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