Treponema pallidum Tp0751 alters the expression of tight junction proteins by promoting bEnd3 cell apoptosis and IL-6 secretion.

BACKGROUND: Neurosyphilis is a serious complication caused by the invasion of the central nervous system by Treponema pallidum subsp. pallidum (T. pallidum). However, the molecular mechanism by which T. pallidum crosses the blood-brain barrier has not been fully elucidated. OBJECTIVES: The primary purpose of this experimental design was to explore the effect of the T. pallidum adhesion protein Tp0751 on the blood-brain barrier and cerebrovascular endothelial cells. METHODS: BEnd3 cells were used to construct a monolayer blood-brain barrier model in vitro. The integrity of blood-brain barrier model was evaluated by a transendothelial cell resistance meter and transmission electron microscope after the stimulation of recombinant protein TP0751. Hoechst 33258 staining and flow cytometry were used to detect the apoptosis rate. Western blotting assay was used to measure the expression of tight junction proteins and apoptosis-related proteins. The enzyme activity detection kit was responsible for detecting the enzyme activities of Caspase 3, Caspase 8 and Caspase 9. The expression of pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 at the transcription and translation levels were detected by qRT-PCR and ELISA, respectively. RESULTS: The results showed that, the tight junction structures between cells showed no obvious fragmentation, but the levels of the tight junction proteins zonula occludens-1 and occludin were reduced by the effects of Tp0751 on bEnd3 cells. In addition, further research demonstrated that after incubation with bEnd3 cells, Tp0751 induced cell apoptosis in a concentration- and time-dependent manner via the caspase 8/caspase 3 pathway. These apoptotic processes may have contributed to the changes in tight junction proteins expression. Furthermore, the Tp0751 protein may be involved in the pathogenic process by which T. pallidum crosses the blood-brain barrier by promoting secretion of the proinflammatory factor interleukin-6. CONCLUSIONS: On the whole, this study is the first to reveal and highlight that Tp0751 may affect the expression of tight junction proteins by inducing apoptosis and promoting the secretion of the inflammatory cytokine IL-6, thus playing a role in the progression of neurosyphilis caused by T. pallidum.

Neurosyphilis: a series of 178 cases at the 3rd-level hospital of Marrakesh (Morocco).

Neurosyphilis (NS) is an infection of the central nervous system (CNS), caused by Treponema pallidum. Up to 4-10% of patients with untreated syphilis may develop NS which still constitutes a health challenge. The aim of this study is to analyze epidemiological, clinical, paraclinical, therapeutic, and progression profiles of NS in the south of Morocco. Authors analyzed retrospectively 178 files of patients with neurosyphilis, collected in the Neurology Department of Marrakesh over 25 years from January 1994 to March 2019. In our study, the mean age was 46 years (17-75 years). The number of males was dominant (87.6%). The most common presentation was meningoencephalitis. Four cases were atypical (late congenital syphilis, amyotrophic lateral sclerosis, neurosyphilis associated with neuro-Behcet's disease, and acute polyradiculoneuropathy). All patients had positive TPHA and VDRL serologies in blood; CSF-TPHA was positive in all patients, and CSF-VDRL was positive in 64.0% of patients. CT scan and brain MRI showed cortical atrophy in the majority of cases. One hundred seventy-seven patients were treated with intravenous injection of aqueous penicillin G. Neurosyphilis is still a significant medical problem in developing countries, and its occurrence in HIV infection is the reason for a growing number of new cases in developed countries. Given the frequent atypical manifestations of the disease, screening for neurosyphilis should be considered in all patients with neurological or psychiatric symptoms.

A Novel Nested Real-time Polymerase Chain Reaction for Treponema pallidum DNA in Syphilis Biospecimens.

