Paraproteinemic Neuropathies With Dr. Benjamin Becker

Paraproteinemic neuropathies can present with a wide range of clinical phenotypes and may signal an underlying hematologic disorder. In this episode, Dr. Benjamin Becker discusses a practical phenotype-based approach to evaluating neuropathy in patients with paraproteins, highlighting key diagnostic clues, laboratory testing, and important disorders such as anti-MAG neuropathy, POEMS syndrome, and amyloid neuropathy. Learn how to distinguish incidental monoclonal gammopathies from clinically meaningful causes of neuropathy and when additional evaluation is warranted. In this episode, Gordon Smith, MD, FAAN, speaks with Benjamin E. Becker, MD, author of the article "Paraproteinemic Neuropathies" in the Continuum® October 2026 Peripheral Nerve and Motor Neuron Disorders issue. Dr. Smith is a Continuum® Audio interviewer and a professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia. Dr. Becker is an assistant professor in the Neuromuscular Division of the Department of Neurology at the University of Michigan in Ann Arbor, Michigan. Additional Resources Read the article: Paraproteinemic Neuropathies Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @GordonSmithMD Full episode transcript available here Dr. Smith: What set of disorders can cause ophthalmoplegia, rapidly progressive ataxia, autonomic failure, distal weakness, asymmetric severe pain? Turns out paraproteinemic neuropathies can cause all of these phenotypes and more. And if, like me, you see patients with peripheral neuropathy frequently, or if you see patients with any of these phenotypes, keep listening.   Dr. Jones: This is Doctor Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.   Dr. Smith: This is Doctor Gordon Smith. Today, I'm interviewing Doctor Ben Becker from the University of Michigan, Go Blue, about his article on paraproteinemic neuropathies with a co-author, Amro Stino, who's not able to join us today. This article appears in the October 2026 Continuum issue on peripheral nerve and motor neuron disorders. Ben, welcome to the podcast, and maybe you can begin by introducing yourself to our listeners.   Dr. Becker: Thanks for having me, Gordon. Yeah, my name's Ben Becker. I'm a neuromuscular neurologist here at University of Michigan with an interest on acquired neuropathies and paraproteinemic neuropathies as well.   Dr. Smith: Well, it's always great to talk to a fellow Wolverine. So, this topic, Ben, is one that's kind of near and dear to my heart, and it's also something that I think causes a lot of confusion for people. And I really liked your article because you and Amro created a framework that allows us to think through it in an organized fashion. You articulate this phenotypic type of approach. And I wonder, before we kind of dive into details, if you can maybe just describe the overall approach, this phenotype-based approach to thinking through paraproteinemic neuropathies.   Dr. Becker: Yeah, yeah. Excellent point. And, and I think that's kind of what drew my interest to this area, too, is as a trainee or now working with trainees, it was always kind of imposing seeing this monoclonal gammopathy come back abnormal. "Oh, what do I do with this?" And so, we feel like this has been hashed out very well in prior Continuum articles, mostly through the lens of what the SPEP shows or what the labs show. And we were really hoping to try to take a different novel lens of saying, "Hey, we can all send the lab, but what should make me concerned?" You know, the patient in front of you, I guess, is always the utmost concern. And so, what should I be looking there that makes this slightly abnormal or abnormal lab value have meaning?   Dr. Smith: Awesome. I want to talk more about phenotypes here in a moment, but I wonder if maybe we can begin with basics. And it doesn't get more basic here than what's a paraprotein?   Dr. Becker: Yeah, paraprotein are, I think a lot of people prefer the term monoclonal gammopathy. We prefer the paraprotein term in this article, but it's essentially you have too much of a particular kind of protein. It almost takes a good visualization if people have time to Google it, but, you know, your SPEP shows a quite broad-based area of enlargement in the gamma region, which is just all of your immunoglobulins. And when you have one plasma cell that proliferates abnormally, it's going to produce a particular immunoglobulin. And then when that particular immunoglobulin is in excess of your normally spread out ones, you'll get that spike.   Dr. Smith: And then how do we evaluate this from a laboratory perspective? You mentioned SPEP. I think this is one of the areas that people get really confused because you got the SPEP and then you've got fixation and a bunch of other things you can do. So, walk us through the, uh, approach. So, maybe we can take it from the perspective of we're screening a patient with a distal symmetric polyneuropathy for a monoclonal gammopathy. What do you send?   Dr. Becker: I will typically send a combination of 3 things, a serum protein electrophoresis, an immunofixation, and then serum free light chains. The serum protein electrophoresis is probably what's most well known. I think it was in the practice parameter that originally came out and is the original thing that I mentioned where it can pick up a spike of any particular protein, assuming it's above a certain level of 0.5 grams per deciliter. The immunofixation will subtype that particular spike. The SPEP just tells you that the spike's there or not there. The immunofixation will tell you, "Hey, this is an IgG spike, an IgA spike, an IgM spike." But it also has an increased sensitivity down to about 0.1 grams per deciliter. So, I think it not only increases your specificity or tells you the characteristics of it, but increases the sensitivity as well. And then there are some light chain paraproteins that we may or may not get into that might be missed because they're smaller, they might not produce as big of a spike. And so those are better picked up if you send a separate kappa and lambda light chain. And then particularly, we pay attention to the ratio. Most labs will tell you the individual components and the ratio.   Dr. Smith: Yeah. So, could you talk more about that? I think that's the test that many people don't send is the serum free light chains. How do you interpret that? It's a little confusing because you've got a range based on the ratio where it can be abnormally low or abnormally high. Words of wisdom in how to interpret that?   Dr. Becker: Yeah, absolutely. And, and I agree. I think when I mentioned at the top, almost universally, some component of this SPEP is flagged as abnormal, and the patient comments, you know, "Do I have cancer or malignancy?" And most commonly, I find that the kappa in particular is slightly elevated in, in a lot of people that we test, right, because they're often older and kappa light chains are often higher in, in people that are older. And so, I think the most important thing is the ratio abnormal. Certainly, you would want the both the ratio and that component. So, if the kappa lambda ratio is high, you'd also want the kappa to be high. If the kappa lambda ratio is low, you want the lambda to be high. And so, I do think an individual component without an abnormal ratio means much less to me.   Dr. Smith: I will say that our listeners should definitely check out the article for a whole bunch of different reasons, but the discussion of interpretation of the ratio is really good and helpful. I think it provides a nice way of thinking through these less important abnormalities and really allows you to determine what's clinically meaningful. How about a UPEP? When do you send a UPEP?   Dr. Becker: I will send a UPEP if I have a big concern for things that are found. The light chains can be found there, so a light chain paraproteinemia. Most often in my clinical setting, it's like, am I concerned for amyloid in particular? Because that can cause a lot of the light chain paraproteinemias. Or if they have known renal dysfunction, that'll tell us if these light chains are, or even the heavy chains are leaking out into the urine. Is that the driver of the renal dysfunction? And really, I don't find it practical to send on everyone, but I know a lot of people do, and I don't think it's wrong to.   Dr. Smith: Can you talk about the CRAB criteria? It's something that I think a lot of neurologists don't think about, but it's a cool way of remembering them. Actually, a great name. So, from here in Chesapeake Bay, yeah, what are those?   Dr. Becker: It's one of those acronyms I feel like we learned in medical school and still is applicable, which is helpful. And so, the, you know, everyone is somewhat aware of the C standing for hypercalcemia, R for renal dysfunction, A for anemia, and B for bony lesions. These are features that define multiple myeloma, one of the more common malignant forms of a paraproteinemic disease or monoclonal gammopathy. It's really a sign of end-stage dysfunction. We are obviously often looking at this in the context of, is the paraproteinemia causing neuropathy? This paraproteinemia can also cause electrolyte imbalance, hence the hypercalcemia. Those excess plasma cells can push out other hematopoietic cells, causing the anemias, and then also can those paraproteinemias can gunk up the kidneys, causing the renal dysfunction. That's not part of my routine workup. It might be where we're originally going with this. I'll usually do it once if I get an abnormal M spike. If I'm like, "Oh, maybe this is leaning towards multiple myeloma or at least a high-risk MGUS," then I'll send those labs. And luckily, they're pretty routine labs with the exception of the looking for bony lesions.   Dr. Smith: So, Ben, let me maybe put this within clinical context. So, let's say I'm evaluating a 70-year-old man who has a fairly generic distal symmetric polyneuropathy. No neuropathy red flags, no weakness, rapid progression, autonomic dysfunction, none of that stuff. And, uh, we find that he has a low-level, say, IgG monoclonal gammopathy. What's your next step in the evaluation? He's not anemic, normal renal function. What do you do next?   Dr. Becker: Yeah, I think that's a great question. What I'll often do is I might monitor that paraproteinemia a few times more, but realistically, in, in the setting of someone who I believe you said was in the age range of 70, a paraproteinemia is not uncommon. And in the setting of idiopathic neuropathies increasing in prevalence with age, too, an IgG is very unlikely to be related, luckily, to a distal symmetric polyneuropathy. I think this is an area that isn't as well researched, and so something that could expound on further. But with the current state, this is very likely incidental, and I get this question a lot where, "Well, what do I need to do?" And I'm often reassuring, "Well, we don't need to do anything."   Dr. Smith: Without any other red flags, would you do a bone survey, or do you ever send these folks to hematology? I see a lot of my colleagues, for instance, at the 1st sight of a monoclonal gammopathy will send off a heme, heme referral.   Dr. Becker: I won't, personally. I know we have great hematologists here, and I've always asked them, "Am I flooding you with consults?" And they're always very happy. So, having a good hematologist around for the better interpretation of that. What I'll often do is I'll probably monitor it once or 2 more times or recommend a primary care. But personally, I think this is very likely, you know, an MGUS currently. Could it evolve into something and need follow-up? Absolutely. But luckily, it's, it's not related to us, and I won't immediately send these tests.   Dr. Smith: Yeah, and I think the article provides a whole host of information about long-term outcome and prognosis that maybe we can come back to, but I'd like to maybe spend some time talking about phenotypes. Is that okay, Ben?   Dr. Becker: Yeah, yeah. That's what we're here for.   Dr. Smith: There are a lot of phenotypes, and your article does a really great job of taking specific phenotypic features and tying them together into kind of archetypal patterns, which is a really great approach. But I wonder if maybe we could do a bit of a mix and match game, so to speak, where I will give you a phenotype or a part of a phenotype, and then you can just give us a couple of sentences of wisdom for each vis-a-vis thinking through a paraproteinemic neuropathy when we see that particular phenotype in one of our patients. Does that sound okay?   Dr. Becker: Absolutely.   Dr. Smith: All right, cool. Let's start with distal weakness. So, let's say dorsiflexion and mild hand intrinsic weakness.   Dr. Becker: I'd be worried about with a distal predominant phenotype, something along the spectrum of a IgM monoclonal gammopathy or specifically an anti-MAG. Those are very distal. There is even this term that's often thrown around, DADS, that has been variably associated with Waldenstrom's or for CIDP. And so, I would certainly make sure we send the appropriate paraproteinemia looking for IgM. And then I might, instead of stepwise reflexing to MAG, I might send it more early on in the course.   Dr. Smith: Got it. How about prominent ataxia?   Dr. Becker: Yeah, so the ataxia could go along with that prior phenotype in the MAG, but also might raise your concern for this CANOMAD or CANOMAD-type syndrome, where there's these more exclusive antibodies, the disialosyl groups that we don't often send in people. We would probably send a little bit earlier. Also look out for more ocular bulbar symptoms that while we're focusing here on the feet, make sure we look up at the face and not miss anything with that.   Dr. Smith: So how about someone who has a, a rapidly progressing axonal neuropathy? Say they also have weakness involved with that.   Dr. Becker: Yeah, I think there are 2 phenotypes that that could really go into. Certainly, we often more think along the amyloid spectrum when we hear about the predominant axonal, uh, phenotype. And so, making sure that we send our light chains in this individual, look out for autonomic signs and symptoms that we might not always ask every single person, but this is certainly a group that we would not want to miss that for. But rapidly progressive weakness also makes me think of stuff that CIDP likes, such as POEMS.   Dr. Smith: How about patients who have a demyelinating pattern on their nerve conduction study?   Dr. Becker: Yeah, I think demyelinating always at the top of our head, we float to familiar things like CIDP, but there is a thought that everyone with CIDP should get a paraprotein evaluation just to make sure that they don't have these mimics, like what I'm going to get to in, in particularly POEMS is the prototypical CIDP mimic. A lot of these other ones, anti-MAG and CANOMAD, also are demyelinating. But when I hear demyelinating and paraproteinemia, I'm always saying, "Okay, let's make sure we're not mixing up POEMS for CIDP."   Dr. Smith: Maybe we can drill down and talk about a couple of the more commonly encountered specific situations. And you mentioned POEMS. Tell us more. What do our listeners need to know about when they should suspect POEMS?   Dr. Becker: POEMS is, as I said, I think very closely tied in its phenotype to CIDP. So, I don't think it would be wild to say you might encounter it in a patient suspected to have CIDP. You're not doing our lab workup like we had on this prior hypothetical case of just a typical DSP. But what really makes it stand out, obviously it might look like CIDP, but does not respond to IVIG. Otherwise, it's a osteosclerotic myeloma, so there's gonna be those myeloma-like features, bony lesions. It also has these endocrinopathies and, and other abnormal biomarkers like VEGF is the, is the very typical biomarker, as well as a thrombocytosis, which is very uncommon in other demyelinating neuropathies.   Dr. Smith: POEMS patients don't always have a gammopathy, right?   Dr. Becker: Mm-hmm.   Dr. Smith: So, when do you dig deeper and how do you dig deeper in a patient, let's say, who has received a diagnosis of CIDP and isn't responding to therapy? How do you dig into that more?   Dr. Becker: I was talking with my colleague here recently about a case very similar, you know. "Hey, the CIDP patient's just not responding," which a lot of people do respond to IVIG, luckily. And so, I do think truly at the sign of, uh, lack of response, I would start looking at, hey, do I need to think about this? Sending those biomarkers, like I said, checking their platelet count, sending their VEGF. I don't think it's unreasonable to look for these bony lesions and even those other organomegaly features such as the O in POEMS with either a full body PET CT can pick up both those things, which is fairly helpful. So really, I think about it early on when they're non-responding to IVIG. Other features that would make you think about it is the EMG not showing conduction block. Is it just straight demyelination, more uniform demyelination, I should say? Or so if the EMG shows that more uniform demyelination or is it more of a mixed demyelination and axonal kind of feature on the EMG, that certainly would make me, uh, kick that on the differential early, but often easier to find in hindsight.   Dr. Smith: You mentioned in the article papilledema, which I found can be kind of a helpful thing. And as a neuromuscular neurologist, we don't spend enough time looking in the eyes, perhaps.   Dr. Becker: Yeah, yeah, no, I think it's something that we could all use some refresher on checking more regularly in these patients. You know, it doesn't take much time, and, but it's, as you said, not my go-to when I see I have my CIDP patient there in my seat in front of me.   Dr. Smith: Yeah, but I mean, this is sort of one of the things you think about in, in CIDP patient not responding. How about MAG? Or you can pick another one, but that to me seems like the other commonly encountered situation in patients who have anti-MAG neuropathy. You talked a little bit about the phenotype during our mix and match game, but tell us more about the typical phenotype and diagnostic clues for anti-MAG neuropathy.   Dr. Becker: MAG is the big one that most articles on paraproteinemia neuropathy spend most of their time on, and that's because we have some modest treatment, but described because of an antibody towards myelin-associated glycoprotein, which is a protein right at the end of the myelin sheath where it meets the nodes of Ranvier. Has a very good pathomechanism and pathology that it can see these spreading out of these lamellae. What's interesting is while we have such a great patho mechanism, the phenotypes and treatments really haven't led to a lot of improvement in a lot of our patients, unfortunately. The, the phenotype is a very slowly progressive often. There can be rapid progression later in the course. And as we hinted at earlier, by progression, it's often very distal predominant sensory motor changes. And the hallmark and workup for it is if there is a lot of conduction slowing or demyelination features on the nerve conduction studies. Just in that distal portion. And so, what I've often seen is, oh, you know, you get a distal latency in your median nerve conduction velocity, whoop-de-doo, a lot of people have carpal tunnel, but you're seeing it in a lot of these median motor nerve, ulnar motor nerve, peroneal motor nerve. And then you-- that makes me think, oh, there's this TLI or terminal latency index equation that, that makes me bring that up and, and search for it a little bit more.   Dr. Smith: Now, rituximab is sort of the things, uh, folks go to fairly early. How helpful do you think rituximab is for anti-MAG neuropathy?   Dr. Becker: I think that's a great question and one that we're getting into a lot. It's well-documented that there's a proportion of people that do respond, and that number can range, you know, a 3rd to maybe half of patients. For me, that's a sizable enough portion of the population that I usually offer it, unless there are lots of contraindications. But I do think that there's probably something that we're missing, right? This, this means that that population of anti-MAG neuropathy, we need to figure out why, what makes a non- responder and what makes a responder. And that is the part that our field is currently looking into a little bit more. As you said, rituximab is the standard. There are some other things that have been kicked around, like concomitant chemo and rituximab or, or IVIG, but really rituxan. We have a few active clinical trials that I'm very interested in following once they get published that hopefully can clarify this picture of is there a way to distill out the phenotype that will respond to rituximab, or now there are even newer treatments that we're getting into that might work with or in lieu of rituximab.   Dr. Smith: I wonder if maybe we can wrap up by kind of dealer's choice. You know, there's obviously a whole bunch of different specific paraproteinemic neuropathies we haven't talked about in any length. What do you think the most important other thing that we haven't talked about our listeners should be aware of after our conversation today?   Dr. Becker: I'm a very practical person, and I really like probably what I see a lot of, and that's people that have multiple myeloma and get referred after they develop some kind of neuropathy. And so, focusing on that a little bit more, you know, I think our questions are often is, is this chemo-induced peripheral neuropathy or CIPN or, or from the multiple myeloma itself? It's interesting. Neuropathy from multiple myeloma is, is relatively rare. Certainly, less than half of people with multiple myeloma that are treatment-naive have clinical signs of neuropathy. Interesting. And then see, when you get into the electrical diagnostics, some of them might have subclinical neuropathy that they're not describing. But unfortunately, a lot of the treatments up until this point in multiple myeloma have been highly neurotoxic. The bortezomibs, the, the lenalidomide, while previously thought to not be super neurotoxic, newer literature points maybe more in that direction. And so, I think it's important to always rely on our basics. History, history, history will tell us the difference between if this is multiple myeloma-induced neuropathy or from the chemo itself. And similarly, with the other lymphoproliferative disorder related to that, Waldenstrom's macroglobulinemia, a large proportion have, much larger have neuropathy, but some of those chemotherapeutic agents, if it really started around the time that they started the chemo, very likely chemo.   Dr. Smith: Yeah, such a common problem. Thank you. What a great conversation. Really appreciate you joining me today, and congratulations to you and Amro on a really great article. I hope all of our listeners read it.   Dr. Becker: Thank you, and I appreciate everyone spending the time to listen. Have a great day.   Dr. Smith: Well, thanks, Ben. Again, today I've been interviewing Dr. Ben Becker about his article on paraproteinemic neuropathies, which he wrote with co-author Amro Stino. This article appears in the October 2026 Continuum issue on peripheral nerve and motor neuron disorders. Be sure to check out Continuum Audio episodes from this and other issues, and thanks to our listeners for joining us today.   Dr. Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

