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Welcome to the deep dive. Our mission today is well, it's clinical mastery of one of the most complex multisystem infections out there, syphilis.

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It really is.

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We're going to dive deep into its natural history from that very first lesion all the way to its uh its most frightening tertiary forms and pull out everything you absolutely need to know for practice.

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Right. So syphilis is caused by this spear sheet, Triponema palatum, and it's called the Great Mimic for a very, very good reason. This thing has an unnerving ability to infect, well, pretty much every organ system.

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And transmission is primarily sexual, but the numbers are just staggering.

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They are. I mean, after a single unprotected encounter with an infected partner, the risk of actually getting it is somewhere between 30 and 50 percent. It's incredibly efficient.

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That statistic alone just tells you why you have to be on top of this. So we're going to organize this deep dive around infectivity and time, early infectious stages, so less than a year, versus the late non-infectious stages, which is over a year.

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And we'll weave in all the core stuff: history, physical, diagnostics, management, and of course prevention.

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Okay, so let's jump right into the clinical journey because the presentation really dictates everything. It all starts with primary syphilis. What's the timeline we're looking for?

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Aaron Powell So after inoculation, the lesion itself usually appears about 10 to 90 days later. The average is say three to four weeks. But the history can be vague, you know, which is why the physical exam is so so important.

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Aaron Powell And the hallmark of that exam is the chonker.

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Aaron Ross Powell The Chonker, a solitary superficial ulcer.

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Aaron Powell So what are the specific clinical characteristics that separate this from, say, a herpes outbreak or something else?

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Aaron Powell The defining feature is its lack of pain. It's classically described as having a clean base and a firm, uh an indurated or raised border.

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Right.

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Now you contrast that with the I mean the agonizing pain of a genital herpes vesicle or the painful soft ulcer of chancroid. The syphilis lesion is often so painless that people just miss it, especially if it's somewhere like the anorectal region or the back of the throat.

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And if that primary lesion is missed, then the organism really starts to spread, which brings us to secondary syphilis. So what do patients actually complain about when it goes systemic?

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Aaron Powell Well, weeks to maybe six months after the chakra shows up or even disappears, the patient starts getting systemic symptoms. It's often like a flu-like prodrome. Fever, malaise, just feeling tired, muscle aches.

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Aaron Powell But the illness itself isn't that dramatic compared to the physical signs, right?

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Aaron Powell Exactly. The systemic illness can be pretty mild, but the physical findings are, well, they're dramatic.

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Aaron Powell Which brings us to that signature rash. I mean, if you see this in the clinic, it should be syphilis until you prove it's not.

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100%. We're looking for a generalized maculopapular rash that is classically non-proritic.

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It doesn't itch.

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It doesn't itch. And the crucial pattern recognition point, the thing that needs to stick in your mind, is that this rash shows up on the palms and the soles in about 80% of cases.

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Aaron Powell The palms and soles, that's the classic.

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It is. And you might also see other things like generalized, non-tender, lymphodenopathy, and sometimes even patches of hair loss. It's described as moth-eaten alopecia.

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You know, given how many skin rashes there are, how often does this get misdiagnosed as something, you know, less serious?

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Oh, quite often. Yeah. It can look a lot like pitiasis rhizaea or even some drug eruptions. But the presence of specific mucocutaneous lesions really helps you nail the diagnosis.

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Like what should we be looking for?

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You want to look for condylamata alata. Now, these are not genital warts. They're broad, flat, weeping papules in moist areas, and they are highly infectious. Or you might find painless mucus patches in the mouth. Those findings, plus the palm and sole rash, your suspicion should be through the roof.

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Okay, so after that very active infectious stage, we move into latent syphilis, where the diagnosis is basically made by a lab result in a calendar.

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It is entirely serological, and the big clinical distinction is just the timeline. So you're in the early latent stage if the infection was less than a year ago.

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And these patients are still infectious.

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Still infectious to partners. And they can actually relapse back into that secondary symptomatic phase. But once you cross that one year mark, the patient is in late latent syphilis. Now, crucially, they're generally not infectious to sexual partners anymore. But, and this is a big but, the risk of vertical transmission in pregnancy is a lifelong concern.

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Aaron Powell And if it's still left untreated, we get to tertiary syphilis, which, I mean, this is some of the most dramatic and devastating pathology in all of medicine. Tell us about the three main ways this late-stage infection presents.

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Aaron Powell The three major systems are the skin and bone, which is gummatous, the heart, cardiovascular, and then the brain and spinal cord, neuro syphilis. Gumma to syphilis is where you get these granulomatous lesions called gumas, and they can literally destroy skin, bone, or even the liver.

