Asthma

-Diurnal variation, PEFR >20%
-PEFR >15% improved, 200ml, beta agonist MDI 400mcg or neb 2.5mg or prednisolone 30mg/d for 2 w
-PEFR>15% worsened, 6min exercise or metacholine test

Positive CSF VDRL, Negative Serum RPR, VDRL‏

I'm sending this article because of the two recent unusual patients with positive CSF VDRL 1:1024 but negative serum RPR (elderly lady has negative serum VDRL too).

Both have headache of 1-2 weeks duration as an indication for LP. One an elderly 60-year-old with concomitant salmonella sp sepsis, lymphadenopathy and scalp abscess. Another a young 14-year-old lady who presented with 1 week history of fever, headache and neck stiffness. The younger lady's CSF was all normal (normal protein, glucose, no cells, no crypt ag, only pressure>34, Normal MRI). Both have no STD risk factor and have negative HIV serology.

Question:
Can one has positive CSF VDRL (high titer) but negative serum RPR & serum VDRL?

Yes. As mentioned below, "Unfortunately, the nontreponemal tests (VDRL and RPR) may be nonreactive in late neurosyphilis, particularly in tabes dorsalis. When there is suspicion for late forms of neurosyphilis, serum treponemal tests (FTA-ABS, TPPA, or syphilis EIA) should always be performed"

Therefore, we must still do serum TPHA. If serum TPHA is negative, then we can probably conclude that the CSF VDRL test is an error since both patients cannot have neurosyphilis without first having syphilis. And I believe the younger lady cannot have late neurosysphilis (esp tabes dorsalis) because this condition takes 15-20 years to develop.

Appreciate your thought.

Thank you.

Regards,
HG
Neurosyphilis

Author
Christina M Marra, MD

Section Editors
Francisco Gonzalez-Scarano, MD
John G Bartlett, MD

Deputy Editor
John F Dashe, MD, PhD

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2013. | This topic last updated: Jun 19, 2013.

INTRODUCTION — The term "neurosyphilis" refers to infection of the central nervous system (CNS) by Treponema pallidum (T. pallidum), subspecies pallidum. Neurosyphilis can occur at any time after initial infection.

Early in the course of syphilis, the most common forms of neurosyphilis involve the cerebrospinal fluid (CSF), meninges, and vasculature (asymptomatic meningitis, symptomatic meningitis, and meningovascular disease). Late in disease, the most common forms involve the brain and spinal cord parenchyma (general paralysis of the insane and tabes dorsalis). Each form has characteristic clinical findings, but in some cases there is overlap between these findings.

This topic will review the pathogenesis, epidemiology, clinical findings, diagnosis, and treatment of neurosyphilis. Other aspects of syphilis are discussed separately. (See "Pathophysiology, transmission, and natural history of syphilis" and "Pathogenesis, clinical manifestations, and treatment of early syphilis" and "Pathogenesis, clinical manifestations, and treatment of late syphilis" and "Epidemiology, clinical presentation, and diagnosis of syphilis in the HIV-infected patient".)

PATHOGENESIS — Neurosyphilis begins with invasion of the cerebrospinal fluid (CSF), a process that probably occurs shortly after acquisition of Treponema pallidum (T. pallidum) infection. The organism can be identified in the CSF from approximately one-quarter of untreated patients with early syphilis [1,2]. Although investigators in the first half of the 20^th century did not believe that there were "neurotropic strains" of T. pallidum, a study conducted in the antibiotic era suggested that strain variability may affect the characteristics of the infection [3].

Unlike other bacteria that can infect the CSF, invasion of CSF with T. pallidum does not always result in persistent infection, as spontaneous resolution may occur in some cases without an inflammatory response. In other cases, spontaneous resolution may occur after a transient meningitis.

Persistent meningitis is the result of failure to clear organisms from the CSF. Patients with persistent meningitis have "asymptomatic neurosyphilis", and individuals with this form of neurosyphilis are at risk for subsequent forms of symptomatic neurosyphilis (figure 1) [4]. Studies performed in the early 20^th century showed that the more abnormal the CSF in asymptomatic meningitis, the more likely that symptomatic neurosyphilis will develop [5].