CIDP is a treatable immune-mediated neuropathy, but both delayed diagnosis and misdiagnosis are common and can have significant consequences. In this episode, Drs. Jeffrey Allen and Arjun Seth review the key clinical and electrodiagnostic features of CIDP, discuss common diagnostic pitfalls and mimics, and explain how updated diagnostic criteria can improve accuracy. They also highlight objective methods for monitoring treatment response and discuss emerging therapies that are expanding the treatment landscape for CIDP. In this episode, Kait Nevel, MD, FAAN, speaks with Jeffrey A. Allen, MD, and Arjun Seth, MD, authors of the article "Chronic Inflammatory Demyelinating Polyradiculoneuropathy" in the Continuum® October 2026 Peripheral Nerve and Motor Neuron Disorders issue. Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana. Dr. Allen is a professor of neurology in the Department of Neurology at the University of Minnesota in Minneapolis, Minnesota. Dr. Seth is an assistant professor of neurology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. Additional Resources Read the article: Chronic Inflammatory Demyelinating Polyradiculoneuropathy Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @IUneurodocmom Full episode transcript available here Dr. Nevel: What if nearly half the people diagnosed with a rare disabling neurological disease don't actually have it? Chronic inflammatory demyelinating polyradiculoneuropathy, CIDP, is one of the few neuropathies that can often be treated successfully, yet it remains difficult to diagnose. For some patients, a delayed diagnosis can mean irreversible nerve damage. For others, a misdiagnosis can lead to years of unhelpful and expensive treatments. Good understanding of updated diagnostic guidelines for CIDP has never been more important as newer therapies enter the field and the stakes grow higher.   Dr. Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.   Dr. Nevel: Today, I'm interviewing Doctors Jeff Allen and Arjun Seth about their article on chronic inflammatory demyelinating polyradiculoneuropathy. This article appears in the October 2026 Continuum issue on peripheral nerve and motor neuron disorders. Jeff and Arjun, welcome to the podcast, and please introduce yourselves to the audience.   Dr. Allen: Hi, Kate. Thanks so much for having us. I'm Jeff Allen. I'm a neurologist, Professor of Neurology at the University of Minnesota. Do a lot of work in CIDP and really interested in trying to find better ways to diagnose and treat that condition.   Dr. Seth: And hi, I'm Arjun. I'm a neurologist and neuromuscular specialist at Northwestern University, and I'm Assistant Professor here. I also help run our neuromuscular fellowship program. I also have an interest in CIDP and working with Jeff and others to help really diagnose and treat this condition.   Dr. Nevel: Wonderful. Well, thank you so much again for being here, and really looking forward to talking to you both about your article. I always like to start by asking, what do you think is the most important takeaway for the practicing neurologist?   Dr. Allen: I'll kick off with that one. Yeah, I think CIDP can be a challenging diagnosis to make. We know it's tough because there's no diagnostic test. It's rare and heterogeneous. So really being confident about the diagnosis, I think is really, really important. The guidelines published in 2021 can really be helpful to integrate and put a lot of that information together. From a treatment side, we know things that work. We also know that the treatment landscape for CIDP is really, really evolving rapidly. Speaks to the importance of really understanding the diagnosis and making sure we're confident with the diagnosis.   Dr. Nevel: Great. Thanks for that. And I look forward to talking more about some of those points that you made. Why is delayed diagnosis and misdiagnosis of CIDP so common?   Dr. Seth: So, I think there's a lot of reasons that the diagnosis of CIDP is delayed. I think, one, it's hard sometimes for primary care providers and neurologists to recognize the clinical syndrome, specifically if it's a progressive neuropathy worsening over at least 8 weeks with proximal and distal weakness predominantly, and can take a long time actually to get electrodiagnostics for certain patients. So, I think that ends up leading to a lot of delayed diagnosis. The misdiagnosis of CIDP, I think, is also, uh, quite common. I think things are misinterpreted, perhaps. Electrodiagnostics with diabetic neuropathy, for instance, or something doesn't really quite fit and patients get started on treatments when, in fact, they have a different diagnosis altogether. Or they're diagnosed actually with, they have Charcot-Marie-Tooth disease, they get treated with IVIG, but they don't actually have CIDP and are treated for CIDP with IVIG, but have CMT.   Dr. Nevel: Right. And what are some of the risks to the patient with delayed diagnosis or misdiagnosis? What have you guys seen in the patients that maybe have come to you who have been misdiagnosed or have a big delay in diagnosis?   Dr. Allen: Yeah, we know that this is on both sides of the coin, where delayed diagnosis is a problem, misdiagnosis is a problem. From the delayed diagnosis standpoint, we know time from symptom onset to diagnosis often takes a year or more in most patients. And all that time, patients are progressing, they're developing more axonal degeneration, axonal loss. So, you delay the diagnosis, you delay the initiation of treatment, which is a potential opportunity or missed opportunity to intervene in a meaningful way, and patients develop irreversible deficits that maybe aren't going to come back no matter what we do with treatment. On the overdiagnosis question, yeah, we know that can be challenging, too, in part because it exposes patients to treatments that they probably don't need, and that has certain costs and risks associated with it. It also misses an opportunity to maybe treat what's actually causing their problems. Has a lot of emotional, psychological, and health downsides that we want to avoid if possible.   Dr. Nevel: Great. Thanks for that. And so, kind of getting into how we make this diagnosis, then. How do we make it as accurately as possible in light of, as you mentioned, there's no, like, blood test or specific marker that gives us a yes-no answer in terms of, does this person have CIDP? Can you talk a little bit about the clinical features specifically that are expected or in the guidelines, maybe required even, and what features are common or thing, kind of ancillary symptoms that people have that maybe don't fall into that category if they have to have them, or that's something that you really expect in everyone?   Dr. Seth: Yeah, I can take that. So, I think, uh, we think of CIDP as, like, two different sort of types, so typical and then variants of CIDP. The typical sort of, uh, symptoms is really progressive, relapsing, remitting symptoms or progressive symptoms of proximal and distal weakness with sensory involvement affecting an arm or leg or two limbs in general. You can have different variants of CIDP where it can be just distal, sort of involving just distal sensory loss as well as distal lower extremity weakness in a multifocal, sort of an asymmetric pattern, focal really involving one arm, one leg, or motor predominant variants with just weakness or sensory variants. But really, the clinical syndrome is really progressive symptoms over at least 8 weeks with strong electrodiagnostic criteria, electrodiagnostics that help support that diagnosis. So, you need those 2 big features, and then it's really trying to put them in a bucket. Is it a typical CIDP or a variant of CIDP and what type? And then you decide on treatments based on that.   Dr. Nevel: Great, thank you. What are some other symptoms that are pretty common in people with CIDP?   Dr. Allen: It can be a couple of different things. The disease is really defined by weakness and numbness, as Arjun highlighted. Those are really defining symptoms, and they can differ on which of those is more predominant or which part of the body is affected, but those are really the key features that define the disease. Which not to say other things can't happen. Tremor happens in some patients. We see that quite frequently. Pain and fatigue can happen being part of this disorder, yeah, but they're usually not front and center. It's usually weakness and numbness, and pain and fatigue are usually less of a problem. And certainly, balance is affected in a lot of patients with the disease, and hand function and fine finger tasks. It's rare that cranial nerves get affected, but on occasion, we can see it, especially a 7. Respiratory almost never gets affected. That'd be really uncommon for CIDP. Just not to say it can't happen, but it's quite unusual.   Dr. Nevel: Great. Thank you for that. What are some red flags that when you're seeing patients alert you that maybe this isn't CIDP? Maybe you're thinking about CIDP or it's in your differential diagnosis. What are some things that would lead you to consider an alternative diagnosis, either clinically or maybe on electrophysiologic testing?   Dr. Seth: I can start with the electrophysiologic testing piece first and then go to the other red flags. Physiologically, if you see uniform conduction velocity slowing, for instance, that would be pointing more toward a genetic neuropathy, perhaps, like CMT, Charcot-Marie-Tooth 1A, for instance. Or if you see very prolonged distal median motor latencies with very slowed conduction velocities, that could point toward something like anti-MAG neuropathy, for instance, or POEMS syndrome. If they have really rapidly progressive symptoms with a lot of pain, and it's really sensory-predominant symptoms alone with no weakness, you think of other things that could be driving it instead of just CIDP alone, though that can happen. It's just a little bit unusual for that to happen. Or the other systemic signs and features such as autoimmune conditions, other inflammatory conditions that could be associated with it.   Dr. Nevel: Great. Thanks for that. Can you share some of the tables from your article that I found very helpful? Tables 6-1 and 6-2 had some information on clinical features, and then 6-6, some guideline-driven definitions on CIDP and possible CIDP. And we're used to when there's this guideline-driven definition of a diagnosis having definite, probable, possible. Can you talk a little bit about why this is a little different? It's just CIDP versus possible CIDP.   Dr. Allen: Yeah, sure. I can start with your last question on why definite is dropped. Definite CIDP was dropped from those definitions because there is no single diagnostic test that says you for sure do or you do not have CIDP. So, to say something is definite CIDP is just a little bit fooling ourselves that we can land on a diagnosis with that degree of confidence. So that definite label went away, and now we just call it CIDP or possible CIDP. Before getting into those specific ones, maybe just a couple other red flags that always pique my interest a little bit. Whenever I see a disorder clinically that's really a pain or fatigue dominant disorder, that makes me a little concerned. The electrophysiology, whenever I see slowing that's under the guideline definition of slowing, especially with axonal degeneration, that's always a concern. Was it really secondary demyelination from axonal loss, or is it really true demyelination that's a problem? Slowing across compressible sites is an issue as well. Family history is a big red flag. You know, if there's a family history, be worried about that diagnosis of CIDP. On your lab testing, if you see a monoclonal gammopathy, dig a little deeper, especially if it's an IgM. And then the treatment response is another big red flag. We consider that patients that are suspected of having CIDP, if you improve after an immunotherapy, then that supports your diagnosis. And if that logic is true, then the opposite must also apply, where if you start a treatment, you do it at a dose and a frequency and a duration that makes sense, and there's no response, that probably suggests that maybe you don't have CIDP. It doesn't mean you don't, but it might suggest that maybe you should look a little bit deeper. So that's a big red flag for me. But going back to the CIDP or possible CIDP, those are kind of how the guidelines now label the diagnosis, so two different diagnostic categories. So, it was collapsed from 3 to 2 in part to make it a little bit more simple. Not to say that it's simple, but at least it's two categories instead of 3. Both of those categories require patients to meet one of the clinical definitions of CIDP that we talked about, either the typical definition or one of the accepted variants. So, you have to meet that clinical definition in order to get in the door. The next step is the electrophysiology, and the difference between CIDP and possible CIDP is essentially how strong your electrophysiologic data is. If you've got 2 nerves with a predefined demyelinating abnormality, then you go up into the CIDP category. If you only have one nerve with a predefined demyelinating abnormality, then you're possible CIDP. And all that supportive stuff that we talk about, spinal fluid imaging, response to treatment, nerve biopsy, if you have a couple of those that are abnormal, as we might expect in CIDP, then you can bump up from possible to CIDP. So, it's all about diagnostic confidence.   Dr. Nevel: Great. Thank you for that. That was really informative. Can you tell us more about the autoimmune nodopathies and when we should consider these in the differential? When should we consider sending antibody tests? Do you send these in every patient that you see who you suspect may have CIDP?   Dr. Allen: You know, it's been an exciting development in CIDP, just kind of recognized within the last 10 or so years, a couple of antibodies that really target that node of Ranvier or the paranodal structures, and those are neurofascin-155 and contactin-1. Caspr1 also is now recognized. Yeah, but those patients typically present with more ataxia, tremor early on, tend to be earlier in life, can have a lot of axonal damage early on, especially the contactins. We know that clinically they behave a little bit differently than typical CIDP or the variants. They progress a little differently. We know that the physiology is much different because we have a specific antibody in those disorders. We also know the treatment response is much different, where they tend not to respond as well to IVIG. So I don't check them in every patient, but certainly people with those clinical features, I'll check them early on because I know it's going to make a difference with my treatment approach. And in patients that maybe it's a little softer call, but they don't respond to IVIG, that's one of the things that I'll go back and look for. Really important to look for those.   Dr. Nevel: What are 2 immune-mediated demyelinating neuropathies that have a fair amount of clinical overlap but do not meet criteria or not included in the CIDP definition?   Dr. Allen: Maybe the 2 most controversial things that weren't included as part of the CIDP under that umbrella is number one, the nodopathies, and number 2, CISP. CISP is a little trickier in whether that's really a different disorder or not. You know, the Mayo Clinic has done some outstanding work actually biopsying those dorsal nerve roots, and it turns out that the pathology they see is much like what we see in CIDP. So, whether that disorder truly deserves its own label separate from CIDP is, I think, still not a fully told story. But certainly, the nodopathies, there's enough different about them that that's something different than what we typically think about as CIDP.   Dr. Nevel: Great. Does CISP respond to therapy similarly as kind of more typical CIDP?   Dr. Allen: Yeah, it seems to. It seems to respond to steroids and IVIG similar to CIDP. It's a little harder to measure because it is a pure sensory disorder. Diagnosis is really challenging because your nerve conductions, by definition, should be normal because it's all proximal to the dorsal root ganglion. But often you'll see high CSF protein, you'll see enhancement on MRIs. Nobody, or almost nobody outside of Mayo could biopsy those dorsal nerve roots, but if you did, you might see similar changes, and the treatment response should be similar. There's kind of this entity that also goes by CISP+ or sometimes referred to as distal or CISP-plus, where you have pathology of the dorsal root, but it sort of bleeds out beyond the dorsal root ganglion, and you can start to get some sensory involvement, which is probably an extension of that disease as well.   Dr. Nevel: So that segues into my next question, which is, how do you assess for response to treatment? What kind of things are you looking for? Do you have any objective measures that you can use to really determine if somebody's benefiting from the therapy that you're giving them or not?   Dr. Seth: We try to use objective measures in clinic, really, to assess different areas of whether it's causing impairment or disability. Essentially, one is grip strength, so using either Jamar grip strength or a vigorometer to actually measure grip strength improvement as an objective response to treatment over several months. We also use, like our MRC scale, so strength assessment. We use something else called the Inflammatory Neuropathy Cause and Treatment scale, which is a disability score to tell us how much it's impacting the arms and the legs. Those are objective measures. We don't really have a good biomarker as of right now to tell us how active a disease is. There are some that are being studied, such as neurofilament has been studied, paranodin has been studied, but we can't reliably use those right now to tell us if someone's active in their disease.   Dr. Allen: I really love testing grip strength in clinic. And so, the 2 big buckets that I like to look at for following patients with CIDP, one, how are you assessing disability, and 2, how are you assessing impairment? And impairment, it's usually strength impairment. For disability, the I-RODS Disability Scale, I think, is really helpful. It's in the public domain. You can use it. It's a 24-item questionnaire that was developed for folks with CIDP. It's actually patient-reported outcome measures, so what I'll often do is give it to patients either through the electronic record or in paper format while they're sitting in the waiting room or waiting for me to see them, so I have that information available for me. It takes essentially no time and no cost. For grip strength, it takes about 30 seconds to a minute to do that, and you get an immediately available quantifiable result. It's a good reflection of overall strength impairment or disability in patients with CIDP. So, it's great, and patients love to follow grip strength. I do those for every patient, every visit, follow up prospectively. It tells me something a little more objective about how they're doing disability-wise and how they're doing impairment-wise.   Dr. Nevel: So, thinking about treatment options for people with CIDP, how do you choose between steroids, IVIG, maybe PLEX, maybe some new treatment that I'd love to hear about a little bit, but which one works best?   Dr. Allen: The ones you mentioned, the big 3 that we've used historically for CIDP, IVIG, corticosteroids, and plasma exchange. We know they all work. There's, of course, no head-to-head data, so we don't know which one works better. I think all of the studies that looked at those show response rates for treatment-naive patients between 60 and 80%, maybe up to 90% in one recent IVIG study. But it always comes back in that range. I think which one you start with is one of practicalities, which one we can- Obtain quickly. Comorbidities, of course, play a role in selecting treatments. Putting a patient diabetes on chronic steroids is probably not a good idea. Plasma exchange has some logistical challenges to add to it. So often, IVIG is our go-to, in part because it avoids some of those side effects of some of the other treatments. We know it works, it's proven effective, it's not immunosuppressant, so it's got a really strong role for induction and early maintenance therapy for CIDP.   Dr. Nevel: What's new in treatment in CIDP over the last few years?   Dr. Seth: There have been a lot of new developments that have come out for CIDP. So Fc receptor antagonist, so specifically efgartigimod was studied in CIDP and showed fewer relapse, risk of relapse as compared to placebo. So that was approved actually in June 2024 for CIDP as the 1st new novel therapy. It's pretty easy, once-a-week injections, so it does work decently. I think there's been some concern about switching patients from, let's say, IVIG to that drug, perhaps with some reports of worsening disease status afterwards. So that's being studied and investigated actually in a trial right now. Other drugs that are in the pipeline are complement inhibitors. So, we know complement plays a role in CIDP, and so complement inhibition, specifically with C1 inhibitors and as well C2s are being studied right now.   Dr. Allen: Yeah, I think one of the exciting things in the field is, especially as we move into a landscape that's got more targeted therapies, is if we can take a person with a heterogeneous disease like CIDP and understand which of these options might be the best for an individual person. So right now, all of CIDP and variants we treat in a similar way, usually with immunoglobulin to start with, but we have a hard time understanding which patient might be a better fit for steroids versus immunoglobulin. Maybe we can tweak that a little bit, knowing that there's a small percentage of patients with the motor variant of CIDP that worsen with corticosteroids similar to what happens in MMN patients. So, we might stay away from steroids in that group, but otherwise we treat it very similarly. Now that we've got efgartigimod approved, an FcRn-targeted therapy, how can we better select patients that were good candidates for that and those that maybe aren't so good? I don't have an answer for that right now, but it's something to really keep an eye on and think about how targeted therapies might be applied in specific clinical scenarios to know where we've got a good match and maybe where a different treatment would be a better option.   Dr. Nevel: Patients are pretty savvy, and they see things online. So, what do you tell your patients who come in and they say, "I see efgartigimod, and I really want to be on it." How do you consider who's appropriate to maybe switch from their current therapy to efgartigimod, and what do you tell your patients?   Dr. Allen: Well, it's always a personalized discussion, where they're coming from, how they've done on their existing treatments, what's the risk and potential benefits. Sometimes we don't know those things, but we can make an assessment. There are certain advantages to efgartigimod from a logistical standpoint. It certainly is a lot easier for patients to get it. It's a subcutaneous injection, pre-filled syringe. You do it once a week. It takes about 60 seconds, which is a far lower treatment burden than IVIG or subcutaneous IG. As Arjun mentioned, there are probably a small group of patients that have a challenging time transitioning from IVIG to an FcRn antagonist. Maybe they are at risk for getting worse. I think that risk is small and uncommon, but it seems to be there. I think there's a couple of red flags for me to say when you should probably stay away from an FcRn and when maybe it's a good idea. And when it's a good idea, I think, is when you have somebody that has clear disease, clearly responding to a treatment like immunoglobulin, but really, really struggles with that treatment, either from a side effect standpoint or a feasibility standpoint. Getting a IV infusion that lasts 3 to 5 hours is just not a good long-term plan. I think those patients are really good candidates for something like efgartigimod or maybe other therapies. On the other hand, if you've got somebody that tolerates immunoglobulin well, they respond well, why switch them? There's probably not a good reason to switch them over to something that may well work, but their current treatment is working well already. I think the other thing to keep an eye on is that the FcRns do a great job at lowering IgG levels and presumably IgG autoantibodies, but they don't do anything to IgM, they don't do anything to IgA. So, if you've got somebody where you suspect maybe there is an IgM or IgA component, maybe you have a monoclonal gammopathy or maybe you've identified some other IgM antibody, ganglioside antibody, certainly those patients I would not switch over to an FcRn. Where it falls in the treatment-naive patient, I think, is something we have to think about more. It's a good option, it's proven effective, but in the absence of head-to-head data with IVIG, knowing which of those is the best is something we need to figure out.   Dr. Nevel: Great. That makes a lot of sense. Thank you both so much for chatting with me today. I really learned a lot and enjoyed hearing all things about CIDP and CIDP-related conditions. Again, today I've been interviewing Doctors Jeff Allen and Arjun Seth about their article on chronic inflammatory demyelinating polyradiculoneuropathy. This article appears in the October 2026 Continuum issue on peripheral nerve and motor neuron disorders. Be sure to check out Continuum Audio episodes from this and other issues. And as always, I urge our listeners to read the article. There's lots more really great information that we just didn't have time to get to today. And thank you to our listeners for joining today, and thank you, Arjun and Jeff, for sharing your expertise with me today.   Dr. Allen: Thank you.   Dr. Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audiocme. Thank you for listening to Continuum Audio.

