Cerebrospinal Fluid Biomarkers of Symptomatic Neurosyphilis in People With HIV Compared with Uninfected Individuals.

We evaluated the diagnostic clinical performance characteristics (DCPC) of cerebrospinal fluid (CSF) total protein (TP), white blood cell count (WBC), and lactate (LA) with different cutoff points as adjunct biomarkers of confirmed or presumptive symptomatic neurosyphilis (NS) and the impact of HIV infection. From 5,640 participants who underwent lumbar punctures, 236 participants were included, and classified as either people with HIV (PWH) or people without HIV (PWoH) according to the CDC criteria for confirmed NS (n = 42), presumptive NS (n = 74), systemic syphilis (SS) (n = 38), serological diagnosis of syphilis (n = 18), PWH without SS and NS (n = 10), and negative control (n = 72). In PWoH, for presumptive NS, the combination of CSF TP > 45 mg/dL and/or WBC > 5.0 cells/mm3 is valuable for screening, whereas in PWH, it is not recommended for either screening or case-finding NS, however the DCPC were better in the suppressed group. In PWoH, the value of CSF TP > 45 mg/dL is adequate for both screening and confirmation of presumptive NS, subject to prevalence. For WBC count > 20 cell/mm3, the positive predictive value (PPV) of the test is almost perfect, suggesting a confirmatory test. In PWH, CSF TP is an inadequate marker of NS. The WBC count, with cutoffs of > 10 or > 20 cells/mm3, was moderately applicable for screening.As conclusions: CSF WBC count and TP showed distinct DCPC in confirmed or presumptive NS, better in the former. These biomarkers could be included for presumptive NS diagnosis. DCPC of these biomarkers for the diagnosis of NS is greatly affected by HIV co-infection.

Diagnostic role of CXCL13 and CSF serology in patients with neurosyphilis.

BACKGROUND: Considering the unknown prevalence of neurosyphilis in West China, and the confusing diagnosis of neurosyphilis, the role of CSF_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_CXCL13 and syphilis serology for neurosyphilis, another 116 CSF_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_TRUST ≥1:16 and sero_TPPA titre ≥1:10240) can be good predictors of neurosyphilis, as well as syphilis CSF serology (CSF_TPPA ≥1:320, CSF_TRUST and venereal disease research laboratory). The sensitivity of serology in neurosyphilis can be complemented by CSF_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_CXCL13 or other biomarkers should be further investigated.

Increased CCL24 and CXCL7 levels in the cerebrospinal fluid of patients with neurosyphilis.

BACKGROUND: Monocytes are recruited into the cerebrospinal fluid (CSF) of patients with neurosyphilis, suggesting abnormal chemokine expression. We aimed to investigate the aberrant expression of chemokines in the CSF of these patients. METHODS: CSF and serum samples were collected from patients with neurosyphilis between July 2017 and June 2019 in the Dermatology Department, Second Affiliated Hospital of Zhejiang University. Differences in the expression of 38 chemokines between patients with and without neurosyphilis were detected using RayBio® Human Chemokine Antibody Array C1. CCL24 and CXCL7 levels in the patients' CSF and serum were further measured using RayBio® CCL24 and CXCL7 ELISA kits. RESULTS: Ninety-three CSF and serum samples of patients with syphilis were collected. Antibody array analysis showed that the CSF levels of CCL24 (P = .0185), CXCL7 (P < .0001), CXCL13 (P < .0001), CXCL10 (P < .0001), and CXCL8 (P < .0001) were significantly higher in patients with than without neurosyphilis. ELISA confirmed significantly higher CCL24 and CXCL7 levels in the CSF of patients with than without neurosyphilis (CCL24: 6.082 ± 1.137 pg/mL vs 1.773 ± 0.4565 pg/mL, P = .0037; CXCL7: 664.3 ± 73.19 pg/mL vs 431.1 ± 90.54 pg/mL, P = .0118). Increased CCL24 and CXCL7 expression was seen throughout all neurosyphilis stages, had moderate diagnostic efficiency for neurosyphilis, and correlated poorly with CSF cell count and Venereal Disease Research Laboratory titer. CSF CCL24 levels also correlated poorly with CSF protein concentration. CONCLUSION: Abnormally high CSF chemokines levels may play a role in the pathogenesis of neurosyphilis.

