Linda Peckel

Technological developments over the past decade are now leading to long-awaited advances in the management of Parkinson disease (PD). These tech-driven approaches—including exergaming, virtual reality, and the use of wearable devices—have not only helped improve rehabilitation but may also provide more accurate measures of therapeutic efficacy for new treatments undergoing clinical trials.

The role of virtual reality and exergaming in PD physiotherapy

Virtual reality has been used to drive purposeful, targeted exercise therapy for a number of progressive disorders affecting muscular function, including traumatic brain injury, cerebral palsy, stroke, and PD.

 Virtual reality–based games are available on widely available gaming systems and have demonstrated specific benefits for improving balance, gait, functional mobility, and overall quality of life for individuals with PD.

 Results of a recent study from Brazil showed that the weekly addition of Nintendo Wii exercises significantly magnified the therapeutic effects of conventional exercise therapy alone.

Exergaming, virtual reality, augmented reality, and their variants come in many shapes and sizes, said Jeffrey Hausdorff, PhD, director at the Center for the Study of Movement, Cognition, and Mobility at the Neurology Institute at the Sourasky Medical Center in Tel Aviv, Israel, who has been involved in many of the trials of digital technologies for PD. “In general, interventions based on these technologies can be very helpful as ways of enhancing and augmenting the impact of other, more conventional behavioral interventions for Parkinson disease. Engaging ‘games’ can heighten motivation and increase [adherence]; this in turn leads to a stronger impact of the therapy. They can also provide specific aspects of therapy that may be difficult to deliver otherwise,” he told 

In one multicenter, randomized, controlled study (RCT) designed to examine the added value of a relatively simple virtual reality system, Hausdorff explained that subjects walk on a treadmill with a screen attached to it that allows them to envision themselves walking through an environment with obstacles and challenging conditions where they have to learn implicitly, in a game-like fashion, how to walk and do other things at the same time, including dual tasks such as motor and cognitive challenges.

 In another study that included older adults as well as patients with PD, Hausdorff and colleagues found a significant reduction in falls among the participants who trained with a treadmill and virtual reality system compared with an active control group who performed treadmill training alone.

 “With this type of system, we can target certain aspects of cognitive function that are important to daily walking and cannot be targeted with treadmill training alone,” he said.

Managing progression in Parkinson disease

Long-term management of PD presents many clinical challenges as the status of the patient deteriorates over time. “In the early phases of the disease, typically patients respond well to pharmacotherapies,” explained Paolo Bonato, PhD, director of the Motion Analysis Laboratory at Spaulding Rehabilitation Hospital in Boston, Massachusetts, “but unfortunately, as the disease progresses, it 

becomes more difficult to control their symptoms.” Patients often report experiencing a roller coaster of parkinsonian symptoms, recognized clinically as motor fluctuations. Bradykinesia might respond well to treatment, but patients might experience severe dyskinesia as a result.

“A significant portion of patients with Parkinson disease experience motor fluctuations, meaning their symptoms are not constant over time,” Bonato said. The severity of dyskinesia often varies within the interval between medication intakes; patients might experience episodes within the first hour of taking their medication (onset dyskinesia), at the peak of the medication’s effects, or at the end, as the effects are wearing off. These symptoms are quite disruptive to their ability to perform activities of daily living, Bonato noted, and they are a significant focus of clinical attention during the later years of the disease.

Although levodopa-induced dyskinesia is a common complication in PD, recent research indicates that dyskinesias develop as a function of disease duration rather than accumulation of levodopa. This has led to recommendations to initiate levodopa therapy without delay early in the disease course, but the problem with motor fluctuations remains once the disease progresses.

Bonato observed that as neurologists titrate the patients’ medications to better manage their symptoms, a major challenge is that patients do not have an objective perception of their motor status, in part because of the cognitive effects of their disease. Patients are simply not able to report reliably on the effects of changes in the medication regimen. But more than that, Bonato pointed out that proper assessment of the severity of symptoms is very challenging, even to clinicians. “In fact, clinical researchers undergo training to administer the MDS-UPDRS [International Parkinson and Movement Disorder Society Parkinson’s disease rating scale], which is the clinical scale to assess the severity of parkinsonian symptoms that is most commonly used,” he said. 

Wearable technology has been able to detect fluctuations occurring in increments of as little as 5 minutes compared with 

patient-reported symptoms in diaries, which monitor changes at only 30-minute intervals at best, according to Bonato, who plans to publish these data soon.

"We used to think that walking was primarily a motor ability that required intact muscle and skeletal function and sensory function for feedback. Those abilities are certainly critical components of safe ambulation. However, there’s a key ingredient that’s missing in that view, and that’s cognitive function," Hausdorff stated. 

Falling is a complex type of dysfunction that involves multiple aspects of cognition. “Safe ambulation also involves executive function, a set of higher-level cognitive functions that include the ability to walk and multitask and the ability to plan and adapt to one’s environment,” Hausdorff explained. “We used to think that walking was primarily a motor ability that required intact muscle and skeletal function and sensory function for feedback,” he said. “Those abilities are certainly critical components of safe ambulation. However, there’s a key ingredient that’s missing in that view, and that’s cognitive function.”

Some of his studies looked at the role of cognition in helping the patient maintain attention to tasks of mobility.

 “The virtual reality technology that we evaluated in the RCT mirrors many real-world walking situations, such as walking outdoors, which requires being able to do multiple things while walking, such as listening to head- sets, talking to companions, thinking about what we’re going to be doing next, and negotiating obstacles. If you just walk on a treadmill alone without that added virtual reality component, it’s training just for the motor part while not focusing at all on the cognitive aspects of walking that are needed for safe ambulation,” Hausdorff said.