Guillain-Barré syndrome is a neurologic emergency with a broad range of clinical presentations that can make diagnosis challenging. In this episode, Dr. Mamatha Pasnoor reviews the classic features of Guillain-Barré syndrome, highlights important clinical variants and diagnostic red flags, and discusses how to interpret cerebrospinal fluid findings in atypical cases. She also shares practical guidance on treatment decisions, including the management of treatment-related fluctuations and distinguishing Guillain-Barré syndrome from chronic inflammatory neuropathies. In this episode, Aaron L. Berkowitz, MD, PhD, FAAN, speaks with Mamatha Pasnoor, MD, FAAN, author of the article "Guillain-Barré Syndrome" in the Continuum® October 2026 Peripheral Nerve and Motor Neuron Disorders issue. Dr. Berkowitz is a Continuum® Audio interviewer and a professor of neurology in the Department of Neurology at the University of California, San Francisco, in San Francisco, California. Dr. Pasnoor is a professor of neurology, program director of the neurology residency, and associate program director of the neuromuscular fellowship at the University of Kansas Medical Center in Kansas City, Kansas. Additional Resources Read the article: Guillain-Barré Syndrome Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Full episode transcript available here Dr. Berkowitz: When we learned about Guillain-Barré in medical school, we learned the classic presentation of a post-infectious acute ascending paralysis with areflexia. But Guillain-Barré is a syndrome that can have a large number of clinical variants, and much of what we learn about the classic presentation and diagnostic findings also has a lot of variation in clinical practice. I'm very excited today to talk with Dr. Mamatha Pasnoor, an expert in Guillain-Barré syndrome, about some of the large spectrum of clinical findings, CSF findings, and some of the exciting updates in treatment of this condition.   Dr. Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.   Dr. Berkowitz: This is Dr. Aaron Berkowitz, and today I'm interviewing Dr. Mamatha Pasnoor about her article on Guillain-Barré syndrome. This article appears in the October 2026 Continuum issue on peripheral nerve and motor neuron disorders. Welcome to the podcast, Dr. Pasnoor, and would you please introduce yourself to our audience?   Dr. Pasnoor: Thank you, Dr. Berkowitz. I'm Mamatha Pasnoor. I'm from Kansas University. I'm a professor of neurology here, and I am the program director for neurology residency program and also the associate program director for neuromuscular diseases and fellowship. I'm also the medical advisor for GBS/CIDP Foundation International, and that's my area of interest in research and is autoimmune neuromuscular diseases, including CIDP and neuropathies and various other neuromuscular diseases, including myasthenia gravis.   Dr. Berkowitz: Fantastic. Well, I'm very excited to talk with you today. I really enjoyed reading your article. Lots of clinical pearls, very comprehensive and detailed review. I encourage our listeners to go ahead and look up your article and read it. We won't have time to even scratch the surface of all of the topics related to Guillain-Barré that you discussed in the article, but we will talk about some highlights and some things I certainly learned reading this. So, I imagine when many of us learned about Guillain-Barré in medical school or in residency, we learned the classic illness script of a post-infectious ascending paralysis and sensory symptoms with areflexia, albuminocytologic dissociation on CSF analysis, and usually demyelinating, but sometimes axonal features on nerve conduction studies. But as you review in the article, the clinical spectrum of this disease is really quite varied. The CSF can actually be normal or can show up pleocytosis. The nerve conduction studies can be normal, and the only more specific biomarker, the ganglioside antibodies, are only really associated with some variants, and even those are not always present. And in any case, you'll be waiting a long time for the results while the patient is in front of you with their acute illness. So today, I really want to focus our interview amongst the many topics you discuss in your excellent article on the spectrum of Guillain-Barré syndrome to make sure we know when should we be considering it, what's sort of atypical but fair game, what are some red flags that should lead us away from this diagnosis. So, let's begin with the clinical presentation. Could you talk to us a little bit about the classical presentation, the typical textbook presentation, and then some of the broad range of variants that can be seen under the umbrella of what we call Guillain-Barré syndrome?   Dr. Pasnoor: Yeah, that's a very good question. I think the 1st thing is all of us should recognize GBS because it is a neurological emergency, and usually the diagnosis is clinical. You really don't need any LP or spinal tap, MRI, or any of these to diagnose. It's mainly the progressive course is important of the patients. It should be a progressive less than 4 weeks, and if it's beyond 4 weeks, we are considering other conditions. It's symmetric weakness, and absent reflexes is one of the classic finding in this. And some of the patients may present with significant autonomic features, and some of them may present with respiratory problems. So that's very important for us to recognize early, you know, treat them early. So, this is the most common presentation of the GBS is progressive limb weakness, areflexia, and symptom progression less than 4 weeks. Some patients may have distal paresthesias. We talked about it. Numbness, as you mentioned. Ascending paralysis may start in the legs and goes up into the arms. Cranial nerve involvement may be seen, autonomic dysfunction and respiratory dysfunction may be seen in some of them. On the variants, basically this is the classic form, but the GBS, we need to identify the variants. The variants are like they can be paraparetic, that is like just involves the legs and arms distally, or they can involve the face, the pharyngeal-cervical-brachial variant. We see bifacial weakness of both the face and the limbs and paresthesias, pure sensory. These are all variants that we see. And other than that, we all remember from our earlier reading is, or learning is Miller Fisher variant and the variants associated that look like Miller Fisher, and we call them as Miller Fisher syndromes, which includes the typical and incomplete forms as well as Bickerstaff encephalitis into this category of the Miller Fisher variant syndrome.   Dr. Berkowitz: Thank you. Yeah, there's such a broad spectrum of variants. On the East Coast, when we see facial palsy, I trained and spent many years on the East Coast, in the summer, we always think about Lyme disease. And some cases even of bifacial palsy, we would think of Lyme disease. And some of those cases would turn out to be variant you mentioned bifacial weakness with acroparesthesias that on the East Coast might get mistaken for Lyme facial palsy with polyradiculitis. Any other variants that you've encountered or encountered in your reading and have your eye out for that are very atypical part of the spectrum?   Dr. Pasnoor: I think the motor GBS would be another, like, you have to keep that in mind. Because when we talk about classic GBS, we are talking about motor sensory, but then there can be a purely motor variant, and they can mimic many other conditions. I mean, especially you talked about, like, when they have facial involvement, you're thinking of, like, myasthenia gravis, you know, motor neuron disease. So, you need to think of these other conditions when you have a variant like motor GBS can be a variant that you're thinking of.   Dr. Berkowitz: Yeah. So pure motor, pure sensory, pure cranial nerves, pure ocular, and then struck reading your article and other articles I've read as I've encountered atypical cases that we ultimately thought were Guillain-Barre. Sometimes the patients keep their reflexes.   Dr. Pasnoor: The hyperreflexia in some cases of, AMAN, the motor variants, you do see some, and obviously in Bickerstaff's you have to remember that too. So, there could be some variants may come in with... Although we talk about this being areflexia, there sometimes can see hyperreflexia. Very rare. I wouldn't take that. That would be actually one of our red flags to say that this may not be GBS, because I know you brought this up earlier, which is very important for people to know, is there are some red flags that you think of when the GBS, when you're trying to see if this is GBS or some other condition is, like, if they have prominent bowel, bladder dysfunction at onset. I know these patients do have, people with GBS do have autonomic symptoms, but if you have a significant bladder, bowel involvement earlier on, or if they have fever, they have altered consciousness, these are red flags you have to think about. And obviously, if it's progressing beyond the 4 weeks, you think of other conditions. And the other thing is pleocytosis. We talked about LP. Although most of the patients, most of the people with GBS may not have high CSF protein in the 1st week,   Dr. Pasnoor: but majority of them convert to having high CSF protein in the 2nd week. About 90% may show that what we discuss about albuminocytologic dissociation. But if you look at it, pleocytosis, what is the cutoff of considering a pleocytosis? That's also important, I think. Some people, even up to 50 cells per cubic millimeter, we are thinking of still GBS, you know, so less than that. But if you're having more than that, think of other conditions rather than thinking of GBS.   Dr. Berkowitz: Fantastic. Yeah, there's a lot of great pearls there that I want to discuss with you. Yeah, we talked about the very broad spectrum and that Guillain-Barre can really be in the differential diagnosis for a lot of presentations, whether motor, sensory, multiple cranial neuropathies, ataxia, some combination of these features. And you started to get into another area I want to talk to you more about, which is some of the red flags. Let's talk a little bit about clinical. You mentioned prominent bowel or bladder. Again, it would be very, very atypical to have the sphincter involvement in Guillain-Barre, right? We said you could, just in the spirit of talking about the spectrum of variance, but if there was prominent bowel or bladder and setting up otherwise ascending, quote-unquote, "paralysis sensory loss", where would that point you to as far as diagnosis and workup?   Dr. Pasnoor: I would think more of a spinal cord lesion more than anything else. So always make sure that they do not have, like, transverse myelitis or, you know, other bowel. I think a spinal cord would be my 1st inclination to look at.   Dr. Berkowitz: Yeah, that's a great point. Yeah, I remember one of my mentors telling me about a case that looked a lot like Guillain-Barre and had areflexia, and it was actually an epidural abscess. And of course, with spinal shock, there's absent reflexes. So acute spinal cord versus acute polyneuropathy can be tricky to distinguish. You also mentioned something you discuss in the article that is the rate of progression. So you mentioned Guillain-Barre is usually going to nadir around 2 to 4 weeks, and you mentioned one red flag is if the disease keeps progressing beyond 4 weeks. What sorts of things enter into your differential diagnosis for something that begins looking clinically like Guillain-Barre syndrome, maybe even has CSF findings suggestive of Guillain- Barre, we'll talk more about CSF in a moment, but continues to progress beyond 4 weeks. What sorts of things do you think about there?   Dr. Pasnoor: Yeah, I mean, the 1st important thing is why do we even care about, like, you know, beyond 4 weeks? That's important for us because of the management varies with beyond 4 weeks in this condition. So, if you're thinking of GBS, but it looks like a demyelinating process, and if it is progressing beyond 4 weeks, then you're thinking coming into subacute form of this or even chronic, that is CIDP, that's again, the treatments vary with the CIDP versus GBS. And then also looking at treatment-related fluctuations, sometimes we see that, you know, they get better. The treatments again have worsening again. Or the other thing we are also looking at, could this be like an acute onset CIDP if they have more than 3 episodes within the 1st 8 weeks? You know, you're thinking of, again, acute onset CIDP. That's also important to be able to identify earlier on and diagnose them so that you can treat them in the right way.   Dr. Berkowitz: Perfect. We talked about bowel, bladder as a red flag in a patient otherwise presenting with symmetric, rapidly progressive sensory motor dysfunction. You mentioned the time course. In the beginning, we won't know when it's week one, week 2, week 3, but condition that continues to progress or fluctuate significantly beyond 4 weeks, start thinking more about CIDP spectrum, subacute inflammatory neuropathy type conditions. Any other clinical red flags before we talk about the CSF to alert our listeners to beyond bowel, bladder, and then the sort of progression beyond 4 weeks or fluctuation beyond 4 weeks?   Dr. Pasnoor: I think, uh, we talked, briefly about upper motor neuron signs. You know, that's definitely another red flag is if they have brisk reflexes. You know, again, there's a few variants that can have that, but if they have increased tone, brisk reflexes, like upper motor neuron signs, then you need to think of other conditions too, rather than GBS. Obviously, like central signs like, being uncoor-- or, uh, decreased level of consciousness, that would be another red flag for us.   Dr. Berkowitz: Perfect. And as you mentioned before, each of these red flags sort of has exceptions on the other side, right, that the Bickerstaff variant does have cephalopathy and can have upper motor neuron signs, but again, highly atypical, very rare syndrome, right? So, it, so it would push us away. Great. And you started to mention this a little bit earlier, but those are some important clinical red flags, and we should question the diagnosis of Guillain-Barre. What about CSF findings? You mentioned we could see up to 50 cells, but you might start to wonder if you have the right diagnosis here. You also mentioned the CSF can be normal, even though every board's question, right, it's gonna be GBS, the, there'll be albuminocytologic dissociation. Can you talk a little bit about CSF findings, what's acceptable and fair game, um, to still call it GBS, and what are things where you'd say it may still be, but we really need to look into other diagnoses, or things where you say, "No, no, no. This CSF is not compatible with a diagnosis of GBS."   Dr. Pasnoor: One is, like I mentioned earlier, if the CSF is drawn, like if we, if we get the CSF very early on, like within the first week, it can be normal. So normal does not, uh, rule out GBS in that case. That's why this, as we know, this is a supportive evidence. It's not a primary, uh, for diagnostic, for diagnosis of GBS. So, we need to make sure that with, if it is within one week, it may be normal. And if it is beyond that, usually majority of the patients, more than 90 percent may, uh, show the albuminocytologic dissociation, which we are talking about, like cells may be normal, but the protein is high. What is high protein, again, it varies also with age, so we have to remember that, you know, again, with age it may vary. And also, someone who has diabetes can-- you're looking for a higher protein compared to the normal, um, other patients who not, who are not diabetic. And the number of cells, they-- in, in previous studies, uh, we have seen even up to 50 cells per millimeter, which is, I think is pretty high. But, uh, you know, again, if, if it's more than 50, definitely you need to think of other conditions. But if it is up to that, then you look at the clinical scenario and, uh, like o-obviously, if the patient has fever, uh, you can still think about other conditions like, uh, other infectious conditions. But if it is more than 50 cells per cubic millimeter, uh, definitely think of non-GBS conditions.   Dr. Berkowitz: Yeah. So again, like the clinical picture, right, such a broad range, and you discussed this in your article, broad range of CSF findings from normal to somewhat cellular, right? Maybe you'd see 6, 7, less than 10 cells, and you'd say the clinical picture fits. It's still dissociation, right? The protein is high, the, the cells. But gee, 20, 30, 40, 50 cells, I would be pretty uncomfortable, right?   Dr. Pasnoor: I agree with you. I think, uh, once it gets above 10, I think I get a little uncomfortable with that. I definitely wanna, like, make sure there's no other cause for that. Although we, we say it's up to 50, but, you know, I would still look for other causes if it is beyond 10.   Dr. Berkowitz: Um, for completeness in our discussion here, what are some of the other things you would be looking for when you see what looks like Guillain-Barre syndrome? It appears to be peripheral, it's rapidly progressive, and yet you're surprised on the CSF to find 45, 46, up to 50 cells. What are the things that you want to evaluate for a rule out, um, when you see that red flag of high cell count?   Dr. Pasnoor: I would definitely look for any infiltrative or infective cause. Like, if it's an elderly patient, you're looking at could this be lymphoma or some kind of infiltrative, like, malignancy or an infectious process. Like, again, there is, uh, like West Nile virus, you know, that's another thing that we think of in, patients, with the motor presentation specifically, like may see West Nile virus. So, there's infective or infla- uh, inflamm-, I would be more worried about those conditions.   Dr. Berkowitz: That's very helpful. Okay, we've spent most of our interview talking about the clinical spectrum and CSF spectrum, and those were areas you focused on in your paper with lots of pearls that I thought would be helpful for our listeners to hear more about. In our final moments here, let's talk briefly about treatment. Again, there's a lot more on treatment in your article we won't have time to get to today. I think all our listeners are familiar, right, with the, the sort of mainstay of treatment being either IVIG or plasma exchange along with intensive supportive care. Given that this is a disease, as you mentioned, that can have respiratory complications, autonomic complications, and all the complications that can come along with a neuromuscular emergency and critical illness. One question that often comes up in practice, and I was so glad to see addressed in your paper, is what to do when the patient doesn't respond to treatment. You 1st point out the important clinical pearl that something I also like to teach our residents that when you give IVIG or plasma exchange, it's not like the patient gets better immediately, right? I think of it as you're sort of putting out the fire of inflammation, but the myelin still has to grow back. But there are some patients who even you wait a few weeks, they're really not getting better, or they seem to improve and they get worse, what are called treatment-related fluctuations. What does the literature tell us about how we should be treating these patients? Should a patient who doesn't improve get another round of IVIG or another round of plasma exchange, or a mix of IVIG and plasma exchange, or plasma exchange and IVIG? If they fluctuate, is that different than if they just don't get better? How do you approach these dilemmas after you've done the initial treatment and the patient is still not improving or continuing to kind of fluctuate in their clinical status?   Dr. Pasnoor: Yeah, that's a great question, actually. So, if you look at... I mean, these patients can be varied presentation. Some people may come in with, like, severe disease, and they may not improve right away with the treatments. And one of the things that I teach our residents is that we need to wait. You know, in some cases they do. Once we give the treatment and they are either plateaued or, like, stabilized, you know, we just, we have to wait and continue with the supportive treatment like physical therapy or multidisciplinary care. We do that. So, we do not routinely do, like, corticosteroids or 2nd course of IVIG. There's no benefit with 2nd course of IVIG, in the patients normally. And in fact, actually giving another IVIG, there's more risk than benefits, and you'll see that in the article. And, uh, sequential PLEX followed by, immediately by IVIG has also not been... This hasn't shown much difference. One of the things that we need to make sure when you have a patient who comes in with not responding to treatment or is continuing to progress is making sure that this is not CIDP. And again, when we talked about fluctuations, the treatment-related fluctuations are a little different from acute onset CIDP. So, identifying that is very important because, again, if it's CIDP, like acute onset CIDP, the treatment varies. There, we are thinking of corticosteroids and other treatments, whereas if you're thinking of, treatment-related fluctuations, again, we usually don't... I mean, in general, like for GBS, we, we are not treating another treatment. And whether you use IVIG or plasma exchange, both are equally effective treatment options for these patients.   Dr. Berkowitz: So, that's helpful. So, if the patient has not gotten better, there's been no fluctuation, obviously we need to wait. But if you've waited and it's still not getting better at all, and you're convinced you have the right diagnosis, really no evidence for retreatment or mixing and matching IVIG, plasma exchange. But for these patients who appear to be getting better after their nadir and then decline again, and as you mentioned, this could be suggestion of CIDP, but if it's just one or 2 fluctuations, not a lot of fluctuations over a more subacute time course, those are patients that I understand that you would consider retreatment. Yeah. Okay. Um, good. And there's a lot more discussion of this in the literature that backs it up, but I thought of the treatment topics, those were some of the ones that are most challenging in practice and the data on them relatively recent, right? The, the repeat treatment, I think, relatively recent in the past few years that paper was published on that. Yeah. I learned a lot from that, as I did from the rest of your article and from talking to you today. So again, today I've been interviewing Dr. Mamatha Pasnoor about her article on Guillain-Barre syndrome. The article appears in the October 2026 Continuum issue on peripheral nerve and motor neuron disorders. Be sure to check out Continuum Audio episodes from this and other issues, and thank you so much to our listeners for joining today.   Dr. Pasnoor: Thank you all for listening today.   Dr. Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audiocme. Thank you for listening to Continuum Audio.

Inflammatory and autoimmune axonal neuropathies can cause rapidly progressive weakness, sensory loss, and pain, but recognizing treatable cases can be challenging. In this episode, Dr. Qihua Fan discusses key clinical patterns, diagnostic strategies, and common mimics of inflammatory axonal neuropathies, emphasizing the importance of careful follow-up and realistic treatment goals. Learn how electrodiagnostic studies, biomarkers, pathology, and emerging imaging techniques can help guide diagnosis, monitor disease activity, and assess treatment response. In this episode, Teshamae Monteith, MD, FAAN, speaks with Qihua Fan, MD, author of the article "Inflammatory and Autoimmune Axonal Neuropathies" in the Continuum® October 2026 Peripheral Nerve and Motor Neuron Disorders issue. Dr. Monteith is the associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida. Dr. Fan is a neuromuscular specialist, neuromuscular medicine fellowship director, and director of the ALS Clinic at Virginia Commonwealth University in Richmond, Virginia. Additional Resources Read the article: Inflammatory and Autoimmune Axonal Neuropathies Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @headacheMD Full episode transcript available here Dr. Monteith: A patient presents with rapidly progressive weakness, sensory loss, and severe neuropathic pain. Is this an inflammatory neuropathy requiring urgent treatment, or a mimic that could lead to a misdiagnosis? Today, we'll discuss how to recognize inflammatory and autoimmune axonal neuropathies, navigate the diagnostic workup, and apply emerging advances in biomarkers, imaging, and treatment.   Dr. Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum. This exclusive Continuum audio interview is available only to you, our subscribers. After listening, you can get CME by going to continpub.com/audiocme. We hope you enjoy the interview.   Dr. Monteith: This is Dr. Teshamae Monteith. Today, I'm interviewing Dr. Qihua Fan about her article on inflammatory and autoimmune axonal neuropathies. This article appears in the October 2026 Continuum issue on peripheral nerve and motor neuron disorders. Welcome to our podcast. How are you?   Dr. Fan: Good. Thank you so much for having me.   Dr. Monteith: Please introduce yourself to our audience.   Dr. Fan: My name is Qihua Fan. I'm an Assistant Professor in Neuromuscular Medicine at Virginia Commonwealth University in Richmond, Virginia. It's nice to be here.   Dr. Monteith: And what got you interested in this field?   Dr. Fan: I was very lucky to meet a lot of brilliant thinkers along the way and a lot of really great role models. I was really blown away by how they're able to take a lot of different pieces of data. So, for example, meeting somebody in the emergency room and then doing their exam and doing their electrodiagnostics, then their pathology, and putting it all together and kind of seeing them from end-to-end care. They taught me how to think about things in a different way, and I've been hooked ever since.   Dr. Monteith: Cool. And so, what were the goals of your article?   Dr. Fan: The goals of this article was to try and pull out a couple of pearls in kind of approaching inflammatory axonal neuropathies. I think one of the trickiest things in axonal neuropathy management is we don't want to miss the treatable, reversible etiologies. But when we get it, it takes so much patience to not rush into judging whether or not we're successful, just because nerve recovery and axonal processes take such a long time. And so, we have to be used to kind of sitting there and waiting for 3 to 6 months to see if we're even on the right track. So, the biggest takeaway that I want folks to get out of this, is that stability is the goal in axonal inflammatory axonal neuropathies, and to be patient and to be creative about the modalities that we're using to see if our treatments are working.   Dr. Monteith: Why don't you help our listeners understand, as a group, how do you describe autoimmune axonal neuropathies?   Dr. Fan: So, a couple of principles in diagnosing and recognizing immune and inflammatory-mediated axonal neuropathies. One is that the tempo typically tends to be subacute. Number two, is you need to be able to recognize the typical patterns in which they'll present. So, the most common textbook one is the mononeuritis multiplex, subacute stepwise progression. That will coalesce over time into another pattern, asymmetric axonal polyneuropathy. A third pattern is sensory ataxia or sensory neuropathy or neuronopathy. And a fourth pattern is, it's a mouthful, it's radiculoplexus or plexus syndromes. So that will be similar to your diabetic amyotrophy. And then your exam electrodiagnostics should be working together to confirm that pattern. So, once you have that pattern recognized, then you're looking for labs, electrodiagnostics, pathology, and then treatment responsiveness to help support that hypothesis every step along the way.   Dr. Monteith: Why don't you tell us a little bit about some of the areas that you're most excited about in terms of latest developments in the field?   Dr. Fan: Yeah. So, I think a lot of us are seeing the role of neurofilament light chain entering into our practice, and I think this has been a huge game changer in the area of inflammatory axonal neuropathies in particular. I'll give an example. So, if we see a new vasculitic neuropathy, right, somebody who is dropping nerves left, right, and center, and you see a very precipitous decline, you want to do everything you can to try and stabilize that. But the most satisfying short-term thing that we can achieve in the past was just stability, so that they stop losing nerves, they stop progressing in terms of their weakness, stop progressing in terms of their sensory loss, but they still have a lot of pain, and it's very challenging to manage. But with the development and commercialization of neurofilament, we're able to kind of demonstrate a normalization in a very quantifiable way to say, "Hey, look, we were burning through nerve very quickly before, and now this is a data point that can help support our treatment decision to say, yes, we're on the right track."   Dr. Monteith: Great. Maybe you can speak a little bit more about the approach to the evaluation. I read in your article that two key areas is determining the subtype and then the extent of nerve injury.   Dr. Fan: Right. So, it's a little bit of pattern recognition, and we talk about four different common presentation patterns. The classic one that we get taught is the mononeuritis multiplex subacute stepwise progression. But a lot of times, once the inflammation has been there for long enough, we've picked off enough nerves that the pattern has coalesced into a more length-dependent pattern. Typically, there's a little bit of asymmetry, and so that's the second pattern, is an asymmetric sensory motor polyneuropathy. The third type is a sensory ataxia. Somebody's coming in, their balance is way off, they can't do fine motor tasks, but there's not much other cerebellar findings, but their sensory examination is shot. And then the fourth type is an LRPN. So, this is much more like your diabetic amyotrophy phenotype is, is one example, and a lot of times that will be monophasic. So those are kind of the four patterns that can commonly present as inflammatory axonal neuropathies.   Dr. Fan: Once you think that this might be inflammatory or axonal in etiology, you want to kind of gather data points and see if it's treatment responsive. And so, when you're thinking about autoimmune or inflammatory etiologies, you want to look for biomarkers, for example, pathology to say, "Yes, there are inflammatory infiltrates that are attacking the nerve." One of the most surprising and clinically important findings that I learned about this when I was a fellow, is that you can see inflammation on pathology in conditions that are not immune-mediated neuropathies. So, for example, even in diabetic neuropathy, you can find a dusting of perivascular inflammation on pathology, and that creates a very confusing interpretive picture because inflammation on biopsy doesn't automatically establish that this is an immune-driven problem or that immunotherapy will be helpful. So, the key takeaway is that the pathology alone is not enough. You still have to demonstrate that the disease is biologically active and that it's treatment responsive over time. So, you can confirm inflammatory neuropathy on pathology, but you need to show that you can alter the disease course, that it's treatment responsive, and you can't just go off of seeing inflammatory cells under a microscope.   Dr. Monteith: So how do you pivot away from that?   Dr. Fan: So that's why you have to build in multiple levels of confirmation. So, you have the pattern recognition to say, "Hey, I think this is, this might be an inflammatory neuropathy." Number two, I still look for the pathology for confirmation. I find it and then say, "Okay, if this is true inflammatory neuropathy, it should respond to treatment over time on exam, on biomarkers, on functional assessments, in the way that axonal neuropathy is expected to respond." So, you have to follow the exam over time, follow your biomarkers, and see if things are mapping out the way that you expect it to.   Dr. Monteith: Great. So, you gave some nice pearls in the article about ways to elicit temporal progression, and the extent of the disease. Can you talk a little bit about that so that someone who's in the ER at the bedside, we can get a bigger sense of the problem?   Dr. Fan: Sure. I think it's very helpful to kind of nail it down in two different ways. One is kind of starting from where we are and working our way backwards. So, if I'm seeing them in the emergency room, or if I'm seeing them in the clinic and they're coming in with a gait aid of some sort, right, they're coming in with a walker, they might not always have walked with a walker. So how long have you been needing to use a walker for? Were you using a cane before that? And so, that kind of gives you discrete moments in time to help build a case of, when did this walking problem start, for example. You can use the same concept for other aspects of their function. So, if they're not able to type or if they're not able to play the piano the way they used to, you know, how long has that been going on for? The limitation is that it doesn't distinguish very well between sensory deficits or motor deficits, but at least that gives you a timeline. The other thing I'll add for the exam is not only do we have to establish whether or not there's a deficit, but we also have to establish a very reproducible and reliable baseline so that as we're seeing them back in a couple of months, in a year, we have very reliable data to look back at and say, "Okay, is the exam worse? Is their nerve function worse, or are they stable, or are they even doing better and starting to recover?"   Dr. Monteith: And speaking of exam, what are some barriers to the evaluation, and what are some ways to mitigate those barriers?   Dr. Fan: I think the trickiest part, especially in neuropathies, is sensory exam is very, very difficult and very difficult to quantify. A couple of the ways that I've found to be helpful in being consistent and having a reproducible exam is trying to keep it as clear and dichotomous as possible. So, rather than asking somebody, "Does this feel as sharp on your toe as it does on your shin?" That can lead to patients not being able to describe what they're feeling very well. They're wanting to be helpful, and the way that they describe things will change over time, even if it's the same type of sensation. So, one way that I try to keep it as simple and clear as possible is, can you feel the difference between sharp versus dull? And we'll test with their eyes closed, the pointy side of a safety pin and say, "Can you tell, tell me if this is sharp or dull?" And if they can distinguish, then at least we have that to go off of. And same thing for vibration, right? If they have paresthesias and they can't tell me the difference between vibration or no vibration at the toes, that's something that is reproducible, demonstrable over time. It doesn't give the nuance that a lot of patients would like to give you in qualitative characteristics, but at least you have something very, very clear to go back on in 6 months or a year.   Dr. Monteith: And what are some mimics that we should consider when thinking about the differential diagnosis, or what are certain conditions that could lead to a misdiagnosis?   Dr. Fan: The differentials will depend on the presenting phenotype, and so that's why it's really important to figure out which pattern are you starting off with. So, for example, if it's a mononeuritis multiplex pattern, stepwise progression picking off individual nerves, you wanna make sure it's not something hereditary, right, like HNPP. If it's a rapidly progressive asymmetric sensorimotor neuropathy, again, you wanna make sure that it's not something hereditary, or atypical hereditary, like TTR or amyloid neuropathy. If it's a sensory ataxia, you can have metabolic or toxic etiologies like B6 toxicity or platinum exposure that can progress quite rapidly. And then for your LRPN syndromes, you wanna make sure that it's not something infiltrative like a hematoma or a tumor that's causing this picture. So, it really, really depends on the initial presenting phenotype, the pattern of presentation, and then you can kind of figure out your differentials from there.   Dr. Monteith: Can you remind us what some of the hallmarks are of the electrodiagnostic testing?   Dr. Fan: Yeah. So, the things that you're looking for are asymmetry from side to side. Electrodiagnostics should confirm that there is a sensory motor or sensory polyneuropathy. The red flags that you're looking for on EMG to say that this is not just a garden variety type of neuropathy, is that there is a very significant asymmetry from side to side. So, you want to increase the yield by testing the affected limbs and the affected parts of the body, and then compare to the other side and see, is there a marked asymmetry or not? I'll take an example of vasculitic neuropathy again. So, if you catch something that was recently, very recently affected and you do the exam too soon, the Wallerian degeneration hasn't had time to manifest yet on electrodiagnostics, and so it could show up as a pseudoconduction block. If you stimulate above the lesion and the lesion below, it looks like the signal's just not traveling well through that one segment. And so, then it's important to kind of put everything into context and look at your whole clinical picture and say, "Well, could this be a pseudoconduction block? Are things evolving the way I would expect a demyelinating neuropathy to do, or is this something that might be early axonal neuropathy and come back?" If you feel like my exam's not matching up, my data points aren't matching up, my lab values aren't matching up, am I missing something? And then come back and retest again to see if it's really axonal.   Dr. Monteith: Can you speak a little bit more about your approach to follow-up? You mentioned key points like stability, but also making sure that you've identified early anything that might possibly be reversible, but then also not repeating electrodiagnostics too early.   Dr. Fan: Yeah. So, I think in terms of seeing people for follow-up, at every step of the way, it's really important to ask yourself, am I sure about the diagnosis and am I sure about the treatment? If we are, and if the disease is progressing or responding the way that we expect it to, then that's great. Then our job as a neurologist is probably threefold. So one is to make sure that we get a really good quality exam to say, is this stable, better, or worse? Number two, is to look at the immunotherapy plan and say, well, one, is this going to be monophasic or chronic? So, do they need maintenance immunotherapy? And if they are on maintenance immunotherapy, do we need to change that in any way? So, have we been able to achieve pharmacologic remission? And then number three, is symptom management. So, a lot of these patients will have pretty significant pain, significant morbidity, disabilities that still need to be treated and supported even if their disease is in pharmacologic remission. And so that's important to address.   Dr. Monteith: What clinical pearls should we be thinking about when it comes to treatment?   Dr. Fan: For treatment, we'll take the example of vasculitic neuropathy. First and foremost, you want to make sure that the inflammation is still active and that it's not burned out. If it's active inflammation, then there are two main aspects that you want to think about. One is what does it take to address the active inflammation and make that stop? Unfortunately, a lot of our options for stopping active inflammation, for example, in vasculitic neuropathy, is corticosteroids, which comes with pretty significant side effect burden and not really a great option for long-term treatment. So, the second level that you want to think about, is this a disease that will require chronic maintenance immunotherapy? Is this monophasic or is this chronic? If it's going to be chronic and there's a risk of recurrence, then you want to start the patient on some sort of maintenance immunotherapy right away so that by the time you're tapering the corticosteroids, the maintenance immunotherapy has had time to kick in and take effect and take over. When you're prescribing and managing these immunomodulation transitions, it's very important for us to know how long does it take for the treatment to kick in, how long does it take to wear off, and once we know that, then that will guide how quickly can we taper corticosteroids and how quickly can we expect a steroid-sparing therapy to be able to take its place.   Dr. Monteith: And one thing you had also mentioned is the potential use of MRI or PET imaging for targeted therapy. Can you speak a little bit about that as well?   Dr. Fan: So, the use of these technologies like MR neurography and FDG-PET, they've existed for a long time, but this is an emerging role in inflammatory neuropathies, especially in diseases where inflammation can be very patchy and can be very hard to localize. So, having a modality in which we can really visually find areas of inflammation that's attacking the nerves can be very, very helpful in evaluating the state of disease and how they're affecting the nerves.   Dr. Monteith: Well, I think that sounds like a really exciting area.   Dr. Fan: Yes, I think so.   Dr. Monteith: Thank you very much for being on our podcast. I really enjoyed this conversation. I know I learned a lot as well as many of our listeners.   Dr. Fan: Thank you so much for having me. Pleasures all mine.   Dr. Monteith: Today, I've been interviewing Dr. Qihua Fan about her article on inflammatory and autoimmune axonal neuropathies. This article appears in the October 2026 Continuum issue on peripheral nerve and motor neuron disorders. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.   Dr. Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. We hope you've enjoyed this subscriber-exclusive interview. You can get CME by completing the evaluation at continpub.com/audiocme. Thank you for listening.