[Expressions of CXCL8, CXCL10 and Th1 /Th2 cytokines in the serum and cerebrospinal fluid of patients with neurosyphilis].

OBJECTIVE: To investigate the levels of chemokines 8 and 10 (CXCL8 and CXCL10), Th1 cytokines (IL-2, IL-12 and IFN-γ) and Th2 cytokines (IL-6 and IL-10) in the serum and cerebrospinal fluid of patients with neurosyphilis and elucidate their roles in the immune response and pathogenesis of neurosyphilis. METHODS: Using ELISA, we detected the expressions of CXCL8, CXCL10, IL2, IL-2, IFN-γ, IL-6 and IL-10 in the serum and cerebrospinal fluid of 42 cases of neurosyphilis, 44 cases of syphilis and 40 cases of non-inflammatory diseases of the nervous system (the control group). RESULTS: The serum levels of CXCL8, CXCL10, IL-2, IL-12, IFN-γ, IL-6 and IL-10 were significantly lower in the neurosyphilis group than in the syphilis and control groups (P < 0.05), and so were they in the male than in the female neurosyphilis patients (P < 0.05). However, the expressions of CXCL8, CXCL10, IL-2, IL-12, IFN-γ, IL-6 and IL-10 in the cerebrospinal fluid were remarkably higher in the neurosyphilis group than in the syphilis and control groups (P < 0.05), and so were they in the male than in the female neurosyphilis patients (P < 0.05). CONCLUSIONS: Patients with neurosyphilis have cellular immune dysfunction, and their immune response involves CXCL8, CXCL10 and Th1 / Th2 cytokines.

Exosomal microRNA profiles from serum and cerebrospinal fluid in neurosyphilis.

OBJECTIVE: Changes in microRNAs (miRNAs) in the cerebrospinal fluid (CSF) are associated with different neurological diseases. Since alternations of miRNAs in neurosyphilis are insufficiently investigated, we analysed miRNAs in the CSF of patients suffering from neurosyphilis. METHODS: Exosomes were isolated from serum and CSF. Levels of 44 miRNAs were determined using quantitative real-time PCR-based miRNA array. RESULTS: In patients with neurosyphilis (NSP), miR-590-5p, miR-570-3p and miR-570-5p were upregulated in the CSF and serum, when compared with patients with syphilis without neurosyphilis (SP). miR-590-5p and miR-570-3p were significantly upregulated (p<0.001). The expression of miR-21-5p was upregulated only in the CSF of NSP. Significant downregulation was observed for miR-93-3p in the CSF and serum of NSP. No statistical difference was found in the expression of miR-7-5p, miR-1307-5p, miR-203a-3p, miR-16, miR-23b-3p and miR-27b-5p in the CSF and serum of NSP and SP. CONCLUSION: For the first time, regulation profiles in miRNA in the CSF and serum were analysed in NSP. We found significant differences in upregulation and downregulation. Therefore, miRNAs may be potential biomarkers for the presence of neurosyphilis.

The performance of rapid plasma reagin (RPR) titer in HIV-negative general paresis after neurosyphilis therapy.