BACKGROUND: Early diagnosis of Treponema pallidum infection is helpful for disease management, and conventional PCR is suitable for lesion swabs of patients with probable early syphilis. We thus tested nested and real-time PCR (NR-PCR) in various biosamples from syphilitic patients. METHODS: Samples were collected from syphilis patients before treatment. Specific primer sequences targeting the T. pallidum gene polA were designed for NR-PCR. RESULTS: Across syphilis types, most samples assayed with NR-PCR returned a positive result, including earlobe blood (92.0%), cerebrospinal fluid (CSF) (90.2%), lesion swabs (74.3%), serum (66.9%), and whole blood (64.2%). No significant differences were observed in positive samples for whole blood, serum, and lesion swabs between primary and secondary syphilis (P > 0.05 for all comparisons). However, more whole-blood samples from patients with secondary syphilis were positive for NR-PCR than whole blood samples from patients with tertiary and latent syphilis (P < 0.05 for all comparisons). For neurosyphilis patients, significantly more earlobe blood samples tested positive than did whole-blood samples (P < 0.05), but there was no difference in positive results for earlobe blood and whole blood in latent syphilis. Significantly more serum samples tested positive in latent syphilis patients with rapid plasma regain (RPR) titers of 1:8 or greater, compared to those with RPR of 1:4 or less. CONCLUSIONS: Nested and real-time PCR can be used to identify T. pallidum DNA in biosamples from syphilitic patients, especially earlobe blood.

Early neurosyphilis presenting with multiple cranial nerve palsies: A case report of management by combined penicillin-corticosteroid treatment.

Early neurosyphilis commonly appears in basilar meninges, and its meningeal inflammation can spread to neighboring cranial nerves, resulting in some cranial nerve palsies. Herein, we report a case of a 51-year-old man who presented with right peripheral facial nerve palsy. His symptoms completely disappeared with prednisolone monotherapy without antibiotics use and were not exacerbated during clinical treatment. However, 2 months after remission of seventh cranial neuropathy, fifth and eighth cranial neuropathies appeared on the right side. Serologic tests for syphilis were revealed to be abnormal. Finally, the patient was diagnosed with early neurosyphilis with multiple cranial palsies. His neurological symptoms were markedly improved by combined penicillin-corticosteroid treatment. Systemic corticosteroids could be effective as adjunctive therapy to ameliorate neurological sequelae in early neurosyphilis.

Screening for asymptomatic neurosyphilis in HIV patients after treatment of early syphilis: an observational study.

OBJECTIVE: To determine the prevalence of asymptomatic neurosyphilis (ANS) in HIV-positive individuals after treatment of early syphilis with single-dose benzathine penicillin G (BPG) or oral antibiotic alternatives. METHODS: Patients at high risk of neurosyphilis (defined by serum rapid plasma reagin (RPR) titre ≥1:32 and/or peripheral blood CD4 lymphocyte count ≤350/µL) underwent lumbar puncture (LP) at a median time of 8.2 months post treatment. ANS was diagnosed by a reactive cerebrospinal fluid (CSF) RPR test or CSF white blood cells (WBC) >20/µL plus a reactive CSF Treponema pallidum particle agglutination (TPPA) ≥1:640. RESULTS: Of 133 eligible patients, all were men who have sex with men. Of these, 64 consented to LP. Full CSF results were available for 59 patients. Inclusion criteria were serum RPR (21/59), CD4 count (22/59) and combined RPR and CD4 (16/59). The LP patients were white British (82%), median age 40. Syphilis stages were primary (17%) secondary (43%) and early latent (41%). Syphilis was treated with BPG (47/59), doxycycline 100 mg two times per day for 14 days (10/59) and for 21 days (1/59). Azithromycin 500 mg one time per day for 10 days was given to 1/59. At the time of LP, 100% of patients had achieved serological cure, and 66% were taking antiretroviral treatment. Only 1/59 was diagnosed with ANS. The CSF showed: RPR non-reactive (59/59); TPPA non-reactive in 54/59; WBC ≤5/µL in 51/59. CONCLUSIONS: Although the number of patients in our study is modest, single-dose BPG appears to be highly effective even in patients at high risk of neurosyphilis.

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.

Diversity in clinical manifestations and imaging features of neurosyphilis: obstacles to the diagnosis and treatment (report of three cases).

OBJECTIVE: To explore the clinical manifestations and imaging features of neurosyphilis and to discuss the obstacles in the diagnosis and treatment of neurosyphilis. METHODS: We present this case study involving three cases of definite neurosyphilis, focusing on their clinical data. RESULTS: Case 1 is a patient with numb and weak left lower limb. Case 2 showed slow reaction and dementia behaviors including worse memory and the decrease of calculation and orientation ability in this patient. Case 3 is a peripheral incomplete left oculomotor nerve palsy patient. Magnetic resonance imaging findings of three patients are different. And single photon emission computed tomography showed the regional cerebral blood flow was all hypoperfused. There were some difficulties in diagnosing and treating the patients in these three cases. CONCLUSION: The clinical manifestations and imaging findings of neurosyphilis are diverse. Clinicians should pay attention to neurosyphilis. After clear diagnosis, patients would receive norm treatment in time.

