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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
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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.
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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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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.

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