So hello everybody. Good morning. My name is Dr. Karen Greenberg and thanks for your patience. We were having a little technical difficulties on our end, but as an emergency physician, my mantra is always to adapt and overcome, and that is what we are going to do. I am an emergency medicine physician and I am also double board certified in neurocritical care. I have spoken to you guys in the past and thank you for the opportunity to be back with you today. You guys actually have to hear from me three times in a row, so I will try to keep this moving along and try to monitor the chat for your questions. I really want to thank you guys for your attendance today. This first talk that we are going to do is literally going to leave you in the top 5% of your peers for knowledge. This is a topic that has been around now for almost two years, but nobody really knows about it. So again, thanks for being here and I hope that you guys are going to learn some cutting edge treatment today. You are probably thinking, why are you talking to me about Alzheimer's disease? As the surgical team, we don't really take care of Alzheimer's patients. That is a medical complaint and I am going to make you think twice about that. I do have one disclosure, that relationship is no longer ongoing. In our egyptics today, you are probably recognizing words on here, abbreviations that you don't even recognize. ARIA, ATT, by the end of this talk you will know what they are. You are going to differentiate ARIA from similar conditions in the emergency setting. You are going to learn how to manage ARIA in patients that are on these ATTs following what the current best practices are. Alzheimer's disease is important. It is a leading cause of cognitive impairment and dementia in older individuals greater than 65 throughout the world. Here in the United States, we have about 6 million with this diagnosis and we do think that number will double by the year 2050. There are several gaps in care with some of these new treatments that we are going to talk about. Thanks to our friends at the University of Michigan, they actually just published this study in 2023. 1.4 million times a year, people with Alzheimer's disease and other forms of dementia visit the emergency department and seek emergency care in some way. Together, they make up nearly 7% of all emergency visits for people over the age of 65. To put that in perspective for you, chest pain is a complaint that we see about 7% of the time in the emergency department. For the Alzheimer's population, that is a very high percentage that they are coming to visit us. If you have 1.4 million visits and 6 million patients in the U.S. with Alzheimer's, it is 23% of ED visits for the Alzheimer's population. One of the first objectives, what does ATT stand for? ATT stands for amyloid targeting treatment. What these treatments do, they are antibody infusions. It is not a pill, it is an IV infusion. What they do is they target the amyloid beta plaque. They are anti-amyloid beta antibodies. When we talk about Alzheimer's disease, the way that these plaques form is they start as monomers. They proceed to protofibrils, to fibrils, and to plaque. The different drugs that we have work on the different stages of that plaque formation. The key with this is that in order for these antibody infusions to get where they are going, they have to transverse the blood-brain barrier. While they are doing that, they are actually weakening the blood-brain barrier. That is where the complications arise. This topic is actually ever-changing right now. The first drug that came out was aducanumab. That drug actually no longer exists. The current drugs that are out there right now is lacanumab. That has been approved for a little bit over a year. Donatumab literally just got approved in July of 2024. July of 2024 is only four months ago. It was actually really interesting. This drug had to go to a special FDA advisory panel because of the risks that the drugs can cause. Now, that panel did unanimously approve Donatumab. It gives you a little bit of insight into some of the controversies over these drugs. What you have to understand is that neurologists and patients are extremely excited about these new therapies. For the longest time, the drugs like Aricept, they really just slow the progression of the disease. They work on things like acetylcholine receptors. This is a totally new class of drugs. Again, neurologists are excited to have another treatment in their toolbox. Most importantly, patients and their families are craving a treatment like this to help themselves or their loved ones. What you're looking at in the images here is you're looking at a PET scan. All of this orange is positive amyloid. This is an Alzheimer brain before treatment. After treatment, this image on the right, all of that orange is gone. All of that plaque is gone. It's really an incredible result. We're seeing about 30% slowing of the disease progression over 18 months. Again, it's not a cure, but it is slowing down disease progression. Again, these are