 So next we're going to hear from Dr. Mike Burl, one of our PGY-3 residents, who's going to be discussing a case that's likely non-physiologic. And then Dr. Becca Gincher is going to close our morning discussing a case of apnea neuropathy and end stage renal disease. All right. So this is a case from when I was on call a little over a year ago. So in December 2017, I was called by the children's ER. They said the words that are music to my ears. You don't need to see this patient, but can you help me schedule follow-up, please? And I said, well, okay, what's going on? They said a nine-year-old girl had come in, brought by her mother, complaining of some vision, some blurry vision, a little bit, maybe some double vision. And her mom was the one that actually said, you know, I think she just wants glasses. She's kind of been mentioning this for a little while, but it's kind of a teacher lesson I'm bringing her in. And the ER doctor didn't examination and didn't find anything abnormal, so agreed, but just wanted to get her in and see if she needed a pair of glasses. I said, okay, well, tell me a little bit more about what the patient is describing. And she said, well, she says she only sees two images when both eyes are open, but it's not always two images. Sometimes she looks at her face and she sees three eyes and two noses and one and a half mouths. And just the story wasn't fitting very well. I mean, I don't think it's very often that you get someone that young that can be that precise about what they're seeing. And so it just didn't sit very well. So I said, you know, I'm here, why don't I come and just check in with the patients and see what's going on? I got there and, well, before I actually even went in the room, mom even pulled me aside and said the same thing. She said, thanks for seeing us, but hopefully this doesn't waste your time. And said again, I think she just wants a pair of glasses. But there's a little bit more to her story about one week prior to coming in. So this was around Christmas Eve. Mom said that she or the patient had said she felt dizzy. She took a nap and then she even had an episode of nausea and vomiting. But mom just kind of thought it's from eating too much junk food from the holidays. She then started to say she was seeing two images of certain things. But again, mom kind of brushed it off a little bit. Talking to the patient, she said it doesn't last all day, but it would happen for some time period of every day for at least the last week before she came in. And then, like I mentioned before, is intermittent horizontal binocular double vision, but not always the exact same. At the time she said she wasn't having any vision problems, but she was before they got roomed in the emergency room. She had no other pertinent medical history. She wasn't taking any medications, no eye problems in her, and then just a few medical problems that had run in the family. Her initial exam, so she was 20, 20 in both eyes, she had full color vision with almost full color vision without any red desaturation. And her stereopsis was full. Her visual fields were full, her pupils were normal, her extracurricular motility was full, and on just alternate cover testing at bedside there was no tropiophoria elicited. She had a little bit of end gaze and stagmus, but the kicker was she had some subtle up-beat, nice stagmus, and primary gaze, and worsened on up gaze. Her ILPs were normal. And then just to kind of appease mom more than anything, I told her, well, I'll just throw on a pair of readers, and she miraculously says everything's better, maybe, so I threw on a pair of readers, and she said, no, things still seem a little blurry, but at this point I think the jig was up. The rest of her exam was completely normal. Of course, the lab exam was normal, and her dialy to fund this exam was normal. So, in summary, we had a nine-year-old, otherwise healthy girl, recent episode of nausea and vomiting, and had one week of this intermittent horizontal obinocular diplopia with normal visual acuity and stereo acuity, but she had up-beat, nice stagmus, and primary gaze, worsened on up gaze. So differential, so that kind of makes, you know, your hair stand on in a little bit when you find somebody that has up-beat, nice stagmus, so a broad differential for up-beat, nice stagmus would be so lesions in the brainstem, so whether it's infarction ischemia, neoplasm, or demyelinating disease, and then, of course, you have toxic and metabolic causes, seizures and cephalitis, meningitis, vasculitis. Chiari male formations are a common one, a more common one, and then cerebellar degeneration, and then there's also drug induced. She really didn't fit any of the bottom ones. She hadn't had any imaging, and we're on a few of those, but certainly there was concern for possible neoplasm. The pathophysiology of up-beat, nice stagmus is not fully understood. It's suggested that, because this is most often seen in lesions with the pontometallary or pontomesophallic regions, that it's an imbalance in the vertical vestibular-opular pathways. But again, the exact mechanism is unclear. Just a few examples of some of those lesions. This is not our patient. So it was kind of a bummer to kind of tell mom, like, you know, I came in, thought maybe just a pair of glasses would do it, but I actually think she needs an MRI, and mom was distraught at this point, just worried, you know, of course not upset that she brought her in, but just a little more worried. So we sent her for an MRI, and this is her MRI, which showed pontine tumor faction, most likely neoplasic and etiology, and strongly suggestive of what's called DIPG or diffuse intrinsic pontine glioma. So we'll talk a little bit more about this specific tumor. And she was admitted to the hospital. So this was the day after she's admitted to the hospital. She underwent biopsy of the tumor, which I thought was really interesting. I didn't even think that was something they would pursue, but she did have stereotactic biopsy, which talking to, you know, luckily a neurosurgery resident on the neurology, or Neuro ophthalmology service right now, so I was talking to Brandon, and he kind of