TYPE Review

PUBLISHED 11 January 2024

DOI 10.3389/fneur.2023.1340321

Neurosyphilis: insights into its

OPEN ACCESS pathogenesis, susceptibility,
diagnosis, treatment, and
EDITED BY
U. K. Misra,
Sanjay Gandhi Post Graduate Institute of
Medical Sciences (SGPGI), India

REVIEWED BY
prevention
Mukesh Kumar,
T. S. Misra Medical College and Hospital, India
Pradeep Nair, Sirui Wu, Fei Ye, Yuanfang Wang and Dongdong Li*
Jawaharlal Institute of Postgraduate Medical
Education and Research (JIPMER), India Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China

*CORRESPONDENCE
Dongdong Li
[email protected] Background and aim: Invasion of the central nervous system by Treponema
RECEIVED 17 November 2023 pallidum can occur at any stage of syphilis. In the event that T. pallidum
ACCEPTED 27 December 2023 is not cleared promptly, certain individuals may experience progression to
PUBLISHED 11 January 2024
neurosyphilis, which manifests as cognitive and behavioral abnormalities, limb
CITATION
paralysis, and potentially fatal outcomes. Early identification or prevention
Wu S, Ye F, Wang Y and Li D (2024)
Neurosyphilis: insights into its pathogenesis, of neurosyphilis is therefore crucial. The aim of this paper is to conduct a
susceptibility, diagnosis, treatment, and critical and narrative review of the latest information focusing exclusively to the
prevention. Front. Neurol. 14:1340321.
pathogenesis and clinical management of neurosyphilis.
doi: 10.3389/fneur.2023.1340321

COPYRIGHT
Methodology: To compile this review, we have conducted electronic literature
© 2024 Wu, Ye, Wang and Li. This is an searches from the PubMed database relating to neurosyphilis. Priority was given
open-access article distributed under the to studies published from the past 10 years (from 2013 to 2023) and other
terms of the Creative Commons Attribution
License (CC BY). The use, distribution or
studies if they were of significant importance (from 1985 to 2012), including
reproduction in other forums is permitted, whole genome sequencing results, cell structure of T. pallidum, history of
provided the original author(s) and the genotyping, and other related topics. These studies are classic or reflect a
copyright owner(s) are credited and that the
original publication in this journal is cited, in
developmental process.
accordance with accepted academic practice. Results: Neurosyphilis has garnered global attention, yet susceptibility to and
No use, distribution or reproduction is
permitted which does not comply with these
the pathogenesis of this condition remain under investigation. Cerebrospinal
terms. fluid examination plays an important role in the diagnosis of neurosyphilis, but
lacks the gold standard. Intravenous aqueous crystalline penicillin G continues
to be the recommended therapeutic approach for neurosyphilis. Considering its
sustained prominence, it is imperative to develop novel public health tactics in
order to manage the resurgence of neurosyphilis.
Conclusion: This review gives an updated narrative description of neurosyphilis
with special emphasis on its pathogenesis, susceptibility, diagnosis, treatment,
and prevention.

KEYWORDS

neurosyphilis, Treponema pallidum, HIV, susceptibility, pathogenesis, antibiotic

treatment, prevention

Introduction
Neurosyphilis (NS) is a neurological infection caused by the spirochete Treponema
pallidum. T. pallidum can affect the central nervous system (CNS) during any stage of
syphilis (1). Estimates from the WHO indicate that approximately 22.3 million individuals
worldwide had T. pallidum infection, with 7.1 million new cases, in 2020 (2). However,
most regions have not monitored neurosyphilis at the national level, and there are few
studies reporting the incidence of neurosyphilis (3). As 1.2% to 1.8% of patients with
early syphilis will develop neurosyphilis, there is persistent prevalence of neurosyphilis

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Wu et al. 10.3389/fneur.2023.1340321

