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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
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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
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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
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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
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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
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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
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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.