From the Department of Medicine, University of North Carolina, Chapel Hill, NC
Correspondence: PF. Sparling, MD, 5113 Bioinformatics, 130 Mason Farm Road, University of North Carolina, Chapel Hill, NC. E-mail: email@example.com.
Received for publication February 8, 2010, and accepted February 12, 2010.
One of the persistent areas of uncertainty in modern infectious diseases is the diagnosis and treatment of neurosyphilis.1 Early syphilis is a systemic disease, not only in the secondary stage, but also in many patients in the primary stage. Examination of the cerebrospinal fluid (CSF) in early syphilis demonstrates Treponema pallidum in 20% to 40% of cases, either by rabbit inoculation, and/or molecular amplification of T. pallidum DNA.2,3 Untreated, as many as a third of patients progress to late stage disease, of which neurosyphilis is most common. Nevertheless, lumbar puncture (LP) is rarely performed in early syphilis. Reasons for this are several-fold. LP is uncomfortable for the patient and time-consuming in the clinic, and most patients have no symptoms of meningitis despite presence of spirochetes in CSF. Most important, a single intramuscularly injection of long acting benzathine penicillin G 2.4 MU (million units) usually results in clinical cure in a neurologically normal patient regardless of CNS involvement,3 even though serum levels of penicillin are too low to penetrate the CNS reliably.4 Failure rates of 10% to 20% after benzathine penicillin therapy of patients with early syphilis, defined by serological criteria, may be due either to reinfection or relapse of the initial infection.5 Examination of CSF is not considered necessary in early syphilis in patients without neurologic, ocular or auditory symptoms or signs. LP in later stages is required to rule out neurosyphilis regardless of symptoms or signs,6 but many physicians treat patients with asymptomatic latent syphilis of uncertain duration with 3 doses of benzathine penicillin, reserving LP for patients with signs or symptoms of neurosyphilis, or failure of decline of RPR titers after therapy.6
Reports of progression of neurosyphilis in HIV-infected persons after benzathine penicillin therapy7 resulted in a move to treat neurosyphilis in HIV-infected patients with intravenous penicillin G.6,7 The rationale is straight forward: neurosyphilis is a form of bacterial meningitis or meningoencephalitis, and should be treated as are all bacterial CNS infections with antibiotics that reach the infected site in adequate concentrations. Current United States Public Health (USPHS) guidelines call for routine use of intravenous penicillin G in all patients with demonstrable late stage neurosyphilis, regardless of HIV status, although benzathine penicillin is still the standard for early syphilis.6 Given the apparent necessity of treating late stage neurosyphilis with intravenous penicillin, accurate diagnosis is imperative. If it were shown that CNS invasion results in a greater risk of treatment failure in early syphilis with single dose benzathine penicillin therapy, it would be more important to do LPs in early syphilis. There have been no controlled trials of therapy of neurosyphilis, in any stage of the disease.
Diagnosis of neurosyphilis is not straightforward by either laboratory or clinical criteria. Examination of CSF is the only way to diagnose asymptomatic neurosyphilis. A positive CSF VDRL is considered specific for neurosyphilis, but is not sensitive; CSF Venereal Disease Research Laboratory (VDRL) is positive in no more than about 50% of patients with symptomatic neurosyphilis. Elevations of CSF white blood cells (WBCs) and protein are both insensitive and nonspecific. The classic triad of positive CSF VDRL, elevated WBCs and elevated protein is found in only 10% of patients with neurosyphilis. Many patients with neurosyphilis have a positive CSF treponemal test, but this probably reflects passive transfer of antitreponemal antibodies across the blood brain barrier (BBB), based on a direct relationship between serum and CSF titers (Christina Marra, personal communication, January 30, 2010). Lack of such a relationship between serum and CSF titers of antiphospholipid (VDRL) antibodies (Christina Marra, personal communication, January 30, 2010) argues for intrathecal synthesis of VDRL antibodies, consistent with specificity of the CSF VDRL test for neurosyphilis. Thus, most clinicians use a positive CSF VDRL as a “rule in” test, but only use CSF treponemal tests for “rule out” purposes: a positive treponemal test is consistent with but not diagnostic of neurosyphilis.
