From ALS to myasthenia gravis to Guillain-Barré syndrome, potentially aggressive neuromuscular disorders can present with a range of nebulous symptoms. In this talk for PCPs, neurologist Priya Dhawan, MD, FRCPC, describes how she puts together the puzzle pieces – such as weakness, weight loss and a foot drop – to arrive at a diagnosis. Through case examples, she offers keys to in-person evaluations, lab test interpretations, and using electrodiagnostic studies to confirm a suspicion, identify subclinical disease, uncover clues to causes, or show whether a treatment is working. Learn about needle exams and nerve biopsies, and get clarity on the red flags that warrant a speedy referral.
Uh the caveat here is that neurology is vast and overwhelming. And neuromuscular diseases are vast and overwhelming. And certainly this will by no means be an exhaustive or comprehensive review of neuromuscular diseases. That's impossible. But I, I picked a couple of areas that I thought might be of consideration and um reviewed a couple of cases and maybe some red flags to consider when to prompt referral and when to think that something is not acting like the way it should. Um and to start with that, um I just, I think everybody knows this. But when, when those of us in the neuromuscular clinic in EMG lab, think about a patient with a potential neuromuscular etiology to their, their presentation, this is the picture that's in our head all the time. And so one of the things that we do when we evaluate patients is to try to localize exactly along this pathway where the problem lies. And so for us, the peripheral nervous system really begins here in the anterior horn cell in the spinal cord where the motor nerves have their, have their cell bodies. And then you know that comes out of the spinal cord and we have nerve root diseases. We have plexus diseases, we have diseases of the peripheral nerve, which we actually think quite separately kind of in, in differential and localization from nerve root disorders. Then we have the interaction between muscle and nerve, the neuromuscular junction. Um and then we have the muscle and so, you know, sometimes when a patient comes in and they're presenting with weakness, we don't actually know where along this axis it lies. And so we use our clinical examination and then we use our electro diagnostic studies, which are an extension of the clinical examination to try to sort out what's going on. And so so much if we do what we do is dependent on the ability to examine a patient. So you'll, you'll notice when any of us see the patient, we always, we may start with a tele visits, but we'll always bring the patient in to examine them because that's really important for us. So I think all of you are very familiar with ordering emgs, but just as a very, very, very basic overview of what we do, there's two parts to the electro diagnostic test. We do the nerve conduction studies in the beginning and we always do a needle examination uh to follow. So the nerve conduction studies um essentially involves creation or detection of a motor and sensory response. Um And essentially when nerve action potentials get summed, they are become robust enough if, if they're healthy to produce a waveform. And so when we look at these waveforms, we can look at how robust in amplitude the waveform is, which tells us about the health of the axon. And then we also can look and see how long it takes for that waveform to produce and what velocity is like over the course of a nerve. And this tells us about the health of the myelin. And so there are features on these studies that can help us determine whether a process is genetic or not genetic. Um And then we can also interrogate that neuromuscular junction to look for disorders like myasthenia gravis with our nerve conduction studies on our needle examination, uh particularly in patients who are weak, they always needed a needle examination. Our nerve conduction studies will not very tell us that much. Always about a patient who is weak. And when we have, when we stick a needle in a muscle, there's a little microphone in there and we listen to the way the muscle sounds and the action potentials that are or the motor units rather that are generated based on this needle examination can tell us is this a process reflecting a nerve pathology or is this a myopathy? Um Does this look like a myopathy that is irritative or inflammatory or dystrophic? Um And does this process look old or active or chronic? So, for example, if someone has a lumbosacral radiculopathy, we can actually tell if this looks like it happened years ago or if this is active or irritated. So when we come into the EMG lab, we come in with a clinical impression. So say, I'm assuming this patient has a brachial plexopathy. And so my job in the lab is to determine is that diagnosis or clinical assumption, correct. But also if it's not correct or if it is correct, is there other other processes going on that could maybe confound or explain the patient's clinical presentation? Because if I just look for carpal tunnel, maybe the patient has carpal tunnel. But if I don't do a thorough examination, I might miss the brachial plexopathy or the cervical radiculopathy or the more