Understanding Patient Preferences in the Treatment of Multiple Sclerosis: The Need for Switching Disease-Modifying Therapies

May Han, MD
Stanford University School of Medicine, California

Key Takeaways

  • Early initiation of disease-modifying therapies (DMTs) for multiple sclerosis (MS) has shown to delay relapse and disease progression but determining first-line therapy can be challenging due to the number of DMTs available and other factors, including patient preference that must be considered.
  • The decision to switch therapy, which should be a collaborative one between the clinician and patient, may be driven by lack of appropriate response, disease progression, or side effects.
  • There is no “one size fits all” treatment protocol as goals for treatment, disease activity, medication history, and personal preferences vary considerably among patients.
  • Clinician and patient priorities for switching therapy can differ, but patient preference must be a major consideration because it affects adherence to treatment.
  • The financial burden of therapy must be considered in the selection of a DMT as some drugs may not be covered by the patient’s health insurance or may be too costly even with insurance coverage.

May Han, MD, is an associate professor of neurology and neurological sciences at Stanford
University School of Medicine, in California. She also is a board-certified neurologist
and clinician-scientist who specializes in multiple sclerosis and central nervous system
demyelinating diseases. Her research focuses on utilizing a systems biology approach (eg,
genomics, transcriptomics, and proteomics) to identify targets for therapy in MS and
neuromyelitis optica. Dr. Han is an attending physician at the Stanford Neuroscience Health
Center’s Neuro-Immunology Clinic and at Stanford Hospital in California.

In patients with MS, DMTs have been shown to reduce the frequency and severity of relapses. They also can reduce the development of new lesions in the brain and spinal cord and slow the development of disabilities associated with MS. With DMTs, is there a standard protocol that patients initially receive, or is treatment more individualized to the patient?

We do know that early initiation of a DMT decreases the relapse rate and can prevent  progression of the disabilities associated with MS.1 As to how therapy is selected, we first determine what type of MS a patient has. We then clinically characterize the phenotype and narrow down our treatment choices to a suitable medication with which to begin therapy. But, as there is a growing number of medications now available for relapsing-remitting MS, choosing the most appropriate drug for an individual can be challenging.

While we do not have a treatment algorithm recommended to us by the US Food and Drug
Administration (FDA), we do have guidelines. We look at 3 factors: disease activity, size, and location of visible lesions on the magnetic resonance imaging (including evidence of spinal cord or optic nerve involvement), and lesion activity (all active, active and chronic, or just chronic). We also determine if the patient has 1 or 2 lesions or if the lesions have been progressing for a while. Based on these factors, we decide if the patient is appropriate for treatment with a DMT as first line therapy.

Clinicians typically opt for an oral medication or, less commonly, an injectable drug. Studies
have shown that patients who were on oral medications were less likely to relapse.2 Oral
medications, such as teriflunomide and dimethyl fumarate, reduce the frequency of relapse and
many patients find that they can remain on these medications for years due to the drugs’
tolerability and fewer severe adverse events.3,4

However, if the patient has highly active disease and other risk factors for poor outcomes, such
as older age, male gender, spinal cord involvement, and other comorbidities, we may opt for a
high-efficacy therapy such as ofatumumab or cladribine. Importantly, all of these drugs have
safety risks, so we don’t want to overtreat the disease, but we also don’t want to undertreat it.
We want the treatment to be efficacious enough for the level of disease activity in the patient.
Studies focusing on patients with relapsing-remitting disease show that patients who are placed
on high-efficacy therapies early on benefit from this initial aggressive therapy.5

The patient’s treatment preference is important because we want the patient to be able to live
his or her life rather than be consumed by therapies and the disease. Some people do not mind
getting injections and others just can’t do it. Some patients prefer oral medications, but others
often forget to take their pills. Fear of disability and impact on lifestyle can drive some patients’
desire for a high-efficacy DMT despite the success of their current treatment.6 Patient
preferences and behaviors certainly must be considered in treatment decisions.

