Episode 428: Neurology VMR – Diplopia and fever

Welcome back, clinical problem solvers. Maddie and Yusuf here. At CP Solvers, our mission is to make clinical reasoning accessible to learners worldwide. We invite you to join us for our live virtual morning reports, where we break down cases and sharpen our diagnostic reasoning together. Now over to you, Youssef.

Thanks, Maddy. Just a quick reminder, this podcast is for educational purposes only and is not a substitute for medical advice. Patient details have been modified to protect their privacy and the views expressed here are our own, not those of our employers. Now, let's dive into the case. Enjoy the show! Hi, everyone. Welcome back to our Neurology Podcast.

This is A. I'm one of the neurology research team members at Washington University in St. Louis. Today, we have an amazing neurology case discussion with Dr. Aaron Baggerwitz, Vali, and Sebastian. Philly is a Medicaid graduate from Peru and applying neurology residency this year. Sebastian is a neurology resident from UCLA. We have an amazing case presenter, Dr. Yusuf Patel, and he is a neurology resident from Cape Town, South Africa.

I hope you enjoyed this episode and if you would like to present a neurologic case, please reach out to us and we are more than happy to have you. Yeah, so just to go through the chief complaint, it's Diploplia.

associated with fever. Diplopia and fever, fantastic. Valeria, do you have an approach to, let's stick with the diplopia for now, the neurology, and then we'll pull the fever back in later. Yeah, I think it's a classic chief concern at this point for us, which is amazing to get that space repetition. Yeah, I think when we talk about diplopia, we have to think about misalignment of the eyes.

first we should focus on or determine if this is monocular or binocular diplopia to kind of get the taste if this is an ophthalmologic or a neurologic problem itself, even though monocular diplopia can also present as a neurological problem.

process, particularly involving the cortex, the occipital cortex, but I think that's more niche. So when it comes to misalignment of the eyes, we should think about, you know... assuming that it's binocular diplopia, we should think about the muscles that kind of dictate the movements, so like the superior obliquus, inferior obliquus, the lateral and medial rectus.

in the nerves that innervate those muscles, like the third, fourth, and sixth, and not forgetting the neuromuscular junction, and as those components kind of leave the optic socket through the up the canal and then going through the cavernous sinus, especially with the concomitant symptoms. In this case, I'm very worried about something there, which would be like an emergency. Then they travel through the base of the skull.

and get to the brainstem where they have all the nuclei, particularly in the midbrain and pons. So yeah, I think that's where I would love to learn more about the temple. Fantastic. Yeah, I think for some reason I take this the same way as you do, Belir. I feel like it's easier for eye stuff usually to work from the eyes backward, even though we usually work from the top of the system down. So yeah, you mentioned that the eyes are controlled by muscles.

Those muscles are controlled by nerves. There's a neuromuscular junction between them. Those nerves originate in the brainstem. Between the brainstem and the orbit, pass through the cavernous sinus. And for diplopia, there's probably just one other...

structure that should be named. It's a little bit, guess what I'm thinking about that makes sure the eyes are aligned when they're moving conjugately. Structure in the brainstem failure that when affected can also cause diplopia. Do you know where I'm going with this? Yeah, the PPRF and the MLF. Ah, the MLF specifically. Yeah, MLF, right. And what does the MLF do, Valeria, just to remind everyone? Yeah, it's part of the horizontal conjugate gaze.

center. So we can coordinate the third and the sixth to move together. Perfect. It's a white matter pathway. And we usually learn in medical school, right, that it connects the third nerve nucleus on one side and the sixth nerve nucleus on the other side so that for horizontal gaze, the eyes are yoked.

In fact, it's sort of a highway that has exits for 8, 3, 4, and 6, and so it also coordinates the vestibulo-ocular reflex, vertical eye movements, anything that's involved in conjugate eye movements, it's sort of like a line with. lots of branches coming off each side. So it connects 8, 3, 4, and 6, and then bilateral. Good. So as Valeria said, if we have diplopia and its neurology morning report, so we'll take out monocular diplopia, which is usually some I.

ophthalmologic type of thing. We have misalignment of the eyes, that's why the patient is seeing double, and that could be from diseases anywhere along this pathway, right, which could be something in the orbit restricting movement, like thyroid eye disease or an orbital mass, could be...

working backward. The muscles themselves could be the neuromuscular junction, as is affected in myasthenia. It could be the nerves themselves, 3, 4, or 6, as Valeria said. It could be their nuclei in the brainstem or the interconnection of the nuclei. You mentioned the PPRF, that's a horizontal gaze center. So if that's affected, which is where you actually get a conjugate gaze policy, the eyes can't look in the direction of the PPRF. That would be super nuclear.

Good. Anything to add here, Sebastian? I don't have too much to add to Bolliers. I just basically said it back. I love the discussion. I agree with thinking about binocular versus binocular causes of double vision. I love the structural approach, starting distally and working back proximally through.

the anatomy of eye movements. I think I would maybe add that with the existence of fever, there's a couple of specific things that I'm worried about. Just pulling the Venn diagrams together, I'm thinking about especially emergent causes.

You know, are we missing a preceptal orbital cellulitis that's structurally causing rinocular difficulties that sort of can't misdiagnosis? And separately, I'm starting to think about whether there's an infectious process of the cranial lip nuclei themselves. Is there some sort of... skull base infectious process going on here. So that's where my mind is headed with this initial chief complaint. Fantastic. Appreciate how you both took the...

two words on either side of with there and worked with them. Yeah, so we have the structural localization approach. We have to invoke something along that pathway if there is diplopia. And then Sebastian's folding in the fever makes us think of infection and what types of infections could you have.