diffused process. Similarly, if a patient has a foot drop and I just look at the leg that's weak. I may diagnose that patient with a ridicule. And I may, if I don't study other muscles, I actually may miss something more diffuse like motor neuron disease. And that actually happens. Um quite, quite, quite a lot. Um It can also help guide additional testing like which muscle to choose for a muscle biopsy, which genetic test to get. And in patients with inflammatory muscle disease, it can help say, hm, is this patient being treated effectively or not? So we'll just start with the case. Um I don't know how many of you have a presence in the hospital, but I think this case will be um illustrative. Nevertheless, even if you're not. Um, so we had a, these are all real cases, by the way. So we had a 78 year old female admitted to IC U for aspiration pneumonia. Um, their pneumonia was treated, it wasn't a bad pneumonia and they didn't really know why she was aspirating, but she pneumonia was treated, but they just were not able to wean her from the ventilator. Um, when taking a history, the family states that she really hadn't had any difficulties with, with weakness or anything, but she had been losing a lot of weight. Um And when indeed on examination, she was wasted everywhere. Uh her limbs were actually strong but she had a lot of wasting. Uh she had present reflexes, maybe they were a bit brisk. Um But that was kind of the notable there, those are the notable features on her exam. So you don't have to share if you don't want to. But if there are there any initial thoughts that you make that jump out at you uh in patients such as this um that you might be thinking about, feel free to pop it in the chat. I don't know if you guys can, can speak or not or unmute. So in that, in, in that vein, we think about where the case went. So because she had had so much weight loss, the initial IC U Neurology team thought about a perineoplasty cause. And so the patient had antibodies done, they had a pan scan was negative and the patient received ivigiv steroids without any benefit. And then they said, hm, well, maybe we'll look for a neuromuscular etiology. And emg and nerve conduction studies were ordered. And so routine nerve conduction studies were normal. Um So sensory responses, motor responses were normal. We did what we call repetitive nerve stimulation. Looking for myasthenia gravis or decrement or fatiguing of the muscle associated with myasthenia gravis. That was normal. But when we did put the needle in her muscles, her mind, you her very strong muscles, we noticed that there were fasciculation potentials and fibrillation potentials in almost every muscle we studied. And then there were what we call large motor units. So motor units that were large fuddy and had difficulty recruiting. And so we call those neurogenic units. Um And so this essentially reflected a neurogenic process that appeared active because of the, the the fact that the motor units were unstable and there were fibrillation potentials that was diffused because all the muscles we studied in cervical myotomes, thoracic myotomes, lobo sacro, myotomes and the diaphragm, they were all affected. So this shows that this is a diffuse process. And based on, you know how we interpret the studies, either the process is a process involving nerve roots or it was involving the anterior horn cells. And so we go to our kind of differential diagnosis of failure to wean. And this list is not exhaustive but these are some of the big things that we see. So, a LS or motor neuron disease is a big one. Myasthenia gravis, big one. There is, if you've heard of Pompeii disease, there's an adult onset Pompeii disease or acid multi sufficiency, which can cause a muscle disorder that pre it has a predilection for res respiratory muscles. There is an entity called critical illness, myopathy or neuropathy that happens in patients who have been hospitalized for a long period of time. In the IC U, patients may have undetected Guillain Barre syndrome and less likely to be subclinical and incidentally found. But inflammatory muscle disorders such as dermatomyositis can also cause failure to wean and so failure to wean happens when this process has been slowly going on and it has not been identified or recognized. And then the patient because they have bulbar weakness gets an aspiration pneumonia. And because this process has been going on and perhaps the bulbar muscles or the diaphragm are weak, they can't, they don't have the reserve to wean off the ventilator. And so in this patient, this patient was diagnosed with motor neurone disease. And the reason I bring this up is because I think when motor neuron disease is obvious, it's obvious, but there are many steps before it becomes obvious that the patient can potentially be detected in the primary care setting. And in that case, should be referred to an A LS clinic. Um I think I cannot stress enough that the A LS clinic, uh, unlike some of our other neuromuscular clinics where we kind of really want a good suspicion for a neuromuscular cause before sending the patient when it comes to A LS. Yeah, you can absolutely refer these patients to the A LS Clinic even if you don't know if they have