MS Team Meeting: The Impact of the Invisible Symptoms of MS

Patients and providers learn to address the invisible symptoms of living with multiple sclerosis, including fatigue, pain, and cognitive difficulties, in this four-part video series.


Multiple sclerosis (MS) is a major neurologic disease of the central nervous system that affects the brain, spinal cord, and optic nerve. Many of its symptoms are easily noticed, but others are not visible to the naked eye and make day-to-day life with the disease difficult to navigate for millions of patients

This panel of renowned faculty, who specialize in MS, are reflective of the multi-disciplinary healthcare team that’s required for the care and management of patients living with MS. In each of these four episodes, you’ll hear from Lillian, a patient who was diagnosed 30 years ago. She describes the “troublesome” invisible symptoms of the disease in a candid conversation with a neurologist and psychiatrist, nurse practitioner, and neuropsychologist. Lilllian sheds new light on the course of treatment, standard of care, and latest research insights that improve the quality of life.

Visible and Invisible Symptoms of MS

Some of the most obvious, or visible, symptoms of MS include gait impairment, balance and instability, tremors, and difficulties with speech. It’s the invisible symptoms that can take a physical, mental, and emotional toll. Lillian calls fatigue and cognitive dysfunction “the evil twins of MS,” something she’s found difficult to explain to those who haven’t experienced it themselves.

The Physician’s Role on Behalf of Patients with MS

Listening to patients is key for physicians to “untangle the ball of yarn” that this disease presents. The subtle and even non-verbal clues are important to get to the crux of what patients are experiencing and how providers can address it through medication, psychotherapy, lifestyle modifications, and especially the latest research. Recent clinical trials like OPTIMUM and TRIUMPHANT-MS hold the keys to important disease-modifying therapy.

Episode 1:

“ [00:00:06] Dr. Patricia Coyle Welcome to our discussion about the impact of invisible symptoms on MS. My name is Dr. Pat Coyle. I'm a Professor of Neurology and Director of the Stony Brook MS Comprehensive Care Center at Stony Brook University in New York. I'm joined by my two colleagues, Pat Melville and Tom Preston. Pat.

[00:00:27] Patricia Melville, NP Yes. Thank you, Dr. Coyle. My name is Pat Melville. I'm a nurse practitioner at the Stony Brook MS Comprehensive Care Center.

[00:00:35] Dr. Thomas Preston And I'm Dr. Tom Preston, Director of the Neuropsychology Service at Stony Brook University Hospital and a
Clinical Associate Professor of Neurology here at Stony Brook.

[00:00:44] Dr. Patricia Coyle So today we're going to really be focusing
on symptoms of MS, but with a particular emphasis on the invisible symptoms that can be so difficult to evaluate and manage. MS is the major neurologic disease of young adults, it's estimated close to a million Americans have MS. This is a major central nervous system disease
affecting the brain, the spinal cord and the optic nerve. When I think about the treatment of MS, of course, we have our disease modifying therapies that decrease damage to the central nervous system. We have treatment of the acute attacks, relapses, of MS and a very important component is appropriate lifestyle choices following a wellness program and recognizing and optimally treating any comorbid conditions because that helps CNS reserve. But the final important treatment involves the symptoms of MS, which can be both visible and invisible. Pat, can you tell us about visible versus invisible symptoms in MS?

[00:01:52] Patricia Melville, NP Yes, I'd be happy to. So in MS you can have visible and invisible symptoms. Visible symptoms are what you might expect. Patients who might have difficulty with gait and needing to use a cane or walker. Patients who might have tremor or spasticity. These are things that are going to be very visible to the naked eye. Many of our
patients suffer with invisible symptoms, things like pain, bladder and bowel dysfunction, cognitive difficulties, mood disorders and fatigue.
Fatigue is one of the most common invisible symptoms that we see in our MS patient population, affecting up to 90 percent of patients with
MS. The fatigue can be overwhelming and can have a very negative impact on our patients' quality of life. The fatigue that patients
experience with MS is oftentimes not relieved by rest or sleep. The
fatigue is multidimensional and can have a negative impact both on their

vocational, social and psychological well-being.

