Neurosyphilis is characterized by a compartmentalized and robust neuroimmune response but not by neuronal injury.

BACKGROUND: Neurosyphilis is increasing in prevalence but its pathophysiology remains incompletely understood. This study assessed for CNS-specific immune responses during neurosyphilis compared to syphilis without neurosyphilis and compared these immune profiles to those observed in other neuroinflammatory diseases. METHODS: Participants with syphilis were categorized as having neurosyphilis if their cerebrospinal fluid (CSF)-venereal disease research laboratory (VDRL) test was reactive and as having syphilis without neurosyphilis if they had a non-reactive CSF-VDRL test and a white blood cell count <5/µL. Neurosyphilis and syphilis without neurosyphilis participants were matched by rapid plasma reagin titer and HIV status. CSF and plasma were assayed for markers of neuronal injury and glial and immune cell activation. Bulk RNA sequencing was performed on CSF cells, with results stratified by the presence of neurological symptoms. FINDINGS: CSF neopterin and five CSF chemokines had levels significantly higher in individuals with neurosyphilis compared to those with syphilis without neurosyphilis, but no markers of neuronal injury or astrocyte activation were significantly elevated. The CSF transcriptome in neurosyphilis was characterized by genes involved in microglial activation and lipid metabolism and did not differ in asymptomatic versus symptomatic neurosyphilis cases. CONCLUSIONS: The CNS immune response observed in neurosyphilis was comparable to other neuroinflammatory diseases and was present in individuals with neurosyphilis regardless of neurological symptoms, yet there was minimal evidence for neuronal or astrocyte injury. These findings support the need for larger studies of the CSF inflammatory response in asymptomatic neurosyphilis. FUNDING: This work was funded by the National Institutes of Health, grants K23MH118999 (S.F.F.) and R01NS082120 (C.M.M.).

[Neurosyphilis or not - a case of a differential diagnostic challenge]. / Neurosyphilis vagy nem ­ egy differenciáldiagnosztikai kihívás esete.

We report the case of a 42-year-old woman with paraparesis associated with transverse myelitis. For differential diagnostics detailed microbiological, cerebrospinal fluid (CSF) and neuroimaging examinations were performed. Syphilis was confirmed, but diagnosis of neurosyphilis was only probable based on the CSF microbiological test results. The beneficial treatment response to application of the therapeutic protocol for syphilis supported the supposed diagnosis of syphilis-associated myelitis in our case. In this case report we reviewed the differential diagnostic tools of myelopathies/myelitis.
Nowadays regarding to growing prevalence of syphilis worldwide physicians should face on its presence and medical consequences.

Clinical prediction and diagnosis of neurosyphilis in HIV-negative patients: a case-control study.

BACKGROUND: Early diagnosis and treatment of neurosyphilis is of great significance for regression. There is no gold standard for the diagnosis of neurosyphilis. We did this study to explore the factors associated with the clinical diagnosis of neurosyphilis and assess their accuracy for the diagnosis of neurosyphilis. METHODS: We retrospectively reviewed 100 cases of syphilis patients who underwent lumbar puncture at a major dermatology hospital in Guangzhou, China between April 2013 and November 2016. Fifty patients who were clinically diagnosed with neurosyphilis were selected as case group. Control group consisted of 50 general syphilis patients who were matched with age and gender. The records of patients were reviewed to collect data of socio-demographic information, clinical symptom, and laboratory indicators. Multivariable logistic regression was used to explore diagnostic indictors, and ROC analysis was used to assess diagnostic accuracy. RESULTS: Neurological symptoms (odds ratio (OR) = 59.281, 95% CI:5.215-662.910, P = 0.001), cerebrospinal fluid (CSF) Treponema pallidum particle agglutination (TPPA) titer (OR = 1.004, 95% CI:1.002-1.006, P < 0.001), CSF protein (OR = 1.005, 95% CI:1.000-1.009, P = 0.041), and CSF white blood cell (WBC) (OR = 1.120, 95% CI:1.017-1.233, P = 0.021) were found to be statistically associated with neurosyphilis. In ROC analysis, CSF TPPA titer had a sensitivity of 90%, a specificity of 84%, and an area under curve (AUC) of 0.941. CONCLUSION: CSF TPPA can potentially be considered as an alternative test for diagnosis of neurosyphilis. Combining with neurological symptoms, CSF protein, CSF WBC, the diagnosis would have a higher sensitivity.

