OVERVIEW: What every clinician needs to know
- Are you sure your patient has syphilis? What should you expect to find?
How did the patient develop syphilis? What was the primary source from which the infection spread?
- Which individuals are of greater risk of developing syphilis?
What laboratory tests should you order and what should expect to find?
- What consult service or services would be helpful for making the diagnosis and assisting with treatment?
OVERVIEW: What every clinician needs to know
Are you sure your patient has syphilis? What should you expect to find?
The clinical presentation of syphilis can be divided into early syphilis and late syphilis.
Primary syphilis: The primary ulcer or chancre, as it is formally known, may be located on the genitals, perianal skin, within the rectum, oral cavity, and any other skin or mucous membrane surface exposed to an infectious lesion that was present on the source sexual partner.
The average incubation period is 3 weeks but can vary from 10 to 90 days.
Classically these lesions are few in number (often only one) clean based, indurated, and painless to palpation.
However, this description only fits about one third of lesions: so any genital ulcer should be considered to be syphilis until proven otherwise.
The lesions of primary syphilis will resolve within 3 to 6 weeks without treatment. Of course, the individual remains infected and will become infectious again with the advent of secondary syphilis.
Secondary syphilis: Left untreated the organism disseminates hematogenously from the site of the primary infection to all parts of the body. This occurs within a few weeks or months of the onset of the primary lesions.
Cutaneous and/or mucous membrane lesions are the most common clinical manifestations of the phenomenon and occasionally the primary lesion persists.
Initially erythematous macules which evolve into hyperpigmented papules often with a thin rim of scaly hyperkeratosis.
Rarely the lesions may be pustulo-squamous or nodular.
Skin lesions are usually present on both the palms and soles and any rash with this distribution should immediately bring secondary syphilis to mind.
However sometimes the palms and soles are spared so their absence cannot be used to rule out the diagnosis.
Mucosal lesions are generally superficial, ulcerated, and painless with gray borders. Similar lesions may be found on the foreskin, penile head, and intravaginally. These are sometimes confused with multiple primary lesions. This is of little clinical consequence as long as the diagnosis is established.
Condyloma lata consist of multiple raised whitish or grey lesions in warm moist areas.
Patchy alopecia can be a manifestation of scalp involvement in secondary syphilis. When multiple lesions are present the appearance is described as "moth-eaten."
Low grade fever, malaise, headache, and generalized lymphadenopathy (75% of patients) often accompany dissemination.
Uncommon systemic manifestations of secondary syphilis include gastritis, mild hepatitis, and aseptic meningitis.
As with the primary chancre, the manifestations of secondary syphilis also will resolve spontaneously over time but over a period of a few years there may be relapses of secondary disease. This occurs in about 20% to 25% of patients based on studies done in the pre-antibiotic era.
Early latent syphilis: This refers to an asymptomatic person with a normal physical examination who is diagnosed serologically and has a history of syphilis exposure within the preceding 1 year or had a documented negative syphilis serologic test within the past 12 months.
Patients seldom provide this information, so the majority of such patients are diagnosed as "latent syphilis—duration unknown."
The significance is that the latter group of patients should be treated as if they have uncomplicated late latent syphilis rather than for early syphilis. (See the treatment recommendations section.)
Persons who have syphilis and symptoms or signs suggesting neurologic disease (e.g., cranial nerve dysfunction, meningitis, stroke, and hearing loss) or ophthalmic disease (e.g., uveitis, iritis, neuroretinitis, and optic neuritis) should have an evaluation that includes CSF analysis, ocular slit-lamp ophthalmologic examination, and otologic examination. Treatment should be guided by the results of this evaluation.
Acute syphilitic meningitis: The incubation period for this relatively rare syndrome is usually less than 1 year based on studies done in the pre-antibiotic era though manifestations may take up to 5 years to appear. The condition is discussed here, as in the modern era it is usually not possible to know when the primary infection occurred so treatment is the same as for late disease.
Symptoms and signs of meningitis are the first clinical manifestations in only a quarter of patients.
Cranial nerve palsies, especially of nerves 3, 6, 7, and 8 occur in approximately 40% of cases along with symptoms of increased intracranial pressure.
Deafness is present in 20% of patients and may be the single presenting complaint. Thus syphilis must be considered in every case of new-onset hearing loss in relatively young persons.
In some of these patients the cerebrospinal fluid (CSF) examination is normal, particularly those with isolated 8th nerve disease, though the majority have modestly elevated cell counts, increased protein, and positive CSF serologic tests or a combination of these results.