Along the way, you could have something in the orbit, as you mentioned, a receptal cellulitis. Valeria mentioned the possibility of some type of cavernous sinus syndrome. The other thing to think of here... We were so precise with the diplopia localization, we have to remember that you can get a sixth nerve palsy as a false localizing sign, right, if the intracranial pressure is elevated. The sixth nerve, some people say, is the longest nerve.

That's sort of like a trick question. The vagus is the longest nerve. It has to get all the way down to the abdomen, right? But there's a sort of tortuous path over the skull base, over the clivus, through the cavernous sinus. That's one of the longer, maybe it's the longest. I'm not sure.

inch per inch versus four that has to come out the back and go around. But in any case, for some reason, it's susceptible to elevated intracranial pressure. So a less sort of anatomical, but more just sort of broader view could the diplopia be from unilateral or bilateral six nerve palsies from elevated intracranial pressure and then with fever could this just

simply be meningitis or an abscess or something like that. If we sort of start with the fever, think fever and neurology, and then wonder how we could get diplopia. And you mentioned the brainstem. We'll obviously hear more of the history. to understand if there's something in the brainstem. Probably if there's something in the brainstem affecting 3, 4, and or 6 and causing fever, probably the patient's going to have a lot more.

to show for it if they're even awake because there's just so much packed into a small area in the brain stem. Infection of the brain stem is pretty rare. We call that rhombencephalitis from the rhombencephalon embryological term. the classic either of you know probably valeria or sebastian an infectious rhombencephalitis yeah i think the classic one is listeria but i've also learned like interoviruses

Some herpes viruses love the space as well. And I remember a case I saw a couple months ago of mycoplasma affecting the rain stem as well. So yeah, I think those are my thoughts on that infectious bucket at least. Yeah, the classic one is lysteria. I'm not sure I've ever seen a case of lysteria rhombencephalitis, but it's reported. And then, yeah, mycoplasma is sort of on the list of infections that can do anything. I think someone once showed me a case of encephalomyeloridiculitis from...

from mycoplasma, so from top to bottom of the nervous system. Okay, so what types of things? Sebastian, would you be asking on the history here if this was the... page and you are calling down to the emergency room, if that's where this patient is, or calling the primary care doctor back or internist back. And what are the things that you're going to be keyed into on the history here to try to make further diagnostic progress?

Yeah, I mean, I think initially I'd be triaging the case. And as you said, just checking the GCS, what's the state of consciousness? How much of emergency is this as the patient?

had a seizure, you know, they got an old state of consciousness, just asking for any signs or symptoms that could suggest a much wider and more acutely concerning neurologic insult. And then more broadly, calling back on the phone, I think I would also define... um just at least confirm the visual or the ocular complaint you know is this actually oscillopsia is this actually dizziness with sort of visual blaring is this you know so i think i would want to tease that out a little bit better

And obviously, as we always talk about in neurology, the tempo is key. I'd want to know how long this had happened for again to help me triage the etiology. And then I would briefly want to know what their exam was. I specifically would be interested to see if there are any other cranial nerve palsies.

to see if there are any obvious ocular defects or any swelling or abnormalities of the face that were apparent. I mentioned checking mental status. And then, again, helping me localize, I'd probably briefly ask about any change of the peripheral nervous exam. I think that's where I'd start. And then I think obviously I would be seeing this patient pretty quickly anyway. I think any neurologic complaint with fever is always a red flag. So I wouldn't be sitting on this for long.

Fantastic. Phenomenal. Yeah, I agree with everything that you said there. Yeah, so things you'll want to understand from the history, either from the consulting provider or obviously from the patient as well. Yeah. Are we truly dealing with diplopia?

which is probably not the word the patient would use unless they're in healthcare, but is it really double vision or is it just blurry vision, as Sebastian said, or is it something else? And presuming it's diplopia, we can ask the patient, have you noticed, is it worse when you look to the left, the right? People are saying, is it hard to hear me? I think I hear you well. I don't know if... Okay. Someone wrote in the chat, it's hard to hear me. Okay. All right. So...

So, right, we'll want to get a sense. We can ask the patient, is it worse when you look in one particular direction or close up or far away? Obviously, we're watching their eye movements as their... as they're giving the history and then as sebastian said of course time course time course time course although diplopia my mentor marty samuels like to say diplopia is always acute because your eyes should have just aligned enough

to keep the image fused until they're not and so there's not really sort of gradual diplopia but one might notice that it's been getting worse and worse but there's sort of a moment before you have diplopia and then a moment when you have diplopia even if you've been

slowly developing something there. And of course, if we're trying to figure out is this a cranial nerve or a muscle or a neuromuscular junction problem, anything else to go with those? Have they noticed the diplopia is fatigable? That would suggest... Myasthenia, which almost always involves the eyes of presentation. Of course, myasthenia shouldn't cause a fever. I don't know with botulism. I've never seen a case of botulism. I don't know if they usually have fever or not.

But something to just keep in mind as I's neuromuscular junction as we're talking about that. Yeah, and if we think about the cranial nerves as Sebastian said, are there any other cranial nerves involved? Is there facial numbness, which could put us... back in the cavernous sinus as their facial weakness, which would maybe make us think of something more skull-based, meningeal, if that's going along with 3, 4, ender 6. And...

Are there any long-tracked signs? Is the patient weak or numb in the extremities? Again, multiple cranial neuropathies, either you're sort of in the brainstem or you're not. And if you're in the brainstem and you have multiple cranial nerves involved,

Probably, they're not always going to see long track signs or changes in level of consciousness. So those are things that will help us with the localization a little bit more with the diagnosis. And of course, we're curious, the past medical history is this patient immunocompromised?

Is this patient immunocompetent? Do they have any other salient medical history that would make us frame these chief concerns differently? Okay, so with those questions in mind, let's hear Yusef a little bit more of the history.

and see how those questions end up getting answered and what new information we get. Sure. So the patient is a 36-year-old female, no past medical history of note prior. She essentially came in with a one-week history of double vision, fever, lethargy and unsteadiness and also reported that her right side of the face was becoming weak and numb.