the first disease-modifying therapies for Alzheimer's patients. ARIA stands for amyloid-related imaging abnormalities. This is really important. Amyloid-related imaging abnormalities. What happens is you can get ARIA-E, which is edema, or you can get ARIA-H, which is hemorrhage. You've learned that ATT stands for amyloid-targeting therapy, and you've learned that ARIA stands for amyloid-related imaging abnormalities. How does this work? We talked about it's an infusion. It's an antibody. What it does is it binds to that amyloid beta, but in order to clear it, it's weakening blood vessels. It's got to cross that blood-brain barrier. If you weaken the blood vessel and you leak protein, you're going to end up with edema of the brain. If you weaken the vessel to the point where you're leaking blood, you're going to end up with ARIA hemorrhage. What are the symptoms that you might see? Look at this list. Headache, confusion or altered mental status, dizziness or vertigo, and nausea, vomiting. First of all, that sounds very similar to a posterior stroke presentation. I've probably talked to you guys about that in the past, how to identify some of our dizzy patients and not blow them off as peripheral patients, but more central. These are very vague complaints that patients can present with who are on these ATT therapies. Luckily, most cases are asymptomatic, but when it is symptomatic, you can see that the complaints can be very nonspecific. You can also see visual disturbances. It can present like a stroke with an acute onset of a specific neurodeficit. It can cause gait disturbances and it can cause seizures. When you look at the statistics here in phase 3 trials, so remember, we're not even going to talk about aducanumab anymore because they're not making it. It's just shifted to leucanumab and dunatumab. The incidence of ARIA-E for leucanumab and dunatumab is about 12% to 24%, and for hemorrhage, it's 17% to 31%. That means that 1 out of every 3 patients who are taking these infusions are either going to experience ARIA edema or ARIA hemorrhage, whether it's asymptomatic or symptomatic. That's a really, really high percentage that we need to be aware of. Luckily, most of the cases of ARIA are mild. Typically, they're asymptomatic. Maybe they're mildly symptomatic, but if you stop treatment, it will be reversible. About 1% of patients do have severe ARIA, and we're going to talk about those cases coming up. There were no deaths reported during the trial phase of leucanumab, but there have been 3 deaths in the trial phase of dunatumab. Now that leucanumab, remember I told you it got approved in July of 2023, so it's been a little over a year, there's already been 4 fatalities reported so far in the extension phase of leucanumab. What do I want you guys to consider and what do I want you to take away at the end of this half hour? These amyloid targeting therapies remove plaque from the brain, but again, it's at the cost of weakening those blood vessels. So concomitant anticoagulation or lytic therapy can skyrocket your risk of intracranial hemorrhage. CAT scan is not enough. These patients need to have MRI to pick up these edema and hemorrhage changes. These infusions happen every 2 weeks on leucanumab and every 4 weeks on dunatumab. There's a very stringent MRI schedule where they're getting MRIs 2 weeks in the beginning and then it gets spread out to every 4 weeks. So you would need to have access to the drug and in order to qualify for the drug you need to be able to have an MRI. We're talking about patients that are cognitively impaired at baseline. If this patient comes to my emergency department with some of those vague symptoms, seizure, maybe they're presenting like a stroke or headache, are they going to be able to tell me that they're on one of these newer agents? I can't tell you how many stroke alerts I take care of where EMS notoriously says the family is right behind me. And that means if you're lucky they show up several hours later. So it kind of begs the question should patients who are on these new medications, should they maybe have like a medical bracelet or something so we can identify them? Right now I think that this number is a little low, that there's 800 patients taking in the United States. It's difficult to know exactly how many patients are on these, but there was a very recent article just this past week that talked about 600 patients in UCLA, a couple hundred patients down in Chapel Hill and Duke. So just taking those patients alone, we're probably up to well over a thousand patients taking these here in the United States, with many more to come. And the key is that emergency physicians don't know about this, radiologists don't know about this, even neurosurgeons don't know about this and the complications that can come with it. So let's take a look at some case reports. Case number one is a 65-year-old female who presents 30 minutes after acute onset of aphasia and left gaze preference. So that sounds concerning, right? Left gaze preference and aphasia do go along with stroke. Her