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.).

Psychiatric manifestations of neurosyphilis over past two decades: Findings from a tertiary care neuropsychiatric hospital in south India.

OBJECTIVE: To assess presentation of neurosyphilis with a focus on the psychiatric aspects. METHOD: File review of the cases with a positive cerebrospinal fluid venereal disease research laboratory test between 1999 to 2020. RESULTS: Medical records of 143 neurosyphilis patients were analysed. Hallucinations, delusions, and catatonia were the commonest psychiatric symptoms. Brain atrophy was the commonest neuroimaging finding. The number of neurosyphilis patients and the proportion with delirium or catatonia declined during the second decade (2010-2020). CONCLUSION: Atypical presentation of psychiatric symptoms around the fifth decade, with associated neurological symptoms or brain imaging changes, should prompt evaluation for neurosyphilis.

Large-Scale Proteome Profiling Identifies Biomarkers Associated with Suspected Neurosyphilis Diagnosis.

Neurosyphilis (NS) is a central nervous system (CNS) infection caused by Treponema pallidum (T. pallidum). NS can occur at any stage of syphilis and manifests as a broad spectrum of clinical symptoms. Often referred to as "the great imitator," NS can be easily overlooked or misdiagnosed due to the absence of standard diagnostic tests, potentially leading to severe and irreversible organ dysfunction. In this study, proteomic and machine learning model techniques are used to characterize 223 cerebrospinal fluid (CSF) samples to identify diagnostic markers of NS and provide insights into the underlying mechanisms of the associated inflammatory responses. Three biomarkers (SEMA7A, SERPINA3, and ITIH4) are validated as contributors to NS diagnosis through multicenter verification of an additional 115 CSF samples. We anticipate that the identified biomarkers will become effective tools for assisting in diagnosis of NS. Our insights into NS pathogenesis in brain tissue may inform therapeutic strategies and drug discoveries for NS patients.

Clinical parameter-based prediction model for neurosyphilis risk stratification.

Accurately predicting neurosyphilis prior to a lumbar puncture (LP) is critical for the prompt management of neurosyphilis. However, a valid and reliable model for this purpose is still lacking. This study aimed to develop a nomogram for the accurate identification of neurosyphilis in patients with syphilis. The training cohort included 9,504 syphilis patients who underwent initial neurosyphilis evaluation between 2009 and 2020, while the validation cohort comprised 526 patients whose data were prospectively collected from January 2021 to September 2021. Neurosyphilis was observed in 35.8% (3,400/9,504) of the training cohort and 37.6% (198/526) of the validation cohort. The nomogram incorporated factors such as age, male gender, neurological and psychiatric symptoms, serum RPR, a mucous plaque of the larynx and nose, a history of other STD infections, and co-diabetes. The model exhibited good performance with concordance indexes of 0.84 (95% CI, 0.83-0.85) and 0.82 (95% CI, 0.78-0.86) in the training and validation cohorts, respectively, along with well-fitted calibration curves. This study developed a precise nomogram to predict neurosyphilis risk in syphilis patients, with potential implications for early detection prior to an LP.

Meningovascular Neurosyphilis with Cerebral Hemorrhaging in a Human Immunodeficiency Virus-1-positive Patient.

Meningovascular neurosyphilis is a rare manifestation of early neurosyphilis that causes infectious arteritis and ischemic infarction. We herein report a 44-year-old man with meningovascular neurosyphilis who presented with cerebral hemorrhaging. He complained of nausea, vomiting and lightheadedness. The patient tested positive for human immunodeficiency virus (HIV), and head computed tomography showed cerebral hemorrhaging in the upper right frontal lobe and left subcortical parietal lobe. Positive cerebrospinal fluid syphilis tests confirmed the diagnosis. He recovered after treatment for neurosyphilis and anti-HIV therapy. Our case highlights the importance of considering meningovascular neurosyphilis in young patients with multiple instances of cerebral hemorrhaging.

Diagnostic value of cerebrospinal fluid chemokine c-x-c motif ligand 13 for neurosyphilis: A systematic review and meta-analysis.

The diagnostic value of cerebrospinal fluid chemokine c-x-c motif ligand 13 (CSF CXCL13) for neurosyphilis was assessed by meta-analysis in this study. PubMed, Web of Science and Embase databases were searched to identify relevant articles by using MeSH and free terms of CXCL13 and neurosyphilis. A total of 720 syphilis and 338 neurosyphilis individuals in 6 articles were involved in this meta-analysis. The pooled sensitivity and specificity were 0.82 (95% confidence intervals (CI), 0.77-0.87) and 0.84 (95% CI, 0.79-0.87). The pooled positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio and the area under receiver operating characteristic curve were 5.10 (95% CI, 3.90-6.60), 0.21 (95% CI, 0.16-0.28), 24.00 (95% CI, 14.00-39.00) and 0.88 (95% CI, 0.84-0.90), respectively. In subgroup analysis, human immunodeficiency virus infection and diagnostic criteria for neurosyphilis were identified to be associated with heterogeneity. Based on limited evidence, CSF CXCL13 can be helpful in diagnosing neurosyphilis.