So she was seen in our emergency unit. The tempo is that... it started quite suddenly with regards to the double vision so she said she woke up the one morning and she was seeing double and then the fever ensued etc etc they initially saw their general practitioner who then referred across to the emergency unit because they identified this as a potential emergency. When we saw her there, we just elicited further history, just basic with regards to social background and so forth.

HIV negative, which we did test as well. No significant smoking or ATOH history. And in terms of occupation, worked as an administrator, so not really exposed to any toxins or any significant metabolic agents. There was no bulbar complaints. problems with regards to bowel and bladder at the time no limb weakness but as i mentioned she was complaining of unsteadiness

especially when she would stand and when she would walk. And we also noted that on examination. So just to move towards the examination, just on general, she was tachycardic. She was running. with a pulse of about 125 she had a blood pressure of 120 over 75 and her temperature was 38.7 and this was all during the triage in the emergency unit. She was disorientated to some degree. She was aware of herself, but she was not aware of the location and the time.

diaphoretic as well, so she was sweating profusely. The rest of the systemic examination was otherwise normal, but coming towards the neurological examination, she had no meningism, no neck stiffness, but with regards to her cranial nerves.

She had quite a few deficits, so I'll just go through them in order. So she had ptosis of the left eye with a down and out pupil, but the pupil was of normal size and reactive. She had... partial restriction of the right eye when she would look laterally so we thought that she had a partial cranial nerve 6 palsy she had numbness to the face on the right side

and she had weakness as well with an upper motor neuron pattern and then she had gaze evoked nystagmus as well, direction changing but worse when looking to the right compared to the left. The rest of the cranial nerve examination was otherwise normal. just to go through the motor examination and the rest of the examination. Everything else was otherwise fine. So strength in all the limbs were normal. Tone was normal. Her reflexes were normal as well. And sensation was also normal.

Just with regards to coordination, she... She did have dysmetria on the right with a finger nose test and also with a heel to shin. And she was ataxic when we asked her to walk and she was falling over to the right. And I mentioned her nystagmus early on. Okay, well, thanks, Yusuf. There is a lot there. Very detailed exam that you performed. Just since it didn't make it into the transcription here, the down and out eye was at the left eye.

That was on the left. And the pupil was reactive on both sides. Yeah, and equal. Okay. First, since there's so much going on there, Valeria, do you want to just summarize in neurologic terms, as in naming?

the deficits, what all we've got here. Yeah, so going straight to the exam, I think we have a third nerve palsy on the left side. left, third nerve palsy, well, if there's people sparing third nerve palsy, a partial sixth nerve palsy, if I heard correctly, on the right side as well, right? And then we have right facial numbness. So it was just like a complete fifth on the right side, palsy. Then we have...

what you described as an upper motor neuron pattern of right facial nerve involvement. And then we have signs of some cerebellar. classic signs of Dismitria on the right and Ataxia Gate. I think for me, it's quite confusing because we have a third left. And then we have a lot on the right. And then we have the cerebellum. And I think I'm still most likely localizing. And then we have the fifth. The fifth is kind of weird. But I'm...

With all these cranial nerves going on, I think I'm most likely localized it to the brainstem. Even if we have like an upper motor neuron pattern of facial weakness, I believe if the nuclei are affected right before the nerve is going out, it could explain maybe what is going on right here. So I think maybe we are on the rovencephalitis schema after all. That's kind of my suspicion, but I would love to learn from both of you if you're on the same track. Yeah, great.

Brilliant thoughts. Blair, before I get your thoughts, Sebastian, just to clarify, Yusuf, was it checked which modalities of sensation were affected in the face? I forget if you mentioned that.

So it was soft touch, specifically soft touch, yeah. And pin click, sorry. For pins specifically. And just asking that as far as there's some different localization in the brainstem depending on... the nuclei five that are affected or if it's all modalities might suggest outside the brainstem but light touch okay and it was the whole face not one particular distribution yeah and the upper motor neuron pattern facial weakness we just want to make sure we heard that correctly yeah

Correct. Forehead with spirit, yeah. Forehead with spirit, got it. Okay, Sebastian, what are you doing with all this? And then listening to both of you gives me time to try to figure out what I want to do with all this. Yeah, I think localizing this, so there are a few useful cues for me in this exam. So I think I'm moving away from cavernous sinus because you mentioned dysmetria and unsteady.

gate. So I'm thinking more about vestibular and eighth nerve nuclei, which obviously exists, and tracts which exist outside of the cavernous sinus. So I'm really localizing it, as Blair said, towards the brainstem. Specifically,

Mixed signs. So is there a disease that's just crossing both sides? Is this either a very messy vascular phenomenon? Is this an invading inflammatory infectious phenomenon that anatomically is picking off multiple nuclei? But I'm localizing this mostly to at least the right...

pons and medulla, given that we've got, you know, so we're involving the spinal trigeminal nucleus potentially on the right, given loss of, actually, you said pain, was it, I don't think Aaron was asking this, the trigeminal, so it was just...

just light touch so we don't know if it was you know pain or even proprioception right up in the midbrain for the fifth note but potentially something quite longitudinally extensive and i think that's the case also because invoking the sixth on the right we're also invoking the eighth on the right

So I think there's something invasive within the pons and the medulla on the right side, but then we're also getting this left third nerve pattern, which is pupil sparing, which confuses me, which suggests maybe there's something encroaching within the fourth ventricle.

You know, anatomically something that's spilling over and affecting nuclei on both sides. Yeah, so that's where I'm at. I'm localizing it. Definitely, you know, going back to our initial schema, certainly now obviously away from the more distal structures around the eye approximately, not really thinking about... the individual nerve tracts or cavernous sinus per se and really thinking about brain stem structures potentially extending through the ROM encephalon towards the cerebellum as well.