a LS. So if they've never had an EMG, that's ok. We'll do the EMG here in the A LS clinic. If you, if there are red flags in your clinical history that you think the patient has a LS, please send them. And the reason for that is there's a lot of data to support early intervention being favorable. And I don't just mean the new three or four drugs that we have available, I actually mean multidisciplinary care. And so it act uh there's a lot of data to support that the quality of the life of the patient is extremely, extremely ameliorated by early multidisciplinary care. And the A LS clinic has a lot of funding for physical therapy, occupational therapy, speech therapy, et cetera. So these patients can really benefit. So as I'm sure, you know, a LS is a combination of upper motor neuron symptomatology and lower motor neuron symptomatology. So upper motor neuron being spasticity, spastic dysarthria, elevated reflexes, and then the lower motor neuron component, which is because that anterior horn cell dies, you get dense weakness and you get dying back of the motor nerve. So you get a lot of atrophy and as a consequence of a circulation, um the big point that I can't stress enough is that the CIA or wasting may outweigh the degree of weakness as clearly evidenced in this patient, the patient just lost weight. Um and they were wasting away. Uh and they didn't actually have a lot of weakness on strength examination. Most of their weakness was in axial and bulbar respiratory muscles. And so any patient with unexplained weight loss, you can, you should, you should tickle your mind to think about motor neuron disease. Um Obviously, uh apologies, there's a typo there, this should be dysphagia. Uh um difficulties with swallowing, any unexplained aspiration, pneumonia should prompt consideration of neuromuscular weakness, fasciculations. And the big one that I see a lot is a patient gets diagnosed with a foot drop or develops a foot drop. And an MRI of the lumbar spine is done and perhaps there's a little bit of degenerative arthritis, but there's really no obvious structural pathology to explain that foot drop. And so the patient gets sent to a surgeon and the surgeon is like, I don't think this is may be relevant, but maybe I'll decompress you anyways and then the patient continues to progress. So it's always a red flag for me when I see a patient referred for foot drop and look at their MRI spine. And I'm like, uh, oh, there's no structural disease. I'm not saying that's always a LS, but it, it's quite often it happens that way. There's a couple of phenotypes. Uh We have the classic presentation which is limb predominant and asymmetric, but you can have bulbar only variant. You can have flail, arms or flail leg. You can have like our patient isolated diaphragmatic involvement, you can actually have dropped head syndrome as well. Um So basically, the patient just develops a head drop. And the other, the differential diagnosis for that actually includes myasthenia gravis, and uh certain myopathies as well. Um And then you can kind of get isolated upper or lower motor neuron, predominant phenotypes. And what is increasingly recognized is the FTDALS phenotype. So patients with a LS motor phenomenon but also predominant cognitive impairment. And I think historically, we thought a LS, it was only a very small subset of A LS that had ftdals, but an increasing recognition of the cognitive impairments that a company A LS is, is quite uh is developing just I wanna highlight a couple of things in the patient with dense weakness. Uh inclusion body myositis is a non treatable uh inflammatory muscle disorder. Um that present as one of the most common myopathies in age over 50 to 60. And classically, these patients present with quadriceps, weakness and finger flexor weakness. Um and the EMG can sometimes be confounded with A LS. Um as can the multifocal motor neuropathy and motor C ID P. So these conditions are conditions that we see and can mimic A LS. But essentially any patient with progressive weakness should be referred to us for an electro diagnostic evaluation. Um The one thing that I want to point out that's uh not often recognized is the concept of the radiation induced plexopathy. So say you have a patient who had intensive pelvic radiation for a malignancy and then perhaps 5 to 10 to if even 15 years later, the patient starts getting progressive weakness and atrophy in the in the hip girdle and thigh muscles, that patient may have radiation induced damage. And it's very interesting that radiation induced injury to peripheral nerves and muscle can present in a very, very late fashion. So it can, it can be decades actually after the initial radiation and it is a bit dose dependent. So the more radiation they got, the more likely they are vulnerable to this injury. And the pathophysiology is thought to be a progressive fibrosis. And so that's why these patients can have progressive disease. And so if they had head and neck radiation for like head and neck cancers, and they get progressive bulbar dysfunction, that can very much mimic A LS. So just to keep that in mind to ask a history of radiation, upper motor neuron, predominant findings include, you know, mimicking conditions