Another key issue in choosing treatment is the financial burden on the patient due to the cost of
the drugs, which have steadily increased over the years.7,8 Drugs to treat MS are expensive in the
United States and insurance coverage varies based on factors such as drug cost and the
patient’s co-pay. If a drug costs $300 a month out of pocket, for example, and the patient cannot
afford it, then treatment adherence will be an issue. So then we must go with the next best
option, because at the end of the day, the treatment has to be something that is affordable to the
patient since they may be on this drug for a long time.

As you can see, choosing the right drug is an art in itself. Ideally, we would like to do genetic
testing and use biomarkers, as is done in determining treatment strategies for cancer, but we do
not yet have that information for MS. That is a focal point of my research now.

Individual response to existing therapies for MS varies among patients as does the risk of adverse events. When should switching DMTs be considered and are there any formal guidelines for doing so?

There are no clearly defined guidelines on switching DMTs, and the decision to do so should be
a collaborative one between the clinician and patient. We have to take into consideration a
variety of factors, including goals of treatment, disease activity, medication history, and
personal preferences. One of the main reasons to switch a medication is if the patient is having
either clinical or radiographic breakthrough relapses. Some patients with relapsing-remitting
MS experience disease progression so in these cases, the therapy should be changed.

There also are specific circumstances for changing therapy. For example, a patient may have
tolerated natalizumab very well but now shows antibodies for anti-John Cunningham virus in
serum, which means an increased risk of developing progressive multifocal leukoencephalopathy.9 Other examples are B cell-depleting therapies, such as ocrelizumab, which, while convenient for some patients because it’s given via infusion twice a year, can place patients at a higher risk of infection, especially in patients with known risk factors. This in turn raised concerns during the pandemic about the potential risks of the COVID-19 virus on patient with MS who were receiving immunotherapy.10 The immune response to the COVID-19 vaccine also may be blunted due to the patient being immunocompromised.

As MS most often develops in young adults, pregnancy also is a factor for consideration. Most
medications that are used to treat MS symptoms are not compatible with pregnancy. Therefore,
treatment is generally stopped, and steroids are used to manage relapses during pregnancy.

So, from the physician’s perspective, a switch in medication becomes essential when the therapy
is not managing the disease activity, when the patient is experiencing relapses or regressing, or
when the patient is not tolerating side effects.

For patients, often the first reason for wanting to switch therapies is intolerance to a medication. While we consider some drugs to be well-tolerated, many patients never get used to the side effects. The second reason for wanting to switch is difficulty with adhering to a therapy’s administration. Some patients can never remember to take their evening pill or are unable to give themselves an injection. The third reason for wanting to switch is due to a change in the patient’s insurance coverage and the cost of treatment has increased. In these cases, we may need to use a generic version of a drug. The last most common reason for the desire to switch is lifestyle. In some cases, patients prefer to just get an infusion once a month or every 6 months and then not have to worry about it. Studies also suggest that patients have a higher preference for therapies that improve their symptoms and delay progression over those that decrease relapse rates.11 The frequency of dosing also has been identified as equally important as a therapy’s efficacy and safety.12

Considerations in the treatment of MS during pregnancy
During pregnancy, treatment is generally stopped and steroids are used to treat relapses.

Patient preferences in desiring to switch therapies (as opposed to switching due to
clinician-assessed efficacy) may include the therapy’s route of administration and side
effect profile, among other concerns. Patients also may place a higher value on certain
efficacy endpoints, such as effects on quality of life. How much input does the patient
have in the treatment decision?

It is a joint decision between the clinician and patient, and how much trust the patient has in the
clinician plays a role in this joint decision making. Most of my patients want to stay with me as
their clinician because of this partnership. I give my patients the best possible information that I
can, based on the evidence, and I give them the tools they need to make their decisions.
Sometimes they may be hesitant and feel uncomfortable about a therapy’s potential side effects,
for example, and in these cases, I give them the best explanation I can, backed by scientific
evidence. But, at the end of the day, it is their body and they need to be comfortable with the
treatment decisions. As their clinician, it is my role to support them while determining the
best course of therapy.

