Hi, guys. Thank you so much for coming today. And I am really looking forward to talking to you about ICP monitoring, potential ocular biomarkers of intracranial injury. So I am, just as I was nicely described, and I appreciate that, an assistant professor in the Department of Neurology and Neurosurgery at Boston University Chobinian and Evadesian School of Medicine. I'm a clinician scientist and neurointensivist who focus on the development and validation of data-driven tools to support clinical decision-making. I receive research support, however, have no disclosures related to this talk. Some of the learning objectives that I want to talk to you guys about today will be to know available ocular non-invasive biomarkers that you can use to assess potential evolving intracranial pathology. Two, I want you to be able to recognize what is an abnormal value. And three, let's understand the potential and the limitations of these modalities because that's going to be increasingly important to determine how do you interpret them. So let's continue our case. Our patient was resuscitated, got three units of PRBCs and three units of FFP, and pressers were weaned. He was admitted to the SICU, and pupils on repeat examinations were briskly reactive. But several hours later, he no longer opened his eyes, and he localized bilaterally only. So you just heard an excellent talk about what you can do for imaging. But say you had just gotten imaging, and the imaging was OK. Are you going to send them back down? Are we going to do hourly imaging? Will your radiologists allow you to get hourly imaging on your patients? Maybe not. And so then we revert back to what is our clinical exam, and how can we use some non-invasive tools to be able to better assess, does this patient potentially need imaging? So what is the standard of care? Clinical anisocoria, or a difference in pupil size, is typically regarded as a difference in your resting pupil size of greater than one millimeter. It can prompt a clinician page. It can prompt a clinical assessment by either the nurse or the doctor, and neuroimaging. But what we've found in our data is that clinical anisocoria occurs in more than 60% of all neuroICU patients, or patients who have neurologic diseases. Are all of them experiencing an emergent neurologic decline? They're in the neuroICU, so maybe. But does it happen at every single time this is occurring? We have to really understand these values better. Doctors agree on pupils being non-reactive less than 50% of the time. So if you're just having your nursing assessments or your physician assessments looking at the pupils, you may not have a very reliable assessment as to whether they're actually reactive. And only 66% of subjectively assessed non-reactive pupils are actually non-reactive. That means a third of the time, somebody who's saying that, yep, the pupils are not reactive, this patient might be dead, then they're not actually non-reactive. So what's another way that we can assess some of the information that we see, the windows into the brain through the eyes? A fundoscopic exam. Maybe some of you remember learning in medical school, you get that really, really big tool out, or the smaller ophthalmoscope, and you're trying to look in, and you say like, oh yeah, I saw it, but you're not sure that you actually saw it. You can look and assess to see whether there's papilledema, but that's if an ophthalmoscope is around in your unit. And it's if a clinician can obtain a window and recognize papilledema. And it's also if elevations and intracranial pressure have been occurring over time. So if this is the first time you have acute ICP crisis, and the intracranial pressure shoots up to 40, you still need some time to develop this finding to see this true papilledema, so it may not help you in that very acute setting. So what's the mechanism of pupil and optic involvement due to increased intracranial pressure and mass effect? In the case of mass effect from tumors, or ischemic strokes and swelling, or bleeds, it can compress the pupillary pathways anywhere along the afferent pathway coming down through the optic nerve, down into the midbrain, either ventrally or dorsally, and then coming back through in the efferent pathway through the third nerve. This can happen most commonly. We remember that this occurs ipsilateral to the lesion, or on the same side of the lesion. So we think that the change in pupil abnormality that you might see, that means that the lesion will be on that same side. However, in infrequent cases, this can occur on the contralateral side due to something called a phenomenon of Kernighan's notch. Increased elevations in intracranial pressure can also increase nerve sheath diameter. The mechanism of this is that the pressure pushes everything upwards, and the CSF extends through the subarachnoid granulations, and that will extend something called the optic nerve sheath diameter. And we can use this information and leverage it to look at these different quantitative biomarkers. So in these quantitative modalities, I'm going to speak mostly about quantitative pupilometry. And the most common