What is Neuropathy and How Can It Be Managed?

Transcript of Presentation.

(00:01): Marla O'Keefe: Introduction. Hello, my name is Marla and I will be your moderator this afternoon. Welcome to the workshop What is Neuropathy? How Can It Be Managed? It is my pleasure to introduce to you today's speaker, Dr. Sasha Knowlton.

(00:14):  Dr. Knowlton is an associate professor and director of cancer rehabilitation at the University of North Carolina. Her clinical and research interests are in cancer rehabilitation with the goal of improving the function and quality of life of cancer patients during all aspects of cancer treatment and survivorship. Please join me in welcoming Dr. Knowlton.

(00:37): Dr. Sasha Knowlton: Overview of Talk. Thank you so much and thank you for inviting me to present today. So we will be having a crash course in neuropathy. Oftentimes when I teach trainees, residents, therapists, et cetera, this lecture can be at least an hour, if not longer. So I'm going to try to present to you the highlights of neuropathy and what defines it.

(01:03): So disclosure, I actually got paid a very small sum from Harvard where I used to work for giving a lecture.

(01:13): So here's an outline of the lecture. So essentially, the first part of this is we're going to define what neuropathy is in general, but also how chemotherapy-induced peripheral neuropathy is distinguished from neuropathy for other reasons. We'll review risk factors, the prevalence of it, and common culprits, and then also review symptoms and treatment strategies for neuropathy.

(01:40): So what exactly is neuropathy? It's a term that, as I was discussing earlier with some of the moderators, has become quite in vogue, if you will, with lots of people questioning if they have it, what caused it. "Oh, it's all due to the chemo," or, "It's all due to the immunotherapy I've had," but what exactly is it?

(02:01): So the definition of the word neuropathy refers to the damage or dysfunction of the peripheral nerves. Nerves, once they've exited the spinal cord, allow us to feel things. They allow us to move our muscles, and they also control what's known as autonomics.

(02:17): So when we talk about sensation with the nerves, and I'll go through this a little bit more later, we're referring to things like hot and cold temperatures. We're also referring to things like soft touch, for example, feeling a piece of silk or feeling a piece of cotton.

(02:32): We're also referring to things like vibration and the sense of proprioception, which refers to your sense of where your body is in space. A great example of that is when you close your eyes when you're washing your hair in the shower, you know that your feet are flat on the ground, and you know that you're in the shower even though your eyes are shut. And that's because our nerves allow us to have what we call joint position sense in the world.

(02:58):  In terms of movement, they also control our muscles. And autonomics refers to things like our heart rate, our blood pressure, our temperature control, et cetera, and they also control these aspects of our daily life.

(03:14): Neuropathy is common after chemotherapy. So how common is neuropathy after chemotherapy? Depending on the type of chemotherapy, essentially, this is a little bit of an older study, but almost 70% of individuals who completed chemotherapy at one month had symptoms of neuropathy, that at that time point of three months, 60% experienced some symptoms of neuropathy. And at the end of six months, 30% of patients in this one particular study experienced symptoms of neuropathy. Again, this is an older study. This is based on one drug, but you can see that neuropathy unfortunately has some lingering side effects.

(03:58): Chemotherapy-induced neuropathy often improves over two to three years. And neuropathy, if it's due to chemotherapy, does get better over time. That timeline, what I generally give patients, is anywhere from 18 months to three years. Nerves regenerate starting at the level of the spinal cord. They regenerate about a millimeter a day or an inch a month. So depending on how tall you are, really dictates how in some ways, how quickly you'll see recovery from neuropathy if it's strictly due to chemotherapy.

(04:31): So generally speaking, if you read the textbooks, people will say, "Oh yeah, after three years, people should have, if it's only due to chemotherapy, people should have 100% resolution of their neuropathy symptoms." I will tell you in clinical practice, as someone who's done this for a period of time that is not always the case, and a lot of times people will have some lingering symptoms for years after completing chemotherapy.

(05:04): There are several risk factors for chemotherapy-induced peripheral neuropathy.  What increases your risk for getting neuropathy? So not surprisingly, if you have a history of neuropathy from, say, diabetes or vitamin-related issues, unfortunately your nerves have already taken a hit, if you will. They've already been injured because of the diabetes or because of the prior vitamin issue. And so that increases your risk of getting neuropathy after you get chemotherapy or immunotherapy.

(05:31): Unfortunately, the older you are, it also increases your risk of getting neuropathy because your nerves have been around for a longer period of time and potentially sustained more damage.

(05:41): If you're a smoker. If you have decreased creatinine clearance, which refers to the function of your kidneys, so if your kidneys are not working at their maximum capacity, then it also increases your risk of neuropathy theoretically by not being able to clear the chemotherapy as quickly as one would like. And also if you sustained some sensory changes during your chemotherapy administration as well.

(06:12): So when people talk about developing symptoms of neuropathy, and these two pictures here that you're seeing are some pretty cool microscope pictures that I found of nerves on the internet that I thought were quite pretty because they are such complex structures, so symptom development, it can be slow and progressive, insidious. Sometimes people don't get any neuropathy until they're at 11th or 12th cycle. Other times they get neuropathy symptoms with the very first dose of chemotherapy. And sometimes, it's quite abrupt.

