I want to thank the AANEM for inviting us to give this session on toxic polyneuropathies and myopathies from a toxic etiology. My name is Kian Sala-Jageh, I'm a Deputy Chair of the Department of Neurology at the Boston VA and also the Chief of Neuromuscular Division EMG Lab Director there. I'm also a Social Professor of Neurology at the Brigham and Women's Hospital and Harvard Medical School, and my area has been neuromuscular disease and, you know, different aspects of it, and so Dr. Dodd agreed to give this talk with me today, and so we begin. Now this is a streamed session, so some questions are going to be coming online to us. We try to probably answer some of them, but I think the best way is to keep the questions until the very end, and then we'll try to kind of answer the ones here, which is through the microphone, and also the ones we kind of get on our tablet here. So my disclosures include honoraria from some companies, nothing to do with this talk today, and some recommended medications that I will give are not FDA approved, but they're based on evidence. So toxins in general are small molecules that could be peptides, proteins, elemental, and they could cause damage to body tissue by interacting with macromolecules. These could be enzymes, could be cellular receptors, could be structural proteins and so forth, and they lead to damage. Now the mechanism of some of these may be diverse, so from different aspects or may not even be clear, and we'll try to address the ones we know the best we can. So to diagnose these, of course first of all we have to make sure we exclude the more common etiologies that could cause these presentations, either neuropathy or myopathy, but we always have to have a high degree of suspicion for toxic etiology because it may be easily missed. So things to think about are medical issues that the patient could either be from a toxin, so may tell you or give you an idea about that, or actually could cause a previously non-toxic drug, for example, to now become toxic. So medications are important to remember that other than, because now we kind of go through the electronic medical record and kind of look at that. Patients may get medication from another provider or could be over the counter or could be a supplemental that could cause toxicity. We have to ask them about it. Important to know about their environmental exposure, for example, well water. Need to know their occupation. Some toxins could be actually coming from their work. And also their hobbies for the same reason. You know, they do gardening, maybe they're doing welding. They could, where they traveled could give you some hint, especially if it's an acute onset disorder, and that could give you some hints. And also whether they're using drugs or any other habits they have. And finally, diet, particularly, you know, as we'll discuss later, for some heavy metal exposure that is important to know about their diet for the diagnosis and also for the evaluation that we're doing. So this was basically the introduction, so I kind of put it all together and then I'm going to go into the toxic neuropathies. And after that, Dr. Dodd is going to go over the toxic myopathies. So the neuropathies, depending on the population and also the age group, you know, around two to three, some numbers go up to 5% of the neuropathies could be toxic. And I'm going to point out to our typical presentation, and that is when it basically is a length dependent, axonal, sensory more than motor polyneuropathy, usually painful, paresthesia and so forth. And maybe this is a weakness or just purely sensory. That's a typical presentation I'm going to point to from now on, but, you know, any other presentation could be possible depending on the type of toxin. Some could be predominantly motor. Some could be demyelinating. Some could look like a sensory ganglionopathy, even get the cranial nerves. And I'll try to point to those as we go through them. And also have to remember that, you know, the risk of something becoming toxic, especially medication someone has been on for a long time, A, could actually be stable for many years, but that becomes toxic because of another agent or something changes in the patient. For example, liver dysfunction, kidney dysfunction, or there's just aging, weight loss. So things that could kind of make something have a higher chance of causing toxicity should be also thought of here. So in terms of the diagnostic presentation, most of these, the typical form would have sensory amplitude loss on your conduction studies, more than motor. Again, motor may be spared. And if it's a small fiber neuropathy, which some are, as you know, could be completely normal routine study. EMG could show neurogenic changes in the distal muscle. And now this is a typical, but again, for the other types, they could look exactly like, let's say, demyelinating neuropathy, ganglionopathy, and I'll point to those. Nerve biopsy is not usually done because we have a toxin most of the time and we can stop it or other ways to see if that is correct. We will do a workup. But if done, most of these, a typical form would have loss of both the myelinated and the non-myelinated fibers. And most of these actually improve with stopping the drug. Now they, because of the degree of nerve damage may be too much, it may not completely recover, but they should stop progressing or get better. You have to remember that some of these medications may actually have a coasting effect. So basically, once you stop the medication, the biological effect continue, even may start after you stop the drug or continue on for a couple of months. You have to think about that always. Or some may trigger an immune response that takes life of its own, kind of treat it as an immune-induced kind of neuropathy. So there is a lot to cover, and hopefully you'll be awake towards the end. I'm going to go through some medications and of course leave some of them out. Dr. Amato's book, which most of it is kind of based on, neuromuscular book, has a nice chapter that kind of covers more than what I'm mentioning today. And there are also nice reviews to look at. So I'm going to talk a little bit about alcohol and some other medications. And I'll put the neurochemotherapy agents a little bit separate, so I'm going to talk about some of those. And finally, a few heavy metals that are important to think about. And the industrial toxins are a lot. I'm not going to go through them, but I'm going to list them so you can look at them. And they, again, mostly cause a typical neuropathy, but they could have caused other issues, systemic issues. And so I'll leave those for later review by you. So starting with alcohol, so as you see, the possibility of having an alcohol neuropathy in someone who is a chronic alcoholic is very wide. Many factors are important, in particular, how much they're drinking. There are different numbers out there. But basically, it's a cumulative dose over time. So approximately, you can say 100 mL of alcohol per day for three years on average. However you want to calculate that, let's say around three liters of beer, maybe, or 300 mL of hard spirits. There are other numbers out there. But basically, over time, this accumulative dose, some feel that wine, for example, because of impurity in it, or maybe lead could have a higher chance of toxicity. And the neuropathy is usually typical, of course, unless there's a binge and it could cause other stuff too. But you know, someone who's chronically drinking alcohol is a typical neuropathy, maybe a bit of slowing of conduction, but not to a demyelinating range. And same, the extra-diagnostic, EDX from now on, and biopsy are typical. And the reason is not clear. Definitely, alcohol has a toxic effect directly or by creating some free radicals. But there also could be a nutritional component to it, and they could actually be combined. So it's always important to make sure that there is no nutritional deficiency that needs to be addressed as you're treating this. The treatment, of course, is to stop drinking or reduce the amount, which is easier said than done. Most chronic alcoholics cannot do this. What I sometimes negotiate with them is, you know, why don't you try reducing or stopping for a few months, of course, under supervision, and see if you get better. And then they can decide. At least they know what's going on, and they can decide if they want to continue, reduce it. So sometimes they do actually do that and see the results and decide. And again, always want to make sure given the necessary vitamins that they need. So the medications I'm going to start with, first of all, is Dapsone. So this is used for leprosy treatment, which is shorter, but also could be used for dermatitis herpetiformis, so more of a chronic use. And this is one of those that causes a primarily motor neuropathy. So it could happen as early as a few days to chronically years, again, depending on the amount. So there could be a wrist drop, could be a finger drop, for example, like a radial neuropathy you would see. It could be in the feet, foot drop. Sensory symptoms could be there, but they're not very common. And the EDX will show motor more than sensory involvement, and the mechanism is not clear. The thambutol is important for treatment of tuberculosis, and it could cause mostly a typical neuropathy, sometimes could be more of a diffuse sensory neuropathy. Also important, it could cause optic neuropathy, and that is why these patients get screening, make sure that is not affecting their eyes. And in terms of the EDX, it is mainly axonal sensory, as I said, typical, but sometimes more, maybe a bit long-length dependent in some cases, and the mechanism is not clear. So eizonizide, another important drug for tuberculosis, could cause a typical neuropathy. One of its most common side effects, usually with longer-term use. And now, if people are older, malnourished, which actually may be someone with tuberculosis fitting this profile, or those who are slow acetylators may actually have more propensity for the toxic effects. But could also cause more systemic CNS issues, seizure, encephalopathy, and so forth, that should be thought of. The EDX and BiFC are typical, and it is thought that it could cause a functional B6 deficiency, and hence the effects. So we usually put people on paradoxine high-dose, 100 mg per day, when they're on eizonizide. Now, it is important to remember, as I'll discuss later, that once you stop the medication, you have to also stop the B6, and we'll point out to why later. So fluoroquinolones, I mean, they