Managing Neuropathy After Transplant

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Managing Neuropathy after Transplant

Wednesday, April 21, 2021

Presenter: Kelsey Barrell MD, Assistant Professor Neurology, University of Utah Health

Presentation is 38 minutes with 19 minutes of Q & A.

Summary: Neuropathy (nerve damage) is common after high-dose chemotherapy and a stem cell transplant. Peripheral neuropathy can cause tingling or pain in the arms, hands, legs and/or feet. Other types of neuropathy can cause symptoms ranging from dizziness when standing, problems with digestion and urination to loss of balance, numbness, and muscle atrophy.

Highlights:

• Peripheral neuropathy is the most common type of neuropathy that occurs after transplant.
• Autonomic neuropathies affect involuntary bodily functions, like digestion and urination, and are sometimes confused with normal symptoms of aging.
• Exercise can actually cause new nerves to grow to replace damaged nerves.

Key Points:

(02:03) Peripheral neuropathy tends to affect the longest nerves from the toes up through the knees, to the hands and arms.

(04:26) Autonomic nerve damage can affect balance, the digestive system, urination and sexual function

(05:41) Sometimes neuropathy can cause both too much sensation (pain) and not enough (numbness).

(09:08) Diagnosis of neuropathy can be done with a basic screening exam and confirmed with additional diagnostic tools.

(13:50) Neuropathy can affect quality of life with balance issues, chronic pain and psychological distress.

(15:59) Chemotherapy-induced neuropathy is common, but does not occur in all patients, or affect every patient in the same way.

(18:51) Bortezomib (Velcade®) causes neuropathy in 35-50% of patients.

(22:04) Tacrolimus and cyclosporine can cause optic neuropathy.

(26:15) Exercise can promote nerve regrowth and improve symptoms of neuropathy.

(29:53) There are treatments for pain caused by neuropathy, but not for the numbness.

Transcript of Presentation:

Note: In this presentation the speaker sometimes uses the terms “BMT” or” bone marrow transplant.” For purposes of this presentation, both of those terms also apply to patients who have been through a stem cell transplant.

(00:01) [Julie Sinnema]     Introduction. Hi, my name is Julie Sinnema. Welcome to the workshop Managing Neuropathy after Transplant, Lessons from the Clinic. Please join me in welcoming Dr. Kelsey Barrell.

(00:12) Dr. Barrell is an assistant professor of neurology in the Division of Neuromuscular Medicine within the Department of Neurology at the University of Utah. She is also the neurologic specialist in the Regional Utah Amyloidosis Program at the Huntsman Cancer Institute, where she developed a comprehensive multidisciplinary neuromuscular oncology clinic to improve the access to and care for those with a wide range of neuromuscular disorders. Dr. Barrell's academic interests include cancer and chemotherapy-related neuromuscular complications and amyloidosis. Please welcome Dr. Barrell.

(00:52) [Kelsey Barrell]      Overview of Talk. Thank you so much for that kind introduction, Julie, and it truly is a pleasure to be here talking to you all on what I feel is a very important subject. But today we're going to be talking about managing neuropathy during and after transplant. We're going to begin by discussing the basics of peripheral neuropathy, what it is, what symptoms might be associated with it, and other forms of neuropathy you might encounter. Then we'll go into some of the diagnostic tools and risk factors associated with neuropathy, discuss the treatment related causes of neuropathy specific to bone marrow transplant and other cancers. And most importantly, we're going to end in discussions of what we can do about it.

 (01:39) So, what is a peripheral neuropathy? Other terms for this would be a polyneuropathy, and essentially this means damage to our peripheral nerves. Our nerves are the structures in our body that carries sensation from the tips of our limbs up to our brain. Then also carry signals back down to our muscles and tell us to move. So, very essential for living.

 (02:03) “Stocking-glove” neuropathy is the most common form of peripheral neuropathy.  A classic peripheral neuropathy, so the most common thing I'll see in my clinic and the most common form of a chemotherapy-induced problem, will be what I call length-dependence or stocking-glove neuropathy. So, that means that it tends to affect the longest nerves, first in the toes, climb up the legs and only once it reaches around the level of the knee, do people start feeling it in the fingers.

(02:30) Why is that? Well, if you look at the structure of a nerve here, you see that there's a cell body at the top, a long connector called the axon and then nerve endings at the end. That axon is very key, it's like a roadway carrying the energy produced in the cell body to where we need to use it, and then carrying the signal back up. This structure, even though it looks short in this picture, is actually very long.

(02:56) The longest nerves are most susceptible to damage. So, if your axon was the size of a spaghetti, piece of spaghetti, that axon would be long enough to go around a full football field, which if you think about how the nerves work, they're like a roadway. And if we're in charge of keeping our roadway operational, you can imagine the longest roadways are going to take the most work. You need the most supplies. So, that's why the longest nerves are often the most susceptible to damage.

 (03:26): Symptoms of neuropathy depend on the type of nerve affected. There are many symptoms of a peripheral neuropathy and that's because the symptoms depend on which type of nerves are affected. The smallest fibers are carrying pain and temperature, and these nerve fibers don't have much insulation around them.

(03:44) When I talk about nerves, they're essentially like a copper wire. There's the wire carrying energy and that's the axon, and then there's a sheath of insulation, in this case called the myelin. So, in the smallest nerve fibers, they don't have much, if any, insulation or protection, and that's why these can be injured first.

(04:07) When they're injured, people describe a lot of painful symptoms. It can be a burning pain, tingling, pins and needles, shocks, you name it. There's a wide array of symptoms that people report. This is most common, especially early in the course or with even mild case.

