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Original article
Re-evaluation of serological criteria for early syphilis treatment efficacy: progression to neurosyphilis despite therapy
  1. Pingyu Zhou,
  2. Xin Gu,
  3. Haikong Lu,
  4. Zhifang Guan,
  5. Yihong Qian
  1. STD Institute, Shanghai Skin Disease Hospital, Shanghai, China
  1. Correspondence to Professor Pingyu Zhou, STD Institute, Shanghai Skin Disease Hospital, 200 Wuyi Road, Shanghai 200050, China; zpyls{at}yahoo.com

Abstract

Objectives To study 17 cases of secondary syphilis that progressed to neurosyphilis despite appropriate treatments and whose rapid plasma reagin (RPR) titres showed a fourfold decrease within 6 months but did not revert to negative.

Methods Secondary syphilis patients with the following criteria were analysed: (1) RPR titres declined fourfold within 3 months after therapy, (2) patients denied high-risk sexual behaviours following treatment, (3) RPR titre remained serofast 24 months after treatment, (4) reactive cerebrospinal fluid (CSF)–venereal disease research laboratory (VDRL) and CSF–Treponema pallidum Particle Agglutination Test (TPPA) and (5) HIV antibody negative.

Results 14 male and three female patients met the criteria. 13 patients were asymptomatic. The CSF leucocyte count was elevated in 10 patients of whom nine also had elevated CSF–proteins. The RPR titres following secondary syphilis treatments were ≥1:32 in five cases, 1:16 in four cases, 1:8 in six cases and 1:4 in two cases. Following treatments for neurosyphilis, four cases with neurological or psychiatric manifestations resolved or improved, nine cases with raised CSF–white blood cells returned to normal and nine of 12 cases with raised CSF–protein declined to normal.

Conclusions Neurosyphilis may be detected in immunocompetent patients despite appropriate therapy for early-stage syphilis and appropriate serological responses. Clinicians should consider a CSF examination in any treated patient with evidence of disease progression irrespective of prior treatment history and serological response.

  • Syphilis
  • treatment
  • diagnosis
  • serology
  • antibodies
  • penile warts
  • skin disease
  • venereology
  • Treponema pallidum
  • STD clinic
  • neurology
  • MRI
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Introduction

Evaluation of treatment efficacy for early syphilis has been a clinical problem because there are no direct measures of disease activity. There are also problems of reinfection and drug resistance. At present, most countries use resolution of clinical lesions and the fourfold decline of non-treponemal antibody titres to judge the effect of therapy. Treatment is considered effective in early syphilis if the non-treponemal antibody titres decrease fourfold within 6 months after therapy.1 ,2

However, in some cases, a fourfold decrease in serological titres and resolution of lesions may not predict success since clinical manifestations may spontaneously resolve and titres may decline even in the absence of therapy. Studies have shown that the recommended dosage of penicillin regimens used to treat early and late latent syphilis may be insufficient when the central nervous system is affected.3 ,4 We report treatment failures occurring in secondary syphilis cases whose clinical lesions resolved and non-treponemal antibody titres declined fourfold within 3 months after therapy.

Methods

From May 2000 to April 2010, 17 secondary syphilis patients who fulfilled the following criteria were included in our case series: (1) serum rapid plasma reagin (RPR) titres showed a fourfold decrease within 3 months but failed to revert to negative at least 24 months following treatment; (2) reactive cerebrospinal fluid (CSF)–VDRL and CSF–Treponema pallidum Particle Agglutination Test (TPPA) at the time of neurosyphilis diagnosis; (3) no history of high-risk sexual behaviours following initial syphilis treatment and (4) negative HIV antibody testing.

The criteria for initial secondary syphilis diagnosis were (1) reactive serum RPR confirmed by reactive TPPA and (2) skin or mucocutaneous lesions consistent with secondary syphilis. The criteria for neurosyphilis were the reactive CSF–VDRL and CSF–TPPA tests in the absence of substantial contamination of CSF with blood with or without (1) elevated CSF leucocyte count (normal: white blood cells <8×106/l) and/or (2) elevated CSF–proteins (normal: 150–450 g/l).

Lumbar punctures were performed if patients had (1) neurological or psychiatric signs or symptoms, (2) more than 2 years' serofast state and (3) patients are anxious regarding their serofast state. Of the 17 cases, 11 patients had their lumbar puncture performed in other hospitals and CSF was sent to our hospital for analysis. After neurosyphilis was diagnosed, the patients were referred to our hospital. The other six patients were from our hospital.

To better assess the scope of the problem, during the same period, we also performed lumbar punctures on 106 treated patients with secondary syphilis whose titres remained serofast.

Charts of all syphilis cases were reviewed for patient's demography, history of prior syphilis, sexual behaviours and sexual partner's syphilis diagnosis and treatment. Clinical manifestations were recorded, and laboratory tests included HIV antibody, RPR and TPPA before and after treatment. The study was approved by the Shanghai Skin Disease Hospital Ethical Review Board. All participants provided informed consent.