worldwide (4). In Europe, the estimated annual incidence of periplasmic space between the two membranes (17). T. pallidum
neurosyphilis varies from 0.16 to 2.1 per 100 000 adults; in can swim by rolling or undulation of the cell body driven by the
Australia, the annual incidence of neurosyphilis from 2007 to 2016 rotation of periplasmic flagella and it is the existence of periplasmic
was 2.47 cases per 10,0000 people; in the Canadian province of flagella maintains its helical shape (18). The cytoplasmic filaments
British Columbia, the incidence of neurosyphilis increased from anchored to the inner surface of the cytoplasmic membrane are
0.03 cases per 10,0000 people in 1992 to 0.8 cases per 10,0000 arranged in a ribbon configuration (17). The cone-shaped structure
people in 2012; in Guangdong province of China, the incidence locates at the end of spirochetes outside of the peptidoglycan
of neurosyphilis increased from 0.21 cases per 10,0000 people in layer (17). However, the exact role of cytoplasmic filaments
2009 to 0.31 cases per 10,0000 people in 2014 (5–8). In high-income and cone-shaped structure remains unknown (17). The defining
countries, the prevalence of syphilis is extremely high among men; characteristic of T. pallidum is the low density of membrane-
in low-income and middle-income countries, syphilis is prevalent spanning proteins and sufficient lipoproteins, which may reflect its
among the general population; WHO estimates that the prevalence capacity for host immune response evasion (19).
of syphilis in Africa was the highest in 2016, which may be related to
insufficient health education, human and infrastructural resources
(9–11). It is speculated that similar patterns also exist in patients
The mechanisms of invasion of the
with neurosyphilis (10). Neurosyphilis not only imposes a great CNS by T. pallidum
economic burden on patients but also causes a decline in quality
of life due to the stigma associated with the disease (12). Current research suggests that T. pallidum does not release
As pathogenic treponemes, yaws and syphilis treponemes toxins into the host, but is one of the most invasive spirochetes
exhibit genetic similarity of more than 99.8% in their genome (20). It has been demonstrated in rabbit models, mouse models,
(13). However, yaws are unlikely to affect the CNS, suggesting and human subjects that T. pallidum is capable of invading
that certain small genetic changes might be responsible for the the CNS early in the disease (21). Pham et al. found T.
differences in pathogenesis among these organisms (13). Exploring pallidum in brain tissue, which was confirmed by 16S ribosomal
the genomes, neuroinvasion properties, and transmission routes RNA sequencing (22). Additionally, metagenomic next-generation
of T. pallidum is essential for comprehending the pathogenesis sequencing (mNGS) detected T. pallidum nucleic acids in the CSF
of neurosyphilis and developing effective clinical strategies. at low levels (23). These studies provide substantive evidence for
Benzathine penicillin G, the preferred drug for treating primary the neuroinvasive capacity of T. pallidum.
syphilis, secondary syphilis, and tertiary syphilis patients with The presence of T. pallidum in the CNS suggests its ability
normal cerebrospinal fluid (CSF) examination, cannot reach to evade the immune system and actively invade the CNS,
an effective concentration in the CSF (14). Thus, identifying leading to sustained damage. Macrophages are critical immune
syphilis patients at a high risk of developing neurosyphilis would cells, especially microglia in the CNS, acting as the first line of
allow for targeted intervention. While the exact pathogenesis immune defense (24). A case report of neurosyphilis observed
is not completely understood, certain factors, such as genetic severe proliferation of microglia in the cerebral cortex (25). CSF
susceptibility, for neurosyphilis have been identified (15). sTREM2 (a biomarker of microglial activation) was observed to
Despite this, numerous clinical and preclinical questions remain be at significantly higher levels in neurosyphilis patients (26).
unanswered due to the complexities of real-world practice. This Further study revealed that T. pallidum promotes microglial
review describes the strain factors and mechanisms behind the apoptosis and inhibits microglial migration as a means of evading
neuroinvasion property of T. pallidum, as well as risk factors, clearance (27, 28). The balance between phagocytic uptake and T.
predictors, diagnosis, treatment and prevention of neurosyphilis. pallidum evasion is influenced by production of opsonic antibodies,
Additionally, it addresses existing controversies and provides a with TP0326 (BamA) and TP0751 (pallilysin) being identified
discussion on future prospects. as opsonic targets (29, 30). In addition, Tp47 can activate the
To compile this review, we have conducted electronic literature NLPR2 inflammasomes in macrophages through PKM3 dependent
searches from the PubMed database relating to neurosyphilis. glycolysis, thereby mediating the infection of T. pallidum (31).
Priority was given to studies published from the past 10 T. pallidum exhibits various effects on host vascular endothelial
years (from 2013 to 2023) and other studies if they were of cells, potentially linked to its invasion of the CNS (32) (shown in
significant importance (from 1985 to 2012), including whole Figure 2). Scanning electron microscopy revealed that T. pallidum
genome sequencing results, cell structure of T. pallidum, history of can directly adhere to human brain microvascular endothelial cells
genotyping, and other related topics. These studies are classic or in vitro (36). TP0751 shares the same endothelial receptor with
reflect a developmental process. other neurotropic pathogens, and thus mediates interactions with
endothelial cells (37); TP0751 alters expression of tight junction
proteins, influencing the permeability of the blood-brain barrier
The biological basis of T. pallidum (BBB) by promoting bEnd3 cell apoptosis and IL-6 secretion (38).
Similarly, recombinant TP0965 shows a higher level of endothelial
In contrast to gram-negative bacteria, T. pallidum has a helical permeability induction (39). Both intercellular junction pathways
shape with a fragile dual-membrane structure and peptidoglycan and lipid raft-mediated endocytosis mechanisms for traversing
layer, but lacks lipopolysaccharides (LPS) (Figure 1) (16). The endothelial barriers were observed in T. pallidum, but without
flagella motors are fixed in the cytoplasmic membrane and arranged disruption of barrier permeability (35). The latter view seems more
in a row, allowing the flagella filaments to extend into the reliable due to the normal or only slightly increased quotient

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FIGURE 1
The cellular architecture of T. pallidum. The figure was created in BioRender.com.