(06:45): With the onset of neuropathy, sensory symptoms are often evident before motor nerves are affected and weakness occurs. I've had patients describe instances where within the first 10 minutes of chemotherapy, they start noticing some tingling in their fingers and toes. And then like I said, on the other side of the coin, other people say, "Oh yeah, I didn't feel anything until my last cycle of chemo."

(07:02): But why do people notice sensory symptoms before the motor symptoms, before they notice weakness? The reason why, and this is a little bit of a throwback to biology or anatomy and physiology classes, is that because the cell bodies of nerves are located in, for the sensory nerves, the ones that allow us to feel things et cetera, are located outside of the blood-brain barrier in a structure called the dorsal root ganglia or the DRG. So the motor nerves are the ones that control our strength, are located inside the blood-brain barrier. So essentially there's an extra layer of protection for the motor nerves, the strength nerves, compared to the sensory nerves, which is why people tend to experience sensory symptoms before they start to notice weakness.

(07:57): Pain and hypersensitivity are common symptoms of neuropathy. So when I talk to patients about neuropathy, I try to group it and make it as easy as possible, and I do it in buckets known as positive or negative symptoms. Positive symptoms don't mean something that's happy. They mean that you gain something as a result of the neuropathy. So in a lot of cases, people gain pain. They can describe the pain as a shock-like sensation, a burning sensation, knife-like, et cetera. They can also experience hypersensitivity. A lot of times people will say, "Oh, going to bed is the worst because when I feel bedsheets it drives me nuts and it's really uncomfortable and painful." They can have dysesthesia, which means altered sensation. They can gain tingling sensation. They can also get a sense of itching and cramping as well. So that's the positive symptom bucket.

(08:46): Numbness is a common symptom of neuropathy. They also can develop negative symptoms, meaning they lose something. Again, no happiness, but more that they lose something. So numbness is oftentimes a big complaint, so they lose the ability to feel things, which gets a little bit dangerous sometimes when people are trying to self-treat their neuropathy symptoms because a lot of times they'll say, "Oh, heat makes it feel so much better," and they'll stick their feet in a hot bucket of water. Well, I've unfortunately seen some people who have gotten burns from that or burns from using a heating pad because their sense of how hot something is off. And so I always tell people with numbness, maybe not necessarily uncomfortable, but it's something you have to be a little bit proactive about when checking your skin and doing these things.

(09:34): Proprioception or not knowing where your body is in space can occur along with balance symptoms. Another negative symptom is that loss of the ability to tell where your body is in a space or what we know is proprioception. Why is that important? Because sometimes people will say, "Oh, now that I think about it, my balance is not as good as it used to be," or, "I'm dropping things more often than I should," or, "I can't feel where buttons and zippers are and my handwriting has gotten atrocious." That's because they can't describe or understand where their body is in space.

(10:03): Functionally speaking, as I said, balance becomes an issue. Things like fine motor skills become an issue, and that is concerning because that's how people fall. Additionally, they can also get weakness where they lose the ability to do things with their muscles. And a lot of times people will have foot drop where they can't lift their foot like they're lifting off a gas pedal or a brake pedal. And they may not notice it until they come in to see me and I start doing an exam and I ask, "When did this start?" And they're like, "Oh, actually I have no idea, but I have noticed that I'm walking funny and I'm shuffling." So those are the broad categories of symptoms that people can get. And not every neuropathy is the same. Sometimes people get mostly positive, mostly negative symptoms, or they get a combination of any or all of these, and there's no way to really predict what patients may experience if they do experience it.

(11:00): So quick minute about autonomic neuropathy. Autonomics, as I said, are nerves that control our vital signs, so things like blood pressure, temperature control, heart rate, et cetera. Fortunately in the setting of neuropathy from chemo, this is not that common. People may get a little bit, but it's not as clinically significant, if you will, or as prevalent as the other types of neuropathy. So that's why I didn't want to spend too much time on it, but definitely deserves a mention.

(11:37): Neuropathy is diagnosed by identifying symptoms, evaluating the patient’s balance and functional status, and ruling out other medical problems that might cause the symptoms. So how do you get diagnosed with neuropathy? So when people come to see me, and it's probably the number one, number two reason why people come to see me after they get treated for their cancers, is I want to make sure it's actually neuropathy and it's not something else.

(11:50): And how do I do that? So I sit and talk with patients and ask a lot of really hard questions. I ask about their symptoms. I go through that list of positive and negative symptoms that I showed you two slides ago. I also ask about their functional status, asking about their fine motor tasks. Are they dropping coffee cups? Has their handwriting changed? Are they having issues with buttons and zippers and that sort of thing? I also ask about their balance and falls because that's how that proprioception shows itself, if you will.

(12:22): Additionally, another area where proprioception can rear its ugly head is going downstairs. I have lots of patients with neuropathy who are terrified to go downstairs because they have no idea where they can put their foot safely.

(12:36): I also ask about comorbidities. I ask, "Do you have a history of diabetes? How long have you had it? Do you have a history of vitamin issues? Have you had gastric bypass in the past because that affects your ability to absorb vitamins in your day-to-day diet?"

