Strategies to Manage Neuropathy after Transplant

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Strategies to Manage Neuropathy after Transplant

Friday May 3, 2024

Presenter: Kelsey Barrell MD,  Assistant Professor in the Division of Neuromuscular Medicine, University of Utah

Presentation is 37 minutes long with 21 minutes of Q & A

Summary: Many bone marrow/stem cell transplant patients experience neuropathy (neuropathy).  This presentation describes the various types of neuropathy patients may experience and reviews popular treatment options.

Highlights:

• Peripheral neuropathy damages nerves in the spinal that extend down through the limbs to the hands and feet. Symptoms include pain and a burning sensation,  numbness and loss of sensation, or weakness and muscle wasting.
• Autonomic neuropathy affects nerves that control body functions such as digestion, blood pressure and heart rate, bowel and bladder function, sexual function, urination, vision and sweating.
• Several prescription and over-the-counter medications are available to treat neuropathy. Physical therapy can slow the progression of neuropathy and promote nerve regrowth.

Key Points:

(03:41): Neuropathy after transplant is usually related to factors that occurred prior to transplant, such as a diagnosis of multiple myeloma or amyloidosis, rather than the transplant itself.   

(12:23): Certain types of chemotherapy, such as bortezomib (Velcade®) can cause painful neuropathy. Chemotherapy-induced neuropathy improves or completely resolve over time for most patients.

(17:36): Long-term use of immune suppressants can contribute to neuropathy.

(18:05): Neurologic exams subjectively measure neuropathy. A more objective measure of neuropathy is a nerve conduction study or EMG. Skin biopsies and lab results are sometimes needed to properly diagnose neuropathy.

(23:06): Exercise can improve quality of life, physical function, balance and strength, and neuropathic pain.

(26:18): A regular fitness routine is highly recommended for improving neuropathy symptoms.

(27:24): There are no proven treatments to prevent chemotherapy-induced but prescription medications are available to help with painful symptoms including duloxetine (Cymbalta), gabapentin, amitriptyline, and Pregabalin.

(28:53): There are a number of good over-the-counter agents that can help manage the pain associated with neuropathy including some that are lidocaine-based, Biofreeze®, capsaicin and CBD.

(29:35): Prescription medications that can help with neuropathy include duloxetine (Cymbalta®), gabapentin (Neurontin®) amitriptyline, and pregabalin (Lyrica®).

(31:51): Acupuncture and massage don’t change the progression of neuropathy or restore nerve growth. However, massage has been shown to help with symptoms.

Transcript of Presentation:

(00:06): [Marla O’Keefe]:   Introduction of Speaker. Welcome to Strategies to Manage Neuropathy after Transplant. My name is Marla O’Keefe and I will be your moderator for this workshop.

(00:10): It's my pleasure to introduce to you today's speaker, Dr. Kelsey Barrell. Dr. Barrell is an Assistant Professor of Neurology in the Division of Neuromuscular Medicine at the University of Utah. She's also the neurologic specialist at the regional Utah Amyloidosis program at the Huntsman Cancer Institute, where she established a comprehensive neuromuscular oncology clinic to improve the access and care to those with a wide range of neuromuscular disorders. Dr. Barrell specializes in amyloidosis, neuropathy and cancer and chemotherapy-related neuromuscular complications. Please join me in welcoming Dr. Barrell.

(01:01): [Dr. Kelsey Barrell]:  Overview of Talk. Thank you so much for that kind introduction, Marla, and I'm just really excited to be here. I've always enjoyed these discussions and learned so much from the patient's experiences. So thank you all for attending and I look forward to answering our questions. So we'll make sure we have plenty of time for that.

(01:19): So as Marla mentioned, I'm going to be going over strategies to manage neuropathy after transplant. And this is what we'll be covering today. Starting at the basics of what a neuropathy is, what are the different types of neuropathy patients can have, common symptoms of neuropathy, and then when during the transplant journey neuropathy can come up, how we make the diagnosis, how we manage it, and what type of specialist can help you with your symptoms.

(01:52): Peripheral neuropathy is damage of the nerves that are in the spinal cord and travel all the way down the length of your limb to sensory endings in your toes and your feet. So starting at the basics, what is a neuropathy? Essentially the definition of neuropathy is this kind of umbrella term that refers to damage of the peripheral nerves. And the peripheral nerves are the nerves that are in the spinal cord and travel all the way down the length of your limb to kind of sensory endings in your toes and your feet.

(02:15): Neuropathy typically affects  the longest nerves first. With a neuropathy, it typically will affect the longest nerves first. We call that a length-dependent process. And clinically what that will look like is a stocking glove pattern. So imagine the neuropathy starting in your toes, working up your feet to kind of at the stocking level right below your knees and then at that point starting in the fingertips.

(02:36): And why is that? Well, a nerve is very long. It's a long narrow structure. So if it was the width of spaghetti, it would go around an entire track. And because it's so long and narrow, it doesn't have protection that whole way. Those longest nerves are most susceptible to damage. Those longest nerves have trouble carrying all that energy produced in the cell body in orange all the way to the end tips. And so those longest nerves tend to suffer the earliest on in neuropathy.

(03:08): Peripheral neuropathy involves numbness, tingling, or burning. There are many different types of neuropathies. We will go into detail on these five types of neuropathies that can come up during the transplant journey, starting with peripheral neuropathy. So a peripheral neuropathy usually is marked by numbness, tingling, burning, which starts in the toes and slowly creeps up. It's usually symmetric, meaning it's equal from the left and the right side of the body. And as it progresses, patients often will notice impaired balance as well as some weakness.