include uh MS and some hereditary spinal cord disorders such as metabolic myelopathy. And then I'll just skip this over with the exception of Grove syndrome, which is a genetic disease that causes achalasia, a la hermia, um and adrenal insufficiency and interestingly a motor neuron disease phenotype. Uh We always check for thyroid uh studies and a hy parathyroid studies in patients with a LS because thyrotoxicosis and parathyroidism can cause dense weakness and hyperreflexia. And so that can mimic A LS. Ok. Let me know if there's any questions. So we have another case. Um, A 65 year old gentleman presented with two months of progressive arm and leg weakness. He reported a mild aching in the muscles. He denied any dark colored urine CK however, was very elevated at 9000. He had been on a statin for two years. Um His prestin CK was normal and we did an EMG that showed an irritative myopathy. So, a myopathy with fibrillation potentials and when we see that we say, hm, there's an underlying pathological substrate there that suggests either muscle fiber inflammation or necrosis is happening or muscle fibers splitting or maybe there's vacuoles. And so something is, is, you know, interrupting the ultra structure of the muscle. Um Any thoughts as to what might be causing his symptoms. Ok. We'll keep going. So this is his muscle biopsy. And so this is a this over here is a normal muscle fiber, these are normal muscle fibers, but this clearly is not ab abnormal, this is not normal, this is what we call a necrotic muscle. And these are all inflammatory cells. But if you notice that the inflammatory cells are within the confines of the muscle fiber, they're not in the per mei all scattered around. So, basically, these are just mu inflammatory cells that are digesting a muscle fiber that's dying. Well, so what we call this is, we call this a necrotizing myopathy. We do not call it an inflammatory myopathy. We call it a necrotizing myopathy. And indeed his anti HMG coa reductase antibodies were positive. So this is what we call an immune mediated necrotizing myopathy. And I'm sure you might have seen these in your practice, but essentially these, this is not a quote statin neuropathy, statins may cause cramps and maybe a little bit of elevated CK. Um but it's, it's a rare complication of statin use is this immune mediated process. And so the process is not directly caused by the statin damaging muscle. It's caused by an a faulty autoimmune response against the enzyme that is inhibited by the statin. So, hmgc reductase. And so, in fact, sometimes after stopping the statin, the patient may actually get worse, they certainly don't get better, but they may not, they may, they may actually get worse because now, HMG coa reductase is upregulated and that immune attack persists. And so this is thought to be a humor mutated or B cell mediated process, which is why we don't see a lot of inflammation on the biopsy. We just see necrosis and the way these patients present is they'll get limb weakness, proximately predominant. They may also have a lot of bulbar weakness or neck weakness and their CK is elevated to the tens of thousands. Um The, the reason I mentioned this is twofold. Number one, it may be associated with malignancy. So they require a malignancy evaluation. But number two is these patients require early and aggressive treatment. Uh I've seen a lot in the community sometimes, um perhaps they see a rheumatologist for this and the and the physicians will kind of monitor the CK and see if maybe following the statin over time, sorry, following the CK over time after cessation of the statin may make the patient better. And I would say that just don't feel shy about referring these patients to us quite early because if they don't get treated aggressively, they may not have any meaningful recovery. Because what can happen is the muscle gets fibrosed and then becomes recalcitrant into treatment. And so they need aggressive treatment with Ivig and other kind of immunosuppressant medications. There are other immune and necro myope that are not associated with the statin. Um We also treat them similarly. Um So I talked about necrotizing myopathy, then we have the immune me sorry, the inflammatory myopathies. And these are patients that you might see in the context of presenting with proximal weakness, respiratory weakness, muscle pain, these are much more painful and they may have rash. So patients with dermatomyositis often have rashes on their face, around their eyes, on the extensor surfaces of their hands. Um and they may actually progress very, very quickly to developing respiratory dysfunction. So these patients would be referred to rheumatology or neurology quite quickly. Their CKs may be normal. And so it can kind of fool you, you think the CK is gonna be super sky high like the um immune as the mud necrotizing myopathy. But that doesn't always happen. These patients definitively have an increased malignancy risk. And there are antibodies that we check to determine which patients are more likely to have a cancer and which patients are more likely to have. For example, uh interstitial lung disease. And we treat these with immunotherapy as well. OK. How are we doing for time reasonably