The mechanism of T. pallidum clearance from CSF is probably similar to the immune response that occurs in peripheral infection, where opsonized organisms are cleared by activated macrophages. Supporting evidence comes from a study of nonhuman primates infected with T. pallidum; the number of CSF CD4+ T cells and the amount of gamma-interferon produced by CSF lymphocytes increased throughout the period of bacterial clearance, consistent with a "Th-1-type" cellular immune response [6].

EPIDEMIOLOGY — Neurosyphilis was common in the pre-antibiotic era, occurring in 25 to 35 percent of patients with syphilis [4,7]. Of these, approximately one-third had asymptomatic neurosyphilis, one-third had tabes dorsalis, and at least 10 percent had paresis. Meningovascular syphilis was seen in about 10 percent, with the remaining patients having other forms of neurosyphilis, including symptomatic meningitis and cranial nerve abnormalities.

In the current era, early neurosyphilis is more common than late neurosyphilis, and is most frequently seen in patients with human immunodeficiency virus (HIV) infection. This association may simply reflect the fact that syphilis is most common in men who have sex with men, many of whom are HIV-infected, or it may reflect a true difference in susceptibility [8]. (See "Epidemiology, clinical presentation, and diagnosis of syphilis in the HIV-infected patient".)

HIV-infected persons with lower peripheral CD4+ T cell counts are more likely to have symptomatic neurosyphilis than those with higher CD4+ T cell counts [9].

The frequency of the late forms of neurosyphilis (general paresis and tabes dorsalis) has declined in the antibiotic era, with the result that these forms, particularly tabes dorsalis, are now uncommon [10]. Many experts believe that this decline is due, at least in part, to the widespread use of antibiotics for unrelated illnesses.

CLINICAL MANIFESTATIONS — Neurosyphilis can be classified into early forms and late forms (figure 1). The early forms typically affect the cerebrospinal fluid (CSF), meninges, and vasculature, while the late forms affect the brain and spinal cord parenchyma. Most of what we know about the clinical manifestations of neurosyphilis comes from observations made before the advent of penicillin [4,7].

Early neurosyphilis

Asymptomatic neurosyphilis — By definition, patients with asymptomatic neurosyphilis have no symptoms or signs of central nervous system (CNS) disease, although they may have evidence of concomitant primary or secondary syphilis. Asymptomatic neurosyphilis can occur within weeks to months after infection, but less commonly occurs more than two years after infection.

The diagnosis is based on the identification of CSF abnormalities, including a lymphocytic pleocytosis that is typically <100 cells/microL, an elevated protein concentration that is usually <100 mg/dL, a reactive CSF-Venereal Disease Research Laboratory (VDRL), or a combination of these abnormalities.

In patients with suspected asymptomatic neurosyphilis who do not have HIV infection, a CSF lymphocyte count >5 cells/microL or a protein concentration >45 mg/dL is consistent with the diagnosis of neurosyphilis. Establishing the diagnosis of asymptomatic neurosyphilis in patients who have HIV infection with CSF pleocytosis but nonreactive CSF-VDRL is difficult because mild CSF pleocytosis and elevated protein can be due to HIV itself. (See 'Diagnosis' below.)

Patients with asymptomatic neurosyphilis, regardless of CSF-VDRL reactivity, should be treated for neurosyphilis to prevent progression to symptomatic disease. (See 'Treatment' below.)

Symptomatic meningitis — Most often, symptomatic meningitis occurs within the first year after infection, but it can occur years later. As with asymptomatic neurosyphilis, peripheral findings of early syphilis may coexist, particularly the rash of secondary disease.

Patients with symptomatic syphilitic meningitis complain of headache, confusion, nausea and vomiting, and stiff neck. Visual acuity may be impaired if there is concomitant uveitis, vitritis, retinitis, or optic neuritis. Signs include cranial neuropathies, particularly of the optic, facial, or auditory nerves. (See 'Ocular syphilis' below and 'Otosyphilis' below.)

Meningitis may cause hydrocephalus as well as arteritis of small-, medium-, or large-sized vessels, leading to ischemia or infarction of brain or spinal cord. (See 'Meningovascular syphilis' below.)