(12:52): And so I ask about all those things and then I take a step back and say, "Is there something else that could be causing the neuropathy? Is there a family history of some funky genetic condition like Charcot-Marie-Tooth, or is there some other sort of family history, personal history of the patient that may contribute?"

(13:11): Once I get all that information, I take a step back and I say, "Does this story make sense?" The reason why I ask that is neuropathy typically happens during chemotherapy if it's only due to chemotherapy. It starts during chemotherapy, or in the case of oxaliplatin, can start within the three months following the last dose of chemotherapy.

(13:34): Examining patients for chemotherapy-induced neuropathy may discover other illnesses like diabetes. If patients come to see me five years after they completed their chemotherapy with symptoms of neuropathy, it's probably not because they got chemotherapy five years ago. That story does not make sense. And so in that case, I start asking additional questions to see if there's another contributing cause of neuropathy. Unfortunately, especially here in the south, I've diagnosed a lot of folks with diabetes. I also have diagnosed people with myelopathy or cervical stenosis after doing an exam. I've also diagnosed people with vitamin issues, et cetera. So it's really getting all that information and then taking a step back and asking if the story makes sense.

(14:20): I also do an exam. I check their weakness. I check to see their proprioception. I check their sensation. I check their balance. I check how they're walking. I always like to joke with patients that they come in and they have to walk my little runway to see if they are having functional issues

(14:37): Nerve conduction studies can also clarify a diagnosis of neuropathy. And then to confirm a diagnosis, sometimes I will get a test called a nerve conduction study or an EMG, which is a barbaric study. I've had about 30 done to myself because when we are going through our training in rehab medicine, we learn how to do these, and we actually practice on each other before we practice on patients. It's a great bonding experience. But functionally, nerves are like light bulbs. There's a wire called an axon, and in the wire there's an internal wire part called an axon, and then on the external component there's a sheath or a protective layer like insulation called myelin. And for lack of a better word, nerves conduct electricity.

(15:24): And so we actually use, in this study which I've shown one setup here in this picture, we shock people and we see how are the electric wires working. Then using the light bulb analogy as the muscles as the light bulb at the end of the wire, we stick a very teeny tiny needle in certain muscles, look at them at rest to make sure the light switch is off, and then we ask people to do certain activities, certain movement to make sure that there's no short circuit, if you will, to make sure that the light bulb is actually turning on and off appropriately. So that's the official way to diagnose neuropathy, if there are further questions. But like I said, history and exam are really important as well.

(16:08): So with neuropathy from chemotherapy, it's what we call a diagnosis of exclusion, meaning that a story has to make sense. As I said before, I want to make sure that there's nothing else contributing to the neuropathy. Is there a thyroid issue? Is there a vitamin issue, diabetes, or less common things like genetic predispositions, et cetera? And you can get that from a really good history.

(16:30): Some chemotherapy agents are more likely to cause neuropathy that others. So not all chemotherapy agents cause neuropathy. Which drugs cause neuropathy? I've listed the biggies here, but there's actually been some more research that has come out, especially with the immunotherapies that are now used a lot in oncology care, showing that certain immunotherapies are also well-known offenders to cause neuropathy.

(16:55): And again, as these drugs are getting developed, as we learn to treat different cancers better, we're learning more about them. And so I wouldn't be surprised if in the next five years this list doubles or triples in size. But essentially these are the classic ones that when I look through a patient history and I talk to them, I screen for these agents to see if can they cause it. Because if they didn't get one of these agents and they now have neuropathy, again, I have to make sure that there's not something else contributing.

(17:27): Physiatrists - doctors who have trained in a field known as physical medicine and rehabilitation - as well as neurologists and neuro-oncologists can diagnose neuropathy. So who can diagnose and treat neuropathy? Physiatrists, like myself, are physicians who have trained in a field known as physical medicine and rehabilitation. Essentially, many people are unfamiliar with physiatrists. The best way to tongue-in-cheek describe it is we are doctors who help people with disabilities. Our field was created to care for people with amputations, to care for people with spinal cord injuries, to care with people who have traumatic brain injury, strokes, et cetera. But that's when I tell people when I'm first meeting people like, "Oh, what do you do?" And it's like, "Oh yeah, I am a doctor who helps people with disabilities." But also neurologists and neuro-oncologists, who are neurologists who train in fellowship training for an additional two years in the field of neuro-oncology, can also diagnose and treat neuropathy.

(18:26): Physiatrists are doctors who evaluate people’s ability to do daily functions and whether neuropathy is compromising those functions. Why should we care about it? So I'm a doctor who looks at people with a functional lens. I want to make sure that they are able to do the things they want to be able to do. And as I mentioned before, neuropathy causes pain. It causes bad balance. It causes fine motor issues. It causes weakness. So those are all things that affect function. And when people aren't functioning well, they don't have a good quality of life.

(18:50): And also they may fall. They may hurt themselves. And so safety also becomes a consideration too. So all of these three factors, as I've listed here, are reasons why people should care about neuropathy.

(19:03): Patients who have chemotherapy-induced neuropathy report a poorer quality of life. In terms of quality of life, this has been studied in people who have a neuropathy from chemotherapy, and not surprisingly, people who do have neuropathy report worse quality of life. And overall, the more symptoms of neuropathy that you have, whether it's more pain, whether it's more altered sensation, whether it's more impaired function, et cetera, the more you add them together, the worse quality of life people report. And that's been shown over and over again in multiple research studies.