(04:26) Autonomic nerve damage can affect balance, the digestive system, urination and sexual function. The next size up is the autonomic nerves. These are nerves that carry autonomic information. We'll talk more about what really the autonomic nervous system does. When these are affected, people have a whole array of symptoms, including lightheadedness with standing, issues with gut, like digestion and urination, and sexual dysfunctions.

(04:51) Damage to larger nerve fibers can cause numbness, weakness, or muscle atrophy. The larger nerve fibers carry touch and pressure. So, if you have these fibers involved, you may have numbness. So, the lack of sensation in your feet, imbalance, where there's difficulty really feeling where your feet are on the floor.

(05:07) And the largest fibers carry our motor nerves. So, those carry information to your muscles and to your joints. When these are involved, people will have weakness, loss of muscle mass, this is called muscle atrophy, and further trouble with balance, because our position of our legs, that's called proprioception, depend on these nerves. So, if you can't really feel where your foot is in space, it's hard to know that it's firmly planted on the stair and not in-between stairs.

(05:41) Sometimes neuropathy can cause both too much sensation (pain) and not enough (numbness). Often, unfortunately, there's a combination of the above, making these very confusing. And it's the ultimate paradox. A lot of patients say, "How is this possible? How can I both simultaneously have too much sensation, meaning pain, extra sensitivity in my toes, I can't stand the sheets, but at the same time also can't feel the floor?" And that paradox is because different nerve fibers are involved in the course of a neuropathy.

(06:09) Autonomic nerves control involuntary body functions. Now, what about autonomic neuropathy? These are the nerves that control involuntary bodily functions. So, if anybody's heard the term fight or flight, rest and digest, these are the body systems that are either important for running from a tiger or sitting around enjoying a meal. And often these go on without our recognition until something goes wrong.

(06:35) Autonomic neuropathy can cause decreased sweating, difficulty adjusting your eyes to dark rooms, and lightheadedness, digestive problems and/or sexual dysfunction. So, these systems control a lot, starting from the head, it can lead to decreased sweating, if you have autonomic neuropathy, or difficulty adjusting your eyes to a dark room. A really common symptom is something called orthostatic hypotension, that's lightheadedness with standing. If we break down those terms, orthostatic means upon standing, so upright, and hypotension means low blood pressure. So, what's happening when you go from laying or sitting to standing, all of a sudden you're fighting gravity in that blood gets pulled down into the legs and you lose your blood pressure, making you feel faint.

(07:16. Digestive issues can be common, and it can be any combination, diarrhea, constipation, bloating, or poor appetite. Urinary issues can result in urinary retention, frequency or urgency. And then sexual dysfunction is also very common.

(07:34) Carpal tunnel syndrome affects one particular nerve and can cause numbness, pain and/or weakness. Many of you may have heard of something called carpal tunnel syndrome. This is what I call a focal neuropathy, meaning it involves one specific nerve and it's caused by compression of a nerve that runs through the wrist, called the median nerve, at a tunnel in the wrist. So, carpal means wrist. So, carpal tunnel is simply a structure made by your wrist bone shown here, and a ligament going over the top. And that nerve travels through this tight space and can get compressed there.

(08:06) The typical symptoms are numbness in this distribution of the first three and a half fingers on the palm of your hand. Frequently, people will have either action-induced or episodic symptoms, because the wrist is really sensitive to certain positions or repetitive tasks. So, frequently people will describe waking up from sleep needing to shake out their hand, they feel pins and needles or dense numbness. Or having recurrence of symptoms when they're typing or driving or doing a repetitive task.

(08:41) When this is more severe, people can notice dense numbness in that distribution, really significant pain in the wrist, in the hand, and sometimes up the forearm. Then at its most severe form, it can lead to weakness, usually in the grip muscle. So, having difficulty opening a jar and that kind of thing. This is important to know about, because there are very good treatment options that we'll discuss a little later.

(09:08) How is peripheral neuropathy diagnosed? Now we know the most common forms of neuropathy that we may encounter. How do we diagnose it? Well, we actually don't need to have a trained neurologists like myself to make the diagnosis. With a good history that you provide and then a basic screening neurologic exam, most primary care physicians and oncologists feel pretty comfortable making the diagnosis.

(09:33) The neurologic exams can be done in a clinic room and essentially what we do is we check your sensation to pin and temperature and vibration, and then we'll check reflexes, strength and see how you walk. Based on what we find, we may have a very strong suspicion that there's a neuropathy at play.

(09:53) A nerve conduction study (EMG) is used to confirm a diagnosis of peripheral neuropathy. Now, a way to confirm the neuropathy is through an electrical procedure called a nerve conduction study, EMG. This is a procedure done in a lab room and this electrical study essentially measures the nerve function, so, you can see how severe the neuropathy is. You can describe where the neuropathy is. Is it just in the legs or have that reached the hand? Or is it just in one nerve like the carpal tunnel syndrome?

(10:20) Essentially what happens is we put stickers on certain areas of the limb and then administer a little shock. It feels like a static electricity. And we can see how quickly your nerves carry electricity. The problem with this study, so it's slightly uncomfortable, but not terrible, but the problem with this study is that it could miss early cases. So, with mild cases or early on, the study can be completely normal.

(10:46) A skin biopsy can help diagnose peripheral neuropathy, particularly milder cases. A skin biopsy is a even more sensitive measure of your nerve integrity or health. This is a study that can really help with those earlier milder cases. So, what we do is take a very small, eraser size punch of just the top of your skin from a few sites in the legs. We stain it and we look at it under the microscope. We measure how many stains, dark nerves cross the horizontal gray line.