[00:02:51] Dr. Patricia Coyle To truly understand the impact of MS and the symptoms of MS, we need to walk in the shoes of somebody who lives with this disease day in and day out. So I'm very happy to welcome
Lillian, a person with MS. Lillian, welcome.

[00:03:07] Lillian Thank you, everybody. It's a pleasure to be here.

[00:03:10] Patricia Melville, NP Lily, can you share with us today some of the symptoms you've experienced?

[00:03:14] Lillian Yes. Having been diagnosed with MS for 30 years now, it kind of hits you at the peak of your life when you're independent. You are career driven, you're healthy, one day you're out there playing soccer with your kids and then you get this diagnosis and it's devastating. For me, I've had pain issues from spasticity and neuropathy. But the most troublesome symptoms for me are really the invisible disease. I call
fatigue and, and cognitive dysfunction the evil twins in MS. It is so hard to explain to someone who isn't experienced with MS what fatigue really, really is. I've gotten people saying, "Oh, just go upstairs and rest and then you can come to the party." That's - you can't rest it away. You wake
up - you sleep, you get a good night's sleep, you wake up and you're tired. And then cognitive fog. It's like, it's very difficult to explain because people just don't understand. I have closed down my circle of friends who really understand me, who don't get upset because I have to cancel or walk away from a conversation with several people. And I can't
multitask anymore. I can only do one thing at a time. You know, I re-read the same thing several times. And yet, I have to re-read it because it doesn't stay in.

[00:04:56] Dr. Patricia Coyle I think it's so important to hear what Lillian says, the dramatic impact of these invisible symptoms of fatigue and cognitive difficulties where somebody might look great, they seem to have no motor impairment, there's no gait issues yet debilitating, impacting on a daily basis on their life. It's really important to hear that from the individual living with MS so we have a greater understanding of the impact of these invisible symptoms and what we hope is to prevent them or develop truly
effective treatments.”


[00:00:09] Dr. Thomas Preston Lillian, I want to expand on what you just said, because it's so important. We see this in all the patients we assess in the neuropsychology service who have MS who are referred to us at various stages of the disease. The psychological and mood impacts are really quite profound. The dysphoria associated with having the disease and the reaction to the diagnosis, the cognitive symptoms that you described about interacting with things like fatigue and pain. It's critically important that providers like us really learn, continue to learn, I should say, to listen to patients. And it's really important that we acknowledge these invisible symptoms, the cognitive, the psychosocial, the mood symptoms that accompany MS. So Lillian, how is your relationship with your provider? Tell me - tell us all why it's so important.

[00:01:08] Lillian I have a great relationship with my provider. She educates me on the latest treatments and the latest research that's coming up. She collaborates with me. She makes me, the patient, part of her team. It's not a passive role. She gives me options as far as treatments and then lets me decide. And but - but the most important thing is that my provider really listens to me when I'm in that exam room with her. It's like she shuts the rest of the world out, and I am the only person right then that she is thinking of.

[00:01:49] Dr. Thomas Preston So Lillian, what are some of the, oh, I don't know if it's recreational or fun particularly, but - but the things you do to try to adapt to your situation to enhance your quality of life?

[00:02:03] Lillian OK, well, I practice meditation every morning. I do gentle chair yoga and then stretching, and then I try to walk a little bit every day. I used to be a big walker and now I can't do that anymore. I go with the cane now and I'll go one block and come back. But I'm always trying to find balance because MS took so much of who I am away. And so I try to live in the moment and not worry about the future. And I play my classical guitar. I - I knit.

