on 20-Jan-2024 (Sat)

FreeRTOS applications that use the Linux port will not exhibit real-time behaviour.

here are two different types of processor commonly used in embedded systems: application processors and microprocessors.

The different between these is that application processors have a memory management unit. An MMU virtualizes and ‘looks after’ memory for you. As the memory is virtual, an MMU is able to prevent memory fragmentation and the subsequent slowing down of the system by mapping data across to other parts of the same program after memory has been freed.

Another advantage of an MMU is memory protection, which manages the memory access rights of programs, and helps with debugging.

Where do Linux and FreeRTOS come in? Embedded Linux requires an MMU to run, whereas FreeRTOS does not. Having the MMU decreases development effort and improves system support, however increases the memory footprint of the application.

A morpheme is the smallest meaningful constituent of a linguistic expression

Ontology reasoning finds a relevant application in the so-called ontology-based data access, where a classical extensional database (EDB) is enhanced by an ontology, in the form of logical assertions, that generates new intensional knowledge which contributes to answering queries.

Secondary syphilis can also affect mucosal surfaces [28]. Patients may develop mucous patches, whitish erosions on the oral mucosa or tongue (picture 9A-C), and split papules at the oral commissures. Large, raised, gray to white lesions called condylomata lata may develop in warm, moist areas such as the mouth and perineum (picture 10A-D). Condylomata lata occur most often in areas proximate to the primary chancre and may reflect direct spread of organisms from the primary ulcer [27]. Mucous patches and condylomata lata contain large numbers of T. pallidum organisms (picture 11).

The rash can take almost any form, although vesicular lesions are uncommon. As examples:

• The rash is classically a diffuse, symmetric macular or papular eruption involving the entire trunk and extremities (picture 7A-F) including the palms and soles (picture 8A-D). Although involvement of the palms and soles is an important clue to the diagnosis of secondary syphilis, localized lesions can also occur [29].

Individual lesions are discrete copper, red, or reddish-brown and measure 0.5 to 2 cm in diameter [27,28]. Although lesions are often scaly, they may be smooth. In addition, nodular lesions also may be seen. On occasion, the rash may be pruritic.

• Pustular syphilis can take the form of small pustular syphilide, large pustular syphilide, flat pustular syphiloderm, and pustular-ulcerative syphilide (ie, malignant syphilis) [29].

Rash is the most characteristic finding of secondary syphilis. However, in one series of 105 patients with secondary syphilis, more than 20 percent had lesions that were not appreciated by the patient [28].

Renal abnormalities — Patients with secondary syphilis can have mild transient albuminuria, nephrotic syndrome, or acute nephritis with hypertension and acute renal failure [34]. Pathologically, membranous glomerulonephritis or diffuse endocapillary glomerulonephritis, sometimes with crescents, can be seen. Resolution of renal abnormalities follows treatment for syphilis.

Visual/auditory findings — Ocular or otic infection can occur at any stage of disease but is most commonly identified during the early stages [35]. Otosyphilis is diagnosed less often than ocular syphilis.

Ocular syphilis – A sometimes-underappreciated manifestation of syphilis is eye involvement, which has been increasingly reported in the last several years and may be more common among persons with HIV [36-38]. One report suggests ocular syphilis may be associated with certain strains of T. pallidum [39].

Patients can develop anterior uveitis, posterior uveitis, or panuveitis, which is often granulomatous. Most patients with ocular syphilis develop diminished visual acuity secondary to posterior uveitis (picture 13) [36,40]. Posterior uveitis typically presents as multifocal chorioretinitis; however, other manifestations include retinal necrosis and optic neuritis.

Otosyphilis – Otosyphilis typically presents with cochleo-vestibular symptoms, such as tinnitus, vertigo, and sensorineural hearing loss [35]. Hearing loss can have a sudden onset and be unilateral or bilateral. Symptoms can progress rapidly and in some patients may result in permanent hearing loss.

Late syphilis — Approximately 25 to 40 percent of patients with untreated syphilis can develop late disease. The clinical events may appear at any time from 1 to 30 years after primary infection [2]. It is not necessary for individuals to have experienced clinically symptomatic primary or secondary syphilis prior to developing late syphilis.

The most common manifestations include:

● Cardiovascular syphilis (especially aortitis)

● Gummatous syphilis (granulomatous, nodular lesions that are rare, can occur in a variety of organs, usually skin and bones)

● CNS involvement (particularly general paresis and tabes dorsalis)

A confirmed case of late syphilis with clinical manifestations requires the demonstration of T. pallidum in late syphilitic lesions by special stains (eg, Warthin-Starry silver and immunofluorescent staining), polymerase chain reaction, or equivalent direct molecular methods. A probable case is diagnosed when characteristic abnormalities or lesions are noted along with a reactive treponemal serological test. A detailed discussion of diagnostic testing for syphilis is found elsewhere. (See "Syphilis: Screening and diagnostic testing" and "Neurosyphilis", section on 'Diagnosis'.)

Tertiary syphilis describes patients with late syphilis who have symptomatic manifestations involving the cardiovascular system or gummatous disease (granulomatous disease of the skin and subcutaneous tissues, bones, or viscera).

Cardiovascular syphilis classically involves the ascending thoracic aorta resulting in a dilated aorta and aortic valve regurgitation. The disorder is thought to be a consequence of vasculitis in the vasa vasorum leading to a weakening of the wall of the aortic root [41]. The onset is typically insidious; most patients present with an asymptomatic murmur or with left heart failure. Clinical manifestations typically occur 15 to 30 years from initial infection in the untreated patient. Syphilitic aneurysms rarely lead to dissection.