(Qalb ) level in neurosyphilis patients in clinical practice (40). In mechanisms involved. The typing schemes frequently used in
addition to interacting with macrophages and endothelial cells, T. pallidum are CDC typing (CDCT), enhanced CDC typing
the biochemical system, antigenic variation system, and matrix (ECDCT), and multilocus sequence typing (MLST), based on
metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases analysis of restriction fragment length polymorphism (RFLP) or
(TIMPs) imbalance are involved in the pathogenesis of T. direct sequencing (46, 47). The loci detected in CDCT schemes
pallidum (41–43). include the acidic repeat protein (arp) gene and the T. pallidum
repeat family genes [tprE (tp0313), tprG (tp0317), tprJ (tp0621)]
(48). Compared to CDCT, ECDCT adds the sequence analysis of
Association of T. pallidum genome, the tp0548 gene and has stronger discrimination against strains,
genotypes and neurosyphilis while MLST focuses on the analysis of four genes (tp0136, tp0548,
tp0705 and 23S rDNA genes) and further improves the typing
The T. pallidum genome comprises a circular chromosome resolution of SS14-like strains (48, 49). For ECDCT, consistent
with a total of 1041 predicted open reading frames (ORFs) (16). observations indicate a higher likelihood of neurosyphilis with
Two major T. pallidum lineages (Nichols and SS14) cocirculated strain type 14d/f (Table 1) (47, 48, 50, 51). Correspondingly, MLST
across multiple continents, with a worldwide predominance of SS14 type 1.1.2 appears to exhibit greater neuroinvasion (47). Except for
lineages, which may be explained by its resistance to macrolides South Africa, the majority of the CSF specimens (54%) inspected
(44). Whether this lineage is related to neurosyphilis has not been involved the 14a strain type, though subtype 14d was commonly
studied, but the genotype has and is discussed below. Notably, the found in genital ulcer specimens from syphilis patients during the
genome exhibits a distinct set of repeat gene family sequences, same period (46). However, the nonuniform inclusion criteria of
particularly the tprK gene, which is involved in immune evasion neurosyphilis patients and the lack of enough subjects limit the
and has potential as a latent vaccine (41). Furthermore, the genome universality of these studies. Considering that strain type 14d/f
displays a considerable number of motility-associated genes (e.g., is predominant among syphilis patients, the base effect linked to
FlaB1, FlaB2, FlaB3, FlaA, FliG), enabling efficient movement of T. this subtype predisposing toward the development of neurosyphilis
pallidum in highly viscous environments such as connective tissues should be taken into account (52). A systematic review and meta-
by traveling planar waves (16, 17). The periplasmic flagella and analysis concluded that CSF from patients with late neurosyphilis
flexible peptidoglycan layer are the structural basis for achieving had low typing efficiency (46.4%) (53). The typing efficiency of
this movement (17). lesion exudate was higher. However, it was difficult to collect
Findings from the rabbit intravenous infection model have from neurosyphilis patients (47). A more sensitive CSF typing
shown that certain strains of T. pallidum, such as Sea 81–4, method for T. pallidum deserves further investigation. Chen et al.
exhibit a particular affinity for the CNS (45). This finding provides developed a suite of PCR-LwCas13a syphilis assays with excellent
valuable clues regarding the association of strain typing and sensitivity and specificity, which may be a promising alternative to
the neurosyphilis phenotype, and the potential microbiological genotyping (54).

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FIGURE 2
Mechanisms of T. pallidum for Crossing the BBB. (A) The BBB is composed of brain microvascular endothelial cells, astrocytes, and pericytes.
Attaching to the host cells is the first step in T. pallidum neuroinvasion (33). (B) Several T. pallidum proteins are identified to be adhesins, including
laminin- (TP0751) and fibronectin- (TP0136, TP0155, TP0483) binding proteins (34). (C) T. pallidum adheres to endothelial cells at the site of
intercellular junction, resulting in a notable reduction in the expression of tight junction proteins ZO-1 and occludin through TP0751, and disrupting
VE-cadherin, thereby entering the BBB through a paracellular pathway; TP0751 coordinates intercellular transport by engaging with host receptors
(LamR) in lipid rafts and inducing endothelial uptake and transport in a cholesterol-dependent manner (35). The figure was created in BioRender.

