Diagnosing Syphilis, caused by the spirochete Treponema pallidum.  Seems simple — just draw a Venereal Disease Research Laboratory test (VDRL) or a Rapid Plasma Reagin (RPR).  In my experience, few diseases are as poorly understood.

We’ll go through a lot of detail, & end with a summary that you can also find under Reference Tables at the very top.


There are two types of tests: Non-Treponemal and Treponemal.

Non-Treponemal Serology  —  This is the RPR and VDRL.  I’ll only refer to RPR, though the two can be considered interchangeable.  Just don’t compare titers of one with titers of the other.  Main points:

  • Titers increase progressively with new infection, then gradually decrease with treatment
  • Titers also gradually decrease over the years with no treatment, even to “non-reactive”
  • New increase in titers (at least 4-fold) after successful Tx = reinfection
  • Various conditions cause “Biologic False-Positive RPR/VDRL,” including HIV, Lupus & other collagen-vascular disorders, Pregnancy, various infections (varicella, measles, mono, etc. etc.).

Treponemal Serology  —  This includes the Fluorescent Treponemal Antibody Absorption (FTA-ABS), the Treponemal Pallidum Particle Agglutination (TP-PA), and the Micro-Hemagglutination T. Pallidum (MHA-TP) tests.  All are interchangeable.  TP-PA seems most common today.  Main points:

  • No titers.  Either “Reactive” or “Non-Reactive.”
  • Once positive, they usually remain positive for life.
  • Called “confirmatory tests” because they confirm whether a positive RPR is true or false.  A negative Treponemal Test means the RPR was false-positive.
  • Useless in terms of reinfection

In general, we diagnose or screen for syphilis with an RPR.

  • If the RPR is positive, we need a treponemal test to confirm it’s not a false-positive
  • Will discuss false-negatives under different stages

NOTE:  There is no way to Dx Syphilis by culture or nucleic acid testing (PCR).

In order to understand the diagnostics, it’s absolutely essential to appreciate the…


There are 4 clinical stages of Syphilis: Primary & Secondary (both considered “early syphilis”), then Late-Latent & Tertiary (both considered “late syphilis”)

Incubation Period  —  2-6 weeks from infection until initial symptom.

Primary Syphilis  —  Diagnosed by finding a Chancre: a painless sore (ulcer), usually with heaped borders, at point of inoculation.  May be atypical, just a nodule, in person with HIV.

Chancres are often not noticed, since they’re painless.  They’re certainly not noticed if inside vagina, mouth, or rectum.  Non-tender regional lymphadenopathy appears.  The chancre lasts usually 4-8 weeks, resolves spontaneously on its own.

The Chancre is extremely infectious, by direct contact.   In contrast to HIV, syphilis is easily transmitted by oral sex.  However, a person with HIV and a syphilitic chancre will transmit HIV too, since chancres teem with both T. pallidum spirochetes and HIV-invaded lymphocytes.

Diagnosis:  Both Non-Treponemal & Treponemal Tests are negative during 1° syphilis!  They both seroconvert just as the chancre resolves.  Diagnosis of 1° Syphilis depends on Darkfield Microscopy, which is rarely available.  Darkfield isn’t useful for oral chancres, since non-pathogenic commensual spirochetes colonize the mouth.

So essentially, we diagnose 1° Syphilis clinically, by a chancre.

Secondary Syphilis  —  Symptoms begin after the chancre has resolved, occasionally as it is fading (approx. 6-16 weeks after infection).  Manifestations are protean, may range from florid to asymptomatic.  They last 2-6 weeks, but may relapse within a year.  Findings include:

  • Malaise, myalgias, arthralgias, pharyngitis, headache
  • Fevers
  • Rash: macules / papules / nodules, smooth or scaly [not vesicles], come and go
  • Rash on palms & soles is highly suggestive
  • Generalized adenopathy (incl. epitrochlear, axillary, post. cervical)
  • Condylomata Lata: moist gray plaques in intertriginous areas (buttocks, axilla, etc)
  • Mucus Patches: Superficial painless erosions on mucus membranes
  • Patchy alopecia
  • Specific Organ System Involvement: Iritis, Retinitis, Nephritis, Periostitis, Arthritis, GI ulcerations
   General Lab Tests:
  • CBC normal
  • LFTs may be elevated, esp. the Alk Phos

Click the link [but not right after lunch] for pictures of the different stages of Syphilis.  Caution: not for the light-hearted.

Serology is 100% sensitive for 2° syphilis (both non-treponemal & treponemal tests).

  • RPR titers are very high, usually >1:16.  I’ve seen 1:1024.