BACKGROUND: Repeated nontreponemal serologic test for syphilis titers is recommended to evaluate treatment response. However, it is unknown whether serum rapid plasma reagin (RPR) titer can serve as a surrogate for determining the efficacy of treatment in general paresis (GP) remains unknown. METHODS: We retrospectively reviewed data from 105 GP patients, who were divided into two groups (62 CSF RPR+ patients and 43 CSF RPR- patients) according to reactive RPR test status in CSF. Clinical assessment included the Mini-Mental State Examination (MMSE) scores, CSF examinations (WBC count, protein concentration and RPR titer), and serum tests (RPR titer and TPPA). Among the 105 GP patients, 13 CSF RPR+ patients and 6 CSF RPR- patients had a 12 months follow-up of CSF, serum measures and MMSE. RESULTS: The median serum RPR titer was significantly higher in CSF RPR+ patients than that in CSF RPR- GP patients, 1:8 [IQR 1:4-1:32] vs. 1:4 [IQR 1:4-1:8] (P < 0.001). The number of CSF RPR+ patients with serum RPR titer≥1:32 was significantly higher when compared with CSF RPR- patients (P = 0.001). For CSF RPR+ patients, the MMSE scores improved or remained constantly after penicillin treatment. For CSF RPR+ patients, the CSF RPR titer declined four-fold in 85% (11/13) of the patients, whereas the serum RPR titer declined four-fold in only 46% (6/13) of the patients, the odds ratio is 6.4 (95% confidence interval 1.0-41.2). CONCLUSIONS: A four-fold decline in CSF RPR titer is a good predictor for treatment efficacy in CSF RPR+ GP patients within 12 months after the completion of therapy.

Comparison of Clinical and Laboratory Characteristics of General Paresis and Non-Neurosyphilis Dementia.

BACKGROUND: The differential diagnosis of general paresis (GP) and non-neurosyphilis (NS) dementia is not clearly defined. The present study examined the differences in clinical and laboratory features of GP and non-NS dementia. MATERIALS AND METHODS: We retrospectively examined clinical and laboratory features of 85 GP patients and 196 non-NS dementia patients. Data were collected from Zhongshan Hospital between June 2005 and June 2014. RESULTS: The GP group had a higher percentage of males (83.53%, 71/85) and younger median age ([52 [interquartile range 47.0-61.0] vs. 76 [68.3-82.0] years) than the non-NS dementia group. GP have higher Mini-Mental State Examination (MMSE; Z = -5.809; p = 0.000) than non-NS dementia. Distribution of CDR scores were significantly higher in the non-NS group than GP group (χ2 = 29.153; p = 0.000). The laboratory findings showed significantly different total cholesterol (CH), low-density lipoprotein CH and homocysteine levels between the 2 groups. Serologic testing for syphilis revealed that the GP group had higher seropositive rapid plasma reagin (RPR) and Treponema pallidum particle agglutination (TPPA) rates than the non-NS dementia group (96.47% [82/85] vs. 0.51% [1/196], Z = -2.663, p = 0.008; 100% [85/85] vs. 1.02% [2/196], Z = -2.663, p = 0.008). Interestingly, cerebrospinal fluid (CSF) biochemical indices, including pleocytosis rates, increased protein levels, and positive RPR and TPPA rates in the GP group were higher than that in the non-NS dementia group. CONCLUSIONS: Based on these preliminary data, patients with clinically evident symptoms of dementia, especially middle-aged males, should undergo blood tests for syphilis. All patients with positive serology results should undergo CSF examinations to diagnose GP dementia before further pharmaceutical and behavioral interventions.

Neurosyphilis Increases Human Immunodeficiency Virus (HIV)-associated Central Nervous System Inflammation but Does Not Explain Cognitive Impairment in HIV-infected Individuals With Syphilis.

