• • Central nervous system (CNS) or ophthalmic signs or symptoms of CNS syphilis (neurosyphilitic syndromes).
  
• • Serologic evidence of syphilis infection (positive results on nontreponemal and treponemal tests).
  
• • One of the following findings: positive cerebrospinal fluid (CSF) Venereal Disease Research Laboratories (VDRL) test result, CSF protein concentration greater than 40 mg/dL, or CSF white blood cell (WBC) count greater than 5 mononuclear cells per microliter.

Approximately 7% of patients with primary and secondary syphilis, if untreated, develop some form of symptomatic neurosyphilis. In 1990, the number of cases of primary and secondary syphilis reported to the US Centers for Disease Control and Prevention (CDC) peaked at over 50,000. By 1996, the incidence had fallen dramatically, and in 1997, fewer than 10,000 cases were reported. Many counties, however, report an incidence of more than 4 cases per 100,000 population. As of 2006, cases of primary and secondary syphilis are again increasing in the United States, particularly in populations of men having sex with men, thus increasing the risk pool for neurosyphilis.

The nervous system is affected early in syphilis, and 10–25% of patients have CSF abnormalities at the time of the development of the secondary stage. CSF inflammation eventually occurs in approximately one-third of patients with syphilis, with the peak of CSF abnormalities seen 12–18 months after the primary infection. Of patients with CSF inflammation, 30% will develop some form of neurosyphilis. In those with normal CSF examination findings 5 years after the primary infection, the risk of neurosyphilis is approximately 1%. Each of the clinical forms of neurosyphilis is a manifestation of this inflammatory response that continues, in reaction to Treponema pallidum invasion, over decades (see Figure 20–1).

There has been some experimental evidence regarding treponemal strain specificity and neuroinvasion. The sheath proteins of T pallidum have conserved and variable regions that differ between strains. Strain-specific differences in neuroinvasion in rabbits have been demonstrated, and the possibility that these proteins may explain T pallidum tropism is being studied.

Neurosyphilis can occur in both early and later stages of syphilis. Prevention of neurosyphilis can be primary—through the prevention of sexual exposure and syphilis infection—or secondary—through treatment in early stages to prevent the progression of syphilis.

Symptoms and Signs

The inflammatory process in the subarachnoid space produces the classic spectrum of presentation, which comprises acute syphilitic meningitis, arteritis (meningovascular syphilis), meningoencephalitis (syphilitic dementia, general paresis), and dorsal root ganglionopathy (tabes dorsalis). These entities may overlap; however, relatively pure forms predominate, demonstrating a characteristic time course and presentation following the initial primary infection (see Figure 20–1).

Acute syphilitic meningitis is the earliest symptomatic subtype and often accompanies the rash of the secondary stage of syphilis. When the meningeal inflammation involves blood vessels in the subarachnoid space, vascular syphilis occurs, usually within the first 5 years. The parenchymal forms follow over a more protracted interval of several decades. The syndromes of neurosyphilis most commonly seen in recent years are syphilitic meningitis and cerebrovascular syphilis (see Table 20–1), because these are the earliest forms seen following a new infection.

Laboratory Findings

CSF Analysis

CSF abnormalities are the hallmark of each stage of neurosyphilis. Lymphocytic pleocytosis with cell counts ranging from 10–500 WBCs/μL is found in the most acute form, syphilitic meningitis. Decreasing numbers of cells are reported in syphilitic vascular disease, paresis, and tabes dorsalis. The glucose concentration may be mildly reduced in syphilitic meningitis. The protein concentration, the least specific of CNS parameters in neurosyphilis, is rarely greater than 200 mg/dL in syphilitic meningitis, syphilitic vascular disease, and paresis. Isolated protein elevations should be interpreted with caution. Protein concentrations of less than 100 mg/dL are the rule in tabes. The gamma globulin portion of the CSF protein is commonly elevated, and oligoclonal bands may be present, as is characteristic of any chronic meningitis. In late, “burned out” tabes dorsalis, after the period of inflammation, CSF findings may be normal, although positive CSF VDRL serologic test results may be retained.

Abnormal cellularity of the CSF defines disease activity, the potential amelioration of symptoms with therapy, and the adequacy of response to treatment (see Table 20–2). Therefore, repeat CSF examination should be performed after treatment (see later discussion). Persistence of CSF VDRL titer elevation following antibiotic treatment and cell count normalization is of uncertain significance.

Serologic Tests

A negative treponemal serologic test result in blood (fluorescent treponemal antibody absorbed [FTA-ABS] or T pallidum particle agglutination [TP-PA]) excludes the diagnosis of neurosyphilis. A positive nontreponemal CSF serologic test result (CSF VDRL) establishes the diagnosis of neurosyphilis (and an increased cell count in response to the spirochete documents the presence of active disease).

Whether true negative CSF VDRL serologic test results occur in the presence of presumed active neurosyphilis is an unresolved question. The classic literature relied on the relatively insensitive Wassermann reaction, and the clinical case series in patients with early neurosyphilis (meningeal and meningovascular) were contaminated by nonsyphilitic syndromes of viral meningitis and cerebral vascular disease that were unrecognized at that time. Thus, data from these clinical groups are of uncertain value. Where clinical diagnoses were clear in the older literature (eg, paresis and tabes dorsalis), the large numbers of reported cases suggest that seronegativity (even with the Wassermann reaction) was very rare. CSF serologic diagnosis in early syphilis remains a problem. For this reason, patients with a compatible clinical diagnosis and a mild elevation of cell count but nonreactive CSF VDRL are referred to as having “probable” neurosyphilis.