Diabetic neuropathy is more than a disorder of numbness and pain in the feet. In this episode, Dr. Vera Fridman discusses diabetic neuropathy as a complex, multisystem condition, highlighting the importance of recognizing autonomic involvement, identifying high-risk patients early, and addressing factors that influence progression. Learn practical strategies for screening, prevention, symptom management, and recognizing when symptoms may suggest an alternative diagnosis. In this episode, Kait Nevel, MD, speaks with Vera Fridman, MD, author of the article "Diabetic Neuropathies" in the Continuum® October 2026 Peripheral Nerve and Motor Neuron Disorders issue. Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana. Dr. Fridman is an Associate Professor of Neurology and Neuromuscular Medicine Fellowship Director at the University of Colorado in Aurora, Colorado. Additional Resources Read the article: Diabetic Neuropathies Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @IUneurodocmom Full episode transcript available here Dr. Nevel: Diabetic neuropathy affects millions of people, but in our neurology clinics, are we thinking about it too narrowly? In this clinic, Dr. Vera Fridman emphasizes that diabetic neuropathy is not simply a disease of the feet, revealing it instead as a complex neurologic syndrome with consequences that reach far beyond numbness and pain.   Dr. Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.   Dr. Nevel: Hello, this is Dr. Kate Nevel. Today, I'm interviewing Dr. Vera Fridman about her article on diabetic neuropathies. This article appears in the October 2026 Continuum issue on peripheral nerve and motor neuron disorders. Vera, welcome to the podcast, and please introduce yourself to the audience.   Dr. Fridman: Hello, it's great to be here. I'm Vera Fridman, and I'm located at the University of Colorado Medical Center. I'm a neuromuscular neurologist with focus on neuropathy clinically and in my research, and it's great to join you.   Dr. Nevel: Wonderful. Looking forward to talking to you about your article and learning more. So, I always like to start these interviews with the question, what is the most important takeaway from your article for the practicing neurologist?   Dr. Fridman: I think to me, in thinking about this article and writing it, the most important message and take-home is that we need to start thinking about diabetes-associated nerve injury as a complex disorder that's multisystemic. So rather than sort of just focusing on the peripheral nerve involvement we're used to seeing at the bedside, to really start taking that early clinical presentation of numbness or tingling as a warning sign, as a heralding sign of something that is widespread, complex, systemic, the way we might think about other multi-organ systemic disorders.   Dr. Nevel: Great. And that leads me into my next question, because you really do emphasize that throughout your article, all the different ways that this kind of more systemic diabetic nerve injury can impact a person and affect their morbidity and even their mortality. So, can you tell us a little bit more about this more widespread diabetic nerve injury beyond the kind of classic diabetic peripheral neuropathy that maybe we think of as neurologists?   Dr. Fridman: Yeah, I think the idea here is that we have nerves innervating a lot of different organs, and they are also not siloed. They're interfacing with other parts of our biology, vasculature, you know, the impact of inflammation. All of these things are converging, and they are complicated. And so clinically, when I think about diabetic neuropathy associated with systemic injury, I think about cardiac autonomic neuropathy, about gastrointestinal and urogenital neuropathies, and that these symptoms can be really diverse, and they can be nebulous. And so, in seeing someone who just says, "I have a little bit of numbness and tingling in my toes," I think the clinician has to sort of force themselves to imagine that there's all this asymptomatic disruption in the person's presentation that they have to dig for to understand better.   Dr. Nevel: What else should we be asking to kind of delve deeper to investigate or identify a more widespread diabetic nerve injury?   Dr. Fridman: When I think about what sort of trainees and early clinicians miss, like when I see histories come from people who haven't been thinking about diabetic neuropathy for a long time, it's usually the autonomic that's missing. Do you have lightheadedness? Have you noticed decreased or increased sweating? Do you get full easily with meals, what we call early satiety? Patients don't know that word. Do you have sexual dysfunction? That's an enormously important question because it can actually herald that there's more widespread neuropathy, more severe neuropathy, and that there's autonomic involvement or potentially vascular involvement. So those are the ones that I see missed. And then the others would be related to the risk of ulceration. What is your foot care approach? Have you had ulcers in the past? I think a lot of people don't realize that having had an ulcer, even if it happened some time ago and healed, is a major risk factor for recurrent ulceration. You're going to pay attention differently to that patient. And then the other question that doesn't necessarily relate to symptoms, but I think is hugely important to ask is, what are your barriers to caring for your diabetes and for yourself? What is getting in the way of those preventative measures, which are really the only really reliable preventative things we can do, right? Like, we don't have good treatments for this disease. So why can't you exercise? What are some of the reasons why you can't? Really in a non-judgmental, guilt-free way, because we know diabetes increases the barrier to these things substantially, and that patients are struggling just to get through their day. So, I think understanding those obstacles early in the therapeutic relationship is where you can make the most impact.   Dr. Nevel: Thanks for sharing that. Can you tell us a little bit more about cardiac autonomic neuropathy and why that's so important?   Dr. Fridman: Yeah, well, it's important because basically the largest driver of mortality and cardiac death in this population. And I think sometimes even with well-managed diabetes, we are sort of heartbroken to see patients who have gone on to have really terrible outcomes from cardiac autonomic involvement that we didn't necessarily know was there. The other reason it's so important is because it stays asymptomatic for a very long time. So, it's one of these sort of elephant in the room entities that if you don't ask about, you don't look for intentionally, you're just not gonna know, and the patient's not gonna know. They're gonna think they're lightheaded from their medication, which is a very reasonable postulation when someone's taking neuropathic pain medications and blood sugar is going up and down. But it may just be that there's autonomic disease underlying. The other reason it's important is because it's difficult to test for. So even if you have the awareness that you have to think about it and ask about it, it's not always clear to clinicians what they're supposed to do next if those symptoms are there or how to evaluate them. And so, I think for all those reasons, it's probably the most undetected complication, and it's hugely common, and in some cases preventable through aggressive management of disease. So, I think for all those reasons, it comes out as the one that we need to remind ourselves about.   Dr. Nevel: How do you evaluate for cardiac autonomic neuropathy in your clinic?   Dr. Fridman: That's a great question. I think I start really with the questions that will be included in this article of kind of these detailed questions about symptoms that they may not know come together as indicating autonomic disease. Then at the bedside, I do a quick heart rate screen to see if they have resting tachycardia. Unfortunately, resting tachycardia is a late manifestation of cardiac autonomic neuropathy, so once you see it, it's probably too late. The next thing is to just perform orthostatic vital signs in the clinic and trying to get in the habit of having the patient lying and sitting and standing and taking the time. And in a busy clinic, that's actually quite a big ask. But if you can get a medical assistant trained and ready to do it on most patients, that I think is really important. If I'm concerned about it, then an EKG, which obviously wouldn't necessarily happen in the same visit, can help look for heart rate variability. And then the next layer is really talking to their primary care about a cardiology referral, because at that point, I think neurologists need help. And that's the other, I think, salient message from my thinking about this field is that this is not something that one practitioner can take on alone, and there has to be a really strong multidisciplinary network, just like we would do for our other complex disorders.   Dr. Nevel: Yeah. Do you see in the future there being more multidisciplinary engagement between neurology and cardiology for these patients if this is such a difficult to diagnose problem, but big cause of mortality in these patients?   Dr. Fridman: I think that's already happening, but maybe not enough and not in a more algorithmic way. It's happening also through our other diseases that we treat, right? So, we have the emergence of sort of modifying therapies for amyloid, and so that has led to these really close collaborations. I think most neuromuscular clinics now have cardiology that they can contact. And so really broadening that to diabetic neuropathy and creating those pathways for patients early. You have to be a little sensitive that these patients see a lot of doctors, and so, make it as easy as possible. I think that's the key, and getting everyone in one clinic is, of course, financially and sort of logistically very difficult. But having a close relationship to say, "Hey, I saw this patient and noticed this or that on, you know, at the bedside. What would you do next?" I think those relationships are really critical.   Dr. Nevel: Yeah. So, kind of moving on into your article, this is kind of a hypothetical situation, but if you could evaluate or only perform one part of your physical exam in a patient with diabetes, what would it be and why?   Dr. Fridman: Yeah, I mean, I think looking at their feet and then looking at the sensation at the distal toe, probably with pinprick and light touch, if you had to do one thing. If you have bandwidth to also check vibratory perception, that would be helpful. But I think early on, we know that those small fiber involving neuropathies are more common. And what that tells you in a patient who maybe doesn't even have diabetes, I mean, I think that's another important thing to stress. They may be glucose intolerant and just have a slightly elevated hemoglobin A1c, but we all know that if you look carefully at those patients, a lot of them will have some subtle sensory loss at the toe already. And that's really the patient you want to treat. I mean, that's when you want to intervene. And so, the guidelines currently say to screen at time of diabetes diagnosis, but that's actually probably late. And this isn't discussed in the article because we're sticking to the current day guidelines, but I'm imagining those will be revised as we understand more and more that it's the preempting of the neuropathy that we want to focus on. So, the exam findings of ankle reflexes, for example, that I think a lot of people do sort of semi-automatically in a patient looking for neuropathy, you can have preserved ankle reflexes for quite some time and have important diabetic neuropathy manifestations and cardiac autonomic neuropathy already. And then the foot exam, I think we somehow have to convince ourselves that really small foot deformities like a hammer toe or a bunion or something that maybe in a non-diabetic patient would never be a big deal is a huge deal because that could be a lost limb. And again, it takes that extra intentionality to think about that, right? But that's when you say, "I really want you to get attention from a podiatrist." And, you know, thinking about things where we can have impact, that sensory loss or loss of protective sensation, those subtle foot deformities, that's the beginning.   Dr. Nevel: Yeah. And on that note, you know, early recognition, you emphasize is important so that we can take these preventative measures. What things can our patients do to reduce their risk of progression of their diabetic nerve injury?   Dr. Fridman: That's a really complex question, actually. So, what we say kind of formally and based on current knowledge is that they can control their diabetes, and they can control their metabolic risk factors. So, we understand more and more about the contribution of obesity, truncal obesity, metabolic syndrome, hypertriglyceridemia, right? These things that maybe weren't as much emphasized in the past because we were very glycemia-focused. So that's changing, and I think most internal medicine doctors understand that better, and as do neurologists. So, we tell them these things, right? But what we maybe forget to tell them is that in type 2 diabetes, that doesn't necessarily ensure the lack of progression of neuropathy, that they may be doing a wonderful job with their diabetic control and working really hard and still be stuck with a lot of neuropathic pain and progression in the sensory loss. And that's just, that's just a fact, right? And I think it actually is important to communicate that upfront to patients so that they don't blame themselves when things are not going well. The other study-proven research-based intervention is exercise. This is, I think, essential to discuss with every patient with diabetes at every appointment. So, as I'm asking questions, one of my questions will always be, "What do you do for exercise? How often do you exercise? What are the barriers to exercise?" We know that exercise can, in smaller studies, show reinnervation of nerve fiber density. We know that there's reductions in neuropathic pain, that people feel better. Energy is a huge problem in diabetes in general. And so, the hurdle to exercising in type 2 diabetes and type one diabetes is high. And so, our job is to facilitate that they do the minimal amount that will be helpful to them that they can tolerate and then slowly build that up. And there's a recent publication looking at physical activity in patients with diabetes that shows that it's actually just under 10 minutes a day of intense exercise that can make an impact. So, if you think about that, even for people who are having a lot of difficulty starting exercise, five to seven minutes a day is a pretty low bar, and then you work from there. So, I think that's important for us to know, right, that that actually can impact in small amounts.   Dr. Nevel: Yeah, that's really helpful, and I imagine as a patient would feel a lot more achievable for somebody maybe who hasn't been engaging in physical exercise to hear from their doctor, "I'm just asking you to try five minutes a day or something like that." 30 minutes or 20 minutes each time that has been kind of previously, I think, the metric.   Dr. Fridman: Yeah. Agreed.   Dr. Nevel: What are some red flags that should alert the clinician that diabetic peripheral neuropathy may not be the culprit of the patient's symptoms?   Dr. Fridman: Always with neuropathies, we think about are they sensory, are they motor, are they symmetric, asymmetric? The classic teaching is that it's gonna be a sensory predominant length-dependent neuropathy that you see with diabetes or other idiopathic sort of slowly progressive nerve disorders. When that is not the case, so when there is initial symptom presentation in the hands, when there is marked asymmetry, and when there's early weakness or early substantial autonomic symptoms like presyncope that comes early in disease, those are all sort of red flags for other etiologies. And because we're in an era where there are some treatable conditions that can mimic slowly progressive sensory loss, such as TTR amyloid, right, I think you have to cast a broader net with patients. Comorbidities, I mean, in patients who have other medical issues, you have to be a little bit careful. I also think there's a tendency to say, "Oh, they have diabetes, and therefore they have a diabetic neuropathy." We see this all the time. But really, if their progression has been subacute and more aggressive than we'd expect in, like, 3 months of sudden onset symptoms, that's not diabetic neuropathy. So just being careful to really ask those questions about timing, progression, symmetry, length dependency, and autonomic symptoms.   Dr. Nevel: Yeah. Well, pain is not necessarily universal for patients with diabetic peripheral neuropathy. Obviously, as your article points out, many do experience pain. What do we know? You mentioned spontaneous remission of pain among some patients with diabetic peripheral neuropathy, and how should this knowledge inform our medication management? How do you approach this in your clinic in patients who are on neuropathic medicine who have good control? At what point might you consider tapering them off their medications, or how do you go about that?   Dr. Fridman: Yeah, no, that's very important. I'm glad you're highlighting that. There's a few scenarios, and like everything with diabetes and diabetic neuropathy, it's like heterogeneous and it's different for different people. So, some people progress, their neuropathy gets worse, but their pain gets better. I think patients have this kind of perception of, their nerves are dead, like they don't feel anything, and that actually may not be inaccurate, but there's at some point that nociceptive response changes in conjunction with the progression of sensory nerve loss. The other possibility is their neuropathy improves, right? So, they exercise, they get really vigilant with their diabetes, they're really on top of it, and then they're in that lucky category of people for whom there's actual reversal. And there's a paper, a natural history five year study of diabetic neuropathy showing that a small percentage of patients legitimately improve on nerve fiber density testing and electrophysiology. So that's another possibility. How does it guide my treatment? So I hate medications. I find them onerous. I find the side effects really difficult for my patients. And they hate medications. A lot of my patients don't wanna be on these medications. So, I make it a rule to ask at every visit what they're on, what they think it's helping with, what the side effects are. I really work through each drug. Like, is it doing anything? What do you think it's doing? And you'll be surprised when you ask that question. People think they're taking medicines for completely arbitrary indications. They say, "It really helps my back pain." You had no idea you were prescribing their Neurontin, you know, for their back pain. And I'm not arguing it's a bad thing necessarily, but you wanna know. Or they'll say, "I think my numbness got a little better." Or other patients will say, "This medicine doesn't work. It's not helping my numbness." Right? And this is where there's this huge education component of, like, I'm prescribing this medicine for these specific symptoms. I want you to keep track of whether they improve, not these other symptoms, right? Because you wanna know if you're targeting the right symptomatology. If you're not, then I take them off. If they're feeling better at every visit, if we're achieving control that is adequate for the patient, they're happy where they are, I start a discussion about reducing. And reducing slowly and then bumping back up. As much as I hate medications, I also think it's, on balance, much more important to control pain than to have people living with it because it disrupts sleep, quality of life, it causes mood disorders. And, you know, I think on balance, it's worse for their health to not treat them. So, I tell them that. But if we have room to reduce carefully with monitoring, I think every patient, every visit.   Dr. Nevel: Thank you. You mentioned research earlier, and I know that's a big part of your career. What's going on in research in this area that you think is most exciting right now?   Dr. Fridman: Yeah, I think I could break it down to a few themes that I think are most exciting. So, one really exciting theme was shifting away from only hyperglycemia as the main area of research, focus of research. I think that that really broadened our understanding of the complexity of this problem in a way that allows for intervention. And there's great animal work looking at dyslipidemia, looking at obesity, looking at the interaction with exercise, all the things that go beyond. Another big theme is thinking about the interactions between axons and Schwann cells, and then also axons and Schwann cells and other cell types in the environment, right? So not thinking about the neuron as like a siloed organ that has this hyperglycemia that it has to manage, but how does, what is the cross-talk with the Schwann cell? What is the role of the Schwann cell in instigating and propelling the diabetic neuropathy biology? Then skin cells, immune cells, all of this sort of micro-environment, right, that we have to really take into account because it appears that these cells that are non-neuronal cells are playing a really important role. And again, I think that lends itself to different and exciting interventions that, that wouldn't have been thought of before. I also think about the study of pathways. So, thinking about pathways that lead to nerve degeneration in this disease and the variable pathways, right? There's, like, many that have been investigated. Some of them interact with each other. And thinking about pathways across different neuropathy types. What are the pathways that diabetic neuropathy might share with genetic neuropathies or chemotherapy-induced neuropathies? We have a good example of that with the SARM1 neurodegeneration pathways and how those might allow for cross-talk across different areas of neuropathy research. So, I think that's all really important. And then the last piece is we're starting in every disease that's common, and though thus far not fully resolved, we're starting to understand the contribution of genetics. If you have a disease where half of the people develop a complication, neuropathy in this case, right, and half don't, it definitely invites the possibility that there may be a genetic contribution. And if we can resolve that, that also gets into more personalized approaches for patients and their risk.   Dr. Nevel: Thank you so much for talking with me today. I really enjoyed learning from you, and I really enjoyed your article. So again, I'm gonna encourage all of the listeners, as always, to please read Dr. Fridman's excellent article on diabetic neuropathies in the latest issue of Continuum.   Dr. Fridman: Thank you for having me, and I will leave off by telling all the younger clinicians and trainees to please not just read the article, but come join.   Dr. Nevel: Absolutely. Wonderful. So again, today I've been interviewing Dr. Vera Fridman about her article on diabetic neuropathies. This article appears in the October 2026 Continuum issue on peripheral nerve and motor neuron disorders. As always, please be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining us today.   Dr. Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audiocme. Thank you for listening to Continuum Audio.  