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And the cardiovascular side.

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Cardiovascular involvement is mainly the aorta. It causes aortitis, which can then lead to these big sacular aneurysms and really critical aortic regurgitation.

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And the neurologic manifestations, I mean, they're legendary for mimicking other psychiatric and neurological conditions.

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They really are. And while neuro syphilis can technically pop up at any stage, the tertiary forms are what you really need to know. There's tabes dorsalis, which is degeneration of the sensory nerve tracts.

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And what does that look like?

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So the patient loses proprioception, they get ataxia, and these characteristic lightning pains. The classic physical finding is the Argyle Robertson pupil. The pupil accommodates, so it constricts when you look at something close, but it does not react to light.

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Accommodates but doesn't react.

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Exactly. And then there's general paresis, which looks just like primary dementia. You see personality changes, memory loss, tremors, all from widespread cortical damage.

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Let's do a quick note on congenital syphilis before we move on. What are the key findings in infants and children?

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In infants, you see early signs like snuffles, that's a persistent bloody nasal discharge, and hepatoflenomegaly. In older kids, you look for the classic stigmas of developmental damage, like Hutchinson teeth, which are notched incisors, a saddle nose deformity from cartilage collapse and saber shins.

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Okay, so once we've spotted these classic signs, the next critical step is proving it. How do we definitively confirm this in the lab?

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So confirmation needs a two-step approach using serology. The first type is the nontroponemal test. That's your VDRL or RPR. These tests detect non-specific antibodies.

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So if that RPR comes back positive, what's our primary use for that result?

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Its greatest use is for monitoring treatment response. The result comes to the titer, like 1 to 32. Successful treatment means that titer has to drop significantly. But you have to remember they are nonspecific. So you always have to think about false positives, especially in pregnancy, autoimmune diseases, that sort of thing.

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Got it. And the second test is the specific confirmation. Aaron Powell Right.

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That's the troponemal test, like a TPPA or the automated EIA or CIA test. These are highly specific for T palatinum antibodies. And the major clinical point here is that once these tests turn positive, they usually stay reactive for life, even after successful treatment.

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Aaron Powell The serology algorithms can be a huge source of confusion. I mean, we used to always start with the RPR the traditional way, but now a lot of clinics use the reverse sequence, starting with the treponemal EIA. Why the switch? And what does that confusing discordant result actually mean?

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Aaron Powell Yeah, the reverse sequence is really just because the trepanemal tests are easier and faster to automate for mass screening. The problem is exactly that discordant result. You get a positive EIA, which is the specific test, but a negative RPR.

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Okay, so what do you do then?

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You need a tiebreaker test. Usually a second different trepanemal test like the TPPA. And the reason this happens is either the patient is very early in their infection and hasn't mounted an RPR response yet, or much more commonly, they had syphilis years ago, got treated, and their RPR is now non-reactive, but that specific EIA stays positive for life.

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Ah. So the tiebreaker confirms if they were ever infected at all. That makes it much clearer. It's about separating active infection from a historical one.

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Exactly.

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So outside of serology, when do we need to look at it directly?

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Dark field microscopy is the definitive test for early active lesions like a chunker or condyle modellata. You can actually see the motol spirochetes right there under the microscope.

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But there's a catch, right?

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Big catch.

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Yeah.

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You cannot use it for oral lesions because there are non-pathogenic trepanoms that live naturally in the mouth, so you'll get false positives.

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Aaron Powell And when do you have to do a lumbar puncture for CSF analysis?

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Anytime a patient has neurologic or ocular symptoms, or if they have evidence of tertiary syphilis, or if you even suspect treatment failure. We're looking for inflammation in the spinal fluid lymphocytes, elevated protein, and the most definitive thing is a reactive CSF VDRL.

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But that's not a perfect test either.

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Aaron Powell No, not at all. It's highly specific, so if it's positive, you have your answer. But it's not very sensitive, so a negative result doesn't completely rule out active neuro syphilis.

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Okay, let's transition now to management clinical intervention. The core therapeutic choice is simple, but the dosing gets really complex.

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It does. But the foundation of all treatment is penicillin G. It's the drug of choice for all stages, and crucially, it's the only drug that's adequate for treating neuro syphilis and for treating syphilis in pregnancy. The difference is just in the concentration and how long you need it.

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So let's nail down these dosing regimens, starting with the most common scenarios.

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For primary, secondary, and early latent syphilis, it's a single dose of benzothene penicillin G. 2.4 million units intramuscularly. Just one shot.

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Okay. One and done for early disease.

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But if the patient has late, latent or non-neurologic tertiary syphilis-like gumas or cardiovascular stuff, we need to extend that coverage. The regimen changes to 2.4 million units IM, but you give it weekly for three weeks.