Neurosyphilis presenting as limbic encephalitis.

A man in his 50s presented with focal seizures and was found to have an inflammatory cerebrospinal fluid (CSF) with bilateral mesiotemporal lobe hyperintensity on magnetic resonance imaging (MRI) of the brain. Corticosteroid treatment was initiated for management of limbic encephalitis. Focal seizures, imaging abnormalities and inflammatory CSF persisted despite treatment and the patient was found to have neurosyphilis after developing neuropsychiatric symptoms. Syphilis is a sexually transmitted bacterial infection with multisystem involvement including neurological and psychiatric manifestations. Case reports have emerged of neurosyphilis presenting as limbic encephalitis with CSF pleocytosis and temporal lobe hyperintensity on MRI of the brain. Persistence of CSF or MRI abnormalities despite immunosuppressive therapy for limbic encephalitis should prompt investigation for alternate causes of chronic meningoencephalitis, which can occasionally include neurosyphilis.

[Syphilis: uncommon presentation forms]. / Sífilis: formas de presentación poco frecuentes.

Uncommon forms of syphilis exist, among which neurosyphilis, otosyphilis, and ocular syphilis are included. Neurosyphilis is the infection of the central nervous system caused by Treponema pallidum. The clinical manifestations of neurosyphilis are diverse and include early, late, and atypical forms. Syphilis can affect virtually any ocular structure and can occur at any stage of the disease, as well as otosyphilis. The diagnosis of these conditions is often challenging. However, it is important to consider them as a differential diagnosis, as most of these clinical manifestations are reversible with appropriate antibiotic treatment. A case series study of patients diagnosed with neurosyphilis, otosyphilis, and ocular syphilis, who were admitted to a tertiary-level hospital, is here presented: syphilitic meningitis with cranial nerve involvement, and seizures (case 1), ocular syphilis (case 2), general paresis (case 3), and tabes dorsalis (case 4). Half of the patients presented bilateral sensorineural hearing loss; and also half of the patients had reactive VDRL in cerebrospinal fluid. All were treated with aqueous penicillin G, and in two of these cases, ceftriaxone was chosen to complete ambulatory treatment. One patient had an unfavorable outcome and died (case 1); another was lost in follow-up (case 4); one completely resolved his symptoms (case 2); and another one experienced symptom relapse six months after treatment (case 3).

Existen formas de presentación poco frecuentes de sífilis, dentro de las cuales se incluyen la neurosífilis, otosífilis y sífilis ocular. La neurosífilis es la infección del sistema nervioso central por Treponema pallidum. Las manifestaciones clínicas de neurosífilis son variadas e incluyen formas tempranas, tardías y atípicas. Además, la sífilis puede comprometer prácticamente cualquier estructura ocular, en cualquier etapa de la enfermedad, como así también la otosífilis. El diagnóstico de estas entidades suele ser dificultoso. Sin embargo, resulta importante considerarlas como diagnósticos diferenciales, ya que la mayoría de estas manifestaciones son reversibles con tratamiento antibiótico adecuado. Se presenta una serie de casos de pacientes con diagnóstico de neurosífilis, otosífilis y sífilis ocular, que cursaron internación en un hospital de tercer nivel: meningitis sifilítica con compromiso de pares craneales y convulsiones (caso 1), sífilis ocular (caso 2), paresis general (caso 3) y tabes dorsalis (caso 4). La mitad de los pacientes presentó hipoacusia neurosensorial bilateral. El 50% presentó VDRL reactiva en líquido cefalorraquídeo. Todos fueron tratados con penicilina G sódica y en el 50% se optó por el uso de ceftriaxona como modalidad para finalizar el tratamiento en internación domiciliaria. Respecto a la evolución de los pacientes, uno de ellos falleció como consecuencia del cuadro de neurosífilis (caso 1), otro se perdió en el seguimiento (caso 4) mientras que, de los dos restantes, el caso 3 presentó recaída de su enfermedad a los 6 meses del tratamiento y el caso 2 resolvió ad integrum su sintomatología.

Neurosyphilis presenting with Guillain-Barre syndrome: a case report.