(11:15) So, if you look at panel A, it's hard to see maybe, but there are some darkly stained, kind of zig-zaggy lines perpendicular to that gray horizontal line. That gray horizontal line is the epidermis or your skin.

(11:29) So, on the right, the panel B, you may notice that no lines are going perpendicular to the epidermis. This shows that you lose those nerve fibers as you have a neuropathy. And it's a very clear objective measure of a neuropathy.

Kelsey Barrell (11:50): Lab tests can help determine what’s causing the peripheral neuropathy. It's also important to check some lab tests to rule out factors which may increase risk of neuropathy. These are things like diabetes, vitamin B12 deficiency, high cholesterol, and something called amyloidosis, which some of you may have heard of, it essentially is a problem with protein aggregation in the body.

(12:14) Autonomic neuropathy may go undiagnosed because patients don’t report symptoms. Now, autonomic neuropathies are a little trickier to diagnose. Often we rely very heavily on symptoms that a patient might report. Unfortunately, they're underdiagnosed, because many people don't talk about them.

(12:30) I think there's a few reasons that providers don't get a rich history of autonomic symptoms. One is that some of these symptoms, let's be honest, might be perceived as embarrassing. Also, a lot of people might not realize that these symptoms affecting their gut or their bladder or their sexual function, they might not know that these are even related to a neuropathy. Then lastly, a lot of these symptoms can happen with normal aging. So, people may just say, "Oh, this is part of aging. This isn't part of my course of neuropathy." So, it really truly is important to let your providers know about any new symptoms that's bothering you and that you notice.

(13:15) Autonomic testing, often in the clinic, can involve just checking your blood pressure and heart rate when you lay down, sit up and then stand up and seeing if that blood pressure drops. That would be a sign of orthostatic hypotension.

(13:28) There are also lab tests, and this is only at a few sites in the US, where we can really quantify how much someone sweats, how their heart rate varies, and then a beat-by-beat measure of how they respond to being upright.

(13:50) Neuropathy can have a considerable impact on physical and psychological health, and quality of life. Quality of life is the crux of the matter. I think everybody realizes that neuropathy can influence the way we live and our outlook on life. I think quality of life is frequently underappreciated by providers. So, it's very important to have these discussions, because neuropathy can have a considerable impact on both your physical and psychological wellbeing.

(14:22) So, often neuropathy can lead to poor balance, which is a big deal that can change the way we recreate, it can change how independent we are, walking to the store. For instance, it can change our ability to have gainful employment.

(14:41) Then, the burden of chronic pain can't be underestimated. So, anybody that had any form of chronic pain realizes this. If we haven't had chronic pain, it's really hard to imagine, but chronic pain is not just pain, it leads to depression, anxiety, insomnia, isolation, among many other things.

(15:00) And unless we talk about these important considerations, a clinician might not be able to really understand how the neuropathy plays into the larger context of life. Fortunately, with improved treatment and survival, researchers are realizing that quality of life is a very important marker of success in treatment. So, quality of life measures are gaining traction in not only clinical trials, but also in clinical encounters with providers.

(15:37) Now, some of you may have heard of Occam's razor, that's basically a principle where the most simple explanation is often correct. In a perfect world, this would be true all the time. But unfortunately it's a bit complex when it comes to neuropathy, especially in the setting of cancer and chemotherapy.

(15:59) Chemotherapy-induced neuropathy is common, but does not occur in all patients, or affect every patient in the same way . So, chemotherapy-induced peripheral neuropathy is a common thing I see. We know that the cumulative dose of a chemotherapy will be your greatest risk factor for developing a neuropathy, but that doesn't tell the whole story, because there's a huge amount of variation between patients.

(16:20) So, one patient might have the same dose of a chemotherapy and have no neuropathy and my next patient I see has the same exact dose and has a debilitating neuropathy. So, there are other things at play, and there's been large studies to look at what else could be contributing to the risk for a neuropathy, for developing this.

(16:39) Pre-existing neuropathy, as well as personal and acquired risk factors increase the likelihood of heightened neuropathy.  There are some personal risk factors, including most obviously a pre-existing neuropathy. If you already have a neuropathy, it's probably going to get worse with chemotherapy or certainly increases the risk of it getting worse. Sensory changes developing during chemotherapy, smoking, having abnormal kidney function, and then more recently, there was a really large study showing that obesity and low activity levels were also independent risk factors.

(17:09) There are some other acquired risk factors of things that we can test easily in the lab. So, diabetes is a very large factor. Vitamin B12 deficiency is also relatively common as is high cholesterol. The important thing is all of these things can be modified.

(17:29) Cancer, itself, can cause neuropathy.  Now on to treatment-related causes of neuropathy. So, when can neuropathy occur? The answer is anytime along the course. So, it can start even before we know we have a diagnosis or before we seek treatment.

(17:47) So, in 15% to 20% of patients with a multiple myeloma diagnosis, they'll have neuropathy at diagnosis. That might be a clue that this could be a multiple myeloma. So, the underlying cancer can cause neuropathy. The best example is multiple myeloma. Another example would be something called amyloidosis.

(18:10) Many, but not all, types of chemotherapy can cause neuropathy during or after transplant. Then, chemotherapy is probably the biggest bucket. A lot of agents that we use to fight cancer can lead to neuropathy. We'll go over some more of those more in detail. During transplant, as well as after transplant, when some may develop graft versus host disease.

(18:31) So, the largest bucket, chemotherapy-induced peripheral neuropathy. Neuropathy unfortunately is one of the most common disabling side effects associated with chemotherapy. And a lot of agents can cause neuropathy, but I try to focus on agents that I thought would be most likely encountered in this group.

