104: StAR: Neurosyphilis

He also serves as clinical chief for STI services at the Baltimore City Health Department. He provides patient care for people with HIV and other STIs as well as those at risk for infection. His research focuses on harnessing diagnostic development to improve HIV STI diagnosis, prevention, and linkage to care. Thanks for being here!

So probably like my number one thing right now when I have time is just to go and stand in the garden for a few minutes at the end of the day.

There's been an almost 80 percent increase in all stage syphilis diagnosis in the, in the last five years. And the element of syphilis that is the most heart wrenching in some respects is congenital syphilis, where we've seen 180 percent increase in congenital syphilis diagnosis in the last half decade and over 30 percent just in the previous year.

And whilst that's not directly related to neurological syphilis as we're spending most of the time talking about, I think for context that both of those facts are really important. And sometimes I talk with clinical colleagues outside of infectious diseases and they'll say, really syphilis still a thing in 2024? Um, and I think there are some perceptions that syphilis is an infection assigned to history, but unfortunately, that's absolutely not the case.

In terms of neurosyphilis or neurological syphilis, I'll use the two terms interchangeably. The question about the epidemiology of, uh, of neurological syphilis is a great one. I can hand wave a little bit and speculate, but I think we really don't collect nationally representative high quality data on neurosyphilis diagnoses.

So I think what we can try to do is to say that as overall syphilis diagnoses are increasing, we expect the rate of neurological complications to increase in tandem with that. But, um, unfortunately, I'm not able to, uh, look at surveillance data and say, these are the, in inverted commas, "real" increases in neurosyphilis.

He more recently has developed periods of confusion and disorientation, uh, and the family thinks that he actually is probably having some memory loss, although they're having a hard time summarizing that for you. And today though, he was brought in more urgently because of an episode of speech difficulty. On his labs, we know that his routine labs are normal. They sent HIV and hepatitis screens, which are negative, but we already know that he has a positive RPR from that initial blood work.

Um, this case is obviously not meant to be a mystery. Our, our listeners kind of already know we're talking about neurosyphilis. Uh, so before we confirm our suspected diagnosis of neurosyphilis, I was hoping you could provide a refresher on the natural history and really the major clinical syndromes associated with symptomatic neurosyphilis because it's not just sort of one representative clinical presentation.

Some of the old natural history studies, particularly in the pre antibiotic era, are quite different to the clinical presentations that we see now, where antimicrobial use is so common, people will have received doxycycline for a skin and soft tissue infection or a Z Pak for a upper respiratory tract infection. So people will have been exposed often to antimicrobials that will have some activity against Treponema pallidum, the bacteria that causes syphilis.

So I think that probably in part explains why the natural history of neurological syphilis is somewhat different compared to historical accounts. But with all things syphilis, the way that I conceptualize it is to, and there's a danger in doing this, but what I do particularly when I'm trying to think about it and, and provide, teaching and training is to try and break it down into different buckets based on clinical stages. And for neurological syphilis, we can apply this same rationale.

So we can think about some of the early neurological manifestations, and then we can think of late neurological manifestations. A point that I would make that many people either have forgotten or never knew is that people can have neurological involvement at any stage of infection, even before they develop a primary syphilitic chancre. So if you look hard, you can see evidence of T.pallidum in the CSF of people who haven't yet developed their primary lesions.

You can see it in people with primary disease, with secondary syphilis, etc. But in terms of some of the early manifestations, and we think about this within the first year of infection, they often present with a a quite typical picture of meningitis, where there will be, you know, headache, there may be cranial nerve involvement.

Sometimes people will present with what looks like a stroke, and occasionally people will have more extensive basilar involvement of the meninges, and cranial nerve pathologies can progress quite, quite rapidly. So sometimes early neurological syphilis can be very similar to other forms of meningitis. And then as time progresses in somebody who hasn't received treatment, then you can sort of break the late neurological manifestations into three buckets.

So the meningovascular, parenchymatous, and then those that we see with gummatous disease. So the meningovascular manifestations are similar to the ones that I've just talked about where people will present with a stroke. They may present with spinal cord disease where there's been vascular involvement of the vessels to the spinal cord. And this can happen anything from 5 to 15 years after treatment.

