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Welcome back to the neuro transmitters, a podcast about everything related to clinical neurology with the goal of reducing your neur a phobia. And I'm your host, Dr Michael Ken Tris. Today, I wanted to try something a little bit different. Let's start with a hypothetical case. It's a Saturday afternoon and John has gone out to have lunch with his family as he goes to places, order a look of confusion comes over his face. He struggles to get his words out and his right face begins to look droopy the staff at the restaurant called the ambulance. And John is taken emergently to the hospital. He arrives at the hospital within the next 15 minutes and in the interim has developed weakness in his right face and arm as well. Some slurred speech he's evaluated by the emergency physician and is found to have an NIH stroke scale score of 10. He immediately goes and has a noncontrast ct of the head followed by a CT angiogram of the head and neck looking for any large vessel occlusion of which none is found given the well known timeline of his symptoms. He's offered thrombolytic therapy with tea pee or tissue plasminogen activator, also known as alteplase and is admitted to the neuro ICU. Now, this is a very clean and straightforward scenario, very often in clinical practice, you find that the timeline is uncertain. Maybe people have woken up with symptoms and there are lots of confounding factors. Maybe he had a recent surgery, maybe you've been off of a blood thinner, maybe he's on Coumadin, but his eye on our isn't therapeutic. So there are lots of things that you have to go through in an acute stroke evaluation in terms of relative risks, contra indications for thrombolytic therapy and so on. And we're going to go into a few of those things today. So as you may have guessed, we're talking about stroke in particular acute stroke. So let's talk a little bit about kind of the epidemiology. So I've pulled some statistics from the CDCs website here in 2021 in six deaths from cardiovascular disease was due to stroke every 40 seconds. Someone in the United States has a stroke and every 3.5 minutes, someone dies of a stroke every year. More than 795,000 people in the US have a stroke and about 610,000 of these are first or new strokes. About one in four of these are people who have had a previous stroke. Most strokes, about 87% are ischemic and stroke is also very expensive in terms of healthcare related costs with nearly 53 billion with A B dollars spent between 2017 and 2018 with stroke related costs. So stroke is a leading cause of serious long term disability, reducing mobility in more than half of survivors age 65 or older. So stroke is very disabling both from a personal and societal aspect, very costly on the healthcare system. Uh And I'll have these statistics linked in the show notes as well on the CDCs website. Now, an unsettling trend, you know, stroke typically increases with age in terms of risk, but they can obviously depending on mechanism occur at any age. Uh in 2014 38% of people hospitalized where stroke were less than 65 years old. And there is evidence in recent studies that show that stroke incidents is increasing in younger people and this is mostly attributed to increasing incidence of traditional stroke risk factors more than any kind of more uncertain etiology. Another paper I'll be referencing back to throughout this podcast is the guidelines for the early management of patients with acute ischemic stroke 2019, update to the 2018 guidelines for the early management of acute ischemic stroke, a guideline for healthcare professionals from the American Heart Association, American Stroke Association and this was published in the journal stroke in 2019. So let's start with some definitions, right? We talked about ischemic stroke, obviously due to an inclusion of a blood vessel and that is around 87 88%. Uh When we look at the other types of stroke, we're talking about civil arachnoid hemorrhages and interest cerebral hemorrhage is making up about 12, the other 12%. So breaking down types of ischemic stroke, we break it down initially into lacuna and non lacunar stroke. And if you look back in the literature, you can see there's many different definitions that go into like, you know, stroke. But the one we're working with today and one that's pretty typical is someone with a typical Lacuna stroke syndrome, someone with a normal CT or MRI of the head or a subcortical stroke measuring less than 1.5 centimeters in diameter on CT or MRI and Lacuna strokes are going to be our typical stroke secondary to small vessel ischemic disease. When we get to our non looking at her strokes, then we have several different ideologies going on there. So we have strokes related to large artery atherosclerosis. This would be stuff like uh carotids, plaque or intercranial uh atherosclerotic disease, cardioembolic strokes, uh cryptogenic strokes or uh embolic strokes of undetermined source. So let's break those down a little bit. A cardioembolic stroke obviously is due to some sort of source of an embolus in the heart. Uh Most commonly, we're thinking of things like atrial fibrillation, but there can be other structural causes that can put people at risk as well. Cryptogenic stroke and embolic stroke of undetermined source or esus esus. So what is esus? So that is essentially you get an MRI of the brain and the pattern looks suspicious for an embolic source, but you've gone through your entire work up, you have not found uh entity or an etiology to attribute the stroke too. And that kind of pears with cryptogenic strokes, which is again, similarly, you have a stroke and you've gone through all the testing and you don't have an etiology for why someone would have had stroke. So this is kind of like the rectangles and squares, right? All squares or rectangles, but not all rectangles are squares. So all esus uh