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And why the longer duration?

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It just ensures you have enough time for the drug to penetrate into tissues that are less vascular.

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And for neuro syphilis or ocular syphilis, you have to hit them much harder.

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Oh, absolutely. That's an inpatient admission. They need aqueous crystalline penicillin G, given intravenously, for a continuous course of 10 to 14 days. We have to achieve vacuousidal levels in the central nervous system.

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But what if they have a penicillin allergy? That's common.

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If the patient is allergic and not pregnant, we can consider alternatives like doxycycline, 14 days for early disease, 28 for late latent, or ceftriaxone.

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You mentioned pregnancy. That's a critical population.

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Aaron Powell It's the highest stake scenario, absolutely. Yeah. Penicillin is the only effective treatment to prevent or treat congenital infection. So if a pregnant patient says they have a penicillin allergy, they must undergo desensitization to get the proper penicillin treatment. No exceptions.

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Aaron Powell That's a huge point. And what about patients with HIV?

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For patients coinfected with HIV, the standard treatments generally work, but we have to monitor them much more closely because there's a higher risk of what we call serologic treatment failure.

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Before we leave therapeutics, we have to talk about the Jerish Herzheimer reaction. It can be terrifying for the patient.

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It can. The GHR is an acute reaction, usually within 24 hours of that first dose. Fever, headache, body aches. It's caused by the sudden mass death of the spirit and the release of all these endotoxins.

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But it's not an allergic reaction.

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Not at all. It's self-limiting, managed with simple antipyretics. The reason we focus on it so much is the risk in pregnancy. It can induce preterm labor, so those patients need to be monitored.

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Okay, moving into long-term management and prevention. After that initial dose, how do we confirm our treatment actually worked?

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We rely entirely on monitoring the non-triponimal titers, the RPR or VDRL. For early syphilis, we recheck those titers and do a clinical exam at six and twelve months.

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And what are you looking for? How do you define success?

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The definition of success is a fourfold decline in the titre. So for example, if you start at 1 to 32, you need to see it drop to at least 1 to 8 or lower.

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And for neuro syphilis, the follow-up is even tighter.

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Much tighter. You're checking serology every three to six months, and you might even have to repeat the CSF analysis if those titers are being stubborn.

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Beyond the individual patient, this is a public health issue. So partner management is crucial education for every provider.

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It really is. This is where presumptive treatment is key. For any sexual contact that patient had within the last 90 days, we treat them presumptively for early syphilis.

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Wait, you treat them even if their own serology is negative?

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You treat them regardless. Single IM dose. If the exposure was more than 90 days ago, then treatment depends on their serology, or you just treat them empirically if you think follow-up is going to be impossible.

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Finally, let's cover screening and prevention. Who needs routine checks?

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So screening is recommended for all pregnant individuals at their first prenatal visit, and then again in the third trimester and a delivery if they're high risk. More broadly, high-risk groups like men who have sex with men and people on HIV pre-EP should be screened regularly, usually every three to six months.

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And there's one piece of patient education that you can't miss.

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You cannot. Because ephylus lesions make it easier to transmit HIV, every single patient diagnosed with syphilis must be tested for HIV.

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And of course, the newest tool in prevention is doxyP.

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Right. Doxycycline post-exposure prophylaxis.

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So tell us about that. How does that work?

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It's a single 200 milligram dose of doxycycline that's taken within 72 hours of condomless sex. And the studies have shown it's really effective at reducing the incidence of syphilis, chlamydia, and gonorrhea, especially in high-risk groups like MSM and transgender women. It's a major shift in how we approach prevention.

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So what does all this mean for you as a future provider? I mean, we've covered a disease that starts deceptively small, that painless chancre moves through a systemic stage defined by that unique, non-itchy palm and sole rash.

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And can end up with things like the Argyll Robertson pupil or general parasis.

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So the key takeaway is what?

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The key takeaway is maintaining an extremely high index of suspicion. Syphilis is the great mimic because it presents everywhere. Mastering the natural history lets you correctly apply the diagnostic algorithms, you know, traditional versus reverse, and confidently manage the penicillin dosing, which changes radically depending on if the disease is early, late, or in the CNS. The disease really demands your attention across all organ systems.

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We've seen that we have this highly effective curative single-dose injection for early disease and now a prophylactic option in doxy PEP for high risk individuals. So here's a final thought for you to chew on. If DOXY PEP becomes widely adopted and successful, and it really reduces new infections, how might that success change the calculus and the necessity of those existing routine periodic screening schedules we have? Something to consider as you move toward clinical practice.