There are no clearly defined guidelines on switching DMTs, and the decision to do so should be a collaborative one between the clinician and patient.
May Han, MD

Ofatumumab is administered as a once-monthly subcutaneous injection while teriflunomide is taken orally as a once-daily tablet. In your experience, what attributes of DMTs are most important to patients that should be included in treatment decisions? Do you find that patient decisions typically lean more towards ease in route of administration or ease in dosing frequency?

Every patient is different. Some do not mind taking an oral drug every day and would in fact
prefer that over an injection, while others would prefer the injection once a month. The ease at
which a therapy works for a patient might be different for another. I have found that the least
preferred regimen was subcutaneous injections 3 times weekly. A sample study found that
intravenous infusions given 3 or less times per year was the preferred regimen, while self-
injection 1 to 3 times per week was the least preferred treatment option.13

In your experience, does patient preference in the selection of DMT typically have an
effect on medication adherence?

Absolutely and sometimes a patient will start on a therapy that they had doubts about only to
discover their fears were unfounded. For example, after getting 1 or 2 infusions, they may feel
that infusion therapy is not a huge deal. Some patients get over their fear of injections to find
out it’s their preferred route of administration. Sometimes, the opposite occurs. The patient may have thought an infusion would be easy but learns they aren’t able to tolerate the side effects. All patients respond to therapies differently and that’s why we sometimes need to switch medications — to find the therapy that is most effective and comfortable for the patient so they are able to adhere to the treatment regimen.

This Q&A was edited for clarity and length.

  1. Schmierer K, Sørensen PS, Baker D. Highly effective disease-modifying treatment as initial MS therapy. Curr Opin Neurol. 2021;34(3):286-294. doi:10.1097/WCO.0000000000000937
  2. Kantor D, Mehta R, Pelletier C, et al. Treatment patterns and relapses among newly treated multiple sclerosis patients from a retrospective claims analysis. Clin Ther. 2020;42(11):2136-2147.e3. doi:10.1016/j.clinthera.2020.09.014
  3. Miller AE. Oral teriflunomide in the treatment of relapsing forms of multiple sclerosis: clinical evidence and long-term experience. Ther Adv Neurol Disord. 2017;10(12):381-396. doi:10.1177/1756285617722500
  4. Gold R, Arnold DL, Bar-Or A, et al.  Safety and efficacy of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: 9 years’ follow-up of DEFINE, CONFIRM, and ENDORSE. Ther Adv Neurol Disord. 2020;13:1756286420915005. doi:10.1177/1756286420915005
  5. Rotstein D, Montalban X. Reaching an evidence-based prognosis for personalized treatment of multiple sclerosis. Nat Rev Neurol. 2019;15(5):287-300. doi:10.1038/s41582-019-0170-8
  6. Maurino J, Sotoca J, Sempere AP, et al. High-efficacy disease-modifying therapies in people with relapsing-remitting multiple sclerosis: the role of risk attitude in treatment decisions. Patient. 2021;14(2):241-248. doi:10.1007/s40271-020-00454-3
  7. Elsisi Z, Hincapie AL, Guo JJ. Expenditure, utilization, and cost of specialty drugs for multiple sclerosis in the US medicaid population, 2008-2018. Am Health Drug Benefits. 2020;13(2):74-84.
  8. San-Juan-Rodriguez A, Good CB, Heyman RA, Parekh N, Shrank WH, Hernandez I. Trends in prices, market share, and spending on self-administered disease-modifying therapies for multiple sclerosis in Medicare Part D. JAMA Neurol. 2019;76(11):1386-1390. doi:10.1001/jamaneurol.2019.2711
  9. Ho PR, Koendgen H, Campbell N, Haddock B, Richman S, Chang I. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-933. doi:10.1016/S1474-4422(17)30282-X
  10. Hughes R, Whitley L, Fitovski K, et al. COVID-19 in ocrelizumab-treated people with multiple sclerosis. Mult Scler Relat Disord. 2021;49:102725. doi:10.1016/j.msard.2020.102725
  11. Wilson LS, Loucks A, Gipson G, et al. Patient preferences for attributes of multiple sclerosis disease-modifying therapies: development and results of a ratings-based conjoint analysis. Int J MS Care. 2015;17(2):74-82. doi:10.7224/1537-2073.2013-053
  12. Poulos C, Kinter E, Yang JC, et al. A discrete-choice experiment to determine patient preferences for injectable multiple sclerosis treatments in Germany. Ther Adv Neurol Disord. 2016;9(2):95-104. doi:10.1177/1756285615622736
  13. Bauer B, Brockmeier B, Devonshire V, Charbonne A, Wach D, Herdin B. An international discrete choice experiment assessing patients’ preferences for disease-modifying therapy attributes in multiple sclerosis. Neurodegener Dis Manag. 2020;10(6):369-382. doi:10.2217/nmt-2020-0034

