Chapter 20. Neurosyphilis

• • 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.

The occurrence of seronegative, active neurosyphilis in HIV co-infected patients has been suggested. However, spirochete penetration into the nervous system is not different in HIV-infected or-uninfected patients. Late serologic conversions in patients with secondary syphilis are well known, and the fact that the cellular response of the CSF may precede serologic positivity in early syphilis may explain many of these cases.

The role of the more sensitive treponemal test (FTA) in the CSF analysis remains uncertain, because the unabsorbed FTA test produces an unacceptably high false-positive response (4.5% of normal) and the addition of sorbent (FTA-ABS) decreases sensitivity to 75%. However, some laboratories now perform FTA-ABS and FTA tests of CSF to exclude neurosyphilis in at-risk patients in whom the CSF is abnormal but the CSF VDRL test is nonreactive.

Clinical Diagnosis of Neurosyphilitic Subtypes

Acute Syphilitic Meningitis

Symptomatic syphilitic meningitis occurs during the first months to 2 years following the primary infection, and 10% of cases occur coincident with the secondary rash. The typical patient is afebrile, with headache, and may have some degree of confusion. Unilateral or bilateral swelling of the optic disk is common. Meningeal signs may be positive. The course is subacute. CSF examination demonstrates a lymphocytic pleocytosis (see Table 20–1). Currently, the most useful serologic test for the diagnosis of syphilitic CNS involvement is the CSF VDRL; rapid plasma reagin (RPR) or other nontreponemal testing of CSF has no role in CNS evaluation.

The meningeal inflammatory process may be concentrated at the vertex or base of the brain. Vertex involvement produces a communicating hydrocephalus, whereas basilar inflammation produces cranial nerve (CN) abnormalities, particularly CNs II and III and those of the cerebellopontine angle (VI, VII, and VIII); asymmetry is the rule. Meningeal enhancement may be seen on magnetic resonance imaging of the brain.

The diagnosis is made in patients with meningeal symptoms, cranial nerve abnormalities, and lymphocytic pleocytosis with a positive serologic test result. A negative CSF VDRL serologic result may occur in a patient with very early CSF sampling, because CSF inflammation precedes seropositivity. The meningeal symptoms may resolve without treatment but leave the patient at risk for later forms of neurosyphilis.

Meningovascular Syphilis

When the CSF inflammatory process compromises arteries within the subarachnoid space, a syndrome of vasculitis involving mid-sized vessels is produced. The middle cerebral artery is most often affected, but any cerebral or spinal cord blood vessel may be involved, producing cortical syndromes or myelopathy in isolation or in combination. The clinical syndrome produced is distinct from that of thromboembolic stroke both in presentation and time course. Patients often have prodromal symptoms of headache, personality change, or emotional lability. The vascular occlusive syndrome is superimposed and, as is typical for a vasculitis, progresses over hours or days rather than occurring suddenly (see Table 20–1).

Increased white blood cell count in the CSF is uniformly seen. A positive CSF VDRL serologic result establishes the diagnosis. Neuroradiologic imaging most often shows involvement of the deep penetrating branches of the middle cerebral artery supplying the central white matter, particularly the white matter in the lenticulostriate distribution (see Figure 20–2A). Angiography shows concentric constriction of medium-caliber vessels (see Figure 20–2B). The angiographic features can be seen in a vascular bed prior to clinical symptoms (eg, cerebral arteritis in a patient being evaluated for a spinal presentation).

Syphilitic Dementia

Parenchymal involvement of the brain by the spirochete produces a dementing syndrome (general paresis or dementia paralytica). This evolution occurs within 3–30 years after the primary infection, with a peak incidence between 10 and 20 years (see Figure 20–1). There is a male predominance. The clinical symptoms are notoriously nonspecific, being those of any organic brain syndrome (see Table 20–3). The classic features of psychosis with grandiose delusional states were uncommon even in the prepenicillin era.