Hydrocephalus is a rare complication and confusion, delirium, and papilledema also may be seen in combination with the other symptoms and signs listed above.
Cerebrovascular syphilis: This disease is caused by a combination of endarteritis and chronic meningitis.
The incubation period is 5 to 12 years after the initial infection.
The most common manifestations are hemiparesis or hemiplegia. It affects the middle and anterior cerebral arteries most frequently.
Other presenting problems include aphasia and seizures.
Onset may be sudden but many patients initially experience gradual worsening of headache, dizziness, insomnia, memory loss, and/or mood disturbances over a period of weeks to months prior to onset of localizing symptoms of cerebral ischemia.
CSF findings are those described above for syphilitic meningitis.
Serum syphilis serology is nearly always positive and is also usually positive in the CSF.
Computed tomography (CT) scan results are consistent with multifocal infarctions characterized by low density areas with variable degrees of contrast enhancement.
Magnetic resonance imaging (MRI) scans show multiple T2-weighted high signal intensity areas within the distribution of involved arteries.
This disease should be strongly suspected in all younger patients presenting with cerebrovascular accidents.
General paresis: Also known as "general paralysis of the insane," this disease, a form of meningoencephalitis, is now very uncommon.
It develops 15 to 25 years after initial infection.
It presents with psychiatric and neurologic findings that mimic many other diseases.
Onset is generally gradual but in some cases it may be acute.
The usual presentation is that of a dementia and thus should always be considered when the following symptoms appear in a relatively young person:
significant personality change
decreased attention to personal hygiene
insomnia (in conjunction with other symptoms)
decreased ability to concentrate
If substance abuse and human immunodeficiency virus (HIV) infection can be ruled out in such patients, syphilis rises to the top of the differential diagnosis list.
As the disease progresses emotional lability, delusions of grandeur, and lapses in moral and social behavior become more common. Seizures or a stroke-like event may be the initial presenting complaint.
Common findings on examination include:
Argyll Robertson pupils (pupils accommodate but do not react to light), slurred speech
expressionless faces, tremors, and abnormal reflexes
The key to the diagnosis is syphilis serology which is almost always positive, both in the serum and CSF. Other CSF findings are as described above for syphilitic meningitis.
CT scans show decreased attenuation of white matter, particularly in the frontal lobes and paraventricular areas. Cerebral atrophy in general is often present along with increased ventricular size. Nodular enhancing lesions as is seen in cerebrovascular syphilis (see above) also may be present.
Generally, treatment does not reverse the damage done but often will arrest further progression.
Tabes dorsalis: Perhaps even more uncommon than general paresis.
Disease begins 20 to 25 years after the primary infection.
Primarily involves the spinal posterior column and posterior nerve root. Hence the symptoms and signs include:
neuropathic lower extremity "lightning pains"
absent ankle and knee jerks
decreased sensation (most commonly vibratory and position sense)
Loss of position sense and decreased pain sensation are the proximate causes of the degenerative joint disease known as "Charcot joints."
Cranial nerves are sometimes involved and pupillary abnormalities are quite common.
It may burn itself out leaving the patient with significant symptoms and morbidity even in the absence of further progression.
Nontreponeme specific serologic tests may be negative.
Treponeme specific tests are almost always positive.
Similarly CSF abnormalities may or may not be present.
Ocular syphilis: Case series of ocular syphilis (uveitis, retinitis, and optic neuritis) have been reported increasingly, beginning in 2014. Most suspected cases were in males, and half were in HIV-positive persons. A significant proportion of cases have been reported in patients with early syphilis. It is not clear that these cases represent a true increase in the incidence of ocular syphilis or just ascertainment bias. Regardless, severe outcomes, including blindness, have been reported in both HIV-positive and HIV-negative patients. All patients diagnosed with syphilis that exhibit ocular manifestations should immediately be treated for neurosyphilis and be referred for formal ophthalmologic examination. Optic atrophy in the absence of signs of inflammation may be found in association with other manifestations of neurosyphilis or may be an isolated finding of late syphilis.
Nonneurologic manifestations of late syphilis (tertiary syphilis):
New cases of cardiovascular disease (aortitis, coronary arteritis, and aortic valvulitis) have not been reported in the western world for decades.
Residual aortic aneurysms and aortic insufficiency are still occasionally encountered in elderly individuals.
Late benign syphilis lesions or gummas (low grade, slowly progressive inflammatory masses primarlily involving bone and skin) also are rarely seen today.
