Robin (00:01):

Hello and welcome to today's installment of Diagnostics and Practice, where we discuss unique diagnostic offerings from Mayo Clinic Laboratories. I'm Robin Huiras, a senior marketing specialist with Mayo Clinic Labs and strong proponent of advanced diagnostic testing to improve patients' lives.

I'm so excited to be here today with our guest, Dr. P. James Dyck, a neuromuscular neurologist and director of the Peripheral Nerve Laboratory at Mayo Clinic, to talk about peripheral nerve biopsy testing. The nerve pathology practice at Mayo Clinic is one of the oldest and most well-established in the world and is one of the few labs in the country offering nerve biopsy testing. Thanks so much for sharing your time with us today, Dr. Dyck.

Dr. Dyck (00:42):

Thank you for having me. It's a pleasure to be here to talk about one of my favorite topics, that is nerve pathology and nerve biopsy.

Robin (00:51):

Awesome. Before we get into the meat of our discussion today, Dr. Dyck, I'm hoping you can share just a bit about yourself and your experience with nerve biopsy testing at Mayo Clinic Labs.

Dr. Dyck (01:02):

Well, my story goes a long way back, and that is because my father, Dr. Peter James Dyck, actually created the Peripheral Nerve Laboratory at Mayo Clinic. My father came here in 1959, and in the 1960s he started seeing patients with peripheral neuropathy and realized there was no way to evaluate them pathologically. Nerve biopsies weren't offered at Mayo Clinic, and so he saw an opportunity and he created the Peripheral Nerve Lab at Mayo Clinic. So throughout the 1960s, he created the lab, he perfected his techniques. He created teased nerve fibers, which is a way of, under a microscope, separating out individual nerve fibers and looking at the length of pathology along individual fibers. And this was new and revolutionary, and so this was all very exciting stuff for him. The first time I personally remember having anything to do with a nerve biopsy was, I was in the lab with him as an elementary school child, and I heard a great explanation.

He says, "This is magnificent. Do you see apple green birefringence?" And I had no idea what apple green birefringence meant. And so he showed me through the microscope that by putting a filter on, that this salmon-colored material turned to an apple green color, and this is diagnostic of amyloidosis. And so I was exposed to nerve pathology as a boy. I grew up in this laboratory. Then as a high school student, I volunteered in the laboratory. I teased nerve fibers for a summer. I saw the benefits of what he was doing and the utility of it. And then my father often would take me to see patients with him at the end of the day, and that was eye-opening for me. We'd go to the clinic and he would sit down and he would systematically take histories, see patients with peripheral neuropathies, ask them probing questions, do examinations that would reveal the problems they had, and at times do nerve biopsies.

And I'd never really considered being a physician. I thought, wow, this is really interesting. This is cool. This is something I may want to do. So that is a little short background of my own experience with the Peripheral Nerve Lab in my formative years.

Robin (03:41):

That is just so fascinating, Dr. Dyck. Love hearing about your history in the lab and how your father introduced you to this specialty area of testing. You really do have a lifetime's worth of experience and such a wealth of knowledge that really highlights the expertise that goes into test development at Mayo Clinic. Now let's really get into what we're here to talk about today.

For patients with hard-to-diagnose neuromuscular diseases, peripheral nerve pathology testing can really be essential to pinpointing their diagnosis. Can you tell me a little bit about the importance of this type of testing in today's medical landscape?

Dr. Dyck (04:18):

Yeah. So nerve biopsy, again, introduced here at the Mayo Clinic in the 1960s. At its height in the 1990s, early 2000s, we were probably doing 600 nerve biopsies a year, something like that. With improved imaging, MRIs, other testing, with improved antibody laboratory testing, with improved genetic testing, the need for nerve biopsy in your average neuropathy has reduced to some degree. So we're probably averaging 350 nerve biopsies a year. However, this is not to say that nerve biopsy has become obsolete. It has not. It is still a vital technique available to neuromuscular neurologists to try to understand what is going on pathologically. We rely on this test to try to help us understand our patients' problems much more than many of our colleagues at other centers do. And I think they don't know what they are missing, because they don't have that at their disposal. So your average patient with peripheral neuropathy, we do not do a nerve biopsy.