(03:41): Neuropathy after transplant is usually related to factors before transplant, rather than the transplant itself.  Neuropathy in general is actually pretty rare due to transplant, but we'll come to see that it is more common from sources before transplant. So only 1 to 5% of patients will develop neuropathy during their transplant. You can see this table here showing that most of the neurologic symptoms occurring with transplant involve the brain or the spinal cord rather than just the peripheral nerves. But when the peripheral neuropathy occurs, we typically see it in the first two years, rather than after two years.

(04:17): Most patients will have a milder sensory form where there's just mostly numbness or impaired sensation, but rarely it can be more severe where patients develop significant weakness. And when this occurs, often it is an immune-mediated process that can be more rapidly progressive. And we'll touch on this again in some later slides.

(04:42): Autonomic neuropathy affects nerves that control involuntary bodily functions. The autonomic neuropathy refers to the autonomic nerves, and those are nerves that control involuntary bodily functions. So these are functions that we kind of ignore when they're working well. We only realize that they're happening when we notice dysfunction. So it's things like blood pressure and heart rate regulation, bowel and bladder function, sexual function, vision and sweating function. And in general it's pretty rare after stem cell transplant, but actually it's more common due to underlying plasma cell disorders, especially in the case of AL amyloidosis, as well as chemotherapy.

(05:24): Mononeuropathy affects a single nerve through compression; carpal tunnel syndrome is one example. There's also something called a mononeuropathy, and if we break this down, mono means single or one. And so this is when a single nerve is impacted. And this is usually due to compression. So many of you probably have heard of carpal tunnel syndrome or maybe have even experienced it. This is the most common form. The second most common form is a ulnar neuropathy.

(05:47): So with carpal tunnel syndrome, that is compression at the wrist of the median nerve. And the median nerve innervates the thumb, the index in the middle finger and half of the ring finger. And then the ulnar nerve innervates everything else, the pinky and half of the ring finger.

(06:05): And with mononeuropathies, these compressive neuropathies, typically patients describe episodic numbness, tingling, or pain, which is worse often at night, waking up and shaking your arm out is very common, or worse with repetitive tasks like crocheting or using electrical tools. This is important to kind of pick up on because there are really good treatment options that we'll discuss later.

(06:35): Plexopathy refers to inflammation of a plexus or network of nerves. You have two main ones of these in your body. The brachial plexus refers to the plexus in the upper arm, kind of around the underarm area, and then the lumbosacral plexus is in your pelvis.

(06:52): Plexopathy is rare but can arise with transplant when a new immune system attacks the nerves. Plexopathy can occur directly due to transplant, usually within the first six months after transplant. It presents as really new or severe pain, often shooting electric searing pain followed by weakness and numbness. And it is very rare. The theory of how it arises is that this represents an abnormal immune system. So your immune system essentially gets wiped out partially to prepare for a transplant. As it reconstitutes after, it can get confused or dysregulated and actually attack its own structures, kind of like an autoimmune condition where your immune system, instead of attacking foreign particles attacks itself. In this case the nerves and the plexus.

(07:47): Optic neuropathy can be a side effect of the medication tacrolimus. Optic neuropathy refers to damage of the optic nerve, and that's the nerve that carries the visual information from the back of your eye all the way to the brain and allows you to see. The most common scenario for this to occur is in the setting of treatment, specifically tacrolimus, but rarely we see it as a complication of transplant. And patients often will describe pain worse with eye movements as well as reduced color vision especially to the color red and then reduced vision.

(08:18): Peripheral neuropathy can cause many different symptoms because it affects different types of nerve fibers. All right, so symptoms of a peripheral neuropathy. Now many patients and caregivers have experienced this kind of paradox of a whole different array of symptoms and how can one process cause both pain and burning but also numbness and loss of sensation. And the reason that patients described so many different types of symptoms is because a neuropathy involves different types of nerve fibers.

(08:47): So different nerve fibers carry different information in our bodies. And if we think of a nerve like electrical wire, there's the copper portion, what in the nerve is called the axon and that's in blue. And then there's an insulation, a sheath around that wire, and that's a myelin sheath in the nerves, and that's in yellow.

(09:07): Our smallest nerves are not insulated with a myelin sheath so they can be the source of pain, burning, and tingling. So the smallest nerves in our body you can see are not insulated. They do not have a myelin sheath. And these nerves carry pain and temperature information. So when they are injured, patients typically have a lot of pain or burning, tingling pins and needles shock-like sensation. And since these are very small nerves, they typically get injured early on in the course. So it's more common early on in the course.

(09:35): The next nerve that we call 'thinly myelinated -, meaning it only has a little bit of insulation - are the autonomic nerves that carry autonomic information that we'll talk about in a second.

(09:47): Large fiber nerve damage can cause very dense numbness so patients cannot feel their feet when walking. As we get larger, we have large nerve fibers, those carry things like joint position sensation, vibration sensation. And so when people have a large fiber nerve damage, they'll experience very dense numbness where you really can't feel your foot in space or can't feel it when you're walking.

(10:04): Motor nerves are the largest and when damaged can cause weakness and muscle wasting. The largest nerves in our body carry information to our muscles. These are called motor nerves. And when these are damaged, patients will experience weakness or muscle wasting. And often this will occur in a length-dependent pattern. So this will occur usually starting below the ankle. And often patients will have a whole combination of different symptoms because multiple types of nerves are involved, especially as we progress through the course of a neuropathy.

(10:36): Damage to the autonomic nervous system can cause multiple problems with involuntary bodily processes like digestion, blood pressure, urination and sexual function. Now, symptoms of the autonomic nervous system. I like the saying 'fight or flight, rest and digest' because these autonomic nerves control the things that you would need to escape from a tiger or sit down and eat a meal. And so going from top to bottom, symptoms could include decreased sweating, difficulty adjusting to the dark because these control how dilated your pupils are.