Variations in Clinical Presentation of Ocular Syphilis: Case Series Reported From a Growing Epidemic in the United States.

Ocular syphilis, a form of neurosyphilis, has been increasingly diagnosed in the United States. This case series summarizes the course of 6 patients recently diagnosed with ocular syphilis, emphasizing the varied sociodemographic factors and the wide range of symptoms and outcomes that are seen in patients with this disease.

Molecular Typing of Treponema pallidum in Ocular Syphilis.

BACKGROUND: Syphilis can have many clinical manifestations, including eye involvement, or "ocular syphilis." In 2015, an increase in reported cases of ocular syphilis and potential case clusters raised concern for an oculotropic strain of Treponema pallidum, the infectious agent of syphilis. Molecular typing was used to examine strains found in cases of ocular syphilis in the United States. METHODS: In 2015, after a clinical advisory issued by the Centers for Disease Control and Prevention, pretreatment clinical specimens from US patients with ocular syphilis were sent to a research laboratory for molecular analysis of T. pallidum DNA. Molecular typing was conducted on these specimens, and results were compared with samples collected from Seattle patients diagnosed with syphilis, but without ocular symptoms. RESULTS: Samples were typed from 18 patients with ocular syphilis and from 45 patients with syphilis, but without ocular symptoms. Clinical data were available for 14 ocular syphilis patients: most were men, human immunodeficiency virus-infected, and had early syphilis. At least 5 distinct strain types of Treponema pallidum were identified in these patients, and 9 types were identified in the Seattle nonocular patients. 14d/g was the most common type in both groups. An unusual strain type was detected in a small cluster of ocular syphilis patients in Seattle. CONCLUSIONS: Ocular syphilis is a serious sequela of syphilis. In this preliminary study, clear evidence of a predominant oculotropic strain causing ocular syphilis was not detected. Identification of cases and prompt treatment is critical in the management of ocular syphilis.

Nongranulomatous Uveitis as the First Manifestation of Syphilis.

PURPOSE: The incidence of syphilis appears to be increasing in recent years. Although any structure of the eye can be involved in syphilis, isolated unilateral anterior uveitis as an initial sign of the disease is rare. We report a case of ocular syphilis presenting as a mild unilateral, nongranulomatous, anterior uveitis in an otherwise asymptomatic patient. CASE REPORT: A 64-year-old white male patient presented with a 3-day history of mildly reduced vision, photophobia, and pain in his left eye. The patient denied prior occurrences, and no contributing ocular or medical history was elicited. Entering corrected distance acuities were 20/25+ in the right eye and 20/20- in the left eye. Slit lamp examination of the left eye revealed a moderate circumlimbal flush, numerous fine keratic precipitates, and mild-to-moderate white blood cells in the anterior chamber. The patient was diagnosed as having acute, idiopathic, nongranulomatous, anterior uveitis, and topical steroid/cycloplegic treatment was initiated. Despite an initially positive, although somewhat sluggish response to treatment, the patient's uveitis suddenly worsened on day 44, exhibiting increased anterior chamber cells, several mutton-fat keratic precipitates, and elevated intraocular pressure. Systemic diagnostic workup led to the diagnosis of neurosyphilis, and the patient subsequently admitted to high-risk sexual behaviors. Treatment with intravenous aqueous penicillin-G 24 million units per day for 14 days led to complete resolution of uveitis. The case was reported to the local health department within 24 h of syphilis diagnosis. CONCLUSIONS: Syphilis, although an uncommon cause of ocular inflammation, is a highly contagious, but curable disease. Given its potentially devastating neurologic consequences, syphilis should be considered in all patients presenting with uveitis. A high index of clinical suspicion and a detailed sexual history are crucial for the accurate and timely diagnosis of ocular syphilis.

Management of Adult Syphilis: Key Questions to Inform the 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines.