I will say that we actually probably biopsy 5% to 10% of our patients, where 90, 94 or 95% of our patients don't get biopsied. So the question then is, who do we biopsy? How do we decide who needs a biopsy? And that is really an important question when evaluating a patient. So most neuropathies are length-dependent, slowly progressive, give you a little numbness in the ends of your toes. Most of those patients do not need a nerve biopsy. The nerve biopsy is not going to be helpful in sorting things out. So where is a nerve biopsy helpful? A nerve biopsy is incredibly helpful in patients who have multifocal neuropathies, focal areas, rapidly progressive, who have severe deficits, who are very weak, who have a lot of numbness, who have a lot of pain. And so it's those kinds of neuropathies that we really go after and try to biopsy.

What are the conditions in which we can diagnose with such nerve biopsies? I think one of the big things we're looking for is inflammatory lesions in nerve. So necrotizing vasculitis, an attack on blood vessels in the nerve, is a really important condition in which we do nerve biopsies on. And the only way really to make that diagnosis is to take a piece of tissue out, look at it under the microscope, and make that diagnosis. Another condition is amyloidosis. I've already referred to that. So amyloid neuropathy, the only way you're going to diagnose that is looking at it with tissue. Lymphoma infiltrating in the nerve. We've written a large paper about our experience with that. That's a very hard condition to diagnose, but by doing biopsies and taking a bit of the nerve and seeing lymphoma, that's really important. And that in some ways segues into another point that I want to make.

Really one of the new revolutionary things that has happened to us over the last 20 years is the use of targeted fascicular nerve biopsy. That is using imaging, MRI, to look at the nerve, see a lesion in the nerve, and know where that lesion is. So this is an area where nerve biopsies are expanding, not contracting, because we can use high-resolution imaging. Say there's this problem here, in a proximal part of the nerve where we never would have biopsied the nerve in the past, and we go in and we do a biopsy. You can't do that in just any center. You need specialized centers to do that. You need expertise in seeing people, a peripheral nerve neurologist; you need expertise in radiologists who have a big magnet and can look at the nerve and recognize what they're seeing when they're looking at the nerve. You need a peripheral nerve neurosurgeon who can go in there, take a piece of that nerve, not cause the patient terrible deficits, because nerves are wires and we don't want to cut those nerves and cause new weakness.

And so Dr. Spinner has great expertise in taking out a piece of the nerve, leaving it mostly behind, and yet making a diagnosis. And then you need what I'm here talking to you today about: the Peripheral Nerve Laboratory, that has big expertise in these patients, working up these patients and making a diagnosis. And at Mayo Clinic, we have all four of those characteristics of those attributes where we can do that. So this has been very exciting, and we've done over 300 of these targeted fascicular biopsies, and this is an expanding way that our practice has grown over the years.

Robin (09:29):

That is just amazing information, Dr. Dyck, and I love hearing about the importance of peripheral nerve biopsy testing for these patients that can't receive diagnosis in other sorts of ways, and also about how the use of nerve biopsy is expanding into new areas to get even more precise. And the fact that Mayo Clinic has the integrated, multidisciplinary teams coming together to really get to the root of a patient’s problem is so unique, and for these patients, such a gift. This area of testing sounds so dynamic, and while some people might think nerve biopsy testing is not as robust as it used to be, clearly there are growing avenues for this testing to expand into. I'd like to talk a little bit about how peripheral nerve biopsy testing fits into the diagnostic picture. Can you share a little bit about the sequence of testing and where nerve biopsy testing falls within that sequence?

