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In 1999, the World Health Organization estimated that worldwide, approximately 12 million new cases of syphilis occurred among adults. Std Test nearest Ina, Illinois. In the United States, the number of cases reported annually rose from fewer than 10,000 in 1956 to more than 50,000 in 1990. The rise in incidence has been greatest among the underprivileged, heterosexuals, blacks, and urban dwellers and has occurred in New York, California, and the Southwest. As the Center for Disease Control and Prevention states, "The burden from neurosyphilis is unknown because national reporting of the disease is incomplete." 13 , 14

The CSF usually reveals elevated protein levels, lymphocytic pleocytosis, and a glucose level within the reference range; 30% of patients with secondary syphilis have abnormal CSF findings. Of patients with neurosyphilis, 10% have CSF protein values of less than 46 mg/dL, 70% have CSF protein values of 46-100 mg/dL, and 10% have CSF protein values greater than 100 mg/dL. The CSF WBC count is normal in 70% of patients, whereas it is 5-10/µL in 20% of patients and greater than 10µL in 10%; it is 4 times more likely to be lymphocytic rather than characterized by polymorphonuclear neutrophils. 23

The pathology of meningovascular syphilis is endarteritis with perivascular inflammation (ie, Heubner arteritis in medium-sized vessels and Nissl-Alzheimer arteritis in small intracranial vessels). This causes fibroblastic proliferation of the intima, thinning of the media, and fibrous and inflammatory changes in the adventitia, with lymphocytic and plasma cell infiltration. Rarely, aneurysmal dilation results. Luminal narrowing predisposes to cerebrovascular thrombosis, ischemia, vessel occlusion, and infarction. Onset of the meningovascular stage occurs, on average, 7 years after the initial infection. 24

Meningeal neurosyphilis usually manifests with the clinical features of acute meningitis, including hydrocephalus, cranial neuropathies, and the formation of leptomeningeal granulomas, called gummas. A gumma is a well-circumscribed mass of granulation tissue (avascular). It results from a cell-mediated immune response to T pallidum. Gummas usually are extra-axial lesions and dura based. The cortex is often involved secondary to invasion and direct extension. Seizures, due to the irritative focus, may develop. Early parenchymatous involvement is also reported. The presentation of mesial temporal encephalitis (limbic encephalitis) with status epilepticus and memory impairment is reported. The manifestations can be altered in the clinical setting of either concomitant HIV infection and/or previously partially treated syphilis. 25

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The neurologic examination may show areflexia, loss of proprioceptive sense with sensory ataxia, and Argyll Robertson pupils. Typically, these pupils are bilaterally small (miotic) and fail to constrict further in response to light but do demonstrate normal constriction to accommodation. This is caused by lesions in the area immediately rostral to the nucleus of Edinger-Westphal (periaqueductal gray). Nonsyphilitic causes of Argyll Robertson pupil include diabetes mellitus, multiple sclerosis, Wernicke encephalopathy, Lyme disease, sarcoidosis, herpes zoster, tumor, and hemorrhage. 26

The onset of psychiatric symptoms of general paresis can be insidious, first noticed by family and friends rather than the patient. These include loss of ambition at work, memory lapses, irritability, unusual giddiness, apathy, withdrawal, and a decline in attention to personal affairs. Later, patients may present with mental changes simulating schizophrenia, euphoric mania, paranoia, toxic psychosis, or presenile dementias. Presenile dementia is most common, manifesting with depression, confusion, and severe impairment of memory and judgment. Std Test in Ina, IL United States.

Certain physical signs and symptoms in neurosyphilis may cause suspicion of a somatoform disorder; they include lancinating pain, transient hemiparesis, transient sensory deficit, paresthesias, headache, ataxia, dysphasias, and multiple sclerosis-like symptoms. The paretic patient may exhibit histrionic behavior with grandiosity, raising suspicion of a primary conversion disorder rather than a neuro-organic etiology. To summarize, the typical neuropsychiatric presentations of neurosyphilis include delirium, mania, hallucinosis or psychosis, dementia, and depression. Coexistent meningovascular syphilis, syphilitic meningitis, and general paresis has been reported. It presents with complex evolving manifestations. 31

Ocular syphilis is a new epidemic. Ocular involvement 32 often includes anterior uveitis or panuveitis (granulomatous or nongranulomatous), retinitis, retinal vasculitis, vitreitis, and papillitis. Std Test in Ina Illinois. 33 , 34 Symptoms of photophobia and dimming of vision obviously could develop. Ina, IL std test. All symptoms can resolve with typical treatment of neurosyphilis, namely, intramuscular procaine penicillin-G. This is a relatively common manifestation of late syphilis. Adhesions of the iris to the anterior lens (synechiae) may be present, which may produce a fixed pupil; this should not be confused with Argyll Robertson pupil. Bilateral tonic pupils have been noted, with light-near dissociation and denervation hypersensitivity. A particular condition—acute syphilitic posterior placoid chorioretinitis (ASPPC)—distinct from ocular syphilis has been reported. 35 Angiographically, there is hyperfluorescence in the area of the perineuritic lesion, often with scattered focal hypofluorescence(leopardspotting). 36