Focal meningeal inflammation may lead to diffuse leptomeningitis or to syphilitic gummas, which are focal areas of inflammation that present as mass lesions contiguous with the leptomeninges (image 1). Meningitis, brain ischemia, or gummas may cause seizures.

Syphilitic meningitis may uncommonly affect the spinal cord and cause meningomyelitis or hyperplastic pachymeningitis with polyradiculopathy. Symptoms and signs include back pain, sensory loss, incontinence, leg weakness, or muscle atrophy.

The CSF abnormalities that accompany symptomatic meningitis are more severe than those seen in asymptomatic meningitis. CSF lymphocyte counts are generally between 200 to 400 cells/microL, CSF protein concentration is typically between 100 to 200 mg/dL, and CSF-VDRL is almost always reactive. Neuroimaging may show enhancement of meninges, spinal fluid, cranial nerves, or spinal roots. Cerebral gummas show focal areas of enhancement adjacent to the meninges, often with a "dural tail", and surrounding edema (image 1).

Ocular syphilis — Ocular syphilis can involve almost any eye structure, but posterior uveitis is most common and presents with diminished visual acuity [11,12]. Additional manifestations may include optic neuropathy, interstitial keratitis, anterior and intermediate uveitis, chorioretinitis, and retinal vasculitis. Ocular syphilis is often, but not always, accompanied by syphilitic meningitis.

Otosyphilis — Hearing loss, with or without tinnitus, should be considered as part of the neurologic symptoms or signs of neurosyphilis [13]. Like ocular syphilis, hearing loss may or may not be accompanied by meningitis.

Meningovascular syphilis — As with other bacterial meningitides, syphilitic meningitis can cause an infectious arteritis that may affect any vessel in the subarachnoid space surrounding the brain or spinal cord and result in thrombosis, ischemia, and infarction. This form of neurosyphilis may present as an ischemic stroke in a young person. Stroke may develop at any time from the first months to the first few years after infection, with an average interval of seven years in a series conducted in the pre-antibiotic era [4].

Many patients with meningovascular syphilis have prodromal symptoms, such as headache, dizziness, or personality changes, for days or weeks before the onset of ischemia or stroke. These symptoms are probably due to concomitant meningitis.

The manifestations of cerebral ischemia may be acute or chronic. The clinical findings with stroke reflect the territory of the vessel involved. The middle cerebral artery and its branches are most commonly affected. Less commonly, meningovascular disease affects the anterior spinal artery and thereby causes spinal cord infarction.

The CSF abnormalities associated with meningovascular neurosyphilis are generally less severe than in those of acute meningitis, with lymphocytic pleocytosis between 10 to 100 cells/microL and protein concentration of 100 to 200 mg/dL. As with all of the early symptomatic forms of neurosyphilis, CSF-VDRL is usually but not always reactive.

Angiography (performed with computed tomographic, magnetic resonance, or conventional catheter techniques) may demonstrate either focal segmental arterial narrowing, focal narrowing and dilatation, or total occlusion, similar to the findings seen in other infectious or noninfectious vasculitides. Neuroimaging shows one or more areas of infarction.

Late neurosyphilis — General paresis and tabes dorsalis are considered "tertiary" forms of neurosyphilis, while the early forms of neurosyphilis are not.

General paresis — General paresis (also known as general paralysis of the insane, paretic neurosyphilis, or dementia paralytica) is a progressive dementing illness. In the pre-penicillin era, general paresis resulted in death within an average of 2.5 years [4]. General paresis usually develops 10 to 25 years after infection, but it can occur as early as two years after infection. In the first half of the 20^th century, this form of neurosyphilis accounted for about 10 percent of all admissions to psychiatric hospitals.

In the early stage of disease, general paresis is associated with symptoms of forgetfulness and personality change. Most affected individuals experience progression of deficits in memory and judgment leading to severe dementia. Less often, patients may develop psychiatric symptoms such as depression, mania, or psychosis.

