1 00:00:02,940 --> 00:00:03,660 Sara Dong: Hi everyone. 2 00:00:03,930 --> 00:00:07,970 Welcome to Febrile, a cultured podcast about all things infectious disease. 3 00:00:08,980 --> 00:00:14,020 We use consult questions to dive into ID clinical reasoning, diagnostics, and antimicrobial management. 4 00:00:14,930 --> 00:00:17,559 I'm Sara Dong, your host and a MedPeds ID doc. 5 00:00:18,000 --> 00:00:20,569 We are back with a Febrile StAR episode. 6 00:00:20,830 --> 00:00:25,240 These are featuring topics and authors from the CID journal State of the Art Reviews. 7 00:00:25,740 --> 00:00:36,929 This is our fourth of four launch episodes, so please make sure you listen to the past three episodes as well as number 97 for a quick introduction from the editors of these reviews. 8 00:00:37,860 --> 00:00:40,349 All right, so I'll introduce our guest stars today. 9 00:00:41,360 --> 00:00:41,709 Dr. 10 00:00:41,709 --> 00:00:49,730 Karen Block is a professor of medicine and associate clinical director of the division of infectious diseases at Vanderbilt University Medical Center. 11 00:00:50,500 --> 00:00:54,690 Her clinical and research interests revolve around infections of the central nervous system. 12 00:00:55,419 --> 00:01:03,139 She is a coauthor on the IDSA guidelines for the management of encephalitis and the international encephalitis consortium consensus statement. 13 00:01:03,279 --> 00:01:04,849 Karen Bloch: Hi, I'm Karen Bloch. 14 00:01:04,900 --> 00:01:08,220 Thank you so much for having us on the Febrile podcast. 15 00:01:08,220 --> 00:01:10,279 I'm really excited to be here today, Sara. 16 00:01:10,869 --> 00:01:11,169 Sara Dong: Dr. 17 00:01:11,169 --> 00:01:16,914 Carol Glaser is the Medical Officer for the California Department of Public Health, Center for Laboratory Sciences. 18 00:01:17,615 --> 00:01:17,905 Dr. 19 00:01:17,905 --> 00:01:25,595 Glaser first trained in veterinary medicine and then attended medical school, followed by a pediatric residency and a pediatric ID fellowship. 20 00:01:26,474 --> 00:01:36,574 Her clinical and research interests focus on the diagnosis of encephalitis and other infectious related neurologic conditions, such as acute flaccid myelitis, as well as zoonotic infections. 21 00:01:36,675 --> 00:01:38,214 Carol Glaser: Hi, I'm Carol Glaser. 22 00:01:38,824 --> 00:01:44,035 Very excited also to be here to talk about one of my most favorite subjects, encephalitis. 23 00:01:44,134 --> 00:01:45,304 So thank you for inviting me. 24 00:01:46,035 --> 00:01:46,494 Sara Dong: Dr. 25 00:01:46,494 --> 00:01:56,394 Arun Venkatesan is a professor at the Johns Hopkins University School of Medicine in the Department of Neurology, where he serves as director of the Johns Hopkins Encephalitis Center. 26 00:01:56,885 --> 00:02:06,164 His interests focus on developing biomarkers of infectious and autoimmune encephalitis and studying mechanisms of CNS injury in the setting of infection and neuroinflammation. 27 00:02:07,250 --> 00:02:09,040 Arun Venkatesan: Hi Sara, Arun Venkatesan here. 28 00:02:09,140 --> 00:02:10,670 Really great to be here. 29 00:02:10,690 --> 00:02:11,430 I'm excited. 30 00:02:11,430 --> 00:02:15,080 I'm, I'm a neurologist amongst a bunch of infectious disease folks here. 31 00:02:15,399 --> 00:02:16,290 That's the way I like it. 32 00:02:16,680 --> 00:02:17,010 Sara Dong: Dr. 33 00:02:17,010 --> 00:02:22,450 David Gaston is a clinical microbiologist at Vanderbilt University Medical Center in Nashville, Tennessee. 34 00:02:22,979 --> 00:02:28,560 He is the medical director of molecular microbiology and is also awarded in adult infectious diseases. 35 00:02:29,325 --> 00:02:34,704 His clinical and research interests focus on developing molecular techniques to advance ID diagnostics. 36 00:02:34,835 --> 00:02:36,545 David Gaston: Hey, Sara, David Gaston here. 37 00:02:36,585 --> 00:02:37,325 This is wonderful. 38 00:02:37,334 --> 00:02:38,405 Thanks so much for having us. 39 00:02:38,674 --> 00:02:44,924 It's just got like these bright lights and my neck's kind of hurting a little bit today, so I don't, we'll see how, we'll see how well this goes. 40 00:02:45,705 --> 00:02:46,825 Sara Dong: Excellent lead in. 41 00:02:47,325 --> 00:03:01,175 Well, before we jump into our discussion, I always ask as everyone's favorite cultured podcast, on Febrile, we do like asking our guests to share a little piece of culture, really just something non medical that brings you happiness. 42 00:03:01,645 --> 00:03:05,144 So maybe I'll start with you, Carol. 43 00:03:05,174 --> 00:03:10,864 Carol Glaser: One of the things that brings me total joy every single day is my incredible Australian shepherd. 44 00:03:10,864 --> 00:03:13,584 Who's, if anybody isn't an Australian shepherd owner. 45 00:03:14,010 --> 00:03:17,950 They don't realize that these are the most superior dogs in the whole world. 46 00:03:18,340 --> 00:03:25,390 And I live in Marin County, and we have tons of rain, so going for a walk with her and seeing waterfalls just totally brings me joy. 47 00:03:25,480 --> 00:03:25,710 Sara Dong: Love it. 48 00:03:26,410 --> 00:03:26,930 Karen? 49 00:03:27,139 --> 00:03:31,799 Karen Bloch: So, I have two dogs, but they don't bring me as much joy as Carol's dog does. 50 00:03:32,049 --> 00:03:44,179 I really love a sub genre of literature, um, cozy British mysteries, and I get a lot of pleasure out of reading about people sipping tea in very rural environments with a very bloody body in front of them. 51 00:03:45,239 --> 00:03:48,859 Sara Dong: There's a lot of murder mystery that gets mentioned in the culture. 52 00:03:49,079 --> 00:03:53,814 I don't know if that is just our population or ID docs. 53 00:03:53,995 --> 00:03:54,965 How about you, David? 54 00:03:55,745 --> 00:04:01,365 David Gaston: I am, I'm a big fan of, so we're relatively new to Nashville, lived here for a little under two years. 55 00:04:01,365 --> 00:04:04,965 So love building community, getting to know people. 56 00:04:05,255 --> 00:04:08,375 This is a really incredible city and an incredible place to be. 57 00:04:08,375 --> 00:04:10,955 So just a lot of creative folks around here. 58 00:04:10,955 --> 00:04:26,054 So being, being in community with others and also just in this state of COVID, where we are now, where we are able to get together and build up some community that, you know, has been lost a little bit over the past three or four years, five almost at this point. 59 00:04:26,054 --> 00:04:31,824 So, so if you ever find yourself in Nashville, come, come down, we'll have dinner, we'll go honky tonking on lower Broadway, it's a good time. 60 00:04:32,614 --> 00:04:33,124 Sara Dong: Perfect. 61 00:04:33,144 --> 00:04:34,865 And then last but not least, Arun. 62 00:04:35,195 --> 00:04:38,965 Arun Venkatesan: Building on that, being with this group, of course, brings me a ton of joy. 63 00:04:38,985 --> 00:04:41,305 It's really awesome to be here with all of you. 64 00:04:41,845 --> 00:04:45,885 The other thing that I was going to mention is probably a bit polarizing and that's pickleball. 65 00:04:45,915 --> 00:04:53,915 I've, I've really been enjoying playing a lot of pickleball and that's something else that, that I think brings people together, but occasionally can be divisive. 66 00:04:54,274 --> 00:04:56,124 So take it for what it's worth. 67 00:04:56,124 --> 00:04:56,554 Sara Dong: Excellent. 68 00:04:57,205 --> 00:05:06,855 Well, I am really excited and thankful to have you all here to talk about a pretty huge topic and the focus of your CID state of the art review, which is encephalitis. 69 00:05:07,474 --> 00:05:20,150 I am going to go very basic just to open the conversation because we often have a pretty large range of learners who are listening, and maybe they don't have the best foundation or framework for what is encephalitis? 