1 00:00:00,001 --> 00:00:03,470 Sara Dong: Hi 2 00:00:05,950 --> 00:00:10,410 everyone, welcome to Febrile, a cultured podcast about all things infectious disease. 3 00:00:10,800 --> 00:00:15,610 We use consult questions to dive into ID clinical reasoning, diagnostics, and antimicrobial management. 4 00:00:15,670 --> 00:00:18,139 I'm Sara Dong, your host and a MedPeds ID doc. 5 00:00:18,250 --> 00:00:20,659 I am excited to introduce our guest today, Dr. 6 00:00:20,659 --> 00:00:21,540 Matthew Hamill. 7 00:00:21,760 --> 00:00:26,200 Matthew is a UK trained physician specializing in sexually transmitted infections. 8 00:00:26,769 --> 00:00:29,659 He is an assistant professor of medicine in the Division of I. 9 00:00:29,659 --> 00:00:29,960 D. 10 00:00:29,960 --> 00:00:31,669 at Johns Hopkins in Baltimore. 11 00:00:32,170 --> 00:00:36,790 He also serves as clinical chief for STI services at the Baltimore City Health Department. 12 00:00:36,850 --> 00:00:42,160 He provides patient care for people with HIV and other STIs as well as those at risk for infection. 13 00:00:42,560 --> 00:00:49,880 His research focuses on harnessing diagnostic development to improve HIV STI diagnosis, prevention, and linkage to care. 14 00:00:50,229 --> 00:00:51,269 Thanks for being here! 15 00:00:51,660 --> 00:00:52,680 Matthew Hamill: Oh, my pleasure, Sara. 16 00:00:52,680 --> 00:00:53,839 Thank you for asking me. 17 00:00:54,940 --> 00:01:06,770 Sara Dong: So before we chat about the article, I always ask, as everyone's favorite cultured podcast, we like to ask our guests to share a little piece of culture, really just something non medical that makes you happy. 18 00:01:07,639 --> 00:01:08,239 Matthew Hamill: Yeah. 19 00:01:08,380 --> 00:01:12,500 There are several things that make me happy, but particularly at this time of year in the spring. 20 00:01:12,580 --> 00:01:26,740 I have this tiny, uh, postage stamp sized garden at the back of my house in Baltimore City, and just being out there and watching the flowers come out and the birds start to collect, um, some nesting materials. 21 00:01:27,099 --> 00:01:29,829 That gives me a huge amount of pleasure at this time of year. 22 00:01:29,829 --> 00:01:36,240 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. 23 00:01:36,704 --> 00:01:37,354 Sara Dong: I love it. 24 00:01:37,384 --> 00:01:37,734 Yeah. 25 00:01:37,734 --> 00:01:39,004 It is the perfect time of year. 26 00:01:39,004 --> 00:01:43,774 I just went and saw a ton of tulips and daffodils last weekend. 27 00:01:44,204 --> 00:01:45,505 Just nice to be outside. 28 00:01:45,934 --> 00:01:46,595 Matthew Hamill: It's really nice. 29 00:01:47,324 --> 00:01:47,535 Yeah. 30 00:01:47,535 --> 00:01:52,464 It's kind of hopeful and optimistic and, I can never really remember where I planted things. 31 00:01:53,755 --> 00:01:56,184 So it's like each spring is a, is an adventure. 32 00:01:57,379 --> 00:01:57,689 Sara Dong: Yes. 33 00:01:58,489 --> 00:02:03,139 Well, we are super grateful to have you here for the latest STAR episode. 34 00:02:03,139 --> 00:02:09,389 So these are focusing on the state of the art reviews and you and your coauthors worked on one related to neurosyphilis. 35 00:02:10,039 --> 00:02:22,359 So we actually have a couple of clinical scenarios that we'll chat about, but I wanted to pause first to just allow you to have a chance to give a quick introduction to the topic and or things that sort of came up as you, you all were crafting this. 36 00:02:23,194 --> 00:02:38,814 Matthew Hamill: In general terms, when we think about syphilis, there are several things that occupy my mind a lot of the time as I spend a fair amount of my professional life either treating patients with syphilis or providing advice to clinical colleagues. 37 00:02:39,224 --> 00:02:46,254 I think a couple of things that are just worth pointing out are the inexorable increases in syphilis diagnosis in the United States. 38 00:02:46,284 --> 00:02:48,074 So we're looking at all stage syphilis. 39 00:02:48,104 --> 00:02:54,784 There's been an almost 80 percent increase in all stage syphilis diagnosis in the, in the last five years. 40 00:02:55,134 --> 00:03:11,844 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. 41 00:03:12,104 --> 00:03:23,404 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. 42 00:03:23,404 --> 00:03:32,124 And sometimes I talk with clinical colleagues outside of infectious diseases and they'll say, really syphilis still a thing in 2024? 