Neurosyphilis, historically caused by Treponema pallidum (T. pallidum) infection, was reported increasing with the expansion of syphilis screening in China. T. pallidum invades the central nervous system (CNS) and may cause severe and irreversible neurologic sequelae in patients if left untreated (1). According to the latest report, the number of newly reported cases of syphilis was 438,199 (32.2 per 100,000) in 2016 and increased by an annual average of 8.6% from 2007 to 2016 in China; moreover, the number of reported cases of tertiary syphilis increased by 8.0% annually from 2007 to 2016 (2). Previous studies showed that the epidemiology of neurosyphilis largely paralleled that of syphilis (3, 4), and most tertiary syphilis cases were diagnosed as neurosyphilis (5), which indicated an increasing incidence of neurosyphilis in China.

Neurosyphilis has puzzled dermatologists, neurologists and psychiatrists in clinical settings for over two centuries because of its atypical symptoms and lack of a golden criteria of diagnosis. Early injury to CNS in neurosyphilis patients affects the mesenchyma, such as the meninges and blood vessels, manifesting within months to the several years after primary infection as meningismus, blindness, stroke, etc., while late injury affects the brain and spinal cord parenchyma within years to decades and presents as general paresis and tabes dorsalis (6, 7). Therefore, the rates of misdiagnosis and missed diagnosis in clinical settings are relatively high because of the diverse and atypical symptoms (8, 9). It is necessary for clinicians to be aware of the most common misdiagnosed diseases and specific clinical features of neurosyphilis when making a differential diagnosis.

Clinical recognition of neurosyphilis depends on the comprehensive assessment of clinical characteristics and cerebrospinal fluid (CSF) findings. However, no single specific and sensitive test for neurosyphilis exists. CSF pleocytosis and elevated protein concentrations are frequently observed in patients with neurosyphilis. Reactive CSF serologic tests are required for the diagnosis of neurosyphilis, and the Venereal Disease Research Laboratory (VDRL) test for CSF is thought to be the gold standard for specificity in the absence of blood contamination, but its sensitivity is still debated (10). The rapid plasma reagin (RPR) test, toluidine red unheated serum test (TRUST), fluorescent treponemal antibody adsorption (FTA-ABS) test and treponema pallidum particle agglutination (TPPA) test for CSF have all been assessed to have variable sensitivity and specificity in diagnosing neurosyphilis (11–13). Besides, no VDRL kits in China gets the approved of State Food and Drug Administration (SFDA) to date. Together the above all, the RPR and TRUST were recommended as the alternative tests by the ‘China National Guidelines for the Diagnosis and Treatment of Syphilis, Gonorrhea and Chlamydia Trachomatis Infection (2020)' (14). The diagnostic criteria for neurosyphilis differed between studies due to the lack of a gold standard test. Consequently, the methodological quality of neurosyphilis diagnosis among studies is unknown and need to be evaluated.

Although many cases of neurosyphilis in China were reported, their clinical features and management information have not reviewed comprehensively to date. In this paper, all cases of neurosyphilis reported in China in the past 13 years were reviewed, and their clinical epidemiological characteristics were presented, which will be helpful to clinicians to early detection and management of neurosyphilis.

The research and reporting methods of this review were consistent with the preferred reporting items for systematic reviews (PRISMA) (Supplementary Table S1).

A total of 962 articles were identified in the PubMed and EMBASE databases, and 412 duplicated articles were excluded. Among the remaining 550 articles, 458 articles were excluded based on full-text reviews. A total of 2,604 articles were identified from the CNKI and Wanfang databases, and 831 duplicated articles and 1,413 articles that were not included in Chinese Core Journals were excluded. Among the remaining 360 articles, 192 articles were excluded based on full-text reviews. Finally, 284 articles that met our inclusion criteria were selected (Figure 1).

This is the first review of the literature on the clinical epidemiological characteristics of neurosyphilis in China from 2009 to 2021, as well as neurosyphilis in patients with other associated diseases. The inconsistent diagnostic criteria in these studies and the heterogeneity among case sources led to limited conclusions.