70 00:05:20,630 --> 00:05:22,500 How is it different from meningitis? 71 00:05:22,530 --> 00:05:25,290 What does it mean when we say meningoencephalitis? 72 00:05:25,290 --> 00:05:29,800 So can you guys tell us a little bit just to set the stage before we talk about our case? 73 00:05:30,149 --> 00:05:31,780 Karen Bloch: That's a really important question. 74 00:05:31,780 --> 00:05:34,579 And it's actually not a straightforward answer to it. 75 00:05:34,820 --> 00:05:42,030 Encephalitis is inflammation of the brain tissues, whereas meningitis is inflammation of the meninges, but there's a lot of overlap. 76 00:05:42,330 --> 00:05:45,800 And both of those are pathologic terms rather than clinical terms. 77 00:05:46,285 --> 00:05:58,615 So, back in 2013, Carol, Arun and I, as well as a number of other folks, got together and, as part of the International Encephalitis Consortium, came up with what we thought was a reasonable case definition for encephalitis. 78 00:05:59,154 --> 00:06:07,905 It was, you know, initially formulated as something that could standardize studies, so you could compare apples to apples, but I think it's really gotten a lot of clinical play as well. 79 00:06:07,905 --> 00:06:28,494 And so, I think the most commonly used definition for encephalitis is altered mental status lasting at least 24 hours with at least two other supporting clinical findings, which could include fever, focal neurologic symptoms, new onset seizures, acute abnormalities on neuroimaging, preferably MRI, and then EEG abnormalities. 80 00:06:29,230 --> 00:06:35,270 I think an important caveat, which my co authors may want to talk about a little bit, is that this is really broad. 81 00:06:35,270 --> 00:06:44,449 And so we, we actually intentionally included a disclaimer that if there was a alternative diagnosis that these criteria, then that would exclude a diagnosis of encephalitis. 82 00:06:45,270 --> 00:06:45,940 Arun Venkatesan: Absolutely. 83 00:06:45,940 --> 00:06:52,729 It's, it's really important to exclude other diagnoses because there's so many things that can mimic encephalitis. 84 00:06:52,780 --> 00:06:58,800 Many, both acute neurological disorders and systemic disorders can do so as well. 85 00:06:59,210 --> 00:07:07,090 You know, really thorough workup, often including neuroimaging and looking for, say, toxins or metabolic abnormalities. 86 00:07:07,465 --> 00:07:10,595 Even primary seizure disorders can mimic encephalitis. 87 00:07:10,655 --> 00:07:12,185 There's a whole range of things. 88 00:07:12,415 --> 00:07:12,845 Sara Dong: Great. 89 00:07:13,845 --> 00:07:16,795 And so I have a, I guess I shouldn't say it's a quick case. 90 00:07:17,504 --> 00:07:20,185 I have a case to help us think about these topics. 91 00:07:20,405 --> 00:07:22,195 So we'll, we'll meet our patient. 92 00:07:22,235 --> 00:07:24,684 So we have a 30 year old previously healthy female. 93 00:07:25,219 --> 00:07:28,640 She has come in with about three days of headache and fever. 94 00:07:29,000 --> 00:07:33,409 And actually her family brought her in because, you know, she's just not acting herself. 95 00:07:33,749 --> 00:07:37,660 And then while in the emergency department, she has a witnessed generalized seizure. 96 00:07:38,169 --> 00:07:39,839 Her vitals are stable. 97 00:07:40,099 --> 00:07:41,469 Her temperature is 38. 98 00:07:41,530 --> 00:07:43,169 1 Celsius at that time. 99 00:07:43,659 --> 00:07:47,020 So just to give a little bit of context, it's summertime. 100 00:07:47,359 --> 00:07:49,400 You're located in the northeastern U. 101 00:07:49,400 --> 00:07:49,530 S. 102 00:07:50,215 --> 00:07:54,145 The patient lives in a studio apartment with her beloved pet cat. 103 00:07:54,684 --> 00:07:59,145 She likes to do a lot of outdoor activities, so hiking and biking and camping. 104 00:07:59,484 --> 00:08:01,784 And then she works as a veterinarian. 105 00:08:01,894 --> 00:08:06,744 So can you walk us through your approach to this patient? 106 00:08:06,804 --> 00:08:12,484 Karen Bloch: Well, I had to smile when you said it's not a quick case because encephalitis cases are never quick cases. 107 00:08:12,884 --> 00:08:16,094 And, although you put in a lot of fodder for us to think about. 108 00:08:16,254 --> 00:08:17,664 That's actually very common. 109 00:08:17,694 --> 00:08:21,044 There's always these interesting little epidemiologic links. 110 00:08:21,044 --> 00:08:23,514 And I think those are really important as we think about it. 111 00:08:23,934 --> 00:08:30,914 When we were formulating the state of the art paper, we decided to sort of separate encephalitis into two buckets. 112 00:08:30,924 --> 00:08:44,760 One were relatively common etiologies that we should think about every single time, and so I'll touch on those, and then I'll have my co authors talk about some of these other possibilities that might be linked to some of her exposures. 113 00:08:45,150 --> 00:09:05,155 The pathogens that we felt like were really important to test for, regardless of any of the clinical findings or epidemiology, would be herpes simplex virus 1, varicella zoster virus, West Nile virus, enteroviruses, and those were really the core, and after that, testing can be guided by additional features. 114 00:09:05,195 --> 00:09:09,225 Carol Glaser: I'm going to jump in here and just, can you confirm what kind of veterinarian she is? 115 00:09:09,265 --> 00:09:10,894 Small animal, large animal, mixed? 116 00:09:11,474 --> 00:09:13,155 Exotic, wildlife, zoo. 117 00:09:13,214 --> 00:09:18,574 Sara Dong: Let's pretend it's small animal, but I'd love to hear insight if she was a different type of veterinarian. 118 00:09:18,574 --> 00:09:21,885 Carol Glaser: Okay, so let's go with the small animal that to begin with. 119 00:09:21,954 --> 00:09:28,984 So in our guidelines, we talk about any animal exposure and depending on what kind of animal to consider certain pathogens. 120 00:09:29,034 --> 00:09:36,910 But given that she's, let's say, a small animal veterinarian, Her exposure to animals is going to be much more than somebody that just owns a dog or a cat. 121 00:09:37,160 --> 00:09:40,640 She's literally going to see hundreds of dogs and cats in a given month. 122 00:09:40,949 --> 00:09:44,140 Many of them will be ill, sometimes with unknown illnesses. 123 00:09:44,470 --> 00:09:53,734 Thinking about what things can you get from a dog or a cat, it's actually a fairly small list of things that are going to give you neurologic manifestations. 124 00:09:53,854 --> 00:09:57,444 I would put Bartonella or cat scratch disease high on that list. 125 00:09:57,474 --> 00:10:05,094 That's a relatively common thing you can get from a cat, healthy or unhealthy, from a bite, a scratch, or even a lick to a wound. 126 00:10:05,145 --> 00:10:07,545 And certainly Bartonella can cause seizures. 127 00:10:07,554 --> 00:10:11,374 So that would not be a bad thought at all to put Bartonella on that list. 128 00:10:12,125 --> 00:10:22,415 And then leptospirosis, for instance, even though we rarely see it causing neurologic symptoms, it always kind of enters the picture particularly in somebody who could be exposed. 129 00:10:22,765 --> 00:10:28,275 And that exposure would generally be from animal urine and it would be probably a dog in her practice. 130 00:10:28,285 --> 00:10:31,605 So that leptospirosis would be another thing I would think about. 131 00:10:32,115 --> 00:10:34,724 And then we can never not think about rabies. 132 00:10:34,724 --> 00:10:37,154 I mean, rabies is indeed the quintessential encephalitis. 133 00:10:39,005 --> 00:10:48,495 Having said that though, it is unusual and very unusual in the now to see a dog or cat with rabies, just because our vaccines have worked so well. 134 00:10:48,705 --> 00:10:54,955 But we know that every once in a while, particularly if a feral animal is brought in, there's a possibility of rabies. 