(18:51) Bortezomib (Velcade®) causes neuropathy in 35-50% of patients. I'm sure many of you have encountered bortezomib, also called Velcade, which is really common in a lot of treatment paradigms. Bortezomib has a high likelihood of causing neuropathy. So, this can happen in 35% to 50% of patients. Often it can occur starting early in the first few courses of treatment and then tends to plateau. Frequently, it will start to improve several months, three to five months, after the course of chemotherapy ends. But in about a third of patients, it will continue to have symptoms up to a year or more out. What's unique to this type of neuropathy is it tends to be a very painful neuropathy. We think back to the beginning of this talk, it tends to affect the smallest nerve fibers first and that's why it causes so much burning pain.

(19:48) Thalidomide causes neuropathy in 25-50% of patients. Thalidomide was used more frequently earlier on in treatment, so many years ago, but some people might have encountered this, and likewise, it has a common risk of causing neuropathy in about 23% to 50% of patients. Unlike bortezomib, this is more likely to cause some weakness and also can cause a lot of constipation. So, it can also affect the autonomic system.

(20:15) Lenalidomide has mostly replaced thalidomide, and fortunately, it's less neurotoxic. So, possible to cause neuropathy, but is much less likely.

(20:26) Vincristine causes neuropathy in 30-40% of patients. I'm not sure some of you may have encountered vincristine. It is used in several relapse cases of multiple myeloma and has a high likelihood in up to 30% to 40% of patients of causing a neuropathy that can affect the sensory nerves. So, lead to numbness or tingling, and also motor nerves causing a little bit of weakness. And a third of patients will have an autonomic neuropathy, usually leading to orthostatic hypotension, that lightheadedness with standing.

(20:59) Changes in the immune system during transplant can trigger neuropathy, though this is rare. During the time of transplant, there are a lot of shifts in the immune system and there can be immune-mediated neuropathies as complication of hematopoietic stem cell transplant. These are quite rare. So, only a third of a percentage of patients will have them and they can have a varied presentation. So, sometimes they can be really focal neuropathies, meaning just a certain nerve distribution, like the ocular nerve, which helps us see, or a facial nerve, which helps us move our face.

(21:31) They can also lead to a plexopathy. So, I've seen several cases where it affects the network of nerves as they extend through the arms or legs. So, here is a picture of the brachial plexus, which is the network of nerves right before they dive into the arm. Plexopathies can cause a lot of pain and weakness in an arm. There isn't very good consensus or understanding of what causes these specific immune neuropathies. So, there's a lot that we still need to learn about transplant-related neuropathy.

(22:04) Tacrolimus and cyclosporine can cause optic neuropathy. Even after transplant, we can develop neuropathies, often because of immune suppressants that we need to be on. So, tacrolimus and cyclosporine can cause a very specific type of neuropathy called the optic neuropathy. It affects the optic nerve shown here, which is the nerve that helps us see, and it leads to our vision. The symptoms of that could be eye pain, loss of vision, loss of color vision specifically, and loss of peripheral vision.

(22:35) Sirolimus is less likely to cause this and usually this would only occur if this was in a combination.

(22:43) High dose prednisone can cause mild muscle weakness. Prednisone is a very common agent post-transplant and in high doses or prolonged use, it can cause some very mild muscle weakness.

(22:55) Some drugs that suppress the immune system, like infliximab, can cause rare neuropathies,  Lastly, there are some immune therapies like infliximab that can cause rare types of neuropathies. One's called Guillain-Barre syndrome, which is a rapidly progressive neuropathy that leads to a lot of weakness. It can cause some focal neuropathies and even cause a problem with our central nervous system.

(23:19) GVHD rarely affects the nervous system. After transplant, chronic graft versus host disease can occur. The most common targets of graft versus host involve the skin, the guts and the liver, but very rarely affects the neurologic system. So, very exceedingly rarely it can cause an immune neuropathy that leads to weakness, and this is much lower than 1% of people who get graft versus host disease.

(23:49) Cancer patients often experience muscle cramps. Treatments are available. A more common experience is to have muscle cramps, this occurs in up to 16% of patients. It can be very mild, but also can be pretty debilitating and is often under-reported, because muscle cramps are common and a lot of people will have some muscle cramps at night even before cancer. So, sometimes we don't recognize that this change, that this severe increase in muscle cramps is due to our treatment course. We just think it's our underlying cramping getting worse.

(24:21) It's important to talk about this, because let's be honest, I just got back from maternity leave and when I was pregnant, I had a bunch of muscle cramps and they are painful. They can be debilitatingly painful. Importantly, there are some agents that can help treat muscle cramps. Very rarely chronic graft versus host disease can affect the brain or spinal cord, which is known as the central nervous system.

(24:48) Managing neuropathy is a combination of preventing the cause and treating the symptoms. Now on to treatment. So, there are two tenets or pillars of treatment. The first pillar is targeting or preventing the actual neuropathy. So, doing something to the disease course. Then, the second pillar is targeting symptoms. In a perfect world, we could just prevent these neuropathies or target them. But usually we have to use strategies from both pillars when we're treating these neuropathies.

(25:20) So, in the first pillar, we can treat the underlying disease process associated with the neuropathy. And that could be multiple myeloma, amyloidosis, something called POEMS disease, which is an offshoot of multiple myeloma. We can treat those comorbid risk factors, which means treating any of the risk factors we identify that contribute to the neuropathy. Things like getting diabetes under better control, treating high cholesterol, and then replacing vitamin B12 if it's low. Then also there's exercise that can help our nerve regeneration. We're going to come back to exercise.

(26:04) Now, targeting symptoms, we have different ways to do that. We can use topical agents, oral prescription or alternative and complementary medicine.