BACKGROUND: Syphilis is associated with a wide variety of systemic presentations, earning it the moniker "The great mimicker". Neurosyphilis is classically associated with meningovasculitis in the acute-subacute stage and tabes dorsalis and dementia paralytica in later stages. However, one of the less well described presentations include Guillain-Barre Syndrome. This case presents a patient with an ascending polyneuropathy suspicious for Guillain-Barre Syndrome who also had other atypical findings including a truncal sensory loss, optic disc swelling, and rash ultimately found to have neurosyphilis. Electrodiagnostic testing was consistent with demyelination, supporting a diagnosis of neurosyphilis associated Guillain-Barre Syndrome. CASE PRESENTATION: A 37-year-old female presented to the emergency department with a weakness and difficulty swallowing. She described a three-month history of symptoms, initially starting with a persistent headache followed by one month of a pruritic rash on her chest, palms, and soles. Two weeks prior to presentation, she developed progressive weakness in her arms, numbness in her arms and chest, and difficulty swallowing. Neurological exam was notable for multiple cranial neuropathies, distal predominant weakness in all extremities, length-dependent sensory loss, and hyporeflexia. Investigation revealed a positive Venereal Disease Research Laboratory in her cerebrospinal fluid without significant pleocytosis, contrast enhancement in cranial nerves V, VII, and VIII on MRI, and a demyelinating polyneuropathy on electrodiagnostic testing. She was diagnosed with Guillain-Barre syndrome, secondary to neurosyphilis. The patient acutely declined and required intubation, and ultimately made a full recovery after treatment with plasmapheresis and penicillin. CONCLUSIONS: This case describes a clinical entity of syphilitic Guillain-Barre Syndrome and highlights the importance of including syphilis in the differential of any patient presenting with ascending polyradiculopathy, especially given the resurgence of syphilis.

A Cluster of Ocular Syphilis Cases with a Common Sex Partner - Southwest Michigan, 2022.

Untreated syphilis can lead to ocular syphilis, otosyphilis, and neurosyphilis, conditions resulting from Treponema pallidum infection of the eye, inner ear, or central nervous system. During March-July 2022, Michigan public health officials identified a cluster of ocular syphilis cases. The public health response included case investigation, partner notification, dissemination of health alerts, patient referral to a public health clinic for diagnosis and treatment, hospital care coordination, and specimen collection for T. pallidum molecular typing. Five cases occurred among southwest Michigan women, all of whom had the same male sex partner. The women were aged 40-60 years, HIV-negative, and identified as non-Hispanic White race; the disease was staged as early syphilis, and all patients were hospitalized and treated with intravenous penicillin. The common male sex partner was determined to have early latent syphilis and never developed ocular syphilis. No additional transmission was identified after the common male partner's treatment. Due to lack of genetic material in limited specimens, syphilis molecular typing was not possible. A common heterosexual partner in an ocular syphilis cluster has not been previously documented and suggests that an unidentified strain of T. pallidum might have been associated with increased risk for systemic manifestations of syphilis. A high index of clinical suspicion and thorough sexual history are critical to diagnosing ocular syphilis, otosyphilis, and neurosyphilis. Coordination of disease surveillance with disease intervention specialist investigation and treatment referral can interrupt syphilis transmission.

Neurological manifestations of syphilis-HIV coinfection in South Africa.

OBJECTIVE: Syphilis and HIV coinfection is highly prevalent in South Africa, and both can cause neurological complications. We describe the clinical presentation and outcome of neurosyphilis in patients with and without HIV coinfection diagnosed at a tertiary facility, Groote Schuur Hospital (GSH), in South Africa. METHODS: We retrospectively analyzed folders of adults with positive cerebrospinal fluid (CSF) fluorescent treponemal antibody absorption test in 2018 and 2019, with follow-up data collected until 2022. RESULTS: HIV-coinfection was identified in 35% of the 69 included patients. Patients with HIV-coinfection were more likely to be female (58% vs 25% female, p < 0.01), and present earlier (median age = 31 years vs. 40 years, p < 0.001). Neuropsychiatric manifestations (confusion, dementia, psychosis), and strokes were the commonest clinical presentations in both groups. Those with HIV-coinfection were significantly less likely to be diagnosed with neurosyphilis by the treating clinician (71% vs. 91%, p < 0.05), as were those with a negative CSF Venereal Disease Research Laboratory (74% vs. 94%, p < 0.05). Accurate diagnosis of neurosyphilis was associated with an increased 12-month survival (alive: N = 36 [63%]) relative to those who did not receive an accurate diagnosis (alive: N = 2 [17%], p < 0.05). Those who were optimally treated with antibiotics had significantly higher 12-month survival (alive: N = 33, 63%) compared to those with suboptimal treatment (alive: N = 5, 29%), p < 0.01. CONCLUSION: Neurosyphilis presented similarly in those with and without HIV-coinfection. Accurate identification and optimal antibiotic treatment of neurosyphilis, particularly in CSF VDRL negative patients and those with HIV-coinfection, is necessary to improve patient survival.

[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.

Case Report: Detection of Treponema phagedenis in cerebrospinal fluid of a neurosyphilis patient by metagenomic next-generation sequencing.

