 Our next presenter will be one of our fearless and knowledgeable chief residents, Dr. Bedes. Fearless, maybe. So this is our time to interview potential residency applicants, and it's also a time for us to show off our program, which I think we have a lot of strengths in our program. One of them is the very strong neuro-athemology curriculum with very well-structured teaching opportunities. And so this is your warning, I've seen it two times during my time here, that Dr. Warner will find you if you haven't done your grand rounds. Even if it's your last week here, so I said to myself, that will not be me. And so this is your only clue. So this is an interesting kid that I saw. So he was adopted at birth, his mother, his biological mother had abused at least prescription painkillers during her pregnancy, and we don't know what else. He was born at a weight of four pounds and had possible developmental delay. His immunizations were up to date, and he lived with his adopted mother, father, and two siblings. So those of us who were kids have all been here, your kids crying, and you're not quite sure what to do. So at age two, he was fussy, irritable, had some upper respiratory symptoms, headache, and was taken to the ER. Where he was briefly admitted, it seems for a sepsis workup, although they didn't do a lumbar puncture, we're not exactly sure why, but blood cultures were negative. Mother describes that during this episode, his right upper lid slowly shut completely, and as it began to open over the course of ten days, she noted that his eyes were off. And so that's what every pediatric ophthalmologist or resident who's on pediatric ophthalmology loves to hear, is that they had discontricate gaze, or that their gaze was off, because you're not quite sure what that means. But nevertheless, they got imaging at that time, it was uncontrasted, again we're not sure why, but it was normal. And over the course of about ten days, his lid went back to normal and his eyes went back to trekking normally. And so this was called a presumed post-viral partial cranial nerve three palsy. And then over the course of the next couple years, he had several other episodes of just upper respiratory infection, chronic sinusitis, bronchitis, occasional headache, and then seven more episodes over the course of the next two years were associated with one of these illnesses, his right upper lid would droop, his eye would start to become abnormally with regards to its trekking. And each time it would slowly resolve over the course of several weeks, the first time ten days, and then more typically over these episodes, three to four weeks it would take for his eyelid to go back to normal, and his gaze to go back to normal. However, each time it was a little less normal, and so progressively it was starting to droop a little bit more as far as his right upper lid, he had a progressive ptosis, and he also had a progressive palsy of gaze. And so they got repeat MRI imaging given this kind of stuttering and progressive nature of the deficits, and so they're worried that they maybe had missed something, right? Either aneurysm or mass or malformation. And so he got repeat MRI imaging during an asymptomatic period, which was contrasted, which also happened to be read as normal. So during this time, because of these complaints, he was evaluated by pediatric ophthalmology and was found to be developing amblyopia in that eye. He was also found to have an abnormal head position associated with his ocular deviation, and so the decision was made for him to undergo surgical correction. And so he did undergo that. It was uncomplicated. He also underwent ptosis repair and was doing quite well, actually. Mother was very happy. Everything was very aligned after the surgeries. His eyes appeared to be open. But then slowly, over the course of the next couple years, again, he began to have recurrent ptosis and recurrent deviation of the eye. He continued to have photophobia noted on his documentation, eye rubbing, frequent headaches. And so this is when he came to us. And so in the neurophthalmology clinic, and this one I saw him, for this recurrent exotropia and ptosis. Fortunately, he's seen quite well, even without correction, perfect color vision, good stereopsis. And so it appears that the surgery was successful in maintaining his acuity and also his binocularity. And so that's good. We did note that his right pupil was slightly larger than the left. He's a very active six-year-old young man. And so we weren't able to determine if he had an afferent pupillary defect. He's also extremely photophobic, and so just squeezes his eyes. You'll note that he has full ABduction of his right eye, but limited superduction, improduction, and ADduction, consistent with maybe a third cranial nerve deficit. Again, he was not very excited about me testing his ocular deviation. But just by the Hirschberg, you could see that he had maybe approximately 15 diapters of exotropia and a slight right hypotropia on Hirschberg, again, consistent with the third cranial nerve. And then he did have a recurrence of his ptosis. So you can see that the MRD1, which is the distance from the corneal light