(11:03): A common type of autonomic neuropathy is low blood pressure. A really common one is a symptom called orthostatic hypotension. Orthostatic means with standing, and sorry this is a typo, it's supposed to say hypotension. That means low blood pressure. And so with standing, the blood pressure drops. The main symptom is going to be lightheadedness with standing or feeling like you're going to faint.

(11:24): Digestive issues are common and that can be diarrhea, constipation, it can be alternating diarrhea with constipation or poor appetite or bloating. Urinary issues can result in frequency or urgency or even retention of urine and recurrent urinary tract infections. And then sexual dysfunction generally presenting with erectile dysfunction is also common.

(11:49): Neuropathy can appear before transplant as a complication of hematologic malignancies. Now when during a transplant will we see some of these neuropathies? The answer is at any time, so including before transplant.

(11:58): So before transplant, neuropathy is actually a common complication of a lot of hematologic malignancies. So in multiple myeloma up to 20% of patients will have a neuropathy. It's about double that in AL amyloidosis with about 40% of patients experiencing neuropathy. And then on top of that, neuropathy is also a common side effect of chemotherapy.

(12:23): Chemotherapy-induced peripheral neuropathy is something that happens pretty frequently. It's actually the second most common side effect of chemotherapy with the first being hematologic abnormalities like abnormal white blood cells or platelets and things like that.

(12:40): Bortezomib (Velcade® ) can cause very painful neuropathy. The biggest offender I see in my clinic is bortezomib, also called Velcade®, which I'm sure many of you have had experience with. Up to 50% of patients will develop a neuropathy and it can occur relatively early on in the first few courses, typically plateauing by cycle five. And what's distinct about this is it can be extremely painful. It often involves the smallest neurofibers, and even though this is in some ways the mildest neuropathy, in that those are the small neurofibers first, it tends to be very, very painful. So we deal a lot with that symptom.

(13:16): Thalidomide is an older agent. I don't think it's used as frequently. Some of you might've had this if you were treated many, many years ago. Neuropathy was common with thalidomide, a little less with its newer generation agent, lenalidomide. But with these agents, patients can have more weakness. So not just that small fiber sensory change, but actual weakness, as well as the autonomic symptom of constipation.

(13:43): Vincristine is common in a lot of different types of cancer treatment. It's very well reported to cause neuropathy. And similar to thalidomide, it can cause problems with sensation as well as the muscle. So sensory and motor neuropathy. It also is commonly going to cause autonomic neuropathy which is mostly marked by lightheadedness with standing or what we call orthostatic hypotension.

(14:10): Chemotherapy can injure nerves through many different pathways. Now I think it's interesting, this is a little picture I drew to show where chemotherapy attacks the nerves or affects the nerves. And on top in blue, that's the cell body and that's right after the spinal cord. And so chemotherapies can directly injure the cell body. It can injure the microtubules which transport information and energy down the length of the axon. It can injure the mitochondria, which is the energy producing cells. It can injure the vessels that help supply the nerve endings. And so really chemotherapy has a lot of different targets on the nerves.

(14:56): Chemotherapy-induced neuropathy will improve or completely resolve over time for a majority of patients. One thing I will mention with chemotherapy, and a question I frequently get is, "will chemotherapy-induced neuropathy resolve or improve?" The answer is it is more likely to go away than not. So two-thirds of patients will have complete resolution of their chemotherapy-induced neuropathy. In the one-third of patients who have ongoing symptoms past a year, they often will notice a certain degree of improvement.

(15:26): So in most cases it does improve over time or go away. It should not get worse after stopping chemotherapy. So it can sometimes still seem to progress two months after stopping chemotherapy. But if you're past two- to-three months after discontinuing chemotherapy, it should not continue to progress.

(15:49): So a question I often get in clinic is: "My chemotherapy was five years ago and I've just recently started noticing acute worsening of my neuropathy. Is it due to that chemotherapy?" And the answer is no. The initial neuropathy might've been due to chemotherapy, but there's something else going on causing it to progress now.

(16:10): How about during transplant? So during transplant there's a lot of changes in the immune system. So often what we see are immune-mediated neuropathies. So when the immune system reconstitutes itself, it can become dysregulated and attack itself as a target. These are actually extremely rare, so less than 1% of patients usually will get this. And risk factors include chronic graft-versus-host disease, CMV viral infection or unrelated donors.

(16:39): One of the most common ways it presents is in that plexopathy, remember that network of nerves. But it can also cause injury to a single nerve or multiple peripheral nerves. And when we think it is due to underlying immune dysregulation, often we'll try treating with immune suppressants like steroids.

(17:01): How about after transplant? So chronic graft-versus-host disease, you would think that it could cause a lot of neuropathies because it tends to affect seemingly all organs, but actually it's very, very rare to cause an underlying neuropathy or an immune neuropathy. What I see a lot more is actually muscular symptoms. So muscle cramps I see in more than 16% of patients and I think this is probably underreported, so probably much greater than 16% will actually experience muscle cramps or muscle discomfort.

(17:36): Long-term use of immune suppressants can contribute to neuropathy. And then a lot of patients are on immune suppressants for a long time. We talked about tacrolimus being associated with optic neuropathy. There are some TNF-alpha immunotherapies that can cause immune-related neuropathy or a neuropathy involving the cranial nerves, the nerves that go to your face. Prednisone is commonly used. And high doses for a long time of prednisone can cause muscle weakness.

(18:05): Neurologic exams subjectively measure neuropathy. A more objective measure of neuropathy is a nerve conduction study or EMG. So how do we make the diagnosis? Well it all starts with a good neurologic exam. And so these are my tools on the right. Usually if you're in my clinic, I'll check something that represents the smallest nerve fibers. So I'll check either your sensation to pinprick or temperature. And then I'll move on to checking the large nerve fiber function and that will be checking vibratory sensation in your toes with a tuning fork that vibrates, as well as position sensation. So if you can feel where your foot is in space, your toe is in space. Reflex exam can show the health of the nerves and the muscles. I check strength. And then importantly balance.