While the neurologic examination may be normal in some patients with general paresis, common abnormal findings include dysarthria, facial and limb hypotonia, intention tremors of the face, tongue, and hands, and reflex abnormalities. Pupillary abnormalities, including Argyll-Robertson pupils, may also be seen. However, pupillary findings are more typical of tabes dorsalis. (See 'Tabes dorsalis' below.)

CSF abnormalities are the rule in paretic neurosyphilis, with elevated lymphocytes of 25 to 75 cells/microL and a protein concentration in the range of 50 to 100 mg/dL. The CSF-VDRL is reactive in virtually all patients, although rare cases with a nonreactive CSF serology have been reported [14]. Neuroimaging most commonly shows atrophy.

Tabes dorsalis — Tabes dorsalis (also called locomotor ataxia) is a disease of the posterior columns of the spinal cord and of the dorsal roots. It has the longest latent period between primary infection and onset of symptoms of all forms of neurosyphilis, with the interval averaging about 20 years, but sometimes as few as three years.

While tabes dorsalis was the most common form of neurosyphilis in the pre-antibiotic era, it is uncommon in the antibiotic era. (See 'Epidemiology' above.)

The most frequent symptoms of tabes dorsalis are sensory ataxia and lancinating pains. The latter are characterized by sudden, brief, severe stabs of pain that may affect the limbs, back, or face and that may last for minutes or days. Less common symptoms are paresthesias and gastric crises, characterized by recurrent attacks of severe epigastric pain, nausea, and vomiting.

Pupillary irregularities are among the most common signs with tabes dorsalis, and the Argyll-Robertson pupil accounts for approximately one-half of these. An Argyll-Robertson pupil is small, does not respond to light, contracts normally to accommodation and convergence, dilates imperfectly to mydriatics, and does not dilate in response to painful stimuli. (See "Tonic pupil", section on 'Differential diagnosis'.)

Other findings seen with tabes dorsalis include absent lower extremity reflexes, impaired vibratory and position sensation, and, less commonly, impaired touch and pain, sensory ataxia, and optic atrophy.

The CSF may be completely normal in tabes dorsalis, or may show a mild lymphocytic pleocytosis with 10 to 50 cells/microL and protein concentrations of 45 to 75 mg/dL. In this form of neurosyphilis, as many as one-quarter of the CSF-VDRL tests are nonreactive.

Atypical neurosyphilis — Some studies from the antibiotic era have reported "atypical" forms of neurosyphilis, a term that is used to describe neurosyphilis that does not fulfill the clinical criteria for one of the "classic" forms (eg, symptomatic meningitis, meningovascular syphilis, general paresis, and tabes dorsalis). As an example, a study from the early 1970s of 289 patients with reactive serum CSF-FTA-ABS tests reported that neurosyphilis was diagnosed in 241 (84 percent) based on the identification of reflex, sensory, or pupillary changes, or seizures [15]. However, similar cases of neurosyphilis were described in the 1940s [4]. Thus, it is likely that such "atypical" forms of neurosyphilis have always existed.

That said, several modern case reports have described patients with neurosyphilis that mimicked herpes encephalitis [16]. These patients generally had acute onset of cognitive changes, although some patients had more slowly progressive presentations. Virtually all had seizures. Brain MRI showed unilateral or bilateral medial temporal lobe lesions characterized by high signal on T2 and fluid-attenuated inversion recovery (FLAIR) sequences, and these temporal lobe changes resolved after treatment for neurosyphilis [16]. In addition to mesiotemporal lobe lesions, other reports have observed MRI signal abnormalities in parietal, temporo-occipital, and thalamic regions [17].

It is difficult to categorize these cases into one of the classic clinical descriptions of neurosyphilis described above (eg, symptomatic meningitis, meningovascular syphilis, general paresis, tabes dorsalis). While patients with a more slowly progressive course could be considered to have general paresis, those with acute onset and temporal lobe imaging abnormalities present a greater challenge for classification. The features of these cases are most similar to meningovascular syphilis, except that the temporal lobe abnormalities do not respect vascular territories. Thus, it is probably best to describe them as an overlap between meningeal and parenchymal disease, rather than attribute them to one of the classic clinical forms of neurosyphilis. The fact that seizures themselves may cause reversible temporal lobe abnormalities further complicates categorization of these cases [18].