Yeah, brilliant. And Sebastian threw in a little pearl there that the trigeminal nerve little-known fact has nuclei at all three levels of the brainstem. He mentioned the little-known mesencephalic nucleus of 5 for facial proprioception. We don't really check that, and I'm not sure.

We would never see that effect in isolation. Then light touch and the muscles of mastication is in the pons and then the pain of temperature is down in the medulla, why it can be affected in Wallenberg lateral medullary syndrome. Okay, you both want to put this in the brainstem. I'm not sure for a couple of reasons. Okay, so let's look at our scorecard of cranial nerves here. We have a left third, and it's pupil sparing.

So before we proceed, Valeria or Sebastian, do you want to tell us what it means that it's pupil sparing? Yeah. So the parasympathetic fibers are usually like... classically thought to be in the periphery of the nerve rather than in the center where the motor fibers are. So, you know, we would assume that the center of the nerve has been affected, which usually, I mean, etiology-wise, we...

of the natural, like, microschemic changes rather than compressive ones that would affect the periphery before the center. Yeah, good, yeah. So the nerve is actually laminated itself with fibers that are headed to the medial rectus and to the superior rectus, to the inferior oblique, to the pupil, to the lid.

I used to imagine in my mind, people say that people in motor fibers are on the outside as if they're circumferential. They're in one particular place on the outside. We won't go into that in detail right now, which is interesting because the classic teaching of if the pupil is spared, then it can't.

be an aneurysm because aneurysms compress from the outside that's actually incorrect if you have a basilar tip aneurysm that's pressing from the bottom then the pupil motor fibers are sort of on kind of the medial superior aspect there and then I think the nerve must turn because then if it's something in the cavernous sinus can also somehow spare it or something like that. Anyway, if you look into this, like anything in medicine, it's much muddier than the rule of pupil sparing means.

It's not compressive. You can get compression from certain aspects that could still hit the nerve and not get the place at that point in the nerves course where the people in motor fibers are. Anyway, for neurologists, neurology trainees or other people who are... big fans of neurotrivia, you can email me and I can send you some interesting papers on that. Okay, so we have a pupil sparing third. To me, that means it's probably not in the brainstem where all the fibers of it are kind of...

back together. I guess it's possible. It could be compressing from one side or it could be infiltrative or it could be vascular. Just taking the third. But okay, we have a left third, we have a right sixth.

I don't know what to do with the nystagmus. When there's a gaze palsy, you can get gaze paretic nystagmus. I'm not sure that's necessarily cerebellar here. It's kind of when you're looking towards the side of the weak muscle and the eyes are misaligned, they're doing their best. And there's probably some... information overload or signal overload and it's just trying to move around so i'm not sure we can use that so we have a three we have a six we have a five um we have

What we're told is an upper motor neuron seven. I take Yousef's word for it, whether it's a partial seven in evolution to keep us in the cranial nerves. I don't know. Because if you were above the seventh nerve nucleus, as you said, Vale, in the upper pons or... In the midbrain where you would still get the classic upper motor neuron pattern of weakness there, you would still be above the level of 6 because 6 and 7 are at the same level of the brainstem.

If that's a true upper motor neuron seventh, I think it's hard to put this all with one lesion. And then we have the cerebellum. So it'd be nice, as Sebastian said and Valerius said, kind of anatomically have things in proximity, something crawling along. in the brainstem and then back into the cerebellum. And the patient doesn't have a normal mental status, but they're awake enough, if I understood it from Yousef, alert, talking to us, participating in the exam, just slightly confused.

To draw a line, connect the dots from left 3 to right 6 and 5, and then to cerebellum. And you somehow, I guess you stayed in the back of the brainstem, you managed not to get any... of the long tracks, except a touch of face, then you'd have to kind of go maybe three, hit it on the way down, and then you haven't really affected the level of arousal.

Feels a little tough to me to make that brainstem lesion unless it's, you know, really kind of making kind of a zigzagging path in there and somehow missing long tracks, missing other cranial nerve nuclei.

and yet we have cranial nerves and the cerebellum. So you may be right, and I'm not saying I disagree. I'm just saying I'm not sure. So let's just zoom out multiple cranial neuropathies.

How do you get multiple cranial neuropathies? This doesn't come up that often in neurology, but when it does, it's good to have a schema. So either you're in the brainstem and you've picked off multiple nuclei or the fascicles. That's the name of the part of the nerve while it's exited the nucleus and is on its way out.

or you're in the subarachnoid space, so meningeal process, or you're in the skull base. We mentioned the cavernous sinus. There are other skull base places you could be. Or you're in what I don't have a great word for, so someone can... Give me their word for it if you have one. Just sort of like in the target organ. So in the orbit, in the face, in the kind of neck, throat area for the lower cranial nerves. So multiple cranial neuropathies I think of as either being in the brainstem.

or outside the brainstem, because the brainstem is its own thing with lots of the long tracks and reticular activating system. If you're outside the brainstem, subarachnoid space, spell base, or target organ, and then you have what I call fake-outs. So you could get multiple cranial neuropathies from Guillain-Barre syndrome or variants because the cranial nerves are peripheral nerves, right? You could get multiple cranial neuropathy appearing deficits from myasthenia, which could cause ocular...

weakness and facial weakness as well. You could get orbital myopathies, myositis, orbital myopathies like oculopharyngeal muscular dystrophy. So those are what I call sort of fake outs where it's not really localizing to particular. place. Okay. So one question I have for you, Seth, did these deficits all kind of come on at once or were they, did they kind of march along? There was one thing and then another thing and the other thing wasn't really clear to the patient.