(26:15) Exercise can promote nerve regrowth and improve symptoms of neuropathy. So, back to exercise and neuropathy, what's the evidence? So, it can seem like a lighthearted discussion, exercise does the body good, I've heard that before, but actually there's really strong evidence showing that it does more than just make us feel good and make us stronger. It actually can lead to nerve regrowth.

(26:39) This exciting evidence came out of many studies, but one was performed at the University of Utah by my mentor, Dr. Singleton, seven years ago. So, I'm going to walk you through this study so you can understand how rigorous this data is and hopefully this will inspire everybody to get out and exercise a little bit more this spring.

(27:01) So, at the beginning of the study, we took a skin biopsy, which you all learned about just a few minutes ago, so a little sample of skin, and we counted those nerve fibers and we want to have a lot of nerve fibers. So, the higher the density, meaning the higher the number of nerve fibers in our skin, the better. So, we counted everybody's nerve fibers.

(27:24) Then, there were two groups. The intervention arm was exercise or exercise group. And that was a group where they had a weekly coaching sessions, which would work on progressive exercise routines. So, increasing the demands of the exercise routine week to week, and this was a combination of cardiovascular exercise as well as weight. There's also a dietitian meeting regularly with patients.

(27:55) Then in the standard counseling arm, this was what most people may experience a few times a year, their providers say, "You should exercise more, you should eat better." After 12 months, every patient repeated that skin biopsy. And if we think about what would be a good result, we know intuitively that the higher the nerve fibers, the better. And if we have a neuropathy, we worry that those nerve fibers are dying back, we're losing nerve fibers.

(28:27) So, in our standard counseling arm, where we did nothing, we wonder, "Okay, will, those patients lose their nerve fiber density. Will they have fewer nerve fibers?" Then, in the exercise arm, maybe those patients don't lose those nerve fibers as rapidly. So, they have less loss. But actually the results were even better.

(28:46) So, here in this table, what we see is two bars, the gray and the white bar. And we'll just focus on the ankle, where we see the most findings, because of the length-dependent nature of neuropathy. Notice that zero would mean there's no change in the nerve fiber density. And the bigger the numbers mean you gained more nerve fibers. If you go under the zero, that means you lost nerve fibers. So, in the standard counseling arm, that little white box at the ankle, you notice indeed, as expected, we lost some nerve fibers compared to where we started.

(29:30) Study showed people who exercise can gain new nerve fibers, while those who do not exercise lose nerve fibers.  interestingly, in the exercise group, we actually gained a significant portion of nerve fibers. The take-home point is that with exercise, your body can increase how much nerves it regenerates, because our body's always trying to regenerate nerves and exercise increases that capacity.

(29:53) There are treatments for pain caused by neuropathy,  but not for the numbness. Other strategies that target the symptoms of neuropathy truly target just the painful symptoms, the burning, the tingling, the itching, the vibration, all of those hypersensitivity-type symptoms. Unfortunately, there are no medications that can help with that numbness. So, all of these agents I'm going to talk about next target the painful symptoms.

(30:17) Lidocaine and capsaicin can help ease pain caused by neuropathy. Starting with topical treatments, these are a good place to start if the symptoms are mild. All of the topical options really in the literature have similar effect. The nice thing about any of these topicals is they're very safe. So, they tend to have very few, if any, side effects. I often start with things that are easy to get over the counter. So lidocaine ointment you can get over the counter and then you can rub that on your feet and it can numb some of the burning pain. There's something called capsaicin, where the active ingredient is chili pepper. Compounding creams have a lot of different agents in them.

(30:55) Some patients find that CBD oil helps to relieve pain caused by neuropathy. CBD is a hot topic, so this is a compound that comes from the cannabis plant, which is marijuana and different states and different countries have different access to these compounds. In general, though, pure CBD or essentially pure CBD can be found in almost any state, because it doesn't have the THC, which is thought to be the addictive compound. So, a lot of my patients are finding pretty good results with topical CBD.

(31:27) Oral prescription drugs are commonly used to treat pain cased by peripheral neuropathy.  Oral prescriptions are one of the mainstays. A lot of these agents work very well and actually between all the first four agents listed, they have equal efficacy, meaning they work equally well. So I really choose which one to use based on side effect profile and individual needs of the patients.

(31:49) Gabapentin (Neurontin) is cheap and effective, but causes side effects in a minority of people. Gabapentin has been around forever, it's also called Neurontin and it's dirt cheap and very effective. There can be side effects, most commonly feeling mildly sedated, like a head fog or sometimes leg swelling. But this only happens in the minority of patients.

(32:05) Amitriptyline helps with pain caused by peripheral neuropathy but can cause dry mouth, constipation  and drowsiness. Amitriptyline is also oldie, but goodie. It's also very cheap. The nice thing about amitriptyline or its cousin nortriptyline is that it can help insomnia when taken at night and it can help with depression. The side effects can involve dry mouth, constipation or sedation. So, if someone's really constipated, I'll probably steer clear of the amitriptyline.

(32:27) Pregbalin (gabapentin) and duloxetine (Cymbalta) are effective for pain caused by peripheral neuropathy, and have few side effects, but are expensive. Pregabalin also called Lyrica is the next generation of gabapentin. So, it works just as well. It tends to have fewer side effects, so less head fog, but the downside is it is more expensive.

(32:40) Then, duloxetine also called Cymbalta is one of the new kids on the block and its benefit is, it doesn't tend to have much if any sedation and it can help a lot with other forms of chronic pain, like back pain or muscular pain, like fibromyalgia. It can also really effectively treat depression. The downside is, it is more expensive.