Freezing gait is a significant problem in advanced PD, in which motion advancement is very small or does not occur at all. Results of recent studies have indicated that freezing is not limited to gait but can also significantly hinder upper limb movements and speech.

 Digital technologies have been extensively studied as cueing modalities to recover attention to specific motor tasks, to rescue the patient from a freezing episode.

Hausdorff and Alice Nieuwboer, PhD, of the University of Leuven in Belgium, are currently collaborating on a study funded by the Michael J. Fox Foundation for Parkinson’s Research designed to detect a freezing event. In this study, subjects wear a sensor on their shoes that measures the movement of their feet and any freezing events as they conduct their daily activities. The sensor’s information is wirelessly transmitted to a smartphone that measures walking in real time. The system is designed to detect when a freezing event occurs and then give a cue back to the user, helping the user to quickly become free from the event. “In the future, it’s hoped that it will also be able to warn of a freezing event before it occurs to further ameliorate the problem,” Hausdorff said.

One of the unique aspects of this study is that all the assessments are conducted in the patient’s home and the intervention takes place throughout the day, wherever and whenever the patient walks. “Testing and treating in the home is especially advantageous at this time, when it is often increasingly difficult for people to make their way to a clinic or hospital,” Hausdorff said.

A primary obstacle to many clinical trials of the 1980s and 1990s that may have contributed to negative results, according to Bonato, was the inaccuracy of the self-reported data being collected from patients. He and colleagues

 published a study early in 2020 that made a strong case for the use of wearable technologies to replace patient diaries in making treatment decisions as well as in clinical trials.

"There are 2 problems with the use of patient diaries,” Bonato stated. “The first and more obvious one is that patients display poor [adherence] with the use of diaries. We know that because we track when patients log on to fill out electronic diaries, and hence we know that they are not doing that on a regular basis. The second and perhaps even more important issue is that we have discovered that motor fluctuations evolve more rapidly than we originally thought. Therefore, gathering data at intervals of 30 minutes, as we do by using patient diaries, is not enough to properly capture the characteristics of the motor fluctuations that patients experience.”

Because clinical trials have relied heavily on patient diaries as measurements for outcomes, this new finding is highly significant. Bonato observed that pharmaceutical companies have started wondering whether the negative results of past clinical trials were the by-product of not having access to the right technology to capture the effects of medications on motor fluctuations. “I anticipate that the large body of work in this area will result in important advances in the field and better treatments for patients with Parkinson disease,” he added.

A multinational task force on technology from the MDS convened in 2018 to produce a set of objectives for the use of digital technologies to obtain more usable data to inform treatment decisions.

 They reported that development of mobile digital devices has reached sufficient levels of “sophistication, versatility, and wearability” to warrant recommending their implementation in routine care for patients with PD.

 With different technologies offering opportunities to improve quality of life and outcomes for patients as they begin to develop advanced symptoms, these tools are increasingly being recognized as necessary supportive therapies over the long term.

"Clinicians, researchers, and pharmaceutical companies are very interested in using wearable technology,” Bonato said. “Clinicians are hoping that this technology may lead to significant improvements in the clinical management of symptoms experienced by patients, and researchers are adopting the technology to collect more reliable data and hence improve their ability to study the effects of new therapies.”

1. Barry G, Galna B, Rochester L. The role of exergaming in Parkinson’s disease rehabilitation: a systematic review of the evidence. J Neuroeng Rehabil. 2014;11:33. doi:10.1186/1743-0003-11-33.

2. Santos P, Machado T, Santos L, Ribeiro N, Melo A. Efficacy of the Nintendo Wii combination with conven- tional exercises in the rehabilitation of individuals with Parkinson’s disease: a randomized clinical trial. NeuroRehabilitation. 2019;45(2):255-263. doi:10.3233/NRE-192771

3. Garcia-Agundez A, Folkerts AK, Konrad R, et al. Recent advances in rehabilitation for Parkinson’s disease with exergames: a systematic review. J Neuroeng Rehabil. 2019;16(1):17. doi:10.1186/s12984-019-0492-1

4. Mirelman A, Maidan I, Herman T, Deutsch JE, Giladi N, Hausdorff JM. Virtual reality for gait training: can it induce motor learning to enhance complex walking and reduce fall risk in patients with Parkinson’s disease? J Gerontol A Biol Sci Med Sci. 2011;66(2):234-240. doi:10.1093/gerona/glq201

5. Mirelman A, Rochester L, Reelick M, et al. V-TIME: a treadmill training program augmented by virtual reality to decrease fall risk in older adults: study design of a randomized controlled trial. BMC Neurol. 2013;13:15. doi:10.1186/1471-2377-13-15

6. Espay AJ, Morgante F, Merola A, et al. Levodopa-induced dyskinesia in Parkinson disease: current and evolving concepts. Ann Neurol. 2018;84(6):797-811. doi:10.1002/ana.25364

7. Maidan I, Nieuwhof F, Bernad-Elazari H, et al. Evidence for differential effects of 2 forms of exer- cise on prefrontal plasticity during walking in Parkinson’s disease. Neurorehabil Neural Repair. 2018;32(3):200-208. doi:10.1177/1545968318763750

8. Ginis P, Nackaerts E, Nieuwboer A, Heremans E. Cueing for people with Parkinson’s disease with freezing of gait: a narrative review of the state-of-the-art and novel perspectives. Ann Phys Rehabil Med. 2018;61(6):407-413. doi:10.1016/j.rehab.2017.08.002

9. Erb MK, Karlin DR, Ho BK, et al. mHealth and wearable technology should replace motor diaries to track motor fluctuations in Parkinson’s disease. NPJ Digit Med. 2020;3:6. doi:10.1038/s41746-019-0214-x

10. Espay AJ, Hausdorff JM, Sánchez-Ferro Á, et al. A roadmap for implementation of patient-centered digital outcome measures in Parkinson’s disease obtained using mobile health technologies. Mov Disord. 2019;34(5):657-663. doi:10.1002/mds.27671

Articles

Advances in wearables and virtual reality present an opportunity to maximize rehabilitative efforts and improve outcomes.

