Managing Peripheral Neuropathy – Lessons from the Clinic

Presented by Kelsey Barrell, MD, University of Utah Health Care

Presentation 46 minutes:  Q&A 10 minutes

Summary:

Neuropathy can occur after transplant, particularly among patients with multiple myeloma. A variety of therapies are available to manage, and occasionally reverse, the symptoms.

Highlights

• Inherited genetic factors, chemotherapy used prior to transplant and, in some cases, graft-versus-host disease may cause neuropathy after transplant
• Testing is required to determine the type of neuropathy a patient has and appropriate treatment
• Some symptoms of neuropathy are under-reported because patients may feel they are part of the normal aging process and not worth their doctor’s time to discuss

Key Points:

00:57  What is peripheral neuropathy? 

02:49  Symptoms of peripheral neuropathy include numbness and tingling in hands and feet

05:28  What is autonomic neuropathy?

06:02  Symptoms of autonomic neuropathy include lightheadedness, digestive problems, increased/decreased sweating, difficulty adjusting to the dark, and problems with urinary and sexual function

10:27  Carpal tunnel syndrome is more common in people who have had cancer or chemotherapy than in the general population

17:00  Risk factors for chemotherapy-induced neuropathy are type and cumulative dose of chemotherapy, prior neuropathy, disease (multiple myeloma most often), and drugs used after transplant to keep the disease in remission or control graft-versus-host disease (GVHD).

27:59:  Exercise can stabilize or partially reverse neuropathy

33:19   Cannabidiol (a compound in marijuana) may help with symptoms of neuropathy

35:23  Gabapentin, amitriptyline (Elavil®), pregabalin, duloxetine (Cymbalta®) are used to manage symptoms of peripheral neuropathy.

37:55  Treatments for autonomic neuropathies

Transcript of Presentation

00:00  Speaker introduction:  So you heard a little bit about my background. I am a neurologist, so I'm not an oncologist or hematologist. So, I'll take you through my world of how bone marrow transplant and its related treatments and diseases can affect our neurologic system. I am a nerve and muscle specialist, but I see the whole range of neurologic issues, so feel free to ask questions at the end, anything that might be going on with you even though we're going on focus on peripheral neuropathy which is the most common neuro toxicity that I will see in this setting.

So, without further ado, I'll take us through some of the basics of peripheral neuropathy and it will be very clinical, but feel free to ask questions. I know we're supposed to ask most of the questions at the end, but if something is not clear I would like to know, and also I'm going to take liberty to ask you guys questions. So I love these small rooms. So you guys are on the spot as well.

00:57  What is peripheral neuropathy?  So, we're going to go into, first of all, what is peripheral neuropathy? What are we talking about today and what are its symptoms? How will it manifest in your loved one or in yourself? There are many forms of neuropathy, many of which people may not think are actually neuropathy, so they might ignore. So, we'll go into some of those so we don't ignore them.

How we make the diagnosis? What other risk factors are involved with neuropathy —so other things to look into —as well as the treatment related causes of neuropathy, so, as related to the bone marrow transplant. How do we treat it and where are we going into the future?

So peripheral neuropathy is just damage to the peripheral nerves. The most common form of neuropathy is a very classic pattern. It's length dependent, leading to stocking glove presentation. And length dependent simply means that it involves the longest nerves first and so tends to start in the toes, and slowly creep up. By the time it gets to the knees, it often can start affecting the fingers. Now why is that? Why is it length dependent?

If you think about the nerves, the peripheral nerves come from the spine and your neck and your lower back and go all the way down your limb, so obviously your legs are a longer nerve.

Those long nerves are very, very thin. So if you think of a football field and you have a nerve tracing around 400 meters, around the football field, it's the size of spaghetti. So it's long and thin. It has to get energy from the cell body in the back, in the spine, all the way to the sensory endings and that takes energy transport. If the nerve is injured from chemotherapy, the first nerves that are going to have trouble relaying information, getting its energy down, is going to be the longest nerves which is why it more commonly affects the toes than the fingers.

02:49  Symptoms of peripheral neuropathy:  And then the symptoms. There is a wide range of symptoms and a lot of times in the clinic, I'll have patients say, I'll ask them, ‘do you have symptoms of neuropathy? Any numbness, tingling?’ They are like, ‘you know, I have these symptoms but I just can't describe them’. And I'll say ‘try’. ’It's just the most bizarre feeling’.

It can really cause a lot of symptoms that no one tells you about and gives you words to describe it. It can range from burning, tingling, numbness, pins and needles, shock like sensations, to more hard to describe— I just can't perceive temperature; I feel like there is gravel or socks bunching in my shoes but I checked them and there is nothing.

03:25  Symptoms of neuropathy depend on the size of nerve affected:  And the symptoms actually depend on the size of the nerves. So I really like to understand why? So why these different symptoms? Why do these symptoms start one way and as it progresses goes a different way. And it has to relate to the sizes of the nerves.

Nerves carry different forms of information down our limbs. The smallest nerves, here, it's like a wire. Like electricity. So, if you think about electrical wire, it has copper wiring and then it has insulation. Nerves are the same way. So, the wire is the axon— that's actually the nerve itself —and then the yellow, here, is the insulation. That's called the myelin sheath.

Now our smallest nerves don't have a lot of insulation. They are just wire or thinly insulated. So, those are very sensitive early on to chemotherapy or any toxic injury, and these smallest nerves carry information on pain and temperature. So early on in neuropathy you often have a small fiber neuropathy, smallest nerve fibers cause pain, tingling, lack of temperature sensation, really burning, irksome symptoms.