How did the patient develop syphilis? What was the primary source from which the infection spread?
Treponema pallidum is a sexually transmitted pathogen passing from an index case with an active skin or mucous membrane lesion to a susceptible partner. However, any contact with an infected lesion, sexual or not, can result in transmission. Following the local primary infection the organism disseminates hematogenously and therefore transmission can occur following blood transfusions or organ donation, though these are rare events as both blood and organ donors are screened serologically for syphilis prior to donation. The organism is passed transplacentally to the fetuses resulting in congenital syphilis. This chapter does not address the subject of congenital syphilis. The manifestations of clinical infections are often missed by patients, particularly women, due to the anatomy of the genital tract, following which the infection becomes latent. Re-activation many years later accompanied by a vigorous host immune response results in neurologic, cardiovascular, and soft tissue disease in some individuals.
Which individuals are of greater risk of developing syphilis?
Syphilis in adults is a sexually transmitted disease (STD).
Approximately 15 years ago rates of early syphilis reached the lowest levels since data collection began.
However, rates have been slowly rising in men-who-have-sex-with-men (MSM) since that time. In 2015, 81.7% of the reported male P&S syphilis cases were among gay, bisexual, and other men who have sex with men.
In the heterosexual population rates over the last few years have been increasing with the consequential increase of cases of congenital syphilis. In 2015, the number of congenital syphilis cases was the highest it’s been since 2001. In caring for patients at high risk for STDs it is important to remember the importance of a careful sexual history including specifics of sexual practices.
For example, MSM often practice rectal intercourse and therefore the perirectal area in these men always should be examined for the presence of asymptomatic primary chancres.
In the United States, many MSM who acquire syphilis often also have HIV, or are more likely to get HIV in the future. All patients with a syphilis diagnosis should also be tested for HIV. HIV negative MSM should be counseled about their increased HIV risk and be educated and offered Pre-exposure prophylaxis for HIV.
It is useful to remember that transmission is most likely to occur within the first few months of infection when apparent or unapparent infectious lesions are present. Recurrences of secondary syphilis lesions in untreated persons are well known so the period of infectiousness may be as long as 1 or 2 years in some individuals.
In the pregnant female as syphilis disseminates hematogenously it is likely to be transmitted to the fetus.
After decreasing from 10.5 to 8.4 reported congenital syphilis cases per 100,000 live births during 2008–2012, the rate of reported congenital syphilis has subsequently increased each year during 2012–2015. In 2015, there were a total of 487 reported cases of congenital syphilis, for a national rate of 12.4 cases per 100,000 live births. (Centers for Disease Control and Prevention. Trends in sexually transmitted diseases in the United States: 2015 national data for gonorrhea, chlamydia and syphilis. Available at:
http://www.cdc.gov/std/stats15/syphilis.htm. Accessed 29 November 2016.)
Association with other sexually transmitted diseases: Any patient with one STD should be considered to be at high risk for others. Therefore, patients with early syphilis should be tested for gonococcal and chlamydial infections. All patients newly diagnosed with syphilis regardless of stage should be tested for HIV infection.
What laboratory tests should you order and what should expect to find?
A darkfield examination of fluid expressed directly from a lesion is the time-honored diagnostic test for patients with the skin lesions of primary and secondary syphilis.
Unfortunately there are few laboratories in the United States which perform this test.
Logistically it is difficult as the specimen is usually obtained by pressing a glass slide directly onto a lesion (a procedure that requires practice for consistent performance) and then placing it immediately under a darkfield microscope for reading by someone trained in its use.
Some public health and private STD clinics still perform the test and so referral of a patient suspected of having early symptomatic syphilis is possible in a few locations around the United States.
Serologic tests are the cornerstone of syphilis diagnosis.There are two general types of tests:
The reagin or nontreponemal assays (NTAs) is based on the fact that human antibodies induced by T. pallidum infection cross react with mammalian cardiolipin. In essence this is an "autoantibody" and therefore it is not too surprising that it lacks specificity.
Conditions associated with false positive NTAs include old age, pregnancy, malignancy, and collagen vascular disease among others.
The advantage of NTAs is the rise and fall of antibody titers reflect the course of disease including decreasing titers in patients who have been successfully treated.
A four-fold reduction in titer over a period of 3 to 12 months is accepted as evidence of treatment success.
An additional advantage is that one of the NTAs, the rapid plasma reagin (RPR) card agglutination test, is relatively quick and simple to perform and can be done in a clinic setting thus providing real time support for the clinical decision making process.
