In this study, two important clinical findings were obtained. First, male sex, psychiatric behaviour disorders, and serum TRUST titre were useful indicators for the diagnosis of neurosyphilis without lumbar puncture. Second, a diagnostic model for neurosyphilis was developed and validated using clinical characteristics and laboratory test data of patients and transformed into a nomogram.
Binary form of Serum TRUST titres is commonly used, reporting positive or negative results in patients with syphilis. However, we found that exact serum the TRUST titre in conjugation with sex and psychiatric behaviour disorders could be used to differentiate patients with reactive neurosyphilis from those suspected of having neurosyphilis. Comparing the results with those for non-reactive neurosyphilis and not neurosyphilis patients, the serum TRUST levels were higher in those with reactive neurosyphilis. Cai et al. also indicated a 5-fold increased likelihood of asymptomatic neurosyphilis in patients with a serum TRUST titre ≥1:64 [17]. Researchers noted that an increase in the serum TPPA titre and serum creatine kinase could serve as a surrogate for CSF clinical abnormalities after lumbar punctures [17, 18]. Unfortunately, we were unable to determine the titre grades of serum TPPAs, since the laboratory system of our hospital automatically sets and reports serum TPPA titres > 1:320 as positive. Xiao et al. suggested that elevated serum creatine kinase was linked to the non-HIV neurosyphilis group (including probable neurosyphilis with negative CSF TRUST, elevated protein or white blood cells in cerebrospinal fluid) in comparison with not neurosyphilis, when precluding asymptomatic patients [18]. Our data for the development cohort showed that elevated serum creatine kinase also was linked to reactive neurosyphilis, when our research cohort included asymptomatic patients.
We used an exploratory approach combing clinical parameters and serum TRUST titres to develop diagnostic models for neurosyphilis. When combined with clinical parameters, the diagnostic performance was improved compared to that with the use of serum TRUST alone. The number of male patients was three times higher than that of female patients in our cohort, and similar to that reported by the Public Health England [19]. The rate of the presence of classic symptoms and photophobia found in this study was consistent with that reported by Arielle, and was approximately 10% in HIV-negative patients with neurosyphilis [9]. The rate of neurosyphilis typical symptoms like Argyll Robertson pupils was seldom reported. Instead, the significant clinical parameters observed in this study were psychiatric behaviour disorders and memory deterioration, consistent with the Canadian and European case series reports of neurosyphilis and research in North China from He et al. [20,21,22,23].
ROC curve analysis was used to assess the diagnostic model’s performance. Approximately 85% of the AUC of the diagnostic model was similar between the development and validation cohorts. When we consider that lumbar puncture may be difficult for patients, nomogram having about 80% diagnostic probability may be sufficient to suggest diagnosis of neurosyphilis. However, in most cases, an 80% threshold probability is not sufficient, especially in cases with a high threshold to perform continuous intravenous antibacterial therapy. In such cases, it is better to complete CSF tests and conduct more specific diagnostic tests, such as the Venereal Disease Research Laboratory (VDRL) on the CSF, a well-known specific test, broadly used to diagnose idiopathic neurosyphilis in America, although it is time-consuming and less feasible, especially in countries with high rates of such patients [24]. The results of this study offer a sensitive screening nomogram for advising candidates with high diagnostic possibility of reactive neurosyphilis to undergo lumbar puncture, complete CSF regular tests, or undergo CSF-VDRL measurements. Furthermore, this nomogram was cheaper than a regular procedure in terms of prices of medical services and tests, referring to prices of these items in 2021 from West China hospital (Supplement 2).
This study had several limitations. First, it might have a sampling bias. We did not exclude patients who received insufficient antibiotic therapy before lumbar puncture. Under the current criterion of group assignment, false negatives were possible due to non-reactive neurosyphilis cases. In theory, disease duration should have been analysed as a risk factor for neurosyphilis, but it was difficult for patients with neuropsychological symptoms to provide the exact time of syphilis infection or information on sexual activities. Additionally, another limitation was the small sample size and that the pathological categories of neurosyphilis with sophisticated infectious degree and loci were not employed here. Our data (nine records of creatine kinase in validation cohort) were not sufficient to validate a model with the addition of an elevated creatine kinase level. Whether patients in each dedicated category had a different prognosis remains unknown due to lack of follow-up investigation. We intend to build a systematic database and prospectively design new studies to improve the quality of the evidence and facilitate more comprehensive patient care. In conclusion, to verify the validity of this model, future studies are warranted.