Fred D. Lublin, MDFred D. Lublin, MD
Over the past decade, the conversation in multiple sclerosis (MS) has been dominated by the influx of available disease-modifying therapies (DMTs). Now, more than a dozen therapies brought to the market successfully has been a bright light for patientsand physicians.

Although highly efficacious DMTs have improved outcomes for a growing number of patients, the majority of people with MS are still subjected to the day-to-day consequences of the disease’s symptoms, including, but not limited to, fatigue, pain, spasticity, cognitive dysfunction, and gait issues. These symptoms often have a more debilitating effect on the patient than the disease itself.1

“Ironically, in many ways, before the first FDA-approved medicine came to market in the early 1990s, a lot of the care for people living with MS was focused predominantly on symptomatic management," Mary Hughes, MD, a staff neurologist focused on MS at Premier Neurology in Charleston, South Carolina, told NeurologyLive. “With the DMTs, we almost turned our attention away from symptomatic management for the renewed hope that the DMTs had in changing people’s prognosis of living with MS. But we kind of forgot along the way that one of the keys is living with MS. That’s where, really, the symptomatic management comes into play—because it’s so important.”

Not only do the symptoms of MS present as the biggest daily challenge for patients, but they can be extraordinarily puzzling for physicians to evaluate, as well, as they can fluctuate and interact.2 Further complicating disease management is the fact that many treatments are poorly tolerated and can often exacerbate symptoms. With so many new treatments available that are limited in both efficacy and evidence to guide their use, much of the physician’s time is spent becoming familiar with the multiple approaches to improving the quality of life of those with MS, as the majority of typical office visits involve symptom management.3

Something Borrowed

As a neurological disease with one of the largest treatment armamentariums against disease progression, a sizable gap remains for symptomatic care in MS. Hughes explained there are few FDA-approved therapies indicated specifically for a symptom of MS, leading the majority of MS specialists in the United States to use treatments indicated for other diseases off-label—many of which are less than novel.

“For the vast majority of the symptoms we have for MS, unfortunately, we are using our clinical skills from other conditions and applying them in the field of MS,” Hughes said. “Many of the medications we use in caring for people with MS have been around for a long time,” she continued. “For example, in spasticity management, baclofen has been around forever. For people with more severe spasticity, the intrathecal baclofen pump has been around for almost 20 years, and yet the number of people who are either aware of the access or have been trained in how to manage the intrathecal baclofen pump is small.”

In addition to baclofen (Gablofen, CNS Therapeutics; and Lioresal, Saol Therapeutics), the list of therapies for treating spasticity include onabotulinum toxin A (Botox, Allergan), originally approved for urinary incontinence; dantrolene (Dantrium, Par Pharmaceuticals), originally indicated for malignant hyperthermia; clonazepam (Klonopin, Genentech), initially indicated for Lennox-Gastaut syndrome; and diazepam (Valium, Genentech), initially approved for anxiety.

As Hughes alluded to—and as is the case for many conditions—there are huge challenges in access to therapies as well. Patients with MS are forced to turn to off-label therapies to help improve their quality of life, and yet many of them are unaware of their additional, albeit limited, options. The baclofen intrathecal pump is the perfect example.

“Really, that’s one of the biggest challenges in access. People aren’t even aware that’s an option, and there are very few people [who] have been trained in how to manage that,” Hughes explained.

A lack of access coupled with a relatively small number of MS specialists and trained neurologists has only added to an overall absence of focus on symptomatic management. Fred D. Lublin, MD, the Saunders Family Professor of Neurology at the Icahn School of Medicine at Mount Sinai, and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis in New York City, mentioned in a NeurologyLive Peer Exchange panel that a colleague of his, Stephen Krieger, MD, often reminds him to keep a focus on symptomatic therapy.

“His mantra is: There’s always something you can do—from the patient who comes in with very early disease, to the individuals that sort of drop off our radar screens because they’re so badly involved, and everything in between,” Lublin said. “We’ve been very excited now for 25 years, almost 26 years, over DMTs. But symp- tomatic therapies are what make people’s lives better.”

Lublin explained that symptomatic therapy in MS is radically different in a strategic sense from what physicians do with DMTs. With the therapies intent on altering disease progression, MS specialists essentially prescribe, then wait and see. With symptom treatment, it’s a much more rapid process.

“But then the onus is on the clinician. You’ve got to keep actively working with the patient for dosing,” Lublin said. “While we don’t use dosing for the DMTs, we do it for things like bladder control— not for dalfampridine [Ampyra, Acorda], that’s a standard dose— certainly for spasticity, and maybe even for depression. So that requires a lot of back and forth and interaction with the patients and constantly working with them over a short period to optimize what they’re doing.”

Most Bothersome Symptoms

Fatigue is one of the most prevalent symptoms among patients with MS, with some estimates at up to 80% of patients experiencing it4 and up to 33% of patients denoting it as the most troubling of all their symptoms, often in conjunction with depression.5 Despite its prevalence, there are no approved therapies specifically for fatigue.