43 00:03:32,554 --> 00:03:41,689 Um, and I think there are some perceptions that syphilis is an infection assigned to history, but unfortunately, that's absolutely not the case. 44 00:03:42,699 --> 00:03:48,289 In terms of neurosyphilis or neurological syphilis, I'll use the two terms interchangeably. 45 00:03:48,609 --> 00:03:53,329 The question about the epidemiology of, uh, of neurological syphilis is a great one. 46 00:03:53,479 --> 00:04:04,694 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. 47 00:04:05,124 --> 00:04:18,009 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. 48 00:04:18,009 --> 00:04:27,457 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. 49 00:04:29,527 --> 00:04:36,307 Sara Dong: Um, all right, so I have a couple of clinical calls from your colleagues, so we'll start with our first one. 50 00:04:36,897 --> 00:04:37,017 Matthew Hamill: Great. 51 00:04:37,677 --> 00:04:40,907 Sara Dong: You get a consult call for a patient. 52 00:04:41,087 --> 00:04:42,717 This is a 50 year old male. 53 00:04:42,767 --> 00:04:49,277 He has a history of hypertension, diabetes, and coronary artery disease who came in with behavioral changes. 54 00:04:49,547 --> 00:04:54,707 The family tells you and the other clinician that he has been really irritable. 55 00:04:54,717 --> 00:04:59,947 He's actually been almost hostile over the past couple of months, which is really out of character for him. 56 00:04:59,947 --> 00:05:03,712 He has had some headaches and just challenges sleeping. 57 00:05:03,722 --> 00:05:14,962 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. 58 00:05:15,022 --> 00:05:20,172 And today though, he was brought in more urgently because of an episode of speech difficulty. 59 00:05:20,867 --> 00:05:24,407 On his labs, we know that his routine labs are normal. 60 00:05:24,457 --> 00:05:31,867 They sent HIV and hepatitis screens, which are negative, but we already know that he has a positive RPR from that initial blood work. 61 00:05:32,647 --> 00:05:35,127 Um, this case is obviously not meant to be a mystery. 62 00:05:35,127 --> 00:05:37,897 Our, our listeners kind of already know we're talking about neurosyphilis. 63 00:05:38,047 --> 00:05:54,432 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. 64 00:05:54,962 --> 00:05:56,022 Matthew Hamill: Yeah, absolutely right. 65 00:05:56,022 --> 00:06:09,102 And I completely agree with that high level summary that, um, is there are, of course, textbooks, examples of particular, uh, neurological syndromes associated with neurosyphilis, but there's overlap. 66 00:06:09,132 --> 00:06:17,337 I think that's one of the important points to make, is that there are overlap between some of the different neurological manifestations. 67 00:06:17,827 --> 00:06:37,167 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. 68 00:06:37,477 --> 00:06:46,387 So people will have been exposed often to antimicrobials that will have some activity against Treponema pallidum, the bacteria that causes syphilis. 69 00:06:46,667 --> 00:06:57,227 So I think that probably in part explains why the natural history of neurological syphilis is somewhat different compared to historical accounts. 70 00:06:57,747 --> 00:06:59,897 But with all things syphilis, the way that I 71 00:07:01,212 --> 00:07:14,792 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. 72 00:07:15,382 --> 00:07:19,512 And for neurological syphilis, we can apply this same rationale. 73 00:07:19,682 --> 00:07:27,952 So we can think about some of the early neurological manifestations, and then we can think of late neurological manifestations. 74 00:07:28,532 --> 00:07:43,572 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. 75 00:07:43,922 --> 00:07:52,362 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. 76 00:07:52,362 --> 00:07:57,082 You can see it in people with primary disease, with secondary syphilis, etc. 77 00:07:57,732 --> 00:08:12,087 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. 78 00:08:12,357 --> 00:08:26,887 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. 79 00:08:27,147 --> 00:08:34,042 So sometimes early neurological syphilis can be very similar to other forms of meningitis. 80 00:08:34,092 --> 00:08:44,622 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. 81 00:08:44,642 --> 00:08:51,992 So the meningovascular, parenchymatous, and then those that we see with gummatous disease. 