strokes are cryptogenic but not all cryptogenic strokes are esus. So having said that let's talk a little bit about acute stroke management. So as always the essentials come first, right? A B CS that is airway breathing circulation. Now, something interesting with stroke is that the body's natural reaction is to try and increase that cerebral profusion pressure. And one of the ways that will do that is by really ramping up your BP. So the tricky thing is that sometimes having significantly elevated BP in and of itself can cause a stroke type syndrome. So we want some parameters on our BP. So we wanna systolic less than 185 and diastolic, less than 110. And we do want to avoid significant drops because that if there is a flow limiting stenosis, let's say like in someone's internal carotid artery, then dropping, that pressure is going to potentially lead to a watershed type event. So we got to make sure that we don't drop it too far. Uh You also want to make sure if this person is hypotensive, correct that if they're hypovolemic, if there's fever, if there's hypoglycemia, uh these things need to be corrected before kind of progressing down to the next step in terms of potential interventions. Other things that we want to do acutely is as mentioned in the vignette, a noncontrast ct head, uh ct a head and neck and in select case is also a ct perfusion of the brain and we'll talk a little bit more about when we might want that. And then we're also going to be performing an NIH stroke scale score. Now, I'm going to take a second and harp on history. So one of the most important things with acute stroke management is the timeline. So making sure you have an accurate time of onset or what's often referred to as the last known normal time, which a lot of times people misunderstand, they might think I found them with these symptoms at this time. But you need to clarify, know when was the last time you saw them without these symptoms. And so that's really important for establishing the timeline, setting expectations, risk stratifying people and deterring. What acute therapies are actually on the table for this person without exposing them to significant risk. So we all know time is brain and the faster we're able to implement treatments, the better the outcome is for the individual patient. So we talked about ideal treatment targets in the hospital setting were talking about a door to needle time for IVTP A of less than 30 minutes and a door to groin puncture time for endovascular or mechanical thrombectomy of less than 60 minutes. If we look at some meta analyses on TP A, uh now the number needed to treat for one additional patient to have an excellent functional outcome from tea pee at 90 days is time dependent. So less than three hours, uh 10 patient's is the number needed to treat in the extended 3 to 4.5 hour window. It's 19. So you can see in just that short period of time that we are almost doubling the number needed to treat. And overall about one out of three patients treated with TP A will have reduced disability as created on the modified ranking scale. Uh as opposed to those who did not receive TP A. But let's go back to CT Scan a little bit here. In particular, the noncontrast CT obviously, before we talk about anything like thrombolytic therapy, we need to talk about, you know, what are the contraindications. So one of the big ones that we would find on a CT of the head would be a hemorrhage of any kind. So, if you do see any blood on CT head, obviously, you're going to deviate from everything we're going to be talking about this particular podcast. So what are the things that we can see on a QCT that might help us guide our therapy a little bit? So there are a couple of things in particular. Um You might see early hypodensities, so that kind of early loss of a gray white differentiation or in more progressed strokes, you might also see some areas that have a little bit of swelling through them. And this is important because it can help you time, the probable onset of symptoms. If your history is unclear. Uh One scoring system that is used fairly often, it's called the aspect score, which is a 10 point score and you lose a point for every area in the icamc a territory that is uh kind of showing signs of hypodensity already. So high score of 10 normal zero, everything's already infarcted. And this can help risk stratify for different interventions in the acute stage depending on the clinical presentation. You may also be fortune enough to see a hyper dense vessel which is essentially a little bit of thrombus in typically uh the middle cerebral artery, sometimes in the basilar, rarely other vessels. And that can sometimes show you like, hey, I don't even know if I need a CT A because I can already see that there is a thrombus sitting right here and you can call up your colleague on the interventional radiology side and kind of get that ball rolling right out of the gate. But most of the time we are still going to want that CT A, even if we see a hyperdense vessel sign, uh it can be helpful, still see the rest of the anatomy and know what you're working with. So we typically we want to see all the vessels from the aortic arch up to the vertex of the head. And there is a good chance even if you did see any intracranial hemorrhage on your initial noncontrast ct, you're going to want that CT angiography to see. Is there an aneurysm? Is there a vascular malformation? Is there any other structural abnormality that might have some flow to it from a vessel that might need intervening on acutely? The last acute modality that will sometimes get is a CT brain perfusion and not, not every patient needs a CT perfusion. Uh It does you know have a bit more radiation, more contrast. So choosing the patient is important. Uh depending on what the symptoms are. Are they a candidate for endovascular therapy? Uh Is there an unknown onset of symptoms? So see TPS tend