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Research Letter
Cerebrospinal fluid TPPA titres in the diagnosis of neurosyphilis
  1. Fareed Shiva1,
  2. David Goldmeier1,
  3. Paul Lane2,
  4. Helen Ethiopia2,
  5. Alan Winston1,3
  1. 1 Genitourinary Medicine and HIV, Imperial College Healthcare NHS Trust, London, UK
  2. 2 Department of Infection & Immunity, Charing Cross Hospital, London, UK
  3. 3 Department of Medicine, Imperial College London, London, UK
  1. Correspondence to Dr Fareed Shiva, Genitourinary medicine and HIV, Imperial College Healthcare NHS Trust, London W2 1NY, UK; fareed.shiva{at}

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Research letter

Treponema pallidum can be detected in the cerebrospinal fluid (CSF) in up to 30% of early syphilis infection.1 The BASHH guidelines2 recommend a diagnosis of neurosyphilis is based on symptomatology plus CSF white blood cell (WBC) >5 cells/µL, protein >0.45 g/L, a positive CSF Venereal Disease Research Laboratory and a Treponema pallidum particle agglutination (TPPA) titre >1:320. Other major guidelines do not recommend CSF TPPA titre assessment.3 CSF TPPA titres >1:320 are considered to have a high diagnostic yield for neurosyphilis.4 This test is however not widely available. We assessed the clinical utility of implementing CSF TPPA titre results in the diagnosis of neurosyphilis (clinical utility being the relevance and usefulness of an intervention in patient care).

Data on individuals undergoing CSF examination to investigate possible neurosyphilis before (period 1: January 2017 to February 2018, n=26) and after (period 2: March 2018 to May 2019, n=23) CSF TPPA titres were routinely available and were assessed and included demographics, HIV status, presenting symptoms and other CSF parameters (table 1). TPPA titre was retrospectively analysed in 16 CSF samples available from period 1. ‘Clinical neurosyphilis’ was defined as positive syphilis serology, neurological symptoms considered related to neurosyphilis, positive CSF TPPA and receiving treatment for neurosyphilis. ‘Laboratory-confirmed neurosyphilis’ (L-NS) was defined as the above plus either a positive CSF rapid plasma regain (RPR) or CSF TPPA titre >1:320. χ2 test was used to calculate p values to compare individuals with and without L-NS.

Table 1

Summary of patient characteristics and cerebrospinal fluid results (n=49*)

CSF TPPA results were positive in 13 (50%) and 12 (52%) and CSF RPR positive in 4 (15%) and 1 (4%) subjects in periods 1 and 2, respectively. In period 2, two individuals had a TPPA titre >1:320. The number of individuals with clinical neurosyphilis was 11 (42%) and 4 (17%) in periods 1 and 2, respectively. In individuals (n=39) with both CSF RPR and TPPA titres available, all with a positive CSF RPR had a CSF TPPA >1:320.

Of 43 individuals in whom a CSF TPPA titre and/or RPR was available, 8 subjects (18%) met the criteria for L-NS. No individual with a CSF protein <0.45 g/L met the criteria for L-NS (p=0.0001). For those with CSF WBC >5 cells/µL, five met the criteria for L-NS and three did not (p=0.0004). There was no significant association between serum RPR of above and below 1:32 and meeting the criteria for L-NS (p=0.51).

In our cohort, the numbers of clinical neurosyphilis diagnoses fell from 42% to 17% since the introduction in CSF TPPA titre measurements. This was despite similar presenting symptoms and CSF findings preintroduction and postintroduction of CSF TPPA titre testing in clinical practice. Introduction of this test aided clinical diagnoses and possibly reduced the number of individuals with a diagnosis of neurosyphilis who did not truly have the disease.

The average cost of managing neurosyphilis in a UK healthcare setting is £4700.5 Addition of CSF TPPA titration does not incur an additional cost compared with assessing a positive/negative CSF TPPA assay, making it a cost-effective measure. Importantly, in individuals with a high index of clinical suspicion for neurosyphilis, if the CSF TPPA titre is <1:320, CSF protein and WBC are required to determine the optimal management plan. Our report has limitations, including the small number of participants and a lack of data on long-term clinical outcomes.


AW is grateful for support from the NIHR Imperial Biomedical Research Centre (BRC).



  • Handling editor Henry John Christiaan de Vries

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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