(19:33): So as I alluded to before, neuropathy affects function. When you can't feel your feet, you can't feel your hands, you can't feel where your feet are in space and you're weak, they don't do well on functional tests. When I ask people to walk during my exams and also outside of the exam room, because a lot of times people will put on their best act when I ask them to walk and then I watch them walk into the exam room and walk out, they don't do as well. They have trouble with their feet. They walk slower. They develop more of a penguin gait. If you can think of a penguin where people waddle, they shuffle; they take very, very tiny steps that actually increase your fall risk. And not surprisingly, when asking about falls, they're like, "Oh yeah, I fall," or, "I use the walls for balance," or, "I almost fall, but I'm able to catch myself."

(20:24): Neuropathy can make several activities of daily living more difficult. And not surprisingly, when you can't function as well, you can't do things on your own as well. People often report a reduced independence with activities of daily living, which include tasks such as getting dressed, taking a shower, and so on. But there's also things known as IADLs (Instrumental Activities of Daily Living) where people also report difficulty with cleaning their house or cooking, et cetera. So neuropathy can affect a lot of different areas of function, which most people are not aware of until I start asking those really hard questions in clinic.

(20:58): Falling is a major risk from chemotherapy-induced peripheral neuropathy. So how does neuropathy affect falls? As I said, when people have impaired balance, they have weakness; they're more likely to fall. And they've actually studied this. People who have neuropathy from chemotherapy increase their odds of falling by two to three times. So say, in general, a person is likely to fall once a year. And again, don't quote me on this, but this is just an example. People, if they're only supposed to fall one time a year, they'll fall two or three times a year. And every time someone falls increases the risk of injury, whether it's a broken hip, a brain bleed, et cetera.

(21:35): So falling is overall bad and I don't like people to fall. And unfortunately, approximately 17% of patients who have neuropathy from chemo fall. So it's a pretty, pretty high number, and it's one that's preventable by asking about function and getting people the right treatment.

(21:56): So who falls? Out of that 17% of people who fall, almost 12% of people fall within the first three months of developing neuropathy from chemo. As I said, contributors to that are related to issues with walking, weakness, that ability to tell where your body is in space. A higher cumulative chemo dose, which makes sense, the more chemo you get, the more likely you are to get neuropathy and more likely to have functional issues.

(22:24): Again, similarly, the next bullet number or the next bullet, which is higher number of symptoms overall, and there's different scales that you can use to grade neuropathy. But the more symptoms you have, more likely you are to fall. If you're weak, you're more likely to fall. And 27% of those who did fall report some sort of functional impairment. So this is patient reported saying, "I have weakness. I have issues with fine motor skills," et cetera.

(22:54): Chemotherapy always carries a risk of neuropathy. So now that I told you all these bad things about neuropathy from chemo, big, big question I get is ‘can it be prevented?’ And the short answer is no. You cannot prevent it unless you do not get chemotherapy, which is a totally separate different conversation that people would have to have with their oncology teams. So the short answer is no.

(23:16): There are no known medications or supplements that prevent neuropathy from chemotherapy. There is a drug called amifostine that the FDA has approved to reduce chemotherapy toxicity. FDA approvals are a totally separate lecture and the whole process behind that, but unfortunately, even though it's approved, the evidence does not support its use. So even if you take it, it's not really going to help.

(23:36): There are a lot of questions out there about vitamin E. The jury's still out on that. There haven't been any definitive answers to say yay or nay that it helps prevent neuropathy from chemo. And there are other agents that are also being investigated.

(23:52): I'm someone who likes to be conservative in giving meds, be conservative when doing treatment, and I don't recommend things that aren't proven to be helpful because, on the flip side, that could be harmful. So I generally do not recommend that people take anything, try anything that has not been proven to be beneficial. And in this realm, there are no medications, no supplements, et cetera, that have shown to prevent neuropathy from chemotherapy.

(24:24): Exercise during chemotherapy may help prevent neuropathy or lessen its symptoms. I will say that there is some early evidence to support that exercising during chemotherapy can help push off neuropathy, and also if you do get neuropathy, it can help reduce the amount or the quantity of symptoms that you get. There's a lot of early evidence to support it.

(24:45): Like I said, it's one of those, should it be officially recommended? Should it not? We're not at that stage yet, but it's just exercise. It's just going for a walk as much as you can during chemo potentially to be preventative, but also exercising during chemo even in short spurts, five, 10 minutes, et cetera, has loads of other health benefits. So generally I tell patients if you can go for a 10-minute walk once a day, that hopefully is going to do nothing but help you in terms of prevention of neuropathy from chemo, but also help with a lot of different factors as well.

(25:24): Neuropathy may be treated by adjusting chemotherapy doses or addressing other contributing causes. How can you treat it? So when people come to see me, a lot of times they've already had symptoms of neuropathy for a couple of weeks. Sometimes they've already had a dose reduction in chemotherapy, whether it's a total dose such as a 10%, 20% reduction. Other times, they have decreased frequency of chemotherapy administration. That's a conversation that's not held with me. That's held with the treating oncologist. But that's one way to treat it, take away the offender.