Dr. Dyck (10:27):

Yeah. So I think it's a good question of where one does a nerve biopsy during the whole evaluation process. I go around and give talks about this, and my standard response is, nerve biopsy is one of the last things that one does. So you see the patient first, you evaluate them, you take your history, you do an exam, you try to understand pathophysiologically what is happening with the patient. You then send them off for different physiological tests, nerve conduction EMG, that will often tell you whether the process is an axonal degeneration process or a segmental demyelinating process. You may do autonomic reflex screen testing; you may do quantitative sensory testing, telling you which populations of sensory fibers are involved. You may do spinal fluid evaluations looking at, is there a pleocytosis in the spinal fluid? Are there elevated CSF protein glucose, other markers? You may do different antibody tests. And really only after those tests are done do you do a nerve biopsy.

Saying all that, I'm thinking, when I see a patient upfront, is this a patient I likely will do a nerve biopsy in or one that I won't do one in? So it isn't an initial step, but I, through years of practice, pretty much can tell early on, who am I going to need to do a nerve biopsy on and whom I'm not going to need to do a nerve biopsy on. And that's partly because Mayo Clinic is a unique practice in that we're not sitting in a large urban center. We're sitting in the middle of a cornfield, and so patients come in, stay in hotels, and want to have an efficient evaluation.

Robin (12:22):

Thanks, Dr. Dyck. Sounds like such a special area of expertise, and curious to know, how can physicians access this type of testing if they're not affiliated with Mayo Clinic?

Dr. Dyck (12:32):

Yeah, no, it's a really good question, and it's something I probably should have mentioned earlier in this too. Let me back up a step. So first of all, what is the typical evaluation of a nerve biopsy? I mean, so we do different preparations. One preparation which I've mentioned already is the teased nerve fiber preparation. So we separate out a hundred individual strands from a nerve. We don't just take the first hundred that we see. We want to do a systematic sampling of the nerve. So we divide the nerve into 10 different segments. We divide each of those segments into five, and then we tease out the left two fibers from each of those. So 10 times five is 50 times two is 100. So we are looking at a hundred different fibers. The reason we do this in this compulsive way is to get an even sampling across the nerve, and we look at different conditions of those teased fibers.

Is it normal? Is there axonal degeneration? Is there segmental demyelination? Are there thickening of the myelin that we call tomacular, or sausages, along the fiber? And that gives us insights into this. We then do paraffin preparations. We do both cross-paraffin preparations and longitudinal paraffin preparations. We stain them with multiple different stains to look at interstitial abnormalities, to look at amyloidosis, to look at inflammatory cells, to look at the density of myelinated nerve fibers. We then do epoxy semithin sections. So these are plastic sections, and this gives us a much better insight to what is happening pathologically in the nerves as far as the nerves’ fibers themselves. So typically you're doing a sensory nerve biopsy. If we really need to understand ultrastructural abnormalities, then we'll do electron microscopy and take it to a much higher level and look at the unmyelinated fibers there. And we also do immunohistochemistry, so different special stainings for different immune cells.

So this is a typical preparation of the nerve biopsy. About a third to two-fifths of the biopsies are done in-house, meaning they're done at Mayo Clinic. We have surgeons such as Dr. Spinner who do them, we collect them and we process them and do them here. But that means that three-fifths or two-thirds of the patients are not having their biopsies performed in the Mayo Clinic. And this is getting at the question you asked. How do outside physicians access this resource? And the way they do it is you can order a nerve biopsy through the Mayo Clinic, and we will send you a kit, and we will send you instructions of how to do that. So we send specific instructions of what we want you to do, how we want you to do it. We send you fixatives so you actually put the different nerve specimens into those fixatives, and you send them back to us. Because what we want is to have nerves that have little artifact.