Next size of the nerves, are the autonomic nerves. So those are thinly myelinated. So, small amount of insulation. And we'll talk more about autonomic neuropathy, because that might be a new term for some [people]. Then we get larger. So more insulation. So it takes a little bit more injury, so this tends to happen later on in most cases. And this is the lidocaine numbness. This is going to the dentist. Getting numbness —that dense numbness feeling. It can lead to trouble with balance, typically.

And lastly, we have the nerves that are in charge of our movements. So, they attach to muscle and when these are involved, people can notice muscle loss— so some atrophy or shrinking of those muscles and weakness. Often, as things progress, you'll get a combination, so it will start at the top and go down slowly over time.

05:28  What is autonomic neuropathy?  And then this autonomic neuropathy. So how many people have heard of the autonomic neuropathy. Let's see hands. So only a few. So good. That's pretty typical in my clinic too. So what is this? This is the nerves that control the involuntary bodily functions. These are the functions that go on without your notice, all the time, and you only notice if they stop working well. So maybe some have heard of fight or flight rest and digest?  Fight or flight being the sympathetic system, rest and digest being the parasympathetic system.

And these are really integral to how our body functions, kind of under our awareness. So, symptoms of autonomic neuropathy really affect the entire body.

06:02  Symptoms of autonomic neuropathy:  So, starting at the top, you can have decreased or increased sweating— usually decreased in this setting— and difficulty adjusting to the dark. Because these autonomic nerves go to the pupils and help you constrict when its bright, and dilate your pupils when you go out in the dark. So, people could say, “you know what? I go outside and I just can't handle the dark anymore. It takes me a minute to adjust to the darkness.’

06:38  A common symptom of autonomic neuropathy is lightheadedness when standing or orthostatic hypotension:  A very common symptom is called orthostatic hypotension. You'll hear that term a few times today. That's lightheadedness with standing. So, why do people become light headed?

It's actually a normal phenomenon in healthy people with low pressure, but in autonomic neuropathy it can just be excessive. And, so, if you think of laying down, your blood can easily go from your feet to your heart and your brain, back and forth. Once you stand up, you have gravity pulling it down to your feet and your blood wants to pool to your feet.

The reason that the blood doesn't just stick to your feet and leave your brain is that your vessels are smart. They have autonomic tone from the autonomic nervous system, and they clamp down those vessels to increase that blood pressure to keep it going up to the brain. So, if you don't have that tight blood pressure control from the autonomic system, your blood will stay in your legs. You won't get enough blood to your brain and you'll feel faint or, in some cases, you will actually pass out and faint.

07:36  Digestive issues are common in people with autonomic neuropathy:  And then digestive issues are the other probably second most or first most common, second to orthostatic hypertension, and that [referring to slide] is the whole gambit of symptoms. Diarrhea, constipation, often alternating which just isn't fair right? Both extremes. Early satiety, which means you feel full really quickly. Bloating. Reflux. Any gut symptoms. Urinary issues are common and that can be the whole range from having trouble going to going too frequently to not being able to void your bladder enough as well as sexual dysfunction which is very common.

08:12  Digestive, urinary, and sexual dysfunction symptoms caused by neuropathy are under-reported:  So, these are under reported. I have three asterisks there. I usually only do one, so I want you to pay attention. This is under reported. Why do you think this might be under reported? We see how much of the system it affects. It's pretty common, yes. Perfect number one reason, exactly. It's under reported.

As we age, you know the prostate gets bigger in men or women have had kids. Urinary symptoms occur. Sexual dysfunction. It doesn't work like it used to, right? We feel light headed when we stand. We just say oh I'm out of shape. So we blame it on something else. And some of these, to a certain extent do happen with aging so it's the company that it keeps that distinguishes it.

Is this part of my chemotherapy cycle? Did it come on pretty suddenly? So several of these symptoms, instead of just one and then slowly over years another. Within one year, did they have severe digestive, urinary symptoms and sexual dysfunction at the same time? It might be neuropathy. Is it more slowly progressive and not linked to the chemo or the transplant or the cancer then maybe it is age related.

Any other ideas of why it's under reported? That's great. Thank you. So people are embarrassed to talk about their bodily functions. That's exactly right. They think that maybe this is aging or they just don't know what to call it. They're like ‘gosh, I don't think this is neuropathy, I don't think this is cancer and it's embarrassing so why would I take my doctor's time on this? We have more important things to talk about’. We need to talk about the cancer. The chemo. So exactly right. So those are the main reasons that we just don't hear about it in the clinic. So, unless I ask about this, usually it will go under- recognized and most of my patients will have some of these symptoms. So, they are modifiable. So, we can help with them.

So, it is important to recognize them and always, if you don't know if you should talk about something with your physician, talk about it. We won't be embarrassed, and often when you talk about it, it takes the embarrassment away, so please talk to us about it.

10:27  Carpal tunnel syndrome is more common in people who have had cancer or chemotherapy than in the general population:  How many people have heard of carpal tunnel syndrome? Almost everybody. How many people have been diagnosed with it? Alright. Yup, a few of you. So very, very common in the general population. Even more common in patients who've had chemo or cancer. And so what is this? This is compression of the median nerve as it crosses through the wrist. The median nerve goes down your arm and innervates these first three fingers. So, your pincher fingers here.

And it travels through what we call the tunnel, the carpal tunnel that's bounded by bone on three sides and, then, this really thick fibrous ligament called the transverse ligament on the top. So that nerve can get compressed at the site and can cause symptoms. So people can have numbness or tingling, most commonly in these first three fingers. But actually a lot of times people don't recognize it's the first three fingers. They say my whole hand is numb.