Risk factors for neurosyphilis in Older age (≥45/60 years) is an independent risk factor for
HIV-negative patients HIV-negative neurosyphilis patients (3, 62). The link involved
may be attributable to the longer courses of disease in elderly
Sex and age individuals. Accordingly, aging is accompanied by progressive
immunosenescence, which raises the possibility of infections (63).
An increased prevalence of syphilis has been observed among Interestingly, neurosyphilis has been found to correlated with
men in China, the United States, and European countries, with a certain neurodegenerative disorders, such as Alzheimer’s disease
significant proportion of men having sex with men (MSM) (5, 55– (AD) (64). Pathological evidence has demonstrated that curly fibers
57). For instance, in the United States, from 2008 to 2018, the discovered in AD correspond to individual spirochetes, and their
estimated number of male patients with syphilis rose from 40,300 aggregation in colonies produces similar senile plaques (65).
to 121,000 (55, 58). However, the prevalence of syphilis is not the
highest in upper-middle-income and high-income countries (59).
On the one hand, wealth can increase the opportunities for MSM Serum non-treponemal test titer
to achieve syphilis by increasing regional mobility (59). On the
other hand, the convenience of syphilis detection and treatment Previous studies have indicated that non-treponemal tests, such
is convenient, which can reduce the spread of syphilis (59). The as the rapid plasma reagin (RPR) test, and toluidine red unheated
prevalence of syphilis depends on the balance of various situations. serum test (TRUST), have stronger specificity than treponemal tests
However, studies conducted in sub-Saharan Africa have shown in the diagnosis of neurosyphilis (66). This may be explained by
that women have a higher prevalence of syphilis, which is related the fact that blood-derived anti-treponemal IgG antibodies can
to the cultural, economic, and social marginalization of women cross through the BBB and enter the CSF, thus leading to false-
in the region (60). Male sex has been identified as a correlating positive results (67). A multivariate analysis revealed that the risk of
risk factor for neurosyphilis, in addition to its epidemiological developing neurosyphilis, but not secondary syphilis, increases with
significance (3, 61, 62). As we strive to better understand the an elevation in serum RPR titer (3). Jiang et al. retrospectively found
pathophysiology of neurosyphilis, studies investigating the impact that HIV-negative syphilis patients with serum TRUST titers ≥1:16
of sex hormones on disease development and progression may yield were eight times more susceptible to developing neurosyphilis
valuable insights (61). (68). Of note, patients with a fourfold decrease in serum RPR

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TABLE 1 Overview of six studies on molecular typing of T. pallidum strains from neurosyphilis patients.

First author Location Specimen Specimen Specimen Typing Strain

(citation) collection type size system
period
Sahi et al. (47) Seattle, USA, 1999–2017 Whole blood, CSF 18 MLST Eight patients had a 1.1.2 strain; no
America patients had a 1.3.1 strain; nine patients
had a tp0705 type 2 strain.

Sahi et al. (47) Seattle, USA, 1999–2017 Whole blood, CSF 18 ECDCT One patient had a 14d/g strain; 16
America patients had a tp0548 type f strain.

Marra et al. (48) Seattle, USA, 1999–2008 CSF 84 ECDCT 22 patients had a 14d/f strain.
America

Dai et al. (50) Shanghai, 2007–2011 Lesion swab 4 ECDCT Two patients had a 14d/f strain; two
China, Asia patients had a 19d/c strain.

Read et al. (51) Sydney, 2004–2011 Lesion swab 2 ECDCT Two patients had a 14d/f strain; two of
Australia, six patients with strain type 14d/f
Oceania developed neurosyphilis, compared with
0/85 with non-14d/f strains.

Molepo et al. (46) Pretoria, South 1999–2000 CSF 50 CDC Seven patients had a 14a strain; four
Africa, Africa patients had a 3e strain; one patient had
a 17e strain; one patient had a 2i strain.
CSF, cerebrospinal fluid; ECDCT, enhanced CDC-typing; MLST, multi-locus sequence typing.

titers after treatment are more likely to develop asymptomatic In addition to male sex, advanced age, and high serological
neurosyphilis (ANS), indicating a correlation between ANS and titers, HIV-positive individuals have several other risk factors
treatment failure (69). regarding immune suppression. Numerous studies have reported
an increased risk of neurosyphilis in patients with higher viral
load and lower CD4(+) T cells count (< 350 cells/µl) compared
to the general population (74, 75). T. pallidum itself can induce
Specific genes carried by the host
programmed cell death of CD4(+) and CD8(+) T cells with
an increase in HIV-ribonucleic acid (RNA) viral load (76, 77).
Single-nucleotide polymorphisms (SNPs) of immune
Actually, the synergism of HIV and T. pallidum is complicated
regulatory genes may influence susceptibility to neurosyphilis. The
and lacks sufficient research. It is well acknowledged that the
−1082 GG and −592 CC genotypes of the IL-10 promoter and the
characteristics of neurosyphilis can be confused with HIV infection,
TLR1_1805GG, TLR2_2258GA, and TLR6_745CT/TT genotypes
as primarily characterized by an increased karyocyte count and
are associated with an increased risk of neurosyphilis (15, 70). At
protein concentration (78). Antiretroviral therapy (ART) may
present, the majority of risk factors found in studies are immutable,
ameliorate this status, but it is still unclear whether ART-naive
posing challenges in intervening in risk factors to reduce disease
patients with syphilis should undergo lumbar puncture (73).
risk. It is imperative to further explore factors such as psychosocial
However, what is certain is that the absence of ART or syphilis
and physical activity factors to broaden our understanding of
treatment represents a significant risk factor for neurosyphilis (70,
potential prevention.
74, 75).