pupilometer used in the United States is the neurooptics pupilometer. It's available in over 400 ICUs at this point. And it gives you a variety of measurements, including resting pupil size, minimum pupil size, constriction velocity, dilation velocity, and latency. They don't show you all of these numbers here, but you can toggle between a screen to get many more of those. And it compiles all of those particular characteristics into one number called the neurologic pupil index. This is a unitless number that goes from 0 to 5. And according to the manufacturer, greater than 3, so 3 to 5 is normal, and under 3 is abnormal. But it's really important to understand a particular caveat to that. Normal was assessed in normal patients, not our ICU population. So there's a lot of work, including work that's done in our lab, to try to really identify what are the numbers and the set of numbers that will really help us understand what we should be continuing action on. And then there's the optic nerve sheath diameter, which you can use a linear probe that should be available in most people's ICUs and a tegaderm to safely be able to assess the optic nerve sheath 3 millimeters away from the globe. And we'll talk a little bit about this. These are non-invasive. They're longitudinal, and they're quantitative. So we can really trend this over time in a safe way for our patients. So pupilometry, we talked a little bit about what's important. Abnormal values include neurologic pupil index of less than 3, a difference in your NPI between two eyes of greater or equal to 0.7, and a difference in resting pupil size of greater to 1 millimeter. But keep in mind this. You might not want to apply longitudinal hourly or every two hour measurements to your trauma patients who have facial fractures, to patients who have irregular pupils to begin with. You may be panicking because you keep on seeing a non-reactive pupil, and then you look in the chart and you're like, oh, this patient has a surgical pupil, and they don't have a pupil that works. So definitely keep in mind thinking about what are the past medical histories and trying to identify who is the appropriate population in which you should be using this. There are several groups who are working to better understand what are those values and how can we use this marker. There's the Outcome Prognostication of Acute Brain Injury using the Neurologic Pupil Index. It's the orange study. These study results should be forthcoming this year. So we're all very excited to see how they might be able to help us in acute brain injury. And one of the things that we work on is to determine if pupilometry can help us identify decline earlier than we see with typical modalities, especially recognition of decreased arousal. This is a particular patient who arrived seven hours after a large ischemic stroke, and she had very good pupil reactivity between 4 and 5, but at hour 17 had a subclinical decline. We probably would make nothing of this NPI pupil reading that went from, what, 4.8 to 4.4. But she also concurrently had an increase in her difference of size between pupils that went past 1, and then she had an increase in her difference in NPI. And all of this preceded decreased arousal that occurred at hour 22 and result in recognition that led to medical and surgical therapy. So how often do we see abnormal results? This is currently unpublished, but from our center at Boston Medical Center, where we're looking at patients who have at least one pupil observation and at least two pupil observations, just in case one was erroneous, in our bread and butter neurologic injuries. And we see that the percentage of patients who have an NPI of less than 3 at least once or at least twice in our diagnoses may range anywhere between 20% and 60%. And if we look at the percentage of patients by diagnosis with a pupil size difference of greater than 1 millimeter, you might see that that number is looking more like approaching 40% and going up almost to 95% in subarachnoid hemorrhage. So there's really a lot of work to be done to not have somebody notify you every single time that there may be one abnormal pupil reading, but to really think about this holistically in terms of what else is the patient doing? When was the last time that the patient was scanned? Have I looked back through my readings to see does this occur commonly and is it associated with neurologic decline or not? We see that the external environment matters. One of the things that I'd like to suggest for anybody who uses pupillometry in their centers, if somebody's calling you with an abnormal value, ask them, did you shut off the lights? We know that in patients who have critical illness, bright light can give you low readings. And so I always ask whenever I'm called about a patient who may have an abnormal NPI, have you shut all the lights off? Have you drawn the shades? And those are easy things to ask somebody to repeat and to determine, do you have fidelity in your readings? We found that different medications also can affect pupil reactivity. In a study of inalgo sedatives, we found very helpfully that most of the inalgo