It can be painful, often at the wrist, but even further up the forearm it can be really painful, and often it's action provoked because that narrowing here gets narrower here if you flex or extend your wrist. So people classically will notice, ‘you know I type a lot. I text. I drive a lot and that's what provokes it’. Even sleeping. So we sleep with our wrists flexed, unfortunately, a lot of times and we wake up shaking our hand out.

I'm sure a lot of you guys have had that experience with shaking your hand for a few seconds when you wake up. In its most severe form it can cause weakness of grip strength. So finger flection. Opening jars can be a big thing. And it's really important to recognize because there are good treatment options and we'll get more into what we can do. So if it's bothering you, please bring it to our attention.

12:20  How neuropathy is diagnosed: I a good history, that's you guys. Onus is on you. And us asking the right questions. Then the neurologic exams. So my toolbox here, this really is what I bring, and so I have that little leather bag and I have all my tools there normally. And I'll do a good exam. I'll check the different modalities of sensation. So, pin prick. Do you feel temperature? You feel a tuning fork? So vibration. How are your reflexes? Your strength and balance is very important. So I'll check your balance.

So, we'll start with a good exam and usually based on the history of the exam, I can be pretty confident that there is neuropathy and what type of neuropathy. But to get more objective data, so that we can follow it over time and gain a little bit more information, an objective way to look at a neuropathy is with this study, a nerve conduction study or an EMG. And that's an electrical study that actually objectively measures nerve function.

And the way it does that is it uses a little stimulation over the nerve, applied stimulation, it feels like electrical shock. Like you've been zapped and it records at a more distal lower down side on that nerve and we can see how long it takes that nerve to conduct electricity and how robust that response is.

So that's a really nice objective way to measure neuropathy and follow its course. And then one thing I want to mention with the nerve conduction study, this is really good at picking up larger fiber neuropathy, and we will talked about that later on. We don't start with large fibers. We start with small fibers. This can miss a small fiber neuropathy. It's not just sensitive enough to test it.

13:55  Skin biopsy is used to detect neuropathy in small nerves:  So what do we do in that setting? Something called a skin biopsy. So, we take a little teeny tiny piece of your skin, you can see, right there, there's a mole. So a teeny, tiny piece. It's three millimeters thick. So paper thin chunk of skin in a few sites on the leg. We do the leg because of that length dependent. The leg is where we expect to see a neuropathy first and then we actually measure how many nerve fibers, those small fibers, go through this junction, the dermis and the epidermis junction. And we actually can get density, very objective density counts, so you'll see these darkly staining, those are nerve fibers crossing  vertically oriented in many cases, through this junction.

So this is a normal control. Then we have a small fiber patient where you don't see any darkly staining, things going vertically. So this is a neuropathy patient where you actually lose those smallest nerves, and that's why you have the numbness.

It's also important to get some laboratory work and mostly to rule out risk factors that can really look like these neuropathies. So looking for things like diabetes, that's the most common cause. Cholesterol. That's the second most common cause. B12 deficiency. It's rare but treatable. And something called amyloidosis, which many people with multiple myeloma might  have co-occurring. And so diagnosing autonomic neuropathy is a little bit trickier than the nerve conduction study, because everything is internal. It's not something I can see or test easily on exam just with my toolbox. So good history and exam is where we're going to start and again we mention it's under diagnosed.

And then we can do a bit of testing. One in the clinic is called orthostatic vital signs. That's where we check your blood pressure and heart rate, laying down, sitting up and standing so we can see if it changes while we're moving you against gravity. And for an even more thorough look, there's autonomic labs at some centers. This isn't a common thing to have—so at Cleveland Clinic, Mayo, we finally have at the University of Utah—where we can  measure all these finer parameters.

So we can measure your heart rate variability beat to beat. We can measure beat to beat changes when we tilt you up in a tilt table test. We can quantify your sweat. So see if you're sweating normally or abnormally.

And then risk factors. Has anybody heard of Occam's Razor? It's this principle, keep it simple stupid basically. So the simplest explanation usually is the most accurate, which usually is true in medicine. So if you could explain one disease state using five different  diseases leading to a presentation versus one, you'll usually go with the one. The simpler is the better in general. But this doesn't explain everything.

17:00  Neuropathy caused by chemotherapy depends on dose of chemo and other personal factors:  And, so, we clearly know with neuropathy in a setting of chemotherapy—I called it CIPN, chemotherapy induced peripheral neuropathy— that the number one risk factor, the number two risk factor, the number three risk factor is accumulative dose. The more dose that you get of a neurotoxic agent, the more likely you are to have neuropathy.

But that only explains a certain bit of it, because in patients who have identical dosing regimens, one might have a really debilitating neuropathy and the other might have no neuropathy, and how do we explain that difference? So obviously there are other risk factors or unique aspects of our body that explain those different responses. Some of them might be personal, things that we're just born with, and others that might be acquired.

17:49  Top risk factors for chemotherapy induced peripheral neuropathy:  There's a good study in the Pain Journal in 2014 that looked at 31 really large studies of chemo-induced peripheral neuropathy and they found these top four being the most likely risk factors.

So, one was pre-existing neuropathy. Duh, right? If you have a neuropathy before, you're more likely to get a worsening neuropathy.

Sensory changes during chemo, so having an early sensory symptom with chemo. Smoking, and abnormal kidney function.

Then later on, there's been more really large studies in 2017 that show that obesity and a sedentary lifestyle, so not exercising much, is another independent risk factor.