well? Uh We may not get through everything but that's OK. Um Here's another case. Uh So just a very brief case of rhabdomyolysis. This is actually a patient I just saw in the clinic recently. So she's a 39 year old female with two episodes of rhabdomyolysis. So she had 111 years ago and one kind of recently, her CK was over 100,000. She had myoglobinuria and she actually had so much protein deposition or a leakage in her urine that she required weeks of hemodialysis. Interestingly, she was in a verbal altercation at both times. So she was in a massive fight and then shortly thereafter, she developed these episodes. But in kind of review of history, she had some more subtle symptoms such that she was kind of feeling unwell for days. She would nauseous and she would get dark Coca Cola colored urine intermittently. And this would happen anytime she was like very emotionally stressed or she had very strenuous physical activity. And while she had normal motor milestones, she, she says, like ever since she was a kid, she could never really push herself physically. She'd always have to take a break and the break was always at the 5 to 10 minute mark. And as soon as she took a break, she'd be good to go, she'd get like a second wind and she could keep going um in between the episodes of rhabdomyolysis. Her CK ranged from 700 to about 6000. So this is her muscle biopsy and um the, the top left here is an agen, a stain is steady and you know, the, the the, the pink is quite normal, but you see underneath the muscle membrane in the sub sarco area, you see these globs, those vacuoles that have like glob like protein aous accumulation. And you can see them on various stains. The stain on the right is, is a past stain which stains for glycogen or glucose. And you can see that these are filled with dark purple staining glucose accumulation. The bottom stain is a stain for a muscle called my phosphorylase. And that's uh an enzyme that's involved in glycogen storage. And so the bottom right is the control and the bottom left is uh the patient and you can see that the patient um has absolutely no myoho phor lase activity. So, even if I didn't do genetic testing on this patient, I know without a doubt that this patient has something called mcardle's disease. And you might have heard of this if you've seen kids or adults with this, but it's a glycogen storage disorder and it's actually not that uncommon. Um And the classic history is one of the what we call metabolic myopathies. And we see this in patients who have exercise intolerance, fatigue and cramping and they get a classic second wind such that after about 5 to 10 minutes, uh they need a break and as soon as they recover from that break, they can keep going, um uh they can tolerate moderate exercise, they do not tolerate strenuous exercise. They get recurrent episodes of rhabdomyolysis and they can have fixed weakness in between. And the way we kind of treat this is we avoid fasting, we give them a, a shot of sugar before they exercise. We encourage moderate submaximal exercise and we supplement them with B six. And so there's a list of these um with, with some of them, they are very, very much more prone to developing after fasting, for example, the fatty acid oxidation deficits. Um I wish I had the time to talk about mitochondrial disease. It's a whole other topic. That's interesting, but it would require another hour or at least so. But, but no, if you ever have a history of these patients with like weakness rhabdomyolysis and exercise intolerance, we think about either the mitochondrial or the classic glycogen or fatty acid storage disease. And we kind of have an algorithm that we go. And basically what we say is when a patient has rhabdomyolysis, either that's rhabdomyolysis in isolation. And if there's an obvious cause or it's rhabdomyolysis in the context of either an inborn error of metabolism, a muscular dystrophy or a mitochondrial disorder. And sometimes you'll get patients in the clinic where they have their CKs elevated, it's maybe moderately elevated or ma massively elevated. And I would say, you know, understand that vigorous exercise can leak CK into the blood. So we don't need to evaluate every single person of these. But if, if the CK is persistently elevated and they're not on a statin, feel free to refer those patients to us because those patients may not be asymptomatic. And a lot of genetic muscle diseases can be diagnosed this way. And I think the importance of having a genetic diagnosis is such that you either can, can give up, you can um screen for associated life threatening conditions. So some of these genetic muscle diseases have cardiac conduction deficits associated with it. And then we can actually give a patient prognostication information and then we can tell them about their risks for their, to their offspring or family. So I think a genetic diagnosis is important. Um I'll go through one, maybe two cases at the most. Um This is a kind of a complicated case, but it illustrates a important point. Um That kind of is relevant to when you see a patient with neuropathy in your clinic. So this is a, I believe I saw this patient in residency or fellowship. So um 63 year old gentleman uh was referred