135 00:10:54,985 --> 00:11:01,655 So we'll probably get to rabies a little bit later in this discussion and why we should think about it or not think about it, but that's important. 136 00:11:01,934 --> 00:11:06,965 And then I would even go so far as to say, well, does she see what we call pocket pets? 137 00:11:07,355 --> 00:11:14,385 And that's gerbils and mice and hamsters, because if she does, then we have to think of, of yet another group of organisms. 138 00:11:14,814 --> 00:11:18,564 particularly something like lymphocytic choriomeningitis virus. 139 00:11:18,785 --> 00:11:31,064 Now importantly, that virus, when it does give you neurologic manifestations, it's often in an immunocompromised host, so I guess I'm going to stop here too and just confirm, is she known to be immunocompetent? 140 00:11:32,475 --> 00:11:34,714 Sara Dong: As far as we know, she is immunocompetent. 141 00:11:35,545 --> 00:11:41,995 Carol Glaser: So LCMV or lymphocytic choriomeningitis can occasionally cause a meningitis in a normal host. 142 00:11:42,165 --> 00:11:46,165 It is unusual, but again, she's going to have above normal exposures. 143 00:11:46,614 --> 00:11:53,635 And as Karen started off by saying, the line between meningitis and encephalitis is often very blurred. 144 00:11:53,714 --> 00:11:58,465 So I would also be considering that at some point in the differential. 145 00:11:58,564 --> 00:12:03,764 Karen Bloch: Arun, Baltimore may be closest to the northeast of any of our geographic locations. 146 00:12:03,785 --> 00:12:08,845 Does her residence in the northeast make you think of any pathogens, particularly with her outdoor activities? 147 00:12:08,845 --> 00:12:09,895 Arun Venkatesan: Yeah, yeah, certainly. 148 00:12:10,005 --> 00:12:13,355 And geography really is super important to consider here. 149 00:12:13,830 --> 00:12:17,600 From the standpoint of the Northeast, there are a couple of interesting pathogens to think about. 150 00:12:17,640 --> 00:12:24,889 One is Powassan virus, of which there are, you know, nowadays, you know, 30 to 40 cases per year. 151 00:12:25,280 --> 00:12:28,320 This is a tick borne encephalitis virus. 152 00:12:28,320 --> 00:12:28,960 It's, uh, it's a flavivirus. 153 00:12:30,740 --> 00:12:38,339 The interesting thing about this virus is that the tick attachment time can be as short as 15 to 30 minutes. 154 00:12:38,400 --> 00:12:44,980 So it's very different than something like Lyme disease, where the tick needs to attach to the host for many hours. 155 00:12:45,170 --> 00:12:46,439 Here, it can be very quick. 156 00:12:46,890 --> 00:12:53,540 Lyme disease, of course, we need to think about as well, although Lyme will typically cause a meningitis as compared to an encephalitis. 157 00:12:54,025 --> 00:12:55,454 You know, anywhere in the U. 158 00:12:55,454 --> 00:12:55,635 S. 159 00:12:55,915 --> 00:13:02,089 one needs to consider West Nile virus as well, and you mentioned that as well as kind of core testing that we would consider. 160 00:13:02,099 --> 00:13:08,680 Karen Bloch: So in the part of the world that we are from, David, I guess we have slightly different vector borne diseases here. 161 00:13:09,080 --> 00:13:18,630 Things that I might think about in a patient if she lived in the Southeast or South Central United States would be things like Lacrosse virus, more common in kids but can be seen in adults. 162 00:13:19,249 --> 00:13:21,009 I think about the tick borne pathogens. 163 00:13:21,359 --> 00:13:25,550 I have tick borne on the brain sometimes during the summer months because it's so common here. 164 00:13:25,829 --> 00:13:30,810 We see both Ehrlichia chaffeensis and Rickettsia rickettsii, both of which can cause CNS disease. 165 00:13:30,810 --> 00:13:36,209 And I think that's sometimes underappreciated, particularly if you consider the fact that they are both treatable pathogens. 166 00:13:36,209 --> 00:13:44,494 Arun Venkatesan: It's something that we might both see, Karen, is Eastern equine encephalitis, which really can present all along the eastern seaboard. 167 00:13:44,515 --> 00:13:51,275 Very few cases yearly, typically, you know, 5 to 10 cases, although some years there can be 3 to 4 times that many. 168 00:13:51,464 --> 00:13:53,675 But that is another pathogen to consider. 169 00:13:54,045 --> 00:13:57,325 Karen Bloch: Carol, what does the West Coast have that we haven't mentioned so far? 170 00:13:57,900 --> 00:14:01,780 Carol Glaser: So West Coast, we mostly have West Nile as far as an arbovirus. 171 00:14:02,310 --> 00:14:05,990 We do, for reasons we don't quite understand, we've had St. 172 00:14:05,990 --> 00:14:06,360 Louis encephalitis. 173 00:14:06,939 --> 00:14:08,939 It kind of went away for a few years. 174 00:14:08,970 --> 00:14:12,280 It's now resurfacing and we're seeing those cases again. 175 00:14:12,630 --> 00:14:15,070 Those are our primary arboviruses. 176 00:14:15,360 --> 00:14:25,410 And like you, we have tick borne diseases, although we don't have nearly as much Ehrlichia as you do, we have Anaplasma, and as you mentioned, all of those can cause neurologic features. 177 00:14:25,719 --> 00:14:31,620 I would also add the fact that she's a veterinarian, she is going to be exposed to ticks that much more. 178 00:14:31,620 --> 00:14:35,809 I mean, we mentioned that she, you know, is hiking and camping, and that will expose her. 179 00:14:35,810 --> 00:14:44,190 But don't forget the dogs and the cats are also bringing in fleas, and ticks into her practice on a daily basis, probably this time of year. 180 00:14:44,260 --> 00:14:55,050 David Gaston: Just to round out that differential, looking at table three from the manuscript here, since she's a veterinarian, if she's dealt with macaques at all, having an animal bite, then herpes B virus is always on there. 181 00:14:55,050 --> 00:14:59,019 But it's wonderful to be able to build such a gorgeous differential like this. 182 00:14:59,049 --> 00:15:02,180 Testing for all of those is a lot harder. 183 00:15:02,650 --> 00:15:19,305 And being able to, to really differentiate which of these is, is she at the most risk for, which of these not, and where do you start testing is a continual struggle with any sort of clinical provider, be it an admitting hospitalist team, be it an infectious disease 184 00:15:19,655 --> 00:15:26,935 consult team, but to really say, where, where do you start and Karen, you start off with saying some of the most common pathogens. 185 00:15:27,025 --> 00:15:41,454 That's a great place to start just to have some of the targeted testing that focuses on the most common pathogens, but also using diagnostic testing that can capture much more and always want to emphasize the basics. 186 00:15:41,790 --> 00:15:55,370 Standard bacterial culture, if the patient is at risk, fungal culture, mycobacteriology culture, those basics are always going to be with us in laboratory medicine and you can learn so much from those. 187 00:15:55,400 --> 00:15:58,429 And we're in the molecular era and it is absolutely phenomenal. 188 00:15:58,429 --> 00:16:01,550 That's my bias towards molecular microbiology. 189 00:16:01,940 --> 00:16:07,670 So focusing on your dedicated PCRs, which are so well tuned and do work very well. 190 00:16:07,685 --> 00:16:20,704 HSV, enterovirus, and then thinking, is this the right kind of patient where you would want to use broader testing, like at a multiplex panel that is able to go through and detect multiple highly likely pathogens? 191 00:16:20,704 --> 00:16:26,155 There are not a lot of pathogens that are on those panels that are too obscure, depends on which panel you're talking about. 