actually were reported to cause, again, a typical neuropathy pretty quickly, maybe within a week or longer-term use. Though later studies have shown this is relatively a rare occurrence. It's not common, but again, important to think about. These are important drugs, used a lot. So if you see someone on these higher-dose, think about them as a potential cause. So mesonidazole and metronidazole related, the first one, radiosensitizer for cancer radiation therapy, and the second one, a very important antibiotic, and they could also cause neuropathy within a few weeks, again, depending on the dose. The EDX and Biopsy are typical, and there is some suggestions of accumulation of neurofilaments on electromicroscopy of the nerve, and the mechanism is not clear. There are some suggestions that it could, you know, directly cause toxicity, it could affect, you know, thiamin, it could also get the CNS, metronidazole especially, causing some white matter changes and some CNS effects, but I don't think the mechanism is definitively accepted yet. So nitrofurantoin, also very important antibiotic, this one for urinary tract infection, could actually cause minor neuropathy, but sometimes in high doses reported to cause an acute rapidly progressive sensory motor neuropathy, even causing quadriparesis in some reports, risk is higher in the elderly and those with renal dysfunction. Now usually, except for the rapidly progressive form, is typical EDX and Biopsy, and again, the mechanism, as you see in a lot of these, is not clear. Linizolid and Tedizolid are very important antibiotics for resistant ground positive organisms, many of them, so very important antibiotics, also felt to cause a typical neuropathy within a few months of their use, also could cause optic neuropathy, so to think about it and screen for it, EDX and Biopsy are typical, and it's felt to be that they're from mitochondrial dysfunction by impairing protein synthesis. Nucleoside analogs, especially the, you know, the, so AZT, as Dr. Daugherty's going to discuss, is more of a, causes more muscle disease, the later ones cause more neuropathy, it is pretty typically painful sensory, predominantly neuropathy, and actually could be the dose limiting factor for these. Now the problem, EDX and Biopsy are typical, and it is due to inhibition of mitochondrial DNA polymerase, hence the effect on nerve, now the problem is an HIV patient could also cause neuropathy from the HIV, sometimes it's hard to decide what is causing what, and one way is to stop the medication, reduce it or change it, and see if they get better was probably toxic effects, or if not, it is the HIV, and so that should be on your differential. Some argue for a lot of these toxic neuropathies, including here that Acetyl-L-Carnitine may be protective, I don't think there is, as far as I know, there is any controlled trials or some open-label studies that have shown some benefit, but that could be tried in some of these patients, so it's off-label use. So Podophilin is another medication that is used for infection, it's topical, Condylomera Acuminata, it's absorbed through the skin, so at high doses it could also cause a typical polyneuropathy, sometimes with autonomic features. It could also, at higher doses, cause more broad effects, it could cause psychosis and altered mental status, so CNS effect, it could cause GI paresis, urinary retention, pancytopenia, liver and kidney, so it could be widespread systemic dysfunction if absorbed, and EDX and Neurobiopsy are typical for the neuropathy purpose. Soramin, used for African sleep sickness, also could cause a neuropathy, seems to be in two different forms, if it's a low dose chronic, it causes a typical neuropathy, but if it's a higher dose, it could cause a subacute demyelinating polyreticuloneuropathy, so basically like GBS or CIDP, and EDX, of course, for the typical, would be the typical form, sensory more than motor, but then you could see actually acquired demyelination for the second form with this medication. Now, biopsy again could be the typical form, as I mentioned, or it could show demyelination, remyelination, infiltration of inflammatory cells, as you see in CIDP, could even be elevated protein in the CSF, and, you know, so the first form, the mechanism is not clear, but the second one is felt to be an immune-triggering and immune response, and you could consider treating it if it don't get better by stopping the medication, by IVIG, plasma exchange, and however you would treat inflammatory or immune-mediated neuropathy. So moving on to the anti-inflammatory agents, so the anti-TNF-alpha antibodies, I mean the whole spectrum of them, could potentially cause a neuropathy. Now, it's a rare condition, so it's not clearly linked as an etiology, but there is association, you know, so important to remember, and they actually cause more of a demyelinating neuropathy, and both in the peripheral nervous system, so like GBS, multifocal motor neuropathy, also could cause CNS demyelination, so mimicking MS, transverse myelitis, optic neuritis, and there is a suggestion again, you know, you have to be careful, think about it, if someone has this, but there's a suggestion that if someone has had these happen, a demyelinating phenomenon before, maybe it's best to avoid these medications, or at least monitor them very, very closely. So in these, we'll mimic CIDP by elevated CSF protein, and EMG will show an acquired demyelinating neuropathy picture. As I said, there's triggering an immune response, and treatment is, you of course stop the medication, and you need to consider giving some immunomodulatory therapy. Leflunomide, we use for treatment of rheumatoid arthritis, would cause a typical neuropathy within a few weeks to months, again, depending on patient characteristics and the dose, typical by C and EDX. And it's felt to be due to inhibition of the pyrimidine synthesis and causing nerve toxicity from that. Chloroquine and hydroxychloroquine cause neuromyopathy, and Dr. Dodd is going to talk more about that later on, but they could also only cause a neuropathy. Someone who's on these, especially with chronic use, and EDX will, of course, show typical neuropathy, but also could show muscle membrane irritability from the myopathy effect. On nerve biopsy, you could see these curvilinear bodies and laminated osmeophilic inclusions in the Schwann cells. And this is because of their structure, that they're amphiphilic, and once they're digested by the lysosome, they're hard to take, get rid of, so they accumulate in vacuoles and cause damage. Again, there are others, again, Dr. Dodd is going to talk about, but colchicine is also another medication that causes neuromyopathy and also amiodarone. So the latter also causes other problems you have to think about, tremor ataxia, thyroid dysfunction, hepatitis, could cause some eye problems, pulmonary fibrosis. So it's a great drug, but also has all the side effects that you should monitor for. So a few other medications worth mentioning, so pyridoxine, as I mentioned to you. So what happens, someone may be on isoniazide and they stop it, but they don't stop the B6, and the continued use of this over time would cause a toxicity, or someone could be using it over the counter for whatever reason. And this actually causes a sensory ganglionopathy, so a non-length-dependent sensory neuropathy or a ganglionopathy, as I said, at high doses. So these patients have a prominent sensory ataxia, they could have a non-length-dependent sensory involvement, even their face, their hands, maybe before their feet. Motor is usually normal, they may have some issues with fine motor coordination because of the sensory input, but they should not be weak. And their EDX also shows the non-length-dependent loss of sensory responses, relatively preserved motor, and exact mechanism is not known. So isoforam or Antibuse is used for alcoholism and to help treat it, and that could also cause a neuropathy typical, but could also cause CNS issues, for example, extrapyramidal involvement and EDX and biopsy are typical, could show some accumulation of neurofilaments in the axon on electromicroscopy. And the reason is felt to be because of its metabolite, which is carbon disulfide, is one of the industrial toxins I'll have on my list at the end, and that could cause issues with DNA-RNA function and damage. Lithium, important for bipolar disease, also causes a typical neuropathy with chronic use, in addition to the other things it could do, could cause thyroid problems, tremor, dysarthria, confusion and so forth. And for the neuropathy part, it's again typical biopsy and a few diagnostic, and again, like many of the mechanism is not clear. And probably not used as much, but also a very important traditional anti-seizure medication, also could cause a typical neuropathy at high doses or with chronic use, again, typical EDX and biopsy, not known in terms of the mechanism. Nitrous oxide is important, could either be anesthetic agent or could be recreational inhalation abused, and it actually causes a myeloneuropathy, so it looks just like B12 deficiency, and you will have a sensory ataxia, you could get, you know, some demyelinating features on your EMG in addition to sensory and motor loss. And so, in terms of imaging, could even see some changes in the dorsal column, T2-ARP intensities as part of the involvement of that pathway. And it's felt to be due to a functional B12 deficiency, the way it works, even cause megaloblastic anemia, and B12 itself may be normal, so probably not a good idea to focus on that, but the other down kind of path metabolized homocycline and methammonic acid that require B12 for processing will be elevated, so that's why it's a functional effect and treatment is to stop it and consider giving them high-dose B12 for its treatment. So going to go on about a few slides about chemotherapy agents, so cisplatin is, predominantly causes a sensory ganglionopathy, as I have discussed before, even could cause lormite sign in the neck, and rarely weakness. Now it has a coasting effect, so it could start again after discontinuation or continue despite stopping the drug, and this EDX would be a non-linked dependent sensory loss, so again a ganglionopathy picture, and felt to be due to cross-linking of DNA in the dorsal root ganglion, hence its toxic effects. Oxaliplatin is within the same group of platins, but it seems to have another kind of effect in the acute stage, it could actually cause within a few hours or a day or two a cold-induced paresthesia and some weakness and stiffness in the muscles, and