(18:49): And a lot of these modalities are things that primary care physicians or oncologists can do. And so often your primary physician might be able to do an exam if they suspect you have a neuropathy.

(19:05): Now you can imagine the neurologic exam is a bit subjective. It relies on patient reporting. And so a more objective way to really define a neuropathy would be a procedure called a nerve conduction study EMG. And that's an electrical study shown here on the left measuring the actual nerve function. And so essentially what we do for the nerve conduction portion, we put stickers on a place in say your hand or your foot and then we shock higher up on that limb and we can actually measure how quickly that shock, that impulse travels through your nerve into those stickers that will then receive that information. So it's a very objective measure. Its weakness is that it cannot measure the smallest nerve fiber function, therefore it can be normal early on in the course of neuropathy.

(19:59): Skin biopsies can measure neuropathy in the smallest nerves. What can measure those smallest nerves is a skin biopsy. And that's where we take a very thin about paper thickness size chunk of your skin in three places in your leg. And we actually measure the density of the small nerve fibers in the skin. So in the pink image, which is a little clearer, you can see kind of these purple staining lines that go perpendicular to the skin. This is the normal density. So we see a lot of these purple lines clearly. And you can see next to it on the right those purple lines we don't see as many of them so it's less dense and the ones we see look kind of thin and bubbly. And so that's how we can measure a small fiber neuropathy if we need to.

(20:45): Lab results can detect contributing factors for neuropathy like diabetes, vitamin deficiency, cholesterol or alcohol overuse. Labs are also important. The reason being we want to rule out factors which can increase your risk of neuropathy or contribute to a neuropathy. The most common risk factor is diabetes, diabetes, diabetes. So we always check for that. Vitamin deficiency, especially vitamin B12 is important. Cholesterol can contribute. And then we always like to screen for alcohol because alcohol overuse can also contribute.

(21:12): And so again, if we feel like the neuropathy is progressing after chemotherapy was stopped, it's important to look for these common risk factors. Usually we'll find one.

(21:22): Diagnosing autonomic neuropathy is based on getting a good clinical history. So asking about things like lightheadedness with standing or gastrointestinal symptoms or urinary and sexual symptoms. There is specific lab testing that can be done, but this is only available at certain academic centers and certainly not at every institution. But what this can do is just objectively pin down how effective the autonomic system is. So it checks for blood pressure and heart rate changes during a tilt table test where we tilt you from horizontal to vertical and then it can measure heart rate variability and it can quantify your sweat function.

(22:08): Treatment for neuropathy can target the underling disease causing the symptoms, such as multiple myeloma, or the just the symptoms. Now moving on to therapy. So very important thing, what can we do for symptoms? So really there's two tenets of therapy. One is targeting or preventing the underlying disease course and the other is targeting the symptoms, especially the painful features of neuropathy.

(22:26): So to target the underlying disease course, we treat the underlying cancer whether it be multiple myeloma or amyloidosis. As we mentioned, chemotherapy can cause neuropathy, and so sometimes we have to decrease the dose or switch to a different chemotherapy. And then we identify and treat risk factors that we mentioned. And exercise. We'll talk more about exercise and the role. And then targeting symptoms. There's multiple ways to do that that we'll discuss. So topical or oral medications, as well as complementary and alternative treatments.

(23:06): Exercise can improve quality of life, physical function, balance and strength, and neuropathic pain. Moving on to exercise, what is the evidence? It is very well established in patients with diabetic or pre-diabetic neuropathy. There was this really groundbreaking study in 2014 by some of my mentors, Dr. Rob Singleton and Gordon Smith ,that objectively showed that exercise can lead to nerve regeneration, so regrowth of the nerves essentially.

(23:32): What they did here is they did a skin biopsy in everybody in this who was enrolled. And then half of these patients about were in this exercise group where they had regular exercise with a weekly coaching session, five days a week of upgraded exercise, meaning you increase your exercise output. You also had a lifestyle coach quarterly working on nutrition and diet, and then the counseling group with standard of care. So like many experience, sometimes their doctors mention exercise but don't go into much detail about what they should be doing.

(24:08): And as the results here on the vertical axis, you can see numbers. Zero means there is no change in nerve fiber density. So they repeated the skin biopsy, they counted how many nerves were in the skin and no change would be the neuropathy stayed the same, right? If you had a negative change down, that would mean that you lost nerve fibers, the nerve neuropathy progressed. If it's a positive number upwards, you have regained nerve fibers. And what they saw in the control group, so in white, you can see it that there's just been a little loss of nerve fiber density over a year and that's what we would expect.

(24:51): Now in the treatment group, we would hope that patients wouldn't lose as much nerve fiber density, but what we found was actually better. So in patients who did the rigorous exercise, they actually improved their density. And what does that mean? The nerves had regrowth. So those nerves can sprout and grow more if you exercise.

(25:12): So how does this apply to chemotherapy-induced neuropathy? There are several rodent studies that show very similar results in nerve density in biopsies. Unfortunately, there is yet to be a similar study in chemotherapy-induced neuropathy in humans that show that nerve density objective measure. But there are a lot of studies that do show improvement in many symptoms.

(25:40): A systematic review of research on exercise for neuropathy showed it can improve quality of life, physical function, balance and strength, and neuropathic pain. So this is a systematic review that was done a year ago and looked at 16 very well-done studies looking at exercise. And the conclusion of this systematic review is four things. So exercise can improve quality of life. It can improve physical function, things like balance and strength. It can improve neuropathic pain. And also intuitively there are no major side effects or risk factors. And so because of this, I think of exercise like a medication. It is an actual prescription that I verbally give to patients.

