The diagnosis of neurosyphilis is predicated on the results of blood serologic tests, clinical findings and examination of cerebrospinal fluid (CSF).1 Although a “gold standard” for the diagnosis of neurosyphilis is not available,2–4 serological testing of CSF plays a major role in the diagnosis of neurosyphilis. TPHA/TPPA/MHA-P and/or FTA-abs tests positive, and increased number of mononuclear cells (>5–10/mm3) or positive Venereal Disease Research Laboratory (VDRL)/rapid plasma reagin (RPR) in CSF are used in the diagnosis of neurosyphilis.4 A reactive VDRL-CSF test is generally considered definitive evidence of neurosyphilis, 2–4 although false-negative and rarely false-positive cases cannot be completely avoided2,5; thus, the VDRL test should be used as a “ruling in” rather than a “ruling out” criteria for neurosyphilis.6 The toluidine red unheated serum test (TRUST) is a serological nontreponemal test for syphilis, but there is no data about CSF-TRUST in diagnosis of neurosyphilis.
In this study, we retrospectively analyzed data from 41 cases of clinically diagnosed neurosyphilis (36 of them were symptomatic neurosyphilis) and 34 patients with non-neurologic syphilis admitted, between January 2003 and December 2009, to the Third affiliated hospital of Sun Yat-sen University in Guangzhou, China. The diagnosis of neurosyphilis was based on CSF-VDRL positivity, or a CSF-WBC count of >5 cells/μL with CSF-Treponema pallidum particle agglutination (TPPA) positivity.4 The CSF was evaluated for reactivity of the VDRL, TPPA, TRUST tests. The HIV-tests for neurosyphilis were all negative. We tested univariate associations using Fisher exact test or χ2 test for categorical variables. Univariate associations of P < 0.05 were considered as statistically significant. Linear correlation was used to study the correlation between Log base 2 serum-TRUST titers and Log base 2 CSF-TRUST titers in neurosyphilis patients.
In our case, we examined the sensitivity and specificity of different serological tests in CSF of symptomatic neurosyphilis. The sensitivities of VDRL and TRUST were 93.1% and 94.7% in symptomatic neurosyphilis, respectively, when compared with the standard, which was CSF pleocytosis plus positive TPPA. The TRUST tests were nonreactive in all 20 CSF samples of patients with non-neurologic syphilis. Therefore, the specificity of the TRUST in neurosyphilis was 100%, which is same as the VDRL, but the specificity of the TPPA is only 58.8% (Table 1).
The TRUST may also be performed quantitatively as VDRL. Of these 41 neurosyphilis, 17 patients had the records of CSF-TRUST titers, in which 14 patients presented CSF-TRUST titers <1:8. Serum-TRUST titers were gained from the medical records of 24 neurosyphilis patients and 21 non-neurologic syphilitic patients. The number of neurosyphilis patients with serum-TRUST titers ≥1:16 was significantly higher when compared with non-neurologic syphilitic patients (P < 0.05). Neurosyphilis remained common in subjects with serum-TRUST titers ≥1:16, with an odds ratio (OR) of 8.04 (95% confidence interval [CI], 1.52–42.43) (Table 2). Of the 24 neurosyphilis with records of serum-TRUST titers, 15 patients had both serum-TRUST titers and CSF-TRUST titers; and, we found the stringent linear correlation (r = 0.615, P = 0.015) between Log base 2 serum-TRUST titers and Log base 2 CSF-TRUST titers. Of the 21 non-neurologic syphilitic patients with records of serum-TRUST titers, 19 patients had both serum-TRUST titers and CSF-TRUST tests. The CSF-TRUST of the 19 patients were all nonreactive. There are only 2 non-neurologic syphilitic patients with serum-TRUST titers ≥1:16.
For the most part, the diagnosis of syphilis is based on clinical grounds and reactivity of serological tests. The nontreponemal tests (VDRL/RPR) have the similar sensitivity and specificity,7 but no studies have been performed on the usefulness of another nontreponemal test, TRUST test, in the diagnosis of neurosyphilis. In this study, first, we examined the effect of TRUST in the diagnosis of neurosyphilis.
The TRUST antigen is easily prepared and made from relatively inexpensive VDRL antigen, and is a satisfactory substitute for other more expensive nontreponemal tests for syphilis and it appears to be stable for long periods. There may be cost savings using the TRUST versus some other screening tests for syphilis.8 The TRUST has been proven in a previous study to be as sensitive and specific as the VDRL slide and RPR card tests.8,9 In China, the largest developing country, the TRUST test has become commercially available and is widely used in the common hospitals, but VDRL not. It must enhance the examination cost of in-patients and contribute to inconvenience of patients. In this study, we investigated the effect of CSF-TRUST on neurosyphilis by qualitative and quantitative method. The sensitivity of the TRUST in symptomatic neurosyphilis was 94.7%, which is similar to VDRL. The TRUST was nonreactive in all 20 CSF samples from patients with non-neurologic syphilis, which is same as VDRL. According to the result of this study, we proposed that a reactive CSF-TRUST can also be diagnostic to neurosyphilis. The TRUST also could be performed quantitatively as VDRL, thereby providing a means to aid in the follow-up of treatment schedules. We have no enough following data about sequential TRUST titer reduction after penicillin treatment, but according to the CSF-VDRL titers normalized by 14.2 months after treatment in 94% of subjects,10 the TRUST titers could be a useful method to predict the response to the penicillin therapy. Recently, a study reported that HIV-uninfected neurosyphilis was 11 times more likely to occur in patients with serum RPR titers ≥1:32.11 Our results showed that 45.83% of the neurosyphilis patients had serum-TRUST titers ≥1:16, and only 9.5% of the non-neurologic syphilitic patients had serum-TRUST titers ≥1:16; thus, the HIV-uninfected neurosyphilis was 8 times more likely to occur in patients with serum-TRUST titers ≥1:16 (Table 2). This finding showed the importance of serum-TRUST titers in the indication of lumbar puncture in syphilitic patients. And we found the stringent linear correlation (r = 0.615, P = 0.015) between Log base 2 serum-TRUST titers and Log base 2 CSF-TRUST titers, which also suggested the importance of serum-TRUST titers in HIV-negative neurosyphilis.
In conclusion, serum TRUST titers could be the indication of lumbar puncture in syphilitic patients, and a reactive CSF-TRUST is considered diagnostic of neurosyphilis.
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