Clinical Manifestations and Cerebrospinal Fluid Status in Ocular Syphilis.

PURPOSE: To review the clinical manifestations, cerebrospinal fluid findings and outcomes of patients diagnosed with ocular syphilis. METHODS: Retrospective case review of all patients treated with ocular syphilis at Groote Schuur Hospital in Cape Town, South Africa between January 2008 and January 2013. RESULTS: A total of 77 eyes of 49 patients were included. Panuveitis was the most common presenting sign (48.9%). A lumbar puncture was performed on 37 patients (75.5%) and 64.8% (24/37) of samples had positive treponemal testing (CSF-FTA) while 24.3% (9/37) had positive non-treponemal testing (CSF-VDRL). Elevated CSF lymphocyte cell count was a strong predictor of neurosyphilis (p = 0.06 for CSF-FTA positive samples and p = 0.03 for CSF-VDRL positive samples). CONCLUSION: The majority of patients (64.8%) who underwent lumbar puncture had cerebrospinal fluid findings suggestive of neurosyphilis. Elevated CSF lymphocyte cell count and total protein count are highly suggestive of neurosyphilis.

Optic neuritis caused by the re-emerging great masquerader.

A 49-year-old Caucasian woman presented with subacute headache and right eye pain associated with scotoma, blurred vision and photophobia. MRI was suggestive of optic neuritis of the right optic nerve and she was treated with steroids. Due to persistent symptoms, a lumbar puncture was performed and cerebrospinal fluid analysis was positive for venereal disease research laboratory and rapid plasma reagin titres. On further history, she recalled experiencing an illness associated with diffuse rash, likely secondary syphilis, 1-2 months prior. She tested negative for HIV. She was treated with intravenous penicillin for 2 weeks following which she experienced improvement in symptoms.

Frequency of Treponema pallidum invasion into cerebrospinal fluid in primary or secondary early-stage syphilis.

Frequency of Treponema pallidum invasion into cerebrospinal fluid (CSF) has not been clear at this present. Since it is impossible to culture T. pallidum in vitro at this present, we need molecular based-approach to detect it in CSF. Additionally, neurosyphilis is usually a late sequela, however it might result in asymptomatic neurosyphilis even at primary or secondary syphilis. This study was to reveal the frequency of T. pallidum invasion into CSF especially at primary or secondary syphilis with polymerase chain reaction (PCR) test. All patients were visited the Aichi Medical University Hospital or Izumi ladies' clinic between 2016 and 2017. Clinical CSF samples were collected from patients with early and late stages of syphilis. The PCR was done using primers targeting the tpN47gene. CSF samples were collected from 9 patients (4 patients with primary syphilis, 3 with secondary syphilis, and 1 early latent syphilis and 1 with late latent syphilis). PCR showed positive reaction in 2 of 7 (28.6%) primary and secondary syphilis patients, in 1 of 1 (100%) early latent syphilis patients, and in 1 of 1 (100%) late latent syphilis patients. Despite its lack of sensitivity for use alone as a diagnostic test, this PCR test should be preferred for the diagnosis of neurosyphilis. Because, T. pallidum was detected in the 28.6% CSF of patients at primary and secondary syphilis, which indicated that they invade the central nervous system from the early stages of infection. However, studies in a larger population are required to confirm these preliminary results.

Meningovascular neurosyphilis with basilar artery thrombosis in HIV patient.

Currently, neurosyphilis is an uncommon disease and may occur at any stage of syphilis. Co-infection of syphilis with HIV can affect the clinical course. We report a case of meningovascular neurosyphilis in a patient with HIV in whom basilar artery thrombosis and reactive VDRL in CSF were detected. Treatment with penicillin was instituted with adequate response showing clinical improvement. Neurosyphilis is a differential diagnosis in young patients with cerebral infarction, especially in HIV patients.

CXCL13 and TH1/Th2 cytokines in the serum and cerebrospinal fluid of neurosyphilis patients.