You know there are acquired risk factors, too, which are things that you develop over time. The most common one being diabetes, followed by high cholesterol and then B12 deficiency is also one. So things to check for.

How about the treatment-related causes of neuropathy? So this is why we came here, you know, unique parts of bone marrow transplant and  the related course that puts us at risk for neuropathy, so these are the usual suspects, also my favorite movie.

19:04  Disease and drugs using during transplant can contribute to neuropathy: So, when can neuropathy occur? So, it can occur from the underlying cancer, and I know probably not a common cancer but some patients here might have had multiple myeloma. This is the most common cancer that we see with bone marrow transplant that will actually cause neuropathy. So in 15 to 20% of patients with multiple myeloma, we will see neuropathy before any treatment has been given.

And then chemotherapy, that's probably the biggest section that we'll discuss. During transplant, so all those immune shifts during transplant and after transplant. So, neuropathy, chemotherapy induced peripheral neuropathy. The most common agent I'll see in my clinic causing neuropathy is something called Bortezomib or Velcade. Most commonly it's for multiple myeloma but there are some other uses of it as well and this can occur in 30 to 50% of patients. It often will occur during the first few cycles and tends to plateau by cycle five.

And what's unique about Bortezomib is it's quite painful. So it's a small fiber neuropathy. It can be really a painful neuropathy. Then there's Thalidomide. This used to be a very common cause of neuropathy. I think it's coming out of favor. It's been replaced by some other chemotherapies, in many cases, but neuropathy is equally as common in up to 50% of patients. And this neuropathy can be more severe in that it can have more motor involvement. More weakness and more autonomic features. Those autonomic constipation orthostatic hypotension.

Lenalidomide is the newer generation of Thalidomide and it's less neurotoxic thankfully. And then Vincristine, this is very common in breast cancer. Sometimes I've seen it in refractory cases of multiple myeloma or some other cancers, so maybe fewer of you guys have heard of or have been on Vincristine but it's one of the most neurotoxic agents that I encounter, and it can affect the sensory and motor nerves and lead to a lot of autonomic neuropathy as well. Yeah?

Then transplant related neuropathy, so this is rare, but severe. So, as you know, with the transplant, your immune system is reinventing yourself and sometimes it can go a little haywire with donor cells in all those changes. So we see immune related neuropathy. So, where the immune system actually attacks its own nervous system, then these can be severe, so a lot of weakness. Very severe, sudden courses. It can be patchy, so it's not necessarily that length dependent common presentation but it can lead to mono neuropathies which mean one nerve distribution so a hand drop or a foot drop. Or something called a plexopathy which is the plexus being the network of nerves as they exit your neck or your lower back and go down your arm.

So, this picture is the brachial plexus, this network of nerves here. And when you have inflammation here, it affects all the nerves in the arm, so it can really have a dramatic course. Luckily it's in less than .3% of patients. So I actually haven't seen many of these cases but it can be severe when that occurs.

Then after the transplant, so as we know the course isn't over at all. Right? We're on a lot of immune suppressants. So some of these agents can lead to neuropathy as well. Tacrolimus is very, very commonly used. It tends to have a unique neuropathy in that it affects the nerves that help us see. So it's called optic neuritis or optic neuropathy. So it's rare but we do see that.

Sirolimus is basically the new version of Tacrolimus and so if we see that often we try to see if the oncologist hematologist will switch to Sirolimus which is not known to be as neurotoxic. So Sirolimus, I've only seen cases of neuropathies, the optic neuropathy when it's used with something else that's more neurotoxic.

Then Prednisone. Who hasn't been on that, right? I've been on Prednisone. We use it for everything. Prednisone is great. It works quickly. It quiets the immune system but over low periods of time and high doses, it can lead to weakness and there is a specific name for it. It's called steroid myopathy. Myopathy is just muscle weakness. It tends to affect the larger muscles, so we call those the proximal muscles. So the large upper arms and the upper legs. And lead to just this slowly progressive weakness. Trouble getting out of a chair that's not related to slowing down or not exercising. It's in addition to that. That's usually with high doses for long periods of time. So that's something to know about.

Then some of the immune ... yup.

24:10  Question about whether steroid induced neuropathy tapers off:  Would that be something that would taper off though? Or is that permanent?

24:14  Yeah. Yeah. So definitely. If you lower the steroid, get you in physical therapy that can definitely taper off. So you actually lose muscle mass with that, but you can regain muscle mass. So that's a great question. And it's compounded by other things. So if you're not moving as much. If you're almost bed bound, it can really make it worse and then that can get better.

Then some of our immune, any of the mabs, right? So some of our immune cells the TNF alphas, can cause really immunologic, so again, the rapidly progressive neuropathies. Guillain-Barre, some of you might have heard of that. That's a really rapidly progressive ascending weakness. That's immunologic and so people can go from walking to not walking in the course of a week. Hugely rare. But I have seen a case or two.

Cranial neuropathies mean the cranial nerves in your face can become weak like a Bells Palsy. If you've heard of a Bells Palsy. And then central demyelinisation. What do I mean here? We've talked about the peripheral nervous system. Central nervous system is brain and spine, so multiple sclerosis or stroke like symptoms in that.

25:25  Graft-versus-host disease occasionally contributes to neuropathy:  So everybody here has heard a ton about graft versus host, and we'll continue hearing more during these two days. Rarely does it affect the neurologic system acutely. So we don't see much acute graft versus host. We more see chronic graft versus host and it's not common, so when it affects the neurologic system, it can be immune. So you know this is the immune system attacking itself, usually on the mucus membranes. But it can affect the peripheral nerves, way less than one percent.

