| (一)The sudy of serological response treatment of patients with late syphilis[Background and Objective] Re-emergence of syphilis, a disease previously believed to be closed to eradication, is a matter of increasing global concern. With12million new cases a year worldwide, syphilis remains a global problem. According to WHO, more than90%of cases occur in developing countries. After standard antisyphilitic treatment, most patients can get resolution of clinical symptom and serological cure. Because of the widespread availability of antibiotic treatment and global challenge to antibiotic-resistant Treponema pallidum, neurosyphilis has gradually increased. Serological cure of early syphilis reach75%-100%after standard treatment. However, some previous studies have found a greater number of serological failures after treatment and a greater risk of developing complications, particularly neurosyphilis. It is widely believed that serological response of neurosyphilis is slower and worse than early syphilis. But there is little report about late syphilis. By prospective cohort design,the goal of our study is to analyse the characteristics of serum and CSF nontreponemal RPR titer; to compare of change of RPR titer after the treatment; to investigate factors affecting long-term prognosis; and to afford reference to the treatment and follow-up of late syphilis.[Methods]1Design methods Prospective Cohort study.2Participants From Jan2006to Jan2012, all the patients with syphilis consecutively admitted to the wards of Guangzhou Brain Hospital or outpatients, were enrolled prospectively.Inclusion criteria①diagnosis of late syphilis according to CDC;②never accept antisyphilis treatment;゛ll patients were informed consent.Exclusion criteria①human immunodeficiency virus(HIV) antibody test (+);②the baseline serology showed a nonreactive RPR (-);③follow-up is inadequate to determine serological outcome of treatment, less than one year.3Procedure Treatment according to standard anti syphilitic regimen according to the United States of America Centers for Disease Control and Prevention(CDC)2010guidelines. Patients returned for follow-up visit at2weeks or1month,6months and1year after treatment. All patients underwent lumbar puncture at baseline and1month, the lumbar puncture was repeated at6and1year only if the previous CSF profile was abnormal. Blood samples were obtained at all follow-up visit. MMSE were scored at pre-treatment and lyear after treatment.4. Variables of interest and definitions(1) The serological prognosis at1year after treatment:①Serological success/cure:refers to a4-fold decrease in the RPR titer or reversion to nonreactive by1year after baseline;②Serological failure:refers to a4-fold increase in the RPR, and no evidence of reinfection according to medical records;③Serological nonresponse or Serofast status:refers to increase or decrease no more than a2-fold from baseline.④The rate of seroreversion:refers to the property of number of patients of RPR reversion to negative.(2) The serological outcome at the end of follow-up and time to serological treatment success:it was defined as the earliest date after treatment documenting a4-fold drop in RPR titers.(3) Normalization of CSF-RPR test was defined as a4-fold decrease in titer or reversion of the test to nonreaction. Normalization of CSF WBC count was defined as a decrease from>10cell/uL to≤10/uL; and normalization of CSF protein concentration was defined as a decrease from>0.45g/L to≤0.45g/L.(4) Sub-group analysis:MMSE scores at pre-treatment and1-year after treatment were compared between the serofast and serological success patients with symptomatic neurosyphilis.5. Statistical Analysis Statistical test were conducted with SPSS version18.0software package. Student’s t-test was used to compare differences in normally distributed continuous variables and Pearson’s chi-squared test for categorical variables. Multivariate Logistic regression was used to analyse the factors related to prognosis at lyear. Cox proportional Harzard model was used to analyse the time to serological success during follow-up. Results were considered statistically significant at P<0.05(2-tailed).