Physical examination may reveal a high-pitched "tambour" second sound, but this finding is neither specific nor sensitive. Chest films often show a calcified ascending arch of the aorta, reflecting the chronic inflammation of the intima; this finding is not usually seen in arteriosclerotic disease (image 1). Syphilis may also involve the coronary arteries, resulting in coronary artery narrowing and thrombosis. Coronary ostial stenosis may sometimes be found on catheterization [42].

Gummatous syphilis is very uncommon. However, several cases of gummas have been reported in individuals with HIV. Most of these have involved internal organs. (See "Syphilis in patients with HIV", section on 'Neurosyphilis'.)

Gummas can occur anywhere, including skin, bones, or internal organs. On the skin, gummas may present as ulcers or heaped up granulomatous lesions with a round, irregular, or serpiginous shape (picture 14A-B). They range from small to very large and may be severe in malnourished individuals ("rupial" lesions). Visceral gummas may present as a mass lesion. If a biopsy shows granulomas, lesions may be mistaken for a number of other diseases, including sarcoidosis, which is characterized by granulomas.

There are many forms of CNS syphilis, some of which may occur as many as 25 years after the initial infection (eg, general paresis and tabes dorsalis). A detailed discussion of the CNS manifestations of late-stage syphilis is found elsewhere. (See "Neurosyphilis", section on 'Late neurosyphilis'.)

Latent syphilis refers to the period when a patient is infected with T. pallidum (as demonstrated by serologic testing) but has no symptoms. The diagnosis of latent syphilis is based only upon the results of serological testing, which is discussed elsewhere. (See "Syphilis: Screening and diagnostic testing", section on 'Latent syphilis'.)

Latent syphilis is typically divided into early (if initial infection occurred within the previous 12 months) and late (if initial infection occurred >12 months ago) [9]. If the timing of an infection is not known, late latent syphilis is presumed.

It is important to differentiate between early and late latent syphilis to understand the risk of transmission to others. As examples:

● Patients with late latent disease are not considered infectious to their recent sexual contacts since they do not have lesions that can transmit disease.

● In contrast, patients with early latent syphilis may have transmitted T. pallidum to their sexual partners through lesions that were recently active but are no longer present. It is also possible that patients with early latent syphilis were not diagnosed because of an obscure or painless lesion that was present but not discovered on physical exam. (See 'Primary syphilis (chancre)' above.)

● Pregnant women with latent syphilis can transmit T. pallidum to their fetus for up to four years after acquisition. (See "Syphilis in pregnancy" and "Congenital syphilis: Management and outcome".)

Differentiating early from late latent disease also has implications for treatment (eg, one versus three doses of intramuscular [IM] penicillin G benzathine) (table 1).

Syphilis is transmissible during primary or secondary syphilis with an efficiency of transmission estimated at approximately 30 percent.

Early local infection — T. pallidum initiates infection when it gains access to subcutaneous tissues via microscopic abrasions [22]. Despite a slow estimated dividing time of 30 hours, the spirochete evades early host immune responses and establishes the initial ulcerative lesion, the chancre (picture 2). During the period of early local replication, some organisms establish infection in regional draining lymph nodes with subsequent dissemination.

The diagnosis of syphilis is most commonly made by serologic testing, a technique first described by Wasserman in 1906 [4].

Diagnostic testing for syphilis should be performed on patients with signs or symptoms of infection. In addition, asymptomatic patients should be screened for syphilis if they are at high risk for having acquired disease or for transmitting disease to others.

All persons who are diagnosed with a new syphilis infection should be treated. In addition, they should be offered HIV testing as well as screening for other sexually transmitted infections (STIs).

Symptomatic patients — Since syphilis can present with a wide range of signs and symptoms, the threshold for serologic testing should be low. We test the following groups of patients regardless of their apparent risk behaviors:

● Those who present with the classic signs and symptoms of syphilis, including but not limited to a painless genital ulcer (primary syphilis); a diffuse, symmetric macular or papular eruption involving the entire trunk and extremities (secondary syphilis); general paresis; or tabes dorsalis (tertiary syphilis). (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Clinical manifestations'.)

● Any sexually active patient with an undiagnosed genital ulcer or a rash that involves the palms and soles. (See "Approach to the patient with genital ulcers" and "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Clinical manifestations'.)

● Patients who present with signs and symptoms that are less specific for syphilis (eg, cranial nerve dysfunction, chronic headache, aortic insufficiency, meningitis, other signs of meningovascular disease, including cerebrovascular accidents), particularly if no alternative etiology is identified. (See "Syphilis: Treatment and monitoring" and "Neurosyphilis".)

Asymptomatic patients — Pregnant women should be screened for syphilis (regardless of perceived risk) to prevent in utero transmission of asymptomatic infection, which can lead to congenital syphilis. (See "Syphilis in pregnancy", section on 'Maternal screening'.)

Screening for syphilis should also be performed in asymptomatic patients who are at increased risk of infection. These include the following:

● Patients with a sexual partner who has early syphilis (ie, primary, secondary, or early latent) syphilis. Such patients should typically receive empiric therapy as well. (See "Syphilis: Treatment and monitoring", section on 'Treatment of early syphilis'.)

● Sexually active men who have sex with men (MSM).

● Individuals with HIV. (See "Initial evaluation of adults with HIV", section on 'Screening for coinfections' and "Screening for sexually transmitted infections", section on 'Patients with HIV infection'.)