reflex to the upper lid, was 1 millimeter on the right and 4 and 1 half millimeters in the left. And so what are we thinking? I mean, how is this happening? Is there something we should think about? So obviously you're thinking about mass. We do have normal studies, but it's been said that neuroentomology is the reinterpretation of previously normal studies. And so you have to look at them yourself. And so we did. And we really didn't see a whole lot, although the first one with that acute episode, the only one that we had during an episode, was without contrast. I had done it outside hospital. So that seemed normal. And then the other MRIs, which were taken because of the recurrence of the symptoms, but in between episodes, were also normal. However, we didn't see any evidence of congenital anomaly or mass. The only thing that we really saw was a slight atrophy of the right medial and inferior recti, which, of course, are supplied by the third nerve. So what else could this be? Could it be a post-viral cranial neuropathy? Certainly it could be, although you'd kind of be expecting him to have chronic seeding or some type of recurrent infection, like a viral or herpetic infection. Otherwise, from the single event, one would not expect that to be recurrent. You would expect that maybe there is a permanent deficit associated with that, but once it's surgically corrected, it should not recur. Could this be orbital pseudotumor given as headaches and the like? Sure. But overall, we thought that this may be fit with ophthalmoplegic migraine, which is a very rare disorder, and that's why I wanted to talk about it today. As such, we told him to come back to get a contrasted MRI during an attack, which we'll talk about why that would be important in a moment, and also for CSF studies, just saying, could this perhaps be a recurrent infection, a current viral etiology for this cranial myon neuropathy? And so that would allow you to get CSF studies during the attack. We'll also talk about some of the other things they've been looking for in the CSF with these patients. And then again, we thought was perfectly reasonable for him to return to pediatric neurophthalmology given the recurrence of his ocular deviation to help make sure that he maintains excellent visual acuity and binocularity. So if you ever want to be in a fun group, lots of fun international classification of headache disorders committee, that sounds like an excellent time. And they've decided to define ophthalmoplegic migraine as at least two attacks characterized by migraine-like headache, followed within four days by precess of any of the nerve's controlling movement of the eye and any of the other ancillary functions that they support. So we'll talk about why that may not be the best definition in just a moment. And then of course you have to exclude other things as I did in this case, including trauma, tumor, pseudo-tumor, infection, inflammation, thrombosis, demyelination, you name it. So this is very rare. The incidence in any given year is about 0.7 per million. However, it's much more common among kids. I wouldn't say common, but it's much more common among kids. It may account for up to 7% of isolated cases of ocular motor nerve palsy in kids. The median age of presentation is about eight years, and that depends on the case reports that you look at. Some say four. This is the largest group that I saw that they had looked back at in the inter-cortile range. So from the 25th to 75th percentile patients are between three and 16 years. And there's a two to one female to male ratio, although our patient did happen to be male, right? So the clinical features of ophthalmoplegic migraine are characterized by bouts of head pain followed by ophthalmoplegia. And so this is an important distinction. So the ophthalmoplegia does not arise during the headache. And so if you're having a patient with headache and their eye is not moving right, you need to think about other things in the ER and any very urgent imaging to rule out hemorrhage and the like in ruptured aneurysm. However, in up to one third of these patients, the headache may be migranous. And so if you're saying this can't be a thalamoplegic migraine because they don't have nausea, vomiting, photophobia, phonophobia, you're gonna miss some of these. And so however, up to 60% of them do describe pain around the eye that may or may not be migranous in nature. And then this is especially tough in kids, right? Because kids not gonna say, oh, this is a throbbing headache on one side. I'm nauseated. So that may manifest as irritability, fuzziness, rubbing of the eye, sensitivity to light and things like that. Or a diagnosis of sinusitis or chronic sinus infections. However, in up to 70% of patients, eventually they'll develop some form of headache that may or may not be migranous. So some within the headache community have advocated renaming this entity of thalamoplegic cranial neuropathy, which seems sufficiently bland as not to offend anyone. Now, the interval between headache onset and ophthalmoparesis can be almost immediate in up to 14 days. So it's not always subacute. The median is 1.6 days, but it can be up to two