82 00:08:52,362 --> 00:08:59,882 So the meningovascular manifestations are similar to the ones that I've just talked about where people will present with a stroke. 83 00:08:59,932 --> 00:09:07,022 They may present with spinal cord disease where there's been vascular involvement of the vessels to the spinal cord. 84 00:09:07,582 --> 00:09:12,572 And this can happen anything from 5 to 15 years after treatment. 85 00:09:13,012 --> 00:09:22,712 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. 86 00:09:23,312 --> 00:09:46,032 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. 87 00:09:46,032 --> 00:09:50,722 And that's where people will present with posterior columns, uh, signs and symptoms. 88 00:09:51,417 --> 00:09:59,837 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. 89 00:10:00,297 --> 00:10:04,627 And this is where somebody will present with features of a space occupying lesion. 90 00:10:05,027 --> 00:10:14,112 And then just to add a couple of additional thoughts, is that ocular and otic syphilis, so syphilis affecting the eye and the ear. 91 00:10:14,462 --> 00:10:18,972 Again, that can occur at any stage of syphilis infection. 92 00:10:19,492 --> 00:10:29,932 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. 93 00:10:30,292 --> 00:10:46,672 Sara Dong: And that's such a good reminder and just to say again, like, like you've been pointing out that neurosyphilis as we think of it can really occur at any stage and I made it pretty obvious for this patient that they would benefit from an LP and we're going to come back to the results of that. 94 00:10:46,722 --> 00:11:02,092 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. 95 00:11:02,102 --> 00:11:07,342 And I actually was hoping before we go back to our patient case that we talk about those scenarios. 96 00:11:07,372 --> 00:11:13,952 When are scenarios that an asymptomatic patient with serologic evidence of syphilis should get a lumbar puncture? 97 00:11:14,122 --> 00:11:15,852 Matthew Hamill: Thank you for asking that question, Sara. 98 00:11:16,032 --> 00:11:24,952 And you're right, you have a very good idea of what my weeks look like when I'm discussing, um, discussing management of syphilis with my expert colleagues 99 00:11:25,002 --> 00:11:31,202 . There are some guidelines that, that help us and I think the CDC guidelines are really very helpful in that respect. 100 00:11:31,762 --> 00:11:51,852 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. 101 00:11:51,852 --> 00:12:00,262 When we are straightforward about what we know and we're also straightforward about the uncertainties in terms of diagnostic. 102 00:12:00,262 --> 00:12:08,282 How certain are we in our, in our diagnosis and how much evidence is there to support a particular management approach? 103 00:12:08,862 --> 00:12:19,882 So all of that said, I think the people with neurological signs and symptoms of syphilis, absolutely, lumbar puncture is indicated and really helpful. 104 00:12:20,322 --> 00:12:27,092 The exception is in people who have only ocular or otic manifestations. 105 00:12:27,092 --> 00:12:42,157 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. 106 00:12:42,987 --> 00:12:58,267 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. 107 00:12:58,297 --> 00:13:07,757 And the first of those is when somebody has a sustained, and I stress the sustained, increase in RPR or VDRL titer. 108 00:13:07,777 --> 00:13:10,177 I'll use RPR just for efficiency sake. 109 00:13:10,467 --> 00:13:24,167 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. 110 00:13:24,927 --> 00:13:30,277 And the individual patient has had no opportunity for reinfection. 111 00:13:30,837 --> 00:13:45,627 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. 112 00:13:45,627 --> 00:13:49,817 So that's one situation where we should consider a CSF examination. 113 00:13:49,817 --> 00:13:59,327 And the reason for that is that they may have undiagnosed asymptomatic neurosyphilis, and that's what's driving this increase in RPR. 114 00:14:00,547 --> 00:14:14,497 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. 115 00:14:14,567 --> 00:14:21,797 So that's another group where one can have a discussion around the pros and cons of CSF examination. 116 00:14:22,467 --> 00:14:31,277 And then the final group are those who have evidence of tertiary disease, so whether that's gummatous disease or evidence of cardiovascular syphilis. 