Diagnosis of neurosyphilis is particularly difficult in the presence of HIV infection, which may result in opportunistic infections of the CNS, and also may elevate CSF WBCs in the absence of any other cause. In earlier publications, Marra et al showed that neurosyphilis is more likely in HIV-infected persons with syphilis if their CD4 count is less than or equal to 350, or if their serum Rapid Plasma Reagin (RPR) titer is greater than or equal to 1:32.8 A CSF WBC greater than 20 was relatively specific for neurosyphilis in the presence of HIV infection, and was more sensitive than CSF VDRL. Their results have been confirmed elsewhere.9
In this issue, Marra et al extend their studies on methods to diagnose neurosyphilis.10 All of their patients were HIV infected, and there was a bias towards symptomatic neurosyphilis (this was a convenience sample, and patients with symptoms were over-represented). One of the strengths of their work is use of symptomatic neurosyphilis as a gold standard against which to measure test performance. Another is the large group of patients studied. Symptoms were either auditory or ocular, consistent with weighting to early neurosyphilis. They report the apparent sensitivity and specificity of the chemokine CXCL13 in CSF for diagnosis of CNS syphilis in patients with HIV infection. Low levels of CSF CXCL13 were a sensitive (90%) but not specific (37%) marker of symptomatic neurosyphilis; high levels of CSF CXCL13 were more specific (79%) but less sensitive (41%). Results were better when applied to asymptomatic neurosyphilis, defined as a CSF WBC of at least 20 without other identified cause: high CSF CXCL13 was 41% sensitive but 93% specific. In symptomatic neurosyphilis, CSF CXCL13 levels were the only CSF test that survived a multivariate analysis for significance.
There is biologic plausibility for use of CSF CXCL13 as a test for neurosyphilis. Previous European reports found elevations of CXCL13 in CSF of patients with neuroborreliosis (NB), and also in a small group of patients with neurosyphilis.11 CXCL13 is a chemokine that directs B cell traffic.12 Marra et al showed that B cells were increased in CSF of patients with neurosyphilis, as compared to patients without neurosyphilis.13 In the case of NB, CXCL13 production involves stimulation of the innate immune response receptor TLR2 on macrophages or dendritic cells by a spirochetal lipoprotein.11 Perhaps T. pallidum produces a similar lipoprotein that acts to stimulate CXCL13 production by microglia, which are CNS macrophages.14 It is possible that CXCL13 as well as antiphospholipid antibodies help clear the infection from the CNS in the absence of effective therapy.
Another interesting aspect is the possibility that chemokines are involved in the pathogenesis of CNS damage after infection. Marra et al do not speculate on this, but there is evidence that the brain responds to a number of locally produced chemokines in addition to CXCL13, some of which act in an endocrine manner, and others may result in apoptosis of brain cells.15 This is a rapidly expanding area of neurobiology.16
How useful is the measurement of CXCL13 for the perplexed clinician? Certainly the test is feasible, since commercial kits are available and they are not excessively expensive. At this stage, however, caution is a good thing. Tumors, autoimmune diseases, and other infections are associated with increased serum CXCL13 levels,17,18 and multiple sclerosis and CNS lymphomas are associated with increased CSF CXCL13 levels.19,20 Despite rather extensive investigation of utility of CXCL13 in diagnosis of NB, the test has not yet been accepted for routine use in Europe, where NB is more common than in the United States.21 We need more research on the utility of CSF CXCL13 in neurosyphilis before it is ready for routine use. Even more in some respects, we need a prospective trial of the efficacy of antibiotic therapy of early syphilis, stratifying results by whether there is evidence for invasion of the CNS, and employing therapies that either reliably penetrate the BBB or fail to do so, such as the current regimens of benzathine penicillin G.