(26:18): A regular fitness routine is highly recommended for improving neuropathy symptoms. And so what I will strongly encourage patients to do is get into a regular fitness routine. And the goal would be 30 minutes, five days a week of something that keeps your heart rate up. So an aerobic exercise would be sustained, keeping that heart rate up. And so that could be anything, biking, walking, swimming, rowing, stair stepper, you name it. But I want patients to exercise to the point where they can't sing a song. So if you're walking with your friend, you might be to have a breathy short conversation but you wouldn't be able to sing a song. You're actually pushing it a little bit. And as you get in better shape, you can push it a little further each time.

(27:00): And now 30 minutes, five days a week is our goal. We don't start at goals. We work towards them. So if you can only do five minutes a day on a recumbent bike, great, start there and then keep working on it. Adding strength training and balance exercises is icing on the cake. So they have benefits, but we're talking specific to nerve function.

(27:24): There are no proven treatments to prevent chemotherapy-induced but medications are available to help with painful symptoms including duloxetine (Cymbalta), gabapentin, amitriptyline, and Pregabalin. There's been a lot of research into different modalities that could theoretically improve or prevent neuropathy in the setting of chemotherapy. And the best guidelines come from the American Society of Clinical Oncology. And what they found was that there is a medication that can help with painful symptoms, but they did not find anything that actually prevented neuropathy from occurring in the first place. And they mentioned that outside of the context of a clinical trial, they really couldn't recommend in favor of acupuncture, cryotherapy, which is like cold therapy, compressive therapy or fatty acid therapy.

(28:09): And additionally, they actually recommended against the following for prevention. And these are a lot of different antioxidants, as well as supplements and vitamins. Not to say that in a single patient vitamin B wouldn't be indicated if they have low levels, but across the board we can't make the recommendation for any of these.

(28:40): There are good topical treatments that can be applied to the skin for focal neuropathy in the hands or feet. So what can we do? I often start with topical treatment if symptoms are either relatively mild or relatively focal, like just in the feet or just in the hands. And these are things that you actually apply to the skin.

(28:53): There are a number of over-the-counter agents that can reduce the pain associated with neuropathy.  So there's a lot of good over-the-counter options, these first three listed all are lidocaine-based, so that's kind of that numbing anesthetic. Biofreeze has the menthol. Capsaicin is actually the active ingredient of chili, which is interesting. And then CBD, many of you might've heard of cannabidiol. That is the pain component of cannabis or marijuana and legality obviously varies by state. And then there's prescription-compounded ointment. The one I use has seven ingredients, a little bit of everything, but that can really help dull that burning painful sensation.

(29:35): Prescription medications that can help with neuropathy include duloxetine (Cymbalta®), gabapentin (Neurontin®) amitriptyline, and pregabalin (Lyrica®). How about prescriptions? One thing to know is that all of these prescriptions are equally effective. Now you might've remembered I mentioned and highlighted duloxetine. That is the best studied in chemotherapy-induced neuropathy in the literature. But experientially all the other agents listed work just as well. It's just they haven't been as well studied as applied to this population.

(30:00): Often I'll start with gabapentin, also called Neurontin. It's been around forever. It's very cheap. We know its side effects and that can include mild sedation or swelling in the ankles.

(30:12): Amitriptyline is also an oldie but goodie I'd say. So this originally was intended to be antidepressant, but it made people too sleepy and so I kind of use that side effect in my favor. So if patients have insomnia or a lot of trouble at night, this is a really good sleep aid and it can also help depression. The side effects, it can dry people out, so cause dry eyes, dry mouth, as well as constipation. So if someone has a lot of diarrhea, this is also kind of a good option so it can help your diarrhea.

(30:48): Pregabalin or Lyrica, it's the newer generation of gabapentin so it's less sedating compared to gabapentin, just more expensive.

(30:57): And then Cymbalta also called duloxetine, again is just the best studied in chemotherapy. It is also used as an antidepressant, so it works very good for mood and it works for a lot of different pain. So if someone has a lot of back and muscle pain in addition to their nerve pain, I'll probably start with duloxetine because it can help chronic pain in general.

(31:25): And I'd say because a lot of our current options are disappointing in that we have not found that they prevent neuropathy and in some patients they don't completely get rid of the neuropathic pain they experience. A lot of my patients seek out complementary medicine. I think the most common one I've seen in my patients is acupuncture. And this is also the best study.

(31:51): Acupuncture and massage don’t change neuropathic progression or restore nerve growth but massage can really help with symptoms.  We know acupuncture's been around for thousands of years. There are a lot of small studies that show that it can help with symptoms management. There are no studies that confirm that it actually changes the progression of the neuropathy or restores that nerve regrowth. And so if a patient feels like it helps their symptoms, I'm in favor of it. There aren't many downsides to acupuncture, but it probably is not going to change the underlying progression of the neuropathy.

(32:23): Similarly, massage can really help with symptoms so patients can feel that it helps with their fatigue or their pain or their stress level, but also those benefits are transient so they last about two days, so it doesn't actually change the underlying neuropathy.

(32:39): We mentioned that there are a lot of supplements that have been studied, and people try. None of them across the board are thought to actually prevent or slow the neuropathy.

(32:51): Physical therapy can promote nerve regrowth. Meditation can help us deal with pain and so, for some, can be a very helpful practice. Physical therapy, especially in the setting of aerobic fitness is a very good option and there is data to suggest that it can slow a neuropathy by promoting nerve regrowth.

(33:11): And then electrotherapy, as you saw in the guidelines, there is no evidence to suggest that this across the board can prevent or slow a neuropathy. However, some patients feel like it helps their symptoms, it helps them feel more. And so if it helps symptoms, I don't see any harm in it.

(33:33): Several strategies can help with symptoms of autonomic neuropathy. Treatment of autonomic neuropathy. So orthostatic hypotension that lightheadedness with standing, one of the first things we'll recommend is compression stockings and abdominal binders which prevent pooling of fluid in these body regions and keeps your body fluid, essentially your blood in your vessels where it belongs.