blood pressure looks okay and her glucose is normal. A CT of her head and a CTA shows a left temporal hypodensity with a left MCA distal M3 occlusion. Now that's interesting because her symptoms only started 30 minutes ago. You really should not be seeing a hypodensity on CAT scan after only 30 minutes. It usually takes hypodensity anywhere from 3 to even 12 hours to show up. But her platelets look good and her INR is normal. Some past medical history for her. She's in the early stages of cognitive decline and she's homozygous for ApoE4 allele. This is super secret neurology Alzheimer's stuff. If you're homozygous for that ApoE4 allele, it puts you at higher risk for events like edema and bleeding. She gets the Leucanomab infusions every two weeks. Remember I said Leucanomabs every two and Dunomanomabs every four. Her latest infusion was four days prior and she's not on any antiplatelets or anticoagulants. She has had prior imaging. Remember all of these patients need regular screening MRIs. Her MRI of her brain about three months ago showed mild small vessel disease, but no microhemorrhages, no edema, and no aurea. The question that you want to think about right now, is this patient a candidate for alteplase or tenecteplase at this time? If she is a candidate, should it be given? Yes, the patient may be a candidate, but fibrinolytic therapy is not preferred. Yes, the patient may be a candidate and fibrinolytic therapy should be given. Yes, the patient may be a candidate, but lytic therapy should only be administered within the first hour. Or no, she's not a candidate. Now truthfully, she's a candidate, right? She's within 30 minutes, her blood pressure is good, her blood sugar is good, she's not on any anticoagulants, and she did receive alteplase. And what happened? 50 minutes later, you get the dreaded, Dr. Greenberg, can I see you in room 5, please? Because 50 minutes after the start of alteplase, her systolic blood pressure rose from 160 to 250. The infusion was stopped and a repeat cascade was done that showed extensive multifocal intraparenchymal hemorrhages. There was no other bleeding. Now this is interesting, right? Because when you have a stroke, we know that lytics can make you bleed, but you bleed in the area of the infarct. This patient has bleeding extensively and multifocally. They tried to reverse with TXA and cryoprecipitate. She persisted with global aphasia, agitation. She went into status epilepticus requiring intubation and she was ultimately made comfort care and died. What you're looking at in your screens here, now this is MRI, right? So black is blood on MRI. If her stroke was only right here, why did she bleed everywhere else? I mean, this looks like her brain exploded. And on her autopsy, you're looking at her actual brain by autopsy, all of the dark red is blood. What if I told you that this case was actually published in the New England Journal of Medicine in February of 2023? That's almost two years ago. Have any of you on the call out there heard of anything like this? Because I'll be honest with you guys. Remember I told you this is a safe place. This is your conference. This did not get on my radar as a neuro emergency medicine specialist, neuro critical care specialist for a good eight months, right? And what the FDA has to say is not that helpful because intrastebral hemorrhages greater than one centimeter in diameter have been observed in patients taking leucanomab, additional caution should be exercised when considering the administration of a thrombolytic agent. And it's kind of like, you think after this case and I can tell you that there are tasks force now, they just did a huge session on this and international stroke conference in February. And there are task force being put together to say that these patients should not be lytic candidates, but nothing has translated to the actual AHA, ASA guidelines at this point. So case number two here, if you look at this MRI, you're looking at an MRI on the right of your screen and the bright white is edema. Okay. There is something called posterior reversible encephalopathy syndrome, which most of you guys have probably heard of that. And it presents with hypertension and seizures and visual changes and altered mental status. And you see symmetric edema, especially in the posterior parts of the brain. Okay. This is a 65 year old female with complaints of sudden onset, increased speech impairment. She's made a coach stroke emergency on her brain MRI. There's no contrast enhancement, recent hemorrhagic ischemic events. There's bilateral asymmetric vasogenic edema in the left parietal occipital lobe, right occipital regions compatible with press. This is the radiology reading. But the patient's last infusion of Leucanomab was 14 days prior. Remember it's every two weeks and she's presenting with a one minute generalized tonic-clonic seizure. So the next question for you, what medications may be best to consider for management of a patient who prevents with severe aria edema? Do you want to heparinize them? Do you want to