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Syphilis and HIV are frequently found in the same patient, given the epidemiologic risk factors. Thus, each should be tested for after receiving consent. CSF abnormalities in patients with the concomitant infections include a higher protein content and more impressive pleocytosis. Additionally, the response to treatment is less pronounced. Therapeutically, some authors purport that highly active antiretroviral therapy to reverse immunosuppression from HIV may help mitigate neurologic complications of syphilis. 14 , 37 , 38 , 39 , 40 , 41 , 42 , 43

CSF abnormalities include elevated protein levels and pleocytosis, which are found in up to 70% of patients. In addition, the CSF VDRL result is reactive. Std Test near Ina Illinois. CSF examination is recommended in all patients with untreated syphilis of unknown duration or of duration greater than 1 year. Because standard PCN-G benzathine therapy for early syphilis does not achieve treponemicidal levels in the CSF, some experts advise lumbar puncture in persons with secondary and early latent syphilis, with follow-up examinations for patients with abnormalities.

Perform lumbar puncture in the evaluation of latent syphilis of more than 1-year duration, in suspected neurosyphilis, and in late complications other than symptomatic neurosyphilis because asymptomatic neurosyphilis may coexist with other late complications. A serum RPR titer of 1:32 seems to be the best cutoff point to decide whether or not to perform a lumbar puncture. 46 Abnormal CSF findings can then be serially monitored as a guide to therapy. Overall, CSF pleocytosis continues to define disease activity. Documentation of resolution of CSF findings following therapy is required to confirm curative treatment.

Syphilitic infection produces 2 types of antibodies, the nonspecific reaginic (immunoglobulin E-mediated) antibody (ie, anticardiolipin) and specific antitreponemal antibody, which are measured by the nontreponemal and treponemal tests, respectively. Of note, cardiolipin is a substance extracted from heart tissue that is used as the antigen in flocculation and precipitation tests for syphilis. Test results can be reactive in persons with any treponemal infection, including yaws, pinta, and endemic syphilis (ie, bejel, which is due to another strain). The VDRL test and the rapid plasma reagin (RPR) test are nontreponemal tests, whereas FTA-ABS and microhemagglutination assay-T pallidum (MHA-TP) are treponemal tests.

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The RPR test is preferred over the VDRL test in an office setting. The 2 tests are equally sensitive. They may be used for initial screening and for serial follow-up. In tertiary syphilis, the VDRL test remains, for the most part, positive indefinitely. Std Test nearby Ina IL. Response to treatment can be assessed quantitatively by evaluating the antibody titers of dilution. For example, the VDRL titers usually reach 1:32 or higher in secondary syphilis; a persistent fall in titer following treatment of early syphilis provides essential evidence of an adequate response to therapy. A rising titer may indicate reinfection or inadequate treatment. VDRL titers do not correspond directly to RPR titers, and sequential quantitative testing must consistently use the same test.

The cardiolipin antigen used in the nontreponemal tests is found in other tissues, resulting in false-positive serologic test results. These false-positive results can be found in persons with nonvenereal treponemal infections (eg, yaws, pinta, bejel), those who have received certain immunizations (eg, smallpox), pregnant women, patients with acute or chronic infections (eg, infectious mononucleosis, malaria), or those with certain chronic conditions (eg, aging, intravenous drug usage, autoimmune disorders, malignancy). False-positive RPR test results are identified by excluding syphilis with a nonreactive treponemal test. Biological false-positive CSF reagin test results may result from tuberculosis or pyogenic or aseptic meningitis. However, even with sufficient treatment, patients sometimes have a persistent low-level positive nontreponemal test, which is referred to as a serofast reaction.

Std Test near Ina, Illinois. More sensitive and specific markers for neurosyphilis have been investigated. These include oligoclonal bands and certain intrathecally produced antitreponemal immunoglobulin M and immunoglobulin G antibodies. Polymerase chain reaction for detection of treponemal nucleic acids in the CSF has been suggested to also be useful and confirmatory. 52 A new, experimental diagnostic approach involves relying on a CSF marker—known as a B-cell chemotactant—termed chemokine CXC motif ligand 13. Laboratory verification of CNS involvement in syphilis remains a challenge. Detection of anticardiolipin and antitreponemal antibodies in CSF in patients with neurosyphilis is problematic. A new commercially available test, the INNO-LIA Syphilis Score molecular test may serve as a new generation of valid tests to identify patients with silent neurosyphilis as well as patients with active intrathecal synthesis of IgG antibodies. 53 Generally, these have not reached a clinical level of usebecause theirroleremains unclear.

