Board Review Neurology

Is there an effective treatment for diabetic sensory neuropathy?

Lawrence Lavery,

Lawrence Lavery, DPM, MPH discusses signs and symptoms of small and large fiber diabetic neuropathy and reviews current studies and reports on non-traditional treatments.

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Goals and Objectives
  1. Review large fiber and small fiber neuropathy in diabetes
  2. Describe the signs and symptoms of DPN (diabetic peripheral neuropathy)
  3. List methods for diagnosis of DPN
  4. Explain the evidence for alternate treatments of diabetic neuropathy
  5. Describe the implications of reported placebo effects during treatment
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  • CPME (Credits: 0.5)

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    Release Date: 03/16/2018 Expiration Date: 12/31/2018

  • Author
  • Lawrence Lavery,

    Professor and Director of Clinical Research
    Department of Plastic Surgery
    University of Texas
    Southwestern Medical Center - Dallas, TX

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    Lawrence Lavery has nothing to disclose.

  • Lecture Transcript
  • Bob: I’ll move on to our next speaker talking about what I believe I’ve said is the most important complication of diabetes that leads to many other complications of long term diabetes, not just neuropathy. So I’ve asked Larry Lavery to give us a talk on neuropathy and is there an effective treatment for peripheral neuropathy that we see so commonly. So I’ve asked Larry Lavery who is a professor of plastic surgery at UT Southwestern in Dallas. And Larry will come up – Larry has got several talks for us today. So let’s welcome Larry Lavery. Thank you.

    Larry Lavery: Thanks Bob. I appreciate the opportunity to participate in this. I love talking about neuropathy because I think it is a, like peripheral vascular disease I think it’s misunderstood by the general medical community and by podiatry and often undiagnosed or misdiagnosed or how we operationalize what neuropathy is poorly done. So it’s an interesting -- just to talk about the diagnosis which I am not going to spend a lot of time on, I think it’s an interesting--.

    Okay, here are my conflicts of interest mostly related to research. There we go. Okay, so I am going to discuss the evidence for some non-traditional treatments for diabetic neuropathy. I am mostly going to focus on large fiber neuropathy rather than small fiber neuropathy. I think some of these are maybe products that you’ve used. There are several more that I'd like to talk about but with time limitations, you know I'll just address these three.

    Okay, so this is an example of, I think how broad the definition for diabetic neuropathy is. So this is a consensus panel's definition of what peripheral neuropathy is and it's -- the consensus definition is, the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes.

    That means if a patient comes in and says, I have some tingling in my feet. Or if you have EMGs and vibration perception threshold testing and you know higher level testing both of those people diagnosed with diabetes. As a profession we have embraced a sole diagnostic tool mostly using a 10 gram Semmes-Weinstein monofilament for loss of protective sensation.

    As a matter of fact students are taught that the physical exam criteria is loss of protective sensation, that’s the diagnosis. So if a student or resident comes into our clinic and I ask them to evaluate someone for neuropathy, they’ll have a 10 gm Semmes-Weinstein monofilament. They will not know how to do deep tendon reflexes or use a tuning fork or ask or interview the patient.

    I mean, we bought into the sole idea that 10-gm monofilament measuring large fiber neuropathy is the only criteria for sensory neuropathy and it’s broader. So I think you kind of short change yourself by diagnosing people that have burning foot pain or subjective neuropathy and no clinical exam findings if you are just so focused on kind of an old traditional way of diagnosing neuropathy.

    So this is from a patient from a paper from our clinic but I think the other thing that we do we don’t do well is differentiate patients that have small fiber neuropathy and large fiber neuropathy. Dr. Vanik has a long talk that goes into this in great, beautiful detail, but I think for 30,000 feet this is all we need.

    So mostly small fiber neuropathy, if you are going to diagnose it it’s going to be a difficult diagnosis based on thermal laws or people not being able to differentiate hot from cold, very difficult to do in private practice. You are going to diagnose most of these people because they are going to come in with symptoms of burning pain or radiating pain in their feet. So this is kind of the classic burning foot syndrome patients.

    What’s interesting to me as I see lots of people whose internist they put them on Neurontin which is I think the only drug that they use. With no diagnosis in the medical record that they have neuropathy.

    Even when they come in with symptoms and they treat it they often don’t diagnose it. What we see and the risk factor that Bob was talking about for diabetic foot ulcerations is large fiber neuropathy. So it lends itself much easier for clinical examination.