prophylactic load them with anti-seizure medication? Do you want to initiate high dose glucocorticoids? Or no medications are recommended, just discontinue the amyloid targeting therapy. Now what's key here is the radiologist is leading you down the path of darkness, right? The treatment for press is to treat hypertension and to treat seizures if they occur. This is not press. This is aria edema. Okay. So to treat aria edema, you need high dose corticosteroids like dexamethasone or methylprednisolone to try to minimize the symptoms. We're trying to figure out if plasmapheresis can maybe help pull out the antibodies that are in the body. The problem is that plasmapheresis will work on the bloodstream, but it won't cross the blood barrier to work on the antibody that's already in the brain. Okay. So this is a case where you would need to tell your radiology, Hey, this is a patient on one of these new ATTs. Are we sure that this is press and not aria edema? Because the treatment is different. And clearly when we talk, these are patients that are ending up in your neuro ICU, right? Hemorrhage, MRI like that is being admitted to your ICU. So it's definitely pertinent. Case number three is a 70 year old female with sudden onset left neck pain and left frontal headache associated with visual flashes and an episode of left upper limb paresthesia. Her symptoms resolve spontaneously. So when you see her, her NIH stroke score is zero. Her last infusion of leucanomab is 30 days prior. That should set off alarm bells right there because the infusions of leucanomab are every two weeks. So why is her last infusion 30 days prior? Because her last safety MRI showed moderate aria edema and mild aria H, which was three micro bleeds. Now I don't think, I think that is very reasonable. If you don't make this a stroke alert, you're at least thinking TIA and you're at least getting some imaging. But do you expect to see this on her cat scan? This is a really big hemorrhage for somebody who has an NIH stroke score of zero. And something that you guys are all very familiar with is the ICH score, right? So she gets zero points for her GCS because she's at a 15, but her ICH volume is greater than 30. So she gets one point for that. There is intraventricular hemorrhage. So she gets one point for that. She's less than 80 and it's not inferential. But this ICH score of two for her translates to a mortality of 26%. So in these cases here, we usually don't treat hemorrhage with high dose steroids. It's usually contraindicated. But for these cases of aria, we do think that there's going to be a role for high dose steroids. And you're thinking like M at multiple sclerosis doses. So you measure a one gram, but instead for three days, you're going to extend it out to five. You're going to treat seizures if they occur. You're going to reverse anticoagulation because she was on Xarelto. You're going to manage blood pressure. And the question is, is plasmapheresis a viable option? And if it is, does your institution do it or do you need to transfer? One final case here. This was actually published in Nature Communications. It was published in December of 2023. So this is less than a year ago. This is a 79-year-old woman. She was in the trial for leucanomab, but she received placebo. So when it went open phase, she decided to enroll so that she would be guaranteed to receive the drug. After her third biweekly infusion, she suffered a seizure characterized by speech arrest and generalized convulsion. MRI showed extensive edema and microhemorrhages throughout the brain. They tried her on anti-epileptics. They tried her on high dose steroids. Interestingly, she also presented a new onset AFib and she was given heparin for that as well. But after several days of treatment, she died five days later. This is a direct quote from Nature Communications. At present, ARIA has rarely been encountered outside of a clinical trial population. So community health care providers would likely benefit from education on the features and risks associated with this side effect. Again, you think? So give yourselves a lot of credit for being here today and hearing about this topic. I'm trying to watch the chat in the background with you guys and I can tell that this is definitely new information. What I'm going to leave you with is another topic here. We saw the case with lytics. We saw the case of the patient who was on rivaroxaban. So what about using antithrombotics with these ATT therapies? Forget about aducanumab, it's gone. In the Leucanumab trials, antithrombotic use was permitted. They said it was not associated with increased risk of ARIA. But the three deaths in the open label extension, they were on anticoagulants or that was the lytic case that I showed you. For donatumab, antithrombotic use was also permitted. They said that they were not associated with increased risk of ARIA. The three deaths during the trial, none were on anticoagulants. So these patients already had bleeding not even on anticoagulants. We know that lytics increased the risk. It seems that