Some investigators have recommended that patients who are infected with HIV have a lumbar puncture to evaluate their response to treatment and that the lumbar puncture be performed at least 6 months after treatment, along with a clinical evaluation and periodic serologic testing for at least 3 years, if not for life, depending on the underlying process. CSF VDRL results may take years to revert to normal after successful treatment; therefore, normalization of CSF pleocytosis must be checked to monitor the response to therapy.

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Patients with general paresis (parenchymatous neurosyphilis) have demonstrated frontocortical atrophy and disseminated frontal high-signal lesions. These patients have also been found to have cerebral atrophy (cortical thinning of the temporal and frontoparietal regions bilaterally, most prominent in the temporal regions); mesiotemporal (amygdalar) T2 hyperintensity; ventriculomegaly; and pathological T2 hypointensity of the globus pallidus, putamen, head of the caudate, and thalamus. In those with general paresis, MRI may be of prognostic value. 56 The iron (ie, ferritin) deposition and increased frontal atrophy correlate with the progression of neuropsychiatric disturbances, apparently independent of CSF changes.

Also reported is newly diffuse white-matter T2 hyperintensity, which was seen to be partially reversible after therapy and thus thought to be due to edema and gliosis. 57 It was not specific for neurosyphilis in that it has also been seen with Binswanger disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, progressive multifocal leukoencephalopathy, HIV encephalitides, and subacute sclerosing panencephalitis. Diffusion-weighted imaging (DWI) on MRI serves well to demonstrate cerebral syphilitic gumma, revealing findings that include juxtacortical lesional nodular enhancement, moderately restricted diffusion, and dural tail and surrounding vasogenic edema. 58 , 59

Single-photon emission computed tomography (SPECT) is a useful method for evaluating an inflammatory state and for assessing the effect of therapy on neurosyphilis. Increased cerebral blood flow is detectable by iodine-123 (123 I) N -isopropyl-p -iodoamphetamine SPECT, consistent with the active inflammatory state of neurosyphilis; its disappearance correlates with successful treatment with penicillin. SPECT can be diagnostically sensitive in the setting of otherwise unremarkable MRI findings. Std Test closest to Ina IL. 64 , 65

Reports of electrophysiologic features in tabes dorsalis indicate absent H reflexes and impeded tibial nerve sensory evoked potentials (with absent cortical potentials) consistent with pathologic involvement of the dorsal roots and the dorsal funiculi (stemming from secondary wallerian degeneration). Some investigators contend that posterior tibial somatosensory evoked potentials are a sensitive marker for detecting subclinical root damage in meningeal syphilis and may aid in evaluating the extent to which neurosyphilitic spinal root damage has developed. Normal findings on nerve conduction studies are usually expected because motor fibers are rarely involved; partial anterior horn cell dysfunction is known to occur. 67

A cure for neurosyphilis does not exist in patients infected with HIV. Std test near Ina Illinois. After treatment for syphilis, PCN fails to produce a biologic cure and relapse is prevented by the immunologic status of the host. In a way, neurosyphilis is considered an opportunistic infection. Prolonged survival despite depleted helper T cells is associated with a recrudescence of syphilis. The course of neurosyphilis is believed by some investigators to be more rapid in patients co-infected with HIV, consistent with a potentiating effect. Others maintain that the course is no more aggressive in HIV-positive patients, nor is it atypical or more refractory to treatment.

Corticosteroids (along with intravenous PCN) have been used in the clinical setting of cerebral gummata. 87 Massive doses (ie, dexamethasone at 12 mg/d intramuscularly for 1 mo, followed by methylprednisolone at 16 mg/d) have been prescribed. On occasion, neurosurgical decompression of coexistent hydrocephalus may be indicated. With treatment, the space-occupying lesions undergo complete resolution on neuroimaging studies and the clinical picture improves. If seizures are present, treat accordingly.

Syphilitic optic neuropathy (SON) (including iridocyclitis and posterior placoid chorioretinitis) has been recently reported to present as the sole and initial clinical manifestation of HIV and syphilis co-infection. 88 , 89 This should be considered upon presentation of bilateral uveitis of uncertain origin, especially if the patient has a rash and/or headache. Adjunctive steroid therapy is touted to be advantageous toward improvement in optic nerve functional outcomes with SON. More rigorous studies are required for validation of this pharmacologic approach. 90 Ocular symptoms in HIV+ patients should be treated as neurosyphilis whereas ocular symptoms in non-HIV+ patients can be treated as secondary syphilis. 91

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Patients should be informed about the possibility of experiencing the adverse Jarisch-Herxheimer reaction. This is the transient febrile reaction after any therapy for syphilis. It occurs within the first few hours and peaks at 6-8 hours. The Jarisch-Herxheimer reaction follows a self-limited course; sedation (eg, with diazepam or haloperidol ) and general supportive measures are indicated. Admit the patient to the hospital if neurologic involvement is noted. Otherwise, treat with steroids and antipyretics, as indicated. Std Test nearest Ina. 93

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