to be most helpful in patients who are potential endovascular thrombectomy candidates in the extended time window. That's kind of like the 6 to 24 hour post symptom onset based on kind of the diffuse three and dawn trials, CTP has a little bit going on. Uh There's several different variables, different values that are being measured. So the main ones that we're looking at here are the cerebral blood flow or CBF. And that is the total vine of blood flowing through a volume of the brain measured in milliliters per 100 g of brain tissue. Then there is cerebral blood volume, which is the volume of blood moving through a volume of brain per unit time. So that's mils per volume per time or seconds. And there's the main transit time, this is the average amount of time of the blood to pass through a given brain region measured in usually seconds. And then there's also T max, which is related to the mean transit time or MTT uh which is a little bit more sensitive and is helpful for defining the penumbra. So we can relate all these together, the cerebral blood flow equals the blood volume divided by the mean transit time. And this does have a role to play in terms of the patterns we see on CTPS in these acute stages. So if we think about what happens in a stroke, we have an occlusion of a blood vessel that is going to increase the mean transit time, right is going to slow things down a little bit. The brain tries to auto regulate that. So bas oh dilates arteries distal to the inclusion. This is going to increase the cerebral blood volume. So we are maintaining our cerebral blood flow or it might be slightly decreased because we are both increasing the blood volume and the mean transit time. So the ratios if the brain is able to compensate will be relatively preserved. And so our CBF are blood flow remains relatively stable as time goes on. However, the mean transit time will increase beyond the vase of dilation capacity of the brain. And so that's when we start seeing a fall in our blood flow are CBF starts to drop and when the CBF starts to fall, that's when we begin to see different patterns of ischemia. So the two main patterns I wanted to talk about our water sometimes referred to as a matched pattern and a mismatched pattern. So the one we hope to see is a perfusion mismatch. And so what we'll see on that is a decreased cerebral blood blow, a normal cerebral blood volume and increased mean transit time and T max. And so what this means is that there are areas with salad herbal tissue that are ischemic but have not yet infarcted. And there have been some studies actually recently that sometimes questioned the predictive value of some of these values. And that's because it's kind of predicated. This is not a static test, this is a snapshot in time of a dynamic process. So potentially, uh if you act very quickly, the even the areas of court infarct, which we'll talk about in a second could potentially have been saved. So some of the predictive aspect of CT perfusion is based off of how long they're expecting it to take for someone to act, to intervene in these cases. So the second pattern is one that we hope not to see. And this is what's called a matched pattern. And in this, we will see decreased blood flow, decreased blood volume and increased mean transit time. So this is considered the court stroke with no penumbra. So that sums up our imaging a little bit. Um Now let's go back again to thrombolytics. So we're gonna be talking mostly about tea pee although tenecteplase TNK is being investigated and uh in being used in some scenarios around the country already. So I think one of the first things to think about with thrombolytic uh considerations is the contra indications and there are quite a few contraindications which can be hard to remember if you're not doing this on a regular basis. I like the way that a book, uh the code stroke handbook approach to the acute stroke patient by uh Miceli at all. I hope I'm pronouncing that correctly and I'll have a link to that book in the show notes as well. Have organized things in a way that kind of groups them together by family if you will. So let's talk about absolute exclusion criteria. So any source of active bleeding or bleeding, diathesis, iss or any hemorrhage on brain imaging, right? We're kind of like, well, we're probably not going to be giving uh them something to make them bleed more. And then we've got a lot of relative exclusion criteria. And this is kind of an interesting phenomenon that we've seen some of these uh contraindications being moved over the last several decades into more relative exclusions over time. So the main categories that they are grouping things into our by history, uh by clinical presentation by neuro imaging and by laboratory values. So, historical exclusion criteria. Again, these are relative history of intracranial hemorrhage, a stroke or serious head or spinal trauma in the last three months, major surgery such as cardiac thoracic abdominal orthopedic in the last two weeks or arterial puncture at a non compressible site in the last week. Clinical uh symptoms suggestive of subarachnoid hemorrhage stroke symptoms due to another non ischemic acute neurologic conditions such as seizure with postictal Todd's paralysis or focal neuro signs due to severe metabolic abnormality. In particular, uh glycemic derangement, hypertension refractory to aggressive antihypertensive treatment. Uh such that you cannot get under the target BP of 1 85/100 and 10 millimeters of mercury or the patient is currently prescribed and taking a direct non vitamin K oral anti coagulant typically with a dose within the last 48 hours on imaging. If your CT is showing early signs of extensive infarction laboratory, uh if they have an eye on our, of more than 1.7 platelets, less than 100 or a blood glucose level under 50. Now, even if they don't have any of those contraindications, there are still risks