walked me through this. So basically they do preoperative imaging, and then once they have the patient in the OR, they're able to kind of link that preoperative imaging with a probe that's able to pinpoint exactly where they want to take the biopsy. They then put the patient's head in a brace, and then they will clear the area where they want to go after identifying it with the preoperative imaging, the burrow hole, and then they're able to go in with the biopsy cannula, if you will, and take biopsies. They took six specimens total, which also seemed like a lot to me, but again, talking to Brandon, that's necessary if you're really wanting to do genetic testing, in addition to pathology and things, and that was the case. Her biopsy revealed the presence of this H3K27M mutation. So DIPG, a little bit about the epidemiology, in general, primary pediatric brain tumors are rare. There's about 2,000, a little more than 2,000 cases annually, but about 15 to 20% of these are DIPG, and unfortunately it has among the most a dire of prognoses. It's the leading cause of death from pediatric brain tumors, and the median age of presentation is seven, and there's no gender prolection. This is a tumor that arises from astrocytes in the pons. It very rarely metastasizes because it's just basically infiltrative of the pons itself, but it can to local sites along fiber tracks, and it's always considered highly malignant, no matter the pathology grade that you would normally assign, whether it's WHO classification, just because of the... I guess the characteristics of progression of this tumor is always considered high-grade. The classic presentation, it kind of has a classic triad, is cranial nerve palsies, especially cranial nerve six and seven, and then long-tracked signs or higher motor neuron signs such as hyperreflexia, clonus, hypertonia, and positive babinsky. I have to admit, I didn't check for babinsky or many higher-order signs in her, but in a follow-up neurosurgery note, there were none that were noted, and then ataxia would completely triad. The symptoms associated with that triad, of course, diplobia, facially symmetry, clumsiness, and ataxia, and then you can also develop signs and symptoms of elevated intracranial pressure, just if there is elevated intracranial pressure from just anatomic blockage of the outflow of CSF. Diagnosis has really historically been just by clinical signs and symptoms and time frames, so this, since it progresses so quickly, symptom duration is usually less than three months at the time of diagnosis, and of course you get imaging, these kind of characteristic findings in imaging. MRI is most common, but CT, you get isodense or hypodense enlargement of the pons, and then MRI, you'll get hypodense enlargement of the pons on T1 or diffuse bright signal on T2 or flare imaging. Variable contrast enhancement, but it's usually absent, and then you can have necrosis in later stages. The prognosis is nearly 100% fatal and without radiation, which is currently only approved, identified effective treatment, the median survival is four months. Post-radiation median survival is between eight and 11 months, so quite a horrible prognosis, and the survival rates are very abysmal. Less, or 30% of one year, 10% of two years, and less than 1% of five years. As I mentioned, the only currently proven treatment is radiation therapy. Many chemotherapeutic agents have been tried, but have not found to be significantly prolonged survival. The barriers to treatment are suggested as just the location itself. It's not amenable to surgical debulking or procedures, and then the blood-brain barriers thought to be preserved in the IPG, which is why the chemotherapeutic options are not helpful. And then there's also a poor understanding of just the underlying molecular and cellular biology just because we haven't ever taken biopsies before. This is such an aggressive tumor. And so I think that's something that's interesting now, and we hear a lot about that. In ophthalmology, too, we talk a lot about these retinal dystrophies that we're now targeting with personalized medicine. And I think that's the case here, too, and it's kind of neat to see. So again, why biopsies really a move towards this personalized medicine? So there's a journal just talking about this H3K27M mutation, and it's told that if it wasn't bad enough that the IPG is such a poor prognosis that the presence of this mutation actually confers a worse prognosis and patients tend to progress much more quickly. That's just a description of what the mutation is. It just... Well, you can read it up there. It leads to the amino acid substitution of lysine from thining, and this just leads to poor physiologic differentiation of the drive to glioma genesis. So last part of this I just want to talk, and on a more happy note, is that there are some novel treatments and diagnostic procedures that are coming up, so two that I want to just really talk about are there's a clinical trial ongoing with this treatment of onc 201, and then I thought there was an interesting method of drug delivery that's being studied right now. It's not in clinical trial stages that I could see, it's in the laboratory stages which is called Magnetic Resonance Guided Focused Ultrasound. So I'll talk about that first. This is just kind of a one slide summary of what that is. In this case, they're testing it on mice, and what they'll do is they'll inject into a tail vein micro bubbles. I think that's been kind of a hot topic for maybe 10 years I've seen in various fields. They inject micro bubbles, and then they're agent of choice, so in this study they're injecting nanoparticle conjugates with gold, and that's just so that they can see if the treatment is actually getting to where they want it. So they injected into the tail vein, they've previously done MRI imaging, and then they target the area where they like the treatment to arrive, and then they use high focus ultrasound to theoretically activate or excite the micro bubbles that then disrupts the blood brain barrier, so the endothelium part of the blood brain barrier allowing the treatment to seep through the area. So I think it's a