Although the incidence of neurosyphilis in China is unknown, the number of reported cases increased over 13 years according to the results of this review (Supplementary Figure S1), indicating an increasing health threat requiring neurosyphilis prevention and control. The regional distribution of cases showed a concentration in the eastern coastal areas, including Guangdong, Fujian, Beijing, Zhejiang, Shanghai, etc. (Supplementary Figure S2). YS Tao et al. found that the incidence of early syphilis in inland provinces has increased over time and has been higher than that in eastern coastal provinces since 2010 (2). Considering that the prevalence of neurosyphilis is similar to that of syphilis, more attention probably be paid to the detection and research of neurosyphilis in eastern coastal areas than inland areas. Therefore, more training in the management of neurosyphilis in inland areas is needed in the future.

Among all the studies, we found that neurosyphilis, as well as ocular syphilis, tended to occur most frequently in middle-aged males, consistent with previous reports (27, 43). We also found that parenchymal syphilis was the main manifestation of neurosyphilis, and general paresis with progressively impaired memory, mental abnormalities and occasional seizures was the most common symptom. This clinical spectrum is consistent with those in previous reports in China but is very different from those associated with cases in Western countries (7). In the penicillin era, early forms, such as meningitis and meningovascular, are more common than late forms in Western countries because treatment can effectively prevent the progression of neurosyphilis (44), as indicated in the most recent reports (45). This result suggests that the early detection and treatment of neurosyphilis in China probably be insufficient. In addition, with the rapid expansion of syphilis screening among all populations, an increasing number of patients infected with syphilis have been diagnosed with neurosyphilis, which has probably progressed to the late stage at the time of diagnosis. It is worth noting that many patients present with atypical, ill-defined neurological complaints (46, 47), causing great challenges in the diagnosis of neurosyphilis for clinicians. Unfortunately, the results showed that the misdiagnosis rate of neurosyphilis was more than 50%, and the most common misdiagnosed diseases were neurodegenerative diseases (including stroke, cognitive impairment, Alzheimer's disease, Parkinson's disease, epilepsy, etc.), mental disorders, encephalitis and ophthalmic diseases. Two studies reporting patients with reactive CSF serological tests and diagnosed with neurosyphilis showed that the prevalence rates of neurosyphilis among patients with CNS-associated infectious diseases and CNS disorders and HIV coinfection were 30.1 and 10.6% (16, 19), respectively. In addition, among patients with syphilis infection, the prevalence of neurosyphilis ranged from 23.2 to 35.5% among patients with neurological symptoms (23–25), 13.6 to 67.7% among patients with suspected neurosyphilis who underwent LP (26–29), and 9.8 to 56.1% among syphilis patients with serofast status (30–35); additionally, the rates were 8.9, 26.9 and 43.0% in individuals coinfected with HIV, malignant syphilis and ocular syphilis (36, 37), respectively. The results suggest that clinicians in neurology, psychiatry and ophthalmology departments should pay much attention to detecting suspected neurosyphilis. Serum syphilis tests can be performed in patients with neurological, psychiatric, or ocular symptoms caused by unknown etiologies, especially patients with CNS-associated infectious diseases or HIV infection, to examine the status of syphilis infection. Moreover, CSF serological testing is recommended for syphilis patients with neurological symptoms, serofast status, coinfection with HIV or the presence of serious skin lesions.

Penicillin G has been demonstrated to be effective for the serological and clinical cure of neurosyphilis since 1940 (48, 49), and it has always been the first-line drug for the treatment of neurosyphilis. Ceftriaxone can be used as an alternative regimen in patients with penicillin allergy, and no difference was found in the efficacy of the two drugs in previous studies (50, 51). The data from case reports studies in this paper also showed that there was no difference in the recovery rate of clinical manifestations of patients treated with penicillin or ceftriaxone. It was worthy to note that approximately 4% of patients did not receive treatment regimens recommended by the national guidelines according to the available data in this review, which will be detrimental to preventing the progression of CNS injury. In addition, neurosyphilis patients need long-term follow-up for clinical management according to the recovery of disease, however, the follow-up results within 6 months were reported in more than half of cases. Hence, medical institutions need to strengthening the management of follow-up and increase the compliance, such as call patients regularly to urge return visits, provide higher quality of health care for patients, provide multidisciplinary therapy, psychological guidance, etc. In addition, we found that 81.7% patients had an improvement of symptoms, and 77.1% patients had a decrease of CSF WBC counts during the follow-up period, however, only 66.7% and half of patients had responses to serological tests of syphilis in serum and CSF, respectively. Therefore, more sensitive and specific biomarkers for assessment of prognosis of neurosyphilis are needed, especially if effective biomarkers can be found in serum in patients unwilling to undergo lumbar puncture during follow-up.