(33:52): Optimizing hydration and salt intake are important with a caveat that if you have heart failure you might be limited in how much water and salt you can get. Raising the head of the bed by 10 to 20 degrees. I'll recommend patients actually just put a six-inch cinder block under their headboard, tilt the entire bed. That can help with the symptom. And then there are multiple medications that can help if these above more behavioral modifications don't work.

(34:21): Altering one’s diet can help with constipation and bloating. Gastroparesis is when you have kind of slow gut emptying, so often presenting like constipation or bloating. So often we start with dietary modifications. So small particle meals, so not large fibrous meals, low fat, regular meals, liquid nutrition and hydration can also improve. There are medications, especially Reglan that can kind of increase your gut movement if you take it before a meal.

(34:49): There are also medications to treat urinary or sexual dysfunctions arising from neuropathy. There are a lot of medications for urinary frequency or urgency. Many of these are also used for things like benign prostatic hypertrophy. And so primary care is well-versed in using these.

(35:02): Similarly, erectile dysfunction, very common symptom as people age. So there are some good options, Viagra and Cialis that most primary care physicians feel comfortable with.

(35:13): Mononeuropathy conditions like carpal tunnel syndrome can be addressed with bracing. Treatment on mononeuropathy. So carpal tunnel and cubital tunnel, usually we start with bracing. So in carpal tunnel, a wrist brace that you wear at night for six weeks, and then cubital tunnel, an elbow brace again you wear at night for six weeks. That prevents that compression that happens when you flex your wrist or your elbow too much. And then if that's not effective, there are some minor surgeries that can be very effective.

(35:45): Begin seeking help for neuropathy with your hematologist or oncologist; they can refer to a neurologist if needed. And who should you seek help with? Well, I think it should always start with your hematologist and oncologist. Many of them feel comfortable making the diagnosis and prescribing kind of the first line treatment medications and doing a little bit of a workup. If there's any atypical features or there's diagnostic uncertainty, a lot of times they will opt to phone a friend, so they'll refer you on to a neurologist or specifically a neuromuscular specialist like myself. So that's a neurologist who really focuses on nerve and muscle function.

(36:25): And then another reason I often get patients referred to me is when the first line agents are not helping sufficiently with the neuropathic pain. And with that I will conclude.

(36:39): Here are my references and thank you so much for your attention and we will take questions.

Question and Answer Session

(36:49): [Marla O’Keefe]: Thank you so much Dr. Barrell for this excellent presentation. We have a number of 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. Someone wants to know, can you discuss vitamin levels or vitamin B levels?

(37:12): [Dr. Kelsey Barrell]:  Yes, yes, I'd be happy to. There's a lot here so I could give you a separate talk on this, but let me just highlight a few things. So the vitamins that I see being abnormal the most are vitamin B12 and vitamin B6. B12 is a problem if it's too low. And interestingly, in a lab when you have your B12 checked, it's normal if it's above say 180 or 200. But most neurologists actually have a higher threshold. We want it above 400 because we know it's so important for nerve health that we actually want a moderate or a high level of B12. So a lot of times you'll see us prescribing B12 supplementation even when your primary care physician checked it and said, "Well, it's within the normal range."

(37:58): Vitamin B12 is also important for energy and cognition like thinking. So I really prescribe a lot of B12 even if it's just borderline low. And usually I start with oral supplementation of B12. If I don't feel like the level's responding to oral medications, then I'll try the injection of B12.

(38:18): And then just quickly, B6 is also important. It can cause a neuropathy if it's too low or too high. And so there's really a narrow window and so it's important if you do need B6 supplementation that we check your level three months after starting to make sure we're not over-correcting because actually vitamin B6 toxicity are too high of a level that can cause a very painful neuropathy. And so that's an important consideration as well.

(38:46): But I don't recommend patients just taking vitamin supplements without actually knowing if they're low because some vitamins, as we heard in vitamin B6 can actually be injurious to you if you take too much. Great question.

(39:04): [Marla O’Keefe]:   Thank you for that. Next question. This gentleman has been told by multiple doctors that after transplant many patients will have muscle spasms. Are they caused by neuropathy? He drinks electrolytes all day long and it's better, but the spasms still continue.

(39:25): [Dr. Kelsey Barrell]:  That's a hard question. It can be. Many things can cause muscle spasms. People with neuropathy are a little bit more likely to have muscle cramping or spasms. So when the nerves are severely injured, they can really get hypersensitive and crampy and twitchy. But actually there's more common causes of muscle spasms and often it has to do with electrolytes. So being deficient in potassium, sodium or magnesium, or medications. There's certain medications like cholesterol or statin medications, which is not to say you shouldn't take a cholesterol medication, but sometimes if you are taking a cholesterol medication and have spasms, you can switch to another cholesterol medication. As well as graft-vs-host disease, which would be possibly delayed after the transplant is a very common cause of muscle cramping.

(40:26) [Marla O’Keefe]:  Thank you. Are there any predictive biomarkers for CIPN for specific drugs?

(40:36): [Dr. Kelsey Barrell]:  Good question. So as far as biomarkers, as far as drug development, there are a few things that can like neurofilament light chains that can show nerve injury that have been employed in research. But as far as in clinical settings, things that we can predict whether people get CIPN, what we found is there are risk factors that make it more likely that you'll develop CIPN, sorry, chemotherapy-induced peripheral neuropathy, but nothing definitive that would say you have this and therefore we're very worried about it.

(41:17): The risk factors that make you a little more likely to develop it include things like renal failure, history of neuropathy in the past, diabetes and obesity. But we really aren't great predicting who will get it. We don't have a great understanding of why some people get really severe cases and others don't get it at all.