Results

Seventeen treated cases who responded serologically but later developed neurosyphilis were analysed. There were 14 male and 3 female patients; the average age was 41 years (range 28–64). The characteristics of the study group are shown in table 1. The patients with secondary syphilis were treated with benzathine penicillin 2.4 MU/qw intramuscular for 2 or 3 weeks in seven cases, procaine penicillin 0.8 MU/day intramuscular for 15 days in four cases, ceftriaxone 250 mg/day intramuscular for 10 days in two cases, azithromycin 2 g/day po for 7 days or 1 g/day po for 14 days in three cases and minocycline 200 mg/day po for 15 days in one case. The highest initial RPR titres of the patients were 1:256 and lowest were 1:16. The RPR titres of all patients declined fourfold within 3 months after therapy but were ‘serofast’ during follow-up (table 2). CSF examinations were performed in these patients after informed consent forms were signed. The CSF leucocyte count was elevated in 10 patients, of whom nine had raised CSF–proteins. The other three had CSF–proteins elevated only. Four patients had normal CSF leucocytes and proteins. Four cases had neurological or psychiatric manifestations (table 2).

Table 1

Characteristics and treatment regimens of the study population (n=17)

Table 2

Symptoms, treatment regimens, RPR and CSF before and after neurosyphilis treatment

The regimens for 13 neurosyphilis patients were aqueous crystalline penicillin G, 4 MU intravenous every 4 h for 14 days, according to the Chinese National STI Treatment Guidelines.2 Four patients with penicillin allergy had ceftriaxone, 2 g intravenous daily for 10 days. All the patients had follow-up CSF examinations (table 2).

Of the 106 serofast cases in our hospital who underwent CSF examination, six (5.7%) had positive CSF–VDRL and CSF–TPPA. The treatment regimens used to manage their early syphilis diagnoses are summarised in table 3. All 106 patients had no neurological symptoms and were HIV uninfected.

Table 3

The treatment regimens for the 106 serofast patients

Discussion

Syphilis rates are increasing in China. In 2009, the incidence of syphilis was 24.66 cases per 100 000 population.5 In 2010, 358 534 syphilis cases were reported by the Ministry of Public Health of China.6 Shanghai is among the areas with the highest reported incidence (provided by Shanghai Centers for Disease Control and Prevention).

The aim of treating early syphilis is to prevent progression of disease and prevent sexual and vertical transmission. Assessment of ‘cure’ can be difficult. Clinical cure implies the disappearance of lesions, which can occur with or without therapy. Biological cure means total eradication of Treponema pallidum, which is difficult to evaluate as treponemes can persist despite effective treatment.7

Because there is no test for ‘microbiologic cure’, evaluation of the patients treated for secondary syphilis depends on quantitative non-treponemal serologic tests. A fourfold decline of non-treponemal antibody titres within 3 to 6 months after therapy indicates effective treatment.1 ,2 A study in the penicillin era suggests that up to 5% of immunocompetent persons treated with BPG for early syphilis failed therapy.8 Another study reported 18% serological failure to respond to benzathine penicillin (with or without enhancement with amoxicillin) treatment at 6 months, and of those patients, 32/131 (24%) had T pallidum in the CSF pre-treatment and 7/35 (20%) post-treatment.9 In the antibiotic era, there are limited data on the progression to neurosyphilis of patients who experienced a fourfold decline in serological titres following therapy for early syphilis, but whose titres remained positive.

Our data suggest that both symptomatic and asymptomatic neurosyphilis can occur in immunocompetent patients whose titres remain serofast following therapy for early syphilis. Although current recommended therapeutic regimens remain highly effective for early syphilis, concerns have been raised because invasion of T pallidum into central nervous system occurs in about 40% of early syphilis.10 Significance of these data in relation to development of neurosyphilis is unknown, given the lack of CSF penetration of most antibiotics used to treat early syphilis. Benzathine penicillin G fails to provide treponemicidal levels in CSF, and patients with either neurosyphilis or detectable T pallidum in CSF can still meet the serological criteria for treatment response.9–12

Our study has several limitations. The possibility of reinfection as a cause of neurosyphilis cannot be excluded though our patients denied high-risk sexual behaviours after treatment, and there was no fourfold increase in their RPR titres following their serofast state. There were multiple different antimicrobial regimens used to treat secondary syphilis, and it was difficult to determine whether some were more likely to result in clinical progression. The clinical significance of asymptomatic neurosyphilis in the antibiotic era is unclear, and most of our patients did not have neurological symptoms. The circumstances under which a CSF evaluation should be conducted for a patient after syphilis treatment are controversial since the benefits are not confirmed. Currently, US Centers for Disease Control and Prevention recommends that the following patients should undergo a CSF examination: (1) neurological signs or symptoms that persist or recur, (2) a sustained fourfold increase of non-treponemal antibody titres when reinfection is ruled out or (3) non-treponemal antibody titres do not decrease by two or more dilutions 6 months after treatment for early syphilis.1 Most of our patients would not have qualified for a CSF examination based on these criteria. Whether the CSF examination improved their long-term outcomes is unclear.

Our data suggest that neurosyphilis may be detected in immunocompetent patients despite appropriate therapy for early-stage syphilis and appropriate serological responses. Clinicians should be aware of these findings and should consider a CSF examination in any treated patient with evidence of disease progression irrespective of prior treatment history and serological response.

Key messages

  • Symptomatic and asymptomatic neurosyphilis can occur in immunocompetent patients whose titres remain serofast following therapy for early syphilis.

  • Clinicians should consider a CSF examination in any treated patient with evidence of disease progression irrespective of prior treatment history and serological response.

Acknowledgments

We would like to thank Frederick Sparling, MD, from UNC School of Medicine, for his contribution to this manuscript. We also thank Mr. Shun Lv for his suggestion, support and help.

References

View Abstract

Footnotes

  • Funding This work was supported in part by the grants from the National Natural Science Foundation of China (30972664) and Shanghai Natural Science Foundation (09ZR1428300).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Shanghai Skin Disease Hospital Ethical Review Board.

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

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