Risk factors for neurosyphilis in Predictive indicators for neurosyphilis

HIV-positive patients risks and treatment responses
According to the European guideline on the management of Predictors can be roughly divided into two types: temporally
syphilis, there is no increased risk of neurological involvement in advanced indicators and heterotopic predictive indicators. Current
HIV-infected patients with early syphilis (57). However, a study that research on predicting the risk of neurosyphilis primarily focuses
did not distinguish syphilis stages has shown that syphilis patients on the latter, particularly certain peripheral blood indicators.
with HIV infection are more likely to develop neurosyphilis (71). Li et al. constructed a prediction model incorporating age,
One possible explanation for this is that HIV-positive patients serum TRUST titer, and various blood routine indicators,
may be more inclined to undergo comprehensive and timely which offers a valuable reference for the empirical treatment
examinations. From a pathophysiological perspective, the CNS is of ANS (79). Serum neurofilament light chain (NfL) and the
a more immunologically privileged site due to the presence of the neutrophil-to-lymphocyte ratio (NLR), which serve as markers
BBB and limited movement of immune cells, combined with the of neuroaxonal injury and inflammation, respectively, show
decrease in CD4 T cells and meningeal lesions in HIV-positive promise as novel predictors for neurosyphilis (80, 81). Although
patients, which weakens the CNS’s ability to defend against T. diagnosis of neurosyphilis necessitates lumbar puncture, peripheral
pallidum (72, 73). blood predictors can to some extent indicate changes in

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the CNS, thereby reducing the need for unnecessary invasive stroke (106), status epilepticus (107), posterior uveitis (108),
procedures (82). Additionally, applications of metabolomics, asymptomatic optic perineuritis (109). These phenotypes suggest
transcriptomics, mRNA modification, SNPs, and neuroimaging that T. pallidum can invade and affect one or more components of
analysis in neurosyphilis have facilitated screening of additional the CNS.
biomarkers (15, 70, 83–86). Among the diagnostic criteria, CSF examination is necessary.
To accurately predict the effectiveness of treatment, temporally Research on susceptibility to neurosyphilis provides key insights
advanced indicators and heterotopic predictive indicators should into the pathogenesis and clinical strategies, though many
both be explored. The serological response, namely, normalization questions still remain, particularly regarding when patients should
or decrease of the serum RPR titer, can to some degree predict CSF undergo CSF testing to screen for neurosyphilis. Based on a
normalization, and the rate of follow-up lumbar puncture may be general survey of relevant guidelines, scholars pay great emphasis
reduced if neurological symptoms resolve (87, 88). As a fourfold to neurological symptoms, syphilis stages, and HIV infection
decline in CSF RPR titer is a reliable predictor for treatment in lumbar puncture (Table 2). As mentioned above, there is
efficacy in CSF RPR-positive general paresis patients within 12 a consensus that syphilis patients with neurological symptoms
months after completing therapy, it is unnecessary to repeat require CSF examination. Additionally, there is limited support for
CSF tests for HIV-negative people (14, 89). A recently developed routine lumbar puncture among HIV-positive and HIV-negative
minimal proteomic array not only allows for disease staging, persons without neurologic symptoms owing to a lack of evidence
but also monitors response to appropriate treatment, helping to that routine lumbar puncture improves clinical outcomes (79). It
confirm pharmacological cure (90). Furthermore, it is necessary is necessary to supplement the probability of ANS developing into
to discuss factors like socioeconomic status, access to healthcare, symptomatic neurosyphilis and the risks and cost-effectiveness of
and cultural influences which may contribute to the outcomes of lumbar puncture must be weighed.
neurosyphilis in the future. We should mention two conditions A positive CSF venereal disease research laboratory (VDRL)
related to syphilis treatment: Jarisch-Herxheimer reaction (JHR) test is considered highly specific for neurosyphilis, whereas
and serofast status. JHR is a transient inflammatory phenomenon a nonreactive CSF fluorescent treponemal antibody absorption
observed in syphilis patients receiving antibiotic treatment (91). (FTA-ABS) test is likely to exclude neurosyphilis (112). The
JHR cannot be predicted reliably, but it was observed that its occurrence of false positive results can be attributed to the ability
frequency increases proportionally with white cell count and total of anti-T. pallidum IgG antibodies to traverse the BBB and access
protein level in CSF (92). The serofast state refers to a situation in the CSF. Consequently, in comparison to non-treponemal tests, the
which non-treponemal antibodies decline after treatment but fail specificity of treponemal tests for CSF examination are lower (57).
to completely revert to a nonreactive state, which may be related Currently, there is no gold standard for diagnosing
to CNS infection (93, 94). Studies have shown that certain genetic neurosyphilis, making it difficult to evaluate the diagnostic
factors, such as the strain genotype of 14i/a, host interleukin-10 efficiency of new methods (113). The key to indirect detection lies
promoter polymorphisms, differentially expressed cytokines and in distinguishing the specific antibodies synthesized intrathecally,
microRNAs, can predict increased risk of serofast status (94–97). and the antibody index of specific anti-Treponema IgG is a
However, regardless of whether it is a risk factor or predictive promising new tool (114). PCR lacks sensitivity as a direct
indicator, there remains uncertainty in the risk or prediction of detection method (115). At present, there have been no successful
disease occurrence, as it only represents a possibility with varying development of T. pallidum antigen detection kits. The prevailing
degrees of likelihood (98). situations may indicate that T. pallidum has the ability to conceal
or attach itself to the human body, and the widespread use
of antibiotics in other diseases, thus posing a challenge for
Diagnosis of neurosyphilis conventional techniques to detect nucleic acids or antigens in
the blood. Overall, application of new technologies with higher
The identification of neurosyphilis typically necessitates sensitivity, such as nested PCR (nPCR) and loop-mediated
the integration of epidemiological information, neurologic or isothermal amplification (LAMP) assay, may pave the way for the
neuropsychiatric manifestations, serologic analysis of blood detection of T. pallidum in CSF. T. pallidum DNA detection rate by
and CSF, and, in certain instances, imaging assessment. For LAMP assay was 87.5% in secondary syphilis, which is higher than
syphilis patients with neurological symptoms, almost all major that in a nPCR study, which achieved T. pallidum DNA detection
guidelines recommend lumbar puncture (99–101). Nonetheless, rate respectively in 47.5%, 60.7% of urine sediment and plasma
the neurological symptoms of neurosyphilis are not specific. Early samples from patients with secondary syphilis (116, 117). Actually,
neurosyphilis can affect the meninges and central blood vessels, researchers have also made many efforts, such as improving sample
including syphilitic meningitis, meningovascular neurosyphilis and preprocessing methods and seeking inspiration from case reports
syphilitic gummas, often manifested as headache, nausea, vomiting, to find new sample types (such as saliva) (118, 119).
blurred consciousness, and neck stiffness; late neurosyphilis affects
the spinal cord and brain parenchyma, including general paresis
and tabes dorsalis, manifested as ataxia, impaired memory, Treatment and antibiotic resistance of
disorientation, depression, hallucinations, and mania (102, 103). neurosyphilis
Furthermore, as a great imitator, neurosyphilis can mimic a wide
range of neurological and psychiatric diseases (104), including In treatment of neurosyphilis, it is crucial to consider the BBB
but not limited to autoimmune encephalitis (105), acute ischemic penetration and effective drug concentrations in CSF (120). The