Actually, there’s a rare “Prozone Phenomenon” in which so many antibodies crowd the test slide as to obscure the agglutination of antigen-antibody complexes.  Astute lab techs can usually tell the difference.  But if a classic clinical presentation of 2° Syphilis yields a negative RPR, have them repeat the test by “diluting specimen to R/O Prozone Phenomenon.”

Early-Latent Syphilis  —  This brief asymptomatic period is defined as the year after relapses of 2° Syphilis relapses have ceased.  It’s identified by a history of prior symptoms.  The stage is important for contact tracing, but the history is rarely elicited.

The 1°, 2°, & “Early-Latent” Stages are termed “Early Syphilis.”  The time frame is around 1½ to 2 years from infection.  “Early Syphilis” is infectious.  It’s treated with a single injection of Benzathine Penicillin 2.4 million Units, IM.  NEVER use procaine Penicillin, or a mixture of Procaine + Benzathine.

Late-Latent Syphilis  —  Completely Asymptomatic.  It’s defined as beginning a year after 2° Syphilis ends.  Late-Latent Syphilis is not really infectious (probably not at all).  The stage lasts forever.  Approximately 1 in 3 infected people will progress to 3° Syphilis, usually in 15-30 years, sometimes sooner.

The only way way to diagnose Late-Latent is by screening Serology.  The RPR is usually positive at low titer (<1:8), but may be negative.  Treponemal Tests are almost always positive [see below for screening strategies].

Late-Latent Syphilis is treated by 3 injections of Benzathine Penicillin 2.4 million Units IM, each a week apart.  But first, be sure to do a careful exam to R/O any possibility of 3° Syphilis.

Tertiary Syphilis  —  Onset up to 30 years after infection.  There are 3 manifestations of 3° Syphilis: the Gumma, Cardiovascular, and Neurosyphilis.

Gummas:  Heaped-up, disfiguring granulomas on skin, bone, or viscera.  They represent the rarest form of 3° Syphilis.  Diagnosis: biopsy, granulomas found on pathology, hopefully with serology positive (see below).

Cardiovascular:  Manifestations include Aortic Regurgitation, and an Aortic Root Aneurysm.  The murmur of A.R. is early diastolic, heard best at mid left sternal border.  Aortic aneurysms occasionally dissect, a cause of syphilitic mortality in the pre-antibiotic era.  Always order syphilis serology for these cardiac findings [see below].

Neurosyphilis: Divided between Early & Late presentations.  “Early Neurosyphilis,” the most common form seen today, occurs in the first few years after infection.  It includes:

  • meningitis
  • cranial nerve deficits (incl. loss of vision or hearing)
  • “Meningovascular Syphilis”: headache, disequilibrium, and/or subtle mental status changes resulting in eventual stroke (especially seen among persons with HIV)

“Late Neurosyphilis” occurs 15-30 years after infection.  Ubiquitous during the pre-antibiotic era, and very rare today, it presents as either “Tabes Dorsalis” or “General ‘Paresis.”

Tabes Dorsalis: Ataxia, often with intermittent severe lancinating pain paroxysms in any part of the body.  Symptoms may include:

  • Wide-based “foot-slapping” gait
  • Loss of position sense
  • Areflexia
  • Argyll-Robertson Pupils (see below)
  • Urinary incontinence or retention.

“General Paresis”: In the pre-antibiotic era also known as “General Paresis of the Insane,” since asylums were full of syphilis patients.  “PARESIS” is also an acronym:

  • Personality Changes
  • Affect — dull
  • Reflexes — hyperactive
  • Eyes  —  Argyll-Robertson Pupils are miotic, don’t react to light, but do converge and constrict with accommodation.  Hence the mnemonic, “Pupils like prostitutes; they accommodate, but don’t react.”
  • Speech — slurred, loss of fluency
  • Intellect — cognitive deficits
  • Sensorium — mania, depression, hallucinations, delirium

Serology:  RPR negative in up to 25% of cases of late 3° Syphilis !!!

  • Treponemal tests ~100% positive
  • RPR almost 100% sensitive in Early Neurosyphilis
  • Neurosyphilis diagnosed by CSF serology (order both types).  VDRL  30-50% sensitive, FTA-ABS 100% sensitive.
  • ↑ CSF lymphocytes & protein (very sensitive, not specific)

Spinal Taps:  Who should get an LP to rule-out Neurosyphilis?  Textbooks say everyone with positive serology & no symptoms (i.e. Late-Latent Syphilis).  Neurosyphilis requires IV Penicillin q4h for 10 days (even if allergic; desensitize in an ICU).

But nobody I know follows this.  We rely on a neuro exam; if it’s normal, we treat for Late-Latent.  Even in HIV patients with positive RPR, when LP is “strongly recommended,” most clinicians omit the LP if asymptomatic.