it goes away, it happens again with every infusion, but also could cause the same kind of ganglionopathy picture as cisplatin with chronic use. The EDX of the acute form could actually show repetitive after discharges when you're studying their motor responses, even normitonia, normitonic discharges on your EMG, and the chronic, as I said, has the same EDX pattern as cisplatin. The first form, the acute form, is felt to be functional channelopathy, and the chronic of course has the same effect as cisplatin. Some people argue that if you see the acute symptoms, there's a higher chance of chronicity and causing neuropathy, and treatment of course is to keep them warm for their first form and of course, you know, stop the medication if they had developed a neuropathy. Increasing and irrelevant also could cause a typical neuropathy with sometimes autonomic features, rarely even cause cranial neuropathies, optic, you know, ophthalmoparesis, hearing issues, and EDX and biopsy are usually typical, unless you get the cranial nerves and so forth, and they actually inhibit axoplasmic transport in the nerve by binding to tubulin, preventing from creating microtubules, and causing toxicity. Etoposide also could cause a sensory ganglionopathy, like I mentioned for cisplatin, with sometimes autonomic features. EDX again is similar to cisplatin, and this actually also could cause microtubule dysfunction, hence its effect. Paclitaxel and docetaxel could also cause either a typical neuropathy, but could also cause a sensory ganglionopathy picture, so I see all these have the similar theme. EDX again depends on if it's a typical form or the ganglionopathy form, and they actually prevent dissolution of the microtubules, so the microtubules accumulate in the cell and cause damage, again, due to microtubular dysfunction, of course. Cytosine arabinozide also could cause a typical neuropathy in some form, but could also cause a severe demyelinating neuropathy, like GBS, in higher doses. EDX depends on whether it's typical or demyelinating, and CSF protein could go up in the latter. So the first form mechanism is not clear, but the second is felt to be due to triggering an immune response. So thalidomide is actually another important agent for multiple myeloma, GVHD, and it could actually cause a typical neuropathy, which has been a dose-limiting factor. Also could have a coasting effect, so as I mentioned, if you stop it, it could continue. This is an addition, of course, there's historical teratogenic effects. EDX and biopsy are typical. Lenalidomide is actually a second-generation thalidomide and has the same effects, but not as severe, so not as high of a risk. But if someone has been on thalidomide before they switched or is on bortezomib for treatment of multiple myeloma, it increased the risk of toxicity. So bortezomib, again, another agent for multiple myeloma, could also cause a dose-dependent neuropathy. Again, higher if it's used with the other agents I just mentioned. EDX is typical and it is felt to be due to blocking the proteasome pathway and causing the toxic effects. Tacrolimus, another important agent for transplant, could also cause a neuropathy, again, within days to weeks, depending on the dose. Now, it could be typical, but there are reports that could actually be a purity motor, could also cause a demyelinating picture by report, and EDX depends, of course, on the type. And in terms of the pathogenesis, it's unclear, again, except for the demyelinating form that is felt to be triggering immune response. And for the latter, you want to consider IVIG and plasma exchange also. Immune checkpoint inhibitors, very important class of drugs now that are used for cancer. As you know, they disinhibit the immune system and could be any of them as listed here. And they actually cause systemic immune attack against different parts of the body. The neurologic effects are not very high, but it's very important, and the neuropathy is kind of less than, you know, it's kind of rare, relatively speaking, less than 1%. So it could take any form, could be cranial neuropathy, could be polyradical neuropathy like CIDP, could be a typical neuropathy, small fiber and so forth. It is suggested that if it doesn't happen within the first five doses, it's probably not going to happen later. And so that's at least maybe helpful to the patients, also for differential, if they have a later onset involvement. Treatment could be stopping the drug or putting them on prednisone or even having to give them IBIGN-PLEX or even other immunomodulatory agents, depending on the severity. There are nice tables you can look at on the side. And most of them improve with these measures. So a few words on heavy metals, we're slowly getting towards the end. So arsenic has different forms, could be organic and inorganic. The inorganic forms are non-toxic, that's called fish arsenic, but important to think about when we're doing the workup for them. It usually causes an immediate GI issue, nausea, vomiting, abdominal pain, diarrhea, and so forth. And in time, so within a week or two, it could cause actually a typical neuropathy with lower chronic toxicity. But actually at high doses, so again, this is a poison that someone has given that could actually mimic GBS in any aspect, in terms of its presentation, in terms of its EDX, and so forth, and could also cause encephalopathy at high doses. So you could also see other, this is all for chronic exposure, you see this patchy pigmentation in the skin, palm of the hands, these lines that develop, show you when the toxicity happened as the nail grows out, you see these white lines. It could also cause anemia with RBC stippling, again, suggestions that this is what's going on. EDX, again, depends on the type, could be typical, or it could show demyelination as the biopsy. And now in terms of the diagnosis, it's a little bit tricky. So in 24 hours, urine is really helpful for the acute kind of exposure or chronic exposure, but you have to make sure that they haven't taken any seafood for at least 48 to 72 hours. If they have, you have to request that they fractionate the arsenic to tell you what forms they are, to make sure it's not the organic form, non-toxic form that is in the body. In the chronic exposure kind of form, you can actually look for it in the hair and the nails, and as I said, a CSF may show a typical GBS picture in the high dose exposure. Treatment is unclear. In the acute stage, you can use British anti-leucide, but for the chronic form, it doesn't work that well. Lead is a very important, and thankfully, it's less now because all the measures are in place, and children especially ingested it and caused problems. Now it's mostly industrial workers that you should worry about. And it actually causes a predominantly motor neuropathy, so again, wrist drop, finger drop, foot drop, not so much sensory, and could cause some autonomic GI issues, but again, mainly a motor neuropathy. And you can see other things. You can see encephalopathy, again, mostly in children, and also unfortunately, more chronic effects on their cognition and memory. They can see bands on the, metaphyseal bands on x-ray. You can see some discoloration in the gum line, blue discoloration. And again, you see the basophilic stippling I mentioned for arsenic here too. Again, these are telltale signs that this lead poisoning. For EDX, the C-maps are the main ones involved, as I said, and you can check for it in a 24-hour urine to look for elevated level of lead. It's felt to be due to abnormalities in the porphyrin metabolism and causing its motor effects. And chelation therapy, again, depending on how much and when could be variably effective for this toxin. Mercury is, again, another interesting kind of toxin here. So it has many different forms. It has organic forms. It has inorganic forms, right? And actually, the organic form is the toxic form that we are worried about, and that is the one, the methyl mercury form that is in predatory fish. And it could actually cause a ganglionopathy picture, so numbness and tingling, paresthesia in the hands and the face, so not so much motor, but could also cause other CNS effects, as you can see, visual, hearing, could cause ataxia, dysarthria. But since the peripheral nervous system is more of a ganglionopathy picture, the ethyl form is not toxic, clears out quickly. That's what you get in vaccines as preservative. And the inorganic form, either as salts, inorganic salts or the elemental form, mainly as a GI or nephrotic syndrome picture, so kidney and GI, could also cause peripheral neuropathy, but the other two are very prominent in this presentation. So ADX, again, you lose the sensory responses in a non-linked dependent pattern, mostly. And treatment is difficult. For the organic form that I mentioned, there's no good test. It goes into the fat, lipid soluble, doesn't get out that easily, so it's really based on history. You can ask the patient what their diet is or what they're exposed to. Sometimes in the acute stage, you can look at the whole blood mercury, but that clears out quickly. For the inorganic and the elemental forms, you can, of course, check 24-hour urine or in the acute form in the blood. So when you do these tests, the urine blood is really not for the organic form that we are thinking about, so you have to be mindful. The pathogenesis is because of binding to the sulfhydryl groups of enzymes and proteins and causing dysfunction, and no clear chelation for the organic form, but we can use it for the salts. So thallium is a rodenticide, and it could also cause a small fiber neuropathy. At lower dose, at higher, it could actually cause proximal weakness. Respiratory muscle could get the cranial nerves, and other features that it has that would be suggestive, alopecia, abdominal pain, increased thirst, psychosis, and so forth. And the diagnosis is, again, 24-hour urine, and if it is recently ingested, you can see radiopaque material on abdominal X-ray. And treatment, again, could be Prussian blue, depending on the level and the chronicity, and you could also consider diuresis and dialysis for the acute exposure. So yeah, I think I'm kind of done with the main ones. I'm just going to actually list. These are the industrial toxins I mentioned to you. As you see, there is carbon disulfide there that I mentioned is toxic. And the others, acrylamide, alpha-nanoxide, hexacarbons, organophosphates, which are mainly could cause muscarinic and nicotinic effects acutely, and then in time, a chronic neuropathy. And other ones here are listed here, so