Diagnostic Tests for Syphilis Continue to Perplex Even the Experts

[Argirios Argiriou]

January 13th, 2020

Diagnostic Tests for Syphilis Continue to Perplex Even the Experts: An Unanswerable Question in Infectious Diseases

Here’s a tricky clinical scenario:

An elderly person with cognitive decline or some other non-specific neurologic symptom sees a clinician.
Clinician sends a syphilis screen with a T. pallidum enzyme immunoassay (TP-EIA), which returns positive.
Lab runs a confirmatory test — a T. pallidum particle agglutination test (TP-PA), or similar, which also returns positive.
The lab then runs a rapid plasma reagin (RPR) test, which returns negative.
There is no known prior clinical or lab history of syphilis exposure, diagnosis, or treatment.
Now what are we supposed to do?

I bring this up because Dr. Thomas Fekete raised just this issue on the IDSA’s ID Exchange message board, generating a spirited discussion.

(I’m citing this discussion and quoting with his permission.)

And every card-carrying ID doctor has been asked what to do in just this setting numerous times since labs started using TP-EIA — and not RPR — for syphilis screening a bit over a decade ago. In one study, this pattern (two positive treponemal tests and a negative RPR) occurred in approximately 3% of individuals undergoing testing.

Here’s why the next step is so controversial:  This exact pattern describes three separate clinical scenarios, each of them requiring very different next steps. Here are the potential interpretations:

The result is consistent with, but not diagnostic of, neurosyphilis. Recommendation: Perform a CSF exam to rule out neurosyphilis. This is hardly a trivial undertaking, especially in the elderly. Further complicating this next step is that the CSF exam is notoriously poor at either ruling in or ruling out neurosyphilis. Plenty of false-positives and false-negatives.
The result suggests late-latent syphilis with an RPR that has reverted spontaneously to negative. Recommendation:  Treat with benzathine penicillin 2.4 million units by intramuscular injection, weekly for 3 doses. In this interpretation, clinicians must consider the likelihood of clinical neurosyphilis to be sufficiently low that this result is unrelated to the neurologic symptoms — which begs the question, why was the test ordered in the first place?
The result demonstrates prior treated syphilis, with an adequate serologic response. Recommendation:  No treatment or further testing necessary. Lots of antibiotics have activity against T. pallidum, so antibiotics administered for other indications over the years have inadvertently provided sufficient treatment.
Let’s add to the quandary by quoting Dr. Fekete on two key points:

I cannot find modern information about the incidence of true tertiary or neurosyphilis in elderly patients with this [testing] profile … These patients would not have come to our attention in the old system for syphilis screening.

Where are the prospective clinical series outlining either actual clinical neurosyphilis — or even CSF abnormalities — in those who have this serologic profile?

Plus, in the pre-TP-EIA era, when we used RPR for screening, neurosyphilis would have been considered “ruled out” unless there was a strong prior probability of this disease (which there hardly ever is).

Sometimes ignorance is bliss!

Want a further wrinkle? Some believe that the recommended treatment for latent syphilis — benzathine penicillin, with its long half-life but low CSF concentrations — adequately treats neurosyphilis as well. The thought here is that the immune system plays a role in clearing the infection, so no need for high CNS concentrations of penicillin — except perhaps in people with immunosuppression, as is seen in untreated HIV.

The data supporting this view (like many other aspects of clinical syphilis) are largely uncontrolled and somewhat dated — but strongly endorsed and frequently cited by advocates nonetheless.

But this position is vociferously challenged by others — again with largely anecdotal and outdated data. This group, now in the majority, inform the current CDC guidelines for treatment of neurosyphilis, which recommend high-dose intravenous penicillin G for 10-14 days — a burdensome treatment not easily (or cheaply!) administered to the  elderly, especially those with cognitive impairment.

It’s not as if this neurosyphilis quagmire were a new problem; indeed, the diagnosis of neurosyphilis has been fraught for decades. Often the leading strategy adopted by a hospital or a practice is the one endorsed the most passionately (or most loudly, in case conference) by the local expert or experts.

All this controversy makes this case scenario a classic Unanswerable Question in Infectious Diseases. And perfect for a poll!

So have it at — and educate us by using the comments section to justify your vote.

A 78-year-old man with no known prior history of syphilis or other sexually transmitted infections is evaluated for mild cognitive decline. As part of the work-up, he has the following blood test results:  TP-EIA positive, TP-PA positive, RPR negative.

What would you recommend next? ( vote )

 1) No further tests or treatment.
 2) Treatment for late-latent syphilis with benzathine penicillin.
 3) CSF examination to rule-out neurosyphilis.
 4) Empiric treatment of neurosyphilis without CSF examination


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