[00:02:39] Dr. Thomas Preston Sure. So now I'd like to address in a little bit more detail the cognitive and emotional aspects of the hidden symptoms of MS which you introduced so eloquently, right? In terms of - of emotions, MS has critical impacts on mood, and it is the the mood symptoms of MS are both biological in nature and reactive and psychosocial in nature. We believe that the prevalence, the lifetime prevalence of mood problems in patients with MS is roughly 25 to 50 percent, which is an astonishingly high figure. That's two-to-five times what we see in the general population. Depression is a critical aspect of MS. It can increase rather dramatically in the immediate aftermath of the diagnosis. There is some evidence that it is related to brain abnormalities, particularly in the left temporal area, but also in a number of other cortical and subcortical parts of the brain. One of the, I think, most problematic parts of dealing with depression and anxiety, because they really exist on a spectrum in MS, is that perhaps the people around you might say, "Well, OK, we've heard this, so get over it, you know, get back up and just keep going." And of course, even though maybe there's an outbreak of depression in the immediate aftermath, in fact, it doesn't go away, as you've so - you've said so well, really. Now, to add a little bit more about the cognitive symptoms of MS.

Here again, lifetime prevalence reported to be between 45 percent and 60 percent, again, a remarkably high rate in comparison to the general population. And in many ways, just as invisible as the mood symptoms. You're a beat slower, it's hard for you to multitask, it's hard for you to shift between - between one thing and the next. To be a little bit more or academic about this, what do we look at in terms of neuropsychological assessment of the symptoms of MS? We look at psychomotor speed, processing speed, those are interrelated, hard to extricate from each other. Cognitive efficiency. How - how efficiently you're able to engage and complete a task. Sustained attention, right, which is in some ways the simplest kind of attention, but also more complex attention. Shifting between one thing and another, screening out distractors, planning ahead, showing mental flexibility when the situation demands it. And of course, again, all of these struggles for someone with MS are intertwined with what Pat was talking about, fatigue and pain. Right? If you're - if you're effectively, you know, being just exhausted by the process of living through your day by maybe mid-afternoon, right? You're not going to be as capable of doing the things you did in the morning. But even the things you did in the morning, you're doing them differently than you were 15 years ago. So I can really see how those difficulties would impact you in a way that's not immediately visible to those around you. The other thing I like to add that's really important is brain reserve, also called cognitive reserve. It's pretty well known at this point that what you have walking into a disease like MS. is going to have an impact on what you have walking through it. So the healthier you were, the more cognitively active you were, the more physically active you were when you got sick. That's going to enhance your adaptation to the disease as you go along. It's not going to make it go away, but it is going to make you more able to cope. And of course, there's an overlap between cognitive symptoms, depression and anxiety, fatigue, pain and the other physical symptoms of MS. They are all mutually exacerbating, right? So those are the kinds of things that interact with each other that MS patients struggle to deal with. This is what we know about cognitive enrichment and I should say, also physical enrichment, and all kinds of disorders, including MS. We know number one, that doing your best to remain physically active, however modestly, is really critical. That's a huge mood enhancer, and it also helps you mitigate the cognitive struggles that you have with MS. Number two, being around the people you care about, the people you love, socializing, psychosocial involvement turns out to be a very, very important mitigating factor with cognition and mood in MS. Cognitive enrichment, the findings have been mixed. However, there is some indication that remaining cognitively challenged, so you mentioned playing your classical guitar, learning a new piece, right, pushing yourself in a way that you haven't done before, right? That does seem to enhance cognition. And Dr. Coyle my understanding now is that gray matter, particularly cortical lesions, are very strongly predictive of cognitive dysfunction in MS.

[00:08:35] Dr. Patricia Coyle That's exactly right. You're looking at cortical atrophy, thinning, and to a lesser extent, deep nuclear gray matter like the thalamus, a thinning that has really been correlated with cognitive issues.


[00:00:09] Dr. Patricia Coyle Often patients can have multiple symptoms, so I like to ask them what symptoms of MS are bothering you and please rank order them because I think it's valuable to see what the patient feels is the most important to them. But then you have to look at that list intelligently, and you may decide that a symptom that was ranked as number three may actually be critically important to focus on first. For example, depression, which is a poisonous symptom, can interfere with the person feeling that they can carry out things and improve themselves. So maybe I might choose that that's the most important thing to work on first. And then I think I get a game plan for every individual symptom, and the approach to treating a symptom is not simply writing a prescription, writing a drug that may be part of it, but it may be lifestyle changes. It may be rehabilitation. It may be using assistive devices. It may be, in unusual cases, surgical or stimulation techniques. I think you really have to have an organized game plan to go after each of those symptoms in turn to try to make them as well as possible. And you can help every single MS patient. You may not be able to take a symptom away entirely, but you can improve it. Pat, how do you approach symptom management in MS?