I'll leave them for you to read. These are nicely written in the chapter by Dr. Amato in more detail, of course, other reviews too, so I will. So please remember to share your feedback. It will help us improve our presentations, and make sure you claim your credits for this session. So I think I have time for maybe one or two questions now, but we'll leave it for the end. Any questions in the audience? Good question. I mean, it could, yeah, it could be. I mean, so most of these have a component of the axonal as well as a demyelinating picture with them. But I think, and remember, these are actually not clearly accepted as causing a problem because they're so heterogeneous, actually, and they have underlying problems themselves. I think it's still not definitive that they cause this. But if you do see more of a demyelinating picture, either peripheral or central, you want to think about these, maybe consider stopping and treating them. But yeah, but that's, but again, it's a very loose, rare association on this. Anything else, Chris? Yeah. Yeah. For elevated B6 levels, how seriously would you take an elevated level in a fasting sample in a patient that is not on supplements, or at least not aware that they're taking supplements? That's a great question. I mean, I always struggle with it myself, whether there is a level or not. And the other thing is what you want to do with it. There's no treatment, right? So if you are sure there's no, you always want to make sure you ask that patient whether they're taking anything that you can eliminate. And it could be a supplement that they're not telling you, an herbal thing they're taking, or some vitamins in a special form that they're taking. But I do see people with the high levels. I have them, as you said, fast. And if it's mildly elevated, I don't do anything about it. I think the important point is that taking it at a high dose is a thing you want to stop and reverse. But if it's elevated a little bit, the question is what is the normal value in different people? I definitely want to do it fasting, because cereals could elevate it in the blood. But that's a great question. I have people with it, and I don't know what to do for them, really. There's no chelation you can do for it. I just make sure I don't miss anything in their diet. One patient did their research and found out that their excessive B6 was from Smoothie King, basically. They added B6 as a power supplement. Yeah. I'm just going to add a quick couple of cases that I've seen recently. People that came in with unexplained high B6, and they ended up having hypophosphatasia, which is a genetic condition affecting alkaline phosphatase and B6 metabolism. There is actually now a treatment for that condition. So if you have a patient that has a high B6, you want to at least make sure they've had an LFT panel in your system, look at that alkphos if it's abnormal. That would prompt screening for that condition, because there is an actionable treatment for those patients. Thank you. My name is Marian de Visser from Amsterdam, the Netherlands. Thank you for a great talk. I have seen a couple of patients, two or three, who were suffering from Charcot-Marie-Tooth disease and developed a very severe tetrapyrosis, polypyrosis, under treatment with vincristine. I don't know whether you have experience with that as well. I'm sorry, with what? Vincristine. Vincristine. Yeah. So as I said in the beginning, if you have an underlying neuropathy, either acquired or hereditary, you actually are a higher chance of causing and getting toxicity. Or if you combine medication that could do this, and there's a higher chance that could do it. But yeah, I mean, that is possible. Yeah. The problem with Charcot-Marie-Tooth disease is that in mild forms, it's often not recognized. That is true, right? And sometimes you just find them on the EMG lab as a first time, yeah. So OK. So I think I'm going to move on and give this stage to Dr. Dottie. So Dr. Dottie is a neuromuscular neurologist at the Brigham and Women's Hospital. And he serves as a clinical director of the neuromuscular division there. And also, he is a dedicated teacher at the Brigham and Women's and has two hats in that role. One is he's a co-director of the Mass General Brigham Neuromuscular Fellowship Program. And also, he is the associate director of the Neurology Residency Program at Mass General and Brigham. And on top of that, with all that work, he still has a very active practice on different neuromuscular conditions. And he actually has a very nice review, two nice reviews, one of them in continuum, that would complement his talk on toxic myopathy. So if you have time, look at that also. So with that, yeah. All right. Well, good afternoon, everyone. Thanks for joining. Thanks for your attention. As mentioned, we're going to spend the next 40 minutes or so talking about toxic myopathies. Here's a brief statement of my disclosures that are relevant to this talk. Over the course of the next few minutes together, we're going to try to hit a few key points in the realm of toxic myopathy. I think this can be a really overwhelming topic, just long lists of medications to memorize. I think it's really helpful to see concrete case examples that show you in real practice how you might recognize a case of one of these. So we're going to go through an approach to a patient that's on a statin and having muscle symptoms. We're going to discuss how to manage and recognize neuromuscular immune-related adverse effects after a checkpoint inhibitor. We'll talk about some of the drugs that are associated with neuromyopathy, and then some of the medications that are associated with mitochondrial myopathy. And then finally, we'll kind of put it all together by giving you some key take-home points for how to actually recognize a toxic cause of myopathy in somebody coming in fresh to your clinic. So we're going to go through four cases that you might see in your own clinic to help you improve your recognition of these disorders. We're going to start with an 83-year-old. She has a history of rheumatoid arthritis, and she's coming in with progressive weakness. So this started about four weeks ago when she woke up and all of a sudden found that it was hard for her to lift her legs to get out of bed. And this has progressed since pretty steadily, to the point where now she is really no longer able to go upstairs independently. She tells you that over the last year she has unintentionally lost about 70 pounds. Before all this, though, she was completely independent in her ADLs. She's known about this rheumatoid arthritis diagnosis for decades, and she's been quite stable on leflunomide treatment for that for the last five years. In terms of her other past medical history, she has a known history of MGUS, hyperlipidemia, hypertension, and hypothyroidism. She's on a daily dose of amlodipine, leflunomide, as mentioned, levothyroxine, and rosuvastatin. In terms of the rosuvastatin, she's been on this same stable dose now for about four years. When you examine her, you find that she has a pattern of moderate weakness, symmetrically affecting proximal muscles in the arms and the legs, normal sensation, normal reflexes, really just this weakness to go off of. Before she comes in to see you, she has seen her primary, who already obtained an EMG elsewhere. This was evident of a generalized irritable myopathy, and you note that there was quite a few fibrillation potentials and positive sharp waves noted in multiple of the muscles in the arms and the legs. CK was also checked by the primary and was elevated at 992. So this is a talk about toxic myopathy, but in reality, if you were seeing this patient in clinic, we would have to entertain a pretty broad differential for this new presentation of a likely myopathy. You know, this patient has a history of autoimmune disease, so really we should be considering an inflammatory condition as a potential cause. With this unexplained weight loss, it would be reasonable to think about even a perineoplastic cause of myositis. Of course, we know she has this history of hypothyroidism. If that has been undertreated, that could potentially impact the muscles. And we know she's on a statin. So of course, it's reasonable to think about whether or not that might be causing a toxic myopathy in this case. So our task is, out of this list, what are the features we could look for that would help us pinpoint a toxic cause as opposed to one of these other alternatives? So when we think about statins, which would be kind of most relevant to this case based on what she's on, we know that statins can rarely cause a necrotizing myopathy. In terms of why that might happen, it's a little bit unclear, but some hypotheses would include that statins deplete the amount of cholesterol in the muscle membrane, which leaves them a little bit more unstable, more prone to breaking open and lysing. This is the case, of course, because statins work by inhibiting HMG-CoA reductase, which is the rate-limiting step of cholesterol synthesis. This pathway is also important for the production of coenzyme Q10 and various glycoproteins on muscle membranes. So there's also some thought that perhaps this impacts energy production in muscle cells, and that's why this toxicity can result. For as much as we talk about statins, though, this is really overall a pretty low-risk scenario. Symptomatic myopathy occurs only about 1 to 2 cases out of 10,000 patient years of treatment with a statin, and full-on rhabdomyolysis occurs only in 2 or 3 out of 100,000 patient years of treatment, so very, very low incidence rates here. What's much more common, and probably something you've seen plenty of, is that patients that are on statins may notice more mild symptoms. So up to 5% of patients will have an elevated CK, but that's just asymptomatic, and up to 20% of patients will have mild myalgias or cramps. What's really important to realize, though, is that any of the placebo-controlled trials that have been done for statins, the rates of myalgia or cramps have consistently been similar between the placebo and statin arms of all of these various trials over the years. And so just because a patient is complaining of muscle pain or cramping and they're on a statin, of course, that alone doesn't mean that the statin is to blame. Recognizing this, the American College of Cardiology actually has a very helpful resource on their website that is essentially a risk calculator for patients that are complaining of muscle-related symptoms on a statin. You put in a few features about the patient