(25:55): And then also if there's a contributing cause like underlying diabetes, vitamin issue, et cetera, treat it. Sometimes I'll get people in to see me saying, "Oh yeah, I had a little bit of neuropathy from diabetes, but now since I started chemo, my symptoms have gotten so much worse." And I'm like, "Well, what are your blood sugars? What's your A1c?" And oftentimes it's not good. And so we have a very separate discussion about, okay, the chemo is one thing that's going to cause the immediate issue, but also there's all of this predisposing stuff that if there's a way to get your sugars under better control, then you should definitely do it in that setting.

(26:35): Duloxetine (Cymbalta®) shows some promise in reducing nerve pain. When managing neuropathy, medications oftentimes come into discussion, as they should. There have been a couple of studies through the years, and there was one recently published last year, I think, that supported this. When going and looking through and doing a literature review of all the studies that have been published to date about treating symptoms of neuropathy from chemo, the number one winner that comes out is actually duloxetine.

(27:01): Duloxetine is known by the brand name Cymbalta, a type of antidepressant. At lower doses, duloxetine does help with nerve pain. And if people are on another antidepressant or another antianxiety medication for another reason, a lot of times I'll talk to them about that if they need to get on a medicine and I'll say, "Look, are you okay with potentially switching over to duloxetine?" And sometimes the answer is yes, other times, no.

(27:30): The main side effect of duloxetine is that sometimes it can cause people to get dizzy. Sometimes it can cause constipation. If you read the pamphlet that the drug manufacturers give you, there's everything and anything listed as a side effect. But essentially those are generally what people report the most.

(27:50): Gabapentin may also help with symptoms of neuropathy. Another medication that is second runner up or first runner up to duloxetine is actually gabapentin. Gabapentin was created years ago as an anti-seizure medication. Sometimes it is still used for seizures. Occasionally it's also used for restless leg syndrome. But for some people, gabapentin works wonders for neuropathy. The main side effect of it is that it makes people sleepy because again, it was designed as an anti-seizure medication. But for some people, it worked great.

(28:22): These other ones that are not bolded on here are my second runner up, third runner up, other medicines. Pregabalin is also known as Lyrica. There's a lot of money behind this drug. I will tell you, I have found people who try gabapentin and don't benefit from it, when they try Lyrica, they also don't benefit from it.

(28:42):  My theory behind that is that they're like cousin medications. They're like one or two away from each other on a molecular standpoint. And so if your body doesn't respond to one type of molecule, if you change one aspect of it, it's not going to respond to that other type of molecule. And the research behind pregabalin, using it for neuropathy from chemotherapy specifically, also supports that it doesn't do all that well.

(29:10): Other medications like tricyclic antidepressants have many side effects. Amitriptyline, nortriptyline listed up here. They are what I call dirtier medicines. The reason why is they're also known as tricyclic antidepressants, again, used as antidepressants, but they're older medications and so they're not as clean. So that means that they have a lot of side effects associated with them.

(29:29): For example, amitriptyline, and nortriptyline too, both work on histamine receptors that are also affected by Benadryl. So a lot of times they can make people sleepy, give them dry mouth, make them constipated, urinary retention, et cetera. So those are my later medications down the line to use.

(29:53): Medications for neuropathy may help with pain but don’t improve numbness. All of that said, medications only work for the positive symptoms. They only work for pain, tingling, et cetera. They don't do a thing for numbness. So I always like to talk to patients about that because if their predominant bothering symptom is numbness, I tell them taking a pill is not going to fix that.

(30:12): Sometimes topical ointments will help; probably more so because of the massage involved with applying topical medicines, but unfortunately the oral medications don't do a lot for numbness. The topicals I've listed here, lidocaine is one of my favorites. It's over the counter as a cream and ointment, as a patch as well.

(30:34): Capsaicin is made from hot peppers, so I always give the disclosure if you use it, use gloves and wash your hands after so you don't touch your eye. There are also mixes and compounding creams out there, which sometimes insurance will pay for, and sometimes they won't, but sometimes these combinations can be helpful too.

(30:50): Rehabilitation medicine or physical therapy may also be helpful in treating neuropathy. So how can rehab medicine help neuropathy? So when people come in to see me and they have functional issues, a lot of times, depending on how severe they are, I'll get them to start exercising or I'll send them to physical therapy. And I've listed some of the techniques here that the therapist will work on with them where they start with standing still, feet together, and then practicing walking and doing things with your hands, working on strengthening the legs, working on that ability to tell where your body is in space. But it's all of those functional components, and all of this is individualized to what the patients are experiencing themselves.

(31:28): Other rehab interventions, if people are having a lot of difficulty with their hands, dropping things, unable to feel things, et cetera, hand therapy with a specially trained occupational therapist can also be really helpful. Sometimes people don't want to go to therapy either. In that case, if they have more mobility issues, that I'll give them exercises to do. If it's more fine motor hand related issues, I'll ask them, “Do you like to knit? Do you like to paint? Get some Play-Doh. I will show you some exercises to do and teach you them because if it's an exercise that you're going to enjoy doing, you're more likely to do it anyway." So I often will have those discussions with them as well.

(32:14): Other rehab interventions for neuropathy. So there are lots of things out there, some of which have been proven to be helpful, some of which are more in the investigative aspect of things.