DIAGNOSIS — In his 1944 text, Stokes wrote, "The frequency of neurosyphilis in general medical practice depends to a large extent on the thoroughness of the search for signs of neuraxis involvement and the frequency with which the spinal fluid examination is employed" [7]. This axiom remains true today.

Clinical suspicion and spinal fluid examination are keys to the diagnosis of neurosyphilis (algorithm 1 and algorithm 2).

• Lumbar puncture should be considered in the evaluation of a patient who presents with neurologic or ocular disease that could be caused by syphilis, but with unknown syphilis history.
• Lumbar puncture should be performed in the evaluation of a patient with known history of syphilis who presents with neurologic or ocular disease that could be caused by syphilis.
• Lumbar puncture should be considered in all patients with HIV infection and syphilis of any stage, even in the absence of neurologic or ocular disease (algorithm 2).

Unknown syphilis history — In the setting of an unknown syphilis history, the first step in establishing the diagnosis of neurosyphilis is confirming that the patient has been infected with Treponema pallidum (T. pallidum), as a patient cannot have neurosyphilis without first having syphilis.

Tests for syphilis include the following:

• Serum nontreponemal tests

• Venereal disease research laboratory (VDRL)
• Rapid plasma reagin (RPR)

• Serum treponemal tests

• Fluorescent treponemal antibody absorption (FTA-ABS)
• Treponema pallidum particle agglutination assay (TPPA)
• Syphilis enzyme immunoassay (EIA)

Confirmation is straightforward when serum nontreponemal tests and treponemal tests are reactive, as they virtually always are in early neurosyphilis. (See "Diagnostic testing for syphilis".)

Unfortunately, the nontreponemal tests (VDRL and RPR) may be nonreactive in late neurosyphilis, particularly in tabes dorsalis. When there is suspicion for late forms of neurosyphilis, serum treponemal tests (FTA-ABS, TPPA, or syphilis EIA) should always be performed. These tests remain reactive for life in virtually all individuals regardless of previous treatment. Reactivity of these serum tests confirms that the patient has had syphilis at some time, and that he or she is at risk for neurosyphilis.

Patients with nonreactive serum treponemal tests do not merit further evaluation for late neurosyphilis. (See "Diagnostic testing for syphilis".)

Known syphilis — In patients with known syphilis, a lumbar puncture with cerebrospinal fluid (CSF) examination should be performed in certain clinical situations to evaluate the possibility of symptomatic or asymptomatic neurosyphilis (algorithm 1 and algorithm 2). The United States Centers for Disease Control and Prevention (CDC) recommendations are that CSF examination should be performed in any of the following situations [19]:

• Neurologic or ophthalmic signs or symptoms in any stage of syphilis.
• Evidence of active tertiary syphilis affecting other parts of the body. (See "Pathogenesis, clinical manifestations, and treatment of early syphilis", section on 'Latent syphilis'.)
• Treatment failure (including failure of serum nontreponemal tests to fall appropriately) in any stage of syphilis.
• Human immunodeficiency virus (HIV) infection with late latent syphilis or syphilis of unknown duration.

A few caveats should be noted:

• Patients who have ocular syphilis or otosyphilis, with or without CSF abnormalities, should receive standard neurosyphilis treatment. The value of lumbar puncture is that if CSF abnormalities are identified, they can be followed to assess efficacy of treatment. (See 'Treatment' below.)
• Some experts recommend LP in all patients with concomitant HIV infection and syphilis, regardless of stage, because of reports of neurosyphilis (asymptomatic and symptomatic) occurring after standard treatment for early syphilis. (See "Epidemiology, clinical presentation, and diagnosis of syphilis in the HIV-infected patient".)
• Patients who have a serum RPR titer ≥1:32, with or without HIV infection, have an increased likelihood of a reactive CSF-VDRL. Available data suggest that the risk is increased approximately 11-fold in those without HIV infection and sixfold in those with HIV infection [20], regardless of syphilis stage or prior syphilis treatment [21]. In addition, in patients with HIV infection, a peripheral blood CD4 count of ≤350 cells/microL conveys an approximately three-fold increased risk of asymptomatic neurosyphilis [20,22]. Compared with the stage-based criteria for lumbar puncture recommended by the CDC for patients with concurrent HIV infection and syphilis, a retrospective analysis reported that performing lumbar puncture in patients with a serum RPR titer ≥1:32 or CD4 count <350 cells/microL resulted in fewer missed cases of asymptomatic neurosyphilis [23].