and their history, and it helps you judge how likely it is that those symptoms are related or not. The goal, of course, is that we don't want to take patients off of a statin that might benefit from a stroke reduction standpoint or an MI reduction standpoint if it's actually not the cause of these muscle symptoms in a given patient. What's even more complicated about statins, though, is that in addition to this rare incidence of toxic necrotizing myopathy, there's another mechanism that we have to consider. Rarely, patients that have been on statins can instead develop an immune-mediated necrotizing myopathy associated with anti-HMGCR antibodies that we can detect in the serum. This, again, is the same enzyme that statins inhibit as their mechanism of reducing cholesterol. The key difference, of course, with this second mechanism is that unlike all the other toxic forms that we've talked about in the neuropathy talk and the toxic form of statin myopathy, the difference here is that just stopping the drug alone is not enough. These patients require immunomodulatory therapy to get better. Being able to distinguish between these two possibilities is obviously really critical. What's the difference between them? If you think about a toxic cause, usually these patients are going to have the onset of their symptoms about one to six months after they've started the statin or after the dose has changed. The typical presentation is going to be subacute, proximal muscle weakness, occasionally with myalgia, but not always, and typically the CK is elevated. In the immune-mediated forms, the challenge is the pattern of weakness is really very similar. It can also look symmetric, proximal, can sometimes be quite severe, but the pattern is similar. Unlike other types of myositis, it's very unusual to have systemic involvement here. Really, this is a skeletal muscle disorder. I think a key feature to remember, though, that might help you distinguish is that the immune-mediated form can have an idiosyncratic onset, so basically any point in a person's course of treatment with a statin, this can come on, even years later. The CK in these cases is often elevated as well, typically quite high, around 10,000. On the surface here, with what I've just told you, this case, we might actually wonder more about the immune-mediated form. This patient's been on a statin, a stable dose, for about four years, but there's one caveat to remember before we kind of conclude that that's our most likely possibility here, and that's the fact that there are other things that can influence the risk of having muscle-related toxicity from a statin. So first, if we think just about demographics, a little bit of a higher rate among both males and those that are above the age of 65. The risk is also dose-dependent, so people that are on a high-intensity statin will have a higher incidence of muscle-related symptoms, but I think for our purposes, you know, the key is over here, in the right column. These are things that can happen later to a patient that might actually influence their risk of getting a statin toxicity. So development of renal or hepatic failure, new, undertreated hypothyroidism, or the initiation of another medication that can be toxic to muscle as well, any of these things can influence our risk. One really important thing that we noticed in this patient was that over the course of the last year, her creatinine had crept upward. Used to be normal. It is now at a new baseline of 1.4, which is abnormal for her. So we were sort of speculating whether maybe that was the trigger for a toxic process, even though she's been on this for quite a while. In terms of the medications to keep in mind that might influence this risk, decently long list, but just to run through, amiodarone, some antifungals, calcium channel blockers, colchicine, cyclosporine, rapamycin, and sirolimus are all some immunosuppressants. Basically any of the other cholesterol-lowering medicines except the new class, the PSK9 inhibitors. And finally, even drinking too much grapefruit juice. This is a CYP inhibitor that influences the metabolism of statin medications across the board. So here I think there's a decent case to be made for a toxic myopathy related to the statin, but it's far from certain. We haven't proven this. There's many other potential hypotheses here in this patient that we have to consider. So this is a very common situation that I think we're sometimes faced with, especially on the inpatient side of things. And so the question is, what's the correct move in a case like this? What do we do? The simplest thing would be just to test your hypothesis. Stop the statin, wait it out, see what happens. But this patient is fairly disabled by her symptoms. She's having a hard time walking. I would be a little bit hesitant to just sort of let this go on for months and months if we're missing a treatable cause that would get her better faster. But I think it turns out that thankfully, in these cases, we can get feedback relatively quickly. So in these toxic causes, oftentimes the CK can normalize quite fast, within a week. It's very unusual for it to take longer than two months for the CK to normalize after a toxic statin myopathy has set in, and you've stopped the drug. Even the pain and the weakness, on average, improves after about two months. So not too, too long. I think, though, there's really no downside to trying to get a little bit more information builds your confidence here, right? And I don't think there's much of a downside to sending serologic testing in a situation like this. As mentioned, these HMGCR antibodies that we can send are very specific for the immune-mediated form. We really do not see them with a toxic statin-related myopathy. So obviously very helpful if you're trying to decide between these two options. It can take a week or two for these to come back. And the other thing to sort of note as you're thinking about sending these is that most of the commercial myositis antibody panels out there don't actually include this one. You have to send it separately. So that's just sort of a nice reminder. So other questions. Would we do a muscle biopsy in a case like this? We'll sort of come back to that point in a second. And then finally, in a patient that's really severely affected, is there ever a circumstance where maybe we would just empirically treat someone out of concern for the immune-mediated form? These are really more judgment calls based on the patient in front of you. I'll kind of come back to this one as well. But I think when we're thinking about the biopsy question, it's really helpful to remember what it is that we actually might see on a biopsy that could help us distinguish between these two possibilities. When it comes to trying to diagnose this immune-mediated form, immune-mediated necrotizing myositis, I think it's really helpful to kind of dig into the details here. So with this condition, as the name implies, the hallmark really is necrosis of muscle fibers. So in an H&E, you can see these pale muscle fibers, and they've been invaded by macrophages that are basically there to clean up the debris. These cells are dead. The normal response of the body is to bring in macrophages to clean up the tissue. That alone doesn't get you to an immune-mediated process, right? Anything that's causing muscle fibers to necrose and die off, it is normal for immune cells to come in and clean up the debris. We need something more. And so the couple of stains that we might rely on in this circumstance would be MHC-1 or MAC, the membrane attack complex, the terminal part of the complement cascade. And key features that we look for in immune-mediated necrotizing myositis would be, one, upregulation of MHC-1 on the membrane of muscle fibers, and then, two, deposition of the membrane attack complex on muscle fibers and small capillaries within the muscle. There's caveats here, though, as well that are really important. So MHC-1 is expressed on regenerating muscle fibers, and MAC can deposit on necrotic cells of any cause, right? And so I think the pitfall here is that if you have somebody that has had a really severe toxic process happen to their muscle, so somebody that's come in with rhabdomyolysis from a statin, and a very high percentage of the muscle fibers are necrotic, your ability to actually look for these specific features in normal muscle cells that aren't already either dead or regenerating is going to be quite challenging, right? And so to be able to pick out these specifics sometimes can be hard in these really acute severe cases. And so over time, for that reason, I've kind of preferred just to rely on the antibody, because it is pretty reliable, and there are these pitfalls with the biopsy. Now in a case like this where, really plausibly, we could consider non-statin-related etiologies, I think the situation is different. And so for this patient, we did a lot of things. We stopped the statin, we sent the antibody, and we did, in fact, get a muscle biopsy. But we were thinking a little bit more about, you know, could they just have something completely unrelated, like a new myositis, separate from the ones we've discussed. Thankfully though, this is not how this went. She did really well. So just three days after stopping the statin, her CK was already down to 369. Other key labs came back normal, so her aldolase was normal, her TSH was fine, her rheumatoid factor, although it was elevated, was very stable from her prior baseline, and her inflammatory markers were essentially normal for age. And then 10 days later, an outpatient follow-up, she was already walking again, that HMGCR antibody had returned to negative, and the results of the muscle biopsy were back. We were able to review all the stains, and really all that was seen was some type 2 fiber atrophy, which we can see in the setting of cachexia, you know, she had this rapid weight loss. So the presumption was that, you know, there was some component of toxicity from the statin, but clearly not in immune-mediated form, given the rapid recovery here. All right, we're going to move on to case number two. This now is a 79-year-old man. He's coming in with ptosis, double vision, some difficulty standing, and new dyspnea on exertion. So he was diagnosed with metastatic renal cell carcinoma three months ago, and he was enrolled by his oncologist in a clinical trial of nivolumab, which is a PD-1 inhibitor. Three weeks after his first cycle, and five days before we're seeing him, he develops very severe ptosis, to the point where he's needing to tape his