117 00:14:32,442 --> 00:14:42,672 Sara Dong: And I'll point out for figure two, there's a nice flowchart for this, but also if they are checking out the CDC STI guidelines also find these. 118 00:14:42,802 --> 00:14:44,632 So thank you for walking through that. 119 00:14:45,152 --> 00:14:49,982 Back to our patient, you learn that the CSF on the LP is clear. 120 00:14:50,352 --> 00:14:52,232 There was a lymphocytic pleocytosis. 121 00:14:52,747 --> 00:14:56,887 The white blood cells are 50 with a lymphocyte percentage of 80%. 122 00:14:57,217 --> 00:15:00,487 Total protein was 50 milligrams per deciliter. 123 00:15:00,587 --> 00:15:03,097 A CSF VDRL is pending. 124 00:15:03,657 --> 00:15:13,947 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. 125 00:15:14,367 --> 00:15:17,157 You know, does the CSF profile seem typical? 126 00:15:17,187 --> 00:15:20,877 What are the best CSF testing options for diagnosing neurosyphilis? 127 00:15:22,257 --> 00:15:23,007 Matthew Hamill: Yeah, thank you. 128 00:15:23,067 --> 00:15:42,377 So, the information that we have so far, so we have the clinical scenario, we have a sense of a pretest probability of, of this being, uh, neurological syphilis, and the, the results that we have available so far are consistent with neurosyphilis, particularly with that raised, uh, white cell count. 129 00:15:42,387 --> 00:15:52,652 There's no question that that is an increased, uh, white cell count, and particularly with the lymphocytic predominance, I think you said it was 80 percent lymphocytes. 130 00:15:52,992 --> 00:16:00,732 So that would be my trigger to initiate treatment and not waiting for any other laboratory results to come through. 131 00:16:01,132 --> 00:16:10,472 I think the CSF protein is probably the least helpful marker that we, that we routinely request when we're investigating neurological syphilis. 132 00:16:10,782 --> 00:16:17,122 And the reason that I say that is that it can be increased in many other conditions. 133 00:16:17,152 --> 00:16:19,872 It can be normal in neurosyphilis. 134 00:16:19,892 --> 00:16:27,362 So whilst I don't dismiss the CSF protein, it's probably the marker that I pay least attention to. 135 00:16:27,762 --> 00:16:47,317 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. 136 00:16:48,057 --> 00:16:51,637 But the white count, I think it's a great marker. 137 00:16:51,647 --> 00:16:53,427 It's really quite sensitive. 138 00:16:54,672 --> 00:17:06,012 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. 139 00:17:06,742 --> 00:17:28,847 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. 140 00:17:29,392 --> 00:17:46,342 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. 141 00:17:46,412 --> 00:17:54,002 In the US, we use the CSF VDRL and that is a very, very useful test. 142 00:17:54,012 --> 00:18:00,732 If it's positive, then I think you can feel very confident that you, you've clinched your diagnosis. 143 00:18:00,992 --> 00:18:07,612 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. 144 00:18:07,612 --> 00:18:14,382 If it is, then one can't really interpret the VDRL because there may be spillover from, from the blood compartment. 145 00:18:14,382 --> 00:18:22,522 But if you have clear CSF and you have a positive VDRL, then I think that that is a anchor of our neurosyphilis diagnosis. 146 00:18:23,112 --> 00:18:32,962 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. 147 00:18:33,352 --> 00:18:39,432 It probably doesn't perform as well as a VDRL, but it will give you comparable results. 148 00:18:39,802 --> 00:18:46,952 In the US, we don't look at TPPA, for example, uh, in the CSF, which is done in other settings. 149 00:18:47,052 --> 00:18:51,332 The other serological test that we occasionally use is the FTA. 150 00:18:51,412 --> 00:19:13,937 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. 151 00:19:14,097 --> 00:19:36,482 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. 152 00:19:36,512 --> 00:19:39,412 In CSF, it doesn't perform as well. 153 00:19:39,412 --> 00:19:51,922 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. 154 00:19:52,507 --> 00:20:06,297 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. 155 00:20:06,767 --> 00:20:21,452 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. 156 00:20:21,752 --> 00:20:39,867 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. 157 00:20:40,217 --> 00:20:45,967 Sara Dong: We'll say this patient's CSF VDRL was positive, confirming what we already thought for our diagnosis. 