And then the parenchymatous disease, again that's broken into two, but that's typically sometime after the meningovascular disease, so up to 20 years after infection.

And the parenchymatous disease we can think of the type that causes a picture very similar to the one that you've described where people will have memory loss, personality change, problems with communication with their families, and then the tabetic form where the, uh, where the parenchymatous involvement is at the level of the spinal cord. And that's where people will present with posterior columns, uh, signs and symptoms.

And then the final is the gummatous disease, which can occur as early as two years after infection and as late as 40 years after infection. And this is where somebody will present with features of a space occupying lesion. And then just to add a couple of additional thoughts, is that ocular and otic syphilis, so syphilis affecting the eye and the ear. Again, that can occur at any stage of syphilis infection.

And embryologically, those three compartments, so CNS, eye, ear, are slightly distinct, but clinically we group them together when we think about treatment in particular.

We all agree on proceeding to LP in patients who have neurologic symptoms, but oftentimes the question of who needs a CSF examination is a bit more challenging than that and probably has led to many phone calls to you and other experts. And I actually was hoping before we go back to our patient case that we talk about those scenarios. When are scenarios that an asymptomatic patient with serologic evidence of syphilis should get a lumbar puncture?

But as I mentioned before, often with things relating to syphilis, black and white is quite rare and we're dealing in shades of grey and, often calls for understanding the nuance of the particular clinical context and that's when it's so important that we engage in shared decision making with our patients. When we are straightforward about what we know and we're also straightforward about the uncertainties in terms of diagnostic.

How certain are we in our, in our diagnosis and how much evidence is there to support a particular management approach? So all of that said, I think the people with neurological signs and symptoms of syphilis, absolutely, lumbar puncture is indicated and really helpful. The exception is in people who have only ocular or otic manifestations.

For those individuals, a lumbar puncture or CSF examination is not mandated for the simple reason is that it will be normal in about 40 percent of people with ocular disease and up to 90 percent with otic syphilis. In terms of when we should consider lumbar puncture outside of the context of people with symptoms, then there are a couple of scenarios where it's wise to really consider it carefully.

And the first of those is when somebody has a sustained, and I stress the sustained, increase in RPR or VDRL titer. I'll use RPR just for efficiency sake. If someone has a sustained increase in their RPR of fourfold or more, and by sustained, I mean that the laboratory test is repeated at least two weeks afterwards, and that increase has remained the same. And the individual patient has had no opportunity for reinfection.

So for instance, you meet with someone, they've had treatment for their syphilis , and they have a sustained fourfold increase in titer, and you take a careful sexual history, and it's very clear that this person has not been re exposed. So that's one situation where we should consider a CSF examination. And the reason for that is that they may have undiagnosed asymptomatic neurosyphilis, and that's what's driving this increase in RPR.

And the other scenario is in individuals who fail to see a fourfold decrease in their RPR titer after stage specific treatment and after the requisite amount of time has elapsed. So that's another group where one can have a discussion around the pros and cons of CSF examination. And then the final group are those who have evidence of tertiary disease, so whether that's gummatous disease or evidence of cardiovascular syphilis.

And so while we're waiting on the results, there's a learner working with you and is hoping that you can give a quick overview of lab testing for syphilis, specifically of CSF testing. You know, does the CSF profile seem typical? What are the best CSF testing options for diagnosing neurosyphilis?

So that would be my trigger to initiate treatment and not waiting for any other laboratory results to come through. I think the CSF protein is probably the least helpful marker that we, that we routinely request when we're investigating neurological syphilis. And the reason that I say that is that it can be increased in many other conditions. It can be normal in neurosyphilis. So whilst I don't dismiss the CSF protein, it's probably the marker that I pay least attention to.

And if it's an isolated finding, then again, I really need to go back and look at the history, look at the exam findings, look at the imaging, and really, I think, long and hard about whether I'm going to make a suggestion that will commit this individual to 10 to 14 days of intravenous treatment. But the white count, I think it's a great marker. It's really quite sensitive.

