 Melissa, go next. She's a neurology resident. She's on her neuro-ophthalmology rotation. She's in her fourth year. She's going to talk about progressive super nuclear palsy. Thanks, Eileen. Thank you guys for having me today. Thanks for the introduction, Eileen. I'm going to talk about the neurophomic manifestations of progressive super nuclear palsy today in regards to a case that I saw on my rotation of neuro-ophthalmology. So the case that we have today is a 70-year-old right-handed man who came into clinic with a three-year history of difficulty reading. He was a previously a really avid reader, so this bothered him greatly that he's had such a hard time. He attributed the change to the fact that he was wearing bifocals now, and he just thought, oh, there's something wrong with my prescription. That's why I'm having such a hard time breathing. He also attested to watery eyes pretty much over the same time course as well, but denied any other visual complaints for the most part. You can see the pertinent negatives there. Over the same time course, we elucidated that he's also noted frequent falls, and he said that these were pretty much exclusively falls backward up to five times daily. They would occur even if he was using a cane or had assistive devices with him. There was nothing mechanical that he could pinpoint that was actually contributing to the falls either. He had slow movements overall, had freezing ups gauge, and also had a change in the quality of his voice, which to him was kind of strained and kind of quiet, and his family attested to that as well. And he'd had memory difficulty, and he'd actually been referred into us from the neurocognitive clinic for evaluation of that memory difficulty. His medical history, past ophthalmic history, he'd worn glasses since 2013, and it was really for reading. He did have light sensitivity noted in previous optometry notes, but no history of surgeries, previously no patching, relays the eye as a child. Pass medically, he had a history of hypertension, gout, hyperlipidemia, sleep apnea, and prediabetes. Surgically, he had only had a replacement of bilateral, or bilateral knee, arthroplasty. Family history was notable for macular degeneration in his mother, and his social history was married, a retired dairy farmer, the interesting guy, and no history of tobacco, alcohol, or illicit substance use. This is a list of his medications. So for his gout, he was on alopear, and now on cultraseam, he was on an aspirin, Prozac, Plasix, Denepazil had been started by an outside physician for his memory complaints, to resist him for BPH, Vrapamil, for his blood pressure, and then vitamin D in fish oil. His ophthalmic examination, his visual acuity in the right was 20 over 25, on the left 20 over 20, and that was with glasses. His pupils were equally reactive, he had no APDs, his visual fields were full to confrontation. Motility, he had a rather interesting exam, so he had normal pursuit, but then had slow saccades, and this was most notably notable in up gaze. He had square wave jerks that were nearly continuous, and had no inducible optokinetic astagmus vertically, and it was not well formed horizontally. His pressures were equal, and he was at 18, and stereopsis was notable for zero out of three animals and zero out of nine circles, but here on the fly, slit lamp, notable for a very poor blood rate, and you can see that on general observation as well, and then a little traction is there, and his lenses had one plus good clear sclerosis much laterally. His dilated funnistopic examination was number one. His general neurologic examination showed that mastfaces on his motor exam, these are just the pertinent positives that he had, he had increased tone of his right extremities, more than his left extremities, and had increased axial tone with neck movements, which was as bad as his forced extremity, and then with coordination, he had reduced amplitude of his rapid alternating movements, and they had decrement as well. So indicative of brain akinesia, and this was more notable on the right more than the left, keeping with his increased tone. He had an outside MRI coming in, and I apologize for the quality of it, it was, the slices were a little bit off there, but you can see this is a sagittal view of the midbrain, and the brain's data, you can see it's actually notable for some atrophy within the midbrain. So putting all of this together with his, with his complaints clinically of difficulty with gait, difficulty with falls over, especially falls backwards over the past couple of years, his cognitive complaints, and then his visual complaints of difficulty reading, coupled with his notable findings on neurologic examination, and his ophthalmic examination. At this point, we were concerned for a diagnosis of progressive super nuclear palsy, but his presentation was pretty classic. So progressive super nuclear palsy, or PSP, is neurodegenerative disorder, and it's due to tau deposition. So similar to the pathology that you would see in Alzheimer's disease or in front of the dementia, it's a type of atypical Parkinsonism, and it's the most common form of atypical Parkinsonism. About 5% of Parkinsonisms that will come through a neurology clinic will be PSP. It's onset is in the 60s, and that's the average age range, and that's about 10 years later than you would see in idiopathic Parkinson's disease. Men are affected more commonly than women. The prevalence in incidence is both five out of 100,000, but this is likely underestimated because it's such a hard diagnosis to make, and