Small fiber neuropathy

Written by:
Dr. Geoffrey W. Rutledge
Chief Medical Officer and Co-founder
Last updated on March 24, 2021

An essential part of HealthTap’s mission is providing opportunities for learning and connection for our doctors. On Sunday, March 21, 2021, at the quarterly HealthTap Doctor Network Webinar, Dr. Bennett Machanic, an experienced neurologist who has been with HealthTap since 2010, gave an excellent presentation on small fiber neuropathy. Dr. Machanic provided concise insights on how to approach small fiber neuropathy for the primary care provider. HealthTap is delighted to share the learnings from his presentation below:


We're going to talk about a procedure, which I instituted into my practice a couple of years ago, and I've actually done about a thousand biopsies. Why I'm going to talk about this is because not only does it reflect how neurologists think about peripheral nerve disease, but how generalists should think about nerves and chronic pain.


And this really is a talk about pain, but it's also a talk about instituting a tool for your practices because a skin punch biopsy, which is the tool used to evaluate small fiber neuropathy, can be used by any physician safely, efficiently, successfully, and insurance covers it. So it enhances the bottom line of your practice. Now, when we talk about small fibers, we talk about the smallest fibers. Those that cannot be seen with the resolution of an EMG nerve conduction study. These are the A-Delta and the C fibers, and the C fibers are the smallest fibers. They lack the insulation or the myelin.


As you can see here, there are different sizes of fibers and different conduction velocities. The larger fibers conduct faster, the smaller conducted slower, the smallest fibers deal with our sensation of pain and temperature. That is, is it a hot and cold? And indeed is pin sensation perceived? The larger fibers deal with light touch. Those are the A betas proprioception of vibration. The A alphas. We can study A alphas and A betas using EMG nerve conduction techniques. We cannot uncover what's going on with the small fibers using these techniques. So therefore we need to be able to put the small fibers under the microscope to see what is going on.


Here's our EMG. Again, we can do a lot of things with an EMG. We can look at amyotrophic lateral sclerosis. We can map out the distribution of a herniated disc. We can look at large fiber peripheral neuropathies. We can of course, focus on motoric function with needle electrode exam. But again, this is not what I'm talking about here. This is not looking at pain management.


Now a small fiber neuropathy presents with normal reflexes, normal vibration and proprioception. Many of these patients seem to be difficult to objectify. So we do an EMG and guess what? The EMG comes back normal. So what do we say as physicians? My goodness, this patient doesn't have anything objective. So we're going to diagnose maybe malingering, maybe a neurosis or an emotional disorder, maybe reflex sympathetic dystrophy, chronic regional pain syndrome. And by the way, I didn't list fibromyalgia, but that should be on this slide.


Our small fiber neuropathy patients may present in a varying fashion. They may be nonspecific. They may be deceptive. Yeah, they're complaining about numbness and tingling. And then they have this pain, that pain can be varying. As you know, pain is subjective. Anyway, it can be a burning, stabbing shooting, prickly electrical. Symptoms can be intermittent — why are they intermittent, even though the anatomy stays the same? Now, that's because we have good days and bad days, we have emotional days and less emotional symptoms may be widespread. Many of my patients complained of total body pain. They were referred to me in desperation. Doctors asking me to do a small fiber biopsy. Well, lo and behold, many of these patients had positive biopsies.


And as you see on this slide, we have the causes, or idiopathic, which means we as physicians cannot discern the cause. However, I found in about two to three years of followup many of these patients wound up having clinical diagnoses that were proven. By far the most frequent diagnosis that I was able to correlate was either diabetes or impaired glucose tolerance, otherwise known as pre-diabetes.

Now there's an interesting situation with Sjogrens. Sjogrens is not a specific disorder all the time. It's sometimes very difficult to diagnose. I picked up a couple of biopsies that were positive for small fiber disease. Patients did have Sjogrens, but didn't have dry eyes, did not have dry mouth. Did not even have lesions on an MRI over the brain. And by the way, Sjogrens can sometimes be confusing for primary progressive MS. Paraproteinemia, as you know is a widespread area. I won't get into that today, that's beyond the scope of the lecture. By the way, guys, I had two cases of sarcoidosis presenting with small fiber neuropathy. They did not have pulmonary or hepatic problems at the time that the diagnosis was made. And you know, the percentages of lung involvement with sarcoidosis go beyond 90%. Both of these patients were diagnosed based on angiotensin converting enzyme levels, and later on, they did develop pulmonary problems.

HIV small fiber neuropathy occurs late. Usually it's not a challenging diagnosis. Celiac disease can be, and many of these patients have small fiber nerve problems. Amyloidosis, and I should include porphyria, are both incidental neuropathies. I had a number of cases of Ehlers Danlos. We already knew they had connective tissue disease but biopsy showed small fiber neuropathy. But these people can have some pretty weird things, like involvement of the celiac plexus. And of course there are other genetic disorders, Fabry's disorder for example. I biopsied one which was positive. They have pain. Maybe that's the reason for their pain. I don't have more than one patient with Fabry's.


Skin biopsies were developed at Johns Hopkins university. They are well-documented, they're safe, they're efficient. They're easy to do. You take a small tube, the width of a ballpoint pen tip, you punch into the skin. You get epidermis, dermis, subcutaneous tissue, pull it out via trochar, put it in a specimen tube, send it to the specialty lab overnight. It's not Quest. It's not LabCorp.


And here you see these little wires. These are unmyelinated nerve fibers. The arrows are pointing to. And you notice slide A has wider density. Slide B has fewer.


Here's normal nerve fiber density. We know the normal numbers by the way, from the specimens we send out.


Here you see, there's just one left.