Yeah, it seemed that we spoke to the patient's spouse and it seems that it progressed over the week. So as I said, initially just the diplopia, then he noticed. facial weakness and then the fever and so forth. And then when she presented to us after one week, she had this full constellation of clinical features. Okay. So we have something evolving over a week. We have fever. We've already kind of been invoked. Infection, which I think...

Probably continues to fit. Okay, so what if we're not in the brainstem? I'm not saying we're not. It's just hard for me to draw a path here and get that pupil sparing third. Makes me feel a little bit like we're outside. Well... The upper motor neuron facial weakness, we've got to be above the level of the facial nucleus. So either we're in the left brain, left upper brain stem, midbrain, upper pons. So maybe there's one central lesion here. It's hard for me to fold this all into one.

place, like I said, unless we've got a zigzagging, very patchy brainstem process that patient lucked out and didn't get level of consciousness. And there's some altered mentation. So is there a meningeal process that also cause an infarct from infectious vasculitis? That's possible. And that would give us some of the central component here, as well as cranial neuropathies.

Over a week, it's probably too slow for bacterial meningitis, but a fungal or tubercular meningitis could look that way. If I took out the fever... Yeah, what if I took out the fever, Sebastian or Valeria? Multiple cranial neuropathies here, ataxia, anything jump to mind? Yeah, a few things. You take out the fever, think about any paraneoplastic.

even leptometrial carcinomatosis, or they might not explain the attacks quite so well. Okay, yep. Really fast for perineoplastic. There is a recently described perineoplastic syndrome with multiple cranial neuropathies. with a rhombencephalitis actually, and usually with hearing loss. I haven't seen it yet. Anyone know this one? Kelch-like 11 protein.

I think it's with testicular cancer. I haven't seen it yet, but it's brainstem hearing loss ataxia. Testicular cancer. This is probably fast for a perineoplastic. Leptomeningeal carcinomatosis. It could pick off cranial nerves. It often layers in the cerebellar folia, though I haven't really seen ataxia. I think it's more radiologic component to it, to my knowledge. Probably be a little bit fast.

Multiple cranial neuropathies and ataxia. Anything else jump to mind? I was playing a little bit. Guess what I'm thinking, but... I'm not sure if... Ophthalmoplegia, ataxia, ataxia. Like Bergerstofcephalitis? Like a variant GES, like Miller-Fisher. Yeah, yeah. Sound like Miller-Fisher syndrome. You might say, but there's not a reflexia.

You actually can have normal reflexes. You can even have brisk reflexes in Guillain-Barre. If you read the large series, you can really kind of have anything or everything. You shouldn't have a fever with Guillain-Barre syndrome, though. Unless the patient does have some subtle bulbar weakness and aspirated, maybe the fever is a sort of red herring-ish or kind of secondary and not part of the primary process. But yeah, without that fever, I think we'd be having a different...

conversation here about Guillain-Barre and then with the altered mental status. So Miller Fisher is a variant of Guillain-Barre. Bickerstaff has a variant of Miller Fisher where there's basically Miller Fisher with altered mental status. That's if we take out the fever. We put it back in, then you shouldn't have a fever with Guillain-Barre unless, like I said, secondary and the patient aspirated for some reason. Okay, anything else we should be thinking of here?

You're supposed to get the pupils in botulism, although if you look at large series, not everybody loses them. Yeah, I just saw a flash in front of me on the chat. Diamond deficiency. When there's funny eye stuff and altered mental status and ataxia, right? It's...

Often the triad or parts of it of Wernicke's encephalopathy are staring us in the face and we don't think of them. We've heard there's no alcohol here. We don't know about the patient's nutritional status. Again, shouldn't cause fever, but you can get any gays. palsy with that and nystagmus and ataxia. That's a great thought. And then if we zoom out and we just said, well, I don't understand all this neurology, but there's fever and there's neurology and there's all that.

all right this is meningitis or encephalitis of some sort and it's probably too slow for bacterial so we'd be in sort of the viral I guess it's not necessarily too slow for bacterial but material, usually a weekend, the patient, I think, be much worse off at this point. But could it be viral? Getting all those cranial nerves, a bit of a stretch.

There's no HIV here, so unless there's an immunocompromise that the patient's not aware of and we're not aware of, shouldn't really be getting fungal meningitis. And then we are in South Africa to know how. Much tuberculosis you see there, but there's certainly tuberculosis there, and that could certainly behave this way, kind of moving along the cranial nerves and the meninges and picking them off.

either from compression or probably vasculitic involvement. I guess the other thing, multiple cranial neuropathies, if you took the fever out, it must be some type of vasculitic process. That pupil sparing third still makes me... think of something vascular, though I have seen that without a vascular etiology, some type of compression or infiltration. All right. Any infections come to mind, Sebastian Valera? Or what do you say? Do you stick with the brainstem? Did I...

lead you to question that i'm not sure i think there's a reasonable possibility this is in the brainstem and it's patchy um and that would certainly make sense contiguously to get all this stuff in one location but somehow that pupil sparing third

multiple levels of the brainstem and the patient's still awake and no long track signs. That makes me feel like it's outside the brainstem or at least part of the process it is. Yeah, I agree that it's something that's... either like multi-lesional there's one disease process that's causing multiple like anatomically separate uh lesions and uh you know that they may be in the brainstem but as we said may also be closer towards like sub-rachnoid space or you know

affecting the peripheral nerves. Yeah, yeah, yeah. I would just add, in the infectious category, I think some fungi that may have some trapezen for the brainstem are like aspergillosis. And then also to not forget like autoimmune inflammatory diseases that girls explain, like the patchy distribution that we're seeing here that could cause meningial infiltration or like direct infiltration on the parenchyma.