What I do see is muscle cramps. So, we might just blame this on aging or dehydration but if they are really severe and came on pretty suddenly, especially in the setting of other graft versus host, it really could be some of that graft versus host affecting the muscles. So in 16% of patients in a good retrospective study actually reported, this but I think it's highly under-reported because we just don't know it's part of graft-versus-host or something to bring to the attention. Then, very rarely, central nervous system. So that's multiple sclerosis like symptoms. This usually is pretty well treated with immune suppressants luckily. Just like a lot of other graft-versus-host. We put you on steroids or something like that.

26:45  Treatment options for peripheral neuropathy:  And so as far as treatment, there's really two main treatment tenets. One would be treating the underlying disease process. So halting or slowing the progression of that natural history, that disease course. And then two would be treating the symptoms,  some type of band aid. And so when we think about treating the underlying disease course, if we think the cancer is causing neuropathy, we treat the cancer. And I've seen this most in multiple myeloma or its related cousins, POEMS disease. which is very rare. Amyloid.

And then risk factors. So, if you have diabetes or B12 deficiency, that could be making your neuropathy worse. So you need to treat that. And then exercise here. We'll talk a little bit more about that.

Targeting the symptoms is more effective with painful symptoms. So if you have lidocaine, just dense numbness, unfortunately we don't have good drugs to make that numbness go away. But if you have positive symptoms, burning, tingling, pins and needles, then we do a pretty good job getting some of those symptoms remitted. Do you have a question?

27:59:  Studies show exercise can stabilize or partially reverse neuropathy:  Okay. So exercise. So what's the deal with exercise. So everybody has heard this from their physician. You should exercise. You should eat well. Well what's the data, right? I feel like unless I explain why I am recommending something, my patients are less likely to take my recommendation. So what is the data? Is this just good for our mindset or aging or does this actually help in some meaningful way with the neuropathy?

Well there is increasing literature on it. So there's a paper published a few years ago by one of my colleagues at the University of Utah. They studied this most in diabetic or pre-diabetic neuropathy because most patients with neuropathy have diabetes But, interestingly, the symptoms and actually the histology— meaning what it looks like under a microscope —is identical in chemo-induced peripheral neuropathy and diabetic neuropathy. So we think there's a common pathway at the end. It looks the same on the nerves. So a lot of times we translate the research back and forth.

But in this study, they took a bunch of patients, and they did that skin biopsy that we talked about. So they took a little sample of the skin before the study started and then they randomized people. Either just standard counseling, which is what most people get, about four times a year. You should exercise. Eat healthy. Alright. Sounds good. Then you go home.

Then the exercise group was a little bit more, took a little bit more effort. And so they had weekly supervised exercise coaching, actually at a gym. And then a home exercise routine that was graded, meaning it got more challenging as the year progressed, as well as monthly or bi-monthly nutritional visits. So they worked on diet as well. Then after 12 months they repeated this. What do you guys think exercise might do to the nerve fiber density? So what do you think the results might be? Stable. Yeah. Yeah. So that's what I would have guessed too, right?

So, we know that as neuropathy goes along, we lose that nerve fiber density. If we could stop it in its track, it would be stable. It would not change over a year, that would be great, right? So that's what I would think. But actually it's more exciting than that. This. So it was really surprising research. So in the gray group, which is the exercise group and if you look here, this is the data. Finding. So zero is that horizontal line. That means no change. So in our counseling standard group, they lost a little bit of the density. So they had a little bit of nerve die out, which would be expected. Neuropathy progresses slowly so over a year, you're not going to see a ton of change.

What was really shocking was in the exercise group, you saw nerve regrowth, so you had a higher density of the nerves in the dermis epidermis. Yup. Yeah, thank for asking that.

31:02  Inaudible question from audience.

That is a great question. So, with the guided exercise, thank you so much. I was meant to mention that and I completely forgot. It was a combination. So it's really the aerobic we think. So it's 30 minutes of aerobic exercise five days a week, so you need the aerobic, getting that heart rate up. But they also did weight training. Aerobic, if you have burning painful neuropathy, it's whatever you can tolerate. So maybe it's a recumbent bike or swimming that's better tolerated. It does not matter how you get the heart rate up, just that you get it up. So great question.

Yeah. So the question is depending on where your neuropathy is, does a certain type of exercise benefit you more? So re-circling your feet. All the nerves are going to be affected at the same time, it's just the neuropathy is worse in the feet so it does not matter what type of exercise, the nerve regrowth should happen everywhere. It just ... we see it in the feet first, because that's where the injury was the most.

We actually saw nerve regrowth. That's exciting because they've studied all forms of antioxidants, vitamins, compounds that we make to see can we regenerate these nerves. Stem cell transplants, right? Can we regenerate nerves? And we haven't found anything as promising as exercise. And it's still early. They are doing studies in chemotherapy induced peripheral neuropathy in rats. We haven't done a lot of good studies in humans yet, but I think this is really exciting.

32:32   Lidocaine, capsaicin for treatment of neuropathy:  And then there's the medical treatments. So topicals are good if you have focal symptoms, meaning just in your feet or in a patch or just in your hands. There are all sorts of them. Lidocaine is the dentist injection, so that's a numbing agent that you can apply as an ointment or a patch.

Capsaicin is nice because it's very cheap. It's actually the active ingredient in chili, so it burns when you put it on. It actually kills those nerve ending temporarily. So numbs them.