The treponeme specific assays (TSAs) are listed in
The TSAs traditionally have been used to confirm that a positive NTA is a true positive test. Following this algorithm when a syphilis serology is ordered on a patient the laboratory first performs a NTA and if positive then automatically performs a TSA test to differentiate between a true and false positive NTA result.
The TSAs generally are more complex tests and take more time so in the case of a negative NTA they are not performed.
Interpretation of syphilis serologic assays following the traditional testing algorithm:
The expected results of serologic testing in patients with untreated syphilis are summarized in are listed in
It follows from the data presented in this figure that neither a negative NTA nor negative TSA rules out primary syphilis.
It follows then that in a patient suspected of having a primary chancre, if the RPR is negative the patient should be treated for primary syphilis empirically. Such patients can be invited to return to the clinic in several weeks to determine if seroconversion has occurred. Confirmation that a patient’s genital ulcer was caused by T. pallidumcan may be very useful in convincing partners that they need treatment.
In contrast to primary syphilis, a negative NTA almost always
doesrule out secondary syphilis.
A caveat here is that a few HIV-infected patients have had biopsy proven secondary syphilis in the absence of a positive serology.
Over a period of years following an untreated primary infection, the NTA test will be become negative in a proportion of patients with late syphilis while the TSA remains positive in almost all cases.
Therefore, if an NTA is negative in a patient suspected clinically of having late syphilis the care provider should order a TSA. Remember that the laboratory only performs this test automatically if the NTA is positive.
A new serologic testing algorithm: Over the last 10 years treponeme specific automated enzyme immunoassays (TSA EIA) have been developed which are much more cost effective to perform than the older TSAs.
Therefore many high volume public health and reference laboratories have reversed the traditional approach of first performing a NTA and then confirming all positives with a TSA.
Figure 3shows the expected results of following this new algorithm. The percentages provided in the diagram are based on the experience of the New York State laboratory with the new testing algorithm in 116,822 patients. (Centers for Disease Control and Prevention. Syphilis testing algorithms using treponemal tests for initial screening—four laboratories, New York City, 2005–2006. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5732a2.htm. Accessed 31 May 2012.)
The data show that the automated test is not perfect as 17% of specimens positive by the TSA EIA were negative by one of the older TSAs and these were considered false positive EIA tests.
Therefore the inclusion of a second TSA in this algorithm is essential. Nonetheless, the majority of the TSA EIA positive cases were confirmed by either the NTA or a second TSA.
Thus this approach has considerably increased the detection of possible late latent syphilis cases. The public health significance of this is unknown. Many of those with positive TSA EIA test results and negative NTA results turn out to be previously treated cases based on the patients’ histories.
A new generation of rapid point-of-care (POC) syphilis diagnostic tests has shown good reliability and can be performed in any clinical setting. These tests can provide fast results during a patient’s initial visit. The first of these to obtain FDA approval for use outside traditional laboratory settings is the Syphilis Health Check™ assay. However, in our clinics we have noticed a relatively high false positive rate for this test, so confirmation testing with traditional laboratory based tests should be performed for all positive results. (Available at:
http://www.ncsddc.org/who-we-are/press-releases/rapid-syphilis-test-approved-use-outside-traditional-laboratory-settings-%E2%80%9C. Accessed 29 November 2016)
List of available serologic tests for syphilis.
Expected results of serologic testing in patients with untreated syphilis.
New algorithm for syphilis serology testing
Indications for lumbar puncture:
Any patient with symptoms and/or signs of neurologic or ophthalmic disease should have an evaluation that includes CSF analysis, ophthalmologic examination, and otologic evaluation.
Patients whose symptoms and/or signs persist posttreatment for early syphilis or recur or who have four-fold increases in their NTA titers should be considered to be treatment failures or re-infected and all should have a lumbar puncture. Patients with latent syphilis who meet any of the following three criteria also should have lumbar punctures:
four-fold increases in titers at follow up
development of signs or symptoms attributable to syphilis
failure of the NTA titer to decline at least four-fold when the initial titer was greater than or equal to 1:16 at 12 to 24 months following treatment
Changes consistent with syphilis in the CSF include the following:
an elevated cell count usually of less than 200 cells predominantly lymphocytes
elevated protein up to 200mg/dL
normal glucose in the majority of patients though it may be modestly decreased in about a third
positive NTA test (TSAs are not used for the diagnosis of central nervous system syphilis)
Patients with abnormal spinal fluid results should have repeat studies performed at 6 month intervals until the cell count is normal. Elevated protein levels and the CSF NTA antibody titer may take longer to resolve and are not important so long as the CSF cell count returns to normal.