So if you work using traditional pathological techniques, the nerve’s fluid will get sucked out, and it'll shrink up and it'll become cremated and it'll look like a kidney bean under the microscope, and it will give you artificial artifact that really gets in the way and it will look ugly. And so again, Dr. Dyck created techniques to avoid this hyperosmolar artifact. He created techniques to try to minimize crush artifact. Nerve is very sensitive. It doesn't like to be put too much pressure on it, and so you can crush it if you squeeze it too much. So all of these things, we give instructions, we give fixations and different fixatives to outside physicians so they can mail those kits back to us and we can really try to minimize artifact and maximize a good quality of nerve specimen.

Robin (16:22):

It sounds like we have a level of expertise and experience here at Mayo Clinic. Are you aware of any other centers across the U.S. that have a pathology practice that even comes close to what we're doing here in our nerve lab?

Dr. Dyck (16:37):

Yeah, that puts me in an awkward position because then I just have to crow about how wonderful we are. But no, I think we are incredible and we are very good. There are other centers in the country who do good quality nerve biopsies. I don't think there's any other center that's doing what we're doing.

Robin (16:55):

You talked a lot about the techniques that your father developed, which is awesome, and I love hearing that history. I'd like to know a little bit from your perspective about the challenges of doing some of these tests in your nerve lab. What are some of the main barriers, I guess, to getting a quality result, and how have you and your team overcome those challenges?

Dr. Dyck (17:21):

There's always a push for efficiency and trying to do things as high quality as one can, but still get the biggest throughput. And I think that is an ongoing challenge. We have traditionally sent a technician to the OR so they can pick up the biopsy right there, but that then takes a technician out of doing work in the lab, and so that's not necessarily the most efficient, and so we work to try to streamline that. I think we are always trying to come up with new and better ways of doing things. One major push for the institution is to transition to AI and to digitized images, and so we are in the process of getting a scanner to scan our tissue in. Some of the issues that have come up with that process is that teased fibers, 90% of the slide is just glass. There's no tissue there, or only 10% have these teased fiber tissues and they have depth to them.

So getting high-quality pictures that show you the depth of the teased fiber has been difficult. This is an ongoing thing. My father developed a morphometry system in the 1970s. He was an innovator, so he would digitize slides using gray-black scales to be able to identify different myelinated nerve fibers, both large and small, and do counts on those fibers, do size distributions on those fibers, and really give one an understanding of what was going on. A huge issue in his career was he wanted to quantify things, and so his life was devoted to coming up with different ways to quantify things. So he developed a scale called the neuropathy impairment score, which was the actual scale that was used in these TTR amyloid drug trials to show improvement in this amyloid neuropathy. So those have been a big success. He developed quantitative sensory testing in which he measured touch, vibration, cooling, and heat pain to show that those were abnormal in patients and paid normal volunteers.

He paid a hundred people to have — normal people of different ages and sex — to have nerve biopsies taken from them so he could understand what a normal nerve biopsy was, to understand how the biopsies that we're looking at are different and quantify them. So we have tried to continue in his efforts to do things at a very high standard and try to quantify as much as we can to understand not just our impressions but hard science to back us up.

Robin (20:17):

Thanks for sharing that. Let's talk a little bit about the expertise of not only yourself but the techs that work in the lab. It sounds like this is such a specialized field. I'm curious to know the type of training and experience that is required to provide top-notch interpretation.

Dr. Dyck (20:37):

No, thank you for the question. It's actually a great question, and it's really an important question and I don't think the techs get enough credit. The techs are amazing and they're great. I'm always wanting to be able to hire more and hire earlier because it takes at least two years to train a technician to process all the things that we do at nerve pathology. We've been incredibly lucky for the last 30 years we've essentially had four technicians who have all been our lab all those 30 years and now they are starting to retire and that has produced gnashing of teeth and wailing because of the sadness to see them go where we rejoice in their ability to retire and go on to the greener fields, but we are very sad for the expertise that has lost. One of our right-hand people is a technician who came in the lab — her first day and my first day were the same.