Then compounded ointments are things that certain pharmacies can mix up for you if directed by a physician. This is something I use a lot just because it has a lot of different mechanisms of action. And so P4 cream is just a compounding cream that we’ll make.

33:19    Using cannabidiol (a compound in marijuana) may help with symptoms of neuropathy:  And then not just because we're in Denver, but I thought I would talk about CBD. And so for those of you who might not know, cannabidiol, CBD, is one of the compounds in marijuana. It is the compound that works on pain receptors. It does not have any central effects, meaning it does not make you euphoric. Give you that high. So it's not thought to be as addictive or centrally acting.

THC on the other hand is the one that makes people euphoric. And so, unfortunately, the legality of even a CBD which is the non-centrally acting agent, varies depending on state. It's really hard to find out how legal it is in your state. I've looked in Utah and it's really hard to find actually what the federal government and the state government says.

And I'm in Utah and so it's interesting. A lot of my patients are conservative and are interested in this. So the hype is there. People all over the place are interested and so it's going to come up again in our state and I'm hopeful, but we'll see. It's been well studied in the UK with a compound that's a mixture of TCH and CBD as well as in Canada and it's been very effective to decrease pain and it helped mood and sleep as well.

And then in mouse models, it's been very effective in chemotherapy- induced peripheral neuropathy related pain and pain sensitivity. Interestingly this was very well studied from 2012 to 2014 and then nothing. So, the government is making it hard to study but I think CBD is something that we'll see more and more of in the future. You can apply it topically or take a tincture, and in my patients who have tried it in Utah, they think it's as effective, if not more effective, than anything else. Almost always they feel like it's as least as effective. Cost, sometimes, is an issue because it's not covered by insurance. But that's where we stand right now.

35:23  Gabapentin works well for patients with neuropathy:  Then oral treatments. These are things that you take by mouth that are prescribed. All of these are equally effective. So, I'll take you through how I decide which one to start.

So, I usually start at the top with Gabapentin. Gabapentin works really well. It's cheap. We know its side effects really well. And you take it usually three times a day, but if your symptoms are worse at night, you take your higher dose or only dose at night. So, you can tailor it a little bit for your symptoms, which is nice.

The downside of Gabapentin, in a minority of patients, not in the majority, people describe a sedation, like a head fog. It's just harder to work or harder to focus. Usually that gets better as your body gets used to it, but if you increase the dose, you might feel it again. Then some people notice some swelling in the legs.

36:16  Amitriptyline (Elavil®) may help with neuropathy:  Then there is amitriptyline, also called Elavil. Been around forever. It was originally an antidepressant, but it made people too tired ,and so it actually works great for pain. And since it was antidepressant, it also helps the mood. Makes you sleepy, so we take it at night and it helps with insomnia.

Also very cheap. So also very affordable. The downside is it dries you out. So it can lead to dry mouth and also a dry system, so constipation or urinary retention. So that's one reason if people have a lot of those symptoms, I might avoid amitriptyline.

36:50  Pregabalin can be used to treat neuropathy:  Pregabalin is basically just the next generation of gabapentin. It's nice because its side effect profile is a little cleaner. So, you have less of that head fog feeling at onset.

Why don't I just start here? Well it's ten times as expensive as gabapentin and most people will tolerate gabapentin if given the opportunity.  So I'll only use Pregabalin if Gabapentin is not tolerated, given the price.

37:18  Duloxetine (Cymbalta®) is an effective, but expensive, treatment for neuropathy:  And then duloxetine or Cymbalta®.  I think there's a lot of publicity, commercials on this. It's something you take once a day so it's very easy. It's used as an antidepressant as well as for different forms of chronic pain.

So, it's great for nerve pain. But it's also good for muscle pain or fibromyalgia or muscle skeletal pain. And it's quite well tolerated in general.

It's also very expensive though. So, in general, insurance wants to see that we've at least tried one of these top two before starting the bottom two. Not always, but that is how I operate usually.

37:55  Treatments for lightheadedness caused by neuropathy:  And then treatment for autonomic neuropathy usually tends to address which symptoms are bothersome. So, if it's lightheadedness with standing, called orthostatic hypotension, then we try to prevent the pooling of the blood in the legs which is usually one of the big causes of it. So compression stockings, which are graded stockings that you wear on your legs. The higher they go, so if they are above the knees, they work better than below the knees. That prevents the pooling.

Abdominal binders do the same thing. So we have a lot of water and blood pooling in our abdomen and if you have a binder it prevents that pooling. And then optimizing hydration and actually salt. So if you can, unless you have a heart condition, you can't have a normal amount of salt.  It's good to get a normal amount of salt because salt is what keeps water in your vascular system. In your blood.

Then, if these do not work, we have medications that keep the blood pressure up. Midodrine and Florinef® are the most common ones and we use those a lot in severe cases.

38:55  Treatments for slow gut (gastroparesis) caused by neuropathy:  And then gastroparesis. So that's slow gut. Delayed emptying due to lack of peristalsis. Peristalsis is that movement of the gut that the autonomic system regulates. And so these patients will feel full really quickly, bloated, constipated, uncomfortable.

Usually we start with dietary modifications, so small meals frequently are better than a big load. Things that don't have a ton of insoluble fiber. Insoluble fiber is the really rough stuff that actually is good for you, but makes it harder to get stuff through. Low fat is better than high fat for this.

Liquids tend to be easier to digest than solids, and so supplementing with protein shakes can be really effective. Avoiding carbonated beverages, smoking and alcohol is important and then staying really well hydrated. So regular hydration.