Sometimes we get lucky. We'll look under the microscope, and we see blebs or swellings in the nerves. Sometimes we see amyloid on Congo red. Sometimes we see clusters of lymphocytes. That's consistent perhaps with arteritis, vasculitis, or perhaps even an immune disorder.


We can biopsy over the trunk. You see small fibers are everywhere. I could biopsy over the face or tongue. My patients weren't happy about that. So they wanted me to do the leg and here again you see there's differences in what we biopsy.


Takes a couple of days to get this done. Uh, this is a promotional slide, the lab is called Corinthian Reference lab (CRL), but you can send this to Johns Hopkins, Mayo clinic. You can send it to UCLA and a lot of labs that can do it. And they just have to be interpreted by experienced neuromuscular neurologist or dermatome pathologists.


So we can objectify people who have small fiber neuropathy. This can give us a differential diagnostic approach. We can take these nerves and compare them over time. We can do serial biopsies. We can see, is our therapy working, or is the patient getting worse? Is it unchanged?

Actually the treatment changes can be seen as little as three months. I often saw changes as late as nine to 12 months. And it was amazing because some of the patients I treated turned out to have no clinical signs or peripheral nerve disease by a year.


Interestingly enough, if the biopsy is positive, you can use the nerve pain suppression medications, the Gabapentins of the world, Lyrica, Cymbalta, amitriptyline. 85% did better on these medications. Of course, these don't cure the neuropathy, but they made the pain controllable. You have 37% of negative biopsies did not respond. That's of interest, isn't it, that's almost placebo.


You can see a number of trials; I'm not going to comment on anything other than medical food Metanx, which is methylated folate, B6, and B12. I was suggesting getting the generics, a lot cheaper. FDA has approved this combination for diabetics' small fiber neuropathy. Acthar is too expensive to use.


Here's where the science is heading. I won't belabor that because of our short time, but there is a future. And if more doctors get involved in this, we're going to get more information.


Now we have less well-defined disease states. I mentioned Sjogrens, which I find to be often poorly defined, although later on it may become classical. But we have this category of fibromyalgia.


Here's a study that was done by the guy who got me involved in this, Todd Levine. He took 56 patients labeled as having fibromyalgia. There were classical cases. They had 18 or more points of tenderness or rebound. They seem to have allodynia at times. And these 56 patients were biopsied in the legs. 61% had small fiber neuropathy. So it's no longer fibromyalgia. 73% of that number were proven to have an underlying diagnosis, which previously had been unsuspected.


How do you do this? Well, I do the leg. Proximal thigh distal thigh, distal calf. Some of my podiatric colleagues do the foot. Usually I did it only unilaterally. Typically I would not do bilateral because the exam was symmetrical.


Here's a way of approaching it. This is a simplified approach. This is not the way we do it now. This is the way we start. But now we have triages. We can look at length-dependent neuropathies where as expected, the problem is worse distally, better proximally. But we also have spotty neuropathies where it is worse proximally, and this suggests we may have auto-immune disorders, vasculitis, et cetera. And as you can see, as you know, there are ways of making clinical correlations with blood studies and that's basically how we start.

So I'm going to leave it at that, at this point, we are short on time.

[Dr Rutledge] Thank you, that was remarkable...

Ben, did you have any final comments you wanted to make to your colleagues on the call?

Yes. I want them to encourage my colleagues if they wish to learn how to do this, it's a simple procedure, it's safe. I had only two infections and those were minor skin infections, when patients got the biopsy sites wet, and ceftriaxone cleared them rapidly. I've never had any scars that I know about. So if you'd like to learn about this, insurance covers it, it enhances the bottom line beautifully. But on top of it, it's very intellectually interesting and we've gone a lot further than I intimate today. So I could provide you additional information. Contact me on the site.

[Dr Rutledge]. If you have such information you'd like to share with the network. I'd be happy to pass it along. As I say, I apologize for not leaving more time for questions and answers after this, but, please feel free to send them to me...And I'm just going to say, thanks again for your presentations today are and have been greatly. Appreciate it.

Thanks so much.

[Dr Machanic] You're most welcome.

[Dr Saghafi] Thank you.

Dr. Geoffrey W. Rutledge

Dr. Geoffrey W. Rutledge

Chief Medical Officer and Co-founder
Geoffrey W. Rutledge MD, PhD, FACMI, Chief Medical Officer and co-founder at HealthTap, is a double-board certified physician who practiced and taught medicine for more than 25 years. He earned a PhD in medical computer science from Stanford, was an NIH-funded researcher, and served on faculty at Harvard, Stanford, and UCSD medical schools. Before HealthTap, he created the first consumer health website and PHR at Healtheon/WebMD. Learn more about HealthTap's Medical Editorial Board at

More articles in Doctor Insights

Doctor Insights

Hypertension Care: Medications and Follow-up Visits

Let’s look at how doctors care for high blood pressure (also known as hypertension) with lab tests, lifestyle improvements and medications, while watching for possible side effects of medications.
Doctor Insights

Home Blood Pressure Measurement

Correct measurement and interpretation of a person’s blood pressure (BP) is essential in the diagnosis and management of high blood pressure (hypertension).
Doctor Insights

Blood Pressure: It’s on the rise

If you experienced a rise in blood pressure (hypertension) during the COVID-19 pandemic, you’re not alone.
Doctor Insights

In Virtual Care, Bedside Manner Matters

Good physician communication skills rank high among surveyed patients
Doctor Insights

Hypertension Treatment Guidelines & How to Incorporate The DASH Diet

Dr. Clarence Grim, MS, MD, an endocrinologist and expert in complex hypertension management, presented new guidance on treating hypertension with a focus on how to use the DASH diet.
Doctor Insights

The Omicron Variant: What You Should Know

Does this new variant pose significant additional risk? The answer is nuanced.
Read more

Not just a doctor —
your doctor