She was hired as a technician. I was just a summer help, but she and I have had parallel careers in this lab, and she's seen a lot of change. She shows up at work every morning at 5 a.m. She comes in on the weekends because volumes of the skin portion, which we haven't yet talked about, have just gone up and up and up, and she feels a responsibility to get that done. I really do want to commend the efforts by the technicians. As far as the peripheral nerve pathologist, the world is full of good pathologists, but your average pathologist has no clue what they're looking at when they're looking at a nerve biopsy. I love that about Mayo Clinic because we take our biopsies all the time to the hematopathologists and the neuropathologists, and we share things with them, but they don't know, and they'll tell you that really what's going on as far as the nerve pathology goes.

And so my colleagues in the Peripheral Nerve Lab — we are five of us — have all been trained by Peter Dyck and by myself and so we read similarly, see things similarly and I think that really builds a big consistency among us and we try very much to be able to communicate in a way that makes sense to neurologists who are getting these reports from us.

Robin (22:59):

Dr. Dyck, it's so amazing to hear about how Mayo Clinic's collaborative and integrative approach supports this type of testing. I want to shift gears just a little bit again because we've talked so much about your dad's pioneering work in this area and I'd love to hear your thoughts on the future of nerve biopsy testing at Mayo Clinic. How are you carrying on his legacy into the future?

Dr. Dyck (23:21):

In typical ways, I think I'm even going to step back and go into that question just a bit of my own personal journey. So I started out with my high school days. In college, I decided to be a physician after spending time seeing patients with my father, but I knew I was not going to be a neurologist because why would I set myself up for comparison with the great Dr. Dyck? So I was going to be anything but a neurologist. But in medical school, I learned to my horror that the best field of all in medicine was neurology. So I decided, OK, I'll be a neurologist. But then I realized my father is a peripheral nerve neurologist. Most neurology is in the brain and the spinal cord. It's in the central nervous system. So I will be just fine. I can just avoid that peripheral nervous system.

But then again, I learned to my horror, by far the best area in neurology is in the peripheral nervous system. Now, why is that? Is that because I'm wired in such a way that I'm similar to my father? Is it because my father is this amazing role model and he just excited me about the wonders of peripheral nerve disease, where I was not as turned on to other areas of neurology? I don't know the answer to the question, honestly, but then I decided, I can be a good peripheral nerve neurologist. I don't need to set myself up to being the great Dr. Dyck. And so I was quite happy throughout my career to be the lesser Dr. Dyck and let my father be the greater Dr. Dyck, and it's been a great relationship. So my father died in July of 2025. He retired in December of 2024. At that time, he was 97 years old. He was the longest-serving member of the Mayo Clinic staff ever.

At his retirement, people were told to hold their applause to the end, and when he was announced, everybody leaped to their feet, and he got a standing ovation. Even in spite of the admonition to shut up and be quiet unitl the end. And I think he deserved it. I mean, he was committed to Mayo Clinic. He was committed to peripheral nerve pathology, peripheral nerve research, and to advancing the understanding. And I get a little choked up about it, too. I mean, he was really my mentor. He was my colleague. It was an amazing opportunity I had to be able to work with him at the Mayo Clinic. He taught me things. We worked together. I mean, it just was a lot of fun. But I feel a responsibility with this incredible legacy that he's created to move us onto the future.

And this is why I went backwards with your question because I do think there is a big future here. Peripheral nerve pathology is not dead. Peripheral nerve pathology still has a life. It is still making diagnoses. I recently saw a patient who presented as a Guillain-Barre syndrome. The nerve conductions all looked demyelinating. It looked like traditional Guillain-Barre syndrome. However, they didn't respond to treatment like they should. The nerve biopsy showed vasculitis. Who would have thought it? But the nerve biopsy changed the diagnosis, and I see that again and again and again. We described a condition called CISP, chronic inflammatory sensory polyradiculopathy. These people have normal nerve conduction studies. They have inability to walk. They're ataxic. Doctors tell them that they're hysterical, but the problem is confined to the sensory root, an area that's very hard to study electrophysiologically, and by doing root biopsies, we showed inflammatory demyelination there.