eyelids open. He can no longer stand up from a seated position without pushing off. His thighs hurt. He has this forward flex posture when he's walking, and when he walks more than a block, he gets very winded. All this is new, of course. In the background, he has hypertension, high cholesterol, and a prior TIA. He's on aspirin. He's on simvastatin, hydrochlorothiazide, labetalol, and lisinopril. All of these have been long-term medicines for him. No known history of alcohol or drug use. He is of French-Canadian ancestry. His oncologist checked his CK when he came in with this new weakness, and it's elevated to 1,700. When you exam him, you find that he does, in fact, have very severe ptosis, right more than left, and impaired eye movements in many directions. You don't get any fatigability that's very clear on your exam. He's also weak in the hip flexors, and has this waddling gait, suggesting additional proximal leg muscle weakness. Here, a very different pattern than case one. This patient's on a statin, but with this pattern of weakness, I don't think that would really be the first place for our mind to jump if we wanted to look for a toxic cause. This patient has ocular weakness, axial weakness that would be very unusual for a necrotizing myopathy like a statin might cause. Here the question is whether the immune checkpoint inhibitor might be to blame. As a reminder, this is a relatively new class of medicines that works by basically unleashing the immune system to attack tumor cells. The idea here is that normally T-cells get activated by their T-cell receptor picking up an antigen from an antigen-presenting cell, but it needs a little bit more than that to get going, basically. It depends on the presence of either co-stimulatory or co-inhibitory molecules on the T-cell interacting with that antigen-presenting cell. To avoid the immune system becoming too active, there's a fine balance between these two sets of molecules. Tumor cells, part of the way that they evade recognition by the immune system is they express some of these inhibitory molecules to basically prevent the immune system from attacking them. The way that immune checkpoint inhibitors are meant to work is they block these components, either on the T-cell side or on the cellular side, to tip the balance in favor of activation of the T-cell and cell-mediated cytotoxicity. This comes at a cost, of course, in the form of immune-related adverse events. By unleashing the immune system, we increase the risk of autoimmune problems affecting essentially any system in the body. On the neurologic side of things, many of the more common ones that we can see involve the peripheral nervous system. Probably the most common of all, actually, in some of the larger case series that have been published appears to be myositis. We can, of course, see neuropathies and myasthenic syndromes, but that's not really going to be the focus of this talk. When we think about myositis, this is still rare, right? Only about 0.4% of patients that are treated with a checkpoint inhibitor will develop this. The risk goes up a little bit when patients are on two agents, so the combination of a CD1 inhibitor and a CTLA-4 inhibitor. This happens usually very early in the course of treatment. The median is 25 days, which would put most patients around their first or second cycle. It'd be very unusual for someone that's been on these for a year or two to have this happen to them. Typically, symptoms come on really fulminantly, like in this case. The CK in these patients is virtually almost always high, sometimes quite high. As I alluded to, the pattern of weakness can be all over the map and can be quite distinct. This is from a small case series of 10 patients affected with myositis after a checkpoint inhibitor. You can see a lot of them have ocular involvement, sort of akin to myasthenia almost. Some of them have only ocular involvement. A lot of them have axial muscle weakness, leading to this flexed forward posture. Some patients have diaphragmatic involvement, leading to respiratory muscle weakness as well. This is obviously a really important clue into this specific toxic cause, because there aren't many myopathies that present in this fashion. Probably the single most important point to remember about checkpoint inhibitor-associated myositis is that there's this frequent overlap. Some patients have myasthenia gravis alongside their myositis. Other patients have myocarditis. Some have all three. The frequency of this is actually not low. About half of patients with myositis will have one or both of these overlaps. If we look at it kind of in the other direction, people that come in with a suspected diagnosis of myasthenia, so maybe they have overt fatigability, the same thing holds. So a lot of these patients will have a high CK, which we would not expect in a patient that has idiopathic myasthenia. The reason to care about this is that these overlap patients usually do worse. So a lot of them have respiratory failure. They do worse with treatment. Among the patients that die, which thankfully is not that common with this complication, virtually all of them have this overlap syndrome. All right, so in a case like this where we have this very sort of suspicious pattern of weakness, we know they're on a drug that does this, do we need to actually do anything else to confirm the diagnosis, or is this sort of a clinical diagnosis that we can make? Largely I would view this as a clinical diagnosis. But if we do more testing, there's some interesting things that can come out. So this is from a systematic review published by Marini and colleagues a few years ago. This actually includes all neurologic adverse events. It's a good paper to look at. But they found 136 cases of myositis in the literature. In 106 of them, antibody panels were sent. About a third of them had one or more antibodies come back. It's all over the map, as you can see. But the most common by far is the striated muscle antibody. And if you look at other case series, this does seem to be a fairly unique and common biomarker in these patients. Rates can be as high as about 60% in some of the case series that are out there. This doesn't necessarily mean that we need to treat them any differently if they have it based on what we know now, but it's sort of an interesting correlation. In terms of the rest of these, it's important to remember that patients that have a pre-existing autoimmune disorder or a perineoplastic disorder, when we rev up the immune system, that can be unleashed, right? So the reason that we have all of these other hits might be that these patients had something simmering that we didn't really recognize or know about. They get put on a checkpoint inhibitor, and now all of a sudden their TIF1 gamma-dramatomyositis becomes super clear and obvious, right? So that's the other situation we can see. If we wanted to do some testing to really hammer home, does this person have myositis or myasthenia, given this ocular predominance to weakness in these patients, a key thing to really note is that among patients that have checkpoint inhibitor myasthenia, many of them actually are seronegative. It's sort of different than the normal idiopathic situation. So we're going to rely a lot more on our exam or our lecture diagnostics in this population. Myocarditis can obviously cause a high CK, so there's other things that we need to do, and I would sort of view as a mandatory part of this workup, to investigate the heart. So these patients should have some form of cardiac imaging, and it's worthwhile to think about sending some markers that are more cardiac muscle specific, like troponin I. When I see these folks, honestly, I usually just consult cardiology to help with this because of this really high frequency of overlap. Many of them are short of breath, you know, it's hard to know if that's from diaphragm involvement or new heart failure, so good to get them on board. Usually not necessary to do a biopsy, but if we do, we can see some interesting things. So here you can see in the affected part of muscle, there is robust inflammatory cell infiltrate in this muscle. If you do staining, it's both CD8 positive macrophages and CD8 positive cytotoxic T cells. One important thing to know is that consistently these findings can be really patchy. So this part of the muscle is like virtually normal on H&E, staining over here. And so getting a negative biopsy, maybe you just had bad luck in terms of where you picked. So our patient, when we did testing, did not have any evidence of myasthenia, but did have a positive striated muscle antibody. Troponin T was elevated, so we got cardiology to help out. Thankfully, they did not have any evidence of myocarditis after a thorough workup. So it came time to decide how to treat this patient. There have been some really helpful guidelines put out, this is now actually the second iteration of this in the Journal of Clinical Oncology. Really, really, really helpful paper across the board for these complications. And what they do basically is spell out, based on kind of how sick the person is, what we should think about doing. So actually in cases of CK elevation without symptoms, it's reasonable to just keep them on treatment and either do nothing and watch or give them a little bit of steroid while they're continuing to get their checkpoint inhibitor. When patients get weak, like our patient though, it is mandatory to hold the checkpoint inhibitor and treat. Our first line is going to be steroids, usually a daily dose of prednisone, but in severe cases, totally reasonable to give a pulse of high dose IV methylprednisolone. What to do after that is really still a matter of clinical expert opinion at this point. There's not a lot of trial data to guide this. The guidelines here would suggest that in severe cases, it's reasonable to think about giving patients IVIG or plasma exchange up front, sort of extrapolating from other diseases that are similar to this. And then if patients are not getting better after a couple weeks on these first line agents, they say that we can think about things like rituximab, TNF alpha blockers, or IL-6 inhibitors. There's some basic science literature that's been done that would suggest these sort of facets of the immune system have relevance, but there's not really like trials that would say one of these are better than the other at this stage. If we sort of dig into how people actually do, it's all over the map. And this really relates to how sick people are or are not. So in that big systematic review that I