Given these data, we suggest lumbar puncture for the diagnosis of neurosyphilis in asymptomatic or symptomatic patients with a serum RPR titer ≥1:32 and/or the presence of HIV infection with a CD4 count ≤350 cells/mm3.

Spinal fluid examination — While a reactive CSF-VDRL establishes the diagnosis of neurosyphilis, a nonreactive rest does not exclude the diagnosis. The CSF-VDRL test may be falsely negative in as many as 70 percent of patients with neurosyphilis. Furthermore, the CSF-VDRL test may be falsely positive when the CSF is visibly blood-tinged and the serum nontreponemal test titer is high.

In contrast to the CSF-VDRL, the CSF FTA-ABS test is sensitive but not specific, particularly in asymptomatic neurosyphilis. In the setting of lymphocytic CSF pleocytosis and a nonreactive CSF-VDRL, a nonreactive CSF-FTA-ABS test excludes the diagnosis of neurosyphilis in most instances [24].

Elevation of the CSF protein concentration is consistent with neurosyphilis. However, it may be less specific than CSF pleocytosis [25,26].

• In patients with suspected neurosyphilis who do not have HIV infection and who have nonreactive CSF-VDRL, a CSF lymphocyte count >5 cells/microL or a protein concentration >45 mg/dL is consistent with the diagnosis of neurosyphilis (algorithm 1). Results of the CSF-FTA-ABS test may be helpful in establishing or refuting the diagnosis of neurosyphilis when protein elevation is the sole CSF abnormality.
• In patients who have HIV infection and syphilis, establishing a diagnosis of neurosyphilis is particularly difficult when the CSF-VDRL is nonreactive in the setting of a mild CSF pleocytosis. The difficulty arises because HIV itself causes mild CSF pleocytosis and mild elevation of the CSF protein concentration. As noted earlier, in patients with neurosyphilis who are seronegative for HIV infection, the CSF leukocyte count is usually elevated to >5 cells/microL. This contrasts with patients who have HIV coinfection, where a CSF leukocyte count of >20 cells/microL is considered to be consistent with neurosyphilis.

One study found that an HIV-induced CSF pleocytosis was independently and significantly associated with three factors [27]:

• Lack of current antiretroviral use (OR 5.9, 95% CI 1.8-18.6)
• CD4 count >200/microL (OR 23.4, 95% CI 3.1-177.3)
• Detectable plasma HIV RNA (OR 3.3, 95% CI 1.1-9.4)

In HIV-infected patients who are taking antiretroviral agents, have CD4 counts ≤200 cells/microL, or have an undetectable plasma HIV RNA viral load, the likelihood of an HIV-induced CSF pleocytosis appears to be reduced by 70 to 96 percent [27]. Thus, a CSF pleocytosis in such patients who have syphilis is more likely to be due to neurosyphilis than to HIV.

TREATMENT — The treatment of neurosyphilis is discussed separately and reviewed here briefly. (See "Pathogenesis, clinical manifestations, and treatment of late syphilis", section on 'Neurosyphilis'.)

The standard regimens recommended by current Centers for Disease Control and Prevention (CDC) guidelines for the treatment of neurosyphilis, including ocular syphilis, are as follows (table 1) [19]:

• Aqueous crystalline penicillin G (18 to 24 million units per day, administered as 3 to 4 million units IV every four hours, or 24 million units daily as a continuous infusion) for 10 to 14 days, or
• Procaine penicillin G (2.4 million units IM once daily) plus probenecid (500 mg orally four times a day) for 10 to 14 days

These regimens can also be used following desensitization to beta-lactams for patients who have a serious penicillin allergy [19]. Desensitization should be managed in consultation with a specialist.

