Lumbar Puncture and Syphilis Outcome
Phase: NA
Conditions: Syphilis
Sponsor: University of Washington

 
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Lumbar Puncture and Syphilis Outcome 
ID: STUDY00001718 
16 Dec 2020 
 
 

 
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Participants were enrolled from September 2013 to March 2018. Study enrollment criteria 
changed over its course because of slow accrual. The original plan was to enroll PLWH with a 
new syphilis diagnosis who had serum RPR titer ≥ 1:32 or peripheral blood CD4+ T cells ≤ 
350/ul who did not meet CDC criteria for lumbar puncture based on symptoms [5] and to 
randomize them to LP vs. no LP. Of note, although CDC criteria for lumbar puncture include 
cognitive dysfunction, we did not consider cognitive complaints as a reason to exclude study 
participants because cognition was the focus of our study. After the first year only 32 
randomized individuals were entered, and the study was opened to persons not infected with HIV 
and to individuals who declined randomization. The latter 186 individuals were not restricted by 
serum RPR titer, peripheral blood CD4 or symptoms, with a plan to match eligible individuals to 
the eligibility criteria for the original study. We systematically collected the reason for not 
agreeing to randomization in 167 participants. The most common was that the provider 
recommended LP (n=132). Individuals who were randomized were not allowed to re-enroll in 
the study with a new episode of syphilis, but those who were not randomized could re-enter and 
could be randomized or not with a subsequent episode of syphilis.  
 
The first randomized visit for individuals who were ever randomized, and the first 
nonrandomized visit for those who were never randomized could be included in the analysis if 
the participant completed the CogState battery. All randomized participants were included in the 
analysis; 2 individuals were randomized after a previous, nonrandomized syphilis episode, 6 and 
8 months later. Of the 186 nonrandomized participants, analysis was restricted to those with 
serum RPR titer ≥ 1:32 or, for PLWH, peripheral blood CD4+ T cells ≤ 350/ul. All 

 
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nonrandomized participants endorsed normal vision, no photophobia or gait abnormality, and 
normal or at most mild hearing loss based on our previous observation that these symptoms 
predicted a reactive CSF-VDRL [8]. Ninety-six individuals were included in the entry analysis 
(Figure 1). 
 
Procedures 
 
Participants underwent a medical history, neurologic examination, blood draw, urine toxicology 
screen, and lumbar puncture, when indicated. The participant’s provider and the participant 
decided whether neurosyphilis treatment was indicated based on CSF abnormalities alone; 
neither were aware of cognitive assessment results.  
 
Neuropsychological assessment 
 
The neuropsychological assessment included the Wide Range Achievement Test-third edition 
(WRAT-3) reading subtest [9] as an assessment of premorbid verbal intelligence, a revised 
version of the Lawton and Brody instrumental activities of daily living (IADL) scale [10, 11] and 
the Medication Management Test-Revised (MMT-R) [10, 12], the Beck Depression Inventory 
(BDI-II) [13], and the CogState battery [14]. The CogState consists of computerized 
neuropsychological tests and has been used in clinical and research settings, including in PLWH 
[15-18]. It includes seven tests spanning cognitive domains of psychomotor function, attention, 
working memory, executive function, and verbal learning. To assess subjective cognitive 
impairment, we used question 19 on the IADL (difficulties due to primary cognitive problems or 

 
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to cognitive and physical problems) and question 19 on the BDI-II (difficulty with 
concentration). Participants were asked to return at 24 and 52 weeks for follow-up IADL, MMT-
R and CogState battery. 
 
Laboratory Methods 
 
Cerebrospinal fluid white blood cell (WBC) enumeration and CSF-VDRL reactivity were 
determined in a Clinical Laboratory Improvement Amendments (CLIA)-certified hospital 
clinical laboratory. HIV RNA and peripheral blood CD4+ T lymphocyte concentrations were 
obtained by medical record review. Serum RPR titers were performed in a research laboratory 
[19]. Detection of Treponema pallidum subspecies pallidum (T. pallidum) DNA in blood was 
determined as previously described [20, 21]. Only samples collected within 8 days of treatment 
of the current episode of syphilis were tested based on our experience that T. pallidum DNA is 
rarely detected in blood samples after this time (unpublished data). 
 
Data analysis 
 
Assessment of cognitive impairment was based on age adjusted normative data from CogState 
and was categorized as none (all test scores > -1 standard deviation [SD] of normative data), 
mild impairment (two test scores < -1 SD, or one test score < -2 SD), moderate impairment (two 
test scores < -2 SD) or severe impairment (three test scores < -2 SD). For the entry analysis, the 
latter two categories were combined. For the follow-up analysis, participants were categorized as 
improved if they had any impairment at study entry and improved by at least one category, or as 

 
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normalized if they improved to no impairment. Participants were categorized as declined if they 
were not severely impaired at entry and declined by at least one category. 
 
For this study, we defined abnormal CSF as WBCs >5/ul. Because we included persons not 
infected with HIV and because our PLWH were largely on antiretrovirals with suppressed 
plasma HIV RNA, we were unlikely to overdiagnose neurosyphilis. 
 
WRAT scores were normalized based on age [9]. Years of education was categorized as 9-12 vs. 
≥13 years (high school or less vs. more than high school), BDI- II was categorized as 0-13 (none 
or mild depression) vs. ≥14 (moderate or greater depression), MMT-R was categorized as <5 vs. 
≥5 [10, 22], and IADL was categorized as dependent vs. independent.  
 
Descriptive statistics are expressed as number (percent) or median (interquartile range [IQR] or 
95% confidence intervals). Proportions were compared by the Chi-square or Fisher's exact test, 
and comparisons of continuous variables by Mann-Whitney U test. Odds ratios (ORs) with 95% 
CI for categories of cognitive impairment at study entry were determined by univariate or 
multivariate ordinal logistic regression. Time to cognitive change was assessed by log rank test, 
and hazard ratios were determined by Cox regression. P-values <0.05 were considered 
statistically significant.