    A 128 hertz tuning fork will help you distinguish vibration sensory loss. This is where the 10gm Semmes-Weinstein monofilament comes in because people’s pressure perception is reduced. Often these people will have absent deep tendon reflexes so if you do deep tendon reflexes on the Achilles tendon or on a patella on normal people you will see that it’s almost impossible to get people in the lab a severe sensory neuropathy and have a foot ulceration.

    So I try to tell students and residents when they rotate, do deep tendon reflexes on everyone and then you’ll know what abnormal is. You know you use your 10gm monofilament on everyone, your tuning fork on everyone then you’ll understand how profound neuropathy is because a normal person feels a very small amount of pressure.

    So when you use a 10gm monofilament and people pause and you have some they say, yes I felt it. And we say where? And they’ll say, my right foot. You are just like, no, no you don’t even get the foot right. So you have to understand the breadth and depth of neuropathy, it’s not a single diagnostic tool it’s certainly just saying diabetic neuropathy can mean a number of different things.

    So our current treatment for neuropathy really focuses on small fiber neuropathy and you know there is several new probably five, seven years now there have been drugs that are FDA approved to treat neuropathy, still the medical community falls on Neurontin or gabapentin I think as a first line of treatment. It’s not FDA approved for neuropathy. I think it’s a hard drug to get people to an effective dose regimen and I see people have been on 300mg of Neurontin with no dose escalation for a year or two years or three years and their internist isn’t very aggressive about dosing it.

    So I am not really going to focus on the traditional pharma approach to small fiber neuropathy, I am going to try to focus more on large fiber neuropathy. So there is some great things that as podiatrist we bought into hook, line and sinker some of these had some actually very interestingly had studies that were published in really good journals and the reviewers missed that that analysis was wrong. So I think a classic example is monochromatic infrared light therapy so this was touted to reverse large fiber neuropathy in a very, very short period of time and to heal wounds if you know it would generally be your cavities, your hair would grow, you’d taller you would lose weight, I mean this was going to be a fabulous treatment.

    If you look at the literature about light therapy and laser therapy and the spectrum of light therapy there is some good data. There is some good animal studies for other modalities but nothing fixes large fiber neuropathy in six weeks. So what’s interesting is there were two – there is some randomized clinical studies, there were two positive studies and two negative studies. There is a strong placebo effect, certainly there isn’t in small fiber neuropathy and people have pain.

    And what I was surprised in one of these studies was to say that I did there is a strong placebo effect and you ask people about their improvement in large fiber neuropathy and you test them. The error in the positive studies that used monochromatic light therapy is they only looked at within group comparison they didn’t compare the change in the placebo and the change in the treatment group.

    So I mean, for podiatrists and a lot of people in medicine, you know, it’s a relatively small statistical nuance but it’s the foundation of the error and we actually use this in our journal because it’s a classical faux pas that you should use in clinical studies. So this is a paper by Lanyard that was published in Diabetes Care, a great journal, usually have rigorous reviews. It was a prospective randomized clinical study that looked at 27 patients, and these guys hung their hat on using the 10-gm Semmes-Weinstein monofilament as their primary endpoint, which is a difficult endpoint because of the quality of monofilaments; they wear out; and the subjective nature of the exam.

    So these are patients that that receive basically six treatments and had serial 10-gm monofilament testing. They -- in their analysis they said there was no change in subjects that had severe neuropathy and they eliminated them from the analysis. Well, you know, now you are not supposed to do that. Actually in 2004 you weren't supposed to do that.

    Everyone that was in was supposed to be analyzed. Intent-to-treat analysis is kind of the flavor of the day and it’s not going any place. So if you look at these groups that were treated and not treated, all they did was they said, you know, we are going to compare the treatment group and their change and the placebo group and their change. And what you want to compare is the change between the groups, not within the groups.

    So there's actually a change within the groups that is not statistically significant, but it’s enough to make the treatment group not significant. So then there was a follow-up study by Arnold, and this was published in, you know, a pretty decent journal and they did the same thing. But what they missed was there was a huge placebo effect in reporting of large fiber neuropathy so in the sham group, you know depending on the site there was a 50 to 70% improvement in sham therapy.

    So you should probably just use sham therapy because it’s you know you get a huge benefit and it cost the patient less. Actually when I presented this data in the meeting an internist said, we should give this to people because 50% active were sham it’s pretty damn good, better than not doing so I’ll do that. So then we did a larger randomized clinical study, all these studies were weeks in length so we did a randomized clinical study it was blinded.