The Technology Behind Optimizing Parkinson Disease Management

Developments in stroke care over the past decade have significantly altered outcomes for patients with stroke thanks to the efficacy of clot-busting drugs such as tissue plasminogen activator (tPA) and thrombectomy procedures to remove large clots. The key factor in preventing stroke mortality and disability is time, as every minute without blood flow irrevocably damages brain tissue. As a result, some of the biggest developments in stroke management have focused on logistical strategies to reduce the time between stroke onset and point of care, from the ambulance call to the emergency department bay.

Despite this, much debate exists over how to appropriately route patients with suspected large vessel occlusion (LVO) stroke to hospitals capable of thrombectomy interventions. Many factors play into this challenge, as it involves a major shift in systems of care. Advancements in prehospital prediction of LVO, impact on clinical outcomes, state regulations, and barriers to reimbursement are all major parts of the puzzle that can make or break the adoption of these lifesaving systems.

Many hospitals are now outfitting mobile stroke units (MSUs) with special equipment and trained health care personnel to initiate stroke treatment at the point of pickup.

 In an interview with NeurologyLive®, Andrew N. Russman, DO, head of the Stroke Program and medical director of the Comprehensive Stroke Center at Cleveland Clinic in Ohio, explained that for lack of better words, MSUs are ambulances on steroids. “The 4-person crew includes a CT technologist, a nurse, a paramedic, and an [emergency medical technician]. They have 2-way audio-visual communications with a stroke neurologist and the ability to deliver clot-busting drugs in the field. They have CT scanners and laboratory testing, which brings many of the capabilities of an emergency [department] to the patient’s doorstep. We perform prehospital stroke severity assessments to determine the right hospital to take the patient to for further care.”

Russman pointed to 2 recent abstracts presented at the 2019 American Academy of Neurology Annual Meeting and the 2020 International Stroke Conference that demonstrated that mobile stroke care is associated with reduced time to treatment and possibly better outcomes.

 With the ability to administer tPA upon arrival at the patient’s doorstep, MSUs effectively reduce stroke treatment times without additional risk of adverse events. At the same time, the MSU team can evaluate the stroke severity to determine the presence of an LVO requiring thrombectomy (TABLE).

“We already know that retrieval of the clot is associated with a very significant improvement. If you look at emergent medical treatments in general, thrombectomy of large vessel occlusion in stroke is one of the most beneficial emergent therapies in medicine. It’s comparable to what angioplasty of a coronary artery does for a patient with ST-elevation myocardial infarction,” Russman said, adding that not only do MSUs reduce “the transport time, but they are incredibly efficient compared with traditional emergency departments. They can usually deliver intravenous tPA 30 to 40 minutes faster than a patient could get it if they were transported to an emergency department.”

James C. Grotta, MD, is director of stroke research and the mobile stroke unit consortium at Memorial Hermann-Texas Medical Center in Houston, which covers about 75% of the entire city. “Although we have a catchment area of about an 8-mile radius, we monitor the fire department radio. If there’s a stroke that occurs 20 miles away, we take advantage of a rendezvous system more than other cities do,” he told NeurologyLive®.

“We monitor 911 calls and contact the fire depart- ment medic if we think the patient might be a candidate for the mobile stroke unit. Then we’ll rendezvous with the ambulance halfway to their destination hospital. The inclusion of rendez- vous calls expands our treatment radius to an average of 13 miles.”

Grotta and his colleagues at Memorial Hermann are currently conducting an MSU randomized trial. Every patient they transport is automatically enrolled into the trial. Follow-up data on all patients are collected after they get to the hospital and for a full year thereafter. “That means we can deliver patients to hospitals only where we can obtain a research agreement, usually by being on the staff,” Grotta explained. Although the city is home to several competing health care systems, including Houston Methodist, Baylor St. Luke’s Medical Center, Harris County Public Health, and the Hospital Corp of America Houston Healthcare, the Houston MSU program has been able to work out agreements with all of them and their hospitals.

“Every time we transport a patient, we’re out of service for another call, so if we know that a patient will not fit into the trial, we don’t respond to the call, and the patient is transported by the fire department per their routine,” Grotta explained. “The Houston MSU rotates between 2 sites within the city on a weekly basis.

The week the MSU is in operation on one site, patients within the catchment of the other site are managed by the fire department, per their standard management, and are enrolled into the trial as the control group.” Trial enrollment will be complete when they reach 1038 patients, which is expected soon.

The main limitations of MSUs are the extensive costs to equip and maintain them. For instance, the New York metropolitan area has MSUs at Stony Brook University Hospital in Long Island, at NewYork-Presbyterian Hospital in Manhattan, and 2 others in Brooklyn and Queens; New Jersey has one in Trenton, and Pennsylvania has another in suburban Philadelphia. Connecticut does not have any. “It is very expensive to operate an MSU, and currently, it’s not fully reimbursable,” Grotta said. “And while we believe in the value of the MSU to stroke care, it hasn’t been proved yet. If our study can show that, it would open the door to appropriate reimbursement, which would facilitate establishing more of them.”