158 00:20:46,937 --> 00:20:53,847 The patient is placed on first line therapy for neurosyphilis, so aqueous penicillin G is on a continuous infusion. 159 00:20:54,327 --> 00:21:00,757 Based on guidance, the plan, we talked about 10 vs 14 days, and the plan is to do a 10 day course. 160 00:21:01,607 --> 00:21:11,987 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. 161 00:21:12,007 --> 00:21:16,517 But your inquisitive medical student on the team asks some follow up questions. 162 00:21:17,102 --> 00:21:25,842 "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". 163 00:21:26,882 --> 00:21:35,452 Matthew Hamill: It's great having astute fellows and medical students, um, isn't it, who, um, who appropriately ask challenging questions. 164 00:21:35,462 --> 00:21:52,487 So to try and unpack that a little bit and take those, uh, alternative treatments one by one, and there are some data, but there are not many data supporting the use of ceftriaxone in somebody who is unable or unwilling to use IV penicillin. 165 00:21:53,097 --> 00:22:03,227 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. 166 00:22:03,357 --> 00:22:10,817 And many of us use that and there is quite a lot of clinical experience about using ceftriaxone in the treatment of neurosyphilis. 167 00:22:11,837 --> 00:22:14,647 The, the trial data just really aren't there. 168 00:22:14,647 --> 00:22:23,697 I mean, there are some small studies and there are some comparative studies, but the evidence base around ceftriaxone is quite limited. 169 00:22:24,227 --> 00:22:33,367 I would add at this point that in, in pregnancy, then the only treatment that is recommended by the CDC is, is penicillin. 170 00:22:33,507 --> 00:22:44,617 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. 171 00:22:44,847 --> 00:22:48,877 So I think ceftriaxone has promise, you know, it is something that's used. 172 00:22:48,887 --> 00:22:51,097 It can be given on an outpatient basis. 173 00:22:51,767 --> 00:22:57,187 If somebody, if you can find a clinical service that would give you your intramuscular injection at a weekend. 174 00:22:57,197 --> 00:23:02,417 So there are some advantages practically for patients to receiving that treatment modality. 175 00:23:03,027 --> 00:23:10,417 In terms of doxycycline, that is not something that is currently considered appropriate in a U. 176 00:23:10,417 --> 00:23:10,747 S. 177 00:23:10,877 --> 00:23:11,517 setting. 178 00:23:11,917 --> 00:23:20,167 So I would reply to the medical student learner that that is something that I would not use in this setting. 179 00:23:20,327 --> 00:23:46,212 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. 180 00:23:46,567 --> 00:23:47,987 Sara Dong: Thank you for walking through those. 181 00:23:48,037 --> 00:23:52,652 And fortunately, our patient is improving, is doing better. 182 00:23:53,242 --> 00:23:56,082 And I actually wanted to talk about one other clinical scenario. 183 00:23:56,082 --> 00:24:00,032 So say you have a clinician who's calling you from a primary care center. 184 00:24:00,222 --> 00:24:08,022 They have a patient in their practice with a new diagnosis of HIV and on those initial evaluation labs has a positive RPR. 185 00:24:08,622 --> 00:24:15,652 So they want to know whether this patient who is asymptomatic needs to be referred for LP, um, and a CSF evaluation. 186 00:24:15,987 --> 00:24:21,327 Matthew Hamill: Are you able to provide me with, I mean, I kind of have an answer for you, but I'm going to drag it out. 187 00:24:21,527 --> 00:24:27,557 I'm going to drag it out a little bit for the sake of suspense. 188 00:24:27,787 --> 00:24:36,777 Um, um, do you have any other information on this person who's newly diagnosed with HIV, like their CD4 count, for example? 189 00:24:37,847 --> 00:24:41,777 Sara Dong: Um, let's say that their CD4 count's like 400. 190 00:24:42,227 --> 00:24:42,747 Matthew Hamill: Okay. 191 00:24:43,257 --> 00:24:45,307 And the RPR titer? 192 00:24:46,467 --> 00:24:50,377 Sara Dong: Uh, one to, oh, I have to do the math in my head. 193 00:24:52,127 --> 00:24:54,387 Oh, I did, I didn't a make up an RPR titer. 194 00:24:54,387 --> 00:24:55,897 Matthew Hamill: So what about one in 128? 195 00:24:55,957 --> 00:24:56,627 Sara Dong: Let's do that. 196 00:24:57,057 --> 00:24:57,347 Matthew Hamill: Yeah. 197 00:24:57,347 --> 00:24:57,687 Okay. 198 00:24:57,877 --> 00:24:58,277 Okay. 199 00:24:58,477 --> 00:25:13,407 In this context, generally speaking, so you have somebody newly diagnosed with HIV, they have evidence of syphilis, presumably they have a positive treponemal test and then as well to provide serological confirmation. 