[Results].1. General InformationA total of172patients with late syphilis were included in the analysis. Most were male, accounting for73.8%. The mean age was (50.29±9.21) years. The median follow-up time was666.50days. Among those,138symptomatic neurosyphilis accounting for80.23%, and89.9%were men.10asymptomatic neurosyphilis accounting for5.82%, and80%were female;24late latent syphilis accounting for13.95%, and almost were female.2. RPR titers pre-treatmentMedian serum RPR titers pre-treatment of all the patients were1:8(interquartile range[IQR]1:4-1:32). Stratified by diagnosis, Median serum RPR titers of neurosyphilis (symptomatic and asymptomatic) were1:8and late latent syphilis were1:4. CSF-TPHA of neurosyphilis (including asymptomatic and symptomatic) was positive. Median CSF-RPR titers were1:2(IQR0-1:4).36.8%of patients with neurosyphilis had a negative CSF-RPR.3. Variation of RPR titer within first month after syphilis therapyOverall,32%of patients showed a serum RPR titer increase in the14days or1month after therapy. Only6.25%of patients showed a CSF-RPR titer increase,6.25%of patients reverted to negative of CSF-RPR within the first month after therapy, and70.3%remained unchanged.4Prognosis at1year after treatment172patients were followed for at least one year. At1year of these,95(55.2%) had serological success,3(1.7%) had serological failure, and74(43.0%) had serofast. Among those patients with symptomatic and asymptomatic neurosyphilis,52.7%had serological success,45.3%had serofast. Only21patients had seroreverted to negative in RPR, accounting for12.2%. The proportion of seroreverted to negative in RPR increased to16.1%at2years after treatment.64neurosyphilis were repeated lumbar puncture at1year after treatment.28.1%of CSF protein concentration was also abnormal;90.6%of patients had seroreverted to negative in CSF-RPR at1year after treatment.Sub-group analysis was conducted with the MMSE scores of thel38patients with symptomatic neurosyphilis. The MMSE scores at pre-treatment were both lower than normal between the serofast group and serological success group(t=0.429, P=0.669); At1year after treatment, both the MMSE scores of the two groups increased, but the patients with serofast were lower significantly than those with serological success (t=2.947,P=0.004).5. Logistic regression analysis factors related to prognosis at1yearBy multivariate Logistic regression analysis, the independent factors related to prognosis at1year were:pre-treatment CSF protein concentration (OR=0.275,95%CI0.124-0.608, P=0.001) and a rise in serum RPR titer within the first month (OR=0.394,95%CI0.185-0.841, P=0.016).6. Cox survival analysis of reaction timeThe estimated median time to treatment response was212.0days (IQR150.5-388.0) days. The independent factors associated with time to serological success were:higher baseline serum RPR titer(RR=1.193,95%CI1.061-1.341, P=0.003), CSF protein concentration(RR=0.513,95%CI0.343-0.770, P=0.001) and young age(RR=0.721,95%CI0.544-0.956, P=0.023).[Conclusion]1. Most of patients with neurosyphilis are36-59years old, the mean age is50years or so, and mostly neurosyphilis patients are male. While, latent syphilis patients are almost female. Female are more likely to be found the disorder selectively.2. Pre-treatment syphilis titers of late syphilis are very low, and median RPR titer is1:8, especially for latent syphilis of unknown duration(1:2-1:4).3.32%of patients show a serum RPR titer increase in the14days or1month after therapy. Only6.25%of patients show a CSF-RPR titer increase.55.2% had serological success,1.7%serological failure,and43.0%serofast at1year after treatment. Only12.2%of patients has seroreverted to negative in RPR,89.1%of the serum RPR titers couldn’t revert to negative in patients with neurosyphilis.28.1%of CSF protein concentration was also abnormal;90.6%of patients had seroreverted to negative in CSF-RPR at1year after treatment.4. The independent factors related to serological success are:baseline serum RPR titer, CSF protein concentration and age. The higher the baseline serum RPR titer, and the younger, the patients with late syphilis have the higher proportion of serological success. The higher of CSF protein concentration, the patients have the lower proportion of serological success.5. Serological response of neurosyphilis is slower and worse than early syphilis.6. Among the neurosyphilis patients with serofast, the cognitive function recover more slowly.(二)The study of neurocognitive function and cerebral white matter micro-structure on patients with serum-resistant Latent Syphilis[Background and objective] According to the first part of our study, the proportion of serofast on late neurosyphilis patients was quite high(45.3%). It was reported that latent syphilis patients (including early and late latent syphilis) was also rather high, about40.8%. Among those serofast patients,46.3%of them are impaired partly on central nervous system, cardiovascular and skeletal systems. So, the serofast latent syphilis should be paid more attention. 