Neuropathy can present in many ways beyond the classic pattern of numbness and tingling. In this episode, Dr. Reza Seyedsadjadi discusses a practical diagnostic approach, highlighting key clinical clues, electrodiagnostic findings, and the role of genetic testing and other specialized studies in identifying common and uncommon causes of neuropathy. In this episode, Casey S. Albin, MD, FAAN, speaks with Reza Sadjadi, MD, author of the article "The Diagnostic Approach to Neuropathy" in the Continuum® October 2026 Peripheral Nerve and Motor Neuron Disorders issue. Dr. Albin is a Continuum® Audio interviewer, associate editor of media engagement, and an assistant professor of neurology and neurosurgery at Emory University School of Medicine in Atlanta, Georgia. Dr. Sadjadi is an assistant professor of neurology at Harvard Medical School and Massachusetts General Hospital in Boston, Massachusetts. Additional Resources Read the article: The Diagnostic Approach to Neuropathy Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @caseyalbin Full episode transcript available here Dr. Albin: The patient comes into your office with numbness and tingling, and it seems like it's probably a pretty straightforward neuropathy. But what about if it's not? Or what if the EMG and nerve conduction studies suggest something else? What if the patient is giving you extra clues about other symptoms where they feel ataxic or have systemic complications as well? All of those things may be part of a neuropathic picture. And today, we are so fortunate to talk to Dr. Seyedsadjadi about just this.   Dr. Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.   Dr. Albin: Hi, all. This is Dr. Casey Albin. Today, I'm interviewing Dr. Reza Seyedsadjadi about his article on the diagnostic approach to neuropathy. This article appears in the October 2026 Continuum issue on peripheral nerve and motor neuron disorders. Welcome to the podcast. I'm so excited to have you here, Dr. Seyedsadjadi. Just love for you to tell us a little bit about yourself and your background and how you got interested in this topic.   Dr. Seyedsadjadi: Hi. Thank you for the kind invitation and the opportunity to contribute to the Continuum. I'm a neuromuscular neurologist. I work here at Mass General Hospital. I got interested in peripheral nerve disease throughout my early training in neurology and continued with the fellowship in neuromuscular disorders, and I've been seeing patients with mostly neuropathy, inherited and acquired neuropathies here in Mass General Hospital.   Dr. Albin: Excellent. And so, you are the perfect person to write this intro article. And so, I always like to start with the basics. The patient comes to you. What are some of the symptoms that you're listening for that help you clue in that this is probably a neuropathy, not somewhere else in the peripheral nerve system?   Dr. Seyedsadjadi: What an excellent question. And it is still difficult to 100% be sure, but overall, I like to put things in different buckets to help you have a pattern recognition with what you think that makes sense to be a neuropathy, a neuronopathy, a radiculopathy. In general, I divide things into positive and negative sensory symptoms in terms of complaints. Positive ones like hyperesthesia, paresthesia, burning, tingling sensation. Negative sensory symptoms are a little bit more tricky, loss of sensation, balance issues. When somebody comes, you have to listen to all of these symptoms in conjunction with the distribution of the symptoms, how they evolve over time, to give you a clue whether this is a neuropathy or just neuropathic symptom related to a different process that could mimic neuropathy. And sometimes it would be difficult to delineate between the two, especially if a patient is very complex, has two different processes going on. But first off, it's good to know if you have positive sensory symptoms, it is more likely that this is a peripheral process than negative sensory symptoms. And some other features that we usually overlook when we see the patient in the clinical setting, especially if it's busy, those are the autonomic complaints that we can talk more about.   Dr. Albin: Yes. And I really wanna double-click on a lot of these features that you brought up. So, I'm hearing you're thinking about not only the symptom quality, but also that pattern of distribution. What about that sort of localized pattern of distribution?   Dr. Seyedsadjadi: Yeah. So typically, the general teaching is that nerves are very long in terms of the course, and when the damage happens to the nerve, the pattern would be a length-dependent pattern, meaning the longest nerve or the tip of the longest nerve will be affected, and this will gradually affect and go more proximally in a symmetrical pattern in more common known types of neuropathy. That's not always true. Sometimes you can have a non-length dependent neuropathy. You can have like an asymmetric neuropathy. But these are all small clues that you can use to see, to help you to narrow your differential diagnosis. So, you can have like a vasculitic neuropathy, which is necessarily not a length-dependent process. It affects one side, not necessarily the other side, and the progression of it, which could be stepwise rather than gradual progression of the disease.   Dr. Albin: I love that. Thinking not only just about the typical numbness and tingling in your fingers and toes, but recognizing that while that is a very common pattern of neuropathic symptoms, that you may have a patchy distribution and that you can still put neuropathy on your differential, even if it's asymmetric and even if it's not starting at tips of the fingers and tips of the toes.   Dr. Seyedsadjadi: Exactly. Nicely summarized.   Dr. Albin: One of the points that I really took away from your article was how sensory symptoms or motor symptoms, whether there's a predominance of one or the other, that actually may have some real importance in helping you think through the underlying process. So, can you tell us a little bit more about that?   Dr. Seyedsadjadi: Exactly. And also, I don't want to confuse this with necessarily involvement of sensory nerves because you can also have positive sensory and negative sensory symptoms. But looking at the signs in terms of how patients present- If you have predominance of, like, motor weakness, you have a patient who comes with the distal upper and lower extremity weakness, but sensory symptoms more than signs, are relatively milder. Obviously, you think more about process that is more chronic, affecting motor nerves more than sensory nerves, or equally at least, you think about more hereditary cases. Whereas when you have more sensory symptoms or predominance of sensory symptoms and less of motor involvement and more recent presentation, you think about more acquired causes of neuropathy. Now, that is not universal because we know that there are acquired neuropathies that affect the motor nerves more than sensory nerves, and we have hereditary neuropathies that purely affect sensory nerves like CANVAS syndrome. But in general, it's good to have, like, a pattern recognition. Now you can more comfortably look for those outliers that would be like a framework that you can approach them by looking for subtle signs and differences that they have from them.   Dr. Albin: I think that's so true of most of what we deal with in neurology. Like, most of neurology is being able to recognize the 75% to 80% that present in the normal typical pattern. But it's learning that for every localization within neurology, there are those variants. They don't read the textbook. But I do love that how if you're thinking about more sensory symptoms and more recent onset, you're generally thinking this is acquired versus that motor really standing out above and beyond the sensory symptoms, thinking more, "Hmm, could this be a hereditary? Should I look a little bit further into the family history?" Great point. And then I heard, especially in our first opening statement, it can be really hard to screen for autonomic symptoms, but that is really a hallmark of neuropathies because the autonomic nervous system is also composed of nerves. So, in a busy clinical environment, how do you suss this out, and what are you asking patients about?   Dr. Seyedsadjadi: It's a great question, I don't think you can never be perfect on that because as you said, in order to do the justice, you really have to go through all systems. One way is to use some of the outcome measures that autonomic symptoms you can ask the patient sort of in ahead of the time. But there are some questions that are more important, and it is difficult to get them from patients if you don't really ask them. And sometimes we shy away for different reasons from those questions. Some of these could be related to the function of the bowel and bladder, erectile dysfunction, specific questions about orthostasis, IBS-like symptoms, early satiety, and some overlap syndrome symptoms like dry eyes and dry mouth could indicate different things. These are the main categories of the questions that you ask. And when you start asking these questions, sometimes patients start adding symptoms, "Oh, I don't have this, but I also have, like, some other dysmotility issue." So, that comes up.   Dr. Albin: Absolutely, because these are symptoms that the patient may not put together as part of the same syndrome. And I think that that's why it's one of those things that, you know, they're coming to talk to you about the tingling that they have in their fingers and toes, and it may not have occurred to them that their constipation was related to this, or that if we're not asking about erectile dysfunction, that may not come up as, like, the patient putting those two together is worthwhile. Certainly, with sicca symptoms, that may give us a not only about the autonomic neuropathy, but could this be part of some other rheumatologic process?   Dr. Seyedsadjadi: Precisely.   Dr. Albin: I think any neurologist has sort of a general framework of, oh, we got to look at hemoglobin A1c. We've got to think about SPEP/UPEP in terms of a paraproteinemia. But one of the things that I think really sets master clinicians apart is the ability to see a neuropathy as part of a larger picture. And so, I think about syndromes like Holmes syndrome, or now I feel like CANVAS has become this new hot topic where everyone with a cough is now needing to be worked up for CANVAS. But how do you tease out the run-of-the-mill diabetic neuropathy from some of the zebras that do exist out there that if we're not carefully looking for, we very well may miss?   Dr. Seyedsadjadi: Yeah, and that's a very good question. What happens is the training, the pattern recognition. Everything makes sense except for something that doesn't make sense, and that raises clinical suspicion for something different. This is neuropathy, but it's not maybe just neuropathy, something else. So, you see a patient in clinic has a bread-and-butter neuropathy, has an EMG consistent with mixed axonal demyelinating neuropathy, even has diabetes, but you see something unusual about them. You see that they have finger clubbing. This is disproportionate to the degree of what you expect they would have. And then the workup ends up showing that they have POEMS, for instance. Or you see a patient, as you would nicely said, a patient has, like, an unusual cough and a neuropathy, or have a neuropathy, but the ataxia is disproportionate to the degree of their nerve sensory neuropathy, or they have abnormal eye movements or ataxia. You think about CANVAS syndrome. So, this goes back to habit developing early on a framework and a pattern recognition, and obviously something that we are all getting more and more guilty of, listening to the patient and paying attention to details that we often miss if we rush through things.   Dr. Albin: Yeah. I think it really comes down to the fact that we are really master diagnosticians when we listen to patients, when we take a history, when we spend a little bit extra time at the bedside. Answering that, "Hmm, my spidey sense is a little bit up. This just doesn't feel completely right." To learn to listen to that intuition and just say, "Let me go back and double-check on... I didn't ask this question, but, like, maybe it's worth my time. Just go back in the room and see." All right, so let's switch gears and talk a little bit about EMG interpretation and nerve conduction studies. Because even if you don't go into neuromuscular neurology, if you're a neurologist, you are going to come across these EMGs and nerve conduction studies. So, when we're thinking about neuropathies, we're going to broadly characterize them into demyelinating and axonal. And I'd love to talk through with you how do those electrodiagnostics differ? Like, what would you see for axonal versus demyelinating? And then why does it even matter to make that distinction?   Dr. Seyedsadjadi: So, electrophysiology complements the clinical assessment of neurology. It helps in terms of, in general, knowing at a mechanism of neuropathy. So, if you know that the process is more or predominantly demyelinating, that narrows down your differential diagnosis. And by looking at the type of demyelination, is it predominantly distal? Is it predominant proximal? Is it uniform? Are there footprints of acquired demyelination, like a conduction block or a temporal dispersion to indicate that this is, like, a potentially an inflammatory process? It can help a lot with terms of narrowing down the differential diagnosis. And if it is axonal, it's, again, helpful in terms of knowing what is the pathophysiology, how it can help you differentiate between different types and severity and chronicity of the process. It is very, very helpful, but there are some pitfalls with neurophysiology, especially with regards to diagnosis of demyelination. Demyelination, in general, you are expecting to see slowing of the conduction velocity, but not every slowing means demyelination.   Dr. Albin: Yes, I saw that in one of your cases, and I thought that that was such a great pearl because as someone who's not a neuromuscular neurologist, when I hear slowed conduction, I think, "Oh, that must be demyelination." But tell me more. That is not the case.   Dr. Seyedsadjadi: Yes. And that's one of the pitfalls of diagnosis of chronic inflammatory demyelinating polyneuropathy, CIDP, is an overdiagnosis sometimes made based on an electrophysiology which is not over-interpreted or interpreted incorrectly. So, there are two things. One is about the degree of slowing. With some axonal loss, you can get some slowing in your nerve conduction studies as well. So especially if your motor response amplitudes drop below a certain level, your velocity can slow down, too. So, you have to be careful not to over-interpret the degree of slowing as demyelination. It may still indicate that there is some myelin dysfunction or what we call informally amongst each other myelin unhappiness, but it doesn't necessarily mean the primary process is demyelinating.   Dr. Albin: To give an example for this, this could be the patient with diabetic neuropathy who has an axonal process, but may also have a little bit of unhappy myelin. Is that fair to say?   Dr. Seyedsadjadi: That's a very good example. In diabetes, you can have involvement of myelin as well. So, you can have a mixed axonal and demyelinating pattern. But as you nicely outlined, it is possible that the findings in a patient with diabetes over-interpreted as a primary demyelinating polyneuropathy, which can lead to a wrong diagnosis.   Dr. Albin: Right. So, we suspect that this is just run-of-the-mill diabetes. It is actually truly just run-of-the-mill diabetes. But if we over-interpret that slowed conduction to say, "Oh, this is demyelination," then all of a sudden, we're thinking about plasma exchange or IVIG for someone who has a diabetic neuropathy and not CIDP.   Dr. Seyedsadjadi: Correct.   Dr. Albin: Got it. So really have to be careful in interpreting these.   Dr. Seyedsadjadi: And also, I have to mention that CIDP is slightly more common in patients who have diabetes too.   Dr. Seyedsadjadi: So that's going to be the tricky part because then you have to go back to what's the clinical scenario, what's the clinical history, and how you're going to interpret these electrodiagnostic testing in this context. So, they can become a little bit tricky, but overall, this is correct. The other problem with electrophysiology is the technical aspect of it. So, the temperature, the lab that is doing it, under stimulation, overstimulation, these are the parts that have to be controlled for, and you have to have reliable data from a reliable lab to be able to make diagnosis.   Dr. Albin: This is a constant source of frustration to us in the ICU. You know, I work in critical care world, and how frustrating it is with all of our electrical interference, our patients are cold, we're not getting the best nerve conduction in EMG. It's a real challenge, you know, to make sure that we're providing reliable results when we're making these really important diagnoses.   Dr. Seyedsadjadi: Exactly. And that's why it's, like, complementary to the clinical judgment rather than replacing the clinical judgment. So, electrophysiology has to always back up what you have from your clinical impression rather than replacing it.   Dr. Albin: I think that that could be a key takeaway for just all of neurology. It comes down to your clinical intuition, your history, your physical exam. On the other side of your great history and physical exam. And so, when I read your article, those three things, the sort of MRI, nerve and skin biopsies, and then the enormous influence of genetic testing. As someone who does this day in and day out, how do you think about meaningfully using those tests?   Dr. Seyedsadjadi: If I want to start, I would say I would go to genetic testing first. Genetic testing, I think, has advanced more than anything else over the past two or three decades, and it's becoming more and more available, and it's becoming cheaper and cheaper. And if you have a genetic diagnosis, it bypasses many other tests that are more expensive and more laborious or have side effects or complications. I have lower threshold for doing genetic testing, obviously because in the setting that I am, I do most of these inherited neuropathies and acquired neuropathies. But once you have a clinical suspicion that somebody has some sort of a hereditary neuropathy based on the clinical scenario that we just talked about or a family history, I think it can, especially, and sometimes that you cannot get electrophysiology to help you delineate between axonal or demyelinating process because the nerves are gone, for instance. Or you have, like, a very young patient or a pediatric case that it would be more challenging to arrange for electrophysiology. Genetic testing can come very early on and can help with an earlier diagnosis. Obviously, we have not yet discovered all the genes that could cause neuropathy, and roughly between 25% to 50% of people who have hereditary neuropathy, they may have inconclusive genetic testing. But if it comes back positive, it would be very helpful nailing the diagnosis and reducing the need for unnecessary treatment or unnecessary testing. And the testing is now more widely available and cheaper. Obviously, there are some pitfalls with that, too. Genetic testing, and you find a variant of unknown significance, and now you have to figure out if that actually has something to do with patient's presentation. So, it has to be done also carefully. It doesn't necessarily mean that you should do it and then you have the answer necessarily. Skin biopsy, nerve biopsy, MRI, they have their own places. So, skin biopsy can be helpful in terms of diagnosis of small fiber neuropathy, predominantly small fiber neuropathy. Obviously, it has some pitfalls, so some clinicians like to use them and some others just rely on patient's clinical presentation. The common pitfall is that it can have abnormal testing depending on the lab that you're using, even if you don't have small fiber neuropathy.   Dr. Albin: And just remind me and maybe our listeners, what is the patient coming in with that would make you suspect that they have a small fiber neuropathy? Like, what are those patient symptoms?   Dr. Seyedsadjadi: Very similar to large fiber neuropathy, which is predominantly in this patient group, they come with positive more than negative sensory symptoms. But that is also possible that they may have negative sensory symptoms as predominant presentation too. And typically, they would have normal electrophysiology, meaning that they don't have abnormal EMG or nerve conduction study. So, the responses are normal.   Dr. Albin: Got it. So, this is a patient who may have numbness, tingling, pain, no motor findings. You do your typical EMG. You don't really find a lot. That's the person who maybe nerve and skin biopsies make sense, although we do have to bear in mind that there could be a sort of false positive report for those.   Dr. Seyedsadjadi: Correct. And/or false negative. So that's the other problem with it, because you can biopsy, which there's a typical biopsy site of where you go above the ankle. But if that area is not affected and your, let's say, small fiber neuropathy is a non-length-dependent process, the test negative, but you still have small fiber neuropathy. The utility of nerve biopsy has significantly changed over the past, again, two or three decades with the genetic testing and other tests that we do. So, we used to do them for everybody we suspected they have vasculitis. Now, with the better serology, we don't have to. But amyloid, a lot of amyloid patients who have hereditary amyloidosis, we don't necessarily need a nerve biopsy to confirm a diagnosis. And for inflammatory neuropathies, again, electrophysiology and some markers can help with the diagnosis. The utility of nerve biopsy has been now limited to, like, mostly with amyloid or inflammatory or infiltrative neuropathies. With regards to MRI, this is something that I often do together if I have to, looking for a process that is affecting a certain nerves in certain pattern to select a nerve for biopsy or to look for the course of inflammation or an infiltrative process affecting the nerves. MRI is getting more used in diagnosis of, or imaging in general, including ultrasound and MRI, in diagnosis of inflammatory neuropathies, like mainly CIDP. You can see enhancement in the course of the nerve, or the nerve roots, and the changes in the structure of the peripheral nerves in the ultrasound, that can give you a clue. And with the more recent diagnostic criteria for inflammatory neuropathies, now these are incorporated with the diagnostic criteria to establish diagnosis of inflammation. And at times, these can be very helpful, especially when you have limited electrophysiology or cases not necessarily a textbook case of an inflammatory neuropathy.   Dr. Albin: Got it. So, it's helping both to sort of the diagnosis of an inflammatory neuropathy, but also if you do feel like you need to go to a biopsy, trying to use a place where you can see some inflammation without maybe complete burnout, so that you're gonna see an active lesion, but not one that's so active that it may just be scar tissue or, I guess, degenerated nerve?   Dr. Seyedsadjadi: Yeah. Or an unhappy nerve.   Dr. Albin: An unhappy nerve, right. We really want to get the biopsy where the nerve is unhappy, but not dead.   Dr. Seyedsadjadi: Not dead. Exactly. And that's one of the pitfalls of biopsy. If you do a biopsy of a sural nerve, somebody who has a very advanced neuropathy, you may just find the fibrotic tissue and may not show you an inflammation or even the type of neuropathy.   Dr. Albin: And this has been such a fantastic way for us to sort of think about this larger picture of neuropathy and motor neuron disease. And I am excited to hear the rest of the interviews with all of our colleagues. Really detailed questions, because I think what you have done is opened the door to say this is actually quite complicated in a lot of ways. And the testing, and specifically in terms of thinking about genetic testing, has really evolved and expanded. We have more tests, but that doesn't necessarily mean that more tests equals better diagnosis in all cases.   Dr. Seyedsadjadi: Exactly. Yeah. It goes back to your clinical intuition.   Dr. Albin: I love it. Again, today I have been interviewing Dr. Reza Seyedsadjadi about his article on the diagnostic approach to neuropathy. This article appears in the October 2026 Continuum issue on peripheral nerve and motor neuron disorders. Be sure to check out Continuum Audio episodes for this and other issues. And thank you so much for our listeners for joining today. And Dr. Seyedsadjadi, thank you so much for being here.   Dr. Seyedsadjadi: Thank you. Thanks a million.   Dr. Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audiocme. Thank you for listening to Continuum Audio

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Noah A. Kolb, MD, who served as the guest editor of the October 2026 Peripheral Nerve and Motor Neuron Disorders issue. They provide a preview of the issue, which publishes on October 2, 2026. Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota. Dr. Kolb is a professor of neurological sciences at the Robert Larner College of Medicine at the University of Vermont in Burlington, Vermont. Additional Resources Read the issue: continuum.aan.com Subscribe to Continuum®: shop.lww.com/Continuum Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @LyellJ Full episode transcript available here Dr. Jones: The human brain is incredibly complex. That's one of the reasons we like to study it and care for patients with neurologic problems. But to translate cognition into action, we need a functioning sensorimotor and autonomic peripheral nervous system. What do we do when those peripheral systems aren't working? Today, we're speaking with Dr. Noah Kolb, guest editor of our latest issue of Continuum on peripheral nerve and motor neuron disorders.   Dr. Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about subscribing to the journal, listening to verbatim recordings of the articles, and exclusive access to interviews not featured on the podcast.   Dr. Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr. Noah Kolb, who is Continuum's guest editor for our latest issue on peripheral nerve and motor neuron disorders. Dr. Kolb is a professor of neurology at the University of Vermont Larner College of Medicine in Burlington, Vermont, where he specializes in the care of patients with neuromuscular disorders, including patients with peripheral neuropathy and other immune-mediated neuromuscular diseases. Dr. Kolb, welcome. Thank you for joining us today. Why don't you introduce yourself to our listeners?   Dr. Kolb: Well, thank you very much for having me. Please call me Noah. I've been a longtime listener of Continuum, dating all the way back to when they came on CDs, so it's really a pleasure to be here. Like you said, I'm a neuromuscular doctor up in Vermont. I take care of the whole scope of neuromuscular disease, but kind of wear 3 different hats. I focus my research primarily in chemotherapy-induced neuropathy, but also do other diseases as well. Obviously, see patients clinically, and then I'm an educator as well, so I run the neurology clerkship and the acting AIs for the medical school. So, it's a fun job.   Dr. Jones: Well, thanks for sharing that little bit of history on Continuum Audio, Noah. I got to be honest with you, I don't know if I've ever seen a Continuum Audio CD. If anybody out there in the audience has a Continuum Audio CD, post a picture online and we'll like and share it. I wonder how many of those are still out there. I really appreciate you not just joining us today, Noah, but also putting together this really stellar issue, a very timely update and overview of peripheral nerve and motor neuron disorders. A lot of good topics for us to dig into today. What I'm going to do before we get into questions is ask our audience Continuum Audio's trivia question. Dr. Kolb and I were talking about this before we started recording here. So, the trivia question, just to frame it up a little bit, the transthyretin or TTR protein receives a lot of attention in neuromuscular medicine as the protein behind the most common causes of acquired and familial amyloidosis. But transthyretin is known in clinical settings by a different name and checked for an entirely different reason. So, the trivia question is, what is the other common name for transthyretin? Stick around, and we'll share the answer at the end of our interview. So, let's get right to it. Our listeners know that peripheral neuropathy is common, right? It affects 2 to 3 percent of the general population and 6 to 7 percent of patients who are older than 60. In your mind, Noah, what's the main thing you would like clinicians to know or do differently in the care of these patients?   Dr. Kolb: Yeah, that's a great question. I think it's something that we spend a lot of time teaching our residents and working with our fellows about is understanding the right workup for people presenting with neuropathy because it's very easy to overdo it with more labs and a broader workup than you need. So, when somebody presents with sort of a garden variety neuropathy that doesn't have red flags, the important things to order in terms of a workup are hemoglobin A1C, B12, and SPEP with IFE, potentially serum light chains, and some thyroid studies as well. Because those are really the most common reasons, and then to make sure that they ask the most important historical questions, like about alcohol use, et cetera. If you're going to find a cause for neuropathy, particularly if it's slowly progressive and sensory predominant, oftentimes the answer is found right in that basic workup.   Dr. Jones: Got it. And I think that's very well taken. And I think one of the questions that commonly comes up in the neuromuscular, but also in the broader neurology setting is, when you're evaluating a patient, especially an older patient who has a new onset length-dependent sensorimotor peripheral neuropathy, you've identified the neuropathy, and you're starting to consider what are those potential underlying disorders or risk factors that that neuropathy could be a warning sign of, right? So, you look for metabolic disease, B12 deficiency, paraproteinemia, et cetera. Where do you stop? In what settings do you do more expanded evaluations, genetic testing, et cetera?   