pretty interesting and hopefully exciting and future opportunity to overcome some of these barriers and treatment of things like DIPG. The other thing I just want to talk about, spend a little bit of time on, is this clinical trial that's going on. There are about 45 clinical trials going on regarding DIPG, which I think is exciting. Most of which are interventional. Our patient has actually been enrolled in this trial for ONC 201. So ONC 201 is a small, selective, direct, competitive antagonist of the D2-like dopamine receptor. So the mechanism is still kind of under investigation, but it's thought that this activates what's called the intrinsic stress response, induces the over-expression of the death or apoptosis ligand, tumor necrosis factor related apoptosis inducing ligand or trail. And then this leads to a cytotoxic effect towards cancer cells in particular. So not clearly interested why it's so directed towards cancer cells, but it's been studied in several other cancers, such as pancreatic, colon breast and cervical, and has been found to be effective. So it's currently being studied in DIPG as well. So back to our patient, so she was diagnosed on the 29th of December in 17, that biopsy was done two days later where she was found to be positive, and then she began radiation. I mean, this is quite a fast moving process, and I think we can all see why, but almost just two weeks later she started radiation. That was done over a period of about six weeks, and then after that six weeks, about a month later she was enrolled in this trial. There's several sites, but she goes to the one in NYU. She does monthly visits for this Oncetool 1 administration, which interestingly is an oral medication. And then she gets interval MRIs here at Primary Children's about every two months. She actually follows with Dr. Jardine at this point and has most recently been seen earlier this year, and her visual symptoms resolved after radiation, and they haven't returned. And she also visits with the He-Mong team at Children's, and she's been relatively picker, symptom-free since receiving radiation. Just as comparison, so this is her most recent MRI. I'm going to pull up some pictures from previous, just for comparison. I think it's quite the change. So I think this was just a really interesting case for me. And I think, like I mentioned, we've had a lot of talks recently about personalized medicine, whether it be in the retinal dystrophies or at a recent FA conference, we talked about Bann's disease, which can be an equally devastating diagnosis. But I do think that it's exciting and important for us to realize that there are clinical trials going on. You know, in Bann's disease, a few of the patients we talked about are being enrolled in clinical trials. And then in our case, in this patient we just discussed, and otherwise very dismal prognosis has led to someone who's had remarkable response to treatment and is already beating the odds and hopefully will continue to do so. And that's it. Any questions? Yeah, Dr. Olson. So first a comment, congratulations. The easy thing to have done would be just to blow the patient along. Is your non-physiologic is a diagnosis of exclusion? Yeah, we just have to be so careful. When I first came here, the chief of neurology had taken the daughter of the head of orthopedic surgery and called her symptoms non-physiologic when it turned out that it was a very aneurysm that later ruptured. And it created incredible ill-will and bad feelings. And so there are plenty of patients in which we can't. We just need to be very, very cautious just blowing these things off because particularly a lot of these subtle things early on and it's hard for patients to describe so it may not sound consistent because they're having a hard time describing exactly what's going on. We come across this in plastics not infrequently and here's a little tip. Supposing you hadn't seen that I presume it was subtle, vertical, stagnant, and you know you don't do a general neurological exact to see gait and stuff normally. You know, a good thing you see me doing this to the emergency patients all the time is I say let me see them in clinic in two weeks or one to six weeks and that business of looking at your patient again two or three times, sometimes with a fresh eyes through a resident like you before I go in and then we sort of discuss this we'll often shed light and we've come across very subtle orbital tumors we've come across very subtle findings of skin cancer which the patient says well I'm sure he's there, you can't see it at first blush so that since you've had you not found anything the answer would have been yes, come and see us you've talked to Dr. Hoffman and Dr. Jardine's clinic and then viewing more than once. Thank you. Okay, just one other comment that I know you want to get going so I love hearing these stories you know we see what we want to see and this goes into the realm of kind of confirmation bias where we see the things we expect to see, there was a really cool study they did where they asked radiologists to find the lung tumor in a chest X-ray and they had inserted pictures of gorillas or other animals that 83% of the radiologists missed the fact that there were these animal images in the chest X-ray and it's so powerful, particularly when when we don't want to find the diplopia in the 5 o'clock patient at the end of the day, you know it's like we want to confirm the things that we're hoping for and particularly being on call, being first line this is vitally important that we keep an open mind, we don't rely on another type of bias which is this expert bias, you know Dr. Olson refers something to me if I don't do my due diligence to ensure that this is the actual diagnosis that's an error on me particularly as you're seeing patients from attendings, keep your mind open thank you just a little tip that it can be relatively easy to see nystagmus using the direct ophthalmoscope whereas without a good scope of ophthalm it might be hard with the naked eye it's hard to see subtle nystagmus with the direct the magnification there is very good very big thank you what is that again how do you turn that on