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TABLE 2 Insights on lumbar puncture in the guidelines of neurosyphilis.

Guideline Continent/Country Suggestions about lumbar puncture

Guidelines for diagnosis and treatment of China Lumbar puncture should be performed on all individuals with syphilis and HIV
syphilis, gonorrhea, and genital Chlamydia infection to exclude neurosyphilis.
trachomatis infection (2020) (110)

Asian guidelines for syphilis (2022) (99) Asia There is no consensus about the need for lumbar puncture in patients with syphilis
without any neurological, ocular, or otological symptoms, except for those with
tertiary syphilis.

2020 European guideline on the management Europe CSF assessment is indicated in patients with: -clinical evidence of neurological,
of syphilis (57) ocular, and auricular involvement, whatever the stage of the disease; tertiary syphilis
(cardiovascular, gummatous).
Some experts still recommend CSF assessment in ANS patients: HIV-positive patients
with late syphilis and CD4 cells ≤ 350/mm3 and/or a serum VDRL/RPR titer >1:32;
in those who have serological failure or are serofast; in those given alternative
treatment for late syphilis.

German guidelines on the diagnosis and German Lumbar puncture is indicated in patients with (at least two out of four are met): CD4
treatment of neurosyphilis (102) cell count ≤ 200 cells/µl; untreated HIV infection; detectable HIV load; high VDRL
titer (>1:64).

UK national guidelines on the management UK Routine CSF examination of patients with latent syphilis is not recommended.
of syphilis 2015 (111)
ANS, asymptomatic neurosyphilis; CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; RPR, rapid plasma reagin; VDRL, venereal disease research laborator.