192 00:16:26,194 --> 00:16:30,925 But for something like meningitis encephalitis, there's a set of organisms that we're looking for. 193 00:16:31,300 --> 00:16:40,720 Those panels are generally designed to be able to target those, depending upon which population we're looking at, too, because there are different pathogens that are more common in children versus those that are more common in adult. 194 00:16:41,569 --> 00:16:47,750 So having algorithms that you work with in your medical system to be able to say, when's the right time to be able to order those tests? 195 00:16:47,780 --> 00:16:55,820 And then if that testing is not revealing, saying, well, when's the right time to really get into testing that we don't fully understand how they perform yet? 196 00:16:55,820 --> 00:17:05,125 Things like metagenomics, where we're coming into a spot that there is certainly a place for those, those testing, but we don't, we don't really know where that is yet. 197 00:17:05,175 --> 00:17:11,565 Is it best to test at the beginning of a syndrome or is it best to test later when everything else has come back negative? 198 00:17:11,615 --> 00:17:15,094 What is the performance characteristic compared to a well tuned PCR? 199 00:17:15,125 --> 00:17:23,685 This is one of those places in, in molecular microbiology where the testing is broader, but you may not have as low of a limit of detection. 200 00:17:23,694 --> 00:17:28,454 There might need to be more organism burden present to be able to detect with something like metagenomics. 201 00:17:28,815 --> 00:17:37,855 And if you're later in a presentation or even in a clinical syndrome, where if it's a virus, if there's a viral load is present, even before symptoms come on, you might miss it. 202 00:17:37,864 --> 00:17:43,034 So there, there are a lot of considerations going into that, but that's why we all work together as a clinical team. 203 00:17:43,324 --> 00:17:56,070 Carol Glaser: David, you point out, you know, how great molecular is, and certainly it's really revolutionized our ability to diagnose it, but there's a lot of limitations and very important limitations I think that sometimes physicians overlook. 204 00:17:56,330 --> 00:17:58,669 One, some false, you know, negative PCRs. 205 00:17:58,719 --> 00:18:05,270 I think, you know, it's not that uncommon for people to be falsely reassured when they have that first negative HSV. 206 00:18:05,730 --> 00:18:16,849 West Nile, I think, is another example where the PCR for West Nile is rarely positive in the spinal fluid because the, the lumbar puncture is done just a little bit too late to pick up viral load. 207 00:18:17,275 --> 00:18:20,005 So, I, can you just talk about that a little bit more? 208 00:18:20,045 --> 00:18:20,445 David Gaston: Sure, Carol. 209 00:18:20,475 --> 00:18:21,465 Those are great points. 210 00:18:21,835 --> 00:18:36,625 You're getting at the normal pathogenesis of a process, so like with West Nile where the viremic phase, the viremic phase is in the CSF, is before someone presents symptoms and then as the inflammatory action is coming in, you're getting more symptoms. 211 00:18:36,625 --> 00:18:38,695 There may not be as much virus present there. 212 00:18:39,175 --> 00:18:44,340 So, even the the most well tuned test, there's always a limit of detection. 213 00:18:44,340 --> 00:18:49,430 There's always an amount of pathogen below which we just simply can't detect it. 214 00:18:49,430 --> 00:18:51,030 And so that can be part of the problem. 215 00:18:51,030 --> 00:18:55,369 But then there are also various tests that are designed differently. 216 00:18:55,399 --> 00:19:04,790 Every test that's performed in a different laboratory, if it's designed by that laboratory is going to perform a little bit different than another test that's performed elsewhere. 217 00:19:04,790 --> 00:19:22,770 So without getting into the weeds of regulatory environments and utilizing tests that are the same test used by everyone, which is not the state that we're in in the United States, nor is it necessarily a state I think we need to be in, you just need to work with your laboratory and the laboratory that is serving you and is serving your patients. 218 00:19:23,199 --> 00:19:25,949 It's our job to know the limitations of those tests. 219 00:19:25,959 --> 00:19:30,850 So to have that kind of ongoing discussion to say, Hey, I'm a well trained clinician. 220 00:19:30,929 --> 00:19:37,139 I have this clinical suspicion that this could be something like HSV encephalitis, yet this test is negative. 221 00:19:37,219 --> 00:19:39,780 Can we talk through some of the limitations of that test? 222 00:19:39,850 --> 00:19:41,510 What's the right way to go forward? 223 00:19:41,970 --> 00:19:43,994 Should we get another lumbar puncture? 224 00:19:44,155 --> 00:19:47,845 In a few days, should we retest using a different test? 225 00:19:47,935 --> 00:19:50,195 Should we broaden our differential to be thinking about something else? 226 00:19:50,195 --> 00:19:52,684 That's something that the lab is there to help you with. 227 00:19:53,035 --> 00:19:56,185 We are effectively a consultant service for the consultants. 228 00:19:56,205 --> 00:19:57,314 So reach out. 229 00:19:57,315 --> 00:19:58,364 We're, we're happy to talk. 230 00:19:58,464 --> 00:20:01,374 Karen Bloch: You mentioned the meningitis encephalitis or ME panel. 231 00:20:01,374 --> 00:20:10,405 And I think that's really revolutionized our ability to rapidly diagnose and expanded the spectrum of pathogens that we're seeing with encephalitis and CNS infections. 232 00:20:10,985 --> 00:20:19,445 One thing I just wanted to raise, and I think the group will have comments on this, is how to interpret a positive HHV 6 PCR test. 233 00:20:19,445 --> 00:20:21,655 David Gaston: HHV 6 is detected quite frequently. 234 00:20:21,715 --> 00:20:32,929 Looking back through our data, it's actually the most commonly detected target on that panel, I'm going to say target not pathogen because it may not be a pathogen in immunocompromised patients. 235 00:20:32,929 --> 00:20:35,439 Carol, you were asking earlier, is this an immunocompromised patient? 236 00:20:35,860 --> 00:20:36,840 Sure, it can be. 237 00:20:37,060 --> 00:20:47,534 Yet in someone who is not immunocompromised, if it's chromosomally integrated, it can be present in the CSF and may not be causing the clinical syndrome that this patient is currently coming in and presenting with. 238 00:20:48,254 --> 00:20:52,534 Carol Glaser: David, I do want to add to that, that that may not be causing the problem. 239 00:20:53,205 --> 00:21:00,135 The issue that we've run into quite a bit here in California with HHV 6 is that sometimes it's the only pathogen that's found. 240 00:21:00,475 --> 00:21:04,655 And so clinicians feel like, well, you know, I have to do something, the patient is sick. 241 00:21:05,065 --> 00:21:11,655 And unlike acyclovir, which is what we use for herpes, drugs like foscarnet and ganciclovir are much more toxic. 242 00:21:11,975 --> 00:21:24,144 Even though we'll talk to clinicians and we'll explain that, you know, there's a very high likely that this is chromosomal integration, that they really feel compelled to do something and in doing something, sometimes we, it does create harm. 243 00:21:24,185 --> 00:21:32,510 So I do worry a little bit that we haven't educated our physicians enough about HHV 6 and the limitations of the testing. 244 00:21:32,620 --> 00:21:50,290 David Gaston: There's power in a name, and this is something that we get to a lot in clinical microbiology of determining how do we present results that are clinically actionable without just presenting more data that can potentially lead folks down a path that is not going to be the most beneficial to the patient. 245 00:21:50,290 --> 00:21:52,070 And there, there's a real balance there. 