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Short report
Screening for asymptomatic neurosyphilis in HIV patients after treatment of early syphilis: an observational study
  1. Andrew Tomkins1,
  2. Shazaad Ahmad2,
  3. Darren E Cousins1,
  4. Caroline M Thng1,
  5. Francisco Javier Vilar2,
  6. Stephen P Higgins1
  1. 1Department of Sexual Health and HIV, North Manchester General Hospital (Pennine Acute Hospitals NHS Trust), Crumpsall, Manchester, UK
  2. 2Department of Infectious Diseases, North Manchester General Hospital (Pennine Acute Hospitals NHS Trust), Crumpsall, Manchester, UK
  1. Correspondence to Dr Andrew Tomkins, The Hathersage Integrated Contraception, Sexual Health & HIV Service, 280 Upper Brook Street, Manchester M13 0FH; andrewtomkins{at}


Objective To determine the prevalence of asymptomatic neurosyphilis (ANS) in HIV-positive individuals after treatment of early syphilis with single-dose benzathine penicillin G (BPG) or oral antibiotic alternatives.

Methods Patients at high risk of neurosyphilis (defined by serum rapid plasma reagin (RPR) titre ≥1:32 and/or peripheral blood CD4 lymphocyte count ≤350/μL) underwent lumbar puncture (LP) at a median time of 8.2 months post treatment. ANS was diagnosed by a reactive cerebrospinal fluid (CSF) RPR test or CSF white blood cells (WBC) >20/μL plus a reactive CSF Treponema pallidum particle agglutination (TPPA) ≥1:640.

Results Of 133 eligible patients, all were men who have sex with men. Of these, 64 consented to LP. Full CSF results were available for 59 patients. Inclusion criteria were serum RPR (21/59), CD4 count (22/59) and combined RPR and CD4 (16/59). The LP patients were white British (82%), median age 40. Syphilis stages were primary (17%) secondary (43%) and early latent (41%). Syphilis was treated with BPG (47/59), doxycycline 100 mg two times per day for 14 days (10/59) and for 21 days (1/59). Azithromycin 500 mg one time per day for 10 days was given to 1/59. At the time of LP, 100% of patients had achieved serological cure, and 66% were taking antiretroviral treatment. Only 1/59 was diagnosed with ANS. The CSF showed: RPR non-reactive (59/59); TPPA non-reactive in 54/59; WBC ≤5/μL in 51/59.

Conclusions Although the number of patients in our study is modest, single-dose BPG appears to be highly effective even in patients at high risk of neurosyphilis.

  • HIV

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In April 2003, we changed our first-line treatment for early syphilis from intramuscular procaine penicillin G (PPG) daily for 10 days to single-dose benzathine penicillin G (BPG) intramuscularly. Two factors precipitated this change. First, PPG became difficult to obtain, and second, many of our patients refused multiple intramuscular injections of PPG and requested oral antibiotic regimens which are second-line treatments. The 2002 UK syphilis guideline discouraged the use of BPG, principally because it does not yield appreciable levels in cerebrospinal fluid (CSF).1 In 2004, Marra et al2 reported that in HIV patients with syphilis, a CD4 lymphocyte count ≤350/μL and/or a serum rapid plasma reagin (RPR) titre ≥1:32 predicted a higher risk of CSF abnormalities consistent with neurosyphilis.


Accordingly, we offered selected patients with syphilis a post-treatment lumbar puncture (LP) to exclude asymptomatic neurosyphilis (ANS). Our sexual health clinic is located in a district general hospital in the north of the city of Manchester. The hospital has a cohort of over 2000 HIV patients. Patients were recruited between October 2004 and February 2013.

Eligible patients were HIV-positive with primary, secondary or early latent syphilis (up to 2 years from infection) treated with a non-PPG regimen. A serum RPR titre ≥1:32 or a CD4 lymphocyte count ≤350/μL were required. LPs were scheduled 6 months after treatment. Criteria deemed supportive of ANS were a reactive CSF RPR and/or CSF white blood cells (WBC) >20/μL plus a CSF Treponema pallidum particle agglutination (TPPA) test titre ≥1:640. Patients were ineligible for the study if they had symptoms or signs compatible with neurosyphilis when treated or contraindications to LP such as thrombocytopenia.

Demographic and laboratory test data were collected from the case records. CD4 lymphocyte counts from routine HIV reviews closest to the time of syphilis treatment were selected. Antiretroviral treatment (ART) status at the time of LP was noted.


Of 133 eligible patients, 64 underwent LP. Full CSF results were available for 59 patients. Inclusion criteria were: serum RPR ≥1:32 (21/59), CD4 ≤350 (22/59) and combined RPR ≥1:32/CD4 ≤350/μL (16/59). Of the 74 non-LP patients, 8 consented to LP but failed to attend, 20 declined LP, and in 45 cases no LP offer was documented. All 133 patients were men who have sex with men (MSM). The following characteristics show LP group (vs non-LP group): white British 82% (93%); median age 40 (41) years; taking ART 66% (52%); CD4 ≤350, 37% (16%); syphilis stage––primary 17% (16%), secondary 43% (47%), early latent 41% (37%). All 59 LP patients were serologically cured at LP. The median time to LP was 8.2 months.

Syphilis treatment regimens were: single-dose BPG (47/59); doxycycline 100 mg two times per day for 14 days (10/59) in patients with penicillin allergy or declining injected antibiotics; doxycycline 100 mg two times per day for 21 days (1/59) in a patient coinfected with lymphogranuloma venereum; azithromycin 500 mg one time per day for 10 days (1/59) in a patient intolerant of doxycycline.