[00:01:35] Patricia Melville, NP I think it's very important to listen to our patients, listen to what they're complaining of, ask them to give you examples. Perhaps if they are complaining of fatigue, ask them to give examples of what tasks they can't complete. Are they having cognitive difficulties? Are they having missing deadlines at work? Often times when I'm speaking to my patients about fatigue and if they also have depression and cognitive difficulties, I oftentimes describe it as a tangled ball of yarn, where fatigue and depression and cognition all get caught up with one another. And it's sometimes hard to unravel where one begins and the other one ends because they are so closely related. And oftentimes, if you can treat one, you can in turn treat the other symptoms as well. I think it's also important to validate their concerns and then work as a partner with them to come up with some viable

alternatives, listening or assessing for non-verbal clues are also important. The way a patient walks into an exam room, speaking to them concisely, but in non-medical language, not using medical jargon, so it is understandable to the patient. So you really do develop a partnership or relationship with your patients. I think that's critically important. Tom, what do you think about that?

[00:02:53] Dr. Thomas Preston What we know about, for example, psychotherapy research is that there are really good techniques for helping people broadly in the cognitive behavioral domain, cognitive reframing, acceptance and commitment. These are really important things. Mindfulness training is very useful, but one of the most important things is, in fact, maybe more important than anything else is the relationship between provider and patient. I think the other things that can help patients are meditation, physical activity, whatever you can possibly do, cognitive challenge, and support groups, support groups with other people. Those can be hard to get up and running and hard to keep running. But when you're with other people who support your own lived experience, right, that can be very, very enhancing.

[00:03:43] Patricia Melville, NP So, Lillian, perhaps you can share with us how you've managed some of these symptoms that you experience and still maintain an adequate or good quality of life.

[00:03:53] Lillian I think it's critical for MS patients to practice and be very intentional about establishing a quality of life because we suffer so much from depression, from fatigue and from cognitive dysfunction, and that all impacts, like Pat said, a ball of yarn, and it's so hard to tease everything out. So I think it's critical for - for MS patients to practice self-care, and that includes really being intentional about it.


[00:00:09] Dr. Patricia Coyle We can always learn a lot from clinical trials, and I'd like to talk about two very recent ones that were published in 2021. The first is the Phase 3 Optimum trial that led to approval of our most recent disease modifying therapy, ponesimod. This is a second generation S1P receptor modulator, a second generation fingolimod. This trial entered over 1,100 relapsing patients. They were randomized to two arms, either oral ponesimod 20 mg daily or oral teriflunomide 14 mg daily. The study ran 108 weeks. Its primary outcome was annualized relapse rate, and that was significantly less by 30.5 percent in the ponesimod arm compared to the teriflunomide arm. But I'm really mentioning it because they had the the courage to add a secondary outcome that evaluated fatigue, one of the major invisible symptoms that we've been talking about. And indeed at the end of the study with a patient reported outcome to look at fatigue, they showed a significant difference in that PRO rated fatigue in favor of the ponesimod arm versus the teriflunomide arm. At the end of the year, fatigue had remained stable with the ponesimod, and it had increased with the teriflunomide. Now, unfortunately, this never got to the label, and I think that was because the FDA didn't feel confident with one single patient reported outcome that you would really say this disease modifying therapy helps fatigue. But I think it really encourages symptoms to be looked at more with regard to secondary outcomes. The second trial I want to mention that was published was Triumphant-MS. This was a small Phase 3. It only entered 141 MS individuals that had significant fatigue on the modified fatigue impact scale, the MFIS. They scored greater than 33 points. This trial examined our three leading oral agents to treat fatigue and MS. So they had an amantadine arm 100 mg twice a day. They had a methylphenidate arm 10 mg twice a day. They had a modafinil arm a 100 mg twice a day, and they had a placebo arm. So they configured it that patients were randomized for for up to six weeks to one of those four treatments, including placebo, would then get a two week washout and then go into the next drug or placebo treatment. And the primary outcome was the modified fatigue impact scale, the MFIS score, five weeks into the treatment. Lo and behold, everybody improved somewhat, even the placebo arm. There was no significant difference between the three leading oral agents to treat fatigue and the placebo arm. You could not show an improvement in fatigue. Now, in a post-hoc analysis, which doesn't count in those that had increased daytime drowsiness or sleepiness, there was a fatigue impact of methylphenidate and modafinil. But post-hoc analyses don't ever count. So how would - what would you conclude from this study? Well, I would say that our oral treatments for fatigue are not slam dunks for sure. It could not show a benefit here, and you saw a potent placebo effect on