BACKGROUND: Individuals infected with human immunodeficiency virus (HIV) who have previously had syphilis may have cognitive impairment. We tested the hypothesis that neurosyphilis causes cognitive impairment in HIV by amplifying HIV-related central nervous system (CNS) inflammation. METHODS: HIV-infected participants enrolled in a study of cerebrospinal fluid (CSF) abnormalities in syphilis underwent the mental alternation test (MAT), venipuncture, and lumbar puncture. CSF concentrations of chemokine (C-X-C motif) ligand 10 (CXCL10), chemokine (C-C motif) ligand 2 (CCL2), and neurofilament light (NFL) were determined by commercial assays. The proportion of peripheral blood mononuclear cells (PBMCs) and of CSF white blood cells (WBCs) that were activated monocytes (CD14+CD16+) was determined by flow cytometry. Neurosyphilis was defined as detection of Treponema pallidum 16S RNA in CSF or CSF white blood cells (WBCs) >20/uL or a reactive CSF-Venereal Disease Research Laboratory (VDRL) test; uncomplicated syphilis was defined as undetectable CSF T. pallidum, CSF WBCs ≤5/uL and nonreactive CSF-VDRL. MAT <18 was considered low. RESULTS: Median proportion of PBMCs that were activated monocytes (16.6 vs. 5.3), and median CSF CXCL10 (10658 vs. 2530 units), CCL2 (519 vs. 337 units) and HIV RNA (727 vs. 50 c/mL) were higher in neurosyphilis than in uncomplicated syphilis (P ≤ .001 for all comparisons). Neurosyphilis was not related to low MAT scores. Participants with low MAT scores had higher median CSF CXCL10 (10299 vs. 3650 units, P = .008) and CCL2 (519 vs. 365 units, P = .04) concentrations than those with high MAT scores. CONCLUSIONS: Neurosyphilis may augment HIV-associated CNS inflammation, but it does not explain cognitive impairment in HIV-infected individuals with syphilis.

Syphilitic dementia and lipid metabolism.

BACKGROUND AND PURPOSE: Chronic syphilitic infection may lead to dementia. It is in general paresis (GP), which is the major late form of neurosyphilis, that cognitive impairment frequently occurs. The association between lipid metabolism and GP is unclear. METHODS: In this study, serum lipids were studied in 188 GP patients, in 241 syphilitic patients without neurosyphilis and in 539 healthy controls. The Mini-Mental State Examination (MMSE) was tested in all GP patients. Thirty-five GP patients had a follow-up evaluation 3 months after penicillin treatment. RESULTS: Significantly lower apolipoprotein A-I (apoA-I) levels were found in GP and in syphilitic patients without neurosyphilis compared to controls. In the 25-44-year-old groups, the male syphilitic patients without neurosyphilis had lower serum apoA-I levels and higher apolipoprotein B (apoB)/apoA-I ratios compared with female patients. A follow-up evaluation of 35 GP patients 3 months after penicillin treatment showed a significant positive correlation between increased apoA-I levels and MMSE scores. CONCLUSION: Abnormal apoA-I metabolism may be associated with the decline of cognitive performance. Long-term decrease of apoA-I level and higher apoB/apoA-I ratio may be contributing factors in syphilitic dementia. These results suggest a similar overlap between syphilitic dementia and lipid metabolism to that occurring in Alzheimer's disease.

Clinical and neuropsychological characteristics of general paresis misdiagnosed as primary psychiatric disease.

BACKGROUND: Neurosyphilis is caused by the invasion of Treponema pallidum into the central nervous system. General paresis (GP) is a type of neurosyphilis. The main manifestation of general paresis is dementia; however, this is different from the other types of dementia, which can be cured by adequate doses of penicillin in the early stage. Neurosyphilis is the "great imitator" because it can mimic many types of medical disorders. In addition, the manifestations of neurosyphilis are not typical. Psychiatric disorders as a cause of general paresis have become more common due to the use of antibiotics. Patients with a psychiatric manifestation are often misdiagnosed. The purpose of this study was to explore the differences in the clinical and neuropsychological characteristics of general paresis between patients misdiagnosed as having a primary psychiatric disease and patients diagnosed correctly upon seeing a doctor. The results may assist clinicians in the early identification of neurosyphilis with a mental disorder. METHOD: The demographic and clinical manifestations, laboratory tests, and neuroimaging and neuropsychological characteristics were analysed in 55 general paresis patients with psychiatric disorders, including 29 patients misdiagnosed as primary psychiatric disease and 26 patients diagnosed as having general paresis after being seen once by a doctor. RESULT: All of the patients had positive assay results for cerebral spinal fluid (CSF) Treponema pallidum hemagglutination (TPHA). Only 43.3 % of misdiagnosed patients and 30.8 % of general paresis patients had positive results for the CSF rapid plasma reagin (RPR) test; 96.4 % patients had abnormal neuroimaging. Mood disturbances were the most common psychiatric disorder in the general paresis patients, especially agitation, between the two groups (patients with general paresis who were misdiagnosed as having primary psychiatric disease and patients who had never been misdiagnosed) (p = 0.011). CONCLUSION: Our findings reinforce the importance of performing serologic testing for syphilis. This should be a part of the evaluation of patients with psychiatric disorders, especially patients with cognitive impairment. When the syphilis serology is positive, the patient should be examined thoroughly for neurosyphilis by lumbar puncture. Brain imaging could also aid the physician in discriminating these patients from those with a functional mental disorder.