for weakness, but the weakness started as cold and numb feet. And then about 10 months later, he developed foot drop. And then a while later, he got hand numbness and weakness and then he had numbness around his mouth. And then six months later, he developed difficulty chewing, difficulty swallowing massive weight loss, and then some autonomic symptoms. So erectile dysfunction and then lightheadedness with standing. Originally, he was diagnosed with diabetic neuropathy and then he was diagnosed with C ID P and then he was diagnosed uh and then he was treated for C ID P with plasma exchange and predniSONE and Ivig and riTUXimab and none of that helped. And so he was ultimately kind of referred to us. Um His medical history is notable for an IgM Kappa monoclonal protein. He's also diabetic and his mother had sudden cardiac death. So, on examination, he was very, very weak, he was very, very atrophic and he was very, very a toxic from a sensory perspective. So he had lost, he had motor and sensory involvement. So we know immediately this is not a motor neuron disease or a muscle disorder or mycin gravis. We know this purple nerves are involved somehow. Um and he did an EMG and indeed he had an axonal wholly ridiculous neuropathy, which means the nerve roots are affected and the nerve nerves are affected. So this is not just a regular garden variety diabetic neuropathy. And at this time, at the institution, I was at uh we had autonomic testing available. And so we did an autonomic reflex screen and it showed orthostatic hypotension. So you can see here the blood pressure, supine starts at 150 systolic and then boom goes down and stays down at around like 70 systolic. Um and this white is the mean ocular pressure, but also, and there is no compensatory heart rate inc increment that we see the reg the rest of the autonomic reflex screen also was quite abnormal. Um This uh we do certain maneuvers in the autonomic lab that look at heart rate, variability with deep breathing suggestive of cardio vagal function that was very blunted. We look at blood pressure responses to the valsalva maneuvers. And what we see in this bottom left is this is a patient with impaired peripheral vascular resistance. So they venus pool and they don't bring their blood back to their heart. And then when the blood does get to their heart. There's no uh aggressive offshoot that happens. So her full vascular resistance is quite low. And then basically, the patient didn't sweat except for in their forearm. So their pseudo motor impairment was prominent. And because for us, anytime a patient comes in with peripheral neuropathy, weight loss and autonomic impairment, we always are concerned for amyloidosis. We did a nerve biopsy because when we do nerve biopsies, we only do nerve biopsies is for looking for something infiltrated or inflammatory in a muscle or nerve. So in the case of amyloidosis, we look for amyloid deposition in the nerve. We don't do nerve biopsies for regular neuropathies. If we don't think we're gonna see something deposited there. And indeed, we saw a lot of both demyelinating and axonal features on the teas nerve bo teeth nerve sample. And then in this blood vessels, we saw this proteas material which is uh exhibits apple green birefringence on polarized light and turns red on congo red staining. So this is amyloidosis. Now, this patient had an IgM Kappa monoclonal protein. And so it's very easy to think that this is a l amyloidosis or a primary systemic amyloidosis related to a hematologic malignancy. But he got mass spec done and this patient had TT R amyloid uh which is a hereditary version of amyloidosis. And at the time this was years ago that we didn't have um pettis and the drugs that we use for hereditary amyloidosis available so easily, they were still in drug trials. And so because he was so sick, he did not meet criteria for those trials. And unfortunately, he died. And so this case is very illustrative because it, he could have been identified earlier. Both the genetic version and the nongenetic primary systemic hematologic version of amyloidosis can be treated. And so it's important to recognize that all patients with a neuropathy, even anybody who presents with a neuropathy in your clinic should at least have a basic autonomic review of systems. And what does that entail? So, do they have symptoms of orthostatic hypotension? Do they need to sit down after prolonged standing? Do they become very exhausted as after they eat? Do they have early satiety? Do they have prominent constipation or diarrhea? Do they have nausea every time they eat? Um Do they have impairment and ability to urinate? Do they have unexplained erectile dysfunction at a young age, dry eye, dry mouth impairments and sweating, overheating and then importantly, have they lost uh energy and have they lost weight? If anyone who's tried to lose weight, knows how hard that is. So, if a patient is coming to you and telling you they lost 20 to 30 pounds without an obvious reason that should be investigated, particularly if they have neuropathy, not many neuropathies have autonomic failure. Amyloidosis is one severe, severe, severe diabetes is another B 12 and copper deficiency can cause severe autonomic