(33:05) There are other pain agents like the opioid class of medications. I never use these for neuropathy, because they just honestly don't work as well for nerve pain. Also, they have a more significant side effect profile and addiction potential.

(33:22) Strategies for managing low blood pressure caused by autonomic neuropathy. Autonomic neuropathy also has some strategies. So, orthostatic hypotension, that lightheadedness when you stand up, usually I'll start with wearing compression stockings or abdominal binders, which prevent the pooling of fluids in the body and it keeps your fluids in your veins, your vessels so that when you stand up, you can have plenty of blood flow reaching your brain. It's important to stay hydrated and make sure you get enough salt, as long as your cardiologist allows you to. Some people have salt and fluid restrictions.

(33:56) Another trick is raising the head of your bed by up to 20 degrees. So, putting cinder blocks under the head of the bed can help with this symptom. If none of these work, there are medications that target this symptom called midodrine and florinef.

(34:13) Strategies for managing a slow gut (gastroparesis), urinary problems, and erectile dysfunction caused by autonomic neuropathy. Gastroparesis, which means a slow gut, also has a lot of strategies to help. So, dietary modifications can do a lot, taking smaller, more regular meals, lower fats and low insoluble fiber, liquid nutrition is often easier to tolerate, and then avoiding carbonated beverages, smoking and alcohol and staying well hydrated. If these strategies don't work, there are some medications, the most common being Reglan taken before a meal, which can help.

(34:44) There are many treatments for urinary symptoms and erectile dysfunction that most primary care physicians feel very comfortable prescribing.

(34:54) Carpal tunnel syndrome is very treatable. Carpal tunnel syndrome, which we talked about before, can be a very, very treatable condition. So, we usually start with a neutral wrist splint worn at night, and that prevents you from bending or extending the wrist and compressing that nerve. If that doesn't work, physical therapy exercises can help or steroid injections to the wrist can help. If none of those strategies do enough, there is a very safe and simple surgery called the carpal tunnel release, where they simply just make a small incision into that ligament to give that nerve essentially room to breathe, and that often has really good results.

(35:36) Complementary and alternative medicine to treat neuropathy are popular, but their effectiveness is not well studied.  Complementary and alternative medicine is really gaining traction among my patients. I think one of the reasons is a lot of the prescription medications can have side effects and don't always help 100%. The nice thing about complementary and alternative medicine is they tend to not have any side effects. So, these are things like massage therapy, acupuncture, acupressure, electrotherapy, physical therapy, meditation, and some supplements.

(36:07) Unfortunately there's a lack of rigorous evidence, not because these different forms of treatments don't work, but because they're very hard to study. So, there's not great data to really point someone towards one over the other. So, I really leave it up to patients to see what fits with their lifestyle and interests. Also, what's affordable is important. So, a lot of my patients will try a combination of these options.

(36:40) In general, acupuncture, I think, has been the most popular among my patient population. There are some acupuncturists at our Cancer Institute that are really focused on neuropathic pain.

(36:54) Physical therapy can help with balance issues. As I mentioned, exercise is important. So, physical therapy is always something that I recommend and can really do a lot to help with balance, which can be a big issue.

(37:05) Beware of over-the-counter vitamins and supplements: more is not always better. Supplementation, there are a lot of people who take vitamins, which often is fine, but it really should be managed by a physician, because if you take too many vitamins, some vitamins can cause harm. So, I just want to give a little warning that the more is not necessarily merrier with vitamins, you really have to be aware that they can have side effects and only take them when providers recommend them.

(37:42) With that, I want to say, thank you. Here's a picture of the University of Utah with our snow-capped mountains in back, it's a beautiful spring day today. Hopefully it is for you too. It sounds like there's some snowstorms in some places, but it's been a pleasure talking and I really look forward to any questions you may have.

(38:05) [Julie Sinnema]     Q & A.  Thank you, Dr. Barrell, for this excellent presentation. We will now take questions. As a reminder, if you have a question, please type it into the chat box on the lower left-hand corner of your screen.

(38:17) So, our first question is, Can long-term neuropathy cause more damage to your nerves?

(38:27) [Kelsey Barrell]      So, that's a very good question. In general, the longer a neuropathy has been going on, the harder it is to completely reverse it. So, what I mean by that is if someone has had neuropathy symptoms for a decade, it is unlikely that we're going to be able to reverse it versus if someone only had neuropathy for a few months over the course of chemotherapy, it's more likely that we'll get them back to a state where they no longer have those neuropathy symptoms.

(39:02) But the interesting thing about neuropathy is symptoms don't always give a sense of severity. So, having long-standing symptoms, even if they're very painful, doesn't necessarily mean your neuropathy is more severe and that's because the smallest nerve fibers causing a lot of pain are often the earliest affected and represent the most mild neuropathies.

(39:25) So, it can be the case that people with a lot of pain, even if that nerve pain is getting worse, if you actually study their neuropathy using more quantitative measures, like the nerve conduction study or the skin biopsy, their neuropathy is not much worse, but it's more symptomatic. So, it's really hard to know whether worsening symptoms indicate the neuropathy is getting worse, or if it's just more of the same and it's just a more symptomatic case. So, I think, long story short is, in general, the longer you have a neuropathy, it indicates the harder to reverse it is, but it doesn't necessarily mean it's a more severe neuropathy.

(40:06) [Julie Sinnema]      Okay, great. The next question is, this person's neuropathy showed up 14 years after transplant. Is this transplant-related or old age?

(40:19) [Kelsey Barrell]      So, this is a great question. Thank you so much for answering it. It is highly unlikely to be transplant-related. I'm just going to say it's not transplant related. That's too long of a time interval. You would expect if it's due to a medication to have occurred several months from the last time you took that chemotherapy at the latest. So, this is most likely due to something else.