mentioned, reason for optimism in that a lot of patients actually improved, but unfortunately, a decent number also died, right? So there's these really dichotomous outcomes that can happen. Patients that come in with a mild form of this are the ones that generally do well. So in a small cohort series of patients with mild myositis, virtually all of them got better and they got better very quickly with just prednisolone. In a different cohort that had more of these overlap patients, as mentioned, they improved overall less frequently, more commonly required a second agent. However, the patients that did actually get better still did so very quickly. So you're going to get some feedback early on about how you're doing in these folks. So in our patient, we trialed them on pyridostigmine just in case, didn't help them at all. So then they were on prednisolone. They noticed improvement very quickly and their CK responded pretty quickly as well. Thankfully still a good outcome two years later for this patient. They were switched to a new cancer treatment. They've been doing very well on this and virtually all of their myositis symptoms have been kept at bay even off prednisolone at this point. And this kind of plays out in the literature. So even patients that have these immune related adverse events, there's really no evidence that it influences their eventual oncologic outcome, thankfully. And actually, there's some evidence that it can be reasonable to even re-challenge patients with a different checkpoint inhibitor after they've had a case like this. The final thing I'll say here is that, you know, cancer care is changing very rapidly nowadays. There's, you know, seemingly new options coming out every month. And it's really important as this happens that we as a field kind of remain vigilant about, you know, whether similar things might happen with other treatments. And you know, this is very contemporary, right? This just came out a couple months ago. This is basically a different way of unleashing the immune system. I have no idea how to say the name of this drug, so I'm just going to let you read it. This is an antibody against CCR4. It's been approved to treat T-cell leukemia. And the way that this unleashes the immune system is to deplete regulatory T-cells, basically. And in one case series that's been published so far, we're kind of seeing a similar trend, where rarely patients can have myositis or myocarditis in a similar fashion to the checkpoint inhibitors. So more to come, I'm sure, as drugs like this continue to come out. All right, we're going to jump to case three. 72-year-old guy, he's coming in with six months of weakness and two months of numbness. So his first symptom was noticing some difficulty rising from a chair. His weakness has been slowly progressive since, and he's now having some trouble lifting his arms up over his head. And then finally, over the last few months, he also finds numbness in the toes. It's not painful. He has a known history of gout, chronic kidney disease, polymyalgia rheumatica, and high blood pressure. And he's on colchicine, 0.6 milligrams twice daily. He's been on that for three years now for his gout. And he has a low dose of prednisone on board for the last year for his PMR. No alcohol or drug use. On exam, he has weakness of proximal muscles in the arms and the legs, but also the ankle dorsiflexors. So a little bit of a different pattern than before. And most importantly, he also has some sensory loss. So he has diminished vibratory sensation at the toes and the ankles, and his reflexes are actually absent at the ankles and diminished elsewhere. So all findings, obviously, that we would not suspect with an isolated myopathy. Again, we already have an EMG here, ordered by the primary. Shows sort of similar findings. So sensory responses on nerve conductions are actually absent in the legs and reduced in the hands, amplitudes, I should say. The EMG demonstrated fibrillation potentials and early recruitment of small motor units in the proximal muscles, and then a very different pattern in distal muscles, where there was reduced recruitment of high-amplitude, long-duration motor units. So like the exam, evidence of both a proximal myopathy and seemingly a length-dependent sensory motor polyneuropathy. So this is not a pattern that we see every day, right? Concurrent development of both a muscle and a nerve disease. Put another way, a myoneuropathy or a neuromyopathy, however you wanna say it. And Dr. Salajega was sort of alluding to this, but there's three kind of classes of medications that can cause this pattern. Amiodarone, chloroquine, and its cousin hydroxychloroquine, and colchicine. Couple other things to keep in mind that can do this in the toxic realm would be alcohol abuse, as well as critical illness. Patients can have concurrent critical illness myopathy and critical illness neuropathy. And then there are some rare inflammatory and genetic causes, including amyloid, that we could think about, but we're gonna focus on these toxic forms here today. So in terms of colchicine, as mentioned earlier, this is an antimicrotubular agent. How this actually affects muscles is that its effect also interferes with the clearance of lysosomes within cells. So these toxic vacuoles will accumulate within muscle fibers that are filled with material that was eventually meant to be degraded by the cell, but now it's just sticking around. Usually it takes quite a while for this to happen to patients. Patients usually need to be on a fairly high dose, this patient was, for a long time before symptoms occur. Like statins, renal failure is a major risk factor, and so actually this patient, with a known history of chronic kidney disease, you might argue probably should have not been on that high of a dose of colchicine to begin with. And in some patients that have more abrupt renal failure, we can see very severe rhabdo-like forms of this toxicity in patients. Again, common theme, other medications can influence this risk, including statins. Unlike some of the other drugs we've mentioned, usually this is a slow burn. These patients have chronic progressive symptoms over months rather than a really acute course over a few weeks. Usually it's unnecessary to biopsy these patients, but if you do, the classic finding is the presence of these vacuoles that I mentioned, as you can see here. These will stain positive with acid phosphatase as a helpful kind of ancillary test. And the findings are very similar among the other classes that have been alluded to. So in terms of these other medications, I'm gonna run through this quickly because Kian mentioned these. But just a couple things to mention. Cardiomyopathy can also occur with chloroquine and hydroxychloroquine, so that's important to screen for if you're suspecting this condition with those drugs in particular. And unlike colchicine, it is actually common that with these other drugs, the CK can be normal. So we shouldn't be using this alone as like our screening test in patients that are on these medications. Thankfully though, the EMG does appear to be reliable in this setting. All right, so the final thing you might be wondering, well, this patient was also on steroids, right? Why aren't we talking about that as a potential contributor to a toxic myopathy? Whenever this has been looked at, typically the dose that's required to lead to a steroid myopathy is around prednisone 30 milligrams a day or its equivalent. And this needs to be on board for at least a few weeks. We would of course not expect distal weakness and of course not neuropathy from steroids, so that alone would kind of clue us into this alternative. But I think in general, when you're thinking about steroids, a very important point is that even patients that have a severe steroid-related myopathy, their CK can be normal, their EMG can be totally normal as well. The reason for this is that steroids really cause, sorry, type two fiber atrophy, which is very hard to see on EMG. And if they're just atrophying and not lysing open, of course the CK is gonna stay normal. All right, here's our final case. This is a quick one. 26-year-old man, he's coming in with chronic hepatitis B infection, and he's presenting with proximal muscle weakness. So he was diagnosed with this 15 months ago after on just a routine visit to his primary care doctor, his LFTs were grounded to be up and a workup was done. 12 months ago, he was started on lamivudine monotherapy to treat the hepatitis B. He moved here to the US three months ago for graduate school, and his primary kept, sorry, new primary here kept him on the same regimen because it was working, wasn't having side effects, no real reason to switch. Two months ago, he noticed some difficulty rising from a chair. On exam, he has weakness of the bilateral deltoids and the hip flexors, normal sensation, normal reflexes. So again, sort of a symmetric proximal pattern of weakness. CK is up, it's 1,100, and deltoid muscle was biopsied out of concern that this young patient might have a new inflammatory myositis given that he's otherwise pretty healthy. So on biopsy, the H&E was pretty unremarkable. There was certainly no inflammatory infiltrate. I'm gonna highlight two stains that were done that kind of get us where we need to go here. So in terms of our Gamori trichrome, what you see here is the presence of a ragged red fiber, which we can see with mitochondrial abnormalities, and cytochrome C oxidase staining, which again is a mitochondrial enzyme, shows that these cells are completely deplete of any staining with this enzyme. So a couple different things that are pointing us towards a mitochondrial etiology for this patient's myopathy. So this type of toxic myopathy was really first described in detail with AZT. So back in the early stages of the HIV epidemic. Patients that were treated with high dose monotherapy with AZT back then, about 20% of them would get a myopathy. The reason for this is that the way that this drug worked is it's basically an analog of normal nucleosides, and it sort of competes with these nucleosides to interfere with HIV's reverse transcriptase. In doing so though, it can have these side effects by interfering with the mitochondrial DNA polymerase in human cells, leading to this unintended effect. Nowadays, it's very unusual to see this because AZT is virtually never used in this country, and where it's used elsewhere, it's used in multi-drug regimens. So the dose that's needed is actually much lower, and this is a dose-dependent effect. Now though, there are other antiretrovirals that