And a CSF white count of 50, even in the setting of somebody who's living with HIV, again, that it's high enough to trigger action in terms of treatment. So, for people living with HIV, we know that their, that their white count may be higher than somebody who's, uh, who's not living with HIV, so you can increase the sensitivity of a neurosyphilis diagnosis by considering a white count up to 20 as, uh, potentially normal in, in somebody with, uh, particularly with untreated HIV infection.

And then we're waiting for the, for the rest of the tests to come back, and depending on where you work in the world will dictate the suite of serological tests that are available to you. In the US, we use the CSF VDRL and that is a very, very useful test. If it's positive, then I think you can feel very confident that you, you've clinched your diagnosis. What I would say is that the person doing the LP needs to look at the CSF and make sure that it's not blood stained.

If it is, then one can't really interpret the VDRL because there may be spillover from, from the blood compartment. But if you have clear CSF and you have a positive VDRL, then I think that that is a anchor of our neurosyphilis diagnosis. In other places in the world, such as in the UK, where I'm from and worked for many years, then we use a CSF RPR instead of a CSF VDRL. It probably doesn't perform as well as a VDRL, but it will give you comparable results.

In the US, we don't look at TPPA, for example, uh, in the CSF, which is done in other settings. The other serological test that we occasionally use is the FTA. If you have a patient who has a history that's consistent with neurosyphilis and you have a negative VDRL, and in some situations, you can ask the laboratory to send off, unless they do it in house, it's usually a send out test, um, to do it, to do an FTA, and that can help you to make a diagnosis in less clear cut cases.

So we talked about protein, we talked about white counts, we've talked about some of the serological markers, there are PCR assays that are available for, for diagnosing syphilis, and they can be incredibly helpful, particularly when people have lesions, so primary chancres and in more secondary lesions, and a PCR is really great, is very sensitive and specific. In CSF, it doesn't perform as well.

It's not a test that most people in the United States have access to, and I think the performance characteristics are much, much less well established compared with syphilis, where somebody actually has a lesion that you can swab. And the Holy Grail, one of the Holy Grails of syphilology is trying to find a biomarker that provides a reliable, robust, independent marker to say, yes, this is neurosyphilis or this is definitely not neurosyphilis.

And as you can probably tell by my preamble, um, we don't have a biomarker currently, apart from the ones that I've described, that can currently be used to aid us in diagnosing or excluding neurological syphilis. There are biomarkers that have showed promise, such as CXCL13 in the CSF, and there are many, many biomarkers that have been looked at, but I think the current state of play is that really we don't have anything that replaces the CSF VDRL at the present time.

And the patient actually had a listed allergy to penicillin on the chart, which fortunately, your awesome ID fellow actually de labeled, as it was not a true allergy that needed desensitization. But your inquisitive medical student on the team asks some follow up questions. "I thought I saw that you could use ceftriaxone or doxycycline, like what if that patient had a true allergy and that, gee, that sure seems simpler than penicillin".

So the CDC definitely sanctions the use of uh, ceftriaxone at the dose of one or two grams daily, either by an intramuscular or intravenous route. And many of us use that and there is quite a lot of clinical experience about using ceftriaxone in the treatment of neurosyphilis. The, the trial data just really aren't there. I mean, there are some small studies and there are some comparative studies, but the evidence base around ceftriaxone is quite limited.

I would add at this point that in, in pregnancy, then the only treatment that is recommended by the CDC is, is penicillin. So if the question was being asked in the context of pregnancy, then I would not, uh, based on current evidence, recommend treatment with anything other than penicillin as you described. So I think ceftriaxone has promise, you know, it is something that's used. It can be given on an outpatient basis.

If somebody, if you can find a clinical service that would give you your intramuscular injection at a weekend. So there are some advantages practically for patients to receiving that treatment modality. In terms of doxycycline, that is not something that is currently considered appropriate in a U. S. setting. So I would reply to the medical student learner that that is something that I would not use in this setting.

