection. Thus the former recommended regimen of single-dose penicillin G benzathine may not reliably eradicate T. pallidum from the CNS. Residual organisms may serve as a reservoir for relapse and dissemination in an immunocompromised host.

IgG subclasses levels in the CSF and sera were measured in 15 patients with neurosyphilis. Intrathecal IgG and IgG subclasses synthesis was studied as well. There was an elevation of IgG1 and IgG3 subclasses in the CSF and IgG1 elevation in the sera of patients with neurosyphilis. General IgG index was elevated in 46% of the patients. This was due mainly to IgG1 and IgG3 intrathecal synthesis. Oligoclonal IgG bands were present in the CSF in seven out of 15 studied patients. These results may be helpful in the first stage of the diagnostic procedure before specific serological tests are performed.

Objective: To determine the prevalence of abnormal neurologic findings and cerebrospinal fluid abnormalities in hospitalized patients with serologic evidence of latent syphilis., Design: Cross-sectional survey., Methods: Consecutively admitted hospital inpatients from an inner-city population were screened for serologic evidence of syphilis with reactive plasma reagin and confirmatory fluorescent treponemal antibody absorption assays. In those with reactive tests, such clinical findings as a history of treatment for syphilis, neurologic abnormalities, presence of human immunodeficiency virus infection, and rapid plasma reagin titer were correlated with cerebrospinal fluid white blood cell count, protein level, and VDRL result., Results: Of 490 consecutive patients, 52 (11%) had serologic evidence of syphilis. Forty-three (83%) of these underwent lumbar puncture. Of the 43, 31 (72%) were seronegative for human immunodeficiency virus and 12 (28%) were seropositive. No patient had a reactive cerebrospinal fluid VDRL test. Cerebrospinal fluid abnormalities were seen in 32% of human immunodeficiency virus-seronegative patients and in 67% of human immunodeficiency virus-seropositive patients. Cerebrospinal fluid abnormalities were not predicted by history of treatment for syphilis, abnormal neurologic findings, or an elevated rapid plasma reagin titer. Cerebrospinal fluid IgG indexes in patients with elevated cerebrospinal fluid protein levels suggested that the protein abnormalities were not caused by local antibody production. Nonreactive cerebrospinal fluid fluorescent treponemal antibody absorption tests suggest that the cerebrospinal fluid abnormalities were not the result of neurosyphilis., Conclusions: There was a high prevalence of cerebrospinal fluid abnormalities in hospitalized patients with latent syphilis detected by routine screening. Because of the nonspecificity of the cerebrospinal fluid findings, routine lumbar puncture for such patients appears to contribute little to the treatment of latent syphilis.