● Individuals receiving pre-exposure prophylaxis (PrEP). (See "HIV pre-exposure prophylaxis", section on 'Patient monitoring'.)

● Patients currently engaging in high-risk sexual behaviors (eg, patients diagnosed with a sexually transmitted disease, people who exchange sex for drugs or money, individuals having condomless sex with multiple partners). (See "Screening for sexually transmitted infections", section on 'Screening recommendations'.)

● Individuals with a history of incarceration or commercial sex work.

When deciding which other sexually active persons to screen for syphilis, clinicians should assess if the patient is from a demographic group in which the prevalence rates of syphilis are particularly high [5].

For patients taking PrEPs, testing for STIs should be performed every three months in asymptomatic MSM and transgender women (TGW) at risk for recurrent STIs (eg, those with recent STIs or multiple sex partners) or every six months for all others taking PrEP who are sexually active [11,12].

The CDC suggest annual screening for sexually active MSM [6]. However, in such patients, testing as often as every three months may increase the detection of syphilis [7].

Serologic tests — Serologic tests provide a presumptive diagnosis of syphilis. There are two types of serologic tests for syphilis: nontreponemal tests and treponemal-specific tests. The use of only one test is insufficient for diagnosis since serologic testing (especially nontreponemal tests) can be associated with false-positive results.

False-negative results can also occur since serologic testing relies upon a humoral immune response to infection. Thus, the use of serologic testing may be limited in patients with advanced immunosuppression and/or early disease. As an example, although the majority of patients have a positive serologic test when they present with a chancre (ie, two to four weeks after exposure), approximately 20 to 30 percent have a nonreactive nontreponemal test [13,14]. For such patients, serologic testing generally turns positive within the next two to four weeks. (See 'Negative nontreponemal test in early syphilis' below.)

Nontreponemal tests — Nontreponemal tests (also known as tests for reagin antibodies) are based upon the reactivity of serum from infected patients to a cardiolipin-cholesterol-lecithin antigen. Although these screening tests are nonspecific, and therefore not definitive, they have traditionally been used for initial syphilis screening due to their relatively low cost, ease of performance, and ability to be quantified for the purpose of following response to therapy.

Nontreponemal tests include:

● Rapid plasma reagin (RPR)

● Venereal Disease Research Laboratory (VDRL)

● Toluidine Red Unheated Serum Test (TRUST)

In general, these assays are semi-quantitative in that the amount of antibody present (both IgM and IgG) generally reflects the activity of the infection. Positive nontreponemal tests are reported as a titer of antibody (eg, 1:32, which represents the detection of antibody in serum diluted 32-fold). Titers tend to wane over time even without treatment, but successful therapy accelerates the pace of antibody decline. Changes in titer are followed after treatment to detect a therapeutic response.

Treponemal tests — Treponemal tests have historically been more complex and expensive to perform than nontreponemal tests. Thus, they have traditionally been used as confirmatory tests for syphilis when the nontreponemal tests are reactive. However, newer versions of these tests have been automated, enhancing simplicity and facilitating ease of use. As a result, these tests are increasingly used as an initial screening test for syphilis rather than as confirmatory tests (reverse screening).

Specific treponemal tests include:

● Fluorescent treponemal antibody absorption (FTA-ABS)

● Microhemagglutination test for antibodies to T. pallidum (MHA-TP)

● T. pallidum particle agglutination assay (TPPA)

● T. pallidum enzyme immunoassay (TP-EIA)

● Chemiluminescence immunoassay (CIA)

Treponemal tests usually remain positive for life. However, some people who are treated during primary syphilis may become seronegative after two to three years [16]

The TP-EIA test has become the favored treponemal test in many laboratories, particularly those with large numbers of specimens for testing. Combinations of treponemal tests directed at different antigens can be used to diagnose late latent syphilis in some patients with discordant treponemal and nontreponemal serologies.

POC serologic tests that incorporate a nontreponemal component to distinguish current from past infection are being evaluated [20,26-28] and are available in some countries. In a study using 1005 stored serum samples, a dual treponemal/nontreponemal POC test was compared with standard tests [26]; the concordance for samples with high titer nontreponemal antibodies was 94.3 percent, and the concordance for samples with low titers was 90.1 percent. However, the concordance with past/treated infections was 27.5 percent, and the concordance was only 78.1 percent among stored samples from patients without syphilis.

However, further evaluation of the SHC is needed before widespread use of this point-of-care (POC) test can be recommended since the sensitivity of the test has been lower in postmarketing studies compared with the FDA trial studies [23,24]. In a meta-analysis that included data from 10 prospective studies, the pooled sensitivity was 87.7 percent (95% CI 71.8-97.2) [24], which was lower than the >95 percent sensitivity and specificity that were reported by the manufacturer [25]; however, with the use of nontreponemal supplemental testing, the sensitivity improved to a pooled sensitivity of 97 percent (95% CI 94.8-98.6).

Darkfield microscopy and direct fluorescent antibody (DFA) testing can be used to detect the organism (picture 1); however, neither of these tests are routinely available in clinical settings because these methods require special equipment to perform the test as well as considerable experience and expertise to properly interpret the results. Thus, for most clinicians, such tests are now viewed as alternative diagnostic tools [6].

Polymerase chain reaction testing — Some laboratories have developed polymerase chain reaction (PCR) tests to detect T. pallidum DNA from clinical specimens. Assays are based upon detection of various DNA target sequences and use a variety of methods (eg, classical PCR, nested PCR, reverse-transcription PCR, and quantitative PCR) [29-33]. These tests must be validated for use in each laboratory since there are no commercially available test kits.