Features useful in differentiating syphilitic dementia from other causes of progressive dementia (in a patient with a reactive treponemal serologic test) are the relatively early age of onset in syphilitic dementia (most commonly between 30 and 50 years) and the fact that untreated cases of syphilitic dementia are fatal within a few months to a few years. Furthermore, the CSF is always abnormal in syphilitic dementia, showing lymphocytic pleocytosis. The blood and CSF VDRL serologic results are positive. Several instances of unilateral or bilateral medial temporal lobe high-intensity magnetic resonance imaging T2 or fluid-attenuated inversion recovery imaging abnormalities, with or without associated atrophy, have been reported in patients with the mistaken diagnosis of herpes simplex encephalitis (see Figure 20–3). The high-intensity signals resolve with treatment, but the presence of atrophy may predict a fixed cognitive deficit. Seizures, including status epilepticus, may be the presenting manifestation of parenchymal syphilis, again offering a presentation similar to that of encephalitis.

Tabes Dorsalis

Tabes dorsalis occurs within 5–50 years after a primary syphilitic infection, with a peak incidence 10–20 years after infection. This form of neurosyphilis in now uncommon. In the prepenicillin era, a marked male predominance occurred. The classic triad of symptoms—tabetic “lightning” pains, sensory ataxia, and bladder disturbances—are combined with a triad of signs—pupillary abnormalities, areflexia, and the Romberg sign. Lightning pains (localized, transient, agonizing, shooting pain, most often in the legs but affecting any body region) eventually occur in 75–90% of patients.

Either vibration or position sense may be affected out of proportion to the other. This proprioceptive sensory loss produces a wide-based gait with impaired balance that is exacerbated by eye closure (the Romberg sign). Whether the primary pathologic site is in the proximal dorsal root segments within the root entry zone or in the dorsal root ganglion remains an unresolved question.

Argyll-Robertson pupils are a characteristic finding but occur in only half of patients with tabes dorsalis. These pupils constrict to accommodation but not to light (the so-called light-near disassociation phenomenon). The typical pupils are small and irregular, bilaterally, but a host of other abnormalities can be seen. A lesion location involving the midbrain tectum has been proposed to explain this phenomenon. The differential diagnosis of these pupils includes diabetic autonomic neuropathy (pseudo tabes) and pineal region tumors or other lesions of the midbrain tectum.

The sensory impairment also results in the phenomenon of Charcot joints and distal ulcers. These phenomena and lightning pains may persist despite treatment.

Altered or Atypical Neurosyphilis

Modified or atypical presentations of the classic clinical syndromes of neurosyphilis have been suggested to be common in the antibiotic era, particularly in HIV-coinfected patients. Several series of patients confirm the classic spectrum of clinical presentations of neurosyphilis, in the setting of HIV although tabes dorsalis is now rare. In one series, no marked differences in clinical patterns were noted in 518 syphilis patients seen at the same hospital in 1930–1940 compared with 121 syphilis patients seen during 1970–1984. An increase in the number of cases of asymptomatic syphilis in the latter time period was attributed to the availability of more refined treponemal-specific tests. Another series, which compared neurosyphilis patients with and without HIV coinfection, found no clinical or serologic differences among patients, and a postmortem study concurred.

The serologic response to treatment does not markedly differ in early syphilis patients with or without HIV coinfection. In CSF, normalization of pleocytosis (the marker of disease activity) does not differ in patients with or without HIV coinfection, although normalization of CSF VDRL results and protein concentration may be impeded in HIV patients. The significance of such serofast states in immunocompromised HIV-coinfected patients is uncertain.

For acute syphilitic meningitis mimics include lymphocytic menigitides due to other infections agents, particularly tuberculosis and fungus as well as meningeal cancer. The angiographic differential diagnosis of meningovascular syphilis includes subarachnoid hemorrhage with spasm, tuberculous meningitis, and drug-induced vasculitis. Alzheimer’s disease and degenerative dementing diseases can mimic paresis (see Table 20–3). MRI changes may be useful (see Fig. 20–3) As previously noted, the differential diagnosis of Argyll-Robertson pupils includes diabetic autonomic neuropathy (pseudo tabes) and pineal region tumors or other lesions of the midbrain tectum.