The MSU becomes a critical factor in determining which patients should be taken directly to comprehensive stroke centers with endovascular thrombectomy (EVT) capabilities. These interventional treatments have been in use for decades, but only in the past 4 years have study results shown benefits up to 24 hours after symptom onset, Russman said. “You have to be able to figure out in the field that they might have a large vessel occlusion. Mobile stroke care takes this to another level because we can deliver the clot-busting medicine at the scene and deliver the patient to the right hospital the first time,” he said.

This is where hospital bypass becomes important. When patients have a significant blockage, emergency medical services (EMS) takes them directly to an EVT center, often driving past a closer hospital that does not have EVT capabilities, Russman said. “Identifying this need in the MSU spares the patient from being transferred to a second hospital, which causes a significant time delay,” he added (FIGURE).

The latest policy statements from the American Heart Association

 suggest that EMS should drive an extra 15 minutes to get to an EVT-capable center for patients who have prehos- pital stroke severity scale scores suggestive of LVO. “Time is brain, so for every minute the brain goes without blood flow, 1.9 million neurons are dying,” Russman said. “If you are having a severe stroke and live in a community that doesn’t have a stroke center with thrombectomy capability, then EMS should bypass the closest hospital to get you directly to the hospital that does have thrombectomy capability, as long as you don’t have to drive more than 15 minutes extra, according to the current recommendations. That time you’re saving—15 to 30 minutes or more&mdash; means reduced disability for the patient.”

The bypass model significantly reduces time to thrombectomy for patients with the most severe strokes. A large study of 1941 US stroke centers

 found that 713 (37%) had EVT capabilities, which an estimated 61 million (19.8%) Americans could access within 15 minutes. Extending the time frame to 30 minutes meant access for 95 million (30.9%) individuals. This varied by state. In Texas, an estimated 22% of the state’s population lives within 15 minutes of the 65 existing EVT centers. Rates in New York were 20.9%; in California, 25.5%; and in Illinois, 15.3%.

 supported these data, demonstrating that following prehospital assessment by EMS of a suggested LVO and appropriately bypassing to hospitals within this 15-minute margin for thrombectomy increased EVT access to millions of people.

Grotta pointed out that “the problem with bypass is that most ambulances do not have CT scanners that the MSUs have. Without an [MSU], you have to rely on the medic’s judgment, and using imprecise grading scales in the hands of medics is not all that reliable and will miss LVOs.” Although taking a patient who does not need EVT to a comprehensive stroke center is not efficient, he noted, it is a better alternative than missing patients who do need it. The added benefit is that for patients who do not have CT evidence of an LVO, the trained team in the MSU can immediately begin tPA treatment en route to the primary stroke center.

The decision to bypass rests on a balance of 2 factors: time versus the probability of an LVO, according to Grotta. “Within Houston, almost all hospitals are comprehensive stroke centers, so for us, bypass is not a big issue. In more rural or suburban areas, the MSU staff will have to weigh the evidence of an LVO against the time it will take to get to an EVT stroke center,” he said. This represents the crux of the current debate over MSUs, as the average ambulance team is simply not equipped to make these decisions. On a standard EMS call, in settings where an EVT-capable hospital is farther away than a local primary stroke center, EMS will often take the patient to the closer hospital first for an evaluation, only to have the patient transported again for thrombectomy. “In our MSU, we do a CT angiography for anybody we suspect of having a larger artery stroke. If it shows that the patient has an LVO, we take them directly to an endovascular center. It doesn’t matter how far it is,” Grotta said. “In reality, about 80% of the US population lives in urban areas, so bypass does not really present as much of an issue in metropolitan areas.”

Should More Hospitals Become EVT Capable?

Although certain urban areas are successfully implementing MSUs and bypass, health providers must modify their use in each community to meet the specific demands of the population. Geography, topography, state regulations, and political climate all contribute to the type of systems that are needed to succeed.

The models suggest 2 main solutions: to expand availability of MSUs or convert more hospitals into EVT stroke centers. The current distribution of thrombectomy-ready hospitals would suggest that conversion, or “flipping,” of standard non-EVT stroke centers to ones that are EVT capable would solve the problem. However, this comes at a sacrifice to other types of care and with high costs that have to be justified by need within a community. The Sarraj study

 reported that almost one-fifth of Americans have direct access to EVT centers. Their predictive model estimated that nationwide, flipping the top 10% non-EVT centers to EVT-capable ones in all states would result in an increase of 7.5% in 15-minute direct access. This was less than half of the gain in coverage of 16.7% achieved by bypassing non-EVT centers for existing thrombectomy centers by 15 minutes.

For the most part, MSUs have not been evaluated in rural areas and might present a time solution there. “Generally, if you know that it’s an LVO, it’s better to just travel to a thrombectomy center than to turn more hospitals into them,” Grotta said. “Through rendezvous with EMS units farther out, the MSU would end up getting the patient treated with tPA halfway to the stroke center, saving half the time of the long drive; but all of this is modeling. It needs to be proved in real-world settings.”

Everything boils down to getting the right patient to the right treat- ment in the shortest amount of time. As studies evaluate the benefits of MSUs, states and communities also need to consider whether building more stroke centers with thrombectomy capability makes more sense than rerouting more patients to the centers that already exist.

The policies for a given region need to be more clearly exam- ined and identified, Russman suggested. “Bypassing one hospital for another has a lot of political and financial ramifications, which is why states have to lay down EMS triage, transfer, and destination protocols. You have to have the right system to bypass hospitals, taking into account time and distance factors to get to the hospital, with the capability that you need. Most states do not require that stroke severity scale scores be factored into the destination decision, nor do they provide directions to EMS agencies that hospital bypass is needed to get the right patient to the right hospital the first time,” he said.