    It was a nice study because the group that got the sham therapy just the lights went on. They didn’t get you know the monochromatic infrared light. So everyone thought they got active treatment. We enrolled 69 subjects with type 2 diabetes or type 1 diabetes and type 2 diabetes their VPP [phonetic] 0:12:06] had to be between 20 and 45 and they got active in sham group.

    They used this at home 40 minutes a day for 90 days so all these other studies were weeks, this is for three months. We compared four different grade levels of 10gm monofilament we did nerve conduction studies, vibration perception threshold studies that give you a semi quantitative measurement of neuropathy. We looked at quality of life. So when you looked at Semmes-Weinstein monofilament back down everyone else said was significant.

    We had a significant improvement in the level of monofilament people can feel, in 11 patients that receives sham therapy and six people that received active therapy, so obviously no difference.

    When we looked at vibration perception threshold, again there is no difference. If you look at the people that got the monochromatic light therapy and active treatment group essentially there is no change, no significant improvement in vibration perception threshold in either group.

    When you look at nerve conduction studies which is kind of the gold standard for sensory change, no difference when you compare T1 in the first and second time interval. So more rigorous study, longer treatment period, no difference.

    I think the previous studies just did not make sense physiologically; you’re not going to change large fiber neuropathy in 6 or 8 weeks, you’re not going to change it probably in 90 days. So we need not bite a sales rep of enticing the information.

    Next I want to talk about Metanx. A lot of you have heard about this. There have been some interesting small studies. It’s a medical food product, has been kind of grandfathered into the FDA as a medical food, it’s dispensed by prescription. So there are some prospective non-blinded series, there’s some animal studies, and there’s some randomized clinical studies that help support this.

    We’ll start with the animal studies because I think this is where pharma goes and where I think we should go, that start maybe get a little taste to see if this looks like it’s a good product in animals. So Zucker from LSU did the study. They used a Zucker fatty rat which is an obese type-2 diabetic model rat.

    They treated one group with Metanx and they had a control on that didn’t get Metanx. So they looked at nerve conduction results, and the treatment group demonstrated a significant increase in the sensory component of nerve conduction velocities compared to controls. I mean, if you see the setup to do NCBs in a rat -- I mean, you think it’s interesting in humans. It’s -- you know, you have to find these little nerves in rats because we've tried to recreate this.

    Then they looked at some of the histo of these patients. There was a 26% loss of small nerve fibers, and only a 15 in the treatment group the nerve fiber density was 15% higher. So change in physiology at this as well. So a little taste, maybe there’s no facts, the nerve conduction velocities that reflects things on the cellular level, so then there’s a couple of prospective cohort studies; not the strongest evidence but still pretty. Small studies, 16 patients with diabetic neuropathy that had sensory loss using TSST testing.

    The outcomes were measured at baseline six months and a year. So when you look at this, you can see the sites that were casted and a baseline compared to six months and one year, there were some significant changes.

    So at the 2-point discrimination, the great toe at the medial heel, okay. Small study, maybe there are some selection bias, but you know, maybe there is something to this, and then there was a comparison of Metanx to patients that had a partial response from pregabalin to manage their diabetic neuropathy.

    With results from a 20-week open-label study that was relatively, again small cohort study, you can see that there is this interesting change of reduction in the results of these people after failing from the standard of care for small fiber neuropathy, that the mean absolute pain reduction at 20 weeks in the study group was 3 compared to 0.25. Most of us would love to have that benefit on their patient. So a small fiber neuropathy study looks pretty good.

    So this led to a relatively large placebo controlled randomized clinical study that was performed at six sites and published last year in the American Journal of Medicine. So this study was only 6 months duration which I think is one of the flaws of the study, but was kind of a proof of concept study.

    So it was really assessed that this medical food compared to placebo in 214 people with large-fiber neuropathy, maximum fiber neuropathy. We looked at change in vibration perception testing as the primary clinical outcome. That may have been the wrong outcome as well.

    And then we looked at neuropathy symptom scores, various compounds in the study as well. So if you look at the score, there was a significant reduction in their symptoms, not in the vibration perception threshold. So large fiber neuropathy clinical findings were not improved. The self-reported symptoms though, there was a significant improvement.