And to ask, you know, maybe in the Ross question, if there are signs of systemic diseases, you know, ulcers, if there's, you know, dry eyes, dry mouth, stuff like that, that is often, it's, you know. Easy to miss. That's great. Yeah, immune-mediated processes, a flare of an immune-mediated condition, right? MS wouldn't behave this way, but...

NMO, we always think of M and O, right? Myelitis and optica. But NMO actually is now NMOSD, NMO spectrum disorder. And there are actually six syndromes of NMO that are described. Myelitis and optica, optic neuritis, are still the most common.

But you can get the area postrema syndrome, which this patient doesn't have with hiccups, coughing, nausea, vomiting. There's an acute cerebral syndrome, which I haven't seen, which is pretty rare with confluent white matter lesions that are usually enhancing. There's an acute brainstem syndrome, which... this could in principle look like. And there's a diencephalic syndrome with narcolepsy and hypothalamic types of problems, SIDH and whatnot.

So without fever, could this be a flare of NMO? And then when you said ulcers, you were thinking of something else, I think. But I haven't seen Bechet's disease, but when it affects the nervous system, it has a propensity for the brain stem. And so if you had oral or genital ulcers or a history of those and a brainstem syndrome, again, I wouldn't expect them to have fever, I guess. Although, why not if they're kind of acutely inflamed, maybe a low-grade fever.

South Africa is not along the so-called Silk Road, but many people live in South Africa from all parts of the world. So that could be something else to think of. Okay. So Sebastian, Valeria, if you could order one test now, I know we can order lots of tests, but if you could order one test, what's the first test you would order? I'm going to take the MRI with contrast.

Yeah, an MRI with contrast. I agree, Sebastian. I agree. MRI brain with and without contrast. And do you think we're going to get the answer here? I think it would be very helpful to us if the MRI is normal. We're excluding a lot of our, well, I think we're reasonably excluding a lot of our concerning differential diagnosis. Do you think it's going to be normal? No, because of the presence of fever.

Oh, because of the pressing of fever. Interesting. Yeah, always good to predict what you think you're going to see. It's actually pretty rare, at least for us in the U.S., that you see the patient and they haven't had a scan already by someone else. So it's good always when you haven't seen the scan to say, wait. What do I think this is going to show? Yeah, if we have a fake out here, a Guillain-Barre botulism, yeah, the MRI will be normal. And then, as you said, it will be...

Either this is lesional or it's not, right? Yeah, go ahead, Valeria. No, I just want to say that I've had some cases of like autoimmune and like paraneoplastic that at first don't show on the... on the MRI. So I think it could be fair. I recently, I'm not going to say that because I'm going to present that case to you in the future. All right. Good, I heard that.

Oops, somebody signed me out. Am I back? Yeah, okay. Booted me off and then put me back. Okay. I think we're going to see something here. Yeah, either there's the brainstem process you both anticipated. I still can't imagine in my mind if that's what this is going to be or not. I say it could go either way. Or there's going to be some enhancement of the leptomeninges here, or both.

Are we going to get a definitive answer from the scan? That I'm not sure. But as you said, Sebastian, if it's normal, then a lot of things fall off the differential pretty quickly. Is it going to be normal? I think there's a reasonable chance, but my sense is that it is not going to be normal. Okay, well, why don't we ask you, Sif, what did the MRI show? So before I get there, I just want to take you on a journey.

through our experience in South Africa in the sense that we're not able to get an MRI on every single patient due to our division of state and private. So we have one MRI in the tertiary hospital that I train in.

And we have to be very judicious in terms of who gets an MRI and we usually follow protocols. So just to go very briefly through some of the biochemistry, because I think it might just... help a bit and then some other imaging and then I'll get to the MRI so with regards to her UNE that was normal her white cell count was raised the CRP was raised and the ESR was raised significantly she had an LP

But prior to the ALPI, we did a CT plane of contrast, which was absolutely normal. We reviewed that with the radiologists and then we reviewed that independently. Her LP was reactive. She had polys of 5. She had lymphocytes of 253. The protein was... 1.27, glucose of 4.2, the clot was negative. The gene expert for TB was negative, and the TB culture, which came out later, was also negative, and the MCNS was unremarkable. So at this time...

We also did a blood culture, which came back negative. But we just felt that we had to treat her potentially for listeria, even though that the blood culture was negative, knowing that a blood culture is not 100% sensitive for listeria. So she showed some improvement with IV antibiotics over three weeks, and she was subsequently discharged. So at that point, we thought that it was probably an infective cause.

And that we just would treat her empirically. We saw her in our clinic a few weeks later. She was stable, no progression.

No remarkable improvement from discharge, but she was stable at that point. And then we saw her two months later. And on that second clinic visit, it seemed that she had a relapse. She was, again, very unwell. tachycardic, pyrexial. She had similar symptomatology and clinical features, but in addition to the previous index presentation, she now had a hemiparesis on the right side.

So at this point, we wanted to admit again to our ward. We repeated another LP, which again was reactive, very similar to the first with regards to the protein being raised and a high lymphocyte count. And then we were able to order an MRI, which took a few days. But in that period of time, and I think this is important, we were able to speak to other family members and we were able to do a complete thorough examination and we identified.

on that examination that she had these postular lesions somewhat acne form in the head and she had a she had scarring in her genital region indicating that she had genital ulcers in the past. And then on speaking to her sibling, the sibling noted that from her teenage years, continuously she would actually have ulcers, oral ulcers recurrently. So in the previous year when she presented to us she had about four events of

oral ulceration. And I think that essentially helped us clinch the diagnosis, but we obviously waited for the MRI. And if Zakaria can perhaps put that up, we can take a look at that. Fantastic, Yusef. Thanks so much for telling us about that.

context there. Here, let's pause before we take a look at this. Worth knowing that if you can't get an MRI, which in many parts of the world is the reality or it's difficult to get it or the patient would have to pay for it or sometimes the MRI is down or it's... Even I have in San Francisco, some of the places where I work, you want an MRI overnight, you have to call the tech in. It's not just immediately available and you have to decide, is this really going to change my management overnight?