Grotta agreed. “Everybody is looking at these questions, and there are no 1-size-fits-all solutions,” he said. “If we were to recommend a strategy within a dense metropolitan area, it would be to bring everybody to the comprehensive stroke center. But the right fit definitely reflects geographic and population differences.” Using the example of Connecticut, which has several large cities surrounded by suburban and rural populations and no MSUs, he suggested, “If you’re in an area that’s busy enough that patients are being bypassed to Hartford and New Haven all the time, then you might be better having physicians in your area learn to do thrombectomy because they might have enough local cases, and then it would be better to convert the hospital to an EVT center.”

Ultimately, Russman and Grotta concluded that each county in each state should make its own determinations of what is best for their populations. The current studies under way will help point the direction to building systems that function best in each area. 

1. Yamal JM, Rajan SS, Parker SA, et al. Benefits of stroke treatment delivered using a mobile stroke unit trial. 

 2018;13(3):321-327. doi:10.1177/1747493017711950. Published correction appears in Int J Stroke. 2018;13(3):NP4. doi:10.1177/1747493017743617

2. Russman A, Shimbo D, Sheikhi S, et al. Clinical outcomes after pre-hospital thrombolysis on a mobile stroke unit. 

3. Ebinger M, Siegerink B, Kunz A, et al. Effects of pre-hospital acute stroke treatment as measured with modified Rankin scale; the Berlin — Prehospital Or Usual Care Delivery (B_PROUD) trial. Presented at: 2020 International Stroke Conference; February 19-21, 2020; Los Angeles, CA. Abstract LB2. Accessed May 1, 2020. https://www.abstractsonline.com/pp8/#!/7927/presentation/5405

4. Ehntholt MS, Parasram M, Mir SA, Lerario MP. Mobile stroke units: bringing treatment to the patient.

. 2020;22(2):5. doi:10.1007/s11940-020-0611-0

5. Thrombectomy-capable stroke center certification. The Joint Commission. Accessed May 1, 2020. https://www.jointcommission.org/accreditation-and-certification/certification/ certifications-by-setting/hospital-certifications/stroke-certification/advanced-stroke/ thrombectomy-capable-stroke-center/

6. Sarraj A, Savitz S, Pujara D, et al. Endovascular thrombectomy for acute ischemic strokes: current US access paradigms and optimization methodology. 

. 2020;51:1207-1217. doi:10.1161/STROKEAHA.120.028850 

The “time is brain” mantra continues to drive innovation in a specialty that will not settle for mediocrity.

Improving Stroke Systems of Care for Better Outcomes

Treatment of multiple sclerosis (MS) has reached a new milestone, in which discontinuation of therapy for some patients may be possible. This is a unique therapeutic situation, a crossroads of the benefits of long-term treatment with disease-modifying therapies (DMTs) in preventing progression of disability and a point when the disease course naturally wanes. In theory, if patients with MS can maintain function long enough, they will outlive the active period of the disease and no longer need therapy.

Since their introduction in the 1990s, DMTs have demonstrated significant efficacy in reducing the incidence of relapses and the appearance of new T2 lesions indicative of disease activity in MS, as well as the capacity to slow progression of disability.

 Perhaps one of the most significant clinical realizations recently is that DMTs are most effective in slowing progression of MS when they are initiated in the disease’s earliest preclinical stages, at the first sign of clinically isolated syndrome.

 Results of research have shown that aggressive treatment at the time of the first attack with drugs such as interferon beta, glatiramer acetate, and terifluno-mide can delay conversion to clinically definite MS and lead to a milder course of disease that preserves patient function longer.

The notion of being able to “retire” from a costly, long-term therapy associated with adverse effects and the risk of life-threatening infections holds great appeal to many patients who have for decades faced the effects of MS and its treatments. “It’s all rooted in the idea that the window of opportunity for most effectively treating MS is early on in the disease,” Robert Bermel, MD, director of the Mellen Center for Multiple Sclerosis at Cleveland Clinic in Ohio, told NeurologyLive®. “Additionally, there’s been some research showing that not only are the DMTs less effective the older people are, but the disease is less active the older people are.” Taken together, he said, these factors suggest that continued lifelong therapy may not be necessary or even bene-ficial, but determining which patients will remain disease free after discontinuation has been a major obstacle to implementing a general plan for stopping MS treatment.

As the efficacy of DMTs has allowed patients to achieve and main-tain very low levels of disease activity, the question of whether these benefits would continue even with cessation of drug therapy has become increasingly relevant. According to Tanuja Chitnis, MD, an MS neurologist at Brigham and Women’s Hospital and Massachusetts General Hospital, and professor of neurology at Harvard Medical School, both in Boston, Massachusetts, “We’re entering an era where we have more patients who have been on DMTs long term and have been doing well, so we have a unique situation now.” Unfortunately, previous studies of interruption of DMTs focused on patients with ongoing disease activity who were nonadherent or who could not tolerate their therapies at earlier disease stages. Data on the outcomes after deliberate, medically endorsed discontinuation of DMTs in patients with stable disease are still largely lacking.

Bermel and his colleagues at Cleveland Clinic have been increasingly introducing patients who have been on long-term therapy to the concept of discontinuation. “We do believe that at some point, it’s appropriate to consider discontinuing DMT. We usually require that the person [has] been stable for 5 years or more, with no relapses and no new MRI [magnetic resonance imaging] activity,” he said. 

Chitnis, who is also the director of the Partners Pediatric MS Center at Massachusetts General Hospital for Children in Boston, takes a more conservative approach—at least for now. “There were some early studies, including ours,

 that suggested that there might be some patients for whom it might be safe to discontinue treatments,” she told NeurologyLive®, “but I think we are finding now in our further work, as we and others are looking into our cohorts of patients who have discontinued, that some patients continue to have disease activity. So I think we need to have better indicators, such as maybe biomarkers or biological mechanisms, to identify who might be safely discontinued.”