Although neurosyphilis is itself a complication of syphilis, untreated neurosyphilis can have its own complications, including permanent paralysis, dementia, and death. How reversible some complications may be depends on the duration and extent of untreated disease. Treatment of neurosyphilis can be lifesaving, so if neurosyphilis is suspected and cannot be excluded, most experts would recommend treatment.

Pharmacotherapy

Table 20–4 outlines recommended and alternative treatment regimens for neurosyphilis. Penicillin G remains the treatment of choice, administered as 12–24 million units daily via intravenous infusion or in six divided doses for 10–14 days; or as procaine penicillin, 2.4 million units by intramuscular administration once daily for 10–14 days with concomitant probenecid, 500 mg orally four times daily. A trial of ceftriaxone and penicillin (intravenous and intramuscular forms) produced similar results among the three treatment regimens. Treponemicidal drug concentrations have also been reported with tetracycline and doxycycline, and with chloramphenicol. After completion of the neurosyphilis treatment regimen, an additional one to three weekly doses of penicillin G benzathine (long-acting, 2.4 million units) is recommended.

A comparative trial of penicillin G and ceftriaxone (2.0 g intravenously or intramuscularly once daily for 10–14 days) for neurosyphilis in HIV-coinfected patients showed no difference in the improvement of CSF analytes between drugs. HIV coinfection did not alter the responsiveness of early syphilis to penicillin G benzathine, nor was the clinical responsiveness of primary and secondary syphilis patients to penicillin G benzathine, with or without amoxicillin and probenecid, affected by HIV coinfection.

Response to treatment is documented by the CSF results. The CSF cell count will normalize over weeks (see Table 20–2), with the CSF protein concentration and CSF VDRL titers normalizing more slowly. Serologic results may remain abnormal (“serofast”), a finding that may be more common in HIV-coinfected patients, particularly those with low CD4 T-cell counts. However, there is no known clinical significance to this finding. The CSF examination should be repeated at 6 and 12 months to document continued normalization. Although data in HIV-infected patients are not available, in the pre-HIV era, relapses did not occur if normalization persisted at 2 years.

Treatment of Elderly Patients with Abnormal Syphilis Serology

To make the diagnosis of neurosyphilis, CNS or ophthalmic signs or symptoms of CNS syphilis (neurosyphilitic syndromes) must be present. If neurologic signs are not present (eg, patient appears to be a normal 80 year old despite abnormal serologic results), the patient should be followed. Referral to a neurologist should be made if there is uncertainty about the diagnosis.

Patients who demonstrate signs of dementia require further evaluation, including CSF analysis for the presence of abnormal cells. Syphilitic dementia is progressive and fatal, leading to death in an average of 2.5 years if untreated. The absence of inflammation (WBC count <5 cells/μL) indicates no active disease and no need for treatment. If a diagnosis of syphilitic dementia is made, treatment for neurosyphilis is indicated. If there is no clear diagnosis, or if CSF analysis is not possible, some experts have given penicillin G benzathine, 2.4 million units per week intramuscularly for 3 weeks, although there is no clinical evidence of benefit and that form of penicillin has poor CNS penetration.

Patients with an uncertain diagnosis or those who have failed to respond to therapy should be referred to an infectious disease specialist or neurologist with experience in the management of neurosyphilis. For elderly patients with dementia and reactive serologic tests, consultation with an infectious disease expert or neurologist is recommended.

The prognosis for patients with neurosyphilis is good, if diagnosed and teated in the early stages before parenchymal manifestations occur. Syphilitic meningitis and ocular and otic disease respond to penicillin therapy. Residual neurologic symptoms or signs may occur but are uncommon. The response to treatment in patients with cerebrovascular signs, dementia, or tabes dorsalis is quite variable.

• • Abnormal cellularity of the CSF defines disease activity, the potential amelioration of symptoms with therapy, and the adequacy of response to treatment in patients with neurosyphilis.
• • 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.
• • The CSF is always abnormal in syphilitic dementia, showing lymphocytic pleocytosis.