Treponema phagedenis, a human commensal spirochete, has been reported world-wide as a key factor in the pathogenesis of bovine digital dermatitis. Here we report a case of T. phagedenis sequence detection in the cerebrospinal fluid (CSF) of a patient. The patient was diagnosed with neurosyphilis, and T. phagedenis was detected as the only microorganism in his CSF by metagenomic sequencing. The patient went through a round of penicillin therapy previously (2.4 million units of Benzathine Penicillin intramuscularly once a week for three weeks) that did not resolve the symptoms; after the diagnosis of neurosyphilis he was treated with Penicillin G Sodium 4.0 million units q4h intravenous for 14 days then his symptoms resolved. To the best of our knowledge, T. phagedenis has never been reported to be detected in a human's CSF before. This was also the first time it was detected by metagenomic next-generation sequencing. We propose that more etiological tests should be performed including culture and sequencing for more patients with syphilis, which will contribute to a deeper understanding of the pathogenicity of the spirochete.

Neurosyphilis Mimicking Connective Tissue Disease.

A male in his 60s developed a pruritic, maculopapular rash on his torso and arms, sparing his palms and soles. He tested positive for ANA and an initial skin biopsy identified "bullous lupus," supporting the diagnosis of a connective tissue disease. Additional symptoms included headaches, facial nerve palsy and hearing loss, which partially responded to oral corticosteroids. He subsequently developed a steroid-dependent left eye scotoma, neuroretinitis and optic nerve papillitis. Mycophenolate mofetil was added but an attempted oral steroid taper led to a worsening rash, progressive retinitis and papillitis. Neurosyphilis was confirmed by serum positive rapid plasma reagin test, reactive treponema pallidum antibodies, positive cerebrospinal fluid venereal disease research laboratory and positive spirochete immunostain of skin biopsy of lesional (rash) tissue. Treatment with intravenous ceftriaxone resolved his rash and visual symptoms. It is important to consider syphilis as a mimicker of connective tissue diseases.

Neurosyphilis in a young man having HIV infection, blurring of vision and skin rash.

We report a 22-year-old homosexual man, a known case of HIV-1 infection but non-compliant to medications, who presented with a 5-month history of progressive painless non-pruritic coin-shaped skin lesions and recent gradual bilateral blurring of vision. His history divulged a primary syphilitic event 1 year prior to the present clinical manifestations. Investigation led to the diagnosis of neurosyphilis with ocular involvement with concurrent signs of secondary syphilis. Treatment with aqueous crystalline penicillin G, ophthalmic steroid and tropicamide drops, and topical emollients resulted in significant clinical improvement of ocular symptoms and skin lesions. The diagnosis of neurosyphilis requires a high degree of clinical suspicion and should be included in the differential diagnosis of unexplained ocular symptoms, particularly in men who have sex with men and HIV-infected patients. This is necessary for the early diagnosis, appropriate management, and good outcome of these patients.

Identification of potential biomarkers for diagnosis of syphilis from the cerebrospinal fluid based on untargeted metabolomic analysis.

The infection rate of syphilis continues to rise globally, and the difficulty in diagnosis of neurosyphilis promptly needs to be resolved. More specific and sensitive diagnostic markers for latent syphilis and neurosyphilis should be found. Here the metabolic profiles of 88 cerebrospinal fluid samples from syphilis patients and controls were analyzed by LC/MS-based untargeted metabolomics. In total, 272 metabolites based on 3937 features obtained in ESI- mode and 252 metabolites based on 3799 features in ESI+ mode were identified. The experimental process was evaluated by principal component analysis, partial least squares discriminant analysis, and hierarchical cluster analysis. A clear separation between latent syphilis and neurosyphilis was found. Levels of lipid and linoleic acid metabolites, such as 9-oxo-octadecadienoic acid and 9,10,13-trihydroxyoctadecenoic acid, were increased in syphilis patients. In patients with neurosyphilis, significant changes in levels of 5-hydroxy-L-tryptophan (5-HTP) and acetyl-N-formyl-5-methoxykynurenamine (AFMK) in the tryptophan-kynurenine pathway were also detected. Only one metabolite, theophylline, differed significantly between symptomatic and asymptomatic neurosyphilis patients. Additionally, KEGG analysis revealed significant enrichment of tryptophan metabolism pathways, indicating a high correlation between tryptophan metabolism and syphilis symptoms. Levels of linoleic acid metabolites, 5-HTP, AFMK and theophylline were significantly altered in different patients. The role of these differential metabolites in the development of syphilis is worthy of further exploration. Our results may promote the development of biomarkers for diagnosis of latent syphilis from neurosyphilis, and for that of asymptomatic neurosyphilis from symptomatic neurosyphilis in the future.