The sensitivity of PCR using specimens collected from mucosal sites via a swab has been compared with darkfield microscopy and clinical diagnostic criteria (including serology). The sensitivity has ranged from approximately 70 to 95 percent and appears to be greater than that seen with darkfield microscopy. The specificity has ranged from 92 to 98 percent [29-33]. As examples:

● In an observational study of 294 patients with suspected syphilis and 35 healthy volunteers, the results of nested PCR testing for T. pallidum from swab-collected specimens were highly concordant with a clinical diagnosis of syphilis based upon United States Centers for Disease Control and Prevention (CDC) criteria, with a sensitivity of 82 percent and a specificity of 95 percent [31].

Improvements in PCR testing resulting from better antigen specificity and the recognized lack of sensitivity of darkfield microscopy or DFA testing when the number of treponemes is low may explain these results. However, it is important to appreciate that PCR assays amplify both live and dead organisms, a fact that must be accounted for to interpret results accurately.

PCR tests are not suitable for screening asymptomatic individuals, since the sensitivity of PCR testing tends to be much lower in blood and cerebrospinal fluid specimens (approximately 24 to 32 percent) [31].

If a diagnosis of neurosyphilis is being considered, additional testing of the cerebrospinal fluid (CSF) should be performed. (See 'Testing for neurosyphilis' below.)

Serologic testing algorithms — Serologic testing to diagnose syphilis should include the use of both nontreponemal and treponemal tests (algorithm 1 and algorithm 2 and algorithm 3). Either test can be used as the initial screening test. Confirmatory testing is necessary due to the potential for a false-positive screening test result [6]. Screening using an initial treponemal test is favored by many laboratories, especially those that perform relatively high volumes of syphilis testing, since automated treponemal-specific enzyme immunoassay (TP-EIA) testing for syphilis is less expensive than the nontreponemal rapid plasma reagin (RPR) test.

Initial screening with a nontreponemal test – Traditional serologic testing algorithms for syphilis have involved initial screening with a nontreponemal test (eg, RPR). A reactive nontreponemal test is then confirmed with a treponemal test, such as the fluorescent treponemal antibody absorption (FTA-ABS) [6]. In general, for asymptomatic patients, no further testing is needed if the nontreponemal test is negative (algorithm 1).

However, for patients who present early in the course of disease (eg, ulcer, rash), serologic testing may be negative. If there is a high clinical suspicion for syphilis, presumptive treatment should be administered and then repeat serologic testing should be performed in two to four weeks. (See 'Positive nontreponemal/negative treponemal' below and 'Direct methods for diagnosis' above.)

Initial screening with a treponemal test – An increasingly popular algorithm reverses the order and uses a treponemal test (eg, TP-EIA or chemiluminescence immunoassay [CIA]) as the screening test followed by a nontreponemal test for confirmation if the treponemal test is positive (algorithm 2). This approach was first described in 2008 by the United States Centers for Disease Control and Prevention (CDC) [34].

Although observational studies have reported a higher false-positive rate with this reverse screening method compared with the traditional approach described above, it can detect syphilis in some patients with syphilis who would not have been identified if a nontreponemal test was used initially [7]. This includes those with very early syphilis, those with prior treated syphilis, and those with late or late latent syphilis whose nontreponemal test has become nonreactive over time. The approach to such patients with discordant results (ie, the treponemal test is reactive but the reflex nontreponemal test is negative) is discussed elsewhere. (See 'Positive treponemal/negative nontreponemal test' below.)

The positive predictive value and negative predictive value of treponemal EIA tests as a screening approach for syphilis depend upon the prevalence of syphilis in the population. As an example, when the reported seroprevalence of syphilis is 0.71 (the prevalence of syphilis in the United States in 2008), the negative predictive value of the treponemal EIA exceeds 98 percent; however, the positive predictive value is as low as 12 percent [13,35]. When this approach is used to screen higher risk populations (eg, patients seen in HIV or sexually transmitted disease clinics), the positive predictive value can be as high as 90 percent [13].

Testing for neurosyphilis — Examination of cerebrospinal fluid is the only way to definitively diagnose neurosyphilis [36]. A positive cerebrospinal fluid Venereal Disease Research Laboratory (CSF-VDRL) is considered highly specific for neurosyphilis, but sensitivity is poor; this test may be negative in as many as 70 percent of individuals with neurosyphilis [14].

Elevations of white blood cells and protein in CSF are often seen in neurosyphilis but are nonspecific findings. Thus, the laboratory diagnosis of neurosyphilis usually depends on various combinations of reactive serologic test results, CSF cell count and protein, and a reactive CSF-VDRL with or without clinical manifestations [ 6].

If the CSF-VDRL is nonreactive and neurosyphilis is suspected, a CSF FTA-ABS or CSF T. pallidum particle agglutination assay (TP-PA) can be ordered [6]. Although it is less specific than a CSF-VDRL, the CSF FTA-ABS or CSF TP-PA test is quite sensitive, and neurosyphilis is highly unlikely if either of these tests are negative.

The use of nested polymerase chain reaction (nPCR) testing of CSF has been evaluated in persons with syphilis [37]. In a prospective study of 40 patients with presumed neurosyphilis, nPCR had a sensitivity of 42 percent, as compared with 30 percent for CSF-VDRL. The absence of a "gold standard" for diagnosing neurosyphilis complicates interpretation of these findings as some of the tested patients may not have had neurosyphilis. Thus, the true sensitivity and specificity of a positive CSF PCR test is uncertain.