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Neurology Advisor had no role in this content’s preparation.

                                                                                                                                       Reviewed June 2022

Fatigue in Multiple Sclerosis: A Common and Debilitating Symptom

Abbey J. Hughes, PhD
Johns Hopkins University School of Medicine

Key Takeaways

  • Data suggest that up to 90% of patients with MS report experiencing fatigue.
  • Objective measurements of muscle fatigability do not always correlate with a subjective rating of fatigue.
  • Patients with sleep disturbance often report much greater levels of fatigue than do those without sleep disturbance.
  • Helping patients improve their relationship with fatigue can reduce its impact on daily functioning. 
  • A multidisciplinary approach to managing fatigue can have a profound effect on fatigue management.
  • Although access to equitable health care is among the strongest predictors of patient outcomes, significant disparity exists.

In her research and in clinical practice, Abbey J. Hughes, PhD, works with people with MS and their loved ones to optimize psychosocial wellness, self-management, and rehabilitation.
Fatigue is one of the most frequently reported symptoms in people with MS, but its etiology and presentation can vary from patient to patient. In this discussion, Dr Hughes describes her approach to identifying fatigue and her team-based strategy for minimizing its impact on patients’ lives.

Can you describe your approach to identifying fatigue in a patient with MS?

I take both a quantitative and a qualitative approach to identifying fatigue. In every interview, I ask people if they experience fatigue and, if so, how they would describe it.  The reason I start off with this open-ended question is because fatigue is one of the most frequently reported symptoms in people with MS. It is reported in as many as 90% of people with MS.1,2 It can be caused by many different factors, and each person experiences it differently. 
It is helpful for me to understand a patient’s experience of fatigue in their own words. It helps me when taking a mental health history, [as mental illness] can certainly contribute to fatigue, or in assessing sleep, because sleep disturbance that causes fatigue is also a huge part of MS.3 I then look at things like neurologic fatigue, as well as what kind of medications the patient is taking, as sometimes people will say that their medications make them tired.
Another way to go about it would be to divide fatigue into 2 main categories: fatigue severity and fatigue impact.4 I ask people how severe their fatigue is on a typical basis, similar to asking a patient to “rate your pain on a scale of 1 to 10.”  When assessing the impact of fatigue, I ask people how their fatigue interferes with their daily functioning.4 How does it interfere with what they would normally do in their daily life? Fatigue can interfere with their ability to participate in their home activities with partners, families, and friends. It could have a greater impact at work and it can differ among patients, depending on their job and their family situation.

Causes of fatigue in MS
Causes of fatigue in MS
Complications of MS that may also cause fatigue symptoms include chronic pain, anemia, reduced physical fitness, emotional disorders, reduced thyroid function, sleeping issues, and diabetes.