it's under-recognized overall. The mean survival is not very good. It's about five to eight years, which is pretty low compared to idiopathic Parkinson's disease, which is on average around 20 years or so, and causes the most common is just idiopathic. You can also have multi-infarct, which is the second most common, and then there are secondary causes that you can see there as well. Like I mentioned, it's an atypical Parkinsonism, so you have the cardinal motor features of Parkinsonism itself with some atypical features that you wouldn't necessarily see in your path of Parkinson's disease. So Parkinsonism is defined by tremor at rest, bradykinesia, rigidity, postural instability, a flex posture, and then freezing and motor walking, and you add some of those features. And atypical Parkinsonism, you often see ocular dysmotility, that's classic in PSP, early dementia, also classic in PSP, frugal falls, dysautonomia, atypical. So the classic clinical features of PSP, and you can see that, I'm not sure how well that projects, the hallmark features actually have a little blue star next to them. So the gait disturbance is a classic feature. Rigidity, it's mainly an axial rigidity, even though they can't have the, they can't have avid peculiar rigidity as well. Postural instability, this occurs very early on in the course of the disease, one to two years, whereas it would be much later in other Parkinsonisms. Frequent unexplained falls, again super early, and these are typically falls backward, whereas in Parkinsonism, you fall forward. And then the ocular motor dysfunction, the motility dysfunction, with a vertical super nuclear policy is hallmark. Retrocholus is also a classic feature as well as progressive dementia. And overall, these patients are poorly responsive to dopamine replacement therapy. So only about a third of patients respond to the typical treatments that you would get for adiopathic Parkinson's disease, making it a really difficult disease to treat. So the motility abnormalities in our patients had quite a few of these. So there's saccotic abnormalities. Initially it's slowing other vertical saccades, which is actually the first manned bed station, and they actually have also an inability to perform volitional saccades. There's also this progressive super nuclear ophthalmoparesis. So there's vertical gaze policies that can then progress to lateral gaze policies. So the vertical will come first and then the lateral can follow. And these can be overcome by the oculosaphalic maneuver, but as the disease progresses and there's more tau deposition, the brainstem can become more involved. So this can actually even be lost. And this can also be really hard to assess at times because there's so much axiomorality. So it can actually be very, very difficult to check the VOR in these patients. And I apologize this, I think when my computer freaked out there I modified the slides after this. So the videos are in slightly the wrong spots, but I'm going to show you. This video is a patient who has some, she has vertical gaze policies, but then also has some lateral gaze policy involvement as well, which you can see as they try to get her to move her eyes to the left. So this is actually more advanced than just starting off with the initial vertical gaze policy. She can't look up, she can't look down. And then had difficulty with left movement as well, but she has the attack to be more. So this patient is, or this person with PSP is much further on than the patient that he saw in clinic who did not have the vertical gaze policies yet for the VOR zone. Then square wave jerks, which our patient had rabid back and forth and made a psychotic intrusion during fixation. And I'll show you a video on that. And then also hallmarker is reduced optic connective misdiagnosis. The vertical is affected more than the horizontal and this is an early predictor of progression to the super nuclear gaze policy. Fair wave jerks, or a clinical psychotic intrusion. Also, you can see her face, when they first scan a home in our eyes, before a home in our eyes you can see her face with that kind of almost like a grimace. It's just a weird, stawing movement of the mouth or posture of the mouth. Can you open that up a little bit? It's a very quick view as they kind of have a moment in the video. See that, almost like that gridded teeth pull, face, mouth, pull back and look very characteristic. The difficulties for the abnormal optic connective misdiagnosis, this patient has still attacked a vertical gaze and then attacked a horizontal gaze. And then with the OKN ribbon, her horizontal OKN is attacked, but once she gets her vertebrae in her mouth. Eventually there's progression to complete gaze policy, so vertical and horizontal gaze policies. There ends up being involuntary molecular causation as well due to the involvement with volitional gaze, lack of eye blink and then they have this characteristic Mona Lisa face or stone face and these are some of pictures of some patients with PSP with that kind of stony face. As Dr. Werner mentioned that downturned mouth and then they had that for a brow, so they was angry all the time and that's due to Pracera's contraction. I think that's very unfair, Mona Lisa. No, I didn't notice that, I didn't notice that. Maybe stone face. Other ophthalmic manifestations, so ocular dystonias can come about, blood spasm is the most common, if about 30% of patients with PSP will have it and then there can also be a praxia of island opening closure or both and about 33% as well combined. There's some of the attraction