A more detailed discussion of the diagnostic approach to neurosyphilis is found elsewhere. (See "Neurosyphilis".)

Patients with ocular/otic symptoms — In patients with otic or ocular symptoms, CSF evaluation is warranted for persons with clinical signs of neurosyphilis (eg, cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, or loss of vibration sense) [6].

For those without neurologic symptoms, a lumbar puncture (LP) is generally not needed. However, it may be helpful as part of the diagnostic evaluation in patients who present with visual complaints and have serologic testing consistent with syphilis but do not have compatible findings on ophthalmologic exam.

For patients with HIV, the diagnosis of syphilis is generally made the same way as for those without HIV [6,8]. (See "Syphilis in patients with HIV".)

Positive nontreponemal/positive treponemal test — The combination of a positive screening nontreponemal test and a positive treponemal confirmatory test supports a diagnosis of syphilis. For patients without a history of syphilis, these results are consistent with a new infection that must be treated. However, for patients with a history of treated syphilis in the past, the interpretation is sometimes less clear, and the need for treatment depends upon the patient's clinical presentation and the nontreponemal titer. Some patients may not recall their history, and, in such cases, contacting the local health department may prove helpful in providing prior test results and treatment history.

On rare occasion, both nontreponemal and treponemal tests can be falsely positive. This can result from a different infectious etiology (eg, endemic treponematoses such as yaws, bejel, and pinta), or a noninfectious condition affecting immune function [38,39]. (See "Yaws, bejel, and pinta", section on 'Serologic tests'.)

Patients without a history of syphilis — For those without a known history of syphilis, a diagnosis is made when both nontreponemal and treponemal tests are reactive. To determine the appropriate treatment, patients should be assessed for symptoms and stage of disease (table 1):

● Symptomatic persons can be staged as having primary, secondary, or tertiary syphilis. (See "Syphilis: Treatment and monitoring".)

● Asymptomatic persons have either early latent or late latent syphilis. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Latent syphilis (asymptomatic)'.)

Patients with a history of treated syphilis — Although treponemal tests usually remain positive after infection, titers of nontreponemal assays decline following successful therapy and usually revert to nonreactive over time (algorithm 3). Thus, for patients with a history of treated syphilis, the presence of a positive nontreponemal test often indicates a new infection, an evolving response to recent treatment, or treatment failure. In some cases, a patient may have had an adequate decline in titers but the nontreponemal titer does not serorevert (previously referred to as being serofast).

To properly interpret serologic test results, titers should be compared with the patient's prior post-treatment titer. If possible, titers should be compared using the same test methodology since the rapid plasma reagin (RPR) and the Venereal Disease Research Laboratory (VDRL) may differ from one another. If the post-treatment titer is not readily available, the results can sometimes be obtained by calling the local public health department, which maintains a registry of past positive tests.

For patients who were treated and were lost to follow-up, distinguishing new from old infection must be based upon clinical as well as serologic findings. We consider a patient to have a new infection if the patient with reactive serologic tests has any of the following:

● A history of being previously treated with an appropriate regimen and a documented response to that treatment

● Clinical manifestations of either primary or secondary syphilis

● History of new risk factor(s)

● An adequate response following treatment of the possible reinfection (eg, a fourfold decline in RPR titer)

These criteria were used in a study that evaluated 1473 patients with prior syphilis in British Columbia [40]. In this study, reinfection was associated with HIV seropositivity, a history of ever having gonorrhea or chlamydia, being an Indigenous (Aboriginal) person in Canada, or being a man who has sex with men.

Positive nontreponemal/negative treponemal — In laboratories using the nontreponemal test for screening, patients who have a positive nontreponemal test followed by a negative treponemal test are generally considered to have a false-positive syphilis result. It is estimated that 1 to 2 percent of the United States population has false-positive nontreponemal test results [15]. Although false-positive test results tend to be of low titer, the level of the titer alone does not reliably help the clinician differentiate between a true- or false-positive result. Thus, a reactive nontreponemal test must be followed with specific treponemal testing to rule out active syphilis.

False-positive tests are particularly common during pregnancy (see "Syphilis in pregnancy"). In addition, false-positive nontreponemal test results can be related to an acute event, such as an acute febrile illness (eg, endocarditis, rickettsial disease) or recent immunization [41,42]. Test abnormalities attributed to these conditions are usually transitory and typically last for six months or less. Other etiologies include chronic conditions, such as autoimmune disorders (particularly systemic lupus erythematosus); intravenous drug use; chronic liver disease; and underlying HIV disease.

Positive treponemal/negative nontreponemal test — Patients who are tested for syphilis using an initial treponemal-specific screening strategy can have discordant results (ie, a positive treponemal test followed by a negative nontreponemal test). In the New York experience, discordant results were seen in 3 percent of 116,822 specimens [34].

Discordant results often occur in patients with a history of successfully treated syphilis. In these cases, no further evaluation or treatment is needed unless there is concern for re-exposure. When prior syphilis history is unknown, the local health department should be contacted and may be helpful in providing records of prior testing and treatment.