Early treatment with DMTs significantly modifies the natural course of MS. Tobin and Weinshenker

 noted “prolonged periods of disease quiescence during long term treatment of patients with clinically isolated syndrome,” suggesting the opportunity for discontinuing DMTs in these patients. However, the risks of relapse and accumulating disability associated with premature discontinuation of therapy were too high to ignore.

 This illuminated the second challenge, that if patients might indeed no longer need therapy for active MS, at what age could they safely discontinue treatment without reactivating disease?

The answer is not yet apparent. Chitnis was coauthor of a 2019 study by Yano et al

 that found a similar clinical course after 2 years among patients with relapsing-remitting MS who discontinued treatment compared with those who remained on therapy. This pattern was consistent across measures of clinical relapse, MRI event, disability progression, and disease activity, although the results varied by age at the time of discontinuation. “Older subjects (age >45) had a better disease course after discontinuation in terms of risk of MRI event and disease activity, while younger subjects (age ≤45) were more likely to experience disease activity after treat-ment cessation,”

 the authors reported. Likewise, Kister et al

 found that although relapse rates were equivalent between patients with MS (age >18) who discontinued first-line DMTs and with those who continued, time to disability progression was shorter following discontinuation.

Although these studies did not look specifically at outcomes in older patients who discontinued treatment, they did suggest that cessation at a late stage of MS was less likely to result in relapse or renewed activity on MRI. Supporting this, a 2019 investigation by Hua et al

 found that stopping DMTs in patients with MS over age 60 had only a minimal effect on outcomes, yet quality of life (QoL) was reduced. Studies suggest that older patients make better candidates for cessation because they have a more stable course of disease, whereas younger patients are more likely to discontinue therapy on their own.

 Bermel observed that as a result, the strategy of discontinuing DMTs after a certain age is becoming more common. 

"We do believe that at some point, it's appropriate to consider discontinuing DMT. We usually require that the person [has] been stable for 5 years or more, with no relapses and no new MRI activity," Bermel said.

Bermel and Chitnis both observe similar guidelines for discon-tinuation as those outlined by Tobin and Weinshenker,

 who determined, “It may be reasonable to stop immunomodulatory medications in patients who have experienced a progressive disease course for 5 years or longer, particularly those who are over the age of 60 years, if there are no accumulating T2 lesions or gadolinium enhancing lesions on MRI brain or spinal cord after a period of observation of several years. Earlier discontinuation, particularly in patients with active disease, may lead to increased disease activity, especially in patients treated with natalizumab. Clinical and MRI monitoring for recurrent disease activity is warranted in those discontinuing treatment.”

Continuation of immunomodulating therapy in older patients is associated with increased risk of infection and a higher susceptibility to malignancy, as well as a greater potential for drug inter-actions.

 Because it is now common for patients to have been on DMTs for decades, concerns are growing over the adverse effects of these powerful drugs. Adverse events range from non—life-threatening events such as flulike symptoms and local injection site reactions to dangerous infections like progressive multifocal leuko-encephalopathy associated with several DMTs.

"The primary risk to discontinuing is that the patient would have a relapse that would otherwise have been prevented, but we think we can minimize that risk by selecting patients who have been stable for 5 or more years and also who are above age 60, when the immune system becomes more senescent and they are less prone to disease activity,” Bermel said. “The other reason to consider stopping DMTs is [adverse] effects. Interferon is one of the medica-tions that may be worsening spasticity or depression that can make the patient’s quality of life worse, and in that setting, we definitely want to think about at least switching, if not stopping, DMTs.”

Chitnis agreed with the idea of switching therapies. Deciding not to discontinue does not necessarily mean that patients continue on the same therapy, she said. “I think there’s also the concept with older age of immunosenescence, and patients may not need to be on a stronger DMT, as there’s a lesser likelihood of relapse or developing new lesions, which presents an opportunity to either discontinue or step down to a milder therapy,” she said. “That is something I am increasingly considering doing. As patients who are on very high-efficacy treatments are nearing 50 or 60, I start to have the conversation about paring down to something that is milder. Although there are fewer relapses in older age, we know that patients do progress, and there might be benefits to a different profile of DMTs.”

As their base of patients with MS on aggressive drug therapies grows older, clinicians have been weighing the idea of discontinuing DMTs without reaching any definitive conclusions. Chitnis reserved judgment on whether DMT discontinuation is warranted. “I rarely discontinue patients,” she said, noting that they some-times bring up the idea of discontinuing because they might have seen an article on the topic. She will also discuss it with patients over 60, by letting them know this is something being studied and considered. “There are some I will discontinue, if I think based on the literature that they might be a good candidate, especially if they are having difficulty with their disease-modifying treatment, but usually at an older age above 60, at about 70,” she added.

Currently, no protocol exists for how or when to discontinue DMTs. The decision comes down to patient preference and clinical judgment. And although most patients are likely to look forward to not having to take medication (especially by injection) for the rest of their lives, Bermel has had some patients who prefer to remain on treatment, even in the absence of disease activity on MRI. “People who are stable on medication sometimes attribute that to being on the medication, and they’re not comfortable making a change. They feel protected and choose to stay on to avoid risk of relapse,” he said. “The only time we truly object to that is if the patient is having infectious complications or [adverse] effects of the drug, where I feel they would benefit by going off. But if the patient is tolerating it well, it’s perfectly fine for them to continue.”

Bermel reported that Cleveland Clinic has been successfully discontinuing DMTs in older patients in routine clinical practice for at least the past 5 years. “Discontinuation is not for everyone,” he said, “and it’s not across the board but in patients who have been very stable for 5 years or more, and where we consider the risk of the disease activity returning is low, we certainly consider it and may suggest that people discontinue after the age of 60.”