“Fatigue is very debilitating in that it can affect job performance, [and your] social and family [lives], and that really impacts the patient, especially if they cannot be employed because they have this uncontrollable fatigue that is quite different from what you would experience with anything else,” Annette F. Okai, MD, an MS neurologist at Baylor Scott & White Health in Dallas, Texas, told NeurologyLive.

Fatigue in MS is specifically defined as an overwhelming sense of tiredness, lack of energy, or exhaustion exceeding the expected.6 As such, it is very trying for physicians to measure objectively, and the underlying pathophysiologic mechanisms of its cause are poorly understood. Some study findings suggest that a related cause could be overproduction of inflammatory cytokines systemically or within the central nervous system (CNS).6

“[Fatigue has] a very much multifactorial cause, but there is fatigue that is just intrinsic in MS,” Hughes said.

Okai noted that often, the issue of insurance denial arises for physicians when trying to treat fatigue in patients with MS, mainly because of the lack of an MS-specific indication. The most common approach she takes is to use CNS stimulants, such as armodafinil (Nuvigil, Teva)—first approved for wakefulness in patients with obstructive sleep apnea or excessive sleepiness—or methylphenidate, which is often used in attention-deficit/hyperactivity disorder.

“We found that using things like modafinil [Provigil, Teva] helps control the symptoms, but [it isn’t] indicated for that,” Okai explained. “Methylphenidate is a controlled substance, but it can also help with both fatigue and the cognitive problems that we see in MS. Those are the drugs that we tend to prescribe for these patients.”

In addition to fatigue, many patients with MS experience bladder and bowel problems. Managing bowel symptoms often becomes an additional hurdle for neurologists due to a lack of training in how to aggressively address them.

“I was never trained during residency on how to manage bladder control. That was something the gynecologist or urologist managed,” Hughes explained. “In a nonsurgical ideology, many times it falls back on the practitioner that is managing the person living with MS to manage their bladder control issues. How do you optimize the care and assess this population when urologists may not be as engaged in managing them because it is coming from a neurological disease and not a structural one?”

She added that although a symptom like bladder control is present in up to 70% of patients, there are few educational programs offered for bladder management. Even at neurology-focused societal meetings, sessions and programs about bladder control don’t occur.

Supplementing the Pipeline

Compared with the treatment pipeline for MS disease progression, the pipeline for symptom management is rather dry. Neither Hughes nor Okai could recall a novel agent in development for the number of symptoms they treat every day.

“Most of what’s being studied in terms of symptomatic management are the supplements that we have, such as biotin, alpha lipoic acid, and acetyl-L-carnitine. Those are being studied to see how they affect the symptoms of patients,” Okai said. “I cannot
think of any other molecule or pharmacologic molecule that’s in development right now. It’s mostly just other supplemental things that are being studied now to see if they help with the symptoms of MS.”

“Many people are very interested in using supplements; that’s a challenge because the more traditional health care providers have not been trained or are not familiar with the use of various supplements in the management in MS,” Hughes said.

Alpha lipoic acid has been tested in clinical trials, mostly in small studies, with relatively positive results. In a 2016 pilot trial in 51 patients with secondary progressive MS, the findings showed an improvement in patients’ walking speed, although the difference was not statistically significant. Ultimately, the Timed 25-Foot Walk test was reduced by 0.535 (standard error of the coefficient estimate [SEE], 0.358) in the lipoic acid group (n = 27) compared with 0.137 (SEE, 0.247) in the control group (n = 24; 95% CI, –1.37 to 0.03; P = .06).7

Another trial in 2017 that included 54 patients explored lipoic acid as a treatment for cognitive impairment in MS; the results were less promising. The difference between groups on the California Verbal Learning Test-II and the Controlled Oral Word Association Test were not statisticallysignificant.8

Although the evidence is only partially suggestive of a positive effect with lipoic acid, the jury is still out on acetyl-L-carnitine. Evidence to support the use of acetyl-L-carnitine to improve fatigue associated with MS is lacking, and more studies are needed.9 A 2012 literature search of the Cochrane, Medline, and Embase registries returned less-than-encouraging results, with the authors eventually coming to the conclusion, “There is insufficient evidence that carnitine for the treatment of MS-related fatigue offers a therapeutic advantage over placebo or active comparators.”10

Notably, there is some repurposing being done for MS: An ongoing phase 3 trial of amantadine extended-release tablets (NCT03567057) is investigating if this system can be used in a more effective way in MS. Even so, Hughes noted that as an anti- viral agent, amantadine has been used for fatigue in MS for many years. Other than that trial, she said, the pipeline remains relatively empty.

“There are studies that predominantly focused on wellness in MS, so dietary changes and exercise, and trying to promote health from those standpoints,” Hughes explained. “I always say, the better you take care of the machine, the better it’s going to take of you. That’s the direction from which symptomatic management—and I would argue that wellness and disease-modification—is being approached recently.”

Physical therapy and rehabilitation have become popular alternatives in the management of some symptoms. Hughes said that acupuncture and massage therapy have become more popular for pain management. Okai said she sometimes recommends acupuncture for spasticity as well.