Only 1/59 patients (study number 13) was diagnosed with ANS (see table 1).

Table 1

Patients with CSF WBC >5/μL

CSF tests showed: RPR non-reactive (59/59); TPPA non-reactive (54/59); only 2/59 had CSF TPPA ≥1:640, of whom one patient had ANS and the other CSF WBC <5/μL. CSF WBC was ≤5/μL in 51/59 samples. The characteristics of the eight patients with CSF WBC >5/μL are shown in table 1.


We selected a group of patients at much higher risk of neurosyphilis; yet, only one had ANS after treatment. He was diagnosed with syphilis and HIV infection on the same day. Simultaneous infection with T. pallidum and HIV may have impeded eradication of treponemes from the CNS. He may have been infected with a more neurotropic strain of T. pallidum; the 14 d/f strains are more likely to cause neurosyphilis.3 This was his first episode of syphilis, in contrast to 28/59 of this cohort who had reinfection with syphilis which has been associated with a reduced risk of ANS.4 He was not taking ART when LP was performed. When reviewed 2 weeks post LP with the CSF results, the patient had symptoms and signs of secondary syphilis, and his serum RPR had risen from 1:16 to 1:128. He denied any sexual contact, and we diagnosed relapsing secondary syphilis secondary to underlying ANS. He made a full clinical and serological recovery after treatment with PPG, oral probenecid and initiation of ART.

The LP and non-LP groups were well matched, reducing the likelihood of inclusion bias. The low prevalence of ANS might be explained by a lower susceptibility to neurosyphilis of white British MSM. However, there are no data to support this hypothesis. The number of patients in our study is modest, and the homogenous case mix may limit the applicability of our results to different populations.

Using CSF RPR may have contributed to the paucity of ANS identified, as the RPR is less sensitive in the CNS than the VDRL test.5 ,6 However, few UK laboratories use CSF VDRL (Dr Helen Fifer, Public Health England, personal communication, 2016). Had our diagnostic criteria for ANS included CSF WBC >5/μL (on ART) or >20/μL (not on ART), four additional ANS cases would have been diagnosed. However, all four patients had non-reactive CSF TPPA and CSF RPR tests, and we believe this makes ANS unlikely. Similarly, had we used CSF protein level >0.5 g/L as a diagnostic criterion, an additional 11 cases of ANS would have been identified. However, 6/11 were not taking ART, and HIV can cause elevated CSF protein.

There are few data on the performance of the CSF TPPA test in the CSF. Dumaresq and colleagues reported that a non-reactive CSF TPPA had a negative predictive value (NPV) of 84% in HIV-positive patients with early syphilis.7 However, in contrast to our study, Dumaresq included patients with clinical neurosyphilis, which would have reduced the NPV of the test. Neurosyphilis is very unlikely when CSF TPHA titre is <640.8 This influenced our choice of diagnostic criteria for ANS, although we accept that the TPHA and TPPA may have different performance characteristics.

Current UK HIV guidelines recommend ART for asymptomatic patients with CD4 counts <350/μL.9 The LP group had relatively well-preserved immunity (mean CD4 count 417/μL). Just over half the LP patients (31/59) had an undetectable plasma HIV load which will have limited the contribution of ART to the paucity of ANS.

None of the 12 patients treated with oral antibiotics had ANS. Although these findings are reassuring, the small number prevents us from drawing meaningful conclusions.

Dumaresq and colleagues found that high RPR titres alone were not so strongly predictive of neurosyphilis in patients coinfected with HIV and syphilis.7 It is possible that in our patients, a high RPR titre was less predictive of ANS.

Apart from the increased risk caused by immunosuppression and the increased neurotoxicity of some strains of T. pallidum, it is not known why those few patients who develop neurosyphilis do so. It would be helpful to have similar studies with larger patient numbers. The fact that there were neither women nor heterosexual men in this study limits our ability to generalise our findings to the wider population. However, the demographics of our patient group (mostly white MSM) are typical of most individuals with syphilis and HIV coinfection in the UK.

More than a century after the identification of T. pallidum by Schaudin and Hoffman, we are yet to find sensitive and specific laboratory tests for neurosyphilis. The development of novel CSF biomarkers such as CXCL13 is much needed.10 In addition, greater understanding of variations in T. pallidum strain pathogenicity and easier access to strain typing techniques would help physicians to exercise greater vigilance when managing selected patients.

In 2008, the UK guideline on management of syphilis broke with decades of clinical practice in recommending single-dose BPG as first-line treatment for early-stage infection, regardless of HIV status.11 Although a larger, randomised study might provide a definitive answer, our findings suggest that in British MSM coinfected with HIV, standard treatment for early syphilis is effective even in patients at high risk of neurosyphilis.


The authors are very grateful to Professor Christina Marra for her assistance in the preparation of this report.



  • Handling editor Jackie A Cassell

  • Contributors AT conducted data collection and interpretation, and prepared the report. SA conducted data interpretation and collated data on those not undergoing lumbar puncture. DEC and CMT were involved in data collection and provisional interpretation, and reviewed the manuscript. FJV assisted in preparation of the manuscript and guidance, as well as providing support with the provision of procedures for the patients. SPH led service provision, collected and interpreted the results, and prepared the report.

  • Competing interests None declared.

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

  • Data sharing statement Initial findings were presented at BASHH Spring Conference 2014.

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