it would be very dangerous to just even anticoagulate these patients as well. Stop, think, and act with things that are new. What about all of the past medical history that all of our patients have? So what if they present with an acute MI or acute coronary syndrome? What if they're in atrial fibrillation? What if they have a DVT or PE? It can be very dangerous to even just anticoagulate these patients. Now can you imagine me as an emergency department physician telling a cardiologist that I'm not going to anticoagulate their atrial fibrillation patient or acute coronary syndrome patient because they're on one of these new therapies? I guarantee you they don't know about these therapies and what the risks are. So it's our job to be aware and think it through. Again, the FDA, because intracerebral hemorrhages greater than one centimeter in diameter have been observed in patients taking licanumab, additional caution should be exercised when considering the administration of antithrombotics to a patient already being treated. I don't think that that really helps us at all. I think that they're still really hedging, but it's something to absolutely be aware of. So in summary, there are no official guidelines yet for emergency department settings related to amyloid targeting therapies use and the possibility of aria amyloid relating imaging abnormalities. I can tell you that there is a task force that's working on this and we're going to hope to see American Heart American Stroke update, but the consensus right now is do not give lytics for these patients. You need MRI. Yes, of course, CAT scan is readily accessible and that's what you're going to go to first, but these patients are really going to need MRI to identify the abnormalities. If it truly is an acute stroke, get neurology and neurosurgery on board early and see if they can be an intervention candidate rather than giving any type of IV lytic. Watch out for anticoagulating these patients, right? There's very common diagnoses that require anticoagulation. I'm not sure that these patients are really candidates if they're on the ATT. Multidisciplinary approach. Tell radiology what your patient is taking. Get neurology neurosurgery on board and there should be a very low threshold to admit these patients in any type of unclear presentation. So I think I did that in exactly 30 minutes. I can see from the chats here that this is a very new topic for all of you. I would absolutely consider the patient as an intervention candidate rather than doing any type of IV therapy. I can see that somebody did also say that there was a memo sent out to the neuro group to bring awareness. Somebody's stealing my medical alert bracelet. That was my idea, but thank you guys for your attention. If there's any other questions, I can try to answer them. Thank you so much, Dr. Greenberg. If you see further in the chat, there's a couple additional questions. One is, is a TEG scan useful for any reason? You can try, but I think that with these medications being so new, I would not recommend, even based on TEG, I would not recommend in good conscience at this lecture today that they would still be safe to anticoagulate. Very good. Thank you. What about, we're all in the surgical arena here, so what are your guidelines or recommendations on holding any of these medications in the perioperative setting, either pre or post? So that's a great question. Luckily, these infusions happen every two weeks, so it would definitely be my recommendation. I mean, of course, if the patient needs emergent surgery, you're always going to do the right thing, but if it could be something that's planned, I think that you would definitely need to have a multidisciplinary approach as to whether they should continue the medication or put it on hold until post-op. Very good. What is your opinion on the FDA? Do you think they're a little lax in making some guidelines and recommendations to physicians or as far as medication safety? Tell us about that. So it's really interesting with the FDA. I feel like the FDA is always going to hedge their bets, right? And then it's the specialty colleges like American Heart and then American Stroke that'll really give us the practicing guidelines, right? So for example, Alteplase is only FDA approved out to three hours, but it's American Heart and American Stroke that lets us use it up to four and a half, right? I don't really foresee us getting too much help from the FDA. What I'm really hoping, though, is that this task force that has some pretty big name neurologists on it will be able to force the American Heart, American Stroke Association's hand to give us some more discrete guidelines. Wonderful. Yes. Good, good recommendations there. Thank you so much, Dr. Greenberg, and I believe we get to have you for the next session, a couple of sessions as well. Thank you so much. Okay, great. Thank you.

amyloid-targeting therapies

Alzheimer's disease

amyloid-related imaging abnormalities

emergency care

neurocritical care

blood-brain barrier

multidisciplinary approaches