(40:45) Can neuropathy be due to old age? It can. It's also good to look at other factors that we discussed, the B12, the vitamin we mentioned, and diabetes, to make sure there's nothing besides aging that's causing the neuropathy.

(41:04) [Julie Sinnema]     Okay, thank you. This question is about shingles and what can we do, or this person do, to decrease the pain that occurs from a shingles outbreak on their head or face?

(41:17) [Kelsey Barrell]      Very important question, very painful thing to occur. So, I'm sorry that you're living with that post shingles pain. So, the class of medications, those oral prescription medications that we breezed through, we call that class of medication neuropathic pain modulators. So, those four agents mentioned really help with nerve pain. Any of those four would be really good for the shingles pain, which is due to the nerve endings. So, I would recommend trying one of those medications, any of those four should be effective. There's not one over the next that is more effective. Sometimes they actually combined a few of those agents if need be, if the pain is really bad.

(42:05) [Julie Sinnema]     Great, thank you. This particular patient is six years out of transplant and still having neuropathy in their feet. Does TENS therapy help or vitamin B complex? And is there a cure? So, it's a double, it's another two-question series.

(42:21) [Kelsey Barrell]     Yeah. So, great question. I'll answer the second question first. So, is there a cure? Unfortunately, there's not a silver bullet cure, so there's not one thing we can do to take away the neuropathy, but we can do things to stabilize the neuropathy, to treat the symptoms and maybe improve the neuropathy. So, the things that you mentioned, the TENS unit, that is under the scope of complementary or alternative medicine, there's not really strong data in the literature to say TENS actually leads to nerve regrowth or promotes the nerves to grow back.

(43:02) However, in certain patients’ experience and in small trials, some people really feel like it helps with sensation and with pain, and there's absolutely no harm in trying it. So, that's something that in an individual patient, if they want to try it and it helps, I am completely supportive of that.

(43:23) Now, thank you so much for asking about B complex. B complex vitamins has a lot of the different B vitamins. So, there's B1, B3, B6, B12, are some of the most common ones. There's also, in addition to B complex, there's kind of these mega vitamins that some of you might've seen articles in papers or ads out there for, that are like Neurovite or Neuroevite.

(43:56) My general approach to vitamins is I only supplement them if they're low. So, I'll check the important B vitamins and I will supplement that specific vitamin. So, if you're low in B12, I'll supplement that. If you're low in B6, I'll supplement that. The B complex vitamins, often they don't have a high enough dose of a specific B vitamin. So, if you're low in B12, I really just want you to take a large dose of B12. I don't want you to take a little dose of everything. If you don't need the other vitamins, your body's going to just excrete them. You're going to pee it out. So, you'll just have more expensive pee.

(44:36) So, I really target the specific vitamins instead of doing these concoction or combination vitamins. It tends to be a lot cheaper to just supplement the vitamin you need.

(44:47) Also, it will avoid the risk of having too many vitamins in your system. Most specifically, vitamin B6 can cause painful neuropathy, if it's too high. So, you can get toxic with vitamin B6 and cause a neuropathy. So, I've had some patients who developed more painful symptoms because they took too much vitamin B6. They might've taken B6 and then had a B complex and then a multivitamin in addition and it added up to too much. So, wonderful question. And I spent a long time on this question, because it's so important. I recommend just replacing the vitamin you need and avoiding those more expensive combination vitamins.

(45:34) [Julie Sinnema]      Okay. Thank you. Very helpful. This patient's asking about a back itching constantly and the dermatologist and neurologist saying this is a nerve condition. Can you talk about this at all?

(45:47) [Kelsey Barrell]      Yeah. So, this is a symptom that I get not frequently, but you're not alone. I've definitely heard of nerve symptoms presenting with itching. A lot of things can cause itching. So, anytime you have itching, it doesn't mean that you have a nerve injury, but it is a possibility. So, the only thing that's interesting is the location. There aren't many forms of nerve injury or patterns of neuropathy that affect just the back.

(46:24) So, it'd be hard to say without drawing a picture over where exactly it's involved, but a good strategy would be, as long as the dermatologist's made sure there isn't any dermatologic explanation, you could start with steroid cream to make sure it's not just inflammation of the skin. And if that didn't help, some of those topical agents that help with nerve pain could be tried on the back. If that didn't help, you could try those oral agents. If it is nerve generated, if that itchiness is a manifestation of the small fibers, a small fiber neuropathy, then hopefully Gabapentin or one of those other medications would help with that symptom.

(47:11) [Julie Sinnema]     Okay. Thank you. This is about an intervention. Are you familiar with polychromatic infrared energy therapy? UCSF conducted a study, it was inconclusive, but patients I've worked with found it a huge difference with sensory and proprioceptive nerve function.

(47:31) [Kelsey Barrell]      So, good question. So, I'm not familiar with that specific study, but there are a lot of similar studies and different infrared techniques. I've even seen ultrasonic waves, hydrotherapy, many different modalities. Unfortunately, the larger trials, so double-blinded trials, have not had really good supportive evidence. I think one problem with these trials is, it's hard to make a blinded trial of a lot of these therapies. So, it's just really hard to rigorously study this in a lot of people.

(48:15) Some smaller studies have shown promise. I agree, in any one individual patient, I've had a lot of patients try different ones of these more alternative therapies and have great results. So, in any one individual, there might be really great cases. The literature just is lagging behind. So, I don't have any sound literature to stand on when I recommend them. So, in general, I'm open-minded to them, but I think we still need to look for better data out there.

