Asymptomatic NS is dened by CSF abnormalities consistent with T. pallidum in­fection without clinical symptoms. However, no consensus denition of asympto­matic NS exists, and so denitions vary. It is oen dened as a reactive CSF VDRL, or CSF pleocytosis with a reactive CSF treponemal test (FTA- ABS or TP- PA), or CSF pleocytosis alone. In the pre- penicillin era when highly eective syphilis treatment was not available, lumbar puncture (LP) was seen as an imperative. T. pallidum in- vasion of the CSF was common and predictive of the risk of more serious sympto­matic NS (Mills, 1927; Moore, 1922). With the advent of penicillin and the resultant drop in individuals suering from NS, routine LP fell out of favor. However, with the HIV epidemic in the 1980s, there was concern that PLWH were both at higher risk of NS (Taylor et al., 2008) and at higher risk of treatment failure aer standard penicillin G benzathine (Berry et al., 1987; Blank et al., 2011; Musher et al., 1990; Walter et al., 2006). Even in the modern era, we know that PLWH and those without HIV infection develop CNS invasion early during syphilis (Lukehart et al., 1988; Rolfs et al., 1997). However, most people with CNS invasion clear the infection even aer standard early syphilis therapies not targeting the CNS. e ability to clear T. pallidum from the nervous system relies upon the host immune response, and so PLWH might be more vulnerable. Emphasizing the importance of the host immune response, those with HIV with a lower CD4 count are at higher risk, and the use of antiretroviral therapy mitigates this risk of NS (Ghanem et al., 2008; Marra et al., 2004a, 2004b, 2014). Evidence also suggests that single nucleotide polymorphisms in certain human toll- like receptors (proteins that recognize pathogen- associated molecular patterns) may impair the host immune response to T. pallidum and make the host more susceptible to NS (Marra et al., 2014).

neuroaxonal injury (Marra et al., 2022), support the hypothesis that LP may benet some individuals with syphilis.

Contrary to the above ndings, the Pharmacokinetic and Clinical Observations in People over Fiy (POPPY) study, looking at an older population of PLWH and HIV- uninfected controls, found no association between global cognitive function and prior syphilis (De Francesco et al., 2019). Similarly, an Ontario, Canada study of PLWH did not nd an association between prior syphilis and subjective or objec­tive neurocognitive dysfunction (Christensen et al., 2023). Potential dierences in the POPPY and Christensen et al. (2023) studies compared to early studies include better controlled HIV infection with higher median CD4 counts, higher antiretro­viral use, and higher rates of suppressed plasma HIV RNA.

Despite these mixed results, our own work has demonstrated in a population at high risk for CSF- dened NS but without overt neurologic symptoms, objective cognitive impairment on a neuropsychological battery in two- thirds of participants (Table 8.2). CSF pleocytosis increased the odds of more severe cognitive impair­ment with an adjusted odds ratio of 3.8 (95 percent condence interval: 1.4– 10.6, p = 0.009) (Davis et al., 2021). Perhaps most relevant to clinical practice, 40 percent had cognitive decline in the year aer diagnosis and basing treatment on CSF re­sults mitigated cognitive decline (Davis et al., 2021). Additional studies are needed to conrm these results.

factors for NS have been identied, such as RPR titers greater than or equal to 1:32 or in PLWH CD4 cell count less than or equal to 350 cells/ mL or not taking antiretro­viral therapy, and perhaps elevated serum neurolament light chain, these markers remain nonspecic.