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 about40%of early syphilis. From report in the first part of our study, the cognitive function recovered more slowly among the neurosyphilis patients with serofast.There are little report about the cognitive function of patients with latent syphilis. During the chronic infection of syphilis,when and how to happen the impairment of cognition and the mechanism is still a hypothesis. In order to recognize the subtle cognitive impairment of chronic infection of syphilis as soon as possibly, we further explore cognition and cerebral white matter microstructure in serofast patients with latent syphilis. Our study selects the neurocognitive tools recognized internationally. Neuropsychological tests were conducted on patients with serofast latent syphilis, and normal control group with age, sex, years of education matched. combine with quantitative measurement of cerebral white matter by diffusion tensor magnetic resonance imaging to assess the integrity of white matter in vivo.The goal of our study is to investigate:1) the cognitive function of patients with serofast latent syphilis;2) the changes of cerebral white matter microstructure of patients with serofast latent syphilis;3) the relationship between the changes of cognitive function change and microstructural white matter.[Methods]1. Design methods Case-Control design.2. Participants The patients group came from in-hospital or clinic patients of Guangzhou brain hospital from October2009to May2012. The controls group comprised of health volunteers and health spouse of syphilis.Latent syphilis(LS) group:Serum treponema pallidum particle agglutination test (TPPA) and rapid plasma reagin (RPR) test was positive in patients with latent syphilis.(1) Inclusion criteria:①diagnosis of latent syphilis according to CDC;②age between25and70years, at least primary education and ability to understand the requirements of the study, volunteer to participate in this study;③HIV antibody test negative;④at least1year after standard treatment, the titer increase or decrease no more than a2-fold from baseline;⑤the Mini-Mental State Examination (MMSE) score>24.(2) Exclusion criteria:①evidence of clinical manifestations of nervous system;②used hormones and immune inhibitor in past3months;③accompanied with disease which can cause biological false positive;④history of mental illness, serious physical diseases, brain injury, alcohol or drug abuse;⑤hearing and vision impairment.Healthy control(HC) group:serum TPPA test negative and without history of syphilis and psychiatric, neurological disorder approximately matched according to age,sex,and education level. Exclusion criteria were same to syphilis group.3Task and Procedure3.1General information:Socio-demographic and clinical factors were recorded, such as age, gender, education, occupation, present illness, past history,et al.3.2Neuropsychological battery tests:Including MMSE, verbal fluency test (VFT), digital span test (DS), Stroop test, and auditory verbal learning test (AVLT).3.3Prospective Memory study:Using the methods designed by Einstein and Wang K et al, including event-based prospective memory (EBPM) and time-based prospective memory (TBPM) performance.3.4Decision-making under ambiguity cognitive function:Using the Iowa game task (IGT). Calculation the total number of cards chosen from a "safe" deck the number of cards chosen from a "safe" deck minus the number of cards chosen from a "risky" deck.3.5Cerebral white-matter microstructure study:All MRI scans and diffusion tensor imaging (DTI) were acquired using the same GE3.0Tesla clinical scanner. Images were post-processed using a program of the Functool image analysis software on a AW4.4workstation. Fractional anisotropy (FA value) from various white matter regions on the DTI scan using regions of interest (ROIs). ROIs setting and measurement of FA values were performed by an experienced neuroradiologist blinded to the information of patients. ROIs selected as follows:frontal white matter, parietal white matter, temporal white matter, occipital white matter, genu and splenium of the corpus callosum, pyramidal tract, anterior cingulate bundle, posterior cingulate bundle region.4. Statistical Analysis SPSS18.0software was used for statistical analysis. The chi-square test, Fisher’s were used to compare independent proportions and the independent t test was used to compare mean values. Repeated measures ANOVAs was used to compare the numbers selected of different group and different time. Linear Logistic regression was used to analyse the factors related to the cognitive impairment. Results were considered statistically significant at P<0.05(2-tailed).