Intrathecal immunoglobin synthesis and its role in patients with neurosyphilis

Abstract

Background: Intrathecal protein synthesis (ITS) occurs in various central nervous system disorders, but few quantitative studies have focused on ITS for neurosyphilis (NS) in southwestern China. We made a study to quantitatively assess the ITS in patients with NS and to investigate the association between ITS and the stages of NS.

Methods: CSF-serum specimen pairs from 142 patients (66 NS and 76 non-NS/syphilis) were collected for routine CSF and serum tests. The NS group was divided into slight and severe subgroups according to the NS stages. Three formulas for the quantitative determination of the intrathecal synthesis were calculated to characterize the specimens, including the Ig index (Q_Ig/Q_alb), Ig extended index (Ig_EI), and intrathecally synthesized fraction (IgIF) using the hyperbolic function. The role of QTPPA/QIgG as an antibody index (AI = Q specific Ig/QIgG) was also explored.

Results: Sero_TRUST titres (1:16, 1:1-1:256), sero_TPPA titres (1:163840, 1:1280-1:1310720), total protein (MTP), and CSF_Igs (p < 0.05) were found to be significantly elevated in the NS group. Intrathecal Ig synthesis can be identified using all three formulas in the NS group. The pattern of Ig intrathecal synthesis was IgIF-G (48.62%) > IgIF-A = IgIF-M (p < 0.05), with the dominant intrathecal fraction being IgG (median, 48.62%), which was also verified by Q_IgG> Q_alb> Q_IgM = Q_IgA. In the slight NS group, the intrathecal fractions of IgM (>0 in 4 out of 20 cases) and IgG (>0 in 16 out of 20) were lower than the intrathecal fractions of IgM (>0 in 19 out of 35 cases) and IgG (>0 in 33 out of 38) in the severe group (p < 0.05). The area under the curve (AUC) of the CSF_TPPA antibody index was 0.867 (0.792, 0.922), with an optimal cutoff point of 0.81, providing a sensitivity of 88.91% and specificity of 84.62%.

Conclusion: Although the intrathecal synthesis pattern is IgG dominant in patients with NS, brain-derived IgM and IgA can also be found. Moreover, intrathecal IgM and IgG were associated with a parenchymatous type of neurosyphilis. Syphilis-specific antibodies are a new potential tool for NS diagnosis.

Keywords: central nervous system; cerebrospinal fluid; immunoglobulins; intrathecal synthesis; neurosyphilis.

Figure 1

Ig quotient diagram with hyperbolic curves for the upper discrimination line (Q_Lim) of the reference range for blood-derived Ig in CSF. The dark line is Qlim, the upper limit of the reference range for blood-derived Ig in CSF; the dashed line, indicates Qalb(10⁻³)>8; the solid point represents the cases in the NS group, while the hollow point indicates the cases in the N-NS group. Parameters for the calculation of the hyperbolic curves are obtained from a previous study (23).

Figure 2

Association of brain injury and Ig synthesis. Asymptomatic neurosyphilis (n = 5), meningeal syphilis (n = 11), meningovascular syphilis (n = 6), and ocular syphilis (n = 3) were divided into the slight group, while general paresis (n = 38) and tabes dorsalis (n = 1) were classified into the severe group. ns, no significant. *P < 0.05.

Figure 3

The ROC of the TP antibody index in neurosyphilis. The AUC of the CSF_TPPA index antibody index was AUC: 0.867 (0.792, 0.922), with its optimal cutoff points for the identification of NS being ≥0.81, providing a sensitivity of 88.91% and specificity of 84.62%.