An alternative treatment for patients who have a mild penicillin allergy is ceftriaxone (2 gm IV daily) for 10 to 14 days, with careful observation for cross-reactivity [19].

No controlled trials have evaluated the efficacy of the currently used forms of penicillin for neurosyphilis treatment. Thus, recommendations for treatment are based on clinical experience and on predicted penetration of penicillin into the cerebrospinal fluid (CSF) and central nervous system (CNS). Over the years, successively higher doses of intravenous (IV) aqueous penicillin G have been recommended as first-line therapy for neurosyphilis (table 1) [19].

Limited data suggest that ceftriaxone or high-dose doxycycline could be used as alternatives to IV penicillin in patients with neurosyphilis [28,29].

Ocular syphilis and otosyphilis are treated with the same regimen as is used for neurosyphilis, regardless of the presence or absence of CSF abnormalities. Treatment with topical glucocorticoids for ocular syphilis and oral glucocorticoids for otosyphilis is often used in conjunction with antibiotics.

Monitoring — Because Treponema pallidum (T. pallidum) cannot be grown in the laboratory, there is no microbiological test of cure. Thus, the success of neurosyphilis therapy is judged by resolution or stabilization of clinical abnormalities and by normalization of CSF abnormalities.

Neurologic examination and lumbar puncture should be performed at three to six months after treatment and every six months thereafter until the CSF white blood cell count is normal and the CSF-Venereal Disease Research Laboratory (VDRL) is nonreactive. The CSF white blood cell count should decline at six months after successful treatment, and all CSF abnormalities should resolve by two years after treatment. Failure to meet these criteria should prompt retreatment. Retreatment is also indicated if any follow-up CSF sample shows an increase in CSF white blood cell count, or a fourfold increase in CSF-VDRL titer. CSF abnormalities may normalize more slowly in patients who have human immunodeficiency virus (HIV) infection compared with those who are not infected with HIV [25].

Normalization of serum rapid plasma reagin (RPR) titer may predict successful neurosyphilis treatment. Supporting evidence comes from a longitudinal study of 110 patients with neurosyphilis, most with HIV coinfection, who were treated for neurosyphilis [26]. At four, seven, and 13 months after treatment, normalization of the serum RPR test, defined as a fourfold or greater decline in RPR titer or reversion to nonreactive, predicted normalization of CSF white blood cell count and CSF-VDRL reactivity in >90 percent of patients [26]. However, the predictive value of serum RPR normalization was lower for HIV-infected patients who were not taking antiretroviral agents.

SUMMARY AND RECOMMENDATIONS

Epidemiology and clinical manifestations

• Neurosyphilis refers to infection of the central nervous system (CNS) by Treponema pallidum. This disorder begins with invasion of the cerebrospinal fluid (CSF), a process that probably occurs shortly after acquisition of T. pallidum infection. (See 'Pathogenesis' above.)
• Early in the course of syphilis, the most common forms of neurosyphilis involve the CSF, meninges, and vasculature (asymptomatic meningitis, symptomatic meningitis, and meningovascular disease). Late in disease, the most common forms involve the brain and spinal cord parenchyma (general paresis and tabes dorsalis) (figure 1). In the current era, early neurosyphilis is more common than late neurosyphilis, and is most frequently seen in patients with human immunodeficiency virus (HIV) infection. (See 'Epidemiology' above and 'Clinical manifestations' above.)
• Asymptomatic neurosyphilis lacks symptoms or signs of CNS disease, although there may be concomitant evidence of primary or secondary syphilis. Treatment of asymptomatic neurosyphilis prevents progression to the symptomatic forms. (See 'Asymptomatic neurosyphilis' above.)
• Symptomatic syphilitic meningitis is typically manifested by headache, confusion, nausea and vomiting, and stiff neck. Visual acuity may be impaired if there is concomitant uveitis, vitritis, retinitis, or optic neuritis. Signs include cranial neuropathies. (See 'Symptomatic meningitis' above.)
• Syphilitic meningitis can cause an infectious arteritis that may affect any vessel in the subarachnoid space and result in thrombosis, ischemia, and stroke involving the brain or spinal cord. (See 'Meningovascular syphilis' above.)
• The late forms of neurosyphilis (general paresis and tabes dorsalis) are the "tertiary" forms, while the early forms of neurosyphilis are not.
• General paresis is a progressive dementing illness that usually develops 10 to 25 years after infection. Symptoms of forgetfulness and personality change predominate early on, but progression leads to severe dementia. Common signs include dysarthria, facial and limb hypotonia, intention tremors of the face, tongue, and hands, and reflex abnormalities. (See 'General paresis' above.)
• Tabes dorsalis, uncommon in the modern era, is a disease of the posterior columns of the spinal cord and of the dorsal roots. The latent period between primary infection and onset of symptoms averages about 20 years. The most frequent manifestations include ataxia, lancinating pains, and pupillary irregularities. (See 'Tabes dorsalis' above.)