(32:25): Desensitization or techniques that therapists can use using different textures on areas that are hypersensitive to reduce some of that sensitivity.

(32:34): TENS devices, which are transcutaneous electric nerve stimulators, they actually sell them on infomercials, which I do not suggest that you try or buy. I actually suggest that you go to a therapist to try a medical grade TENS unit, learn how to apply the electrodes and then see if it's helpful or not. Those sometimes can be helpful for pain.

(32:56): If they have foot drop, the inability to lift their foot, or they have difficulty telling where their feet are in space, sometimes braces, also known as AFOs, can be helpful. Talking to them about ambulatory aids like a rollator or a cane may also help.

(33:13): Acupuncture has helped some patients with neuropathy. Acupuncture, I don't understand how it works, but some of my patients swear by it and there's actually research evidence to support it. I'm totally fine with it. I tell them, that's great. If you can find a good acupuncturist and it helps, wonderful. It is cumulative, so you can't just go once or twice and expect to see benefits, but a lot of times people like that too. And there's evidence to support it as well.

(33:35): Skin checks are really important. As I had mentioned before, I've seen some cases where people use heat or whatever to help with their neuropathy symptoms. I always tell them skin checks are really important. The reason why, and it's a scary story, but unfortunately quite a true story, my uncle has neuropathy from uncontrolled diabetes, got a really nasty blister, turned into a nasty infection, and ultimately had to have his leg amputated. So again, extreme circumstance, but unfortunately being in rehab medicine, we see this a lot. So the best way to prevent that is to check your skin every day.

(34:17): Exercise for neuropathy has multiple benefits. Other things beyond medication that can help neuropathy include exercise. As I talked about before, there's some early evidence to show that exercising during chemotherapy helps prevent symptom onset from even starting with neuropathy from chemo. It also can help symptoms lessen once neuropathy has already started.

(34:38): The thought and the theory basis is that when you're exercising, you're stimulating your nerves because you're walking or swimming or being active, but you're also increasing blood flow because your heart rate goes up. So the thought is that it's bringing good molecules down to help the nerves repair themselves, taking away the chemotherapy molecules, et cetera.

(35:00): But exercise overall does improve quality of life. People who exercise are happier. They're able to do more things on their own. And as I had mentioned during chemo administration, people who exercise were less likely to have symptoms, and overall those who did have symptoms had less severe symptoms.

(35:20): So there are some guidelines in terms of exercise overall for cancer survivors. The reason why is it's been found to help prevent disease recurrence, help with symptoms, help you live longer, et cetera. The recommendation, these are from 2019, is that you exercise at least 30 minutes a day, at least three times a week at a moderate level, meaning you can talk but not sing, and you add in some strengthening exercises there too.

(35:47): The general exercise statement that I tell people is to avoid being inactive. Don't be a couch potato. Try to get back to normal daily activities. I'm not going to expect people who are non-exercisers to go out and run a 5K. That is completely unrealistic and they're going to hurt themselves. But could they maybe go for a five or 10-minute walk most days of the week? Probably, and then build up from there. So general rule of thumb is to be as physically active as you are able and conditions allow.

(36:15): So when I'm telling people to exercise, what do I tell them to do? We talk about exercise in terms of the FITT principles, frequency, intensity, training, and type. I'm not going to tell someone to go swimming if they hate the pool. If they like walking, great. If they like biking, great. The goal is 150 minutes a week, not... It's nearly impossible to do that for me, unfortunately. I don't have a history of cancer, but I try to practice what I preach, but I tell people to reset the goal every week. If you're able to exercise 30 minutes this week in total, maybe next week, try for 40 minutes. And then strengthening is important as well as is flexibility.

(36:51): But the big caveat is don't start after this lecture and go out and run a 5K. Before you start an exercise program, you must be screened by a physician. Why? Because you don't want to get injured. And then you also want to tailor your exercise program to achieve your goals.

(37:07): I'm not going to recommend high-intensity interval training. As much as I love to do it myself, I'm not going to recommend it for most of my cancer patients. It's not applicable and they will hurt themselves. But at the same time, I want to get people moving so I do strongly recommend that before you ever start exercising, you get screened.

(37:28): Questions that are asked? I want to know when I'm talking to people about exercise, what's their balance like? Are they going to fall, et cetera? Other musculoskeletal disorders, do they have a history of fractures? Do they have a history of a bad back? What about their knees? What about their hips? I will ask about any heart or lung disease. And sometimes, the reason I put a little star there, is chemotherapy can cause heart disease and some chemo can cause lung disease. So again, it's looking back in that history, getting a good understanding of what the lay of the land is.

(38:01): So that being said, take home points in terms of exercise. It's safe. It's recommended. Always talk to your doctor before starting any exercise program. There's modifications that should be made for different medical histories but can help neuropathy. And with that, I finished within 40 minutes and I'm happy to answer any questions you may have.

Question and Answer Session.

(38:25): Marla O'Keefe: Thank you, Dr. Knowlton. That was an excellent presentation. And now, we'll get to some questions. First question we have is can an immunogenerative event such as an infection like pneumonia or vaccines make GVHD-induced neuropathy worse?

(38:46): Dr. Sasha Knowlton: As far as I know, no.