Point-of-care treponemal tests for neurosyphilis diagnosis.

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.

The great imitator--still today! A case of meningovascular syphilis affecting the posterior circulation.

Cerebral ischemia due to meningovascular syphilis is rare and more frequently affects the anterior circulation than the posterior circulation. We describe clinical features and imaging studies of a 50-year-old patient with Parinaud syndrome and a syphilitic dorsal midbrain infarction. Brain magnetic resonance imaging indicated vasculitis of the posterior circulation. The diagnosis of meningovascular syphilis was established by serum and cerebrospinal fluid examinations. Although rare, because of the high impact on treatment, clinicians should always be aware of meningovascular syphilis in the differential diagnosis of stroke, particularly in young and male patients with cryptogenic stroke.

Refining a non-invasive prediction model for neurosyphilis diagnosis by using immunoassay to detect serum anti-TP0435 (TP17) and TP0574 (TP47) IgG antibodies: two-centre cross-sectional retrospective study in China.

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.

Elevated cerebrospinal fluid interleukin-17A and interferon-γ levels in early asymptomatic neurosyphilis.

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.

The rapid plasma reagin test cannot replace the venereal disease research laboratory test for neurosyphilis diagnosis.

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.

Intrathecal Synthesis Index of Specific Anti-Treponema IgG: a New Tool for the Diagnosis of Neurosyphilis.

Neurosyphilis (NS) diagnosis is challenging because clinical signs are diverse and unspecific, and a sensitive and specific laboratory test is lacking. We tested the performance of an antibody index (AI) for intrathecal synthesis of specific anti-Treponema IgG by enzyme-linked immunosorbent assay (ELISA) for NS diagnosis. We conducted a retroprospective monocentric study including adults with neurological symptoms who had serum and cerebral spinal fluid (CSF) samples collected between 2006 and 2021. Two NS definitions were used. NS1 included patients with neurological symptoms, positive Treponema pallidum particle agglutination (TPPA) serology, and CSF-TPPA of ≥320, as well as CSF-leukocytes of >5 cells/mm3 and/or CSF-protein of >0.45 g/L and/or a reactive CSF-VDRL/RPR test. NS2 included patients with acute ocular and/or otologic symptoms, positive TPPA serology, and a response to NS treatment. Controls were patients with central nervous system disorders other than neurosyphilis. Anti-Treponema pallidum IgG were measured simultaneously in serum and CSF, and AI was calculated according to Reiber diagram. We assessed the AI test area under the curve (AUC), sensitivity/specificity, and estimated positive and negative predictive values. In total, 16 NS1 patients, 11 NS2 patients, and 71 controls were included. With an AI of ≥1.7 as a positive test for NS diagnostic, specificity was 98.6% (95% confidence interval [CI 95%] of 92.4 to 100.0) and sensitivity was 81.3% (CI 95% of 54.4 to 96.0) for NS1 and 98.6% (CI 95% 92.4 to 100.0) and 27.3% (CI 95% 6.0 to 61.0), respectively, for NS2. Positive and negative predictive values were >95% for NS1 and >85% for NS2, for prevalence above and below 20%. Measuring an AI for intrathecal synthesis of specific anti-Treponema pallidum IgG is a new promising tool highly specific for NS diagnosis. IMPORTANCE In the context of a lack of a gold standard for the diagnosis of neurosyphilis due to either nonspecific or nonsensitive tests, we present in this article a new promising tool highly specific for NS diagnosis. This new test involves measuring an intrathecal synthesis index of specific anti-Treponema IgG by ELISA.