If cell counts have not returned to normal by 2 years the patient should be re-treated.
Keep in mind that HIV infection causes CSF pleocytosis and elevated protein levels independent of syphilis and this may be an explanation for nonresolution of CSF abnormalities in such persons.
What consult service or services would be helpful for making the diagnosis and assisting with treatment?
If you decide the patient has syphilis, what therapies should you initiate immediately?
Key principles of therapy
Primary, secondary and early latent syphilis
Benzathine penicillin G 2.4 million units intramuscularly as a single dose (the drug should be divided into two doses of 1.2 million units, one administered into each buttock). Occasionally, particularly in patients with secondary syphilis, a Jarisch–Herxsheimer reaction may be induced (fever, chills, and myalgias). Patients should be warned of this possibility and informed that over-the-counter antipyretics can be used to reduce the fever.
Penicillin allergy: Doxycycline 100mg orally twice a day for 14 days. Compliance must be emphasized and follow-up serology is even more important. Pregnant women should be desensitized to penicillin in consultation with an allergist and treated with benzathine penicillin.
A single 2g dose of azithromycin is effective for treating early syphilis. However, in certain localities around the world including the United States, T. pallidum strains have genomic mutations that code for azithromycin resistance. Therefore, this drug should be used only in patients who are intolerant to penicillin and doxycycline.
Late latent syphilis or latent syphilis of unknown duration
Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units intramuscularly at 1-week intervals.
Penicillin allergy: Doxycycline 100mg orally twice a day for 28 days. Compliance must be emphasized and follow-up serology is even more important. Pregnant women should be desensitized to penicillin in consultation with an allergist and treated with benzathine penicillin as for nonpregnant women.
Neurosyphilis (based on clinical assessment and/or CSF examination)
Aqueous crystalline penicillin G 18 to 24 million units per day administered as 3 to 4 million units intravenously every 4 hours or continuous infusion, for 10 to 14 days.
Alternative to above: Procaine penicillin 2.4 million units intramuscularly once daily PLUS probenecid 500mg four times a day both for 10 to 14 days. As this regimen requires two intramuscular injections daily it is poorly tolerated and compliance can be a problem. The availability of home infusion services makes the high-dose intravenous approach more feasible than it was in the past.
Penicillin allergy: Limited data show that ceftriaxone 2g daily either intramuscularly or intravenously for 10 to 14 days can be used as an alternative regimen. However there may be cross allergenicity between this drug and penicillin. Skin testing to rule out penicillin allergy provides confidence in the safety of using ceftriaxone. Patients with a clear history of an immediate type allergic reaction to penicillin (i.e. hives and/or respiratory distress) should be desensitized to penicillin and treated as above. Expert consultation should be sought for the management of patients with penicillin allergy and neurosyphilis. Pregnant women should be desensitized to penicillin in consultation with an allergist and treated with benzathine penicillin as for nonpregnant women.
Treatment of HIV-infected patients with syphilis
Though there is some evidence the HIV-infected patients may be more likely to have higher risk for neurologic complications and may have higher rates of serologic treatment failure the data are not consistent. Enhanced treatment regimens have not been shown to be more effective than those recommended above for HIV noninfected individuals and so the recommendations as provided above should be followed except as noted below. It is important to emphasize follow-up in these patients. See the diagnosis section of this chapter for a discussion of the CSF findings in HIV-infected persons with syphilis. HIV-positive persons with early syphilis do not need lumbar punctures.
Those whose NTA titers do not decrease four-fold 6 to 12 months following treatment for early syphilis regardless of the initial titer should have lumbar punctures and should be treated for neurosyphilis if the CSF is abnormal. In those whose CSF is normal they should be treated with weekly benzathine penicillin as detailed above for late latent syphilis. If the titers do not decrease further following this algorithm additional treatment is not needed unless new symptoms or signs have appeared.
Single dose azithromycin should not be used in HIV-infected persons.
Treatment of syphilis in pregnant women
Pregnant women should be treated as appropriate for their stage of infection with penicillin. However there is some evidence that for pregnant women with early syphilis, an additional dose of 2.4 million units of benzathine penicillin 1 week after the first may be of some benefit. When syphilis is diagnosed in the second half of pregnancy ultrasound of the fetus should be performed to evaluate the fetus for signs of congenital syphilis. If detected there is a greater risk of fetal treatment failure. These cases should be managed in conjunction with a perinatologist. Syphilis treatment during the second half of pregnancy may result in premature labor and/or fetal distress if a Jarisch–Herxsheimer reaction is induced. Pre-medication with antipyretics is advised.