(38:47): Marla O'Keefe: I have cramps in my feet that go up my calf until it turns into a Charlie horse. Is this neuropathy?

(38:55): Dr. Sasha Knowlton: Possibly. It's possible, for sure. Cramps are a tricky thing. Sometimes cramps can be caused by dehydration. Sometimes they can be caused by low magnesium. Sometimes they can be caused by other electrolyte abnormalities, other medications like statins, et cetera. So just because you have a cramp doesn't mean that it's specifically neuropathy.

(39:21): Marla O'Keefe: Great, thank you. I have had random muscle spasms since post-BMT and my neuropathy. Is the random muscle spasms part of the neuropathy or separate? I ask because I have never heard of cramping or spasms associated with this.

(39:38): Dr. Sasha Knowlton: Yeah, yeah. So spasms, like I said, are, I classify them as a cousin to cramping, if you will. Similarly, they can be caused possibly by an overused muscle that's weak and unhappy, if you will, not getting stretched, trying to overwork, et cetera. But they also can be caused by non-neuropathy causes. So that's where talking to your doctor and getting a really good history is important.

(40:06): Marla O'Keefe: Thank you. Would you see a neurologist or another specialist to get your neuropathy diagnosed?

(40:13): Dr. Sasha Knowlton: So as I talked about in my lecture, you can see a neurologist. You can also see a physical medicine and rehab doctor like myself.

(40:26): Marla O'Keefe: Can neuropathy be a side effect for a long-term survivor of an allogeneic stem cell transplant?

(40:34): Dr. Sasha Knowlton: Usually the transplant itself does not cause neuropathy. Sometimes the induction chemotherapies can, depending on the agent used, but not the transplant itself.

(40:50): Marla O'Keefe: Okay. What is the difference between GVHD and neuropathy?

(40:54): Dr. Sasha Knowlton: So neuropathy, as I talked about, is all about the nerves. GVHD affects multiple different organ functions. That can affect the fascia. It can affect the GI system. It can affect the skin. It can affect the joint. It can affect a lot of different thing, whereas the neuropathy is only about nerves. And I think there are other lectures during the symposium to talk about GVHD in more detail.

(41:24): Marla O'Keefe: Yes, there are. Thank you. What treatments have shown the most improvement after two and a half years? I am still having some balance issues.

(41:35): Dr. Sasha Knowlton: So it depends on what symptoms you're still experiencing. If it's more balance issues, I like to tell people that ballerinas are made, not born. So practicing balance exercises should be a part of everyone's routine, but the more you do them, the better you will be.

(41:58): Marla O'Keefe: Can meningitis cause neuropathy? That's a two-part question, so we'll start with that.

(42:05): Dr. Sasha Knowlton: So meningitis means disease of the meninges, which is one of the layers surrounding the brain and spinal cord. Generally speaking, neuropathy starts in nerves once they've exited the spinal cord, so generally not.

(42:22): Marla O'Keefe: Okay. And the second part of his question is, "I'm having balance issues and gait issues and no pain or other positive or negative symptoms as you've defined. Does that rule out neuropathy?"

(42:35): Dr. Sasha Knowlton: It does not, but this is where a good history and physical would become really important with your treating physician team.

(42:48): Marla O'Keefe: Is it possible to have neuropathy in the bladder or colon that affects my ability to go to the restroom?

(42:56): Dr. Sasha Knowlton: It's possible, but generally speaking it's not a common thing by any means. If the bowels and bladder are affected, my concern would actually be closer to the spinal cord or within the spinal cord itself. But that would be something that could be figured out based on a physical examination.

(43:21): Marla O'Keefe: Thank you. I had Bell's palsy on my left side of my face that began 10 days after my CAR-T treatment and lasted 100 days. How common is Bell's palsy in CAR-T?

(43:37): Dr. Sasha Knowlton: Great question. I don't know the answer to that one.

(43:43): Marla O'Keefe: Okay, we will go on. Let's see. What meds taken to address multiple myeloma post-transplant can cause neuropathy, like Revlimid, Darzalex (daratumumab) , et cetera.

(43:56): Dr. Sasha Knowlton: In this lecture, I've listed some of the common offenders for... Lenalidomide, thalidomide, which I know sometimes are used. They can definitely cause neuropathy, but like I said, we're learning more with the newer treatments that are being developed.

(44:14): Marla O'Keefe: Thank you. This person wants to know, would feeling cold most of the time be a symptom of neuropathy or could it be something else?

(44:22): Dr. Sasha Knowlton: It could be. It could, but generally speaking, neuropathy is what we call length-dependent issue, meaning that it affects the fingers and toes before it affects and works its way up. So if it's a general sense of feeling overall cold, like it's a cold day out and you feel cold in other parts of your body, it would always beg the question of is there something else going on too?

(44:54): Marla O'Keefe: Great. Would massage therapy be beneficial for neuropathy?

(45:00): Dr. Sasha Knowlton: It can be, but you need to go to a massage therapist who is not going to cause any injury and knows what they're doing, especially in cases of multiple myeloma, because you don't want someone to be too rough and accidentally cause a fracture, which I've seen before.

(45:19): Marla O'Keefe: Good to know. Are there studies that showed there's neuropathy after a CAR-T cell treatment?