weeks again. Cranial nerve three is the most commonly affected in 83% of cases, but you'll see isolated case reports of any of the nerves affecting movement of the eye. And then very rare reports of multiple cranial nerves being infected. But I think then the burden of proof on you becomes much greater to rule out other intracranial pathology. There's only two reported cases of alternating laterality, meaning that this appears to be a mostly side locked phenomenon, meaning that it occurs in the same distribution on the same side each time. The mean duration is about 21.8 days, so about three weeks. However, these deficits can last up to three months and can be permanent. As we saw with our patient, the ones who are most likely to have a permanent deficit are those with recurrent episodes. And so with each episode, it tends to take a little bit longer to resolve. The deficits tend to be a little bit more severe on presentation, and they have an increased likelihood of having a permanent deficit. So up to 30% of patients who have chronic ophthalmoplegic migraine may develop a chronic ocular deviation because of it. And then if they do have that, it becomes a management just like any other ocular deviation, as we saw in our case. So the deviation is threatening development of normal visual acuity or maintenance of binocularity, then they need surgery. So what might you see on ancillary testing? In up to 86% of cases involving the ocular motor nerve, the others are either the case reports are too sparse to really generate any overlying themes. You'll see focal nerve thickening and contrast enhancement if you take the MRI during the acute attack. And so there's case reports where they've done the repeat MRI even a couple of weeks later and there's no more contrast enhancement. So it's one that you really have to catch if you're trying to catch it. And there's really small numbers, but no other consistent features on MRI imaging. There was a recent review of all the reported cases in literature and they weren't able to find any consistent MRI features. Yes, Russell? After the headache symptoms. And so the deviation may last up to three weeks on average, like we said. And by the time it resolves the contrast enhancement may be gone. So that's a good question. It would be with relevance to the acute attack. So there may be a lag time there. So if the kid has an attack, has a headache and then four days later comes in with ptosis and eye deviation. That's when they would likely get a scan. And so hopefully if that's in that window, then you'd be able to see it. But again, it's a very good question. And the numbers aren't large enough for us to know exactly how long that window is. I think we'd all like to know that. One thing that can persist on imaging, even though the contrast has gone away, if you look really closely or clue the neuro radiologist into this, there may be kind of focal enhancement in the cisternal region of the cranial nerve three. So as it exits the midbrain, there may be thickening there from where the previous attack was. I would imagine that's pretty subtle. So CSF findings, there have been isolated reports of increased IgG or a few oligoclonal glands in the CSF. Now interestingly, these cases were only in those with trochlear nerve palsy. And so there's some question among those who studied this. Is that a different entity altogether? Those patients tended to be older. Was this a manifestation of something else like MS? I don't think that's been answered, but just know that that was a little bit different among the trochlear nerve palsy. And otherwise, labs are normal, so other labs that you might get to rule out infection, inflammation, pseudo tumor and the like would be normal. Again, you're trying to rule those out. So here is just some representative images. These are not our patients. I found these online. So here's just showing enhancement of the third cranial nerve. And then on a sagittal imaging. And then here is, again, repeat imaging done just a couple weeks later, which shows resolution. You could maybe argue to yourself that there's perhaps some thickening in that area, but you kind of have to be hallucinating. So why is this happening? What's behind the etiology of this? So these are listed in relative order of current favor in the literature. So I think the current model is maybe this is perhaps recurrent balance of inflammation and demyelination of the oculomotor nerve. And this would be similar. It might be a cousin to CIDP, so chronic inflammatory demyelining polyridiculopathy. It has very similar course. The headache is thought to be secondarily generated. Some in the headache community think it's due to activation of the trigeminal nerve. So a trigeminal type of headache, which might explain why some of these don't have typical migranous features. Is it antibody-mediated? Like I said, some of those have IgG and oligoclonal bands in the CSF. It'd be kind of weird for antibody-mediated disease to simply affect one portion of one nerve preferentially in all patients. And so that's something that has yet to be explained for that particular etiology. But the idea of recurrent demyelination and