246 00:21:52,500 --> 00:21:56,580 Uh, with tests like an ME panel, it's an FDA IVD certified test. 247 00:21:56,590 --> 00:21:58,950 So what we detect is what we report. 248 00:21:58,950 --> 00:22:02,644 If it's there, then we are obligated to, to report it. 249 00:22:03,264 --> 00:22:22,244 Same with, you know, any test that would be similar but would be a laboratory developed test where you're able to, to really say, hey, we are reporting this because we've done this testing in our laboratory, we know how it performs with our design and, you know, would validate different reporting strategies if that's, if that's part of it, but education is the real point there 250 00:22:22,254 --> 00:22:41,465 to be able to say, And hopefully your consultants would be relying upon your expertise where you say, well, if this is present, that may be true, true, unrelated, um, that it's not, it's not driving this syndrome, but I do worry about anchoring that happens again, being a clinician myself and remembering times where I found one thing and then said, okay, well, this must be it. 251 00:22:41,595 --> 00:22:48,485 And then, you know, a well, very wise person would come around and say, well, David, hold on, maybe, maybe there might be something else going on. 252 00:22:48,544 --> 00:22:51,445 And there's a lot of wisdom in saying, okay, we've got this. 253 00:22:52,304 --> 00:22:53,064 Let's not anchor. 254 00:22:53,115 --> 00:22:54,314 Let's keep driving. 255 00:22:54,365 --> 00:22:55,895 Let's, let's really find the right answer. 256 00:22:55,905 --> 00:23:02,024 Cause if there is that little red flag in the back of your mind that says that might not be it, that's, that's an important red flag to listen to. 257 00:23:02,695 --> 00:23:04,185 Sara Dong: So I'll take us back to the case. 258 00:23:04,665 --> 00:23:06,545 We get a little bit more information. 259 00:23:06,605 --> 00:23:21,515 We have an initial MRI of the head that was completed with gadolinium enhancement, which shows abnormal signal hyperintensity on T2 weighted imaging and FLAIR with diffusion restriction on diffusion weighted images, both involving the left temporal lobe. 260 00:23:22,074 --> 00:23:28,645 Her LP demonstrates a lymphocytic pleocytosis, so she had about 100 white blood cells, 85 percent lymphocytes. 261 00:23:29,145 --> 00:23:33,655 There was a slightly elevated protein, uh, increased red blood cells. 262 00:23:34,205 --> 00:23:41,025 Her CSF sample is sent for bacterial culture, which is pending, but you have back that the Gram stain is negative. 263 00:23:41,635 --> 00:23:48,649 And her initial CSF HSV1 and HSV2, VZV and enterovirus PCRs were ordered. 264 00:23:48,989 --> 00:23:51,060 And I'll just go ahead and let you know that they're negative. 265 00:23:51,120 --> 00:23:53,499 And this is all on her initial presentation. 266 00:23:53,520 --> 00:23:59,609 So we also have HIV antigen antibody screening that was negative and an RPR, which is negative. 267 00:23:59,639 --> 00:24:05,070 She was empirically placed on acyclovir, vancomycin, and ceftraxone while awaiting results. 268 00:24:05,070 --> 00:24:12,230 So now that we have some of this information back, the patient is relatively in the same place that she was before. 269 00:24:13,099 --> 00:24:14,950 You know, what are, what are you considering? 270 00:24:14,950 --> 00:24:16,340 What might be your next steps? 271 00:24:16,785 --> 00:24:30,165 Arun Venkatesan: Well, what's interesting here, Sara, is that there's evidence of temporal lobe involvement, and it's probably of no surprise to much of the audience that herpes simplex virus still needs to be a prime consideration here. 272 00:24:30,165 --> 00:24:39,435 Now, there are other causes of temporal lobe encephalitis, and Carol and I have looked at this previously through the California Encephalitis Project, as has Dr. 273 00:24:39,435 --> 00:24:44,104 Richard Whitley, but certainly HSV 1 still has to be a very prime consideration here. 274 00:24:44,104 --> 00:24:52,480 So, I think it's It's quite reasonable to continue the acyclovir because as was just mentioned, false negatives can occur. 275 00:24:52,480 --> 00:24:54,760 The HSV PCR is a very good test. 276 00:24:54,770 --> 00:25:03,500 The sensitivity is over 90%, but we know that if that lumbar puncture is performed early, that one can have false negatives. 277 00:25:04,079 --> 00:25:13,430 Karen Bloch: Something that I've grown to appreciate over time is the fact that although having temporal lobe focality certainly increases my concern for herpes encephalitis. 278 00:25:13,880 --> 00:25:20,360 What's become apparent with the increasing utilization availability of PCR is that there's a huge diversity of presentations. 279 00:25:20,790 --> 00:25:25,820 And so that the typical herpes simplex virus 1 causing temporal lobe involvement is true. 280 00:25:26,190 --> 00:25:29,180 But we can certainly see atypical presentations as well. 281 00:25:29,180 --> 00:25:31,260 And I think that's particularly true in, in peds. 282 00:25:31,300 --> 00:25:32,370 Isn't that the case, Carol? 283 00:25:32,640 --> 00:25:32,850 Carol Glaser: Yeah. 284 00:25:32,850 --> 00:25:33,440 Thanks, Karen. 285 00:25:33,440 --> 00:25:34,610 That is a great point. 286 00:25:34,649 --> 00:25:50,485 So in pediatrics, even though we sometimes see more of the classic presentation of herpes simplex, similar to what you see in adults, there are a number of atypical presentations and for mainly two things, both in clinical presentations, So they don't always have seizures 287 00:25:50,485 --> 00:25:57,194 and the hemiparesis and the dysphagia, but sometimes they'll have some things like ataxia, which is not normally what you'd think about. 288 00:25:57,525 --> 00:26:03,514 But importantly too, we probably have a higher number of false negatives with our herpes. 289 00:26:03,515 --> 00:26:04,864 We don't quite understand it. 290 00:26:05,175 --> 00:26:12,855 And these are based on relatively small case series, but both in the California encephalitis project, as well as a pretty big study out of Toronto. 291 00:26:12,865 --> 00:26:17,844 We found 20 to 25 percent false negatives on that first LP. 292 00:26:17,845 --> 00:26:37,935 Probably a little bit of an overinflation, partly because we're a biased sample in, with the encephalitis project, but really important to consider in pediatrics that if you have a, negative herpes, and if there's anything that is looking at all like herpes, you really have to reconsider an LP and repeat that herpes simplex. 293 00:26:38,264 --> 00:26:43,055 David Gaston: No test is perfect, even excellent HSV PCR tests. 294 00:26:43,125 --> 00:26:48,745 And that's fun to, it's fun to think through, in just the history of molecular microbiology. 295 00:26:48,745 --> 00:26:56,325 HSV is really what started the current era of molecular microbiology and HSV in CNS infections. 296 00:26:56,354 --> 00:26:59,624 And Arun, you brought up the work that Rich Whitley did down at UAB. 297 00:26:59,705 --> 00:27:01,065 I trained in Rich's lab. 298 00:27:01,184 --> 00:27:02,285 He was my PhD mentor. 299 00:27:02,285 --> 00:27:03,055 He's a great guy. 300 00:27:03,405 --> 00:27:09,254 So the work that he did and Fred Lakeman and others really just set this route that we're on. 301 00:27:09,905 --> 00:27:13,305 And it's remarkable to see where we are, but yeah, that no, no test is perfect. 302 00:27:13,315 --> 00:27:18,330 And there are multiple different HSV PCRs that are used at different institutions. 303 00:27:18,330 --> 00:27:20,620 Some institutions use their own laboratory developed tests. 304 00:27:20,630 --> 00:27:23,840 Some institutions use FDA IVD certified tests. 305 00:27:24,320 --> 00:27:26,950 They're all very similar, but they're not exactly the same. 306 00:27:26,990 --> 00:27:33,529 And so the performance characteristics are going to be different, which again, just getting back to the idea of talk to your lab so that you understand how that works. 