fatigue. This doesn't mean that we shouldn't use them. I think we've all experienced patients that can respond to these treatments, but it really underwhelms for the current pharmacological approach to treat fatigue in MS and really emphasizes the importance of other things, including perhaps cognitive behavioral therapy that can help fatigue, among other symptoms, we haven't mentioned that that yet. So I think there are take-home lessons from these two trials published in the last year that addressed different aspects of fatigue. So in our closing minutes here, I'll ask Pat and then turn to Tom, what final words would you like to say or what important take home for our audience would you have, Pat?

[00:04:30] Patricia Melville, NP So I think it's very interesting that with the ponesimod study, that it actually showed a benefit on fatigue. Traditionally, our DMTs have not shown any benefit on symptom management. However, this is interesting that it showed a benefit for fatigue, and this is really going to be an impact for our patients moving forward. With regards to the Triumphant trial, the fatigue trial, I think this brings home the issue that fatigue and the management of fatigue is really multidimensional and it really requires a multidisciplinary approach. Maybe not only pharmacological but psychological, perhaps getting physical exercise, perhaps treating cognitive dysfunction and quality of life and psychosocial aspects of it.

[00:05:16] Dr. Thomas Preston I'm very interested to hear about the ponesimod trial and the what you just said about the oral agents and their failure to modify fatigue in the other study. It doesn't surprise me a lot. It just again, it brings us back to the issue of hard to quantify but essential physical and psychosocial sort of adaptation modifications for someone like you Lillian, given what you've been through and how well you are working to adapt to the condition.

[00:05:50] Dr. Patricia Coyle So I hope this has been a valuable discussion about MS symptoms and particularly invisible symptoms, we've had a wonderful multidisciplinary panel. We've heard from myself as a neurologist treating MS, from Lillian, a person living with MS, from Pat Melville, a nurse practitioner who takes care of MS, from our neuropsychologist, Tom Preston, who evaluates our MS patient. I want to thank this wonderful panel. It was truly a multidisciplinary approach, and I hope our audience enjoyed this multifaceted discussion very much. Thank you.


Patricia K. Coyle, MD

Dr. Coyle is an expert in multiple sclerosis and neurologic Lyme disease. She has held multiple leadership positions at the American Board of Psychiatry and Neurology, the American Academy of Neurology, the American Neurological Association, and the National MS Society. She has served as an adviser to the Food and Drug Administration and the Institute of Medicine. Dr. Coyle has received research funding from the NIH and the National MS Society and is actively engaged in studies to understand and treat these diseases.

Patricia Melville, RN, MSN, NP-C, MSCN

Patricia Melville is a board-certified Adult Nurse Practitioner and Clinical Instructor at the Stony Brook University MS Comprehensive Care Center. She is the past president of the Long Island MS Nurses Society and the President -Elect of the MS Nurse International Certification Board. She is an active member of the local NMSS Healthcare Provider Council. Ms. Melville has lectured both nationally and internationally on MS and MS Care. She is an author of numerous peer-reviewed articles on clinical care in MS.

Thomas Preston, PhD, ABPP/CN

Dr. Preston is Director of the Neuropsychology Service and Clinical Assistant Professor in the Department of Neurology at Stony Brook University Hospital. Dr. Preston is a board- certified neuropsychologist who has been practicing for over 20 years in medical settings. He obtained his doctoral degree in clinical psychology from Vanderbilt University and completed fellowships in clinical child psychology and neuropsychology at Yale University and the University of Rochester.