Neurosyphilis is a chronic infectious disease with involvement of central nervous system infection by Treponema pallidum. This study was to investigate the contents of B lymphocyte chemokine 1 (BLC-1/chemokine [C-X-C motif] ligand 13), Th1 cytokines (Interleukin [IL]-2, IL-12, and Interferon [IFN]-γ), and Th2 cytokines (IL-6 and IL-10) in serum and cerebrospinal fluid (CSF) of HIV-negative patients with neurosyphilis before and after treatment, aiming to elucidate roles of CXCL13 and Th1/Th2 cytokines in immune response to and pathogenesis of neurosyphilis.Enzyme-linked immunosorbent assay was employed to detect the contents of CXCL13, IL-2, IL-12, IFN-γ, IL-6, and IL-10 in serum and CSF of 47 HIV-negative patients with neurosyphilis, 36 syphilis patients without neurological involvement and 23 controls (noninfectious intracranial disease) before, 3 and 12 months after treatment with high dose penicillin.Results showed that there was no significant difference in blood CXCL13 content among 3 groups (P > .05); CSF CXCL13 content in neurosyphilis patients was significantly higher than in other 2 groups (P < .001), and positively related to leucocyte count, protein concentration, and IgG index. IL-6 and IL-10 contents of the serum and CSF in neurosyphilis patients were markedly higher than in other 2 groups (P < .05 or .01), but IL-2, IL-12, and IFN-γ of the serum and CSF were significantly lower than in other 2 groups (P < .05 or .01). The IL-6, IL-10, IL-2, IL-12, and IFN-γ contents of the serum and CSF were comparable between control group and syphilis group (P > .05). CSF CXCL13 content was positively related with IL-6 and IL-10 content, while negatively related to IL-12 content in neurosyphilis patients. CSF IL-6 content was negatively related with IL-12 content. In neurosyphilis patients, the CSF CXCL13 content reduced significantly at 3 and 12 months (P < .001), the CSF IL-2 and IL-12 contents increased significantly at 12 months, and CSF IL-6 contents reduced significantly at 12 months after treatment (P < .05 or .01).It is concluded that neurosyphilis patients did not have normal immune function. CXCL13 and Th1/Th2 cytokines are involved in the immune response of neurosyphilis patients. CSF CXCL13 and Th1/Th2 cytokines contents may be used for the diagnosis and evaluation of therapeutic efficacy of neurosyphilis.

Clinical manifestations and cerebrospinal fluid status in ocular syphilis in HIV-Negative patients.

BACKGROUND: Syphilis with ocular involvement has reemerged as a critical health problem. The aim of the present study was to explore the clinical manifestations and cerebrospinal fluid (CSF) status in ocular syphilis in human immunodeficiency virus (HIV)-negative patients. METHODS: The clinical records of patients with ocular syphilis presenting to the Shanghai Xuhui Central Hospital in the period from January 2011 to December 2012 were retrospectively reviewed. RESULTS: The median age of 25 HIV-negative patients with ocular syphilis was 53 years, 18 patients (72.0 %) were males and 7 (28.0 %) were females. None of them self-identified themselves as men who had sex with men (MSM). The ocular lesions included: uveitis (13 cases), optic neuropathy (6 cases), retinal vasculitis (5 cases), retinal detachment (3 cases), and neuroretinitis (4 cases). Serum toluidine red unheated serum test (TRUST) titer ranged from 1 to 512, with a median of 64. Overall, 18 (72.0 %) of the 25 patients had abnormal CSF results, 15 (60.0 %) CSF samples had elevated white blood cell counts, 13 (52.0 %) had elevated protein levels, and 9 (36.0 %) had reactive CSF Venereal Disease Research Laboratory (VDRL) test, respectively. Mann-Whitney U tests showed higher serum TRUST titer (>32) correlated with the abnormal CSF results. CONCLUSIONS: The demographic characteristics of patients with ocular syphilis in this study were different from previous reports. The study showed a high CSF abnormal rate in HIV-negative patients. The recommendation for CSF examination from all patients with ocular syphilis, including HIV-negative cases, is strongly supported by the present data.

High frequency of neurosyphilis in HIV-positive patients diagnosed with early syphilis.