sedatives that we use, propofol, midazolam, fentanyl, do not actually, are not associated with a change in the NPI or pupil reactivity. However, we did find that there was a counterintuitive increase in NPI that appeared and was significant after administration of dexmedetomidine or Presidex. We also found that there was a slight increase in the NPI after acetaminophen. We don't understand what are the mechanisms that underlie this, and it's very interesting because of all the sympathetic and parasympathetic pathways that actually modulate what your pupil is doing. We also found in an earlier study that osmotic therapy has a significant association with NPI, and the mechanism that we presume or hypothesize behind that is that we're actually treating the mass effect that's causing the decreased pupil reactivity, and wouldn't it be exciting if we have a non-invasive reliable marker that can help us determine what is the efficacy of our medical therapies for some of that swelling. So then I'm going to go over to optic nerve sheath diameter. You guys might notice that there is a QR code here. This is a cerebral edema survey that we're running that is less than three minutes. If you start it now, then you're going to be able to finish it before the end of this talk. What we're trying to do is assess what practitioners, physicians, nurses, NPs, PAs, pharmacists, and fellows, not residents because we want to give you enough time to make your own opinions, but how they monitor and manage cerebral edema. So anybody who takes care of cerebral edema patients, help us understand better the heterogeneity of practice and what you really want to learn in terms of other strategies that we can use. What we found so far is that of our 230 responders, that 33% of clinicians are using optic nerve sheath diameter in their practice. This can be measured using CT, MRI, or ultrasound with a linear probe. There is variable inter-rater reliability and inter-modality reliability, and most commonly it is measured. There are a couple different techniques, but most commonly it's measured from three millimeters from the globe at the point of maximal dilation. Meta-analyses have concluded that it is a sensitive test for ruling out raised ICP in a low prevalence population, so potentially in your ER, and for ruling in a raised ICP in a higher prevalence population. We'll talk a little bit about how you apply that to your practice. Did this go? I think it might have frozen. Sorry guys, just a little bit of technical issue. It gives you more time to take that picture with a QR code and conduct that survey while we're waiting. Oh, thank you. OK, so what are values to know? What's important? If you measure the optic nerve sheath diameter, and it's less than 5 millimeters, you can be pretty well assured that it's normal. Admittedly, many of your patients may fall within that indeterminate area, where you actually have an optic nerve sheath diameter of 5 to 6. However, if you have an optic nerve sheath diameter that is greater than 6 millimeters, then you really should start getting concerned about whether you have abnormally raised intracranial pressure. You can further test that on your patients. Just kind of like an IVC, the extrapolation from looking at the IVC, is if you take your patient from being completely supine to a 30 degree eccentric gaze, if you see that there is a reduction in your optic nerve sheath diameter by 15%-- yes, you have to do some math. That can also be considered abnormal. The patients that you don't want to apply this to are patients who have narrow canals. So how do you figure that out? If you look at any CT, you want to look at those bony windows that we were talking about before. And you want to look at it in the coronal setting. But you can measure the multiplicative product of the width and the length of your optic canal, as shown here. And if it's over 10, then you're usually set. If it's under 10, then this test might not be reliable. How come I can't? We might need some more tech V to help us. Thank you. OK. And so is this the end-all and be-all of our ocular biomarkers? I don't think so. We're still finding more ways that we can try to non-invasively assess our patients. This is not ready for prime time by any means. However, what we're looking in one of the modalities that we're studying is to determine whether two extra leads on the EEG, a tool that's called electro-oculography, whether we can start tracking eye movements in a low-cost, non-invasive way to give us more information about injury, like location or potential prognostications. Is our patient starting to wake up, but we just haven't noticed because we haven't been doing sufficient neurologic assessments? And then as technology has been getting more portable and improving optical coherence tomography that actually measures retinal thickness, will we be able to get even more granular information about how that might be affected by diffuse elevations in ICP? So maybe if we can get the last slide. And so thank you very much.

ocular biomarkers

intracranial pressure

brain injury

neurologic pupil index

optic nerve sheath diameter