Diagnosis summary

• Clinical suspicion and spinal fluid examination are keys to the diagnosis of neurosyphilis. In the setting of unknown syphilis history, the first step is confirming current or previous infection with T. pallidum (algorithm 1 and algorithm 2). Serum nontreponemal tests (Venereal Disease Research Laboratory [VDRL] and RPR) and serum treponemal tests (fluorescent treponemal antibody absorption [FTA-ABS], treponema pallidum particle agglutination assay [TPPA], or syphilis enzyme immunoassay [EIA]) are virtually always reactive in early neurosyphilis. However, the nontreponemal tests may be nonreactive in late neurosyphilis, while the treponemal tests remain reactive. Therefore, serum treponemal tests (FTA-ABS, TPPA, or syphilis EIA) should always be performed when there is suspicion for late forms of neurosyphilis. (See 'Diagnosis' above.)
• In a patient with known syphilis, we recommend lumbar puncture with CSF examination for those who have neurologic or ocular signs or symptoms, active tertiary syphilis affecting other parts of the body, or treatment failure in any stage of syphilis. In addition, we suggest lumbar puncture for all asymptomatic or symptomatic patients with a serum RPR titer ≥1:32 or the presence of HIV infection with a CD4 count ≤350 cells/mm³. (See 'Known syphilis' above.)
• The CSF-VDRL is specific but not sensitive for the diagnosis of neurosyphilis. In contrast, the CSF FTA-ABS test is sensitive but not specific, particularly in asymptomatic neurosyphilis. Establishing a diagnosis of neurosyphilis is difficult when the CSF-VDRL is nonreactive in patients with concurrent HIV infection and syphilis who have a mild CSF pleocytosis, because HIV itself can cause a mild CSF pleocytosis and elevation of the CSF protein concentration. (See 'Spinal fluid examination' above.)

Treatment summary

• For patients with neurosyphilis who are not penicillin-allergic, we recommend treatment with penicillin (Grade 1B). The standard regimens recommended by the Centers for Disease Control and Prevention (CDC) are listed above and shown in the table (table 1). Patients who have a serious penicillin allergy must first undergo desensitization to beta-lactams prior to penicillin therapy. For patients who have a mild penicillin allergy, we suggest ceftriaxone (2 gm IV daily) for 10 to 14 days with careful observation for cross-reactivity (Grade 2C). For patients with serious penicillin allergies who refuse desensitization or those who cannot be treated with penicillin and ceftriaxone, an alternative is oral doxycycline (200 mg twice daily) for 21 to 28 days. (See 'Treatment' above.)
• Lumbar puncture should be performed three to six months after treatment and every six months thereafter until the CSF white blood cell count is normal and the CSF-VDRL is nonreactive. We suggest retreatment if these criteria are not met by two years after treatment. In addition, we suggest retreatment if there is an increase in the CSF white blood cell count, or a fourfold increase in CSF-VDRL titer, in any follow-up CSF sample. (See 'Monitoring' above.)
• In immunocompetent patients or HIV-infected patients who are taking antiretroviral agents and in whom a follow-up lumbar puncture cannot be performed, normalization of the serum RPR titer can be used as a surrogate for success of neurosyphilis treatment. (See 'Monitoring' above.)