A panel of experts generated 8 "key questions" in the management of adult syphilis. A systematic literature review was conducted and tables of evidence were constructed to answer these important questions. Penicillin is the drug of choice to treat syphilis. Doxycycline to treat early and late latent syphilis is an acceptable alternate option if penicillin cannot be used. There is no added benefit to enhanced antimicrobial therapy when treating human immunodeficiency virus-infected persons with syphilis. If a patient misses a dose of penicillin in a course of weekly therapy for late syphilis, clinical experience suggests that an interval of 10-14 days between doses might be acceptable before restarting the sequence of injections. Pharmacologic considerations suggest that an interval of 7-9 days between doses, if feasible, may be more optimal. Missed doses are not acceptable for pregnant women. A cerebrospinal fluid examination to diagnose neurosyphilis is recommended in persons diagnosed with tertiary syphilis (eg, cardiovascular syphilis or late benign syphilis), persons with neurological signs or symptoms consistent with neurosyphilis, and asymptomatic persons whose serological titers do not decline appropriately following recommended therapy and in whom reinfection is ruled out. Infection and reinfection rates, particularly among men who have sex with men, are high. Frequent serological screening of this population appears to be the most cost-efficient intervention. The Centers for Disease Control and Prevention continues to recommend the use of the traditional rapid plasma reagin-based screening algorithm. The positive predictive value for syphilis associated with an isolated unconfirmed reactive treponemal chemiluminescence assay or enzyme immunoassay is low if the epidemiological risk and clinical probability for syphilis are low. Among pregnant women with serodiscordant serologies (positive treponemal tests and a negative nontreponemal test), the risk of vertical transmission from mother to infant is low. Several important questions regarding the management of syphilis remain unanswered and should be a priority for future research.

Neurosyphilis and ophthalmic syphilis in persons with negative rapid plasma reagin and positive treponemal antibody test results.

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.

Neurosyphilis initially presenting as hemorrhagic exudative optic neuropathy in an immunocompetent patient.

We describe an unusual case of hemorrhagic exudative optic neuropathy as an initial presentation of neurosyphilis in an immunocompetent patient. The clinicians have to be alert to consider a diagnosis of syphilitic optic neuropathy in cases with hemorrhagic exudative optic neuropathy.

Detection of Treponema pallidum by semi-nested PCR in the cerebrospinal fluid of asymptomatic HIV-infected patients with latent syphilis.

BACKGROUND: Neurosyphilis diagnosis is frequently dependent upon the results of serological tests and cerebrospinal fluid abnormalities, but the reliability of findings in patients with HIV-1 infection has been questioned, especially in asymptomatic patients with latent syphilis. In this study, we present the data on the presence of T. pallidum DNA in CSF from asymptomatic HIV-infected patients with the diagnosis of syphilis. METHODS: CSF and serum samples were collected from 12 HIV-infected patients attending a tertiary care clinic located in southern Brazil, during the period 2012 to 2013. RESULTS: In CSF samples from five of 12 patients (40%), we detected T. pallidum DNA. Unexpectedly, in these patients, the CSF cell count, protein and glucose levels were normal. In addition, none of these 5 CSF samples presented a positive VDRL reaction. Serum VDRL titers were similar between patients with positive and negative CSF T. pallidum DNA. Most patients with detectable T. pallidum DNA presented low serum VDRL titers. A higher serum VDRL titer of 1:64 was observed in only one patient. CONCLUSIONS: Our results have shown that asymptomatic HIV-infected patients with evidence of latent syphilis and normal CSF might present detectable T. pallidum DNA in the CSF. The detection of T. pallidum DNA by our seminested PCR provides additional information beyond conventional CSF analysis for the diagnosis of neurosyphilis. The detection of T. pallidum DNA in CSF despite normal CSF findings in HIV-infected patients could also provide a different therapeutic approach including the use of intravenous aqueous crystalline penicillin.

Oral syphilis: a series of 5 cases.

Syphilis is an infectious, usually sexually transmitted, disease caused by Treponema pallidum, subspecies pallidum. Because of the increasing prevalence in Europe during the past few years, dentists could be confronted with patients with oral manifestations of syphilis. Because oral lesions are highly contagious, it is vital to make the correct diagnosis quickly to initiate the proper therapy and to interrupt the chain of infection. We present the cases of 5 patients with syphilis-related oral lesions. These cases are representative because of their clinical presentation, age, and gender distribution and the diagnostic approach. The aim of the present report is to emphasize the importance of the dentist knowing and identifying syphilis in different stages to diagnose the disease and institute treatment at an early stage.

Intracerebral and spinal cord syphilitic gummata in an HIV-negative man: a case report.