have lower reported incidences of myopathy that we do need to keep in mind. Lamivudine is one, you see the others here. Not all of these are so clearly mitochondrial in nature, but a lot of the lamivudine cases at least have been, at least based on pathology, there's evidence there that that's the cause of these. Even these though, I will say, this is an exceedingly rare thing that you may never see. A lot of these medications have already themselves fallen out of favor. So for example, Telbivudine has actually been discontinued in part because of these high rates of myopathy. And even lamivudine nowadays is not used as much because there are other options to treat hepatitis B that have less frequent resistance from the hepatitis B virus itself. When we do see it though, this is something that occurs with chronic use of the medicine, it doesn't happen early. And to see this degree of actual overt myopathy leading to weakness is pretty unusual. More commonly, you would just see an asymptomatic elevation in the CK. Some patients that do develop this can either have neuropathy, as Dr. Salajega mentioned, or muscle pain as well. Thankfully, when we stop the drug, things get better. All right, so how to sort of summarize all this, what we really wanna keep in mind and remember is when we're seeing a patient coming in with new myopathy, what are the things that might clue us in to thinking about one of these toxic causes as opposed to some other cause of myopathy? Well, there's some clinical features, some lab features, some electrodiagnostic features that we can all go through. So on the clinical side, of course, this combination of myopathy and polyneuropathy together, very unusual, that puts us towards a very specific set of medications. Seeing myopathy and myasthenia gravis together in the same patient, of course, is really very strongly pointing us towards a checkpoint inhibitor. Acute, painful neuropathy developing over just a few weeks can be seen with these necrotizing forms of toxic myopathy. We talked a lot about statins, but as a reminder, other lipid-lowering agents, cyclosporine, binge drinking, alveolol, these can all do the same thing. On EMG, we didn't really highlight this very much in the talk itself, but just sort of one thing to point out. Normally, when we think about myotonic discharges, we think about myotonic dystrophy or non-dystrophic myotonia, but any of these medications, actually, when they lead to muscle toxicity, you can actually see myotonic discharges on EMG. And then as a reminder, steroids and chronic alcohol use leading to myopathy are associated with a normal EMG, even if they have a very severe myopathy. And then finally, to highlight some of the biopsy features that we talked about, if we do a muscle biopsy in patients that have weakness like this, the presence of vacuoles, very helpful for thinking about these specific medicines. We just talked about the mitochondrial-associated drugs. As mentioned, corticosteroids can lead to type two fiber atrophy, which is a very specific finding. And then finally, some of these immune-mediated causes, the things that we look for are MHC1 upregulation or staining with MAC on the muscle membrane. All right, so that's it. We will take questions at this point. I'm happy to take questions on either talk from either the audience or from the web. Thanks for your attention. Thank you very much, Dr. Dottie. Wonderful, wonderful talk. Thank you. So actually, so one of the online attendees kind of wanted us to read some of these. So I'll actually give the question that has not been answered yet. Dr. Dottie, so this is yours here. Oh, there you go. Sure, so the question is just to repeat for the folks here is how can we be confident that there truly is concomitant myopathy and neuropathy given that they have different effects on electrodiagnostics and their end stages can overlap? So good point, right? So patients that have a really longstanding myopathy, I think we've probably all seen patients like this where you put a needle in and it actually looks neurogenic unexpectedly, right? But I think the key thing about in particular the case that I presented there is that this patient's, well, first of all, the patient had sensory symptoms, right? It's not just that the EMG alone was pointing us towards a concurrent neuropathy. The neurologic exam at the bedside very strongly pointed towards a neuropathy as well. Of course, you might argue many people are walking around with a baseline neuropathy they're not aware of, but this patient was reporting new numbness. So it's sort of all hung together. And then this was a pretty recent development, all this. You know, the patient six months ago did not have weakness. Usually to see these confounding cases, you know, we are talking about a myopathy that's for much more chronic on the order of years and years, decades even, right? I don't know if you want to add anything to that. No, I think that is actually correct. Now, so they do look different. Now, most of these cause an irritable myopathy. So there are, you know, as Dr. Lodi said, some actually cause myotonic discharges. Most toxic myopathies are irritable. So you see that. And of course, another point that we should, some of these people who are on these medications have other issues that could lead them to these. So they have underlying problems that could cause neuropathy, could cause myopathy in them. But that's, I think, where. So another question that was online that I think someone asked that we repeat them is that to what degree does chemo neuropathy remain chronic or impermanent? Or alternatively, if neuropathy remains after this continuation, does that imply another etiology? And so that really depends on how severe the damage was before you stopped the medication. A, B, is there a coasting effect? And C, is there an underlying cause? Either underlying neuropathy, another agent, or, you know, something else that is going on. I generally, as I said in the beginning, it's always important to make sure that we exclude other common causes of neuropathy before attributing it to a medication. And the reason is these medications are given for a reason. You don't really wanna stop them until you're pretty sure. So at any point in time, definitely, if they don't get better with stopping a medication, of course, you wanna do a full, maybe more extensive neuropathy workup. But always in the beginning, you want to check for any other potential cause before having an important medication stopped. So that was a great question, actually. And so. Yeah, we can take one from the audience here, too. Great talk, thank you. About medications-induced lupus, any comments? I had a patient on minoxidil who developed lupus-like symptoms with positive antihistone antibody. You know, actually, it was diagnosed by the rheumatologist. Any comments about management? Of lupus, or the? So lupus could, I mean, especially we're talking about the neuropathy, it could actually cause vasculitic neuropathy, or other causes of neuropathy, to other forms of neuropathy. So first of all, any autoimmune inflammatory condition, you have to make sure it's not causing a neuropathy itself. As I said, mainly it's vasculitic. Could even reports of CIDP picture with lupus, or any kind of neuropathy for that matter. But you're correct, a lot of these medications we use for it, penicillin, for example, or others that we were discussing, could actually cause a neuropathy, too. It's always a very fine balance as to is it the disease itself causing it, is it the drug, or is it something totally different? And we always try and find out which one it is. I'm not sure if that answers your question, but that's kind of a dilemma we sometimes have. Chris, any, there? That's a great question, yeah. I think we have time for one more, if anybody has anything. All right. I have one, a difficult one for Chris. Thank you for two wonderful talks. For the overlap syndrome in the PD-1 inhibitor, I guess when you're convinced you have a myositis from the drug, how do you really distinguish whether or not myosin is present? Because the electrophysiology is not going to be that helpful in most cases, so the single fiber, for example, probably going to be positive for both. I guess it's helpful if it's negative, because then myasthenia will be very unlikely. But is it more of a clinical diagnosis, and also does it matter in terms of the treatment? No, I think you're spot on there. I think there's real issues with the last diagnostics in these patients. I mean, first of all, the vast majority of them are admitted, so the idea of doing high quality rep stim in a patient coming in with this presentation is challenging, to say the least. And single fiber, obviously, in an inpatient setting, let's be real. I agree. That alone doesn't really prove that you have myasthenia above and beyond your myositis. I think the most important thing is just examining the person, right? Fatigability is not perfect. Certainly patients that are weak from any cause can appear fatigable if you do it just right. So if you have a patient with fatigable ocular weakness, for example, that looks like myasthenia, I think it's reasonable in this circumstance to say, OK, there's probably a concurrence here. I think the two things that it would influence for me are really treatment related. We know myasthenia, at least, has symptomatic benefit from mestinon. These patients are often quite sick, having a hard time swallowing. So if maybe adding mestinon could help them avoid, let's say, an NG tube while they're hospitalized and while they're recovering over the first week, that's great. And then I would certainly be more likely to recommend IVIG in addition to the steroids in someone that I really felt confident had myasthenia gravis as a component, purely extrapolating from how we treat idiopathic myasthenia. It's not like there's actually been trials in this setting that really formally established that. But that's just what I do in practice. Thank you. So the session has ended. But if you have any other questions, we're here for another 10, 15 minutes if you need us. So otherwise, thank you very much for paying attention, and I hope you enjoy the rest of your meeting. Thank you. Great job. Hey, Michael, you're supposed to give us questions before. You're supposed to give us a question before.

toxic myopathy

statin use

symptoms

medical history

laboratory findings

statin-induced necrotizing myopathy

rarity

autoimmune disease

hypothyroidism

temporal relationship

checkpoint inhibitors

colchicine

antiretrovirals