As the treatment of multiple sclerosis continues to evolve and improve, the proposition of lifetime therapy has come under scrutiny.

The Great Debate: Can Older Patients With MS Discontinue Therapy?

New preventative therapies for migraine have been anxiously awaited. Although acute treatments such as triptans have been available since the early 1990s, their use is limited by contrain- dications, side effects, and a lack of efficacy for some patients. At the same time, preventive treatments for migraine are not universally successful, and many patients drop these therapies because of side effects.

In the United States, adherence to oral preventive therapies for migraine is low among patients with chronic migraine (CM) and worsens over time.

 A large retrospective study of 8688 patients with CM found adherence rates of 26% to 29% at 6 months, which diminished to 17% to 20% at 12 months (FIGURE).

 “If you look historically at why patients didn’t continue with migraine medications they were prescribed, there are number of reasons,” Amaal J. Starling, MD, assistant professor of neurology and consultant in the department of neurology at the Mayo Clinic in Phoenix, Arizona, told 

®. “One was lack of efficacy and another was [adverse] effects, but a third reason was that they didn’t want to be on an antidepressant or an antiseizure medication.”

Recommendations for oral preventive therapies for migraine are currently limited to only a few drugs that show good clinical evidence of efficacy. According to Richard Lipton, MD, the Edwin S. Lowe professor and vice chair of neurology, professor of epidemiology and population health, and of psychiatry and behavioral sciences at the Albert Einstein College of Medicine, and director of the Montefiore Headache Center in New York, New York, it is standard practice to offer oral generic treatments first to patients in need of prevention, including β-blockers (propran- olol and timolol), antiepileptic drugs (topiramate and divalproex sodium), candesartan, memantine and riboflavin, among other medications. “For chronic migraine, onabotulinumtoxin A is very helpful,” he added. “If 2 or more of these agents fail, monoclonal antibodies become an important option.” Preventive therapy, however, should not substitute for acute treatment of migraine. In the CAMEO study,

 which Lipton coauthored, patients who halted their acute treatment to start preventive therapy, stopped on recom- mendations from their physician, or due to financial issues, all repre- sented a high level of unmet need, he said.

 showed that a perceived lack of efficacy of preventive medications, combined with significant adverse effects (AEs), contributed substantially to low adherence rates, even among patients with CM (>15 days per month). The authors found this surprising, as the increased frequency of migraine would have been expected to make patients more willing to take a daily pill than those with more occasional episodes.

However, the relevancy of those findings is quickly fading, as in less than 2 years, several new drugs have emerged for migraine prevention and acute treatment that address both the efficacy and tolerability concerns patients have had regarding previous therapies.

 “Preventive care for patients with migraine has changed drastically since the middle of 2018, where we have the development of multiple preventive therapies for migraine and others in the pipeline,” Starling said. “Since May of 2018, we have had 3 new CGRP [calcitonin gene-related peptides] monoclonal antibodies approved by the FDA [for migraine prevention], including erenumab, galcane- zumab, and fremanezumab, which are clinically available, and 1 that is currently undergoing active approval, eptinezumab.” Most recently, the FDA approved the first anti-CGRP in the gepant class, ubrogepant (Ubrelvy; Allergan), for acute relief.

Anti-CGRP Therapy for Migraine Prevention and Relief

CRGPs are the most abundant neuropeptides found in the trigeminal system, and they are widely distributed throughout the body, where they serve many functions related to migraine pathophysiology.

Two types of agents with the ability to block the function of CRGP are currently clinically available and in continual develop- ment, including large-molecule monoclonal antibodies (MAbs) used preventively and small-molecule gepants for both acute relief and prevention.

 Treatments that target the CGRP system have demonstrated a much higher efficacy than other therapies that are less specific.

 Lipton explained that “treatment starts with a maximally preventive dose. This improves adherence by avoiding complex dose escalation.” Whereas oral generic preventive medications are often discontinued due to side effects, he noted that MAbs have few side effects and show favorable adherence, and because treatment is given only once monthly or quarterly, “it reduces the opportunity to miss doses taken on a daily basis or more than once a day,” he said.

CGRP mAbs are large proteins that have been genetically engineered to not have any effect on the immune system, Starling explained, “and they are highly specific for either the CGRP molecule or CGRP receptor.” Fremanezumab, galcanezumab, and eptinezumab all target the CGRP ligand, whereas erenumab targets the CGRP receptor.

Novel CRGP mAbs offer multiple advantages to migraine prevention therapy that can be expected to improve adherence, including improvements in efficacy, tolerability, and dosing, with a significantly reduced AE profile. Because CGRP antibodies are not metabolized in the liver or kidney, dosing frequency can be significantly extended to 30 to 90 days, representing a major benefit overcurrent preventive therapies. “Prior to the anti-CGRP drugs coming out, most of our migraine preventive treatments required daily oral dosing, so patients had to remember to take their medications,” said Mia Minen, MD, MPH, assistant professor of neurology and population health, chief of headache research, and director of headache services at NYU Langone Health in New York, New York. “Some patients also say that they don’t like having to take something daily because it is a constant reminder that they have a debilitating chronic condition. The anti-CGRP drugs can be administered less often, which may improve compliance,” she added.

Results from the CAMEO study reported in 2019 stated that the main reasons for discontinuing standard migraine prevention therapies were switching to an over the counter therapy (45.5%), perceived lack of efficacy (28.2%), and safety/tolerability concerns (24.9%).

 “Unfortunately, with the treatment options that we had available before, because they were not disease specific, they had multiple different contraindications, as well as side effects that patients would experience,” Starling said. “These CGRP monoclonal antibodies seem to be very well tolerated by the majority of our patients, and the AE profile is so much better than with the prior medications we had in the past.”