Are there objective measures clinicians can use to assess fatigue in patients with MS?

Fatigue is complicated, because it is entirely subjective and it is a symptom that only the person experiencing it can feel.  But, that doesn’t mean you can’t get at other things that are related to fatigue. 
We often refer to “fatigability,” which is how easily someone becomes fatigued when they are under a particular challenge or when they are completing a specific task. 5,6  There is research that tests fatigability in patients by having them repeat certain tasks like walking on a treadmill or a fine motor task until their muscles give out from the fatigue.5,6 So, you can measure the muscle fatigability, but the fatigability does not always correlate with someone’s subjective rating of fatigue. Fatigue, as we most commonly assess it and measure it, really falls within that subjective experience.

How can professionals in mental health specifically and in medicine broadly address fatigue in MS?

For management of fatigue in MS, 2 of the most robustly [studied] interventions are physical activity and health behavior interventions.  So, broadly speaking, that’s psychotherapy.5-8 There are a few specific kinds of psychotherapy that have been examined in fatigue: cognitive behavioral therapy, mindfulness-based therapy, and acceptance and commitment therapy.7,8 These are 3 examples of orientations to a behavioral or psychological intervention that helps people manage their fatigue more effectively.
[Other] behavioral interventions that help people manage their fatigue better include pacing, mindfulness, and changing thoughts and behaviors about their fatigue. So, although you may not be able to change someone’s fatigue intensity, you can help them have a different relationship with it, so that it is not as interfering with their daily functioning.
[Editor’s Note: Previously, fatigue medications were observed to be ineffective in MS.9 However, the recently completed phase 3 OPTIMUM study (ClinicalTrials.gov Identifier: NCT02425644), which compared oral ponesimod and teriflunomide in relapsing MS, demonstrated positive results. The study revealed superiority of ponesimod vs teriflunomide across the primary and secondary end points.10 The primary end point was annualized relapse rate from baseline to end-of-treatment, while secondary end points included the measurement of change from baseline to end-of treatment in fatigue-related symptoms. Based on results from the Fatigue Symptoms and Impacts Questionnaire – Relapsing Multiple Sclerosis (FSIQ-RMS), statistically significant effects on fatigue symptoms were observed with ponesimod compared with teriflunomide.10]

What are some of the other nonpharmacologic approaches to broadly managing fatigue in patients with MS?

If we take sleep as an example, knowing that it is a potential contributor to fatigue, managing sleep would help prevent fatigue.3 For example, having good sleep hygiene and making sure that the patient is not sleeping during the day can build up sleep pressure so the patient can fall asleep at night. From a pacing standpoint, we’d advise not packing too many activities into a single period of time to avoid burnout and taking frequent breaks. Allowing for those brain and physical breaks can be a potential disability accommodation in the workplace. 
Eating a moderate, healthy diet — where you’re eating frequently enough but not so much that you’re getting lassitude — is also an important component of fatigue management. In addition, physical activity is important. We are continuing to see in the literature how important regular physical activity is for managing fatigue, although this often seems counterintuitive to patients.5,6,11 They feel that because they are tired they should rest, but the data show that physical activity on a regular basis actually helps reduce fatigue. 
Other types of exercises, like with mindfulness, make us pause and pay more attention to what is happening in a given moment and thus avoid information overload and its associated exhaustion.12,13 Mindfulness allows people to be more deliberate in their attention and to limit their attempts to manage many things at a time.  Pacing and doing one thing at a time form a baseline approach to fatigue management.11,12

Multidimensional Tools for Measuring Fatigue in MS

What are some of the non-MS-related causes of fatigue that clinicians may want to rule out?