307 00:27:33,990 --> 00:27:36,839 And then your point about repeat testing is critical. 308 00:27:37,179 --> 00:27:43,200 The tests do perform, and this is a very broad statement, so take that with a block of salt. 309 00:27:43,470 --> 00:27:45,750 The tests do perform very similarly. 310 00:27:46,310 --> 00:28:08,630 Such that if you retest the same CSF specimen with a different test, that's not necessarily going to be helpful because the limited detection for these assays is so low and the targets are somewhat similar, that may not help, but testing a few days later with a different CSF specimen that can be very beneficial and if you work in pre 311 00:28:08,630 --> 00:28:28,820 test probability into all of this and if you have a patient that still is clinically highly suspicious for HSV encephalitis, but you have a second negative test, then that really makes you start saying, okay, we've got to go back to our differential and go down to say, This gets knocked down lower on the differentials, what comes up higher? 312 00:28:29,889 --> 00:28:37,260 Karen Bloch: One thing I wanted to mention, I think there'd been an emphasis that this was an outdoors person that she enjoyed activities outside. 313 00:28:37,700 --> 00:28:45,000 And because tick borne pathogens are on our list, and again, many of those are treatable if they're in the Rickettsia family. 314 00:28:45,040 --> 00:28:58,689 I would probably advocate for broadening her empiric antibiotics to include doxycycline, uh, either until you found an alternative pathogen or if there's no clinical response after three days, you can be pretty certain that it's not a tick borne infection. 315 00:28:59,029 --> 00:29:02,960 So just something to keep in mind as we consider empiric treatment in this population. 316 00:29:03,040 --> 00:29:16,405 Carol Glaser: Karen, I'll just add, just, you know, being the pediatrician in the group, that In pediatrics, many of us were trained that we shouldn't be using tetracycline or doxycycline because of the teeth staining, but in a scenario, if you were to have a child, 317 00:29:16,465 --> 00:29:24,254 particularly in the ICU, and there was any concerns about tick borne illness, it's absolutely fine to go ahead and start doxycycline. 318 00:29:24,485 --> 00:29:31,594 You're not going to get into the issues of teeth staining with one course of doxycycline, and it can be absolutely life saving. 319 00:29:31,635 --> 00:29:45,510 So, pediatricians in the past have been very reticent to start doxycycline, but in a scenario with a child with encephalitis, with any concerns about tick borne encephalitis, you should consider starting doxy and not waiting for those tests to come back. 320 00:29:46,040 --> 00:29:46,480 Sara Dong: Great. 321 00:29:47,190 --> 00:29:56,760 In our case, the patient ultimately has a repeat LP about six days later, and we have an HSV PCR that returns positive. 322 00:29:56,790 --> 00:29:59,409 So it's diagnosed with HSV encephalitis. 323 00:29:59,410 --> 00:30:04,299 So the antibiotics, the vancomycin, ceftriaxone, and doxycycline are stopped. 324 00:30:04,820 --> 00:30:14,970 She completes about a three week course of the IV acyclovir and has some overall clinical improvement, is able to go home, but actually comes back to care. 325 00:30:15,380 --> 00:30:17,809 And this time her family says, you know, she just. 326 00:30:18,340 --> 00:30:19,520 It's really strange. 327 00:30:19,530 --> 00:30:20,990 She seems really paranoid. 328 00:30:21,290 --> 00:30:22,810 She's not really sleeping well. 329 00:30:22,820 --> 00:30:31,530 We've also noticed that there's these more unusual movements in her hands, and they actually are worried that she might be seeing things that aren't truly there and hallucinating. 330 00:30:31,570 --> 00:30:38,120 A repeat MRI is done that shows some slight improvement in those temporal lobe changes I mentioned before. 331 00:30:38,610 --> 00:30:41,370 And so they're wondering, you know, is this related to her HSV? 332 00:30:41,400 --> 00:30:43,320 Is this something we should expect? 333 00:30:43,350 --> 00:30:51,475 But as a medical team, now they're coming to our encephalitis consult team here to ask, what else should we be considering and thinking about in this scenario? 334 00:30:52,775 --> 00:31:14,185 Arun Venkatesan: It's a really interesting situation, Sara, and certainly something that's been increasingly recognized in recent years, that patients with very adequately treated herpes simplex encephalitis can develop new or recurrent neurologic symptoms in the weeks to several months following the initial infectious encephalitis. 335 00:31:14,185 --> 00:31:16,865 And so then the question is, what's driving that process? 336 00:31:16,895 --> 00:31:21,245 And for a long time, we thought, Oh, well, maybe they're having seizures. 337 00:31:21,274 --> 00:31:23,295 Maybe there's a viral recurrence. 338 00:31:23,564 --> 00:31:31,895 It turns out that in most of these cases, there's an autoimmune process that follows the initial herpes simplex encephalitis. 339 00:31:31,965 --> 00:31:38,634 And that autoimmune encephalitis is often though not always associated with antibodies against the NMDA receptor. 340 00:31:39,075 --> 00:31:50,995 There can be antibodies against other neuronal proteins as well that can develop, and this happens in probably, well, up to about a fifth of patients with herpes simplex encephalitis. 341 00:31:51,015 --> 00:31:55,495 So it's not uncommon, and I think it's something that's really important to recognize. 342 00:31:55,605 --> 00:32:04,125 Karen Bloch: As an ID doctor, one of the questions we frequently get asked on the consult team is often by the neurology team, saying, we have a suspicion. 343 00:32:04,145 --> 00:32:07,725 It's going to take days to weeks before we get the testing results back. 344 00:32:08,735 --> 00:32:18,265 Since we haven't completely confirmed the diagnosis of an autoimmune phenomenon and we can't completely exclude the possibility of infectious, is it safe to start immunosuppression? 345 00:32:18,274 --> 00:32:30,195 That's one reason of many that the infectious disease community really needs to know about the autoimmune encephalitis and think about risk benefit in terms of early initiation of any inflammatory treatments. 346 00:32:30,405 --> 00:32:33,745 David Gaston: One point I'd like to throw in just for clarity on the listener's side. 347 00:32:33,765 --> 00:32:35,775 We're, we're saying herpes encephalitis. 348 00:32:35,795 --> 00:32:37,684 I think we're meaning HSV 1. 349 00:32:37,685 --> 00:32:50,035 Herpes simplex virus in HSV 1 causes an encephalitis that if untreated is fatal, whereas HSV 2 can cause a recurrent meningitis that arguably may not even need to be treated. 350 00:32:50,085 --> 00:32:51,615 Mollaret meningitis. 351 00:32:51,615 --> 00:33:02,664 And once a patient knows that that's what's going on, you could either have a pill in pocket if that is a symptomatic improvement, but not necessarily saying, you've got to be on weeks of IV acyclovir. 352 00:33:03,005 --> 00:33:09,225 Whereas with HSV 1 encephalitis, which is what we're talking about here, yes, that's got to be there. 353 00:33:10,340 --> 00:33:22,319 Back to Karen's point about what follows when is immune suppression needed after that with steroids to be able to help with some of the secondary factors, then, um, I'll, I'll not comment on that. 354 00:33:22,379 --> 00:33:24,090 Arun Venkatesan: Yeah, I can take that one, David. 355 00:33:24,129 --> 00:33:29,099 The presentation of autoimmune encephalitis can differ from that of infectious encephalitis. 356 00:33:29,120 --> 00:33:33,350 And in particular, it can be a little bit more subacute in its onset. 