(45:29): Dr. Sasha Knowlton: Not any that comes to mind. CAR-T is still relatively new, and I think there are CAR-T lectures as well during this symposium, so that might be a better question for them.

(45:42) Marla O'Keefe: Thank you. Yes, there are. How can you tell if you have neuropathy versus something like Raynaud syndrome or carpal tunnel syndrome?

(45:51): Dr. Sasha Knowlton: Yep. So that's based on a physical exam, which can be done with your physician, but the physical exam can definitely distinguish between Raynaud's and carpal tunnel between neuropathy.

(46:07): Marla O'Keefe: Thank you. Can Darzalex cause neuropathy? Did I say that right? Daratumumab.

(46:19): Dr. Sasha Knowlton: That is one of the immunotherapies. Like I said, I know there have been papers published. I read the last one about six months ago. I cannot remember if that one was on the list, to be honest.

(46:32): Marla O'Keefe: Okay. Is there a correlation between diet and neuropathy? Are there any foods that we should avoid?

(46:40): Dr. Sasha Knowlton: Great question. So in terms of overall health, I always tell people a Mediterranean diet is best. Protein is better than sugar for multiple reasons. But yeah, it's overall just a healthy diet, not necessarily foods to avoid but foods to have in moderation.

(47:02): Marla O'Keefe: Thank you. Let me see. I walk in the morning, typically aerobic. And I notice walking late in the day, post 4:00 PM, seems to cause much worse foot neuropathy. Is there a way to exercise late in the day without getting these effects, and is the time of day important?

(47:24): Dr. Sasha Knowlton: So generally the time of day doesn't really matter. It might be dependent on your amount of activity throughout the day. So like I said, it's hard to answer because I just don't know your medical history.

(47:40): Marla O'Keefe: Thank you. My neuropathy has been pretty steady the entire time. It's mild and limited in my toes and the balls of my feet. Will it continue? Or to not progress, are there things I can do to help it?

(47:59): Dr. Sasha Knowlton: Yeah. Again, it's hard to say without knowing the rest of your medical history beyond what I've already presented in this lecture.

(48:08): Marla O'Keefe: Thank you. I know a lot of these are specific, so thank you.

(48:11): Dr. Sasha Knowlton: Yeah, it's really hard.

(48:13): Marla O'Keefe): Right. Let's see what this one is. Does neuropathy affect eyesight or hearing?

(48:22): Dr. Sasha Knowlton: Generally not.

(48:24): Marla O'Keefe: Okay. Let's see. I have been on duloxetine for years, but hand neuropathy is getting worse over time. Is there anything I can do to help that?

(48:38): Dr. Sasha Knowlton: Yup. So I would go to see your physician because there may be something else going on.

(48:44): Marla O'Keefe: Always good to get a second opinion there. I was 35 when I first had vincristine chemo and got neuropathy shortly after. I went on to have a BMT. That was eight years ago and I still have it in the front of my feet and fingertips. I am six feet tall. I didn't have complications you listed at the beginning. Will my neuropathy ever get better?

(49:12): Dr. Sasha Knowlton: Yeah, so there's a possibility it may get better. Like I said at the beginning of the presentation, there's some, I don't want to say disagreement, but in an ideal world, yes. If it's only due to the vincristine treatment that you had, it would get better.

(49:30): But a lot of times people will have lingering symptoms many years beyond. And I don't want to say it's a new normal because I don't like that term, but sometimes it's like I have a really bad ankle, twisted it a billion times and apparently fractured it at some point in my life. That ankle is never going to be strong. I know that. So it's one of those things that it's like, oh, I hope it gets better. I do as much as I can, but if it doesn't, I'm not going to be super disappointed.

(50:02): Marla O'Keefe: Great. These go together. Someone is asking if you have heard of gabapentin causing tiredness or fatigue, and someone else wanted to know if the amount of sleep you have can affect your neuropathy.

(50:19): Dr. Sasha Knowlton: So sleep generally does not affect neuropathy. And gabapentin, as I mentioned, the main side effect is that it causes people to be tired and sleepy. So that's a well-known side effect.

(50:32): Marla O'Keefe: Okay. How do I find a physiatrist that you mentioned?

(50:39): Dr. Sasha Knowlton: You can Google it, you can also go onto the American Board of PM&R, ABPMR, and they have a feature that helps you find a physician and you can search that way.

(50:54): Marla O'Keefe: That's a good resource. All right, this is our last question. My neuropathy for multiple myeloma maintenance therapy is more of a shooting electrical impulse in my extremities, short-lived, and no permanent numbness. Will this side effect remain the same or is it possible to get some type of neuropathy that will not disappear if and when treatment ever stops?

(51:17): Dr. Sasha Knowlton: So as I mentioned, everyone's neuropathy is a little bit different. My hope is that because it's not constant, it's more intermittent that it goes away. It doesn't become a permanent thing, for sure.

(51:35): Marla O'Keefe: Closing. Okay, we got everyone answered. Dr. Knowlton, on behalf of BMT InfoNet and our partners, we want to thank you for your very helpful remarks, and thank you, the audience, for your excellent questions. Please don't hesitate to contact BMT InfoNet if we can help you in any way.

(51:53): Dr. Sasha Knowlton: Thank you so much. I hope everyone has a great day.