recommended treatment for neurosyphilis is intravenous aqueous study has revealed a growing prevalence of macrolide resistance
crystalline penicillin G (18–24 million units per day, continuous in T. pallidum, which coincides with the increased usage of
infusion for 10–14 days) (14). Doxycycline and ceftriaxone are macrolides due to guideline recommendations (133). In fact, the
considered viable alternatives for penicillin-allergic patients with 2020 European guideline excluded azithromycin as an alternative
great BBB penetration ability (121, 122). Doxycycline can be treatment for syphilis at any stage (57). To tackle the potential crisis
administered orally and can also treat other sexually transmitted of drug resistance, subtractive genomics approaches have been
infections simultaneously (123). Similar outcomes have been employed to identify salvicine as a potential therapeutic molecule
observed in patients with neurosyphilis treated with procaine G against T. pallidum (134).
penicillin vs. doxycycline (124). Ceftriaxone, by contrast, requires
parenteral administration, and its therapeutic effect appears to
be controversial (123, 125). A follow-up study suggested that Prevention of neurosyphilis
ceftriaxone was associated with a 23% failure rate of treatment
for HIV-infected patients with ANS (125). However, another Although penicillin treatment is effective in patients diagnosed
prospective pilot study of HIV-infected patients with ANS has with early-stage neurosyphilis, early diagnosis of neurosyphilis
shown no difference in the serologic response to treatment is rather difficult, and prevention is particularly important
with ceftriaxone vs. procaine penicillin plus probenecid (126). considering the poor prognosis of late-stage patients (135). In
Probenecid can reduce renal tubular secretion and inhibit the addition, given the fatal consequences of congenital syphilis,
active transport of intracranial penicillin by inhibiting Oat3, development of syphilis vaccines is of utmost importance for
thereby increasing the bioavailability of penicillin G (127). enhancing public health (136).
An enhanced regimen consisting of benzathine penicillin G, The specific significance of the syphilis vaccine for
ceftriaxone, and doxycycline has demonstrated greater efficacy neurosyphilis is to prevent transmission of T. pallidum from
than the recommended regimen (128). Additionally, a preclinical the infected site and progression to neurosyphilis (137). However,
study has demonstrated linezolid as a promising clinical treatment development of a syphilis vaccine is hindered by challenges,
for syphilis (129). Linezolid is low-cost, safe, and generally well including the difficulty of culturing T. pallidum in vitro, antigenic
tolerated during short course oral administration, with sufficient mutation in TprK, and the low content and vulnerability of the
concentration in CSF (130). The recent breakthrough in in outer membrane proteins (OMPs); thus, no syphilis vaccine
vitro cultivation of T. pallidum has facilitated identification has yet progressed to clinical trials (17, 138). Despite these
of potential candidates for syphilis treatment, as determined hurdles, researchers have shown positive responses to this pursuit.
by the minimum inhibitory concentration (MIC) (131). Future To evaluate the efficacy of a syphilis vaccine, a heterologous
studies involving neurosyphilis-related strains will provide more antigen presentation system (noninfectious Borrelia burgdorferi)
convincing evidence for the selection of drugs for the treatment was designed to express T. pallidum antigens (139). Recent
of neurosyphilis. advancements in long-term culture systems (by cocultivation with
To date, no clinical manifestations of penicillin resistance rabbit epithelial cells in a microaerophilic atmosphere) and in vitro
have been found in T. pallidum, despite reports of increased drug sensitivity testing provide potential solutions for the culture
gene mutations associated with penicillin resistance and that of T. pallidum (138). In addition, enrichment techniques that do
treatment may fail over time (132). Molecular epidemiology not rely on culture, or high sensitivity methods, have also been

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Wu et al. 10.3389/fneur.2023.1340321

TABLE 3 Important unanswered questions in neurosyphilis.

attention to sexually transmitted infections has focused primarily
on HIV infection, while other infections such as syphilis have
Area Questions
gradually been marginalized (148). Preexposure prophylaxis (PrEP)
Epidemiology • How high is the authentic incidence and mortality has been, extensively studied as a crucial intervention to prevent
of neurosyphilis?
HIV transmission but has not been applied to syphilis (149).
• What is the probability of the ANS patients Interestingly, the incidence of syphilis is higher among MSM taking
progressing to symptomatic neurosyphilis?
HIV PrEP than among those who do not in Australia (150). This
Pathogenesis • What is the mechanism of T. pallidum invading the causal relationship may be attributed to a phenomenon called “risk
CNS?
• What is the mechanism of the CNS damage mediated
compensation,” whereby a reduction in HIV risk may cause lax
by neurosyphilis? thinking and increased risky behavior (151). However, a German
• Will HIV infection affect the susceptibility
study believes that HIV PrEP was associated with no impact on
to neurosyphilis? the prevalence of syphilis among MSM and concerns about risk
compensation should not be the barrier to PrEP use in men with
• What genetic factors make humans susceptible
to neurosyphilis? behavioral risk for HIV acquisition (152). It is necessary to carry
out more studies on the impact of HIV PrEP on the prevalence of
Diagnosis • When do syphilis patients need lumbar puncture to
evaluate neurosyphilis? syphilis in other countries or regions. These findings underscore
the significance of employing combination prevention strategies or
• How are specific antibodies produced in CSF of
patients with neurosyphilis? How to developing a syphilis-specific PrEP.
accurately detect? Treatment as prevention (TasP) is an additional method that
• How to early identify neurosyphilis? is effective in controlling the source of infection (153). For
HIV-positive patients, it refers to taking HIV medications to
Administration • What tests can be used to monitor the treatment
response of patients with neurosyphilis?
prevent sexual transmission of HIV. The proportion of infants
born to syphilis mothers suffering from neurosyphilis is higher
• Can standard penicillin treatment improve the
long-term prognosis of neurosyphilis?
than expected. For syphilis patients, antenatal treatment has
demonstrated high efficacy in reducing the risk of congenital
• Will the increase in gene mutations related to
syphilis with the dose of at least 2.4 MU penicillin given at least 28
penicillin resistance gradually accumulate, leading to
the emergence of penicillin-resistant T. pallidum? days before delivery (154). However, a case-control study revealed
that treatment of neurosyphilis remains difficult, even if most
• What are the indications for stopping treatment
for neurosyphilis? pregnant women with syphilis are treated with penicillin, and that
this is related to inadequate treatment of sexual partners (155).
• How to develop a vaccine against neurosyphilis?
Effective management and control of neurosyphilis continues to
ANS, asymptomatic neurosyphilis; CNS, central nervous system; CSF, cerebrospinal fluid.
face significant obstacles.