(41:43): [Marla O’Keefe]:  Thank you. Next question is, I stopped Velcade months ago and my neuropathy is not getting better. How long does it generally take to regain feeling in my feet?

(41:58): [Dr. Kelsey Barrell]: Really good question. Velcade is just infamous for causing neuropathy, so it should not progress or get worse starting about two months after you stop. Sometimes for the first two months it can kind of keep dwindling, getting worse, but once you get to the two, three months point in time, I would expect it to either plateau or improve, and two-thirds of patients will have complete resolution of their neuropathy around a year out or so. But in that one-third who has chronic neuropathy, there still can be some improvement.

(42:40): If you feel like the neuropathy is continuing to progress despite you stopping Velcade say over two months ago, then it'd be really important to see if there's any additional risk factors that are potentiating or contributing to the ongoing neuropathy.

(42:57): [Marla O’Keefe]:   Thank you. Do you have any experience with scrambler therapy?

(43:03): [Dr. Kelsey Barrell]:  I don't.

(43:09): [Marla O’Keefe]:  Okay. What are some solutions for erectile dysfunction from neuropathy and lower back nerve damage?

(43:20): [Dr. Kelsey Barrell]:  Some solutions? So for erectile dysfunction, usually honestly I don't manage this as much. I ask about it and kind of identify it and then most patients will have their primary care physician start treatment, but the symptoms often include pharmacotherapy, so medications. Viagra and Cialis are the best known.

(43:45): If it's not responding to medications, usually primary care physicians or general practitioners will refer on to urology experts because there's a lot of other modalities and treatments to help with erectile dysfunction.

(44:04): [Marla O’Keefe]:   Thank you. I have neuropathy in both hands following Taxol treatments for a secondary cancer. It's been two years and I'm told it's not going to get any better. Is this something that you've also found? We've tried a lot of meds and supplements.

(44:22): [Dr. Kelsey Barrell]:  Yeah. It depends. So two years out it does seem like there's probably a chronic neuropathy that is not in that two-thirds of patients who just improve or go away. But it's not to say that there aren't any other things that can lighten the burden or make it better. So the things I would think about is just carefully screening you for risk factors to see if anything is kind of contributing because say you have B12 deficiency or just pre-diabetes and you manage that, the neuropathy can improve over time, especially if you exercise. So letting those nerves sprout back.

(45:01): The other thing I would think about is considering that nerve conduction study, that procedure that I showed you showed to make sure that you don't have a superimposed process such as a compressive neuropathy at the wrist, the carpal tunnel, or at the elbow, the ulnar tunnel.

(45:21): [Marla O’Keefe]: Let's see. We've had a lot of good ones here. I had severe neuropathy symptoms that got worse after each dose of Neupogen or Neulasta. Have you seen that reaction in other people? Would it be better to avoid or minimize those medications if I need another transplant?

(45:44): [Dr. Kelsey Barrell]:  I haven't heard of that being a common cause of neuropathy, but what I wonder is if it kind of enhances the underlying neuropathy, makes it more symptomatic. It depends on how severe the symptoms are, but I wouldn't discount using this again because it is so important to restore those blood levels with Neupogen and similar stimulating factors. But no, I haven't heard of that being a common side effect.

(46:18): However, it might be one of those things similar to if someone has edema, so you have leg swelling for whatever reason, often people feel like their neuropathy is worse. It's not the swelling or the edema is making your nerves more injured. It's that it enhances your symptoms. There's kind more swelling. There's more kind of inflammatory cells and more reactions in the body that just enhance symptoms. So I wonder if it's just enhancement of symptoms rather than an actual worsening of the underlying neuropathy.

(46:50): [Marla O’Keefe]:   Thank you. Could my neuropathy be related to urinary incontinence? My urinary incontinence is very pronounced.

(47:01): [Dr. Kelsey Barrell]:  Yes. So definitely. So autonomic neuropathies can lead to many urinary symptoms with urinary incontinence being one of them. There are other things I think of as well. So sometimes if there's any spinal cord issue, which would not be related to the neuropathy, that's more of the central nervous system, that's another cause of urinary incontinence. So I think it'd be good since urinary incontinence isn't one of the most common ones we see, just to screen for other causes. But if they don't find any other causes behind it, it really could be related to autonomic neuropathy.

(47:42): [Marla O’Keefe]:   Thank you. I have developed neuropathy in my feet and it has not gotten better. I have numbness around my toes. In the morning, my large and small toes can be blue. Can I keep ignoring this?

(47:59): [Dr. Kelsey Barrell]:  So I don't think it's ever good to ignore anything. So maybe let's not ignore it, but it sounds like maybe a few things are going on. So the numbness, the persistent numbness, that sounds like neuropathy, so injury in those peripheral nerves. So it'd be good, especially if you feel like it's getting worse or negatively impacting you, just to screen for risk factors, see if there's anything that can be done to minimize it.

(48:24): And then for the blueness, those color changes, a lot of times that represents microcirculation, so the smallest blood vessels in our toes and if anybody's experienced their toes getting really cold or purplish, reddish, changing color, that can be that microcirculation. Some of that happens with aging, so circulation can be a little impacted, but a lot of times that also goes along with a neuropathy. So some of the same things that can injure the nerves can injure the smallest blood vessels. And so it's common that we see both, kind of poor circulation at the toes or coldness as well as neuropathy.

(49:10): [Marla O’Keefe]:  Thank you. I'm post-VMT and take tacrolimus in my immunosuppression medications. Is essential tremor considered a part of neuropathy? I know that tacrolimus may contribute to this.