stare and then they have a reduced blink rate as well. Visual symptoms of patients will attest to blurred vision which will be due to decreased blink rate, reduced tear production, which leads to dry eye overall. Sometimes they'll have diplopia, they can have convergence and sufficiency. You can see there's another parminsinism, notably adiopathic parminsin disease as well. Photosensitivity, blepharospasm, they may actually complain about that, difficulty with their eye opening and most will eventually lose the ability to read and to maintain eye contact and that's largely due to the gaze palsies and that was the case really in our patient where he really just can't look down through his five levels to be. So back to our patient again. So the support of findings by history as we kind of already previously went over, the early falls, the overall slowness of movements, his visual complaints, notably, most notably the reading, but he also seems to have had some photophobia when we dug a little bit more into his history and then the change of voice as well and then his supportive examination findings. Really some of the early hallmark features from an ophthalmic perspective is what this patient had with the square wave jerks with his reduced optic connective stagmus and what this slowed saccades and then he also had reduced blink rate and the labor traction stare and neurologically some hallmark examination findings as well with his rigidity, brain condition and postural instability. So PSP is still largely in clinical diagnosis. Autopsy can confirm it, but for the most part we are just going based on clinical suspicion for these patients and classic PSP, which is called Richardson subtype, the criteria we're defining in 1996, there have actually been about five additional subtypes that have been elucidated, so they think that there may be new criteria coming out but these are the ones that we have to go with and the possible or probable, these are the supporting features, so it's a progressive disorder. Generally after 40 years, postural instability falls, the slowing of the vertical saccades never. Definite would require pathologic evidence of the disease and the most important distinguishing signs of PSP based on these diagnostic criteria are the postural instability and then he's super nuclear on that crisis. Imaging, MRI is probably the most helpful, there are other techniques that they're trying to do on a research basis like PETs, that which can be used clinically to add additional information, but MR can be the most helpful. So there's notable atrophy in the midbrain, in the superior cell, or P-gugles, and the anterior and medial thalatic nuclei. Let's see if I can get this to work. Oh, whoops. Is there a pointer on here? The top, the top thing? You can see kind of there in the midbrain region. So it's this appearance of a weak brain stem to the atrophy of the midbrain, and it's called the hummingbird sign. And thinking back to the MRI of the patient that we had, he, his atrophy actually looked like that as well. There have also been studies of the ratio of the volume of the midbrain to the volume of the pons, thinking that potentially this could be used from a diagnostic perspective for PSP as well, because we don't have much else besides the clinical features to go off of. There have been two studies that have looked at that, and they noted that PSP has a reduced volume ratio compared to idiopathic Parkinson's disease, or multiple systems atrophy, which is another type of atymical Parkinsonism, but this isn't routinely used from a diagnostic standpoint necessarily. The pathology, as I mentioned before, it's a tau apathy, so there's abnormal tau hyperphosphorylation, which leads to deposition, and the features that happen a monic feature of it is the tufted astrocyte. And then neurofibrillary tangles are aggregates of hyperphosphorylated tau as well. The distribution, generally sparing the cortex aside from the frontal lobe, which is often affected, and then involving the midbrain, so taking out the, or involving the oculomotor nuclei, the basal ganglia, the pigmented cells of the basal ganglia, the same ones affected in idiopathic Parkinson's disease are affected, and the subthalamic nucleus, also part of that motor circuit that's affected in Parkinson's disease. And then the cerebellum, so the P-duncles are affected and the dentine nuclei can be affected as well so the t-pneumolia. The deposition eventually leads to associative gliosis to generation and atrophy, which leads to the calmart features that we see in P-dent treatment. There's currently no specific treatment. There are ongoing phase one trials, which are looking at immunomodulatory therapy, targeting free tau before it deposits. Those are currently in phase one. For the Parkinsonism, leave a doco trial, so the same medication that you would give in idiopathic Parkinson's disease is recommended just to see if they're responsive, because one third of people will have some kind of response. Probably not super robust and it probably won't last a long time, but they can be responsive. For blood spasm, Botox injections can be very helpful. And ideally, the treatment of these patients should involve a multidisciplinary team because there's a high chance for morbidity with the postural instability with the frequent falls and the other modem manifestations. And then same with occupational therapy for the activities of daily living, speech therapy, social work, and palliative care, considering that life expectancy is really only five to eight years or so. So