BACKGROUND: Syphilis is an infection frequently seen with HIV, and European guidelines on the management of syphilis suggest that HIV-infected patients may have an increased risk of early neurological involvement, sometimes asymptomatic. Recent study shows a relationship between neurosyphilis and cerebrospinal fluid (CSF) HIV viral load (VL), which in turn may be associated with subsequent neurocognitive decline. OBJECTIVES AND METHODS: The aim of the study was estimation of the frequency of neurosyphilis among HIV-positive patients with early syphilis. The study included all patients diagnosed with early syphilis who had lumbar puncture performed in the years 2008-2012. Analysis included CSF parameters (serology, mononuclear cells, protein, glucose, chloride and lactate levels), CD4 count, serum VL and highly active antiretroviral therapy (HAART). Diagnosis of neurosyphilis was confirmed by CSF serology [positive fluorescent treponemal antibody and/or Venereal Disease Research Laboratory (VDRL) test(s)] and increased number of mononuclear cells. Statistical analysis included χ(2) tests with an accepted significance level of P < 0.05. RESULTS: Lumbar puncture was performed in 72 patients, all men, with median age 33 (interquartile range 11) years. Neurosyphilis was confirmed in 65 (90.28%) of the patients. No statistically significant association between CSF parameters and CD4 count was found. However, statistically significant associations were found only between pleocytosis and serum VL > 1000 HIV-1 RNA copies/mL (P = 0.0451), as well as HAART treatment (P = 0.0328). The proportion of confirmed neurosyphilis cases, also in patients with low serum VDRL titres, was very high. CONCLUSIONS: Considering the high proportion of patients who objected to having LP performed in the absence of neurological symptoms and the risk associated with this procedure, it may be preferable to use treatments with good CNS penetration in all HIV-positive patients with early syphilis.

Detection of Treponema pallidum Sp. Pallidum DNA in Cerebrospinal Fluid (CSF) by Two PCR Techniques.

BACKGROUND: Laboratory diagnosis of neurosyphilis is complicated especially when it is asymptomatic, no single laboratory test result being appropriate to diagnose central nervous system infectivity caused by Treponema pallidum. Our objective was to evaluate two polymerase chain reaction (PCR) techniques for the detection of T. pallidum DNA in the cerebrospinal fluid (CSF) of patients with syphilis. METHODS: One hundred twenty-four CSF samples from patients with reactive blood tests for syphilis were obtained. Two PCR techniques (47-PCR, polA-PCR) were used to detect T. pallidum DNA. The laboratory criteria used for the diagnosis of neurosyphilis to which the PCR techniques were compared were those recommended by the IUSTI: 2008 European guidelines on the management of syphilis. RESULTS: Treponema pallidum DNA was detected amplified in 37 of 124 (29.8%) and 30 of 124 (24.2%) samples with the 47-PCR and polA-PCR, respectively. Sensitivities were 75.8% and 69.7% and specificities 86.8% and 92.3%, respectively, for 47-PCR and polA-PCR techniques, respectively. The three CSF samples of patients with primary syphilis did not fulfill the criteria of neurosyphilis and DNA was only detected in one by the 47-PCR. In samples from secondary syphilis and neurosyphilis, three of nine and nine of nine respectively, results were coincident for the two PCR techniques and neurosyphilis criteria. Major discrepancies between the two PCR techniques and neurosyphilis diagnostic criteria were observed in latent syphilis. CONCLUSION: Beyond some limitations of the study, which are discussed here, both PCR techniques seem to be useful for the diagnosis of neurosyphilis, although 47-PCR presents a higher sensitivity and polA-PCR a higher specificity.

Syphilis and neurosyphilis: HIV-coinfection and value of diagnostic parameters in cerebrospinal fluid.