For patients without a history of treated syphilis, a discordant result can occur in very early syphilis or in late syphilis when nontreponemal tests have become nonreactive over time (see 'Negative nontreponemal test in early syphilis' below and 'Negative nontreponemal test in late syphilis' below). For such patients, we first perform a directed history and physical examination to evaluate for risk factors and evidence of syphilis, as this dictates our subsequent approach:

● If a chancre or rash suggesting early syphilis is present, a nontreponemal test should be repeated to assess for seroconversion, and presumptive treatment should be administered at the same patient encounter. The response to treatment should be monitored clinically and serologically.

● For patients with signs and/or symptoms suggestive of neurologic syphilis, a lumbar puncture may be indicated to assess for evidence of central nervous system involvement. (See "Neurosyphilis", section on 'Diagnosis'.)

● If no signs or symptoms of syphilis are present, we counsel patients regarding a possible diagnosis of late latent syphilis. (See 'Negative nontreponemal test in late syphilis' below.)

To further evaluate for latent syphilis, a second treponemal test, preferably one that targets different antigens than the initial screening test (eg, T. pallidum particle agglutination assay [TP-PA]) should be performed. This is often done reflexively by the laboratory when the initial treponemal test is positive and the confirmatory nontreponemal test is negative (algorithm 2).

• If the repeat treponemal test is also positive, we treat for late latent syphilis. (See "Syphilis: Treatment and monitoring".)

• If a repeat treponemal test is negative, we do not do any further evaluation, and we consider the original test a false positive. False-positive treponemal tests can be seen with a variety of other conditions including other spirochetal infections, malaria, and leprosy [3].

This approach is supported by a prospective study of more than 21,000 patients undergoing syphilis screening in a low-prevalence setting where a positive chemiluminescence immunoassay followed by a negative RPR and a negative TP-PA was most likely a false-positive result [43]. However, these recommendations may not be appropriate outside of the United States where the epidemiology of disease may be different.

However, patients with clinical signs and symptoms of early syphilis (eg, ulcer, rash) may have a false-negative test result [39]. For such patients, a false-negative test is typically the result of testing prior to antibody formation or secondary to a prozone effect. A false-negative test can also be seen in those who received early empiric therapy (eg, sexual contacts of patients with confirmed syphilis).

Testing prior to antibody formation — Most false-negative nontreponemal results occur when the test is performed prior to the development of humoral antibodies (figure 1). Approximately 20 to 30 percent of patients presenting with a chancre have been reported to have a nonreactive nontreponemal test for syphilis [13,14]. Although treponemal tests may or may not show a positive result in this setting, they are generally considered more sensitive than nontreponemal tests. The fluorescent treponemal antibody absorption (FTA-ABS) is thought to be most sensitive in primary syphilis (sensitivity of 98.2 versus 92.7 percent for rapid plasma reagin and 72.5 percent for VDRL test) [44]. The sensitivity of the enzyme immunoassay is comparable to the FTA-ABS [45,46].

If there is a high clinical suspicion for early syphilis, repeat serologic testing at a later time point (eg, two to four weeks later) may be diagnostic. Direct methods for visualizing the organism are not generally available. Presumptive therapy, rather than waiting for the results of additional testing, is appropriate in patients at high risk for syphilis.

Prozone reaction — A second major cause of a false-negative nontreponemal test is the "prozone reaction." When antibody titers are high (as often seen in secondary syphilis), an overabundance of antibodies interferes with clumping of antigen-antibody complexes. Thus, a prozone reaction refers to the inability to visualize agglutination, which normally occurs when antigen and antibody bind together to form a complex. This phenomenon occurs in less than 2 percent of samples from patients with syphilis and is usually associated with pregnancy, HIV coinfection, and neurosyphilis [47].

Experienced laboratory technologists may suspect the prozone phenomenon when an apparent nonreactive test exhibits a rough or granular appearance. They can then dilute the specimen so that sufficient agglutination can be seen and the true sample reactivity becomes apparent. Providers can also request that a specimen be evaluated for a prozone reaction.

Early treatment — Some patients will be treated for syphilis prior to testing. Such patients with a history of very early treatment may have no laboratory evidence of prior syphilis because of full seroreversion of the nontreponemal test. Although seroreversion of the treponemal serology can also occur, complete seroreversion of both the treponemal and the nontreponemal tests is uncommon.

Negative nontreponemal test in late syphilis — On rare occasion, patients may have a negative nontreponemal test in the presence of active syphilis. This is typically seen in patients with advanced immunosuppression (eg, patients with AIDS) and is thought to reflect B-cell failure during late-stage HIV infection [48,49].

In addition, during the natural history of syphilis, a positive nontreponemal test can become nonreactive over time, even in the absence of treatment; however, this generally evolves over many years. If such a situation is suspected, screening with the treponemal test may be helpful since these tests are more likely to remain positive for life.

Early latent — Early latent syphilis is diagnosed if an asymptomatic patient has serologic evidence of T. pallidum infection that was acquired within the last 12 months. Serologic evidence of infection includes the following:

● Patients without a past diagnosis of syphilis who have both a reactive nontreponemal test (eg, rapid plasma reagin) and a reactive treponemal test (eg, fluorescent treponemal antibody absorption). (See 'Serologic tests' above.)

● Patients with a prior history of syphilis who have a current nontreponemal test titer that demonstrates a fourfold or greater increase from the last nontreponemal test titer.

A person is considered to be infected within the preceding 12 months if their only sexual contact was within the last 12 months (ie, sexual debut) or they can demonstrate a:

● Documented seroconversion or fourfold or greater increase in titer of a nontreponemal test during the previous 12 months

● History of symptoms consistent with primary or secondary syphilis during the previous 12 months

● History of sexual exposure to a partner within the previous 12 months who had primary, secondary, or early latent syphilis

Late latent — A person with late latent syphilis must also be asymptomatic and have serologic evidence of disease as described above. However, for such individuals, there is no evidence that the disease was acquired within the last 12 months (ie, absence of above criteria for infection within the preceding 12 months).