general conclusions about our patients. He came in with a primary complaint of difficulty with reading and his visual acuity was intact. His fields were intact, but it was largely due to the fact that he has this case palsy, the beginnings of this case palsy, that are resulting in difficulty moving down into his bifolkles to be able to create a pretty massive work-based team. So I'd like to thank the neuro-ophomology team who has worked with me all this month. They've been very helpful, very nice to work with, especially Dr. Warner, who, any questions? So like if we see a patient like who can't look up, are there other things that we need to try to rule out in the different podiodosis? So up-case palsy, as you can actually see, maybe not a full palsy, but you can see up-case restriction as people age, they can have a little bit of up-case restriction that you can see in the commonly Parkinson's disease as well. So it's more the down-case that's the one that's more specific for a specific player. I think that you need to keep in mind that whole differential diagnosis of a vertical-case palsy, there are metabolic disorders that can do it, and of course pineal tumors and chirociphalus can do it. So it has to be the right clinical setting to just say that somebody has PSP or how can we diagnose that in a 20-year-old, for instance, or even especially in a child, you need to be watching out for, you know, catastrophic chirociphalus rather than just thinking PSP. But under the right clinical setting, I think it's a good thought. What about some, I think you touched on this a little bit, but differentiating it from CPL and the more they can actually move their eyes in PSP, it's just kind of the initiation of movements. So, you want to take this one? CPL? CPL, okay, so he's asking about chronic progressive external ophthalmopagia, which is a neuromuscular disorder, not a brain disorder. And so super nuclear implies that the nuclei themselves are still working, the muscles are still working, it's just the brain orders to those centers are not working. So with the ophthalmopagia, you can get the eyes to move when they can't be moved voluntarily. And in the VA, that's like everybody, okay? Nobody seems to be able to follow commands, move their eyes to the VA, but if you can put that around the league and all move their eyes. And somebody with CPEO is really more of a muscle disorder. It's a trophic muscle problem. So to the extent that they can move their eyes, they'll be able to move their eyes the same whether they have opiosephalic score to command. So anything that you ask them to do with their eyes, they can do it. Whereas somebody with PSP, they may be looking around quite naturally looking, but then when you ask them to look, they can't. And then you can always do the opiosephalic maneuver and see that there is a discrepancy. They may not be normal with the opiosephalic maneuver, but they'll be better. And it'll be similar with pursuit. So pursuit is a different strategy for moving your eyes. So somebody with PSP may not be able to look down voluntarily, but they'll be able to pursue downward. I assume CPEO is a younger ophthalm? CPEO typically will start in the teenage years, but it can occur later. The one thing that is similar is that in CPEO, often the eye movements are very slow, but you also won't see the liver tract to stare because most people with CPEO have ptosis and you also won't see the squirrely jerks. CPEO is typically associated with fairly large angle deviations of the eyes. And CPEO at its advanced stages typically patients can still look down, whereas with in advanced PSP, downbeases are the most severely elected. There was a lot of verbiage there. One of the words that Melissa used was retrocholus, which is the awkward reflection of that head, the neck, which is a very unfortunate combination with being unable to go down. So if your head is tilted up and you can't look down with your eyes, then that's a double whammy. Is the postural instability worse than last time? I don't know if our concerns are the same. Much worse. This guy had had dozens of falls. Dozens. I mean, he would fall numerous times per day, two, three, four times a day backwards with a walker. So at a walker, you're bent forward, right? With a walker, it's almost like, you know, but he pulled you forward and he still was falling backward. The classic is they just fall over backward when they put their head up to look at the cover. Boom, where'd he go? And just for no reason, it was not a trip and fall. The other thing that they'll often say is that when they walk into the room, the cat runs out of the room. Because people get stuck in the room. They're out there. So I assume that this would be better if the scene would be just right here? Exactly. Yeah, get his wife to throw in some communication because he, like, literally blinks once a minute, right? And there are some studies showing that there's a sort of a ratio between blink rate and square wave jerks. So the higher the number of square wave jerks and the lower the number of blinks, the ratio makes it more likely that it's going to be PSP. And there are a fair number of studies looking at the high findings of PSP versus Parkinsonism. A lot of people with Parkinsonism complain about blurred vision when they're reading, but usually that's because of the blockerias. And they can have eye movement abnormalities as far as conversions and sufficiency and diversions and sufficiency, but it's different flavor to PSP. We don't have these skateboards. Thank you, Melissa. That was great.