inflammation does kind of jibe with the natural history in that cumulative axonal damage may cause persistent defects over time, as we saw in our patients. And then remyelination of that cranial nerve could cause vocal enlargement, which would be expected to persist, at least for some time after the attack, even after the contrast enhancement had gone away. So another theory is that maybe this is a normal response to a neurotropic viral infection, namely herpes. There have been familial cases of this, where there's recurrent balsyphacial palsy and ophthalmopagea preceded by head pain. If you ask these patients that they're old enough to talk, they will have a family history of those palsy. We obviously don't know any family history on our patient because he was adopted. And then one of the things that they point to in this association is that if you take an MRI, a contrasted MRI of a patient having balsyphal palsy at the time is that they'll have very similar findings on MRI to these patients with aphthalmoplegic migraine. As previously thought, that maybe this was due to an occult schwannoma along the course of the third cranial nerve. There's only been one pathology confirmed case of that in the literature. And there's probably 60 or so cases of these which have been written up. And so that's not expected to be a large cause of this. And then compressive neuropathy from vascular dilation phase of migraine. So again, hopefully by now I've been able to convince you that this is not strictly a migraine phenomenon. Additionally, if this was vascular compression, one would expect more pupillary involvement consistently, right? And so that's definitely not seen among these patients. And so that's not in very much favor at this time either. So there's so few of these patients, there haven't been any prospective blinded or randomized trials. However, like Bell's palsy, some of these patients have been treated with steroids. So mostly oral steroids, but some have been treated with IV steroids. And of those who were treated with steroids that they were able to review in the literature, there was a recent literature review which showed that 54% of those treated with steroids had a perceived improvement. So meaning that their symptoms improved over one to two days as opposed to waiting the average three weeks. And then another roughly third, the effect was unclear. And then in the eighth, there was either no apparent benefit or the patient actually worsened. Again, as we discussed in these young patients, attention to maintenance of proper visual acuity and vernacularity is of the most importance. And so we need to involve our pediatric ophthalmology colleagues for the appropriate interventions. And again, this is unlikely to respond to traditional migraine treatment. So they've tried all kinds of prophylactics and abortives to see if they can have fewer attacks or if the attacks were less severe and that's just not working. And so that kind of bolsters the idea that this is not a migranist phenomenon. So take home points. You have a spider sense for migraine by the time you're finished training here. And so one of the things that should trigger that is a patient with chronic sinus problems or sinus headaches. And I do think intuition gets a bad rap in medicine, but you need to at least listen to your intuition. You don't always have to do what it says, but that should be a cue to you to kind of dig deeper a little bit. And then I think in our young patients with isolated creatomomoropathies, especially a third, just to be aware of this rare clinical entity, and that's part of why I wanted to present it and include it in your differential. And it's slippery because they may not have a headache, they may not be able to complain of a headache. And their headache may not be migranists, even though it's called ophthalmoplegic migraine, but nevertheless, consider it in your differential. And does that change the management? No, not necessarily, but it does change the way that you would counsel the parents. And it may help prevent, if you are able to establish the proper diagnosis, it could help prevent unnecessary imaging in the future if they have a recurrent attack and help them to understand what's going on. So your daily dose of sweetness here. So this is my lovely wife and our new baby Eden. She's six weeks old. I'll have you know she's already a scientist. She's performing sleep deprivation experiments on us. Pretty soon she'll start smiling and that'll be an experiment in classical conditioning and it'll just go from there. So this is my life. I'll take any questions. That's a very interesting question. I don't know, I don't recall. I'd have to look back through the history and see if the patient actually had antibodies drawn. But certainly, with a relapsing type of course, stuttering progressive type of course, that's a consideration. It's my understanding that pediatric myosinia is much more common in the perinatal period. And then again, when they get older, I'm not sure how common it is in this age group. But I think it is a very reasonable consideration. Any other questions? Dr. Warner's not here, but it counts. It counts. It counts.