The term "neurosyphilis" refers to infection of the central nervous system (CNS) by Treponema pallidum, subspecies pallidum (hereafter termed T. 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, 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.

Neurosyphilis begins with invasion of the cerebrospinal fluid (CSF), a process that probably occurs shortly after acquisition of T. pallidum infection. The organism can be identified in the CSF from approximately one-quarter of untreated patients with early syphilis [1,2]. Specific strains of T. pallidum may be more likely to cause neurosyphilis [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 (figure 1).

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 would develop [5]. In the antibiotic era, the risk of developing symptomatic neurosyphilis in individuals with asymptomatic neurosyphilis, particularly after antibiotic treatment of uncomplicated syphilis, is unknown. (See 'Spinal fluid examination' below.)

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, neurosyphilis, particularly the early forms, is most frequently seen in persons with HIV. This association may simply reflect the fact that syphilis is most common in men who have sex with men, many of whom have HIV, or it may reflect a true difference in susceptibility [8].

For persons with HIV, the risk of asymptomatic and symptomatic neurosyphilis is increased in those with lower peripheral CD4+ T cell counts, detectable plasma HIV RNA, and/or no antiretroviral therapy [9-14].

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 [15,16]. Many experts believe that this decline is due, at least in part, to the widespread use of antibiotics for unrelated illnesses.

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].

Asymptomatic neurosyphilis — By definition, patients with asymptomatic neurosyphilis have no symptoms or signs of central nervous system 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 test (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.

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, vitreitis, retinitis, or optic neuropathy. 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) [17]. 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 and panuveitis are the most common and present with diminished visual acuity [18]. Additional manifestations may include optic neuropathy, interstitial keratitis, anterior uveitis, and retinal vasculitis. Ocular syphilis is often, but not always, accompanied by syphilitic meningitis. Ocular syphilis may worsen when the diagnosis is not considered and patients are treated with systemic or topical corticosteroids [19].

A preliminary study found no single or predominant strain of T. pallidum was causing ocular syphilis [22].

Otosyphilis — Hearing loss, with or without tinnitus, should be considered as part of the neurologic symptoms or signs of neurosyphilis [23,24]. 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 neurological deficits 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 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. In a study of 116 patients with general paresis in China, dementia, personality change, abnormal behavior, and emotional problems were the most common findings. On initial evaluation, neurosyphilis was not suspected in 36 percent of patients, which delayed the diagnosis for 1 to 24 months [25].

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-VDRL have been reported [26]. 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 paresthesia and gastric crises, characterized by recurrent attacks of severe epigastric pain, nausea, and vomiting. Bladder dysfunction with urinary retention and overflow incontinence may occur early in the course of disease.

Pupillary irregularities are among the most common signs in patients 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 'Etiologic evaluation'.)

Other findings seen with tabes dorsalis include absent lower extremity reflexes, impaired vibratory and position sensation, and, less commonly, impaired touch, pain, 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 fluorescent treponemal antibody absorption (FTA-ABS) tests reported that neurosyphilis was diagnosed in 241 (84 percent) based on the identification of reflex, sensory, or pupillary changes, or seizures [27]. 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 or autoimmune encephalitis [28,29]. These patients generally had acute onset of cognitive changes, although some patients had more slowly progressive presentations. Many had seizures. Brain MRI showed unilateral or bilateral medial temporal lobe lesions (image 2) characterized by high signal on T2 and fluid-attenuated inversion recovery (FLAIR) sequences, which resolved after treatment for neurosyphilis [28]. In addition to mesiotemporal lobe lesions, other reports have observed MRI signal abnormalities in parietal, temporo-occipital, and thalamic regions [29,30].

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 [31].

This axiom remains true today. As an example, in a study from Seattle, WA, that systematically queried 68 patients with syphilis for symptoms of neurosyphilis, 8 percent had vision or hearing symptoms and approximately 4 percent had symptoms and objective confirmation of neurosyphilis [32]. The proportion with symptoms or neurosyphilis did not differ by HIV status.

In another study of cerebrospinal fluid (CSF) abnormalities in individuals with syphilis, reactive CSF-Venereal Disease Research Laboratory (VDRL), diagnostic of neurosyphilis, was significantly more common in persons with HIV who had photophobia, vision loss, gait incoordination, or moderate or greater hearing loss [ 33]. No relationships between reactive CSF-VDRL and symptoms were identified in HIV-uninfected individuals.

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, otologic or ocular symptoms 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 or current syphilis who presents with neurologic, otologic or ocular symptoms that could be caused by syphilis.

Current guidelines from the Centers for Disease Control and Prevention (CDC) do not recommend lumbar puncture in patients with syphilis who do not have neurologic, otologic, or ocular symptoms, stating "CSF examination has not been associated with improved clinical outcomes in the absence of neurologic signs and symptoms" [34]. This statement is true only because no outcomes research has been published. The issue of lumbar puncture in asymptomatic persons with HIV who have syphilis is addressed below.

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 T. pallidum, as a patient cannot have neurosyphilis without first having syphilis.

Confirmation is straightforward when serum nontreponemal tests and treponemal tests are reactive, as they virtually always are in early neurosyphilis. (See "Syphilis: Screening and diagnostic testing".)