200 00:25:13,407 --> 00:25:37,647 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 201 00:25:37,647 --> 00:25:52,037 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. 202 00:25:52,137 --> 00:25:54,477 The CDC guidelines, again, are really helpful here. 203 00:25:54,477 --> 00:26:07,367 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. 204 00:26:08,432 --> 00:26:10,182 I mean, of course, there are some exceptions. 205 00:26:10,182 --> 00:26:31,522 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 206 00:26:31,582 --> 00:26:42,922 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. 207 00:26:42,922 --> 00:26:51,182 But generally speaking, this person would be treated in the same way as somebody with the same presentation who was not living with HIV. 208 00:26:52,437 --> 00:27:03,887 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. 209 00:27:05,297 --> 00:27:08,487 . Sara Dong: Thank you for humoring my my bonus scenario. 210 00:27:10,217 --> 00:27:10,917 Matthew Hamill: No, not at all. 211 00:27:11,557 --> 00:27:35,637 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. 212 00:27:36,057 --> 00:27:45,117 Sara Dong: Are there new strategies, either that you think maybe folks aren't familiar with yet, or that are on the horizon for thinking about prevention of syphilis. 213 00:27:45,117 --> 00:27:50,197 And this can be more sort of broadly, um, particularly for, you know, trainees and listeners to keep an eye out for. 214 00:27:50,527 --> 00:27:58,457 And I think one question I would love to hear your thoughts is how you think use of DoxyPEP may impact neurosyphilis. 215 00:27:58,747 --> 00:28:03,567 I know there's not going to be a super clear answer, but I'd love to hear insights that you might have. 216 00:28:03,767 --> 00:28:04,187 Matthew Hamill: Yeah. 217 00:28:04,187 --> 00:28:06,267 I mean, I certainly have a lot to say about it. 218 00:28:06,917 --> 00:28:10,847 How well informed it is remains to be seen. 219 00:28:10,847 --> 00:28:32,372 Um, but, um, I think it's a really important question and I think that the data that I very briefly described at the beginning of our conversation about these really alarming increases in all stage syphilis and in congenital syphilis tells me that our current approaches are failing. 220 00:28:33,392 --> 00:28:40,082 And we can't keep doing the same thing and hope that magically this problem will improve. 221 00:28:40,322 --> 00:28:46,622 What I really think is that we have some tools that we know are really useful. 222 00:28:46,982 --> 00:28:59,417 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. 223 00:28:59,427 --> 00:29:01,487 We know that that pays dividends. 224 00:29:01,807 --> 00:29:12,087 The problem is that there has historically been underinvestment in the services that underpin those partner notification approaches using disease intervention specialist colleagues. 225 00:29:12,847 --> 00:29:28,587 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. 226 00:29:29,537 --> 00:29:35,267 There are also some great opportunities for us in the social media era. 227 00:29:35,737 --> 00:29:42,107 For example, disclosure of sexually transmitted infections can be very difficult for some people. 228 00:29:42,367 --> 00:29:52,707 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. 229 00:29:52,967 --> 00:29:57,752 Those conversations can be really difficult, but there are now online tools. 230 00:29:57,752 --> 00:30:11,982 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. 231 00:30:12,032 --> 00:30:14,532 Please follow up with your healthcare provider. 232 00:30:15,562 --> 00:30:19,402 So those are some of the things that we should continue to invest in. 233 00:30:20,072 --> 00:30:36,872 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. 234 00:30:37,222 --> 00:30:48,422 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. 235 00:30:48,852 --> 00:31:11,237 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. 236 00:31:11,587 --> 00:31:14,487 And you can't get neurosyphilis if you don't have syphilis. 237 00:31:14,587 --> 00:31:19,637 So it sounds as if I'm being facetious and I'm not. 238 00:31:19,917 --> 00:31:26,127 It really is acknowledging the potential benefits of the doxycycline post exposure prophylaxis. 