If this doesn't get us where we want to go, there are medications that are prokinetic, meaning increased movement of the gut, so that you can take them before a meal to  get things moving a little bit more.

40:02  Treatment for urinary frequency caused by neuropathy:  There are medications for urinary frequency or symptoms. Most common that I use are terazosin and oxybutynin because some of the other ones can make that lightheadedness with standing, or the static hypotension worse. So we have to be careful with that.

40:17  Treatment for erectile dysfunction:  Then erectile dysfunction. So this is a big issue too. The most common medications are Viagra® and Cialis® but there are a lot more medications and a lot more procedures. So if these don't work, you don't have to stop here, you just need to see maybe someone other than myself to get more help there.

40:35  Treatment for carpal tunnel syndrome:  Carpal tunnel syndrome. So I mentioned before that it's really treatable, so most conservative treatment would start you with a wrist splint. That's a splint that's  short, shown here. You can get it for about $10 anywhere in the pharmacy section and it prevents you from flexing and extending your wrists. You only have to wear it at night, for at least six weeks to give it a trial, and most times the symptoms will improve.

If they don't, or if they’re still really bothersome, then there's a little surgery called a carpal tunnel release that is very effective. So it's one of the only surgeries that I get excited to refer patients to. I'm not a surgeon, so I always worry about a back surgery, what that could mean down the line.  But this surgery is just literally less than an inch incision. Really shallow in the wrist and the success rate is very high. So patients usually are very happy with their response to that.

Is it a surgery for trigger finger?  So not exactly, no. But there are surgeries for trigger finger. The exception is something called amyloidosis which I see a lot in patients that have multiple myeloma, they can also have amyloidosis. And they can get carpal tunnel and trigger finger for the same reason.

And so, but as far as just the neuropathy in chemotherapy, I don't see the trigger finger being common but there is a surgery you can get for that. If it's bother you.

42:03  Future therapies:  And so where are we going into the future? So, the future, I love this quote from Mahatma Gandhi. The future depends on what you do today. So what are we doing these days. And this is me in Peru. Pretty impressive hike, hiking up there, it's maybe like 16,000 feet, so I wasn't feeling great.

42:22  Testing for a genetic predisposition to neuropathy:   But one of the exciting areas of research is genetic predisposition. So, pharmacogenetics are really hot in oncology these days. Many of you maybe have read something about it, which is basically “do our underlying genes give the physicians more idea of our prognosis— how we will do with the cancer or how we will respond to the chemotherapy and whether we're at a risk for chemotoxicity. And we found in a lot of forms of cancer that understanding mutations gives us a much better idea of how we're going to do.

In chemo induced peripheral neuropathy, we're at the adolescent stage. So, we know a lot of genes, over 1000, that seem to relate to how we do with neurotoxic agents, but we haven't really limited it to the highest, most important ones.

So, we're still trying to figure it out. But some of the important ones that I think are interesting, here, are the sodium channel ions. These channels are important to pain, so mutations that cause a more active channel causes increased inherited pain syndrome. So, arthromyalgia, where people have just severe pain and they always have. Then likewise a mutant of this mutation that causes absent or decreased functioning of the sodium channel, causes inherited insensitivity to pain. So sometimes you maybe read or saw in the movies these people —you just can't cause any pain to them. It has to do with that ion channel. So they’re studying if we can modify this ion channel.

And then this glutathion reductase is an important channel that actually helps us detoxify ourselves. So, like antioxidants. It's basically the antioxidant of cells, so can we up regulate that to cause more antioxidant effect in our cells?

The ABC gene, the ATP binding cassette gene, reduces drug accumulation, so that's on the outside and pumping that toxic drug out of the cells.

And then this is one that you'll see a lot in the literature for drug metabolism. So this is an enzyme in the liver that helps us metabolize drugs. That's why you can't have grapefruit and coumadin, blood thinners and the interaction of a lot of drugs, so this is very important at clearing the drug naturally through the liver.

44:56  Functional MRIs may promote better understanding of how pain from neuropathy is processed:  Advanced imaging I'm really excited about. So functional brain MRIs are the next stage of brain MRI's. So, a basic MRI gives you a really nice structural view of the brain.

A functional MRI shows you the function of the brain. So it can both show you the networks, the pathways that are required and activation patterns. So, say in this patient we asked them “picture something that was the most painful thing in your life involving the left leg”. It would show you what brain structures activate when you're in pain, and maybe you could think of treating your pain or actually induce pain during the image and then relieved the pain. So, either imagery or actual physical [pain] and you could see what structures of the brain are activated when we have pain relief.

This gives us a better idea of the central pain organization and processing with chemotherapy induced peripheral neuropathy as well as potential new drug targets. So, we know treating the pain doesn't just involve the nerve receptors but also our brain wiring.

And so that's all I have for you guys today. So I want to thank you so much for the great questions and for the attention and open up to questions.

46:13  Question about products advertised to cure pain related to diabetic neuropathy:  It's my understanding that there are therapies that work for people who have not chemo induced neuropathies. So people who have diabetes. There are things that work in clinics. Is that true? I mean that's what I hear. You see these ads in the paper about will it just take your pain away.

Dr. Barrell responds:  Yeah, and they are always half page ads which always make you worried.

I've had a lot of patients say “gosh there's these ultrasonic waves. There's the stem call.’

No. Unfortunately we've studied it and there has been huge meta analysis on all the studies to prevent diabetic or really any neuropathy, and nothing can actually stop the neuropathy in its tracks or cure it other than modifying the risk factors, exercise, treating the symptoms. So a lot of those page ads are not going to be insurance covered. They are not well studied in the scientific literature and they are going to take your money but give you questionable results. So I always really hesitate.