BACKGROUND: Neurosyphilis might be difficult to diagnose particularly in asymptomatic patients and patients with HIV-coinfection. The objective of this study was to evaluate current diagnostic standards for neurosyphilis in HIV-positive and -negative patients. METHODS: We studied retrospectively patients with an active syphilis infection who had additionally undergone lumbar puncture. Patients where the criteria for the diagnosis of a definite or probable neurosyphilis were applicable were further analyzed for clinical symptoms, CSF, HIV-status as well as Treponema pallidum testing in serum and CSF. Correlation analysis of categorical variables was done by using the Chi-square test or in cases of small sample sizes the exact test of Fisher. p values ≤0.05 were considered significant. RESULTS: Eighty-nine patients were diagnosed with syphilis. All necessary criteria for the diagnosis of a neurosyphilis were available in 67 of them including 35 HIV-positive and 32 HIV-negative patients. A definite neurosyphilis could be retrospectively diagnosed in 13 and a probable in another 25 cases. Normal CSF results were more likely in HIV-negatives (p = 0.016). A neurosyphilis was correlated to a CSF pleocytosis > 5 cells/µl and to an albumin quotient >7.8 mg/dl regardless of a parallel HIV infection. HIV-positives had more frequently a CSF-RPR titre >1:4 than HIV-negatives (p = 0.031). However, the RPR test in CSF in definite or probable neurosyphilis had a sensitivity of only 21 %. DISCUSSION: Our data show that a pleocytosis and an elevated albumin quotient correlate with neurosyphilis. However, the CSF-RPR test as gold standard in neurosyphilis diagnostics has a very low sensitivity.

Treponemal antibody in CSF and cellular immunity in peripheral blood of syphilitic patients with persisting positive rapid plasma regain.

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.

Expression of CXCL2 in the serum and cerebrospinal fluid of patients with HIV and syphilis or neurosyphilis.

The potential mechanisms for blood-brain barrier damage and the diagnosis of neurosyphilis in HIV patients co-infected with syphilis (HIV-S) are unclear. The aim of the study was to determine the expression of CXCL2 in the serum and cerebrospinal fluid (CSF) of HIV-S patients. A total of 34 HIV patients and 7 controls were enrolled in a HIV clinical cohort for diagnosis of neurosyphilis in Taiwan. Serum and CSF concentrations of CXCL2 were determined by ELISA. Neurosyphilis was defined as a CSF white blood cell count of ≧20 cells/µl or a reactive CSF Venereal Disease Research Laboratory (VDRL). Demographics and medical histories were collected. All the patients with HIV-S were males. Most (80%) had sex with men (MSM) and serum rapid plasma reagin (RPR) titers of ≧1:32. The medium age was 37 (range 21-68) years. The medium CD4 T cell counts at the time of the diagnosis of syphilis were 299 (range 92-434) cells/µl. Eight patients (24%) had neurosyphilis based on a reactive CSF VDRL test (n = 5) or increased CSF white blood cell counts of ≧20 cells/µl (n = 3). The concentrations of CSF CXCL2 were significantly higher in patients with HIV and neurosyphilis as compared to HIV with syphilis, HIV, and controls (p = 0.012). There were no significant differences in serum concentrations between the four groups. There was a correlation between CSF CXCL2 concentrations with neurosyphilis (p = 0.017), CSF white blood cell count (p = 0.001), and CSF protein levels (p = 0.005). The CSF level of CXCL2 can be used to distinguish those with or without neurosyphilis in HIV infected patients.

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.

A case of syphilis presenting with initial syphilitic hepatitis and serological recurrence with cerebrospinal abnormality.

We present the case of an immunocompetent 50-year-old Japanese man with a cerebrospinal fluid (CSF) abnormality relevant to syphilis; his original presentation was liver dysfunction, the etiology of which was uncertain until positive serology for syphilis was identified. Liver dysfunction was promptly resolved after oral penicillin therapy; however, serological recurrence developed. CSF abnormality associated with syphilis was confirmed by subsequent lumbar puncture. Syphilis should be included in the differential diagnosis of patients with liver dysfunction of unknown etiology, and possible neurosyphilis should be considered when the treatment becomes refractory, even when there is no evidence of neurological manifestations.

Sensorineural hearing loss due to secondary syphilis.

We present a case of sudden sensorineural hearing loss occurring as a complication of secondary syphilis. Syphilis affecting the inner ear, or otosyphilis, is well described in historical literature, but has rarely been reported in recent times. However, following the resurgence of syphilis in the UK, unusual manifestations such as otosyphilis are likely to be seen increasingly commonly.