Dr. Kolb: Yeah, and I think this kind of goes back a little bit to the last question where the primary focus of the workup that we do is driven by the most common causes. That's why hemoglobin A1C is so important. And so, thinking through what is likely to be the cause in the specific patient setting is kind of really critical. And again, if you don't have red flags, then the labs that we mentioned previously are probably sufficient in terms of a workup. But if there are any of the other red flags, it's really important specifically because there may be treatable causes of neuropathy or things that would affect the prognosis that'd be important to understand earlier so we can make sure we either engage the right therapies or do a broader diagnostic workup. An important part of that is understanding when to use EMG nerve conduction studies and when not to. So obviously, as a neuromuscular doc who does EMGs, I'm very fond of them. But we regularly see patients in our lab who perhaps don't need one. If somebody has a sensory predominant, slowly progressive neuropathy, particularly if you have an etiology, those patients usually don't need an EMG nerve conduction study. When it's asymmetric, when there's prominent weakness, when there's a lot of autonomic symptoms, those are the times when it can be a lot more informative and helpful to try to get an EMG nerve conduction study to see if we can get at what the underlying etiology is.   Dr. Jones: That's very helpful, Noah. Thank you. And so, let's think about a scenario that I think many of our listeners may have encountered in their practice. You're seeing a patient who has a somewhat rapidly progressive, painful neuropathy, which has some small fiber characteristics. They've got a little bit of autonomic dysfunction, and you worry about the possibility of amyloidosis. How do you approach that evaluation and treatment, and why is it important to think about that diagnosis?   Dr. Kolb: Yeah, that's great. It's important to think about that diagnosis because we now have good treatments for AL amyloid and for ATTR-based amyloid. So, because these are treatable disorders, it's really critical that you identify them. And the reality is it's not always straightforward making a diagnosis of amyloid. As you would with any other type of neuropathy, the workup is gonna begin with serum free light chains, SPEP, trying to see if there are any monoclonal gammopathies or elevation in light chains. But importantly, you need to think about what the next diagnostic steps are and understanding how likely those tests are to be abnormal in the setting of amyloid is important as well, because the easier to obtain tests don't have perfect sensitivity. So, once you've moved on kind of from the basic labs, we think about a fat aspirate or a skin biopsy to look and see if there's any evidence of amyloid. But if your clinical suspicion is high enough, it's important to move to a sural nerve biopsy and genetic testing. That's really the best way to confirm this diagnosis.   Dr. Jones: Very helpful. And obviously, that's not just academic, as it might have been at one point. This is something that we now have good disease-modifying therapies for, which leads to another question that I think our listeners may encounter in their practice. When you think about all the available gene tests in panels and other genomic tools that we have to investigate patients, when do you do a broad genetic evaluation for patients with neuropathy?   Dr. Kolb: Yeah, it's a good question. It depends partly on specifically what we're looking for. I think that as with many things in neurology, one of the reasons I got interested in it, and many people did, is we like doing detective work, and the history often lies in the examination and in our clinical history at the bedside. And for that reason, often just in getting the initial history with a patient, you start to get clues that there may be a hereditary component. Sometimes it's in the history where you're able to elicit a family history of disorder, and they may or may not know that the patient had neuropathy, but it may be that somebody walked funny later in life or somebody always complained of foot pain. Or it may simply be when a patient takes their shoes off, or in Vermont, they're wearing sandals, and you see that they have characteristic changes of a neuropathy that is much more longstanding than the patient even recognizes. That's often the case with some of these forms of hereditary neuropathy because sometimes they don't have a lot of pain. And so, you see those characteristic changes in the foot, and it cues you to the need for genetic testing. In my world where I see a lot of patients with chemotherapy-induced neuropathy, I also think about it in patients who seem to be specifically sensitive to neurotoxic agents, where they get a much worse neuropathy than you would expect with exposure to drug, and it's important to consider it in those times as well.   Dr. Jones: That's a great framing. I appreciate the way you put that. One of the great points in the issue is that patients who have sensory findings out of proportion to their sensory complaints, a lot of times it's worth thinking about a familial or genetic mechanism and then digging a little more into that family history, right?   Dr. Kolb: I agree.   Dr. Jones: Yeah. So, let's think of a different scenario. I know you do a lot of work with immune-mediated acquired neuropathies, and we're fortunate now, obviously, we have a lot of immunotherapy tools for the treatment of patients with neuropathies like chronic inflammatory demyelinating polyradiculoneuropathy. When it comes to CIDP, Noah, what's your initial approach to immunotherapy? That's one question. And another is, how do you incorporate some of the newer agents like efgartigimod? What's the role of that drug, or when do you go to rituximab or rozanolixizumab? Walk us through your approach to that.   Dr. Kolb: Yeah, so I think it depends a lot on what the clinical presentation looks like and kind of what the patient's preference is. In taking care of neuropathy patients for what's been quite a while now, you find that some patients have a differing comfort level with sort of the newer drugs like efgartigimod versus some of the therapies that have been around for years and years and are tried and true. So, we know, for instance, that plasmapheresis and IVIG work well. In certain cases, we use steroids because they can work well as well, but also have long-term toxicities that you want to be aware of. It's been really exciting to see that efgartigimod is a new therapy that's on the market, and it's been a really interesting space to be involved in, in neuromuscular medicine as some of these new disease-modifying therapies have come out. The trials for efgartigimod are really exciting, and it was very important to our field when efgartigimod became available. But there have been other trials that showed similar drugs weren't that effective, and there are many studies happening right now for complement inhibition with varying results. So, it's been sort of one of these hot topics in neuromuscular medicine, trying to see what these new therapies are and figuring out how to integrate them. I find that oftentimes with patients, we'll start with the tried and true therapies like IVIG or plasmapheresis, but don't hesitate to reach to efgartigimod, particularly if it's more convenient for the patient. I think the other important point to make, and this is addressed nicely throughout some of the manuscripts, is that there are specific instances where certain drugs are preferred. So, for instance, if you're seeing somebody with CIDP that has hard-to-treat symptoms, is not responding to the normal therapies that we use, it's important to think about whether they may have a paranodal form of CIDP, in which case we often reach for things like rituximab instead because it works better.   Dr. Jones: Outstanding. And so, I think that speaks to the importance of phenotyping, right? As we learn more about these acquired immune-mediated neuropathies, we're splitting, right? We're finding that the mechanisms are different in the tools that we have, the treatments are going to be more tailored, and more personalized to the patient. I think that's a great takeaway from the issue. So, Noah, you're in a unique position here, right? You're a world-renowned neuromuscular expert, and you have just edited a bunch of articles on neuromuscular medicine, peripheral nerve, motor neuron disorders written by experts in their respective fields. So, you have this bird's eye view of the specialty up to the minute, what's the latest. When you think about the entire issue, what would you say is the one topic that our readers or listeners could go to, to close the most important education gap in neuromuscular medicine?   Dr. Kolb: It's a great question. It's akin to asking who my favorite child is, of which is all of them, but I would say that when Amro Estino and Ben Becker submitted their manuscript on paraproteinemic neuropathies, after I read it, I wrote an email back to them just telling them how well I thought it was organized and that it really addressed an issue that constantly plagues trainees and practitioners, is how to deal with monoclonal gammopathies and paraproteinemic neuropathies. It's a nice example of what happens when you give smart people the creative space to organize something in a way that they think makes sense. I certainly learned about the topic reading that, and I think it'd be very high yield for people reading Continuum.   Dr. Jones: Totally agree. It's a wonderful article among many great articles, and that is a persistent education gap. So, I would direct our listeners to that article as well. You know, one of the things that I think about, you're an educator, I'm a clinician educator myself, thinking about the really interesting world of neuromuscular medicine, right? I have a significant part of my practice is in neuromuscular medicine and EMG, and I enjoy that very much. What do you think about trainees who might be interested in neuromuscular medicine, and they want to focus in it or pursue it as a career? How should they approach it? What does the training landscape look like from your perspective?   Dr. Kolb: Yeah, that's a great question and an important one. So, I think that the case to be made for neuromuscular medicine is strong. I talk with the residents and my medical students about this regularly, but I think it's hard to find a place in medicine where the field is evolving more rapidly than it is in neuromuscular medicine, which makes it sometimes hard to stay up to date with everything that's happening, but it also makes it really interesting. To have new medicines coming online for us to change the paradigm for the way we've been treating patients for years and years is very exciting, and I think that those changes are only going to grow. Part of the future of neuromuscular medicine really is going to be in better genetic testing and broader genetic therapies. When you think about hereditary neuropathy as an example, there are tons of emerging therapies that are in pre-clinical trials and some starting in clinical trials. And so, the future of neuromuscular medicine is going to be constantly evolving where we can now treat disorders that we couldn't treat before. I mean, the easiest example is SMA, where previously that was a universally fatal disease for infants, right? And now we have treatments that are very effective. And there are multiple diseases where we're starting to develop therapies like this, so it's really exciting. From a training perspective, there are lots of opportunities for residents as they approach fellowship. There are tons of great neuromuscular fellowships around the program. I would include UVM in there as well, where there's really a wide variety of neuromuscular things that you can learn. And it's a wide and varied field, so people are learning ultrasound, which has been an emerging part of neuromuscular medicine, EMG, electrodiagnostics, Botox, but then also treating autoimmune disorders, hereditary disorders. So, it's really quite a broad field, and you can really sort of super sub-specialize into different areas, which allows you to really focus if that's what you want to do.   Dr. Jones: So now it's time for the answer to our Continuum Audio Trivia question. Just to remind our listeners, what is the other common name for transthyretin? We think about transthyretin a lot, as Noah mentioned, in terms of acquired and familial amyloidosis, but what is the other name for it? Dr. Kolb, do you want to give the answer to our audience?   Dr. Kolb: That would be prealbumin.   Dr. Jones: Prealbumin. Again, we talk about transthyretin all the time because of the neurologic and cardiac presentations of ATTR wild type and variant transthyretin amyloidosis. But the protein itself, in the non-pathologic setting, in the non-amyloid setting, is a stable tetramer. Its normal function is to transport thyroxine and vitamin A throughout the body, but it also has a relatively short half-life. And on electrophoretic gels, it segregates near the albumin band, and therefore, for a long time was just called prealbumin because it was near the albumin band. And because of that short half-life, it's used as a rough or loose marker of nutritional status. So, all those times when I was a medical student and a resident ordering prealbumin to assess nutritional status, I was really checking transthyretin, and I had no idea.   Dr. Jones: All right. So, Dr. Kolb, I really want to thank you for joining us. Thank you for such an outstanding conversation about peripheral nerve and motor neuron disease in the latest issue of Continuum. I learned a lot reading this issue. I learned a lot in our conversation today. I hope our listeners did too. I'm really grateful for your hard work taking on this issue, which I think will come in handy not only to our more junior listeners and subscribers, but also, our more experienced listeners as well.   Dr. Kolb: Thanks for the opportunity to chat with you. I'm excited for the public to see the Continuum manuscripts. I think there's a lot to learn, and it's an exciting issue.   Dr. Jones: I agree. Again, today we've been speaking with Dr. Noah Kolb, guest editor of Continuum's most recent issue on peripheral nerve and motor neuron disorders. Please check it out, and thank you to our listeners for joining today.   Dr. Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. Thank you for listening to Continuum Audio.

Sleep plays a critical role in brain development, learning, memory, and behavior throughout childhood and adolescence. In this episode, Dr. Kristin Seaborg discusses how sleep architecture changes across development, the impact of sleep disorders on attention, headaches, epilepsy, and neurodevelopmental conditions, and why neurologists should routinely assess sleep in pediatric patients. Learn practical approaches to recognizing sleep problems, including obstructive sleep apnea and insomnia, and how improving sleep can enhance neurologic and cognitive outcomes. In this episode, Casey S. Albin, MD, FAAN, speaks with Kristin Seaborg, MD, author of the article "Sleep in the Developing Brain" in the Continuum® August 2026 Sleep Neurology issue. Dr. Albin is a Continuum® Audio interviewer, associate editor of media engagement, and an assistant professor of neurology and neurosurgery at Emory University School of Medicine in Atlanta, Georgia. Dr. Seaborg is an Assistant Professor in the Department of Neurology at the University of Wisconsin–Madison in Madison, Wisconsin. Additional Resources Read the article: Sleep in the Developing Brain Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @caseyalbin Guest: @KristinSeaborg  Full episode transcript available here Dr Albin: In neurology and life, we are all looking for the secret to being attentive, focused, and engaged, and we certainly want that for our children. And what if the answer to all of that was just in sleep?  Dr Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.  Dr Albin: Hello, this is Dr. Casey Albin. Today I'm interviewing Dr. Kristin Seaborg about her article on sleep in the developing brain. This article appears in the August 2026 Continuum issue on the neurology of sleep. Welcome to the podcast, Dr. Seaborg. Thank you so much for being here. I learned a lot from your article. Can you just briefly introduce yourself to the audience?  Dr Seaborg: Sure. Thank you for having me. I'm thrilled to be here. My name is Kristin Seaborg. I'm a pediatric neurologist and sleep neurologist at the University of Wisconsin Medicine. I also run the pediatric sleep neurology clinic at UW Madison.  Dr Albin: That is the perfect person to be writing this article. And every time I read an article about pediatric neurology, I am just so struck that like little tiny humans are not small adults, that they actually have a totally different neurobiology. They are in different stages of development. And this was really a topic that I was not familiar with, and probably for most of our listeners, they're not familiar with as well. And so, I thought we'd maybe just start with some of the basics. What is going on in terms of like pediatric sleep architecture, and how is that different than the adult architecture that we might be m- more familiar with?  Dr Seaborg: Sure. So, a lot of us think that sleep is the thing we do that when, when we're not doing other stuff. But actually, it's completely the opposite. During sleep, our brain is learning and consolidating memory and cleansing what's happened during the day, and that's especially important during infancy and early childhood development, and as a child gets older. If we take infants for an example, fifty percent of their sleep is in a precursor of REM sleep, which we call active sleep, which is much, much more than adults, as opposed to adults have about thirty percent of their sleep in REM sleep. And also, infants need sleep like fifteen to seventeen hours a day. Not all of that is consolidated in one continuous period. They usually sleep over the course of the day, fifteen to seventeen hours, and that sleep time decreases over the course of childhood and adolescence as well.  Dr Albin: Yeah, it's amazing that there's so much more going on. As someone who's had newborns, it feels like, oh my gosh, they're really just sleeping all day. They're not doing anything. But they're doing quite a lot, and that really is so much work for their developing brain. And then one of the things that also really struck me about the article is that as children move from infancy through adolescence, not only is the sleep architecture changing, but the time they go to sleep, the amount of sleep they need, some of the pathology that they may develop, it changes throughout these early years of their life. And so maybe when we are thinking about what patients might come to the clinic with, I assume a lot of parents are kind of concerned like, "Is my child getting enough sleep? Are they sleeping the normal amount? Are they sleeping in the timeframe that would be normal?" Walk us through just in broad strokes, like what is a normal amount of sleep as you go through that pediatric developmental phase?  Dr Seaborg: So that's not a one-sentence answer. And there's a table in the Continuum article.  Dr Albin: Love that.  Dr Seaborg: So, infants sleep like fifteen to seventeen hours, and it's chunked out over the course of the day. Usually they have one consolidated sleep period at night, but then two to three naps during the day. And as you move through early childhood, toddlers and adolescents usually need about fourteen hours of sleep around the time they're one year of age. As they get a little bit older, then they need like eleven to thirteen hours, depending on the child themselves. And then as we move toward like school age, like eight to ten hours of sleep is usually adequate, but especially younger school children need about ten hours of sleep at night. And then the interesting thing that happens in adolescence and early teenage years is that kids need just as much sleep, but they actually naturally fall asleep later because their melatonin is released later. So, it feels like they need to sleep all the time, but actually they just go to sleep later, and when school comes, it's not time or doesn't feel ready for them to wake up. So, adolescents and teens also need about eight to ten hours of sleep a night.  Dr Albin: Right. And I just was struck, you know, we think about it in this article and these issues, we've thought a lot about, I think it'll come up in other podcasts, the importance of daylight savings time and how that actually really is not good for our brains. And I feel so much for these teenagers who are really at a disadvantage because we make them get up early to participate in the world when it's not really aligned with how their natural sleep cycle is, and it feels unfair.  Dr Seaborg: It does. And there's so much to that. So, adolescents have school, and then a lot of time they have like after-school activities, whether that's sports or theater or music or whatever, but that usually happens after school. And then the reality of today's society is they come home, and at least my teenager disconnects or kind of decompresses by looking at her phone forever. And a lot of teenagers and adolescents bring their phone to bed. That exposure to light right up until the time when they want to go to sleep really can disrupt their circadian rhythm too. So they have the natural delayed circadian rhythm, and then they have these lifestyle exposures between activities after school and screens and everything else that really make sleep onset difficult. And so, waking up for school at 6:00 or 7:00 in the morning is really difficult for them.  Dr Albin: Gosh, I feel for that. And I suspect that many patients are coming into the sleep clinic with that exact sort of like my early teen, my preteen, my teenager. They're just exhausted all the time, but they won't fall asleep. They're developing insomnia. It sounds like there's a lot of behavioral changes that need to go along with that. Is that what you're seeing?  Dr Seaborg: Yeah. So, I'm also seeing an kind of a corollary, a lot of kids that come in with headaches because they're not sleeping enough, and they feel awful, or they're coming in with difficulty focusing in school or cognitive fog because they're not sleeping enough, and that they don't always know that that's the chief complaint. But often, as you start asking sleep-related questions, you figure out exactly what's going on. So, their amount they're sleeping and kind of their natural sleep cycle is affecting everything about their life.  Dr Albin: Yeah. It just-- it really struck me that, you know, one of the things that you talk about in the article is that there is, in patients who have neurodevelopmental differences and disorders, they may specifically have some sleep impairment, and they have a neurobiological reason for those sleep changes. But also, like you're saying, sometimes these inattentions or what's diagnosed as ADHD is actually just because they are not sleeping well, and they can't focus. And I imagine that's really hard to tease out. Like, is there something when you're trying to tease that out in the clinic that helps you figure out, is it the dog wagging the tail or the tail wagging the dog?  Dr Seaborg: Sure.  Dr Albin: Which is coming first? Is it, is it really a neurobiology problem where they have nerve developmental disorders and therefore sleep problems, or they have sleep problems causing the symptoms of a nerve developmental disorder?  Dr Seaborg: So, there's so many ways to answer that question. The very first part is you start at the beginning, not only asking the person's chief complaint, like, "Are you having trouble with attention?" But then also, uh, like I'll say, "Okay, what time do you go to sleep?" But not only that, "What are you doing before bedtime?" And then once they're asleep, are they snoring? Are they waking multiple times at night, you know, without trying to? And when they wake up in the morning, do they feel refreshed, or do they really still feel like they could fall asleep for a very, very long time? And then with regards to the neurodevelopmental disorders, it's fascinating. A lot of kids with neurodevelopmental disorders, whether that's ADHD or autism spectrum disorder or a genetic disorder that causes a developmental difference, often some of the pathophysiology of the actual neurodevelopmental difference also impacts the circadian rhythm and melatonin release and the brain's ability to initiate and maintain sleep. So, it's really important as a provider to be cognizant if you're seeing your patient with autism or ADHD to also ask about their sleep-related symptoms. And then eventually you'll ferret it out, but it takes a lot of sleuth work and investigation.  Dr Albin: So, what I'm hearing is actually when people come in with a chief complaint that probably is not like, "Hey, I'm having trouble sleeping," but maybe, "I can't focus" or, "I have headaches," or I have other problems that are being referred to a neurologist or pediatric neurologist, it really does behoove us to pause and take a good sleep history on all children coming in.  Dr Seaborg: Yes, and I'm gonna piggyback on that. Also, very, very important for our patients with epilepsy. There's a super high coincidence with epilepsy and sleep disorders, and there's actually been direct comparisons with children that-- typically developing children and children with epilepsy that's poorly controlled, and the amount of sleep-related complaints and sleep-related symptoms they have is astronomically higher. So, it's important as a neurologist to always have sleep kind of on our front burner, something we're paying attention to.  Dr Albin: No, it's so true. You know, I learned a lot about pediatric sleep and epilepsy through the article, and I think that obviously we wanna refer the listeners to checking out a little bit more. But there were a couple of things that were new terms to me that maybe others are not familiar with, and it does relate to like they are epilepsy, but they are more nocturnal, and they have more nocturnal epilepsies that we might need to really think and consciously consider. So, the new terms for me were SeLECTS, which I assume is actually just said as SeLECTS, but stands for... You tell me, what does it stand for?  Dr Seaborg: Self-limited epilepsy with central temporal spikes.  Dr Albin: Perfect. So okay. So, let's just start with that. Like, what is going on there? What do I need to know about it?  Dr Seaborg: So, SeLECTS was previously known as benign rolandic epilepsy 10 to 20 years ago, and then that, the term evolved to childhood epilepsy with central temporal spikes. But then it evolved again to SeLECTS, which is self-limited epilepsy with central temporal spikes. I think the primary motivation of changing the terminology, at least initially, was to acknowledge that even though this type of epilepsy occurs during childhood and it's self-limited, it is not benign always because seizures can cause some daytime dysfunction, and also there has been some association with ADHD-like symptoms or learning disability symptoms later in life. The other term you just mentioned, developmental epileptic encephalopathy with spike wave activation in sleep. That's a mouthful. That's the new terminology for what we used to call ESES or electrical status epilepticus of slow wave sleep. So, DEE-SWAS, developmental epileptic encephalopathy with spike wave activation in sleep is a broader term to encompass a bunch of epilepsy syndromes that have spike wave activation that during sleep, it is associated with developmental delay and per-perhaps developmental regression.  Dr Albin: And is that typically seen early childhood infancy? Like, I think of that as being something that you're gonna encounter really early in the life cycle. Am I correct?  Dr Seaborg: Not always. Sometimes, like school-aged children, one of the classic presentations is what it can be known as Landau-Kleffner syndrome, where you have spike wave activation during sleep in a, a school-aged child at like between the ages of six and 10, and then they have language regression, and you look at their EEG overnight and you see that they have epileptiform activity for up to 85 to 95% of the night.  Dr Albin: Wow. So, I wanna drill down on this. Since both of these things may come up, and probably are not something that the family is coming to you and saying, "Hey, I've seen these bizarre things happen in sleep," but are coming with daytime symptoms, how is it that you decide who is going to need a pediatric sleep study?  Dr Seaborg: Great question. So, if a child ever or a parent ever comes and complains or with concerns of developmental regression, and I guess I'm biased cause I'm a sleep doctor, but I would always do an EEG recording overnight if there were any concerns. And then if patients come and they just talk about rhythmic movements at night or waking up at night with some facial twitching, or the next day they're really acting tired, then I would order a sleep study. And of course, I would always ask the typical questions: Are they snoring? Are they waking up with a headache or not well refreshed? And ask a little bit more about a sleep history. But developmental regression and rhythmic movements at night definitely should be studied.  Dr Albin: And those questions about, you know, snoring at night, waking up with a headache, you're trying to get to pediatric obstructive sleep apnea. Is that right?  Dr Seaborg: Correct. Yes. Thank you for clarifying.  Dr Albin: Yeah. No, I just wanna make sure, like, because obviously that is a very common problem in the adult patient population. How frequently are you encountering that now in pediatric land?  Dr Seaborg: So actually, it's more common than you would think.  So kids have, especially kids that I'm seeing in the pediatric neurology clinic, sometimes have some different facial anatomy or enlarged tonsils or enlarged adenoids, or they have a primary genetic disorder that gives them a little bit different facial anatomy, and they're at much higher risk for obstructive sleep apnea. Kids with different muscle tone, whether they have cerebral palsy or a different kind of hypotonia disorder, are at very high risk of obstructive sleep apnea. And then kids with epilepsy, for reasons that we don't fully understand, are at higher risk for obstructive sleep apnea. So, it's actually quite common in children. We see it a lot.  