    So this is basically a 6-point scale where you ask people about their numbness, tingling, aching, burning, lancinating pain or allodynia and they rate it. So it’s a subject of review. And then we used a SF-36 for self-reported quality of life, and there was an improvement in the people that were in the treatment group, and actually a small negative change in people that had the placebo in this group.

    So this data is now -- they’ve taken this data and they are now doing a much larger, longer, randomized clinical study with this medical food to see if during a longer period of time, if not only way you continue to get subjective improvement in large and small fiber neuropathy, but you’ll get a real change in large fiber objective measurements.

    So I think it’s promising, I think the jury is still out and it’s going to be probably 5 years realistically before we hear anything about this. I think the company is dedicated to do this directly and it should be a very compelling, interesting study for something this simple to look at.

    I want to finish by talking about electrical stimulation for neuropathy. It’s been around for a long, long time. Recently published a review of a little snippet of the data I’m going to present to you today. There's really some pretty compelling evidence that electrical stimulation increases profusion, that it accelerates wound healing in a variety of wounds, and that it improves some aspects of neuropathy, probably mostly small fiber neuropathy, not large fiber neuropathy.

    So there are a number of prospective clinical trials in this area, but there is a body of randomized clinical studies. Most of them are small. This isn’t, you know, a pharma drug where there’s a lot of [Indecipherable] [0:20:43] and they’re going to enroll 700 people and spend $5 million. So these are small projects, many of them done by physical therapists.

    So this is a table that has a number of studies, I'm going to focus on one of them as an example. So there's 6 randomized clinical studies. They really focus on improved symptom of small fiber disease. The results show no improvement in large fiber neuropathy. They are short studies, they are small sample sizes, so the same problem as the Metanx study, you’re not going to change large fiber neuropathy in a 2-month or 3-month study probably.

    So this is a study by [Indecipherable] [0:21:28] in 2005, and there’s a whole bunch of different wave forms. And you know, it’s kind of like when you talk to people about, how you're still doing the matrix products. They will tell you mine is better because it’s linked or it’s not linked or, you know, everyone else has had the titers and we don’t. I mean, these people will argue about their waveform and they get copyrights for their waveform. It doesn’t seem like it makes a difference in the wound healing literature or their profusion literature.

    A lot of different applications, TENS, high pulsed galvanic electro-stimulation, pulse electromagnetic fields, all seemed to have a positive effect. So this was a small study. Fifteen people got placebo -- or fifteen people got active therapy. Sixteen people got placebo. The great thing about these studies is they're sub-sensory electrical stimulation studies. So the placebo is awesome because most people think they get it.

    So this was also a 10-week study – short study. Probably not short to look at pain changes, but it’s really short to look at large fiber neuropathy. So they looked at patient’s daytime pain level using a visual analog pain scale measurement, kind of classic.

    They looked at between group changes. So there’s a 29% versus improved reduction compared to a 2% increase in the placebo group, so that was significant. The second thing to look at was night pain. People with small fiber neuropathy often have exacerbation at night. Similar to the other group, there was a 25% versus a 9% improvement in night time pain in the placebo group; also significant.

    And then they looked at vibration perception threshold, a measurement of large fiber neuropathy. So very similar to the A9 [phonetic] study, there was no change, or there was a 2 or 3 volt difference. Not only was this greater than 5%, it was like 0.8, no change between groups in vibration perception threshold.

    And then they looked at monofilament testing – no change. So I think you expect that in a small study. I think that the change in small fiber neuropathy is interesting. This is only the things that insurers will pay for is electrical stimulation after people have failed traditional oral medication or traditional approaches for neuropathy. So this is one of the things that you can go to payers and actually get this product for your patient and to pay for.

    So to summarize; I think it’s interesting that neuropathy is such a broad definition, and I think as specialists in this area, it is something that we need to take advantage of. And we can educate other people in medicine and our people that send us consultations by explaining the type and severity of neuropathy people that are patients there.

    I think the evidence for nontraditional treatments is growing. I think we are going to have some interesting study from the medical food part of the world. I think there are some people that I know they’re doing in other parts of the world, not in the United States, that are doing electrical stimulation studies. The body of evidence is growing. I don’t think you need to strip down and jump into the water yet, and prescribe this to everyone, but I think the risk versus benefits for the things that look like they’re good is very favorable.

    I don’t think you're going to hurt anyone with the price that look like they're favorable. They may be a little bit expensive, but I don’t think there’s a bad complication profile. So with that I’ll end. Thank you.