[Results]1. Results of PM1.1Socio-demographic dataThe study included a sample of30patients with serofast Latent Syphilis and30healthy controls. Among the syphils group, the mean age was (48.83±11.37) years, and80.0%were female. The mean education was (9.67±3.46) years, mean MMSE scores (27.87±1.41). There were no significant differences between two groups in demographic data and general cognitive status (P>0.05).1.2Neuropsychological battery testsCompared with healthy controls, Latent syphilis perfomed worse on AVLT-lOmin (P<0.05). There were no significant differences on most of the other tests, such as DS, Stroop, AVLT immediate memory and VFT (P>0.05). 1.3EBPM and TBPMCompared with Health controls ([EBPM]6.13±1.252,[TBPM]4.67±0.922), the patients with latent syphilis were significantly impaired in EBPM (4.33±2.057) as well as in TBPM (3.80±1.400)(t=-4.095, P<0.001; t=6.902, P<0.05). There were no significant difference in the retrospective component of PM (RM1and RM2) between the two groups (P>0.05).2Results of IGT2.1Socio-demographic data and Neuropsychological battery testsThere was no significant differences in demographic data and general cognitive status between26latent syphilis and21healthy controls. Latent syphilis group perfomed worse than the control group on AVLT-10min (P<0.05). There were no significant differences on most of the other tests, such as DS, Stroop, AVLT immediate memory and VFT (P>0.05).2.2IGT testsOn the overall performation measure (decks [C+D] minus decks [A+B]),there was a significant difference between groups (tblock4=-4.102; tblock5=-5.060; P<0.001),with the latent syphilis group showing more risky performance compared to the health control group. Latent syphilis patients chosed more "risky" decks (55.538±7.996) than that of control group (47.143±7.683), the difference was statistically significant (t=3.641, P=0.001). Of course, syphilis patients chosed less "safe"decks (44.615±7.965) than that of the control group (52.571±7.379), there is statistical significance (t=-3.517, P=0.001).2.3Correlation analysis between IGT scores and other cognitive functionTo all subjects, there were independent correlations between the number chosen from "safe" deck and stroop performation (B=-0.332, P=0.016) and AVLT-10min memory scores (B=0.344, P=0.012) significantly. 3the results of DTI3.1Socio-demographicdata and Neuropsychological battery testsThere were no significant differences in demographic data and general cognitive status between20latent syphilis patients and13healthy controls. Latent syphilis group perfomed worse than the control group on AVLT-recognition (P=0.022). There were no significant differences on most of the other tests, such as DS, Stroop, AVLT immediate and delay memory and VFT (P>0.05).3.2FA value of the cerebral white matterCompared with health control group, FA value of patients with latent syphilis showed a significant reduction in the right frontal white matter and bilateral temporal white matter and right parietal white matter (P<0.05). There was no significant difference between two groups of FA value in other ROIs.3.3Correlation analysis between FA and other cognitive functionThere were positive correlations between FAvalue of Bilateral temporal lobe white matter and EBPM and AVLT score. Among those, FA value of left temporal lobe was correlated with EBPM score (r=0.451, P=0.010), and AVLT (immediate memory) score (r=0.439, P=0.011); FAvalue of right temporal lobe was correlated with EBPM score (r=0.418, P=0.017), and the AVLT (immediate memory) score (r=0.366, p=0.036), and AVLT(delayed memory) score (r=0.383, P=0.028). There were positive correlations between FAvalue of right frontal white matter and EBPM score (r=0.349, P=0.047). All the correlations were significant (P<0.05).[Conclusion]1. Both EBPM and TBPM are imaged obviously in patients with serofast Latent Syphilis, due to the impairement of prospective part of PM. 2. Decision-making ability is impaired in patients with serofast Latent Syphilis, reflecting the partly loss of ability on solving social problem.3. There is negative correlation between impaired decision-making and stroop.4. DTI can find the changes of cerebral white matter microstructure of routine MRI examination was normal.5. FA value of some brain white matter of patients with latent syphilis reduce, mainly in the temporal and frontal white matter. These findings suggest that DTI capture clinical relevant information regarding cognitive performation among patoents with serofast latent syphilis and suggests the importance of subtle white matter changes in examing cognitive performance.6. There is significant relationship between EBPM and FA values of bilateral temporal and right frontal white matter.This findings suggest temporal and frontal lobe parcitipate in the perfomance of the PM task. |
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