SUMMARY  (also appears under Reference Tables at top)


1° Syphilis:  Chancre (at site of inoculation)
  • Appears 2-6 weeks after infection
  • Lasts 4-8 weeks
2° Syphilis: Rashes, constitutional Sx / adenopathy / diverse organs
  • Onset 6 wks – 4 mos. from infection
  • Lasts 2-6 weeks
  • Manifestations can relapse for up to 1 yr.
Early-Latent Syphilis:  Asymptomatic; Contagious
  • Defined as up to 1 yr. from end of 2° symptoms
  • Rarely identified; important only for contact tracing
Late-Latent Syphilis:  Asymptomatic; not contagious
  • Onset 1½ to 2 yrs. from infection, lasts a lifetime
  • 1/3 of persons eventually develop 3° Syphilis
3° Syphilis:  Neuro, Cardiovascular, Gummas
  • Early Neuro (meningeal): Up to 5 yrs. from infection
  • Late Neurosyphilis: Onset 15-30 yrs. from infection
  • Cardiovascular & Gummas: >10-15 yrs. from infection


Early Syphilis

1° Syphilis:  Chancre
  • RPR Neg, TP-PA Neg
  • Dx clinically
  • Darkfield if available
2° Syphilis: Rash, myriad of Sx
  • RPR 100% Pos (plus additional biologic False-Pos)
  • TP-PA 100% Pos. (“confirms” RPR)
Early-Latent Syphilis
  • Same as 2° Syphilis

Late Syphilis

Late-Latent Syphilis:  A-Sx
  • RPR only ~75% Positive (approx. 25% False-Neg)
  • TP-PA ~100% Pos
3° Syphilis:  Neuro, C-V, Gumma
  • Same as Late-Latent
  • Early Neurosyphilis: RPR >95% Pos
Late Neurosyphilis: CSF
  • VDRL 30-50% sensitive
  • FTA-ABS ~100 sensitive
  • ↑ lymphocytes & protein ~100% sensitive


With treatment, the RPR usually becomes non-reactive within 2 years.  However, some remain positive at low titer forever (<1:8, usually lower).  This is called “Sero-Fast.”  Treponemal tests remain positive for life.

Reinfection is defined as a 4-fold rise in titer, e.g. from 1:2 to 1:8 (2×4 = 8).  It’s widely accepted among syphilis experts, but I’ve been unsuccessful in finding any reference.  Personally, I’d really like to see a 4-dilution rise, e.g. 1:2 to 1:32, or at least a 3-dilution (1:2 to 1:16), because 1:2 and 1:8 both seem suspiciously close to 1:4, thus open to interpretation error.  But the strong consensus is “4-fold”.

In other words, after treatment for syphilis, RPR titers decrease very gradually.  If they rise, it’s reinfection.  But if they never normalize to “non-reactive,” it’s OK.  I tell worried patients that the test measures antibodies, i.e. the body’s response, not the germ.


Usually we screen for Syphilis with an RPR.  Recently, some centers have begun screening with Treponemal tests.

  • Advantage:  Cheaper, easier for the lab.
  • Advantage: Picks up cases of Late-Latent, which may have negative RPRs
  • Disadvantage:  Once positive, always positive, so no way to find reinfection.
  • Disadvantage:  Some of the TP-PA tests may be false-positive, esp. in low-prevalence populations.  Recommendation is to repeat with another treponemal test (FTA-ABS).  If that’s positive, Dx Late-Latent.  If it’s negative, consider the initial TP-PA screen a false-pos.


Case #1  —  A 40-y.o. asymptomatic man with history of multiple sex partners requests an STD screen; a week later, the RPR returns 1:4.  TP-PA is positive.  There’s no prior Hx of syphilis.  What’s he got?

  • Could be the beginning of 2° Syphilis.  Needs 1 dose of IM Benzathine Pen, and contact tracing.
  • Could be Late-Latent, initial infection 10-20 years ago.  Needs 3 doses, extensive contact tracing not so important.

What to do?  To know for sure, wait a few weeks & repeat the RPR for rising titer (2° Syphilis).  But nobody wants to do that.  So we’d probably just Dx Late-Latent, Tx with 3 weekly shots, & have Public Health trace contacts just in case.

Case #2  —  A 75-y.o woman complains of memory loss.  We find borderline cognitive deficits (e.g. Mini-Mental Status 24/30).  We order a chemistry panel, TSH, B12 level, and RPR (all negative).

ERROR: up to 25% of patients with neurosyphilis have negative RPRs.  So if working up a symptom compatible with 3° Syphilis, order both Treponemal as well as Non-Treponemal tests.

That’s it for Syphilis; wasn’t it fun?

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