We show onion bulb formation there. We found that this was a very restricted form of CIDP. We treated them with immune therapies, IVIG, and these people got up and walked again and made a huge difference to them, and that's all because of nerve pathology. So you cannot convince me that neuropathology is dead. It has a life. It is going strong. It just needs to be used in the appropriate ways. I think our challenges now is, how can we get AI involved to pick up subtleties in biopsies that we ourselves don't see? How can we use digitized pathology in a good way? And then, what are new other staining and techniques that we should add to the lab that we're not doing now? I think we always need to be asking these questions. We need to be innovating. It is what our legacy is, is what Dr. Dyck did, and so I think we need to continue to do that in the future.

Robin (28:27):

Yeah, that's great to hear. It sounds like there's so much to look forward to in the future in this area of testing, and it's great to hear that you have such strong commitment to continuing to improve this very niche area of study. We're nearly out of time today. So I just wanted to ask you if you have any final thoughts on how our testing serves patients before we wrap things up.

Dr. Dyck (28:50):

Yeah. One area that we haven't talked about, which I do think we should talk about just a little bit, is that about 15 years ago we introduced skin biopsies into the lab, epidermal nerve fiber testing. And in fact, this is another area where my father was very innovative in. So Charlie Bolton, who was a resident at the time and he, in the mid-1960s, thought that one way of looking at neuropathy may be to count receptors, sensory receptors in skin, so Meissner corpuscles in skin, to see if this would be a good way to diagnose neuropathy. So they did skin biopsies and counted them. They found that in young-aged people, the density was normal; in middle-aged people, it was sort of scattered but they were there; and in old people, they often didn't find any. So they felt maybe this wasn't going to be a good way to look for neuropathy since most neuropathy happens in old people.

There was a guy called Bill Kennedy who was a resident at the time. He then, when PGP 9.5, a stain to identify nerve fibers in skin became available, he reintroduced the idea of doing skin biopsies to look at small fiber neuropathies. And in the mid '80s he did this. And in the '90s and early 2000s, skin biopsies took off and became the rage to diagnose small fiber neuropathies. Small fiber neuropathies are painful neuropathies, often in the feet and by counting skin fibers in nerve fibers, you can diagnose them. And so we came back to using this technique 15, 20 years ago, even though the idea originally came from us, we didn't do it until somewhat late in the game. This has kind of exploded. This has been one of our challenges is that our numbers of doing these go up and up and up.

Some people think skin biopsies have replaced nerve biopsies. That is a fallacy. All you're really doing with them is counting fibers and really saying yes or no. Do you have a small fiber neuropathy? Don't you have a small fiber neuropathy? But it doesn't get at all the other stuff that's happening in the nerve. So this is also something that we offer. This is also we have send-out kits and people can order. So I just think we should have a conversation about that. Final thoughts as far as the Peripheral Nerve Lab. The Peripheral Nerve Lab at Mayo Clinic is alive and well. There are challenges that we are facing. I think it is an appropriate question to continue to ask ourselves: who needs a nerve biopsy? Who doesn't need a nerve biopsy? We want to order biopsies on people who need them. This is not about making money.

This is about offering a service that's good for patients, but it absolutely changes the lives of many patients. And so I am a strong advocate for nerve biopsy and the continued use of nerve biopsy.

Robin (31:44):

Thanks, Dr. Dyck. You really did hit the nail on the head when it comes to getting the right answers for patients. And it's amazing to hear that we're continuing to evolve and look at new approaches for finding answers for all patients, even those with very challenging and complex conditions. I'd like to thank you again for joining us today and for sharing your time and wisdom and stories with us, especially about your dad and how you worked together through the years to really elevate this practice to be one of the best in the world. I've really enjoyed talking to you, and I sure hope our listeners have as well. And to our listeners today, thanks for joining us. We hope you'll tune in again for our next installment of Diagnostics in Practice.