Follow-up: Following treatment in early pregnancy, titers should be repeated in the third trimester to be sure they are not rising. If this should occur, the 3-week penicillin regimen should be given. A neonatologist should evaluate the infants of all women delivering within 30 days of initial treatment or re-treatment and those with clinical signs of infection at delivery.
Congenital syphilis: Details of the management of this pediatric disease are beyond the scope of this article. Details can be found in the US Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines, beginning on page 36. (Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. Available at:
https://www.cdc.gov/std/tg2015/tg-2015-print.pdf. Accessed 29 November 2016.)
WHAT’S THE EVIDENCE for specific management and treatment recommendations?
"Sexually transmitted diseases treatment guidelines". 2015. https://www.cdc.gov/std/tg2015/tg-2015-print.pdf.(The STD treatment guidelines for the United States are updated every 4 years. This is the latest of these updates.)
Hook EW 3rd, Martin, DH, Stephens, J, Smith, BS, Smith, K. "A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis". Sex Transm Dis. vol. 29. 2002. pp. 486-90.(Reports the results of an early small trial assessing the efficacy of azithromycin for treatment of early syphilis.)
Hook, EW, Behets, F, Van Damme, K. "A phase III equivalence trial of azithromycin versus benzathine penicillin for treatment of early syphilis". J Infect Dis. vol. 201. 2010. pp. 1729-35.(Subsequent clinical treatment trial following the above-noted pilot study that shows the efficacy of azithromycin for the treatment of early syphilis.)
Lukehart, SA, Godornes, C, Molini, BJ. "Macrolide resistance in Treponema pallidum in the United States and Ireland". N Engl J Med. vol. 351. 2004. pp. 154-8.(Important study detailing development of resistance to azithromycin and other macrolides.)
Shann, S, Wilson, J. "Treatment of neurosyphilis with ceftriaxone". Sex Transm Infect. vol. 79. 2003. pp. 415-16.(Reviews the use of ceftriaxone, instead of penicillin G, for treatment of neurosyphilis.)
Hook, EW, Baker-Zander, SA, Moskovitz, BL, Lukehart, SA, Handsfield, HH. "Ceftriaxone therapy for asymptomatic neurosyphilis. Case report and Western blot analysis of serum and cerebrospinal fluid IgG response to therapy". Sex Transm Dis. vol. 13. 1986. pp. 185-8.(Addresses the issue of the appropriateness of ceftriaxone for treatment of neurosyphilis.)
Wendel, GD, Sheffield, JS, Hollier, LM, Hill, JB, Ramsey, PS, Sánchez, PJ. "Treatment of syphilis in pregnancy and prevention of congenital syphilis". Clin Infect Dis. vol. 35. 2002. pp. S200-9.(Guidance for the approach to treatment of syphilis in pregnant women.)
Zetola, NM, Klausner, JD. "Syphilis and HIV infection: an update". Clin Infect Dis. vol. 44. 2007. pp. 1222-8.(Good review of syphilis in the HIV population.)
Stoner, BP. "Current controversies in the management of adult syphilis". Clin Infect Dis. vol. 44. 2007. pp. S130-46.(Excellent overview of the issues surrounding management conundrums with syphilis.)
Saloojee, H, Velaphi, S, Goga, Y, Afadapa, N, Steen, R, Lincetto, O. "The prevention and management of congenital syphilis: an overview and recommendations". Bull World Health Organ. vol. 82. 2004. pp. 424-30.(WHO recommendations aimed at decreasing the risk of congenital syphilis and suggesting treatment when congenital transmission has occurred.)
Genc, M, Ledger, WJ. "Syphilis in pregnancy". Sex Transm Infect. vol. 76. 2000. pp. 73-9.(Thoughtful review of the issue of syphilis in pregnant women.)
"Ocular Syphilis – Eight Jurisdictions, United States, 2014-2015". Morbidity and Mortality Weekly Report (MMWR). vol. 65. November 4, 2016. pp. 1185-1188.(Description of a large cohort of ocular syphilis cases from 8 states. Healthcare providers should be aware of the emergence of this disease so that prompt management can be provided to those affected. CDC issued a clinical advisory to healthcare providers in October 2015.)
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