Although you say “non-MS,” I put depression, anxiety, and social isolation in a category that can be related to MS or can be separate from MS. We know that fatigue is one of the symptoms of depression.27 If I am screening for depression, I automatically ask about fatigue; there’s a lot of overlap there. Sometimes people experience depression as fatigue. They may not be experiencing worthlessness or suicidal ideation that sometimes accompanies depression, but they are feeling down, depressed, and maybe hopeless. When you feel hopeless every day on waking up, it is pretty exhausting. 
Similarly, anxiety is very fatiguing. If you are a person living with MS, there are many things that MS could trigger in terms of depression and anxiety.27, 28 Getting a new diagnosis can change the way that people view themselves, and they have to integrate that into their identity in different ways. Depression can be a reaction to that. Similarly, with anxiety, there are a lot of MS medications or treatments that have side effects, and patients may feel reactionary anxiety about that, which can be very fatiguing. A patient may also have anxiety or depression that pre-existed the MS; once they develop MS, they get a recurrence of the depression or anxiety, and that contributes to fatigue.27-29

Can you describe the healthcare team you work with and your collective approach to managing fatigue in patients with MS?

My role as a rehabilitation psychologist is dedicated to understanding and advocating for and with people with chronic health conditions and disabilities. Most of what I do is team based. The rehabilitation team with which I work closely includes a physiatrist who specializes in the musculoskeletal system and the way it interfaces with the nervous system in physical functioning. A physical therapist, an occupational therapist, and a speech therapist are also part of our MS treatment team for managing fatigue. The physical therapist can help someone build strength in their core, for example, and then in their legs, so that they can walk with less effort. An occupational therapist helps people manage their essential daily activities, like getting dressed, doing the dishes, and doing the laundry. Although these things do not sound like they are very energy consuming, if you have MS and you have fatigue, any one of those tasks can be exhausting. 
As speech therapy is also important, speech/language pathologists assist with cognitive rehabilitation.  Imagine how exhausting talking is, especially if you have dysarthria or aphasia or some of these symptoms that can come along with MS. Working with a speech therapist can help with managing cognitive fatigue and the fatigue that comes with laryngeal and pharyngeal activity.

Can you highlight some gaps in the research that you hope to see addressed in the coming years?

The National MS Society has established task forces that are focused on different aspects of wellness.30 There is a physical wellness group that studies physical activity, there’s a nutrition group, and there’s even a psychosocial wellness group.28 The reason I bring this up is that one of the major criticisms about research in physical activity and MS has been the significant heterogeneity of study design. Do you have a control group? Do patients exercise 5 days a week, 6 days a week, 3 days a week? What kind of exercise do you do? Do you do strength-based exercise? Do you do cardiovascular-based exercise? What is really important is that gaps in the literature are slowly being filled in our understanding of what kinds of exercises are most effective and, again, for whom they are most effective. 
We need to get away from the idea of one-size-fits-all or that an intervention is effective for everyone.  It’s more of, “Okay, you have this weakness. What intervention do we use to address that weakness?” That gets us to personalized medicine and what is called precision medicine. That is the wave of the future of all research, but especially in the self-management of chronic health conditions like MS.

What is a final piece of advice or take-home message that you would like to share with clinicians who might be caring for patients with MS?

One thing that is important to emphasize is that access to equitable health care and insurance continue to be among the strongest predictors of patient outcomes. With the coming of COVID, medicine has moved toward telehealth, which has increased accessibility for so many patients. Yet, insurance companies are not consistently paying for telehealth visits, as they would for in-person visits, even though the research suggests that they are equal in their efficacy, especially when it comes to behavioral interventions.31
When people ask what can I do, where should my efforts be placed, where should money go, I respond that there is an advocacy need at the legislation level for insurance to cover these treatments that we know are effective but that are not being disseminated to the patients who are most in need.  So, we see a divide in care, and we see a divide in patients who can benefit from these services.
I can talk about the research participants who agree to enroll in our studies, but it is a biased selection. Until we can really reach a fully representative sample of patients and have those patients have access to care, fatigue will continue to be an issue.
The Q&A was edited for clarity and length.


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Reviewed October 2020

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