obviously to giving someone TP A, there is around a 6% risk of symptomatic intracranial hemorrhage. And the folks who are going to be at higher risk or those who are older have a high NIH or a low aspect score on the CT head, they have hyperglycemia or uncontrolled hypertension. So given these risks, it is important to have a conversation with the patient of able or with their family or other legal representative as possible to have them consent for treatment. There is also a 1.3% risk of angioedema and a 0.5% risk of anaphylaxis. Uh Some people might say that having a previous treatment with TP A and anaphylaxis or angioedema in the past is also a relative contra indication. But if there is that known history pre treating with Benadryl steroids, things like that would be a potential option in that scenario. So let's say the worst happens. Uh you give T pa somebody bleeds. So a lot of times you can give cryoprecipitates or fibrinogen uh plus tranexamic acid, you're also going to want to make sure you're checking CBC PTTS fibrinog in I and our, get a type and screen and you'll also be getting the ICU and neurosurgical services involved in these patient's care as well. So let's talk about endovascular therapy or mechanical thrown back to me. So most of the studies that were initially done, we're in the 2014, 2015 era. And so there's several of these mister clean escape sweep prime re vast cat extend I A. So these are looking primarily at large vessel occlusions in the anterior circulation's were talking mostly about uh the ICAs, the MCAS uh primarily. So there have been some nice meta analysis of these studies. And the great thing is that the number needed to treat for these patient's is quite low to make a very significant difference. So if we look at uh dominated to treat for an improved functional outcome at 90 days, and they define this as an improvement by at least one level on the modified ranking scale. Uh That is a 2.6. So you need to treat 2.6 people for them to improve just one category of function. And if we're talking about how many do we need to treat for functional independence? And this is defined as an MRS of 0 to 2, that's 55 patient's. So that is just remarkably effective in the appropriately selected patient's. So who are these candidates for this procedure? So there are two groups. So we're going to talk first about those who come in acutely. So within six hours from onset of symptoms, people who have persistent disabling stroke deficit and an NIH score of six or greater, they have an acute intracranial occlusion in the anterior circulation, amenable to retrieval. So this usually will include the distant I see a, the uh M one segment of the MC A or the proximal M to division. Sometimes you will see um interventionalist go after smaller vessels, but that is very much on a case by case basis. And then the last thing you're looking for on the CT scan is there a small to moderate ischemic court which is often estimated using the aspect score. So six or higher uh is considered people who might be potential candidates for thrombectomy. Now, let's talk a little bit about the extended time window. So there were a couple of trials done that we mentioned earlier the dawn and diffuse three. And what they found was that even in these extended time windows, the number needed to treat I was 3 to 4 for functional independence at night, 90 days. But it was not without risk in these patients who are in this extended time window. So the number needed to harm is 35 which is to say one out of 35 patient's will experience a symptomatic intracranial hemorrhage. So there are some risks with this extended time window. So we need to make sure we're selecting our candidates appropriately. So, so similar to with our other thrombectomy candidates, we are looking for a large vessel occlusion that is amenable to thrombectomy. Uh patient's with an NIH stroke scale of six or greater. And this is where our profusion scans tend to come into play. So we're looking for an ischemic court volume less than 70 CC S and a mismatch ratio of 1.8 or greater and a mismatch flame of 15 mL or greater. Obviously, there are always exceptions to these, but these are good guidelines to follow. And one last thing I'll mention about thrombectomy is we've been talking about anterior circulation. There was a recent study uh called trial of thrombectomy 6 to 24 hours after stroke due to basilar artery occlusion, uh looking specifically at that post your circulation population. And I think one of the big takeaways here is that a modified ranking scale score of 0 to 3, which is the primary outcome occurred in 51 patient's in the thrombectomy group. That's 46% as opposed to 26 which 24% in the control group. The other big point was mortality in 90 days was 31% in the thrombectomy group and 42% in the control group with procedural complications reported in 11% of the patients who underwent thrown back to me. So the numbers aren't as good as anterior circulation. But when you think about the consequences of basilar artery uh strokes, things such as locked in syndrome, which can be obviously incredibly debilitating and life ending, then I think these results are very heartening on that front. I think I'll end our talk on stroke here today. If you enjoy this podcast, please rate review and share it on Apple Spotify or wherever you're getting your podcast these days and please subscribe for future episodes when you leave us reviews, that really helps bring the podcast to other people's attention and really helps expand the reach of the show. So I appreciate you taking the time to live. Listen. I hope you found this educational and as always, you can reap me on Twitter at Doctor Ken Tris. That's drkentris or by email at the neuro transmitters podcast at gmail dot com with any questions or show suggestions. Thank you again for listening. I hope you have a great day. We'll see you next time.