Meanwhile, let us applaud Marra et al at University of Washington, Seattle, whose long-term commitment to studies of the pathogenesis and diagnosis of syphilis continue to improve our understanding of this fascinating and still very troublesome disease.
1. Dowell D, Polgreen PM, Beekmann SE, et al. Dilemmas in the management of syphilis: A survey of infectious diseases experts. Clin Infect Dis 2009; 49:1526–1529.
2. Lukehart SA, Hook EW III, Baker-Zander SA, et al. Invasion of the central nervous system by Treponema pallidum
: Implications for diagnosis and treatment. Ann Intern Med 1988; 109:855–862.
3. Rolfs RT, Joesoef MR, Hendershot EF, et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. The Syphilis and HIV Study Group. N Engl J Med 1997; 337:307–314.
4. Mohr JA, Griffiths W, Jackson R, et al. Neurosyphilis and penicillin levels in cerebrospinal fluid. JAMA 1976; 236:2208–2209.
5. Myint M, Bashiri H, Harrington RD, et al. Relapse of secondary syphilis after benzathine penicillin G. Sex Transm Dis 2004; 31:196–199.
6. Workowski KA, Berman SM; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep 2006; 55(RR-11):1–94.
7. Musher DM. Syphilis, neurosyphilis, penicillin, and AIDS. J Infect Dis 1991; 163:1201–1206.
8. Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: Association with clinical and laboratory features. J Infect Dis 2004; 189:369–376.
9. Ghanem KG, Moore RD, Rompalo AM, et al. Lumbar puncture in HIV-infected patients with syphilis and no neurologic symptoms. Clin Infect Dis 2009; 48:816–821.
10. Marra CM, Tantalo BS, Sahi SK, et al. CXCL13 as a cerebrospinal fluid marker for neurosyphilis in HIV-infected patients with syphilis. Sex Transm Dis. In press.
11. Rupprecht TA, Kirschning CJ, et al. Borrelia garinii
induces CXCL13 production in human monocytes through Toll-like receptor 2. Infect Immun 2007; 75:4351–4356.
12. Rupprecht TA, Plate A, Adam M, et al. The chemokine CXCL13 is a key regulator of B cell recruitment to the cerebrospinal fluid in acute Lyme neuroborreliosis. J Neuroinflammation 2009; 6:42.
13. Marra CM, Tantalo LC, Maxwell CL, et al. Alternative cerebrospinal fluid tests to diagnose neurosyphilis in HIV-infected individuals. Neurology 2004; 63:85–88.
14. Ramesh G, Borda JT, Gill A, et al. Possible role of glial cells in the onset and progression of Lyme neuroborreliosis. J Neuroinflammation 2009; 6:23.
15. Callewaere C, Banisadr G, Rostene W, et al. Chemokines and chemokine receptors in the brain: Implication in neuroendocrine regulation. J Mol Endocrinol 2007; 38:355–363.
16. Cartier L, Hartley O, Dubois-Dauphin M, et al. Chemokine receptors in the central nervous system: Role in brain inflammation and neurodegenerative diseases. Brain Res Rev 2005; 48:16–42.
17. Singh S, Singh R, Sharma PK, et al. Serum CXCL13 positively correlates with prostatic disease, prostate-specific antigen and mediates prostate cancer cell invasion, integrin clustering and cell adhesion. Cancer Lett 2009; 283:29–35.
18. Wong CK, Wong PT, Tam LS, et al. Elevated production of B cell chemokine CXCL13 is correlated with systemic lupus erythematosus disease activity. J Clin Immunol 2010; 30:45–52.
19. Sellebjerg F, Bornsen L, Khademi M, et al. Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in active MS. Neurology 2009; 73:2003–2010.
20. Fischer L, Korfel A, Pfeiffer S, et al. CXCL13 and CXCL12 in central nervous system lymphoma patients. Clin Cancer Res 2009; 15:5968–5973.
21. Mygland A, Ljostad U, Fingerle V, et al. EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol. In press.