Dr Albin: Wow, that's fascinating. And then I wanna just in our little limited time together, there were two other sort of neurodevelopmental disorders that came up in the article and I think are at least worth previewing for the listeners. So, autism spectrum disorder, obviously a very large and a range of how patients can present, but sleep really does seem to be a manifestation. Walk us through the association there.  Dr Seaborg: Sure. So, we don't know 100%, but I can give you a few statistics. For instance, 20 to 75% of kids with autism spectrum disorder have some sort of sleep onset or sleep maintenance insomnia or some primary sleep disorder, which is astronomically high. We all know the etiology of autism is multifactorial, and there's not just one gene or one difference that leads to autism, but there are a fair amount of genetic differences that sometimes can lead to a diagnosis of autism spectrum disorder. We've found there's kind of coincidence of some differences in some of the circadian genes. Specifically, time and clock are two of the circadian rhythm genes that have been shown to have higher incidence of differences in kids with autism spectrum disorder. And then kids with autism spectrum disorder also sometimes have some underlying anxiety or hyperactivity in it that also compounds their difficulty falling asleep and sometimes their difficulty staying asleep at night. And so, there's multiple things that are playing in that can make sleep difficult, which in turn can affect their daytime performance and their daytime regulation. So, lots going on there.  Dr Albin: Absolutely. I mean, in reading this, I was struck by, oh gosh, there's a lot of both pharmacological and sort of behavioral therapy that has to go into like readjusting and, and setting normative patterns and expectations. It sounds like melatonin can, in some cases, be helpful here.  Dr Seaborg: Yes, melatonin. So, I know there's a lot of patients will come to me, they're like, "I don't wanna use melatonin 'cause my Facebook group told me it was terrible." There's a lot of literature and a lot of recently published literature to show the safety and efficacy in low-dose melatonin, especially in children with neurodevelopmental disorders and specifically in kids with autism spectrum disorder. Melatonin is safe and okay to use. It's important to educate your patients though. So, a little bit works, and then a patient's kind of natural reaction is, "Oh, if a little bit is good, I'm just gonna give them more." But the more melatonin you give a person, actually the less their brain produces, and it's almost like a negative feedback. So, the studies support using two to five milligrams of melatonin one to two hours prior to bedtime to kind of stimulate melatonin release and then help with sleep onset. Melatonin does not help with sleep maintenance, but for the kids that are on the kind of neurodevelopmental disability or disorder spectrum, it really can help with sleep onset. Dr Albin: Yeah. I was really fascinated to hear that there is some more evidence for the extended-release formula. And is that something that you can just go onto Amazon and get the extended release or is that prescription?  Dr Seaborg: It's not prescription. You can 100% go onto Amazon and get the extended release. Immediate release melatonin will help with sleep onset, but then a lot of kids w- with brains that work differently wake up two to three hours later. The extended release can stick with you for a little bit longer.  Dr Albin: Well, there you go. I always love the things that you're just like, "All you gotta do is get on Amazon and it'll come to your house the next day." We all love a quick fix like that.  Dr Seaborg: Right.  Dr Albin: The other topic that came up is obviously patients with ADHD and, like, how their sleep really can both impact how they are performing and some of their symptoms of inattention, and may also sort of compound, you know, or, or be a, um, manifestation of the fact that there is a neuro biologic difference.  Dr Seaborg: Right. So, ADHD is an interesting kind of disorder, disability, or condition, um, because there's so many things that play into that. Sleep-related stuff, we've been residents before, and, you know, the longer that we're awake, actually the harder it is to focus and concentrate. Interesting, there have been some stereo EEG patients that they've shown that sleep is not the whole brain happening at once, but actually there are parts of the cortex that can ha- fall asleep in, like, micro-sleep or local sleep after prolonged periods of wakefulness even while you're awake. So, it can look like you're inattentive, but literally part of your cortex is falling asleep. So, these patients that have been awake for forever or had prolonged periods of wakefulness can look like they have inattention, but actually they're just sleeping poorly. I see this a lot in kids that have previously undiagnosed obstructive sleep apnea or previously undiagnosed periodic limb movement disorder. The parents come with a chief complaint of inattention or difficulty focusing, and then the sleep studies show that their sleep is very disrupted, and we treat OSA, and all those symptoms are better. Conversely, kids with ADHD, so the neurobiology of ADHD, the neurotransmitters that are implicated in ADHD that kind of regulate wakefulness are also different, so, like, norepinephrine and epinephrine and stuff like that. So, it makes falling asleep harder in kids with ADHD just because their genetic makeup and how kind of their brain and their biology is working. Insomnia is a common disorder in kids with attention deficit disorder.  Dr Albin: Wow. It's just amazing how integral sleep is to just the whole function. I'm not surprised because we certainly feel that having been residents. We, I think we all, as doctors, acutely know how bad it feels when you do not sleep well. We are coming to the end of our time. A lot of these questions that I had posed for you we've actually kind of answered, but I did want to give everyone who's listening in, and maybe they're in the car or cooking dinner, you might not have heard the snippet. This is just rapid-fire questions that you may encounter in neurology clinic or pediatric neurology clinic. Quick answers. My child snores. Is that normal?  Dr Seaborg: No. It's not normal, especially snoring and pausing. So, I, like, the guttural pauses. Never normal. That child should have a sleep study.  Dr Albin: Perfect. The Facebook group said that melatonin is not safe. What do you think?  Dr Seaborg: Low doses of s- melatonin are 100% safe and efficacy or efficacious, excuse me, in children. Um, but low doses. Two to five milligrams at the very most. If it's not working, use less. Don't add on more.  Dr Albin: Love that. My teen is up till midnight. Why?  Dr Seaborg: Unfortunately, your teen is normal, and their biologic clock is moved back as they approach adolescence, and their melatonin release is later. One thing you can do is make sure that the screens are out of the room two hours before bedtime, and that they have some downtime before bedtime.  Dr Albin: And then finally, a sleep study, that seems very intense. Can my child have that?  Dr Seaborg: Your child can 100% have a sleep study, especially the certified sleep centers are really good about dealing with kids that don't like all the sensors or the leads, and they can come in and readjust. I would highly recommend it. It's worth your time, especially cause it's a low-hanging fruit that we often can help.  Dr Albin: Love that. All right. Again, I've been interviewing Dr. Kristin Seaborg about her article on sleep and the developing brain. This article appears in the August 2026 Continuum issue on Neurology of Sleep. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining today.  Dr Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Circadian rhythms influence far more than sleep, affecting neurologic disease expression, treatment response, and overall health. In this episode, Dr. Sabra Abbott discusses common circadian rhythm disorders, the health consequences of circadian misalignment, and practical strategies for managing jet lag, shift work, and disrupted sleep-wake schedules. Learn how circadian biology can shape neurologic outcomes and why considering the timing of behaviors, light exposure, and treatments may improve patient care. In this episode, Katie Grouse, MD, FAAN, speaks with Sabra M. Abbott, MD, PhD, author of the article "Circadian Neurology" in the Continuum® August 2026 Sleep Neurology issue. Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California, San Francisco in San Francisco, California. Dr. Abbott is an Associate Professor of Neurology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. Additional Resources Read the article: Circadian Neurology Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Full episode transcript available here Dr Grouse: Circadian rhythm disruption affects many of our patients in far-reaching aspects of their general health and has likely personally affected most neurologists at some point in their career. Today, I have the opportunity to interview Dr. Sabra Abbott, who is the author of the latest issue of Continuum on Neurology of Sleep.  Dr Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.  Dr Grouse: This is Dr. Katie Grouse. Today, I'm interviewing Dr. Sabra Abbott about her article on circadian neurology. This article appears in the August 2026 Continuum issue on Neurology of Sleep. Welcome to the podcast, and please introduce yourself to our audience.  Dr Abbott: Thanks for having me. I'm Dr. Sabra Abbott. I'm an associate professor of neurology at Northwestern, and I'm also director of our circadian medicine clinic.  Dr Grouse: It's really great to have you today. I definitely enjoyed reading your article, and not only did I learn a lot, but I feel like it's really applicable to a lot of topics that come up in clinic when I see patients. Now, I was wondering if you had to choose one key point that readers of your article would take away after reading it, what would it be?  Dr Abbott: I think the most important thing to keep in mind is that time is an important variable in every single thing that we do. And so, it can impact when your patient's disease is at its best and at its worst, and then it also can impact when it's actually most appropriate to provide medications for your patients. There can be times where they may be more impactful and times where they may actually cause more harm for your patients. So, the short answer is think about time always with your patients.  Dr Grouse: On that topic, I was really amazed to learn about the significant health risks associated with circadian misalignment, including even malignancy risks. Can you review some of these risks and why this might be the case?  Dr Abbott: So, I think the risk that we have the most data for is the risk for cancer associated with circadian misalignment, and this comes from a lot of studies that we're looking at patients who are shift workers. The data has actually come back on two separate reviews indicating that shift work could be a probable carcinogen, and we think that that probably comes down to a lot of different factors. So, when you're a shift worker, you are often working in the middle of the night. You may be getting light exposure at a time when you're normally producing melatonin, and that may be one factor that is actually putting you at increased risk for cancer.  Dr Grouse: And certainly, after reading this and hearing all of these things, I'm not surprised that many sleep specialists really dislike daylight savings time, which also is enough of a factor to potentially increase some of these health risks. Do you agree that daylight savings time is something that's contributing to poor health in our population?  Dr Abbott: So, I think it is definitely something that almost all of us want to get rid of, and I think where everybody is in agreement is that we should get rid of these shifts in the spring and the fall. I think the only benefit to those shifts that I see is it does create a time where we start having conversations about your circadian clock, so people become aware of circadian timing twice a year when we have these shifts. Outside of that, that shift back and forth seems to be very problematic. So, we do see both in the fall and the spring an increased risk for car crashes, an increased risk for heart attacks, stroke. People perform worse at work, and so I think in general, we probably should get rid of it. There's a little bit of a debate as to whether we should go to permanent standard time or permanent daylight saving time. I think most sleep and circadian scientists prefer permanent standard time. A lot of people who really like their evening activities prefer permanent daylight saving time, but I think that's also biased by the fact that daylight saving time, everybody has longer days, and I think they want longer days year-round, and you don't get that no matter which way you shift the clock in the winter.  Dr Grouse: That's really interesting. I do see that debate pop up every, I guess twice every year, and I guess there is a silver lining that at least we are all talking about it and thinking about it. I wanted to take a step back about the topic of circadian rhythm disorders in general. Could you just really quickly, like twenty-thousand-foot view, summarize what these main circadian rhythm disorders are?  Dr Abbott: So, at the moment, we primarily think of circadian rhythm disorders in the context of how they impact your sleep-wake timing. And so, at the largest level, we think of them as either intrinsic disorders, so disorders where your internal timing doesn't match up with the environment. The four key disorders there are advanced and delayed sleep wake phase disorders, so you're either earlier or later. You have non-twenty-four, where you actually generally get later and later each day, so it's like you're living on Mars. And then we have irregular, where you have multiple bouts of sleep that happen both night and day. And then the other two are the extrinsic disorders, so these are shift work disorders. So, you may have a normal functioning clock, but the external environment is forcing you to do things you wouldn't normally, or jet lag, where you again have a normal functioning clock, but then you end up having to shift multiple time zones faster than you can adapt to. Now, I think the interesting thing, and we can talk about this more if you want, is that we are moving into thinking of circadian rhythm disorders as being much more than just abnormalities of sleep-wake timing, and I think that's kind of where the future of the field goes.  Dr Grouse: Tell me more about that.  Dr Abbott: So, I think as the article gets into beyond just these kind of classically recognized disorders, we realize that circadian disruption can play a role in almost any other medical disorder that you can experience. And so, we can see circadian disruption as either a symptom or a potential cause of many other disorders. And then also in the optimal care of pretty much any patient, thinking about all of these other factors that they're experiencing on a day-to-day basis, whether it's their light exposure, whether it's the timing of their meals, whether it's the timing of their medications, all of those can play a role in their overall health and improving your ability to care for them.  Dr Grouse: Now, I did find it really fascinating. This was not something that I had really been aware of prior to reading your article about the fact that it really can make a difference about when you time particular medications for particular types of neurologic conditions just related to the circadian rhythm. And really interesting was the epilepsy connection. Can you tell me about how that affects how we should be dosing anti-seizure medication?  Dr Abbott: So, I think the epilepsy connection is an interesting one that definitely needs far more studies. So, at this point, a lot of this data is really coming from observational studies, looking at when patients have received medications and then how good their outcomes are. And in epilepsy, I think a lot of us tend to time anti-seizure medications so that patients get more of them in the evening and lower doses during the daytime. And I think a lot of this has been driven a little bit more by the fact that many of these medications are sedating, so we tend to put the more sedating medications at bedtime. But it turns out that outcomes in patients are actually better if they get higher doses at night and lower doses in the morning. Now, this is sort of theorizing at this point, but it could either be targets of these medications or your ability to uptake these medications across the blood-brain barrier may change with the time of day component. So, at this point, these are still really observational studies, but I think an area where we really need to do a lot more work.  Dr Grouse: Well, I look forward to hearing more about other ways that we'll learn how best to manage our medications for circadian rhythm function. Now, I wanted to ask, which circadian rhythm disorder do you think is the hardest to treat, and why would that be the case?  Dr Abbott: So, I'm gonna give you two answers to that. In terms of the primary circadian disorders that I see come through my clinic door, I would say cited non-24. These are patients who have normal vision, but they act as though they are living in a world without these external light time cues. And so, they, every single day, get a little bit later and a little bit later, and it's really, really hard to get them from a 25-hour schedule back onto a 24-hour schedule. The second part of my answer to that is shift work disorder, and those, I would say, are much more common patients to encounter. I think every single one of us, as we've gone through our medical training, has probably had some degree of shift work disorder, difficulty sleeping when we need to, staying awake during our shifts. But it's still really hard to figure out what we should be doing because, one, it's a multi-component system, so anything that I do to change your shift schedule has trickle-down effects to every one of your coworkers, and so we can't just tell one person, "Change what you're doing." It's also really hard to figure out what we should be doing. Should you only be working nights forever and ever and become purely nocturnal, and should we adapt everything to that, or we-- should we find some sort of compromise so that you can work the night shift but still have time to socialize and spend time with your family during the daytime? And how do we do all of that while still optimizing your health? And so, I think from a patient population, that is really a large problem we don't have a good answer to yet.  Dr Grouse: Sounds like it's something that you really have to customize to every single patient who walks in and their, their particular scenarios.  Dr Abbott: Absolutely.  Dr Grouse: Jet lag disorders is another circadian rhythm disorder that I think we all have had some personal experience with. Any tips or tricks on how to manage jet lag going east or west, or any resources that you recommend that can help us manage this, or we can advise to our patients?  Dr Abbott: Yeah. When we're talking about individualized, personalized treatment, I would say jet lag absolutely is way up there at the top of the list because it's not only a matter of where do you currently go to sleep and wake up in your current time zone, it is how many time zones are you going across to get to where you're going? Do you wanna keep the same schedule when you're at the new time zone? And all of these other factors in terms of how long you're gonna be there. When are you gonna come back? Does it make sense to fully adapt yourself to that new schedule? With that in mind, the general tips are if you are heading east, generally your goal is to shift everything earlier, and if you're heading west, generally the goal is to shift everything later. There are a lot of online calculators you can use where you can put in your current time zone, your destination time zone, and it will give you very specific information about when you should be getting light, when you should be avoiding light When melatonin may be helpful as another time cue that can help shift you. But again, it really depends on which direction and how many time zones and what time you're gonna arrive. I would say the practical tip that I have is whatever you do when you get to the new time zone, um, most of the time international travel involves overnight flights, so you may arrive in the morning. Resist the temptation to take a nap as soon as you arrive because that's just gonna make things harder and harder to adapt to. So, get out, be active, eat on the new time zone, try to push through that day, and then the homeostatic drive for sleep is gonna help you through that first night.  Dr Grouse: Great tip, and definitely a tip I have failed to follow in past trips and regretted greatly afterwards. There were some other really great points that you made that as an ambulatory neurologist I hadn't thought of that was really, really helpful, including when we take care of patients in the hospital, of course, we-- we're always careful about, you know, potential sort of things we can do to minimize delirium. But in fact, there's probably a lot of things we can do to minimize disruption to circadian rhythms, which we already know that if we're not careful about, can be deleterious to health. What are some things that you recommend generally for patients who are admitted regarding monitoring and treatment that we can try to do to mitigate that effect?  Dr Abbott: So, I would say the number one most important thing that you can do, and I did this every single day when I was on the wards, is when you walk into the patient's room for rounds in the morning, turn on the lights, open the curtains. We did an interesting study a few years ago because there was all of this discussion of nighttime disruption to hospital patients and a lot of concern that they were getting too much light and too much interruption to their sleep at night. But what we found out was actually the bigger problem may be that none of our patients are getting light during the daytime, and so they've just lost that amplitude of light rhythm. And so as much as you can maximize daytime and opening those curtains, turning on the lights, giving them a bunch of light during the day. And then obviously, on the opposite end, you wanna make sure that they're getting dark at nighttime. Being really thoughtful about what your patients actually need to have done while they're in the hospital. And so, do they really need to have vitals every four hours in the middle of the night? Is that gonna change their outcome, or are they just sitting there waiting for insurance to approve their rehab bed, and they're probably gonna be fine overnight without that disruption? I think those are the easy things that you can do. The slightly harder piece is there's a lot of debate about whether we really need to be doing four AM labs on all of our patients, for example. Obviously, that's disrupting everybody's sleep. It's making a phlebotomist be a shift worker. It's problematic in many respects, but at the same time, you need to collect the labs so the labs can actually be processed and you can have the results, and they can be available for rounds, and so you can discuss them so that then you can discharge the patient on time. And so, it's a whole set of moving parts that are sometimes a little hard to optimize specifically for the patient.  Dr Grouse: Certainly, worth a discussion to have, though, and all really great tips. Another question kind of on that same vein. A lot of patients ask for something to help sleep at night. Melatonin is something we often give as sort of an easy, relatively gentle treatment that can help with sleep. Do you agree that that's a good idea? Is that something that you would generally recommend?  Dr Abbott: So, I would say that melatonin on the overall risk versus benefit spectrum probably has very low side effects for your hospitalized patient. At the same time, we actually fought this battle here. On many of the hospital formularies, you have very high doses of melatonin, so it's five, ten milligrams. Now, the problem with that is it takes you long enough to metabolize that ten milligrams of melatonin that it is still gonna be in your system the next day. So, then you go to round on the patient the next day and they're groggy and they're out of it, and it may not be that they've neurologically deteriorated, it may still be that they have melatonin still in their system. So, if you are going to use that as sort of a first-line low-harm option, I would stick to one to three milligrams.  Dr Grouse: Great. One to three milligrams is something I've often heard. Is that generally optimal dose and timing for melatonin, uh, you suggest for patients, or how do you approach thinking about the dose and timing?  Dr Abbott: So, this is where it gets a little more complicated because we actually don't recommend using melatonin as a general hypnotic. It's not that great for treating insomnia in general. So, where we do more often use melatonin in circadian patients is as a phase-shifting stimuli. So, this is something that if you give melatonin at a specific time, it can either move your clock earlier or move your clock later. And that tends to be something that is a little more challenging to sort out. It's a conversation to figure out where your patient currently is from a rhythm standpoint, where you're trying to move them to. So not something I would use typically for insomnia, but more if you're trying to adjust somebody's timing.  Dr Grouse: Excellent point and great recommendations. Now, switching gears a little bit, you had mentioned and you alluded earlier that circadian rhythm disruption can be something that we find in certain neurologic diseases and conditions we all treat and may even be an early sign of some of them. What are some general conditions in neurology that we see circadian rhythm disruption? Dr Abbott: So, I think one of the areas where it's often an early sign of a disorder is in neurodegenerative disorders. So, we often do see that that typical daily rhythm and amplitude, and what I mean by that is that sort of difference between how active you are during the daytime and how inactive you are at night. That tends to become dampened and more fragmented even before you start to see some of the other signs and symptoms of neurodegenerative disorders, so things like Alzheimer's. So, it often can be kind of an early hallmark that something else might be coming. Now, other ways that we can see circadian rhythm disruption in other neurologic disorders, I think probably the more under-recognized is in any disorder where a patient may have decreased mobility, sort of overall inactivity during the day. Maybe they have chronic pain, maybe they have really bad migraines, so they're spending lots of time in a dark room disrupting their sleep schedule. All of these things can lead to patients having more of an irregular pattern, so having chunks of sleep and wake that are just sort of distributed randomly throughout the night and the day, and they lose that overall rhythmicity to their behaviors, which then translates into a loss of rhythm and light exposure, a loss of rhythm in food intake. All of these things can kind of build on each other.  Dr Grouse: Well, that's a really good point. You know, often we think of, you know, sleep disruption causing a lot of these problems, like migraine being a very common one. But don't think about as much of the fact that the migraine itself could be contributing to the sleep dysfunction. So, a very, very interesting point there. Now, I was curious, having read the article, what isn't in the article that you wanted to put in?  Dr Abbott: So, I think the focus of this article really was primarily on the neurologic aspect of things, but I do think it's important that if people are interested in this and excited about this area, that they recognize that it's not just neurologic disorders that are impacted by this. There's a lot of really exciting research going on in the area of oncology, for example. There's some really cool research showing that the timing of your first dose of chemotherapy actually dramatically impacts your outcomes. And so, I think there are a lot of really interesting areas where thinking about your circadian system can really optimize treatment, not just within the area of neurology.  Dr Grouse: That's amazing. Well, I'll be really interested to see where that heads. And then of course, on that same topic, any new treatments or diagnostic modalities on the horizon that our listeners should be on the lookout for?  Dr Abbott: So, I think as a field, we are always looking for better ways of looking at circadian markers within the clinic. And so, multiple groups, including our own, have been looking at blood tests. So, is there a way that with one or two samples we can actually get a profile of what your current biological time is? And so, I think those blood tests are still being validated in patients with disorders. We've mostly looked at them in healthy controls. I think other areas we're looking at new diagnostic tools to actually get a sense of how people are responding to their environment. So, we're doing a study looking at using pupillometry, which is a way of measuring how your pupil responds to light, and using that to figure out whether you may or may not be somebody who responds well to light or poorly to light, and can we tailor your treatments for that? So, I think we're looking at many different ways that we can improve diagnostics in the outpatient setting.  Dr Grouse: Well, that's really fascinating. I can't wait to hear more about what may be coming around the corner. Thanks so much for sharing, and I'm sure you've inspired some of our trainees considering a career in sleep medicine. Thank you so much for sharing, and I really again encourage all of our listeners to check out her wonderful article.  Dr Abbott: Thanks for having me. It was great to have a chance to talk about this, and I second your hope that more trainees will be interested in sleep and circadian medicine. It's really an exciting field to get into.  Dr Grouse: Again, today I've been interviewing Dr. Sabra Abbott about her article on circadian neurology. This article appears in the August twenty twenty-six Continuum issue on Neurology of Sleep. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining today.  Dr Monteith: This is Dr. Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audiocme. Thank you for listening to Continuum Audio. 