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 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.

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 CDC recommendations are that CSF examination should be performed in any of the following situations [34]:

● Neurologic or ophthalmic signs or symptoms in any stage of syphilis.

● Evidence of active tertiary syphilis affecting other parts of the body.

● Treatment failure (including failure of serum nontreponemal tests to fall appropriately) in any stage of syphilis.

A few caveats should be noted:

● Patients who have ocular syphilis or otosyphilis, with or without CSF abnormalities, should receive standard neurosyphilis treatment. Ocular and otologic syphilis may not be accompanied by CSF abnormalities. 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 lumbar puncture for all patients with concomitant HIV infection and syphilis, regardless of stage, particularly those with serum RPR ≥1:32, peripheral blood CD4+ T cell count ≤350/microL, detectable plasma HIV RNA, or those not on antiretroviral therapy. These factors increase the odds of asymptomatic neurosyphilis three- to sixfold.

Controversy exists regarding whether identification and treatment of asymptomatic neurosyphilis results in better patient outcomes. While data in the pre-antibiotic era suggested a benefit, no study has been performed in the modern era to address this question. We suggest lumbar puncture for persons with HIV and syphilis who have increased risk of asymptomatic neurosyphilis listed above, in agreement with European guidelines [35].

Spinal fluid examination — While a reactive CSF-VDRL establishes the diagnosis of neurosyphilis, a nonreactive test does not exclude the diagnosis [36]. Furthermore, the CSF-VDRL test may be falsely positive when the CSF is visibly blood-tinged and the serum nontreponemal test titer is high [37]. Reports of CSF-VDRL sensitivity and specificity vary depending on how neurosyphilis is defined, but the preponderance of data suggest that the test lacks sensitivity. In a monograph on neurosyphilis published during the 1940s when the disease was common, a nonreactive CSF Wassermann test, the predecessor of the CSF-VDRL, was documented in 8 to 19 percent of patients with early neurosyphilis, including meningitis and meningovasculitis, the forms that are most common today [4]. In a modern-era study of 149 patients with laboratory and clinically defined neurosyphilis, the diagnostic sensitivity of the CSF-VDRL ranged from 67 to 72 percent [38].

Because the CSF-VDRL is not available in some areas of the world, the CSF-RPR is sometimes used in its place. The CSF-RPR may be nonreactive in instances where the CSF-VDRL is reactive, making it a less useful test. The CDC syphilis guidelines do not address use of the CSF-RPR for neurosyphilis diagnosis [34]. The European guidelines state that the CSF-VDRL is preferred over the CSF-RPR [35].

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 asymptomatic neurosyphilis in most instances [39].

Elevation of the CSF protein concentration is consistent with neurosyphilis. However, it may be less specific than CSF pleocytosis [40,41].

● In patients with suspected neurosyphilis who do not have HIV infection and who have a 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).

● 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.

One study found that HIV-induced CSF pleocytosis was independently and significantly associated with three factors [42]:

● 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 persons with HIV who are taking antiretroviral agents, have CD4 counts ≤200 cells/microL, or have an undetectable plasma HIV RNA viral load, the likelihood of HIV-induced CSF pleocytosis is reduced by 70 to 96 percent [42]. Thus, CSF pleocytosis in such patients who have syphilis is more likely to be due to neurosyphilis than to HIV.

CSF concentration of the B cell chemokine CXCL13 may be useful in distinguishing between CSF pleocytosis due to syphilis and CSF pleocytosis due to HIV, but this test is not widely available [43,44].

Neurosyphillis - The standard regimens recommended by Centers for Disease Control and Prevention (CDC) guidelines for the treatment of neurosyphilis, including ocular and otosyphilis, are as follows (table 1) [34]:

• Aqueous crystalline penicillin G (18 to 24 million units per day, administered as 3 to 4 million units intravenous [IV] every four hours, or 18 to 24 million units daily as a continuous infusion) for 10 to 14 days, or

• Procaine penicillin G (2.4 million units intramuscular [IM] once daily) plus probenecid (500 mg orally four times a day), both for 10 to 14 days

These regimens can also be used following penicillin desensitization for patients who have a serious penicillin allergy [34]. Desensitization should be managed in consultation with a specialist (see "Penicillin allergy: Immediate reactions", section on 'Desensitization').

An alternative treatment for patients who have a mild penicillin allergy is ceftriaxone (2 g IV or IM daily) for 10 to 14 days, with careful observation for cross-reactivity [34,35,45]. High dose doxycycline (200 mg orally twice a day for 21 to 28 days) also may be an effective alternative treatment [46], but is not recommended by the CDC or European guidelines [34,35].

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.

Neurological worsening after beginning treatment for neurosyphilis has been attributed to a Jarisch-Herxheimer reaction, and may be most common in patients treated for syphilitic dementia [47,48].

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 oral or topical glucocorticoids for ocular syphilis and oral glucocorticoids for otosyphilis is often used in conjunction with antibiotics.

Monitoring — Because T. pallidum cannot be routinely 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. We suggest that failure of the CSF white blood cell count to decrease six months after therapy or failure of CSF-VDRL to decline fourfold (or to nonreactive if the initial titer is <1:2) one year after therapy are indications for re-treatment.

The CSF white blood cell count should decline by 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 HIV infection compared with those who are not infected with HIV [ 40].

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 [41]. At 4, 7, 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. However, the predictive value of serum RPR normalization was lower for persons with HIV who were not taking antiretroviral agents