impairment. And then there are some others which are a little bit more rare. Puria is always a fun one to diagnose, but it's pretty rare. Most patients with Emily, neuropathy will have a painful neuropathy. So painful neuropathy to us is a red flag. They will also have carpal tunnel syndrome. A lot of them because of amyloid deposition around the carpal tunnel. So now in our, in our uh center, we're sending off all carpal tunnel biopsies uh for for perineural tissue gets sent to. So, carpal tunnel releases, we get, we gather perineural tissue and it's sent for pathologic assessment to see if there's amyloid deposition. For similarly, they can kind of get amyloid deposition around the nerves in the lumbar spine and they can get spinal stenosis as well. So you can't test for every disease in every patient that you see. Right. So patterns are important. What is the pattern that a neuropathy patient is presenting with? And if it doesn't present with a norm uh with a typical pattern, then maybe you need to do additional testing. So anybody who presents with subacute course, so rapid onset of symptoms requires investigation. If they have constitutional or systemic symptoms, they require investigation. If they have weakness in their feet or hands, they require investigation. And this is a big one because I think a lot of times I I see that patients are diagnosed with diabetic neuropathy, for example, and they have foot drop and diabetic neuropathy should not cause foot drop. They may have a diabetic neuropathy, but if they have a foot drop as well, or if they have prominent weakness outside of just the toes, they should be worked out for other things. Whether that be spinal stenosis or genetic neuropathies or acquired neuropathies, et cetera, any painful neuropathy, particularly if they are not diabetic requires investigation. And as I mentioned, autonomic symptoms require further investigation. These are some patterns, we definitely don't have time to go over all of them. The most prominent one is a length dependent sensory motor neuropathy, but sometimes the neuropathy is oops, sorry. So, neuropathy is uh reflected only in the small fibers. Sometimes it's only in the motor nerves, sometimes the whole sensory ganglion is affected. So they're, they're, they're completely deerd from a sensory perspective. Sometimes the neuropathy will pick off individual nerves, we call that multiple mononeuropathy and sometimes it involves the nerve roots as well. A poly reticular neuropathy. So just a word on the the classic length dependent neuropathy classically, this is described as a stalking glove neuropathy. But it's important to write like you see in the bottom picture here. But it's important to remember that. In fact, if a patient comes to you and says I have numbness in my feet and my hands and the numbness in the feet and the hands started at the same time, that's actually a red flag because for example, if you take a classic diabetic patient. The diabetic patient develops numb feet and then actually years later, will develop numbness in their hands unless they have carpal tunnel or something. And if they have numbness in the hands and the feet, at the same time, we think of something that's systemic depositing in nerves or inflaming nerves, et cetera. We also wanna make sure they don't have spinal cord compression causing hand and feet numbness. So yes, it's a stocking glove, neuropathy, but the stocking must well precede the glove again. As I mentioned, weakness should prompt investigation of other causes. What I do in basically everybody with neuropathy, I check CBC C MP, hemoglobin A one CB 12 and methylmalonic acid, copper and zinc. Uh immunofixation, sppupptsh light chains and HIV. Um If the sppu pep is abnormal, then you refer the patient to us and we decide if that's relevant or not. Um We're happy to do that. If the patient has painful neuropathy, you want to add cryoglobulins, anca some inflammatory markers and then potentially some testing for alpha galactosidase. So, Febre febre disease, if this is patient is picking off individual nerves, so they have a foot drop here and a hand weakness here definitely refer them. But these patients need to be worked up hard for acquired disorders such as inflammatory disorders like vasculitis in deposition disorders like amyloidosis, um some hereditary disorders and some kind of vascular disorders there. The this is an entire talk in and of itself. But how to deal with the patient with a monoclonal protein. But essentially our algorithm is determining whether the patient has a monoclonal protein plus a neuropathy. Do they have an IgM or a non IgM? So Igaigg and a monoclonal protein. And then do they have any systemic signs or symptoms that would prompt investigation for amyloidosis or Waldenstrom or myeloma or poems? And um these are patients that I actually see a lot of, I see a lot of patients with hematologic malignancy associated neuropathies. And um it they can be very, very complicated. But I think it's just important to remember if a patient has a neuropathy and a monoclonal protein. It's very possible that it's an incidental finding because both are so common in the general population and this frequency increases with age. So