A CT with contrast, people forget that you can get contrast with the CT. It's not just CT or CT angiogram. And if you've gotten a CT angiogram, there would have been no need really to do that in this case. They can just wait and then... run the CT, you know, in the same epoch of the CT, just, I don't know how many seconds or minutes later, wait till the venous phase, and then you get sort of for free a CT with contrast. You don't have to give the patient contrast.

twice. Just one image is time for the arterial phase, one for the venous phase. That can be helpful to look for things like venous sinus thrombosis or enhancement. Of course, the resolution of CT, spatial resolution, is not the same level as MRI, and you might not catch small lesions. the administration of contrast can help you. And if you had a severe meningeal process, probably you would see that here. So that's helpful. And then, yeah, as Yusef and his team thought about what...

is treatable here and that should be treated. Let's start with treating the most serious potential infections and see what happens. And if the patient improved completely, even though you might not have proved the diagnosis, you've proved it by a therapeutic response, or the patient comes back, as in this case, and make the diagnosis the second time. Good. Okay.

So, oral and genital ulcers, even without the neurology, people would already be thinking of a particular diagnosis and now add the neurology. I think, I guess Yousef will teach us more about this. Let's take a look at the scan now, but I believe that the two...

neurologic syndromes you get with Bichette's or either this sort of acute brainstem inflammatory process or venous sinus thrombosis is my understanding. But I think we're going to learn a lot from you. I've never seen a case of this. I think as a student...

medical student, I saw someone with the ulcers and systemic manifestations, not with neurologic manifestations. Okay, let's take a look at the scan. Supposedly, you get a very kind of intense inflammatory, so... t2 hyper intense and enhancing um can we get the mri back up i'm not sure who was displaying that i think it was zacharia if you can perhaps just

The MRI is up. Mary, let me just stop sharing a screen. Oh, yeah. Okay, great. Yeah, so I just took snippets and I sent it to Zakaria. So you can see that on these two axial... flare images, you can see that the diencephalon and the basal ganglia have lesions. So multifocal, I think that was discussed in the discussion earlier, that it could be one entity causing multiple lesions along the neural axis. And then you can just perhaps move to the next slide.

I put axials and coronals. And you can see on this here, you can see in the brainstem that there are lesions. what the hyperintensity is. You can move to the next slide. Yeah, and then this is the coronal. And you can see... in the mesodyencephalic junction, or between the diencephalon and the midrame, you see this classic sign of this hyperintensity, which is called the cascade sign. And that's very specific, or at least the literature says that it's very specific for Neurobetschitz disease.

the Cascade or Waterfall sign. So you can appreciate it here on the left. And then just also to mention, we did a pathogy test for her because that's what the international guidelines also recommend and that was positive. after two days. And so in essence, for those who might not be familiar, what the pathology test is. Yeah, it's just essentially you are...

you prick the patient with a needle and then you measure the response in terms of the inflammation around that area. So there's certain measurements that you have to use and then that would... qualified to be reactive or non-reactive. And it's essentially indicating an autoimmune or an inflammatory response.

Yeah, excellent. Yeah, even at the site where the patient has had an ID, which this patient surely had, you can look for this. If they don't give you the history of ulcers, you don't see the ulcers, pathology response. Good. And the cascade sign, is that...

You were referring to that sign before. That's that thing sort of tracking along the corticospinal tract on the leg. Exactly, from the internal capsule down into the midbrain, into the brainstem. They can carry on with the slides. I just put a few other... images. So this is an image from another patient, but I think this sort of shows the sign quite well.

So maybe not as remarkable, but then again to remember that when she came to us with the relapse, we really started IV steroids. So that probably also, you know, affected the scan. It was done within one week of us ordering. So she was in the ward with one week of IV steroids. And she improved clinically as well. But you can appreciate on her scan that she does have that cascade sign.

Yeah, and as I said, the literature states that this is very specific for Nurebeschitz disease. However, in our population, we have actually found, and we'll probably... complete a paper on this that we've seen other entities that also present with a cascade or waterfall sign. So we are countering. this previously said specific radiological sign for Neurobeschitz. It's probably more common in other entities as well. I think NMO likes this region as well.

Yeah, we're seeing it quite, again, we have a large prevalence of HIV, so patients with PML. We're seeing this amongst the other classical science. And then we've seen in one patient with NMO and we've seen in a few with sarcoidosis. So we're seeing it amongst various other entities.

And then the fever, Yusuf, is that common with a flare of Bichette's disease? Yeah, yeah. So because it's an autoimmune inflammatory process, you know, fever and... A fever and a tachycardia can be seen. It's just, again, the body's inflammatory response to the disease or the disease process causing that.

And for us, this was a great learning point because I think we somewhat in medicine get caught up with the problem of induction, to quote David Humes, that we usually assume that... you know, a patient with a fever and a patient with tachycardia, the cause would be an infective etiology, but not necessarily.

And I think that's what initially caught us out. But when the patient had the relapse, we were able then to do further investigations and also responding at the time to antibiotics. But in hindsight, it was probably that... you know she just remitted at that point and the antibiotics really didn't do much but we created a causal relationship between the two so assuming again that it was an infective etiology.

And she didn't get steroids with meningitis? With the first presentation, no, because we thought that it was most likely a brainstem encephalitis. Just to mention that we did do an autoimmune panel, which was negative as well on that first presentation. But with the steroids, she improved remarkably. And then the MRI was able to help us clinch the diagnosis with all the clinical features and with the pathogen test.