357 00:33:33,610 --> 00:33:37,080 Some of the cognitive changes can be more subtle. 358 00:33:37,845 --> 00:33:40,955 Certainly, behavioral changes can be very pronounced. 359 00:33:41,045 --> 00:33:44,525 For example, psychosis can occur in autoimmune encephalitis. 360 00:33:45,295 --> 00:33:51,445 And what we typically use to treat autoimmune processes, of course, as first line are corticosteroids. 361 00:33:51,465 --> 00:33:57,895 But that may actually be contraindicated in some of these patients because of the extreme degrees of psychosis. 362 00:33:57,895 --> 00:34:09,590 And so other first line agents that we might think about would include intravenous immunoglobulin or even plasmapheresis, plasma exchange in an effort to control the autoimmune process in these patients. 363 00:34:11,289 --> 00:34:17,750 Carol Glaser: So Arun, to follow up about some of the clinical presentations of autoimmune, particularly anti NMDAR. 364 00:34:18,280 --> 00:34:26,070 In the early days of anti NMDAR encephalitis and the recognition of that before there wasn't even commercial tests available. 365 00:34:26,465 --> 00:34:46,775 For that, we were getting a fair number of cases referred into the state health department, people thinking they were rabies, and they weren't rabies, and because actually the tempo wasn't quite right, but there's an incredible overlap with the clinical presentation of some of those anti NMDR receptor encephalitis cases and rabies. 366 00:34:46,815 --> 00:34:51,625 You know that incredible psychosis, the agitation, the autonomic instability. 367 00:34:51,665 --> 00:34:54,555 So keep in mind there can be incredible overlap. 368 00:34:54,595 --> 00:34:59,530 In the textbooks it all looks like they they separate out very nicely, but they really don't. 369 00:34:59,840 --> 00:35:08,410 So both needs to stay on your differential with the idea that the autoimmune are going to be in this country going to be much more common than something like rabies. 370 00:35:08,590 --> 00:35:10,839 But again, in this case, she's a veterinarian. 371 00:35:10,840 --> 00:35:13,210 She's got more than your normal exposure to animals. 372 00:35:13,579 --> 00:35:16,000 So that should be in the back of folks mind. 373 00:35:17,630 --> 00:35:28,250 Karen Bloch: Again, anti NMDAR has sort of stolen the limelight here, but there are a number of other autoimmune antibodies and even some that I think don't have names, but appear to be important causes. 374 00:35:28,250 --> 00:35:38,730 And so I know there are panels out there and Arun, my question for you is when you see a patient where this is a concern, do you send a panel and do you differentiate CSF versus serum? 375 00:35:38,790 --> 00:35:39,040 Arun Venkatesan: Yeah. 376 00:35:39,160 --> 00:35:48,755 So certainly when we're suspicious of an autoimmune encephalitis, It's wise to send a broad panel because like you mentioned, there are many potential antibodies. 377 00:35:48,785 --> 00:35:52,524 There's a lot of clinical overlap between these autoimmune encephalitides. 378 00:35:52,654 --> 00:35:58,485 We like to try to send the CSF because it's a little bit more sensitive in many cases than the serum. 379 00:35:58,515 --> 00:36:02,435 And there can be both false negatives and false positives from the serum. 380 00:36:02,535 --> 00:36:06,865 CSF tends to be better in terms of its testing characteristics. 381 00:36:06,925 --> 00:36:12,785 And then of course, there's often a delay between when we send the testing and when we receive the results. 382 00:36:13,640 --> 00:36:23,640 So, if we think we've reliably excluded infections at this stage, then certainly it makes sense to initiate empiric immunosuppressive therapy. 383 00:36:23,960 --> 00:36:30,170 And like I mentioned, typical first line treatments would be corticosteroids, IVIG, or plasma exchange. 384 00:36:30,180 --> 00:36:32,610 And then there are second line treatments as well. 385 00:36:32,610 --> 00:36:36,420 For example, rituximab or cyclophosphamide or, or others. 386 00:36:36,420 --> 00:36:41,640 There's a growing list of immune modulatory agents that have shown promise in autoimmune encephalitis. 387 00:36:42,630 --> 00:36:53,880 David Gaston: Let's draw the listener's attention to table 10, which back when I was an ID fellow would have loved to have had in my back pocket to look into, which is in categories of autoimmune encephalitis, which has a great list on there. 388 00:36:54,575 --> 00:36:55,285 Thanks, Arun, for that. 389 00:36:55,385 --> 00:36:55,655 It's great. 390 00:36:55,955 --> 00:36:56,275 Sara Dong: Yeah. 391 00:36:56,275 --> 00:37:12,714 And I was going to sort of oversimplify this case and say, this patient is diagnosed ultimately with anti NMDA receptor encephalitis based on CSF studies with oligoclonal bands and IgG anti NMDA receptor antibodies. 392 00:37:13,465 --> 00:37:27,435 But really the reason I'm oversimplifying is to just open it up to talk about any other challenges you see with teasing these apart both for diagnosis and management, because I think, as you all are alluding to, these cases are typically not so linear. 393 00:37:27,615 --> 00:37:35,110 Arun Venkatesan: Yeah, this is a really nice case of an infectious encephalitis followed by an autoimmune encephalitis. 394 00:37:35,120 --> 00:37:36,480 And I think you're right. 395 00:37:36,480 --> 00:37:46,250 It does highlight some of the challenges of trying to distinguish between the two and also remaining really vigilant for the possibility of evolution of symptomatology. 396 00:37:46,989 --> 00:38:03,180 Infections can trigger autoimmunity and this has been something that's been recognized for many decades but has really come to the light now in the kind of neuro ID field with cases of herpes simplex encephalitis followed by autoimmune encephalitis. 397 00:38:03,800 --> 00:38:07,819 Herpes simplex encephalitis is not the only encephalitis that can do this. 398 00:38:07,870 --> 00:38:16,930 Many other pathogens can, even after adequate treatment, then result in an autoimmune encephalitis that follows. 399 00:38:16,960 --> 00:38:21,060 And the thought is that many of these pathogens are destructive. 400 00:38:21,080 --> 00:38:34,285 You're getting release of neuronal antigens that typically don't get seen by the immune system, but once they're released in this way, the immune system sees them, recognizes them as foreign and that triggers an autoimmune attack. 401 00:38:34,445 --> 00:38:39,125 Karen Bloch: Before we knew about anti NMDAR, I think the classic example was ADEM. 402 00:38:39,165 --> 00:38:46,275 Arun Venkatesan: That's right, Karen, acute disseminated encephalomyelitis, which is, you know, classically preceded by an infection. 403 00:38:46,275 --> 00:39:06,445 In fact, any number of infections can do this and is accompanied often by antibodies against components to myelin and results in an acute inflammatory demyelinating process that can respond to immuno modulation, and it's a situation where the infection is typically not seen in the central nervous system. 404 00:39:06,445 --> 00:39:11,435 This is a peripheral process that then results in central nervous system demyelination. 405 00:39:13,040 --> 00:39:16,820 Sara Dong: So I want to thank you all so much for this awesome overview. 406 00:39:17,170 --> 00:39:23,070 We obviously cannot fit everything about encephalitis and even from your review into this podcast. 407 00:39:23,210 --> 00:39:33,920 So I was going to open it up at the end to ask if you could share either a take home point or an interesting pearl related to encephalitis, just because there's so much out there we could talk about. 408 00:39:33,930 --> 00:39:40,815 For me, I am going to put on my pediatric hat and just say, you know, we didn't talk as much about too many pediatric specific things. 