(49:26): [Dr. Kelsey Barrell]:  Great question. It's not an essential part of it. I only see tremor complicate neuropathy when people have very severe neuropathies. Usually this is the case with inherited neuropathies or immune neuropathies that are so severe that it's hard to know where your limb is in space. More likely this essential tremor is unrelated to the neuropathy. And you are exactly right. Tacrolimus is very well known to cause movement disorders like essential tremor. So if you don't have a lot of essential tremor in your family, because it can be a familial or an inherited movement disorder, if you don't have that history, if it just started with the tacrolimus, I think it is very likely related to your tacrolimus.

(50:16): [Marla O’Keefe]:  Thank you. I am two years post-transplant and I still have some tingling from the neuropathy. Will that resolve?

(50:26): [Dr. Kelsey Barrell]:  Two years out, it's hard to say. If you feel like over the last year you've noticed some improvement still from year one to year two post-transplant, then it's possible that you'll continue to notice a little improvement. But it is also possible that you'll have that as a residual symptom.

(50:51): [Marla O’Keefe]:  Thank you. Have you ever heard of bortezomib-induced autonomic neuropathy leading to kidney failure?

(51:02): [Dr. Kelsey Barrell]:  I have not heard of bortezomib-autonomic neuropathy leading to kidney failure. Bortezomib certainly can cause some autonomic symptoms, but I haven't seen the autonomic neuropathy be that severe as neuropathy with bortezomib. I usually see more of a painful sensory neuropathy with bortezomib. And if it was the autonomic nervous system leading to kidney failure, it would have to be a profoundly robust autonomic neuropathy. And the only way I could think of it causing kidney failure is if you're having severe recurrent urinary tract infections that are just kind of going up string and injuring. So I would hazard a guess to say it's unlikely that the bortezomib is the main culprit behind the kidney failure. That maybe it was the underlying cancer or some other factor.

(52:02): [Marla O’Keefe]:   Thank you. Is photo biomodulation safe to use for myeloma patients who have CIPN?

(52:14): [Dr. Kelsey Barrell]:  Yes. So in photo modulation, I think this is phototherapy rather than electro-stimulation therapy. This is one of those kind of complementary treatments and I don't see any major risk to it. At the same time, none of the trials yet have shown any preventative benefit, but like many of these complementary modalities in any individual patient, if they feel like it helps their symptoms, if they like it, if it's not too costly because some of this stuff can be hugely burdensome on the financial status, then I think it's reasonable. But it's not something I recommend across the board. If a patient comes to me and said, "I really like this," I say, "Okay." If there's no risk factors, great, you can do that. But it's not something I'll recommend to all patients.

(53:20): [Marla O’Keefe]:   Thank you. I think you mentioned this in your slides, but maybe you want to touch on it again. Some specific exercises or supplements to treat neuropathy during post-transplant maintenance.

(53:32): [Dr. Kelsey Barrell]:  Yeah. So exercises would be anything aerobic, so that gets cardiovascular fitness and so those are things that get your heart and lungs working. The goal being sustained activity, so keeping your heart rate and your breathing rate up. So that's anything like biking, walking, swimming.

(53:52): There are no supplements unfortunately across the board that we recommend other than if it's low, fix it. So if your B12 is low or your B6 is low, fix it.

(54:04): There is one antioxidant that we use in more general neuropathies called alpha-lipoic acid that we think reduces neuropathy scores a small amount, but it hasn't really been shown in chemotherapy-induced neuropathy to do a whole lot. So it's something that's reasonable to take. If you like taking supplements, that's probably the most reasonable supplement. But across the board, no, there's no supplements other than healthy eating and exercise has the best data.

(54:41): [Marla O’Keefe]:  Will peripheral neuropathy from vincristine get worse over time?

(54:50): [Dr. Kelsey Barrell]:  It will. I imagine you're talking about ... I don't know if you're asking, "I stopped vincristine and now it's getting worse," or "I'm staying on vincristine and it continues to get worse." So I'll answer both of them. If you're on vincristine and you have to be on it for say a year, you've already noticed neuropathy and you're at five months, yes, it probably will continue to get worse as you have future cycles. If you stop vincristine, it can continue to get worse for about two months, but then it should stop getting worse once it's been about two months after discontinuing it. And then it should either plateau or improve from there.

(55:36): [Marla O’Keefe]:   Thank you. I stopped chemo two months ago because it wasn't working. I'm having a CAR-T next month and my neuropathy is getting worse. Could it possibly be because of the vitamin like B6 that I'm taking?

(55:50): [Dr. Kelsey Barrell]:  Yes. I would recommend having that checked to make sure it's not too high, and also checking other risk factors. If it's continually getting worse, then we can no longer blame it on chemotherapy.

(56:04): [Marla O’Keefe]:  Great. I think this is going to be our last question here. What would a therapeutic dose of duloxetine be?

(56:12): [Dr. Kelsey Barrell]:  Yeah. So most patients will get up to a dose of 60, so six zero milligrams every morning because it can give people energy, so it's a good morning med. I usually start at 30 for the first week just to make sure you tolerate it. Rarely people have a little stomach upset with it or nausea. So I'll start at 30 and then quickly after a week get up to 60 and usually stay there. So it's pretty easy to use versus Gabapentin or Lyrica, we can step up slowly over a long time.

(56:45): [Marla O’Keefe]:   Okay. All right. I guess we have time for one more. What about Voltaren for treatment?

(56:52): [Dr. Kelsey Barrell]:  Yeah, so Voltaren, for those of you who do not know is a non-steroidal anti-inflammatory and often it can be like a topical cream or jelly that you put on or patch. That is best for more muscular skeletal pain. So kind of inflamed, tendinitis joints, muscle type pain. Back pain is where I've seen it used most. Every once in a while when my neuropathy patients really feel like it works well, but it isn't targeted as specifically for nerve pain, so it doesn't tend to work as well for nerve pain as it does for muscle or bone pain.

(57:33): [Marla O’Keefe]:   Closing. Well great. Thank you so much. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Barrell for your very thoughtful remarks. And thank you, the audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way.