introduced for assays or genetic analyses (140). Vulnerability to Discussion

outer membrane extraction can be minimized through the use
of gel microdroplet techniques, while bioinformatics methods Taken together, neurosyphilis denotes an infection of the CNS
aid in predicting OMPs without the performance of fragile with a poor prognosis among individuals with syphilis. Although
outer membrane (141). Additionally, antigenic variation can be neurosyphilis has been described for centuries, numerous aspects
addressed by designing strains that impair the ability to alter TprK remain unknown (as outlined in Table 3). To address the dearth
(41). The latest field of molecular biology and bioinformatics of epidemiological investigations on neurosyphilis, it is imperative
provides unprecedented opportunities for the identification of new to conduct additional observational studies and consider the
vaccine targets. Several adhesins, such as TP0136 (142), TP0751 implementation of comprehensive surveillance systems on
(143), and TP0954 (144), have been identified as major vaccine a national or regional scale. As discussed, recent literature
candidates, highlighting their role in invasion and dissemination increasingly indicates the interrelation between neurosyphilis, the
of T. pallidum. Current limitations of these candidates include immune response, and genetic factors. However, time is needed for
the requirement of extremely high doses, lack of cross-protection the specific implementation of these strategies in clinical practice.
and potential side effects of adjuvants (142, 144). Although some In addition to focusing on the T. pallidum itself, pathogen-host
scientists have attempted multicomponent vaccines, complete interactions should also be taken into account, especially the
protection against infection has not yet been achieved (137). pathogens with high neuroinvasion properties and host with high
Undeniably, inducing partial protection vaccines contributes to the susceptibility to infection.
attenuation of transmission and, hence, blockade of progression to Currently, clinical suspicion of neurosyphilis primarily arises in
neurosyphilis (145). The general topic of vaccines for T. pallidum patients with syphilis who exhibit neurological and/or psychiatric
has been thoroughly addressed elsewhere and here will not go into symptoms. In such cases, it is appropriate to consider serum
more detail (136, 146). non-treponemal test titer and serofast status. Accelerating the
T. pallidum is primarily transmitted through skin-to-skin or development of potential serological predictors, standardizing their
mucosal contact during sexual encounters, as well as through use, and promptly introducing them into clinical practice would
vertical transmission (147). Over the past three decades, public greatly assist clinicians in determining the optimal timing for

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Wu et al. 10.3389/fneur.2023.1340321

lumbar puncture. Furthermore, further clinical studies with higher Funding

levels of evidence are necessary to explore the efficacy and long-
term prognosis of antibiotic therapy and prior to implementation, The author(s) declare financial support was received for
both the BBB penetration ability and the potential neurotoxicity the research, authorship, and/or publication of this article. This
must be meticulously evaluated. research received grants from the Key Research and Development
Given the sustained sensitivity of T. pallidum to penicillin, the Projects of Sichuan Provincial Department of Science and
prevalence of neurosyphilis signifies a disregard for prevention Technology (2022YFS0309).
and management, thus necessitating development of vaccines.
However, this endeavor faces significant challenges and lags behind
the development of vaccines for other bacteria. The latest field Conflict of interest
of molecular biology and bioinformatics provides unprecedented
opportunities for the identification of new vaccine targets. In order The authors declare that the research was conducted
to effectively control neurosyphilis, it is also crucial to address the in the absence of any commercial or financial relationships
stigma associated with the disease. This involves not only providing that could be construed as a potential conflict
proper care for the mental health of patients but also engaging in of interest.
scientific education. Moving forward, emphasis needs to be placed
on the most cost-effective strategies of prevention to mitigate the
global burden of neurosyphilis. Publisher’s note
All claims expressed in this article are solely those of the
Author contributions authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
SW: Conceptualization, Visualization, Writing – original draft. reviewers. Any product that may be evaluated in this article, or
FY: Writing – review & editing. YW: Writing – review & editing. claim that may be made by its manufacturer, is not guaranteed or
DL: Supervision, Writing – review & editing. endorsed by the publisher.

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