(48:47) [Julie Sinnema]      Okay, great. Here is one about medications, specifically prednisone, causing damage to their muscle strength and their nerves. Can this damage be reversed?

(49:02) [Kelsey Barrell]      Great question. Yes. So, a prednisone-induced myopathy, myopathy means muscle weakness, is something that we do see usually after someone's been on a long course of prednisone at a relatively high dose. Slowly, it can lead to muscle weakness. Usually if we diagnose this, if we stop the prednisone and then do a steady physical therapy regimen to regain strength and stamina, that strength can get better. So, it is not permanent damage.

(49:43) [Julie Sinnema]      Thank goodness. Good answer. I really like that answer. Here's another one. Can you stop neuropathy from spreading from your feet to your legs and hands?

(49:57 [Kelsey Barrell]      So, great question. It depends on what's causing the neuropathy. So kind of a gray answer. But a lot of things can contribute to the neuropathy. So, if you can find what's causing the neuropathy and take that risk factor away, a lot of times the neuropathy will stop progressing. So, what I mean by that is, say, it's the multiple myeloma causing the neuropathy. You take the multiple myeloma away, you treat it. You treat it aggressively. You try to stop the multiple myeloma. Then your neuropathy progression can stop and often improve. So, often reverse.

(50:39) If it's the chemotherapy that's most likely causing the neuropathy, if you lower the dose of chemotherapy or stop the chemotherapy, which is not always an option, sometimes there's other considerations that are more important like the cancer. But if you can take away that risk factor, that chemotherapy, often you can stop the progression. Likewise, if someone is found to have diabetes or a vitamin deficiency, if you stop those things and reverse those things, often you can stop the progression.

(51:15) [Julie Sinnema]     Okay. This is medication related. Is there anything other than Cymbalta that you would suggest? This person had significant side effects with low urine flow and feeling like a zombie, but it did help with the pain. Anything else recommended with less side effects?

(51:36) [Kelsey Barrell]     Yeah. So, I wish I could talk to this patient individually, because it depends on what else you've tried. So, Cymbalta works great, and the fact that that worked for you is great, because that means that the other neuropathic pain modulators are likely to also help with your symptoms. So, trying one of the other three agents that I mentioned, if you haven't already, would be good.

(52:04) So, there's those four agents on that oral prescription slides that you could try one of the other agents. Something I didn't mention, because it's only used in a few people, but if nothing works, we try all of the oral prescriptions, we try it in combination, we try alternative medications, nothing works.

(52:27) There are some procedures that pain clinics can do that I found really, really helpful for my toughest cases. One of them is called lidocaine infusion. So, it's lidocaine, just like the dentist will put it in your gums, but it's actually an infusion through an IV. So, you go to an infusion clinic and you get one infusion every four weeks or so. That can significantly reduce pain, and tends to have very few side effects. So, that is something to pocket away if the other more standard approaches aren't working.

(53:03) Then, the other thing in a similar vein that pain clinics can offer is ketamine infusions, and ketamine is getting more popular these days to combat anything from pain disorders to depression, but also given through infusion in a clinic tends to be very well tolerated and can be very effective for pain.

(53:29) [Julie Sinnema]     Okay. Thank you. So this will be one of our last questions as we wrap up this session, "My motor neuropathy is manifesting as restless legs, weakness, and leg fatigue, similar to just running a marathon. What are your suggestions for treatment? Would a medication like Requip help?"

(53:49) [Kelsey Barrell]      Yeah. So, great question. Thank you so much for... By the way, these have been the best questions that I've ever had in a presentation. So, these are phenomenal. Thank you so much for bringing this up, because restless legs is a very common symptom and often comes along with a neuropathy. There are other causes of restless legs syndrome, but often when someone has a neuropathy, they may develop restless legs syndrome.

(54:16) For those who haven't experienced it, it's what it sounds like. So, it's often occurring when you're at rest, especially before you go to bed and it's this internal urge and discomfort where you want to move your legs, moving your legs will provide relief only to have that urge and discomfort to build up again. It can make it really hard to fall asleep.

(54:40) One of the first things I'd recommend doing is checking something called ferritin. It carries iron. So, it's essentially an iron store in your body. The reason being if your ferritin is low, it is likely that your restless legs is from low iron stores. It's really easy to fix, you just take iron supplementation. So, that's the first thing I recommend, that you have your ferritin checked with your PCP or oncologist and supplement iron if it's below 50, which is my cutoff, so if it's on the low side.

(55:15) If it's not an iron issue, then that class of medications. So, Requip or a medication called Mirapex are very effective and you take those usually two hours before bedtime. You can start with a really low dose and I've had really good results with both Requip or Mirapex, which essentially are the same drugs.

(55:42) Then, off of that question, the fatigue that you're also describing, kind of more motor symptoms, that's a hard question, because a lot of things can cause muscle fatigue. So, I would have to know more about you to determine whether that fatigue is related to the neuropathy or more likely it's multi-factorial, it's related to maybe some muscle weakness in the setting of other treatments or in the setting of deconditioning or pain or poor sleep. So, that would be a hard question for me to answer without having more clinical information.

(56:22) [Julie Sinnema]      Closing. Really good information with that answer. And I apologize we're not able to get to all the questions today. It does sound like this is a pertinent topic for many of the people listening to this topic. Thank you Dr. Barrell for this very informative lecture on behalf of BMT InfoNet and our partners, thank you, Dr. Barrell, for your very helpful remarks and thank you for the audience for the excellent questions. We hope you have a good rest of your day and we'll join in on other things discussions later. Thank you.

(56:53) [Kelsey Barrell]      Thank you so much. It's been a pleasure.