Expression of matrix metalloproteinases and their tissue inhibitors in the serum and cerebrospinal fluid of patients with HIV-1 infection and syphilis or neurosyphilis.

The potential mechanisms for altered matrix metalloproteinase (MMP) or tissue inhibitors of matrix metalloproteinase (TIMP) function in patients with syphilis and HIV-1 co-infection (HIV-S) was unclear. To determine the expression of MMP-2, 9 and TIMP-1, 2, 4 in the serum and cerebrospinal fluid (CSF) of HIV-S patients, a total of 20 HIV-S patients and 8 controls were enrolled in a HIV-1 clinical cohort for diagnosis of neurosyphilis in Taiwan. Serum and CSF concentrations of MMP-2, 9, and TIMP-1, 2, 4 were determined by ELISA. Gelatin zymography was used to detect the expression of MMP-2 and MMP-9 in the CSF. Neurosyphilis was defined as a CSF white blood cell count ≥ 20 cells/µL or a reactive CSF Venereal Disease Research Laboratory (VDRL). All the patients with HIV-S were males. Most (85%) had sex with men (MSM) and serum rapid plasma reagin (RPR) titers of ≥ 1:32. The median age was 35 years (IQR 30-43). The median CD4 T cell counts at the time of the diagnosis of syphilis were 270 cells/µL (IQR 96-484). Ten patients (50%) had neurosyphilis based on a reactive CSF VDRL test (n=8) or increased CSF white cell counts ≥ 20/µL (n=2). The concentrations of CSF MMP-9, TIMP-1, and TIMP-2 were significantly higher in patients with HIV-S than the controls (P<0.05). The CSF TIMP-4 concentrations were significantly lower in those with HIV-S (452 pg/ml) than controls (3101 pg/ml), P<0001. There were no significant differences in serum concentrations between the groups. The only finding that distinguished HIV-1 patients with from those without neurosyphilis is a significant higher expression of CSF MMP-9. In conclusion, the MMP/TIMP system was found to be dysregulated in patients with HIV-S regardless of whether they met the laboratory definition of neurosyphilis. The CSF level of MMP-9 was the only measure that distinguished those with or without neurosyphilis.

Response of HIV-infected patients with syphilis to therapy with penicillin or intravenous ceftriaxone.

BACKGROUND: Ceftriaxone is commonly used as an alternative antibiotic drug in treating syphilis but clinical data on its efficacy are limited. OBJECTIVE: To evaluate the response of HIV-infected patients with active syphilis to treatment with penicillin or ceftriaxone. - METHODS: A retrospective study involving 24 consecutive patients with a positive Veneral Disease Research Laboratory test (VDRL) and at least one specific treponemal test. 12 patients were treated with different regimens of high-dose penicillin G for at least 2 weeks. Another 12 patients were treated with ceftriaxone 1-2g per day intravenously for 10-21 days. - RESULTS: After a median follow up of 18,3 months all patients of the penicillin-treated group and 11 of 12 ceftriaxone-treated patients showed a ≥ 4-fold decline in VDRL-titers; 91% of them already within 6 months after therapy. - CONCLUSION: Our serological data demonstrate a comparable efficacy of currently recommened penicillin and ceftriaxone treatment regimens for active syphilis in HIV-infected patients.

Neurosyphilis and organic psychosis.

Neurosyphilis is a Central Nervous System infection that can manifest as a psychiatric condition. Although neurosyphilis is not widely considered in the differential when patients present with psychiatric symptoms, routine Rapid Plasma Reagin (RPR) screening is indicated when assessing new-onset psychiatric illness. This case report will illustrate the usefulness of RPR testing for patients admitted to inpatient or outpatient psychiatric treatment.