We present a case of an HIV-negative individual who presented with worsening central and peripheral neurological symptoms and signs. Clinical, serological, histopathological, and radiological features were in keeping with concurrent cerebral and spinal cord syphilitic gummata, a tertiary manifestation of syphilis. Clinical improvement occurred after treatment of neurosyphilis.

Acute hypophysitis and hypopituitarism in early syphilitic meningitis in a HIV-infected patient: a case report.

BACKGROUND: Sexually transmitted diseases and most notably syphilis-infections are rising amongst men who have sex with men. In HIV-co-infected patients, an accelerated clinical course of syphilis neurological involvement is known. CASE PRESENTATION: A 46 year old HIV-positive male patient came in to our emergency department in the late evening with acute fever, rapidly progressive cephalgia and photophobia. Palmar skin efflorescence was evocative of an active syphilis infection. A reactive Treponema pallidum particle agglutination (TPPA) assay with positive Treponema pallidum-specific IgG/IgM immunofluorescence as well as a highly reactive Veneral diseases research laboratory (VDRL) test confirmed the diagnosis. Liquor pleocytosis, liquor protein elevation and a highly positive VDRL test in cerebrospinal fluid (CSF) were interpreted in context of the clinical symptoms as neurosyphilitic manifestations within an early syphilis infection (stage II). Cranial nuclear magnetic resonance scans of the sella turcica, which were performed due to low thyroidea stimulation hormone (TSH) and thyroxin levels, showed signs of hypophysitis such as pituitary gland enlargement and inhomogeneous contrast enhancement. Advanced endocrine laboratory testing revealed hypopituitarism. Fourteen days of intravenous ceftriaxone treatment and levothyroxine- and hydrocortisone-substitution led to complete disappearance of all clinical symptoms. Two months later, nuclear magnetic resonance scan showed normal pituitary size and that the syphilis serology had normalized. CONCLUSION: We report to the best of our knowledge the first case of a HIV-positive patient with acute hypophysitis and hypopituarism due to early neurosyphilis infection. Ceftriaxone treatment and levothyroxine- and hydrocortisone-substitution led to the disappearance of all clinical symptoms. We strongly recommend to exclude syphilis infection in every clinical situation unclear in HIV-patients, especially when additional risk factors are known.

[A case of neurological syphilis mimicking Horton's disease and polymyalgia rheumatica]. / Syphilis neurologique révélée par un tableau évocateur d'artérite temporale et de pseudopolyarthrite rhizomélique.

BACKGROUND: Syphilis has been making a comeback over the last 10 years. Neurosyphilis can occur at any stage of the infection but is difficult to diagnose because of the existence of misleading forms, of which we describe an example below. PATIENTS AND METHODS: A 56-year-old woman presented symptoms evoking polymyalgia rheumatica and giant-cell arteritis in a context of ibuprofen treatment for a few weeks. She also had myodesospsia, syphilids and syphilitic roseola, together with laboratory indicators of inflammation. A lumbar puncture revealed lymphocytic meningitis and a positive Treponema Pallidum Haemagglutination Assay (TPHA) for cerebrospinal fluid, thus confirming the diagnosis of neurosyphilis. Moreover, the ophthalmologic examination showed optic neuritis with papilla lesions of syphilitic origin. This was successfully treated with a 3-week course of penicillin G infusions. CONCLUSION: Symptoms evocative of Horton's disease and polymyalgia rheumatica can reveal syphilis, a disease dubbed "the great simulator" on account of the variety of clinical forms it can take.

Brain disease leading to mental illness: a concept initiated by the discovery of general paralysis of the insane.

In the early 19th century the prevailing alienist (psychiatrists') view was that organic lesions did not cause madness. The history of general paralysis of the insane (GPI) rests on four early publications which changed this concept: Haslam's Observations on insanity, Bayle's Recherches sur l'arachnitis chronique, Calmeil's De la paralysie considérée chez les aliénés, and Esmarch and Jessen's Syphilis und Geistesstörung. Haslam's account is unconvincing, but Bayle's report linking mental alienation with organic brain disease was a polemic that opposed established teachings. Calmeil and Delaye emphasised clinicopathological correlation and stressed the importance of white matter disease in causing dementia. GPI was to prove a crucial starting point in which the causes of mental illness were slowly transformed from psychogenic disturbances of mind and spirits to organically determined diseases.