Dear Editor,

I read with interest the paper entitled “The diagnostic performance of laboratory tests of neurosyphilis: a systematic review and network meta-analysis” which has recently been published in European Neurology [1]. I thank the authors for their thorough evidence-based study, which provides a comprehensive assessment of several aspects of the clinical laboratory analysis of this complication of syphilis.

Because the cerebrospinal fluid (CSF) white blood cell count (WBC) is frequently performed in patients with suspected neurosyphilis, I was interested in the support for this practice in the medical literature. Accordingly, I reviewed the studies used by Ding et al. in their paper for information regarding the utility of elevated CSF WBC in patients with suspected neurosyphilis. Five studies from the paper of Ding et al. had a sufficiently detailed data presentation for me to extract information regarding the cutoff value for CSF WBC and numbers of patients with elevated CSF WBC in the study and control groups [2‒6]. A dichotomous model with random-effect and fixed-effect was used to calculate the risk ratio (RR) and 95% confidence interval. Because CSF pleocytosis is a known phenomenon in human immunodeficiency model (HIV) infection [2], I performed a subset analysis of those studies that excluded HIV-positive patients [3, 4, 6]. A p value of <0.05 was considered statistically significant.

Because the I2 was >50%, a random-effect model was used. The results of the analysis are illustrated in Figure 1. There is a statistically significant greater likelihood of elevated CSF WBC in the neurosyphilis group compared to controls [RR 4.14 (1.07; 15.99), p < 0.01]. A subset analysis of the three studies that excluded HIV-positive subjects and controls had an increased RR [RR 6.11 (0.32; 116.73), p < 0.01] with a modest improvement in heterogeneity (I2 = 80%, compared to 95% for all 5 studies).

Fig. 1.

Forest plots of random-effect model of cerebrospinal fluid white blood cell counts in neurosyphilis patients versus controls in all studies (a) and in studies that excluded patients with human immunodeficiency virus infection (b).

Fig. 1.

Forest plots of random-effect model of cerebrospinal fluid white blood cell counts in neurosyphilis patients versus controls in all studies (a) and in studies that excluded patients with human immunodeficiency virus infection (b).

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In reviewing these papers, there were methodological differences including choice of control populations and variable inclusion/exclusion criteria (two studies specifically excluded asymptomatic neurosyphilis patients [4, 5], whereas the others included both symptomatic and asymptomatic neurosyphilis patients [2, 3, 6]). The types of neurosyphilis were reported in only two studies [3, 4] and were variable, including meningovascular, meningitis, general paresis, tabes dorsalis, tabe paresis, and mixed types. Duration of disease was not reported. Although these issues may account for some of the heterogeneity encountered in these studies, other factors likely add to the heterogeneity. From a laboratory perspective, one likely source of heterogeneity is the continuing challenge of CSF cell count technology. Automated technologies have largely replaced chamber counting, the gold standard, because of the improved turnaround times and high throughput capacity of modern hematology analyzers, including those operating in the low cell count “body fluid” mode [7]. However, automated instruments have unfavorable imprecision compared to chamber counts, and have limited reliability for fluids with cell counts of <20 cells/µL, which makes accurate counting of the CSF challenging. Specialized CSF cell counters are capable of producing accurate results in fluids with cell counts as low as 1 cell/µL [8] but are not yet available in many laboratories. Preanalytical factors may be an even more important factor in CSF cell counts. Since CSF specimens are often collected in tubes that do not contain preservative agents (to maintain the ability to produce an accurate cell count), any delays in processing may result in a falsely low WBC due to cell loss. In addition, hemodilution of specimens, particularly from those collected after the first tube, can falsely elevate the WBC [7]. For these reasons, it is important for researchers to include information about the methodology of cell counting performed in their study and transparently report their efforts to minimize the impact of preanalytical variables.

In summary, I again thank Ding and colleagues for their important study. Based on this additional analysis, the CSF WBC has a potential role in the assessment of neurosyphilis but is limited by problems with specimen quality and the current instrument standard. With continued improvements in laboratory technology, especially improved precision of cell counting in low cell count fluids such as the CSF, it is possible that the CSF WBC will be of increased importance in resolving clinical questions regarding neurosyphilis and other neurological infectious diseases.

The author has no conflicts of interest to declare.

This study was performed without funding.

J.L.F. conceived, designed, and executed this work.

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