not every patient with a monoclonal protein needs a neurology evaluation. But if a patient has a neuropathy, that's bad enough that they're falling or they're very, very attic or they're very, they have proprioceptive loss or they're weak or they have constitutional symptoms definitively, they need to see us. And I'm going to talk about one more case like we won't be able to get to the last one. But this is a, a brief one. A patient I also saw recently 37 year old female with progressive painless weakness following a COVID infection. She had difficulty swallowing and then kind of got better as her COVID recovered, but then she got COVID again and she got weak again, but she never really came back to her baseline. She noticed that some days were better than others. But every time she would get sick with COVID or something else, she would get clinically worse. And at one point, she just stopped getting better and she continued to progress because of her swallowing difficulty. She lost a ton of weight and she would experience double vision while watching TV. And the double vision would go away after covering an eye, anybody have any thoughts as to what this might be the long. So her emg studies were in keeping with myasthenia gravis. She had decrement and repetitive nerve stimulation and she was put on Mestinon pigmy and pig helped her a little bit but not completely, of course. Um And then she got acetylcholine receptor antibodies and they were negative and they were negative twice. And so the Mestinon was stopped and she continued to decline over the course of 12 months, progressively weaker. She lost 40 pounds and then she eventually saw us. So I walked into the room and we kind of knew what the diagnosis was right away because she had a very flaccid dysarthria. She was cic, she had ptosis, she couldn't move her eyes, she had fatigable weakness and a normal sensory examination. So this was for sure, myasthenia gravis. So it's the kind of key feature here is two fold. Number one is that a very small percentage of these patients may actually be sera negative. So they may not have acetylcholine receptor antibodies. Um even in a good lab with a good assay, um these patients may start as ocular and then the majority of the ones that do convert, convert within the first two years and they may or may not have a thymoma associated with it. Um The key features on clinical examination is fatigability. So they get better. They may be better in the morning when they're rested and worse at the end of the day, they may be worse after a physiologic stress like an infection. And in on examination, they have to have weakness. Uh in order to consider myasthenia gravis, we do not consider myasthenia gravis in patients with just fatigue. So the fatigue is not fatigue, it's fatigue ability. So the more you stress the muscles. So uh flexing, extending the arm, for example, repetitively will cause worsening, deltoid weakness, et cetera. Um We always do ac T chest to look for a thymoma. And if they have ptosis or abnormal eye movements, there's a very short list of neuromuscular diseases that cause that for example, A LS uh does not cause this. And so that will really give you a clue that this might be a a neuromuscular junction disorder. The main highlighting point from this slide is that Mestinon is not enough, you cannot treat myasthenia gravis just with Mestinon. We have to treat the disease, which is the immune autoimmune process. So, our goal is we use steroids to put the patient into remission. And then we start a steroid sparing agent to keep them in remission. And we usually treat them for about two years and then we are able to wean them off if they don't have multiple crises. Um Everybody with a thymoma needs their thymus out. But even if they don't have a thymoma, we recommend thymectomy in patients underneath the age of 60. But it's really important to remember that the thymectomy is not gonna work right away and it actually may not get the patient off the medications faster. It's not a treatment in and of itself, they still need to be medicated. I'm gonna skip this last case. Um And I just wanna, I just wanna leave a couple of minutes for questions. I just want to talk about our neuromuscular group. There is a whole bunch of us. We work at Parnas and Mission Bay. Um We deal with uh there's a robust A LS clinic, but then there's also a growing and robust uh non A L SS neuromuscular clinic that's spearheaded by myself and my colleague, Doctor Pakan De Paul, who um we both trained together and uh we see a lot of these patients as well as Doctor TGI Sova um and a, a newer faculty that's joining us. And so I encourage you all to refer to us because we, our wait list is much better than it used to be given our new faculty that I've joined. Um And we're always happy to see your patients with chronic comp uh chronic and complicated neuromuscular diseases. We are increasing our multidisciplinary care. So our multidisciplinary A LS clinics are now becoming multidisciplinary muscular dystrophy clinics. Um And so we are Muscular dystrophy Association and see these patients with physical therapy, occupational therapy, speech therapy, dietician RT, et cetera. And that's it. Any questions?