239 00:31:26,387 --> 00:31:32,907 So this is something that has been on the horizon since about 2018 with the first study that came out of France. 240 00:31:32,937 --> 00:31:49,107 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. 241 00:31:49,777 --> 00:32:00,492 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. 242 00:32:00,832 --> 00:32:22,672 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. 243 00:32:23,872 --> 00:32:47,387 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, 244 00:32:48,687 --> 00:32:57,792 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. 245 00:32:57,792 --> 00:33:09,882 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. 246 00:33:09,882 --> 00:33:11,352 It is certainly not a panacea. 247 00:33:11,352 --> 00:33:12,682 It's not a cure all. 248 00:33:13,602 --> 00:33:22,542 There's worries about antimicrobial resistance both in sexually transmitted infections as well as in other important organisms such as Staph aureus. 249 00:33:23,262 --> 00:33:27,922 There's concerns about the effect on the microbiome, for example, and what that might mean. 250 00:33:28,417 --> 00:33:34,277 And then a question that you asked is, how might this affect our diagnostic certainty around neurosyphilis? 251 00:33:34,287 --> 00:33:34,937 Is that right? 252 00:33:34,947 --> 00:33:36,007 Is that the question? 253 00:33:36,357 --> 00:33:36,657 Sara Dong: Yeah. 254 00:33:36,657 --> 00:33:42,807 Well, really just any, either diagnosis or you kind of alluding to people, people's questions about resistance. 255 00:33:43,117 --> 00:33:43,527 Matthew Hamill: Yeah. 256 00:33:43,547 --> 00:33:46,757 And I think we, the, the honest answer is we don't know yet. 257 00:33:47,677 --> 00:34:09,157 I mean, my worry is that, is that we'll see a blunting of, So, let's say somebody is taking DoxyPep, they acquire syphilis, DoxyPep may abrogate their clinical presentation so that they may not present in a way that they might have done without the DoxyPep, and it might blunt their RPR response. 258 00:34:09,167 --> 00:34:25,127 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. 259 00:34:25,127 --> 00:34:32,732 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. 260 00:34:32,732 --> 00:34:45,172 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. 261 00:34:45,822 --> 00:34:46,032 Sara Dong: Yeah. 262 00:34:46,842 --> 00:34:49,882 Well, I thank you also just for talking in general. 263 00:34:49,912 --> 00:34:56,422 I realize we may not have actually talked or had a episode specifically talking about DoxyPep and what it is. 264 00:34:57,192 --> 00:34:59,092 And you sort of by default talked through that. 265 00:34:59,092 --> 00:35:10,402 So I thank you because, um, I think the take home on DoxyPep though is that this is incredible, cutting down diagnoses by 70 percent ish is pretty amazing. 266 00:35:10,402 --> 00:35:11,472 Matthew Hamill: Yeah, I agree with you. 267 00:35:11,472 --> 00:35:12,552 It really is. 268 00:35:12,562 --> 00:35:19,442 It's one of the most exciting interventions that I've seen in 25 years of, of working within sexually transmitted infections. 269 00:35:20,032 --> 00:35:21,842 There were a couple of really important caveats. 270 00:35:21,842 --> 00:35:28,622 And so I would say that the populations in whom we have evidence of efficacy are limited. 271 00:35:28,672 --> 00:35:33,582 So we have evidence of efficacy in men who have sex with men and in transgender women. 272 00:35:33,942 --> 00:35:40,412 We don't have evidence of efficacy in cisgender women or in men who have sex with women only. 273 00:35:40,432 --> 00:35:56,032 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. 274 00:35:56,317 --> 00:36:02,827 It's likely that that is, as with many things biomedical, it hinged on adherence to the intervention. 275 00:36:03,077 --> 00:36:11,697 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. 276 00:36:11,697 --> 00:36:16,037 That's a group where there's, to my knowledge, a complete absence of evidence to date. 277 00:36:17,472 --> 00:36:35,812 Sara Dong: So we'll wrap up by just giving a moment, if there's, you know, a specific take home point that you want to make sure that we emphasize, or if there's any other additional facts or concepts that you think we missed that would be important for your trainees and other listeners to know about neurosyphilis. 278 00:36:36,672 --> 00:36:38,092 Matthew Hamill: We covered quite a lot of ground. 