The anti-CGRP medications also expand the range of patients who respond, according to Jessica Ailani, MD, FAHS, FAAN, director of the Medstar Georgetown Headache Center and professor of clinical neurology at Medstar Georgetown University Hospital, in Washington, DC. “Because the CGRP medications are created to specifically target dysfunction in migraine, we are seeing patients who have never responded to any other treatment find improvement in migraine frequency with this novel class.”

“CRGP therapies are the only disease-specific preventive migraine medications available on the market right now,” Starling said. “Other drugs that do work have their place in migraine prevention and they can be effective for many patients, but they are not disease specific, and patients as well as clinicians want to be able to treat people with migraine with something that is designed for migraine.” Another exciting benefit, she reported, is the exceptionally rapid onset of action. “Several of the monoclonal antibodies seem to have a preventive benefit where the placebo and the treatment arm separate in as early as 1 week for galcanezumab and as early as 3 days with fremanezumab. With the infusion, eptinezumab, that has been shown to be effective as early as post-infusion day 1.”

Gepants are oral medications that also target the CGRP receptor and were first investigated in an effort to find effective acute therapies for migraine that were not vasoconstrictive, and therefore, would reduce the side effects and contraindications associated with triptan use.

 Unlike CGRP mAbs, they are small molecules that are metabolized and have to be taken on a regular basis, Starling explained; however, 2 investigational therapies, rimegepant and atogepant, have shown promise as possible preventive therapies.

Like the CRGP mAbs studied for prevention, gepants have demonstrated efficacy in several studies. Results from recent studies showed that 31.4%, 32.9%, and 29.7% of patients given doses of rimegepant (75 mg, 150 mg, and 300 mg) were pain free at 2 hours postdose compared with 15% of patients given placebo.

 These efficacy rates were close to those for sumatriptan (35%). In other studies, oral doses of rimegepant were also superior to placebo in freedom from pain and most bothersome symptoms.

 Similar efficacy has been observed in phase 3 trials for ubrogepant, supporting its regulatory approval in December 2019.

The possible benefits of gepants as preventive therapies are also being investigated. For instance, in an abstract presented at the 2019 Annual Scientific Meeting of the American Headache Society,9 David Dodick, MD, professor of neurology at Mayo Clinic, reported that in 834 patients who received atogepant, at least 52% to 62%— depending on the dose&mdash;experienced at least a 50% reduction in average monthly headache days compared with 40% of patients who received placebo.

Most of the anti-CGRP therapies that are currently available are given by subcutaneous injection. Erenumab and galcanezumab are given once monthly via an autoinjector, and fremanezumab is administered once a month via a prefilled syringe, with a higher-dose option available for administration once every 3 months. Ubrogepant is the first oral option approved.

 Notably, the investigational agent eptinezumab is administered via intravenous infusion once every 3 months.

Although patients being treated for other diseases often avoid injectable therapies when able, the experts agreed that this does not appear to be a disincentive to use anti-CGRP therapies. “Much of migraine treatment depends on patient preference,” Minen said. “For some time now, we have already been offering patients oral versus injectable medications, such as botulinum toxin. I have some patients who would rather take an oral medicine over injections and others who prefer the injections because they are quick and generally don’t interact with other oral medications.”

Starling, who sees mostly patients with high-frequency episodic migraine (10-14 days per month) and CM (15 or more days per month) in her clinic, agreed. “My patient population includes a lot of refractory patients who have tried many different treatment options, and they have never had an issue with the fact that this is an injection,” she told NeurologyLive®.

In a 2019 review of emerging therapies, Chan and Goadsby

 reported that, “During the next years, as experience with monoclonal antibodies grows in clinical practice, we can expect an evolution in migraine management to take shape. Clinicians will be able to offer treatment patients want rather than trying to fit migraineurs into therapeutic boxes for their management.”

This optimistic view of the next steps in migraine therapy appears to be widespread. “The hope is always that we are able to reduce abortive medication use if the disease is well managed with a good preventive—as sometimes, it takes layering of medications to achieve better control for some patients,” Ailani suggested. “Maybe, with newer targeted medications, we can start seeing a reduction in prescription acute medication use, although every patient with migraine should always have something on hand to treat a migraine attack,” she said.

Ailani noted that, like the CGRP mAbs, most studies of gepants have shown limited AEs. “If they are well tolerated, I would imagine it would be easier for patients to treat a migraine at the first sign of symptoms and therefore achieve a higher degree of success in relieving migraine symptoms, allowing a return to function,” she said. “If the day arrives when we have an oral gepant for migraine prevention, I think patients may like the option of taking a pill daily versus monthly or quarterly injections. Every patient is different, so options are the key here.”

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2. Hepp Z, Dodick DW, Varon SF, et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. 

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3. Dodick DW, Loder EW, Manack Adams A, et al. Assessing barriers to chronic migraine consultation, diagnosis, and treatment: results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. 

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4. Lipton RB, Hutchinson S, Ailani J, et al. Discontinuation of acute prescription medication for migraine: results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. 

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8. Croop R, Goadsby PJ, Stock DA, et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. 

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9. Goadsby PJ, Dodick DW, Ailani J, et al. Orally administered atogepant was efficacious, safe, and tolerable for the prevention of migraine: results from a phase 2b/3 study. Paper presented at: 2019 American Headache Society Annual Meeting; July 11-14, 2019; Philadelphia, PA. 

Two new classes of medications have quickly expanded the pool of available treatment options for patients with migraine, who now have more power than ever to choose the treatment that fits them best.

Author | Linda Peckel

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