In the UK, for example, then doxycycline at a relatively high dose, so 200 milligrams twice daily for 28 days, is an alternative agent for the treatment of neurological syphilis, but the data upon which that recommendation is based is quite thin, but we have decades of experience in the UK of using doxycycline as treatment for neurological syphilis.

So this person definitely has syphilis, the usual rules apply that you would look at their previous history of syphilis diagnosis and treatment, you'd want to know what their previous RPR was if they had one, and then you would want to stage the syphilis, and that is really important because staging allows us to be confident in terms of the treatment recommendations that we will, that we will

make, but in this context, someone with a decent CD4 count with a relatively high RPR who is otherwise asymptomatic, I most certainly would not rush to suggest a CSF examination in in this context. The CDC guidelines, again, are really helpful here. They make it clear that in most scenarios that people are staged with syphilis and treated in the same way regardless of their HIV status. I mean, of course, there are some exceptions.

If you have somebody, let's say, who had advanced HIV disease and a high RPR, something equal to or greater than 1 to 32, where follow up might be tricky, let's say this is somebody who is an inpatient where they received this new dual diagnosis and you're worried that they're not going to be able to follow up as an outpatient for whatever

reason, then in that scenario, then I would be more willing to consider a CSF exam to be able to exclude neurosyphilis in this patient where follow up might be uncertain. But generally speaking, this person would be treated in the same way as somebody with the same presentation who was not living with HIV.

As I'm sure, will be the case, this person will be started as soon as possible on antiretroviral therapy and receive stage appropriate syphilis treatment if they haven't already been adequately treated. . Sara Dong: Thank you for humoring my my bonus scenario. No, not at all.

You know, it's a really important one because things have changed a lot in HIV management over the last 30 years and things that we may have reflexively done in the past, um, the weight of evidence has really reassured us, that in the vast majority of cases, that HIV per se needn't alter the way that we approach management of a patient with syphilis.

What I really think is that we have some tools that we know are really useful. So things like partner notification to try and contact sexual partners of people who have potentially been exposed to syphilis to have those people come in for evaluation and treatment. We know that that pays dividends. The problem is that there has historically been underinvestment in the services that underpin those partner notification approaches using disease intervention specialist colleagues.

So, I don't want to abandon the things that we already have that work just because we've been doing them for a long time, but I want to recognize that in order to do those things well, then it requires investment, training and political will. There are also some great opportunities for us in the social media era. For example, disclosure of sexually transmitted infections can be very difficult for some people.

For some, the idea of having a face to face conversation or a telephone call with a sex partner to say, I've been diagnosed with syphilis, you really need to go and get tested and evaluated. Those conversations can be really difficult, but there are now online tools. There are websites and apps where you can enter in anonymously the cell phone or email of a, of a sexual contact who will then receive an anonymous notification to say, you may have been exposed to syphilis.

Please follow up with your healthcare provider. So those are some of the things that we should continue to invest in. Regular testing, so mathematical models have shown that one of the most efficient ways of reducing the burden of untreated syphilis, undiagnosed syphilis, is by more regular testing in people who have increased risk for syphilis infection.

I think it's fair to say that even though we have clear guidelines about, uh, testing for syphilis, that most people aren't being tested with the frequency that they should be tested. So that's a whole long winded way of saying, don't throw the baby out with the bathwater, and then it's kind of gearing me up to talk about doxycycline post exposure prophylaxis, which I love, um, I see where there are huge opportunities for preventing bacterial sexually transmitted infections including syphilis.

And you can't get neurosyphilis if you don't have syphilis. So it sounds as if I'm being facetious and I'm not. It really is acknowledging the potential benefits of the doxycycline post exposure prophylaxis. So this is something that has been on the horizon since about 2018 with the first study that came out of France.

And since then, there have been more studies that have demonstrated in different ways, but have demonstrated the efficacy of 200 milligrams of doxycycline given ideally within 24, but up to 72 hours after condomless sex. And the efficacy is, there's been, depending on the study that you look at, is around a 60 to 70 percent reduction in in bacterial STIs.