From the results of the case reports and retrospective case series, the treponemal test positivity rate was over 95%, which was significantly higher than the non-treponemal test positivity rate (~75%), and abnormal CSF-WBC counts and CSF protein levels were observed in nearly 70% of NS patients, supporting the importance of CSF serological testing for diagnosis (52). Although the CSF-TPPA testis diagnostically sensitive, considering that TP-IgG can cross the intact blood brain barrier (BBB), reactive treponemal testing of CSF samples is not specific for the diagnosis of neurosyphilis (53). The specificity of the CSF-TPPA test has been debated and ranges from 49 to 84% in some studies (54, 55), and its recommendation as a diagnostic indicator varies according to different guidelines (14, 56, 57). Moreover, the cases in most studies were retrospectively analyzed and included reactive treponemal test in the inclusion criteria, which probably biased positivity rate toward 100% (53). Therefore, CSF nontreponemal tests combined with treponemal tests are needed to reduce the possibility of misdiagnosis.

Neurosyphilis patients frequently have abnormal neuroimaging findings due to CNS inflammation and impairment. Neuroimaging may also show progression in patients who have no neurological symptoms or signs and in patients who receive standardized treatment (58). In addition, neurosyphilis patients may have specific EEG signal characteristics that are different from those of non-neurosyphilis patients (59), and the EEG-Lempel-Ziv complexity (LZC) value may be used as a diagnostic index and the reference index to assess neurosyphilis cure (60). According to our review, abnormal neuroimaging or EEG findings were observed in approximately 80% of patients, and the neuroimaging findings of 97% cases improved or return to normal on follow-up, supporting the recommendation of neuroimaging and EEG examinations for the differential clinical diagnosis and neurosyphilis follow-up (61).

Progression to neurosyphilis is more common in patients coinfected with HIV (62). We found that 8.9% of patients with neurosyphilis were infected with HIV, but most studies have used HIV infection as an exclusion or inclusion criterion, resulting in inconsistent rates.

Although the diagnostic criteria in most of the included studies followed international or national guidelines, unlike previous reports from Africa (15), approximately one-tenth of the studies provided insufficient evidence for a neurosyphilis diagnosis. Hence, standardized diagnostic criteria and protocols are urgently needed to ensure accurate diagnostic results and research conclusions.

This review had several limitations. First, there were some missing clinical information extracted from many studies, especially the data of treatment and follow-up, may result in information bias. Second, the great heterogeneity between studies according to the different diagnostic criteria of neurosyphilis may result in limited conclusions. Third, we did not review the literature published before 2009 due to the lack of clinical diagnosis and treatment guidelines for neurosyphilis in China before 2008, may lead to selection bias.

In summary, through the review of clinical epidemiology data on neurosyphilis in China, we found that the reported cases of neurosyphilis in the literature presented an increasing trend. More than half of the cases were in the late stage of neurosyphilis, suggesting that early detection of neurosyphilis was inadequate. The most common misdiagnosed diseases and the high prevalence of neurosyphilis amongst patients with CNS-associated infectious disease, CNS disease comorbid with HIV, syphilis with neurological symptoms, serofast status, coinfection with HIV or presesntations comprising serious skin lesions should remind clinicians to pay much attention to the early detection of neurosyphilis among these cases. Meanwhile, standardized treatment and long-term follow-up of neurosyphilis according to the national guidelines should be strengthened to promote the recovery of patients. During follow-up, neuroimaging and EEG examinations should be performed, as they play a positive role in auxiliary diagnosis and the observation of curative effects. Moreover, the combination of CSF non-treponemal tests with treponemal tests should be implemented for diagnosis to reduce misdiagnosis. Inadequate diagnostics remain a great obstacle to progress in understanding this disease. Future well-designed prospective studies are needed to better delineate the incidence and clinical epidemiological of neurosyphilis in China.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

F-ZD, Q-QW, and R-LZ wrote the draft and revised it. F-ZD, H-NZ, J-JL, and Z-JZ selected literature. F-ZD and XZ extracted data from literature. F-ZD performed the statistical analysis. All authors contributed to the article and approved the submitted version.

This work was supported by the Union Innovation Team Project of the Chinese Academy of Medical Sciences (2016-I2M-3021), the National Natural Science Foundation of China (81772209 and 81601804), and the Nanjing Incubation Program for National Clinical Research Center (2019060001).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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