And so if you're interested, and I'm always interested in new things that might work, it just should be done in an academic center or trial. So say stem cell research. That's hot for all things, it is being studied. But do it with a double blinded scientific study rather than going for tourism, you know, to Mexico and getting a stem cell that costs you $5000 that insurance won't cover. You have no promise that it's going to work other than a lot of hype. There are these stories where it cured it. No we haven't found that cure yet unfortunately.

None of my ... so if you look at, it would only be cases. So it has not, in good well-done studies they haven't found it yet that there's that benefit. So, is it possible that some of these things do have some support? It's definitely possible, we just need more information on it before we decide whether it's a safe and reasonable way of going.

48:20  Question from audience about options if gabapentin no longer works:  Okay, so I've been on the gabapentin for a while. And you build up a tolerance to it. Would switching drugs or trying a Lyrica® or the Cymbalta®, would that shake things up and work?

Dr. Barrell responds:  Yeah, so that's a great question. So, a lot of times, as the neuropathy progresses, we do need to make changes. So, the number one reason that gabapentin doesn't work is people are at a low dose. So, a lot of times, non-neurologists feel very uncomfortable increasing the dose. But it has a huge safe ceiling effect. So they might start you on something like 100, 300 milligrams three times a day. So 900 in total a day. I'll get patients all the way up to 900 milligrams, three times a day or 1200 three times a day, so a lot of times, just as the disease progresses, if we know you tolerate it, we know it's cheap, we just increase it a little bit.

If that doesn't work, we have two options. Sometimes we can add an agent that works differently, so Cymbalta® or amitriptyline that works completely differently and synergistically or we can switch.

Audience member:  And I'm really curious about the CBD. We don't have legality for it in my state yet. – New Jersey.

Dr. Barrell:  Okay. Well you're probably closer than Utah.

Audience member:  Yes, we are. We're getting there. Does that have the same effect, though, where you can build a tolerance or is it  ...

Dr. Barrell: I don't know. Yeah it just hasn't been studied well enough. I don't know yet. I think a lot of medications do build tolerance. If you think about people who take medicinal marijuana for pain— cancer related pain or non-cancer related pain— people do tend to ingest or take more as they get used to it. So I think it might build tolerance, but I don't know.

50:09  Audience member question about statins for high cholesterol causing muscle problems: Choleterol can be an issue. and a lot of times on prednisone you have a high cholesterol issue.  And in the treatment, a lot of times they put them on statins and those can cause muscle, the myalgias. What is causing that and why is it that some statins work better than others and it seems like you have to shop around for a statin that will work for your body, but not keeping this cholesterol high and having that problem.

Dr. Barrrell responds:  Yeah, in those individual susceptibilities to both the effective drugs, the positive effect, and also the mal effect, I think it goes back to that genetics slide. I think it goes back to your underlying genetic makeup so we don't know all of those details, but it's not always a class effect. So if you have toxicity to one statin, it doesn't mean you'll have it to all statins. So you keep having to look around.

But you're definitely right that it can cause myalgias in a very real percentage of patients. Myalgia being muscle pain. And some people that have that muscle pain do have a mutation that has been reported. It's called the hmg coa reductase. That's what actually, how statins work, and if you have a mutation on that you might have trouble with that.

So in the most severe forms, where people actually get weak from statins, I have seen that gene. But we don't know all those finer points of why some and not others yet. I think in the future we'll just get some blood from you, do a whole genome sequence and then know everything about your treatments: what treatments will work best and what won't. We're just not there yet. But you're exactly right.

Cholesterol is a huge issue and just try different ones and they seem to get more and more expensive, the less toxic they are. And it's hard because prednisone not only increases your cholesterol but increases blood sugar and helps you retain weight. A lot fluid weight. Makes it harder to exercise.

So watching the types of calories. I'm really into nutrition and so what we eat can really help us lose weight. So it's knowing what type of calories. So eating low glycemic foods, which mean it's less likely to break down into sugars is the way to go. It's hard though. Yeah.

52:38  Question from audience about options, like acupuncture, if gabapentin doesn’t work:  I've been on Gabapentin now for a while and I'm up to the 1200 milligrams. I think it works but what's scary is I'm not really new down the path on this multiple myeloma path. What happens next? The next question I have is, or part two is, what about acupuncture? Is that totally off the table hocus pocus? Or is there something to that?

Dr. Barrell responds:  So the first question what being next ...

Audience member:  Yeah what do you go after you like Gabapentin, your 1200?

Dr. Barrel:  So are you taking 1200 three times a day?

Audience member:  Three times a day and I've done Lyrica® and I've done Cymbalta®.

Dr. Barrell:  Yeah and have you done two at the same time?

Audience member:  Oh yeah. Yeah. At your clinic in the University of Utah. So there we go.

Dr. Barrell:  Yeah, great. So you're at a good dose. Good. Someone knows that you can go up high on gabapentin.

So, a lot of times it would be the topicals, addressing whether there's underlying risk factors, and then there is some promising data in acupuncture. It hasn't been done in really large studies or really well performed studies because it's hard to study, but actually I'm starting a study at the Huntsman Cancer Institute looking at acupuncture in chemotherapy induced peripheral neuropathy and using the functional imaging. So we're trying to get better data.

But I think in certain patients, it really does help and it's hard to predict which patients those are, but I have had patients who have said you know what? That helped. It's transient, meaning you have to keep going back.

I think it's worth a try. There's no risk, there's no side effects to acupuncture.