“MS is a field where complementary and alternative treatments have really found a focus. I don’t know if I consider physical therapy alternative, but it certainly is complimentary,” Hughes said. “There’s a lot of interest in the use of cannabis and tetrahydrocannabinol. It’s been shown to help pain control and spasticity, and the National MS Society has supported legislation that would make it more accessible for people living with MS, for their symptomatic management.”

In addition, Okai said that although neurocognitive therapy has helped with cognitive challenges, cognitive dysfunction is one of the harder symptoms to treat nonpharmacologically. “Cognitive behavioral therapy is something that we also use to help patients, first, cope with the disease, and we also use management techniques to help them get through whatever they are experiencing,” she said.

Cooperation in the Challenges

Despite the deficiency in research and development for the treatment of MS symptoms, when it comes to addressing the challenges these patients and physicians are facing, both Okai and Hughes agree that cooperation between providers across specialties is key. As is the case for the majority of health care, team-based practices are where treatment strategies are trending.

“In a regular office, whenever you’re treating [a patient with MS], I do advise the physicians that they need a team,” Okai said. “Symptomatic management is important for quality of life, and you need a team that can approach your disease comprehensively. That includes the urologist, the physiatrist, the ophthalmologist, and the psychiatrist. The [patient with MS] needs comprehensive care, so that’s why it’s important they go to a center that will provide them that care.”

For the general physician, however, Okai is less confident in the ability to provide comprehensive care—and rightfully so. These physicians see patients with MS less often, for their MS specifically, and much of their care for MS can be part of a team-based approach. However, although the Consortium of Multiple Sclerosis Centers reports that there are 214 MS centers in the United States, 8 states lack a center altogether and another 10 have only a single center for the entire state.11

“One of the realties is that many people who have MS are underinsured or uninsured. The other challenge is mobility and the logistics of just getting to a care provider as we’ve become more fragmented in locations among specialties,” Hughes said.

Because some states, such as Wyoming and North and South Dakota, are more sparsely populated and have fewer patients, for the patients living in these areas, travel to receive the proper care becomes a challenge.

“One of the challenges in health care is coordination of care. It is always a challenge, and generally, we think about perhaps the primary care physician as being the kind of ringleader in making sure all the different kinds of disease states are being managed,” Hughes explained. “For example, with the patient who has cardiac disease or diabetes, the primary care physician may be the person who’s coordinating the care between the endocrinologist and cardiologist.”

In MS, this is not the case, Hughes added. Outside of the comprehensive centers, taking a multidisciplinary approach is incredibly difficult. As a result, the symptomatic care for those patients is often left to the general neurologist or family physician that they can see on a more regular basis. For those doctors, Okai said she tries her best to help them when she can and to encourage them to get in touch with other specialists and better their understanding of MS.

“If someone doesn’t understand what the patient is going through, it’s very disconcerting and treatment may not be adequate,” Okai said. “It’s always good to encourage the patient to have their team together and also to educate the community physician who isn’t an MS specialist. It’s important to involve these other specialties to manage the patient’s symptoms and improve their quality of life.”

Looking Forward

Ultimately, both Okai and Hughes stressed that the field needs to remember to focus as much on symptom management as it has on disease modification, with an emphasis on comprehensive care. She noted that the emphasis on complete care is of utmost importance to both the provider and the patient.

“For my colleagues, if there is one specific symptom or several symptoms that the patient is experiencing, have the patient see a specialist,” Okai said. “Have the patient follow up with a sleep doctor because a lack of sleep can also exacerbate the symptoms. For urinary symptoms, they can see a urologist. The patient has to understand that their MS requires a comprehensive team, and the physician has to understand that treating MS also requires a comprehensive team with multiple specialties.”

“It cannot be done alone by a neurologist. A team needs to be assembled,” she added.

In the MS arena, it will take time for care teams to become the practice norm in more locations, though. For Hughes, right now, the best that physicians can do is work best with what they have, which may require some creative thinking. The MS field has already begun to do this by trying to repurpose agents and exploring the use of other therapies.

“One of the caveats in medicine is that it’s both a science and an art, and sometimes the science doesn’t take us as far as we’d like it to, and we end up really focusing on the art,” Hughes explained. “We know there is a lot of off-label use of medications, but we need to be thinking about that in a creative way. For example, some of the bladder medicines may be more constipating, but if you have someone who has problems with bowel control, then that constipating adverse effect may actually be a benefit in this patient. It’s looking at patients in kind of a broader sense, and using those skills that [you’ve] developed and honed with other disease conditions and focusing them in the care of people with MS.”

Hughes noted that the important thing for physicians treating MS is to not be nihilistic when it comes to symptom management. She stressed remaining proactive and positive and to continue to take on the challenges that they face with a can-do attitude.

“We owe our patients the willingness to be creative and embrace the challenges and the complexities of their care,” she said. “The outcomes and the benefits of doing so far outweigh many of the challenges along the way.”
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