279 00:36:39,772 --> 00:36:40,952 At least I've talked a lot. 280 00:36:42,052 --> 00:36:45,392 Those two things are, uh, mean the same thing. 281 00:36:45,812 --> 00:36:50,152 But to summarize, I would like to reinforce a couple of points. 282 00:36:50,152 --> 00:36:53,882 And the first is that syphilis is still with us. 283 00:36:53,892 --> 00:36:55,012 It's prevalent. 284 00:36:55,092 --> 00:36:56,172 It's increasing. 285 00:36:56,972 --> 00:36:57,742 That's number one. 286 00:36:57,742 --> 00:37:06,362 Number two is if neurosyphilis was an easy diagnostic category, we probably wouldn't be having this conversation. 287 00:37:06,722 --> 00:37:15,382 Um, so what I mean by that is ask if you're not sure, ask somebody who has maybe a little more experience. 288 00:37:15,712 --> 00:37:17,552 I certainly do that all of the time. 289 00:37:17,552 --> 00:37:20,712 I consult with with my peers and senior colleagues. 290 00:37:21,042 --> 00:37:28,097 So there's never a point that one has to feel masterful in terms of diagnosis and management of neurological syphilis. 291 00:37:28,107 --> 00:37:29,967 It's, it's often not straightforward. 292 00:37:29,967 --> 00:37:34,587 And I think consulting with peers is, is incredibly important and helpful. 293 00:37:35,147 --> 00:37:43,297 The other point that I would make is the history is really important when thinking about neurosyphilis. 294 00:37:43,587 --> 00:37:52,327 Often we have an expectation that if a patient has troublesome symptoms, that they will volunteer those symptoms. 295 00:37:52,327 --> 00:37:53,517 That isn't always the case. 296 00:37:53,527 --> 00:38:01,262 So I think if you're concerned that someone has neurosyphilis, then inquire specifically about changes in memory. 297 00:38:02,272 --> 00:38:12,682 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. 298 00:38:13,442 --> 00:38:17,702 People tend to tell you when they have visual changes, because it's so alarming. 299 00:38:17,962 --> 00:38:41,057 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. 300 00:38:41,567 --> 00:38:45,147 I think that probably the take home, I think we need much more data. 301 00:38:45,217 --> 00:38:51,592 We need clinical trials directly comparing different treatment modalities for neurosyphilis. 302 00:38:51,622 --> 00:38:54,792 Do we really need 10 days of IV penicillin? 303 00:38:54,812 --> 00:38:57,922 Could we achieve the same goal with, with less? 304 00:38:57,952 --> 00:39:05,332 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. 305 00:39:05,332 --> 00:39:09,822 And I'd really like to finish with two thank yous. 306 00:39:09,932 --> 00:39:17,632 The first is to my friends and colleagues, Sue Tuddenham and Khalil Ghanem, who are co authors on this neurosyphilis review. 307 00:39:18,402 --> 00:39:21,042 I couldn't ask for better colleagues than that pair. 308 00:39:21,342 --> 00:39:23,812 I say that pair in a sort of smiling way because 309 00:39:26,092 --> 00:39:27,332 they'll appreciate what I mean. 310 00:39:27,332 --> 00:39:28,852 They're, they're wonderful. 311 00:39:28,882 --> 00:39:42,202 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. 312 00:39:42,212 --> 00:39:43,422 I could go on, but won't. 313 00:39:43,912 --> 00:39:55,177 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. 314 00:39:56,017 --> 00:39:57,327 I love my job. 315 00:39:57,327 --> 00:40:04,837 I love being a physician and I love learning from my patients and it's endlessly humbling in a really positive way. 316 00:40:04,837 --> 00:40:11,777 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. 317 00:40:12,862 --> 00:40:14,742 Sara Dong: Thanks for listening to this STAR episode. 318 00:40:14,782 --> 00:40:23,852 You can find the State of the Art Review Neurosyphilis from Clinical Infectious Diseases linked in the Consult Notes as well as the episode information. 319 00:40:24,752 --> 00:40:26,632 Please check out our website, febrilepodcast. 320 00:40:26,902 --> 00:40:32,342 com, where you'll find the Consult Notes, which are written supplements of the episodes with links to references. 321 00:40:33,012 --> 00:40:36,012 Our library of ID infographics and a link to our merch store. 322 00:40:37,712 --> 00:40:42,312 Febrile is produced with support from the Infectious Diseases Society of America or IDSA. 323 00:40:42,652 --> 00:40:47,162 Please reach out if you have any suggestions for future shows or want to be more involved with Febrile. 324 00:40:47,622 --> 00:40:50,122 Thanks for listening, stay safe, and I'll see you next time.