Hypersomnia encompasses a group of disorders characterized by excessive daytime sleepiness that can significantly impair quality of life and neurologic function. In this episode, Dr. Margaret Kay-Stacey discusses how to recognize and evaluate hypersomnia, reviews key features of narcolepsy and idiopathic hypersomnia, and highlights the many neurologic conditions associated with excessive sleepiness. Learn practical approaches to diagnosis, treatment, and distinguishing primary hypersomnia disorders from more common causes such as insufficient sleep, sleep apnea, medications, and depression. In this episode, Gordon Smith, MD, FAAN, speaks with Margaret Kay-Stacey, MD, author of the article "Hypersomnia" in the Continuum® August 2026 Sleep Neurology issue. Dr. Smith is a Continuum® Audio interviewer and a professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia.   Dr. Kay-Stacey is an Assistant Professor of Neurology and Ambulatory Medical Director at the University of Chicago Medical Center in Chicago, Illinois. Additional Resources Read the article: Hypersomnia Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @GordonSmithMD  Full episode transcript available here Dr Smith: So, what do myotonic dystrophy, Parkinson's disease, and traumatic brain injury have in common? It turns out that each can cause clinically significant and meaningful hypersomnolence. And did you know that narcolepsy has the same population prevalence in the United States as myasthenia gravis, something I commonly see in clinic? If you want to learn more about hypersomnolence and how it impacts the patients you care for and what to do about it, keep listening.  Dr Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.  Dr Smith: This is Dr. Gordon Smith. Today, I'm interviewing Dr. Meg Kay-Stacey about her article on hypersomnia, which appears in the August 2026 Continuum issue on the neurology of sleep. Meg, welcome to the podcast, and maybe you can begin by just introducing yourself to our audience.  Dr Kay-Stacey: Yeah. Hi, I'm so glad to be here. So, like you said, I'm Meg Kay-Stacey. I'm a sleep neurologist at the University of Chicago. I'm also the AAN's Sleep Section vice chair.  Dr Smith: Awesome. I didn't quite know what to expect in reading your article, except it was gonna be about people who are really sleepy. I was really amazed at how common these problems are, even, we'll get into this, disorders that I think of as being super rare. So, I know our listeners are gonna really enjoy hearing from you. I wonder if you could begin by just defining hypersomnia and maybe give us a flavor for the impact this has on patients who have primary disorders of hypersomnia.  Dr Kay-Stacey: Yeah. I mean, so hypersomnia is really an excessive daytime sleepiness, so a feeling of excessive sleepiness, feeling like they can't stay awake during the day. And these patients' quality of life is quite impacted by these symptoms, and there's lots of different conditions that can cause it, but it can be quite detrimental to day-to-day living.  Dr Smith: I honestly am sleepy a lot cause I work too hard or stay up late, and sleepiness seems to be a very common symptom. How do you sort out when a patient's excessive daytime sleepiness is pathologic related to lifestyle and the extent to which it may be a sleep apnea versus one of the other disorders that we'll talk about?  Dr Kay-Stacey: Yeah. I mean, you really have to take a good history. So as neurologists, we know that, that we have to do that, but particularly a sleep history and really understand, first and foremost, how much sleep the patient is getting. Really important to understand, are they getting adequate sleep at night, right? Because chronic insufficient sleep can cause daytime sleepiness, right? And can make people appear like they might have a primary hypersomnia disorder when in fact they don't. So that's sort of first and foremost, and then it's assessing the other symptoms that they have. So, it's assessing nocturnal symptoms. You mentioned sleep apnea, so assessing for things like snoring and witnessed apneas, nocturia, and then assessing for what the quality of their sleep like. Is it refreshing? Is it not refreshing? How easy or hard is it to wake up in the morning? And then asking them again about daytime symptoms. Are you falling asleep inappropriately at work? Are, you know, you falling asleep while driving? Are you finding it hard to stay awake even after you've had a full night of sleep? To really try to differentiate what the symptoms might be from. And then it's also assessing things, sleep apnea, for example, physical exam findings. You know, are they obese? Do they have a larger neck circumference? Is the airway more crowded? And then we do have some measures, some scales, so there's the Epworth Sleepiness Scale that we'll use that assesses sleepiness, which is kind of a good way to at least initially assess how sleepy a patient might be during the day.  Dr Smith: So that's great, and we'll talk a bit about sleep apnea, I hope. But when I hear hypersomnia, I always think about narcolepsy, and I wonder if maybe we can begin there.  Dr Kay-Stacey: Yeah.  Dr Smith: I was super interested to learn how common this is. About as common as myasthenia gravis. Actually, the population prevalence number is exactly the same as myasthenia. My Monday morning clinic is mostly myasthenia. So how do we recognize narcolepsy? Cause I'm worrying that I'm missing it.  Dr Kay-Stacey: Yeah. So, narcolepsy, you know, there's two types. There's narcolepsy type 1 and narcolepsy type 2. So, narcolepsy type 1 is a little easier because you have cataplexy. But with both conditions, you're gonna see excessive daytime sleepiness. You're gonna ask about things like sleep paralysis, whether or not they're having sleep-related hallucinations, so hypnagogic or hypnopompic hallucinations. Are they having other sort of REM, intrusion phenomenon? You may also hear things like REM behavior disorder, so acting out their dreams at night, and then some degree of, you know, difficulty waking up in the morning, feeling like they need to nap. Naps are often more refreshing in patients with narcolepsy which is a feature that when we talk about idiopathic hypersomnia kind of helps to differentiate them. So, it's really just asking about sleepiness and assessing for these other symptoms that they can have associated with narcolepsy.  Dr Smith: I was also interested to learn that narcolepsy is the most common cause of REM sleep behavior disorder in young patients, which is pretty cool. But I wonder, you used a term that I've never heard of, and I'm betting some of our listeners haven't, which is REM intrusion phenomenon. Could you tell us more about that? Dr Kay-Stacey: Yeah. So, this is the idea that in narcolepsy, your sleep states are sort of, jumbled up, would be the way of thinking of it. You have these phenomenon where REM will persist into wakefulness. So, sleep paralysis is actually a perfect example of that, right? That you wake up and you feel like you're awake, but your body is still paralyzed, you can't move. Cataplexy is similarly a REM intrusion phenomenon, as are these hallucinations that I mentioned, the sleep-related hallucinations.  Dr Smith: So what pearls do you have for recognizing cataplexy? What's the spectrum of cataplexy?  Dr Kay-Stacey: Yeah. So, I think cataplexy, it's associated with emotion, right? And we most commonly think about it being associated with laughter, right, with positive emotion, but it's key to remember that it can happen with negative emotion too, with fright, being upset or angry. And usually when you're asking patients about it, you wanna phrase it to understand, are they having episodes where they feel like they have brief loss of muscle tone? And it can be subtle. It can be a head drop, their mouth opening, a hand dropping something, and it's brief. Usually it's seconds to just a couple of minutes. These aren't prolonged episodes, and they're not losing consciousness. They're awake, they're just having that brief loss of muscle tone.  Dr Smith: So, what about orexin? I'm particularly interested in how often it's necessary to do an LP and look for CSF orexin levels. Is that a common thing in your practice, or do you rely on clinical phenomenology in a, you know, polysomnogram with multiple sleep latency testing to confirm a diagnosis of narcolepsy?  Dr Kay-Stacey: Most commonly, you're gonna still do the PSG and the MSLT, obviously, because it's less invasive than doing the lumbar puncture. There are scenarios, right, where you may consider doing the LP. I think if someone has cataplexy and you're pretty confident in that and they have a positive PSG, MSLT testing done, you know, you really don't need the lumbar puncture, right? But if you're in that gray area that for whatever reason you have a really high suspicion they have narcolepsy, but for whatever reason the PSG, MSLT either couldn't be done or it was inconclusive, then I might think about doing the lumbar puncture. The other scenario is that there are some patients who have to be on REM-suppressing medications, like antidepressants, for example. In those patients, it can confound the results. And so, if you're not able to stop those for the MSLT testing, then that would be a scenario where I might use the lumbar puncture. Insurance is another reason that, again, if you have some of that inconclusive findings on the PSG, MSLT, that doing the lumbar puncture then can help to confirm the diagnosis, but only useful for type 1 narcolepsy, not type 2.  Dr Smith: And type 2 is like type 1 but without cataplexy?  Dr Kay-Stacey: Exactly. And then you kind of can think of it as sort of on a spectrum, I would say. There's sort of narcolepsy type 1, and there's idiopathic hypersomnia, and narcolepsy type 2 kind of falls in between.  Dr Smith: Do you require the other core features of narcolepsy to make a diagnosis of type 2, like sleep paralysis, hallucinations?  Dr Kay-Stacey: Right. You do. You don't necessarily have to have all of them, but you will see similar features, though most of them are more common in, in type 1 than in type 2.  Dr Smith: So, I'm understanding you need to see, REM intrusion phenomena.  Dr Kay-Stacey: Mm-hmm. Yes.  Dr Smith: I love saying that. Makes me sound like I'm part of the sleep team. Now we're all part of the sleep team, aren't we?  Dr Kay-Stacey: Yeah.  Dr Smith: What about idiopathic hypersomnia? In reading about it and thinking about it, it sounds a lot like narcolepsy without those other features, but there, there are some differences. I wonder if you could give our listeners pearls into how to recognize that as opposed to maybe type 2 narcolepsy.  Dr Kay-Stacey: Yeah. So idiopathic hypersomnia patients are also very sleepy during the day. They're more commonly going to describe that they sleep through the night, often for long hours, and that they wake up and still feel very unrefreshed. They'll have what we call, morning sleep inertia, or some people call it, you know, sleep drunkenness, where when they wake up in the morning, they feel like they're in a haze or a fog. It's really hard to get out of bed. They're often setting multiple alarms. And this is after having a full night of sleep, ten, twelve hours of sleep, and then they just feel tired and sleepy all day. If they nap, their naps will often feel unrefreshing, and when they take naps, they're often longer naps, and then they wake up and again will maybe feel some of that sleep drunkenness or inertia, and it makes it difficult for them to wake up. And then they don't have as many of the REM intrusion phenomena, but you still can sometimes hear things like sleep paralysis or the hallucinations in patients with idiopathic hypersomnia. And so that's where it does get tricky when you're trying to differentiate from narcolepsy. Really, the difference with narcolepsy and idiopathic hypersomnia when you do testing has to do with what you see on the overnight sleep study on the polysomnogram followed by that multiple sleep latency test. In the case of all three conditions, the MSLT should show a mean sleep latency of eight minutes or less. What separates narcolepsy from idiopathic hypersomnia is that in narcolepsy, the expectation's you'll have two or more sleep onset REM periods, so you go into REM sleep very quickly. Whereas in idiopathic hypersomnia, you'll have one sleep onset REM period or less. Traditionally, you'd think of that you wouldn't have any, but you theoretically could have one on that. So, that's sort of one way that we can differentiate the two.  Dr Smith: That's really helpful, actually. Thank you. What about treatment? There are a whole bunch of different medications that you talk about in your article, including, medications that are in the pipeline, which is exciting. What's the treatment approach, maybe starting with narcolepsy?  Dr Kay-Stacey: Yeah. So, with narcolepsy, there are more FDA-approved medications and options then there are for idiopathic hypersomnia, which is, you know, one of the things I hope will change over time with things that are in the pipeline. But with narcolepsy, traditionally often start first with an alerting agent such as modafinil or armodafinil to really help with those daytime symptoms. And then there are a number of other medications that can be used. Sometimes if the armodafinil, modafinil don't work, we'll advance into stimulant medications that are amphetamine containing. At night, there's a medication called sodium oxybate that you can take for narcolepsy. The low sodium oxybate is actually also approved for idiopathic hypersomnia. But sodium oxybate, the idea is that you're taking it at night, and it's helping to reduce the disrupted sleep that occurs in patients with narcolepsy, really kind of enhances slow-wave sleep at night and makes the sleep that patients are getting better quality, which then improves both excessive daytime sleepiness during the day as well as the cataplexy. And then there are some other medications, solrimfetol and pitolisant, that are also used in narcolepsy. I don't wanna necessarily get into the nitty-gritty of all of the mechanisms of action, but definitely read the article to learn more about that. Dr Smith: So that's really helpful. What about cataplexy? Do these medicines also help with cataplexy, or is there a different approach for that symptom?  Dr Kay-Stacey: Yeah. So, sodium oxybate definitely can be used, and the low-dose sodium oxybate can be used to help with the cataplexy. But then we'll also sometimes use medications in the antidepressant category as well. So, SSRIs, SNRIs, and tricyclic antidepressants can all also be used to help in the treatment of cataplexy.  Dr Smith: And how about idiopathic hypersomnia?  Dr Kay-Stacey: Yeah. So, for idiopathic hypersomnia, there are, you know, as I mentioned, less treatment options and not as many things FDA-approved. But, it was exciting, low-dose sodium oxybate was approved for idiopathic hypersomnia, so it's taken at night, similar to how it's used in narcolepsy, and does improve that excessive daytime sleepiness. And then we often will also use some of the other medications off-label, so modafinil, armodafinil, and the stimulant medications. But some of the other meds like the pitolisant and solrimfetol, those are not FDA-approved for the use in idiopathic hypersomnia.  Dr Smith: So, I'm curious if we know what causes these conditions, so narcolepsy type 1, type 2, and idiopathic hypersomnia. I mean, the treatments all seem very kind of neuromodulatory in some way, you know, interacting with the REM system, for instance. What's the current thought regarding mechanism, underlying cause?  Dr Kay-Stacey: So, narcolepsy type 1, it's due to the loss of orexin neurons in the hypothalamus. So that one is sort of the easiest of them that we know that those orexin-producing neurons are lost. There are thoughts that both with narcolepsy 1 and type 2, that there is autoimmune related concept and then also potentially some genetics, though it's not completely clear that it's one mechanism or another. But certainly, easiest is narcolepsy type 1 with that loss of orexin neurons. For idiopathic hypersomnia, we're not exactly sure actually what causes it. Again, some thoughts about maybe there being an autoimmune-related phenomenon for some patients, may begin for them after they've had infection, for example. And then some thoughts that perhaps GABA receptors are impacted in idiopathic hypersomnia.  Dr Smith: Great. Well, that's super helpful, and I'm definitely gonna be on the lookout for narcolepsy. But let me pivot. I wonder if we might play a little bit of a game here. There's so many other things that cause hypersomnia, other disorders and situations, and rather than kind of march through them, I wonder if I could give you a name of a particular neurologic disease or situation and have you provide our listeners just a sentence or two about one thing they should know about hypersomnia in that disorder. You up for it?  Dr Kay-Stacey: Sure.  Dr Smith: So, let's begin with my backyard, myotonic dystrophy.  Dr Kay-Stacey: Yeah. So myotonic dystrophy, we see an association actually with narcolepsy. So, certainly with patients with myotonic dystrophy, you'll see excessive daytime sleepiness, and should be screening them for narcolepsy. You should also be screening them for sleep apnea.  Dr Smith: How about Parkinson's disease?  Dr Kay-Stacey: Parkinson's disease, at least a third of those patients will describe excessive daytime sleepiness. They can also experience sleep attacks during the day, likely has to do with dopaminergic mechanisms.  Dr Smith: So, I'm gonna ask a question in the middle of our game. So, in myotonic dystrophy, it's actually true narcolepsy. So, you would want to screen for that, and then if they meet the criteria, you would treat them similar to we spoke about earlier. All right. How about traumatic brain injury?  Dr Kay-Stacey: Yeah. So traumatic brain injury, very common for patients to experience excessive daytime sleepiness. Those patients will also experience circadian dysregulation. So, when you're interacting, you know, with those patients, you definitely wanna get a good sleep history, understand is there a circadian component, or is it true excessive hypersomnia related to the brain injury?  Dr Smith: How about multiple sclerosis?  Dr Kay-Stacey: So, MS, not as common for it to be hypersomnia per se, more common to hear fatigue in these patients. I do think, again, sleep apnea is probably under-recognized in MS patients, so making sure you're screening for that. But not-- do not classically hear, you know, primary hypersomnia disorders, more so fatigue. But MS fatigue is treated similarly to some of our hypersomnia conditions, often use a modafinil or an armodafinil for that.  Dr Smith: How about medications? Dr Kay-Stacey: So, there's a lot of medications that can cause excessive daytime sleepiness, a lot of medications that we as neurologists give, right? We're very aware that our anti-seizure medications can potentially cause excessive daytime sleepiness. The antidepressants that we use to treat various neuropathic pain conditions and migraines can cause sleepiness. The antidopaminergic medications can cause sleepiness. Benzodiazepines can cause sleepiness. Muscle relaxers can cause sleepiness. So, lots of different, medications that we use to treat neurologic conditions can create sleepiness.  Dr Smith: How about stroke?  Dr Kay-Stacey: Stroke can cause sleepiness too. Also can cause fatigue, and sometimes it can be challenging to differentiate. There's also a higher incidence of sleep apnea in patients with stroke as well, so you definitely wanna make sure that you're screening for that. But yeah, depending on the location of the stroke too, that can also contribute to the sleepiness 'cause if it's anywhere sort of along the ascending reticular activating system, it could cause a problem. Dr Smith: And maybe one more, depression.  Dr Kay-Stacey: Yeah, so depression also can be tricky to differentiate from hypersomnia, and you do really wanna make sure when you're seeing these patients that you're assessing to make sure that it's not the depression that's causing them to be sleepy. You know, patients with depression will often spend long hours in bed and spend a lot of time sleeping, and so you do really kind of have to piece that together and figure out what's what.  Dr Smith: Hey, that was fun, and I think we've probably convinced everyone who's listening to us that they probably should check out and read the article because guaranteed, no matter what you do in neurology, there's something in this article for you. One thing we didn't talk about, one of the kind of eight central causes of hypersomnolence that I thought worth kind of winding up with is insufficient sleep syndrome. I wonder if we might talk about this from the point of view of our listeners. And what advice do you have to neurologists and people who care for patients with brain disease regarding self-care and sleep self-care and not ending up with insufficient sleep syndrome?  Dr Kay-Stacey: Yeah. Great question, and I think I have been thinking a lot about just sleep in general because sleep is so important to brain health, right? I know the AAN has been big proponents of the importance of sleep, and there was lots of talk about it at the annual meeting because of that. You know, the average adult needs somewhere between seven and nine hours of sleep per night. So, if you're getting less than that, you are at risk for insufficient sleep, and that insufficient sleep builds up over time. So, you can't recover from many months or years of insufficient sleep by sleeping for just one night. And so, it is really important to make sleep a priority because when you have chronic insufficient sleep, it can mimic some of these other conditions. You can see narcolepsy-like symptoms where you're falling asleep inappropriately, where it's impacting your quality of life, potentially impacting your ability to drive. So definitely very important to really try to target that seven to nine hours of sleep per night. And I think from a self-care standpoint, if you feel like you are getting that seven to nine hours of sleep per night and you're still feeling sleepy or still feeling unrefreshed or dozing off during the day, then you really should get assessed for an underlying sleep condition that might be causing you to feel that way.  Dr Smith: So, Meg, this has really been such a great conversation, and it's a really great article. I wonder if we might wind up with one more question, which is if there was one thing our listeners should remember from our conversation, other than to kind of wait for their Continuum issue to arrive and immediately read this article, what would it be? What should they remember?  Dr Kay-Stacey: I think that if a patient is telling you that they're sleepy or tired during the day, that you really need to dig in and figure out what it is. Is it something that they themselves are doing that's behaviorally induced? Is it something that's happening with their sleep at night? Or is it an underlying primary hypersomnia condition that you can treat, right? These conditions are treatable, and you can have really a significant impact on quality of life, which is, you know, the best part of our jobs when we can actually make our patients feel better.  Dr Smith: Fantastic. Meg, thank you so much. I know that our listeners really enjoyed this. I know they'll enjoy the article as well. Thank you. Again, today, I've been interviewing Dr. Meg Kay-Stacey about her article on hypersomnia, which appears in the August 2026 Continuum issue on the neurology of sleep. Be sure to check out Continuum Audio episodes from this and other issues, and thanks to you, our listeners, for joining us today.  Dr Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audiocme. Thank you for listening to Continuum Audio.