409 00:39:41,115 --> 00:39:47,215 We did recently have a Febrile episode number 92 on an interesting case of arboviral encephalitis. 410 00:39:47,215 --> 00:39:51,164 So if people want to hear more, I encourage them to listen there. 411 00:39:51,185 --> 00:40:00,665 And then I was going to take the opportunity to reinforce a concept that I definitely was tested on for my peds [pediatric] ID certification, even though I have not seen this in real life. 412 00:40:00,685 --> 00:40:17,985 But the association of EBV encephalitis and the Alice in Wonderland presentation with metamorphopsia, you guys can correct me if I'm wrong, I see nods, but basically these distortions of something like visual perception, like size and body image, and even the experience of time. 413 00:40:18,365 --> 00:40:29,620 And that is not specific to EBV, it can be caused by epilepsy and brain tumors and perhaps drug use, but I thought that was a useful pearl, and it is mentioned in the paper. 414 00:40:29,660 --> 00:40:31,009 So I'll open it up to you guys. 415 00:40:31,010 --> 00:40:33,250 What are some other things you want to share before we wrap up? 416 00:40:33,519 --> 00:40:51,410 Karen Bloch: I think there's a misperception sometimes that outside of herpes simplex virus encephalitis that they're not treatable causes, and we've already mentioned tick borne, but I wanted to throw in one that I don't think got a lot of play here, but is an increasing concern in adult population throughout the United States and internationally as well, and that's syphilis. 417 00:40:51,740 --> 00:40:54,030 Never forget, syphilis is a treatable cause. 418 00:40:54,070 --> 00:40:57,390 It can mimic herpes encephalitis with temporal lobe focality. 419 00:40:57,640 --> 00:40:58,520 It can be chronic. 420 00:40:58,520 --> 00:40:59,450 It can be acute. 421 00:40:59,690 --> 00:41:06,955 So as was the case in this vignette, checking an RPR, antitreponemal antibodies, is really a key part of the workup of any patient with encephalitis. 422 00:41:07,435 --> 00:41:15,084 Carol Glaser: As long as Karen is mentioning treatable things, I want to talk about an organism that up until now we've thought not to be treatable. 423 00:41:15,085 --> 00:41:25,935 We thought that the mortality was close to a hundred percent, but there's a type of free living amoeba called Balamuthia mandrillis, which is traditionally thought to be a very esoteric cause of encephalitis. 424 00:41:26,705 --> 00:41:33,755 In California, where we were diligently looking at it for this organism for years, we were finding it much more than expected. 425 00:41:33,935 --> 00:41:34,674 It's not common. 426 00:41:34,675 --> 00:41:47,665 I don't want to pretend it's common, but it certainly should be considered in individuals with encephalitis when there's a parenchymal lesions and when the spinal fluid is appropriate and you've sort of wiped out the first tier and maybe even the second tier. 427 00:41:48,025 --> 00:42:06,210 But I bring it up as something maybe treatable because there's been a recent case report and I'm aware of another case out there where the investigators used nitroxoline as a drug, which is crazy because it's really a UTI drug that is used in Europe, but we have to always push the envelope with encephalitis. 428 00:42:06,789 --> 00:42:09,544 We can't just sit back and say, yeah, it's, it's. 429 00:42:09,985 --> 00:42:11,555 People are, this is usually fatal. 430 00:42:11,555 --> 00:42:12,835 We're not going to do anything about it. 431 00:42:13,065 --> 00:42:18,105 That's really important to try to push for an early diagnosis because it may make a huge difference. 432 00:42:18,175 --> 00:42:21,395 And certainly we've seen a few success stories with Balamuthia. 433 00:42:22,430 --> 00:42:27,170 David Gaston: I want to play off that idea of pushing the envelope with encephalitis, particularly from a diagnostic standpoint. 434 00:42:27,200 --> 00:42:30,619 It's still a challenging diagnosis to make from laboratory medicine. 435 00:42:30,689 --> 00:42:35,020 And a lot of that is the nature of the pathogens that we're dealing with. 436 00:42:35,060 --> 00:42:54,720 To some degree, that's the nature of the tests that we're using, but want to emphasize the importance of collaboratively working together with the primary teams, with the consultants, with the clinical microbiology lab to really get at what's happening, secure all the points you made of, you know, we're definitely not going to be sitting back to say, well, this is almost universally fatal. 437 00:42:54,720 --> 00:42:59,360 So let's, let's all head home early, but it's hard work to be able to go through and do that. 438 00:42:59,369 --> 00:43:20,455 And it's thrilling to see where the field of diagnosis is going with, again, my bias being molecular microbiology, but moving more towards broad diagnostics like clinical metagenomics and Arun, you're, you're up there at Hopkins and the Hopkins lab has developed an in house metagenomics assay that you can utilize. 439 00:43:20,495 --> 00:43:28,565 There's only one sent out in the US out at UCSF, but I hope that that's a place where we as, as a community can continue moving. 440 00:43:28,615 --> 00:43:29,679 It's going to take a long time. 441 00:43:29,679 --> 00:43:30,265 It's a lot of work. 442 00:43:30,265 --> 00:43:31,815 These are highly complicated tests. 443 00:43:31,815 --> 00:43:39,465 There are a lot of limitations to them, but they potentially can really fill in some gaps and not replace the other tests that we're using either. 444 00:43:39,610 --> 00:43:44,350 There, there will always be a place for culture, there will always be a place for targeted assays. 445 00:43:44,590 --> 00:43:48,640 I think we're learning what is the place for these advanced diagnostics like clinical metagenomics. 446 00:43:49,490 --> 00:44:02,215 Arun Venkatesan: The other thing that we're really learning about is that Yes, these patients come in with an acute syndrome, an acute encephalitis, but the picture can evolve, and it can evolve over weeks to subsequent months. 447 00:44:02,395 --> 00:44:06,715 I think that really highlights the importance of careful follow up of these patients. 448 00:44:06,795 --> 00:44:15,015 It's not enough just to do our best for these patients in the hospital and then send them home or to wherever it is that they go after that. 449 00:44:15,475 --> 00:44:24,760 I think it's really important to keep a close eye on them and make sure that we understand what the biology of the disease is and how it's unfolding in these patients. 450 00:44:25,850 --> 00:44:30,299 Sara Dong: Thanks again to our guest stars, Karen, Carol, David, and Arun for joining today. 451 00:44:30,949 --> 00:44:39,020 You can find their article, State of the Art Review, Acute Encephalitis, from CID, linked in the episode information and on the Consult Notes. 452 00:44:40,110 --> 00:44:44,080 Please be on the lookout for future STAR episodes, which will be noted in the title. 453 00:44:44,665 --> 00:44:50,955 We're still catching up on the previously published articles and then moving forward as we have new releases, we'll bring you new episodes. 454 00:44:51,635 --> 00:44:53,944 Don't forget to check out the website, febrilepodcast. 455 00:44:53,985 --> 00:45:01,545 com, where you will find the Consult Notes, which are written complements to the episodes, our library of ID infographics, and a link to our merch store. 456 00:45:03,365 --> 00:45:11,700 Febrile is produced with support from the Infectious Diseases Society of America, IDSA, Audio editing and mixing is provided by Bentley Brown. 457 00:45:13,110 --> 00:45:17,180 Please reach out if you have any suggestions for future shows or want to be more involved with Febrile. 458 00:45:17,630 --> 00:45:20,069 Thanks for listening, stay safe, and I'll see you next time.