And it seems that some of the data that are emerging out of conferences in 2024, such as the CROI conference, suggest that doxycycline PEP is most advantageous in prevention of chlamydia and syphilis and maybe less advantageous in the prevention of gonorrhea infection.

So doxyPEP is something that is really very easy as a provider to provide to patients, DoxyPep is a really great way of providing patients with autonomy so that they're in control of the prevention strategies that they may choose to use in the same way that HIV pre exposure prophylaxis and post exposure prophylaxis, again, puts the autonomy in the hands of the patients and that's something that I encourage in all of my clinical consultations in order that people feel empowered.

They feel like they're making a decision about their own sexual health and well being and I think that doxyPEP is a really great tool to add to that panoply of prevention interventions. It is certainly not a panacea. It's not a cure all. There's worries about antimicrobial resistance both in sexually transmitted infections as well as in other important organisms such as Staph aureus. There's concerns about the effect on the microbiome, for example, and what that might mean.

And then a question that you asked is, how might this affect our diagnostic certainty around neurosyphilis? Is that right? Is that the question?

So, I think it It's possible that you see someone who looks like they've had an adequate serological response to treatment, but they might not have, um, and really the, the RPR is being pushed down by, uh, intermittent use of doxycycline. I mean, that's a real rabbit hole , can make one's headache just to think about it because there are all these counterfactuals to explore.

But I do think that that is something that we need to pay attention to and just be really thoughtful about what intermittent exposure to doxycycline may have done to somebody's serological markers of syphilis.

There was a clinical trial in Kenya that looked at DoxyPep in cisgender women who are currently taking HIV PrEP, and that study did not show a reduction in incident bacterial STI. It's likely that that is, as with many things biomedical, it hinged on adherence to the intervention. Um, and certainly more studies are required in women and studies are also required in heterosexual men or men who have sex with, with women.

That's a group where there's, to my knowledge, a complete absence of evidence to date.

I certainly do that all of the time. I consult with with my peers and senior colleagues. So there's never a point that one has to feel masterful in terms of diagnosis and management of neurological syphilis. It's, it's often not straightforward. And I think consulting with peers is, is incredibly important and helpful. The other point that I would make is the history is really important when thinking about neurosyphilis.

Often we have an expectation that if a patient has troublesome symptoms, that they will volunteer those symptoms. That isn't always the case. So I think if you're concerned that someone has neurosyphilis, then inquire specifically about changes in memory. If the individual is struggling to be able to provide you with that information, ask if you have permission to speak with a family member, because that corroborative history can be really helpful.

People tend to tell you when they have visual changes, because it's so alarming. People may not tell you when they have mild tinnitus or hearing loss, So when, when you see somebody who with syphilis, please ask specifically whether they've noticed any change in their hearing or whether they've had new onset tinnitus, because that may be the only clue that the, that the individual actually has a neurological syphilis. I think that probably the take home, I think we need much more data.

We need clinical trials directly comparing different treatment modalities for neurosyphilis. Do we really need 10 days of IV penicillin? Could we achieve the same goal with, with less? Um, I think there are many, many unanswered questions and ongoing research is going to help us to answer some of, some of those questions. And I'd really like to finish with two thank yous. The first is to my friends and colleagues, Sue Tuddenham and Khalil Ghanem, who are co authors on this neurosyphilis review.

I couldn't ask for better colleagues than that pair. I say that pair in a sort of smiling way because they'll appreciate what I mean. They're, they're wonderful. You know, I learn all the time from them and, you know, this review was really a joint exercise between the three of us and so I want to both thank and acknowledge their kindness, support, expertise, sense of humor. I could go on, but won't.

And then the, the final word really is thank you to all of the patients that I have had the privilege to work with over the last two and a half decades. I love my job. I love being a physician and I love learning from my patients and it's endlessly humbling in a really positive way. So that's how I'd like to finish thanking all of those people who have trusted me enough to allow me to be involved in their health care.

Febrile is produced with support from the Infectious Diseases Society of America or IDSA. Please reach out if you have any suggestions for future shows or want to be more involved with Febrile. Thanks for listening, stay safe, and I'll see you next time.