Amazing case. Yeah. And if you're able to say where was the patient from geographically? From South Africa, so there was no, I mean, as you mentioned, we're somewhat of a cosmopolitan country, but the patient ethnically is from Africa, from mixed ancestry. and no family lines from the Near East, Middle East, or the Silk Route, as you mentioned. Yeah. I just want to mention, and some people might think this is too good to be true,

But at the time that she came in with the relapse, we had another patient that presented with oral ulcers, genital ulcers, and also long tract signs. And his MRI, which I did not include here, was also... very suggestive of the cascade science. So we actually made another diagnosis concomitantly on another patient at the same time. And in our department, our hospital has been in existence for the past 40 years.

four cases in total. My mentors and professors said that they've only seen two prior to this. So to have two at the same time was quite fortuitous. That's pretty incredible. Yeah, I remember we had a resident in Boston. One of our residents was from, I believe he was from Iran. And we were sort of, we had a case that was a maybe Bichette's and, you know, everyone knew the two, like the two things I said or the two things I knew. And then I think he had gone to medical school and he just.

waxed poetic about you know all the things he had learned and all the patients he had seen and how they can present differently so some parts of the world um this is seen quite commonly and i think you make the important point you said that in the modern global world um people travel and people have mixed ancestry and you can be far from the so-called you know geographic place where this is classic and the step one use the SMLE question right but in real life people move around people

come from all parts of the world and have ancestry from all parts of the world. Phenomenal case. You could certainly write that up as a clinical reasoning case, I'm sure. for something like neurology or practical neurology, if you're interested. And even just that waterfall sign, I wasn't familiar with that. It could be a neurology teaching image or the British journal Practical Neurology, the BMJ journal, as an image of the moment.

where you send an image, write a report. I don't say this as a conflict of interest, but I'm on the editorial board for Practical Neurology, and we're always looking for cool teaching submissions.

would be something definitely worth submitting. And I'm very excited to see your series of the waterfall sign and how it can be seen in different disorders. Yeah, without fever, yeah, as you mentioned, you could have thought of the NMO. One of the places it does like are those sort of corticospinal tract.

lesions. But, wow. Yeah. And the only reason we thought of this before was just the teamwork of Valeria mentioning oral ulcers. I don't know if you were looking for herpes or what you were looking for there or Bichette specifically. made me free associate to Bichette's. But were you thinking of Bichette's there, Valyria? Yeah, but I was totally biased because last Thursday, I think it was last Thursday, we had a case of neuro-Bichette's as well. So, yeah.

And that's why I was kind of, you know, fresh on my rhomboencephalitis schema and I had bishops and that as well. So that's why. Wow. Okay. It's epidemic here and clinical problem solvers too. Good. Okay, any other teaching points you wanted to give us here, Yusuf, in the final moment? Yeah, they can perhaps, but I just had a few others. They can maybe just press the button and it might show up. It was, again, just, you know, that...

Machete syndrome is uncommon and systemic features are not always prominent. It just shows that taking a history is not static. It's a dynamic process. And sometimes you have to go back. Sometimes you need to speak to other members of the family to be able to get a snapshot of different points or phases in a patient's life.

this specific case, we had to go back quite regularly to speak to different individuals. And obviously the patient in her state was not able to give us, even though she... she was awake she wasn't completely orientated she was able to communicate with us but she wasn't able to give us a complete history and nor was her spouse but it was a sibling that was able to help us with that and then again

just a thorough examination. I know sometimes in neurology, we like to focus on the neurological system and we like to get to that, but it just shows that a good clinical general examination is always helpful. And then I think just one point with regards to neurobeschets, it's seen in 10% of beschets patients.

Just to keep that in mind, and as you mentioned, Aaron, you could have either parenchymal or non-parenchymal. Parenchymal more common, and that affects the brainstem most often. And then the non-parenchymal can be... through venous thrombosis and then intracranial pressure and symptoms related to that. And then for us at the end, you know, after we were able to make the diagnosis, the big debate in our department was how do you pronounce

Bechet's disease. So I can speak a little bit of Turkish and Bechet is Turkish in terms of his ethnicity. So I know people say Bechet or Bechet, but if there's anyone, any Turkish speaking person, they can... also chipped in here. But the C with that little mark at the bottom is actually pronounced as in chicken. So it's Bechet's disease. Bechet's disease. Very good. Yeah, he was Turkish. Like I said, I remember this.

Yeah, I know the resident was from Iran. I don't know if he trained in Turkey or just saw a lot of Beshet in Iran, but just had this wealth of knowledge of how these cases can present. And you mentioned, Yusuf, these are... rare conditions that we might see once in a career. So it's very hard to recognize things we only have a very, very kind of thin schema on of just knowing that we're all ulcer, genital ulcer plus neurology.

It also shows the value in really studying some of these neurologic manifestations of systemic diseases, common and rare to no weight. I'm seeing this neurologic syndrome, which primary neurologic diseases can affect this location, as we talked about. Which systemic diseases can cause neurologic manifestations in this location such that had we not heard about the oral ulcers or somehow they didn't get noted or the...

Genital ulcer is not something we usually ask about in our review of systems. And if you said, wow, this patient has sort of a brainstem syndrome, but they have a fever and they're very systemically inflamed, that's a little weird for neurology. Is there any systemic condition that tends to like the brainstem? And then...

So that's why it's worth knowing. Even, like I said, my sort of very bare bones, Bichette's can cause a brainstem encephalitis or venous sinus thrombosis. I know no more, but that helps to say when we see, oh, this is a weird brainstem thing. What else should we be thinking of?

Bichette's could be on the list. And hopefully no one will miss it now that you showed us this case, Yusuf, and taught us so much about it. Fantastic! Thank you for bringing the case, Yusuf and Zachariah. Great discussion, Sebastian and Valeria. Look forward to the next time. Thanks again, everyone.