In the last decade, mechanical thrombectomy has proven to be an efficacious and cost-effective approach to treating stroke.

 Despite this, its use has been relatively limited on a global scale.

As such, members of the Society of Vascular and Interventional Neurology’s (SVIN) global initiative, Mission Thrombectomy 2020+ (MT2020+), recently published a white paper calling for a push to increase awareness, accessibility, and action for mechanical thrombectomy for patients with stroke worldwide.

 The SVIN group ultimately called for 2 primary goals to be achieved: first, the implementation of public health interventions to double global access to mechanical thrombectomy treatments every 2 years for the next decade, and second, to perform 202,000 procedures worldwide by the end of 2020.

To better understand the goals of the initiative and need for increased use of this treatment, NeurologyLive® spoke with the chair of MT2020+, Dileep Yavagal, MD, professor of clinical neurology at the University of Miami and past president of SVIN.

In 2015, mechanical thrombectomy, as a surgical treatment for stroke, became standard of care for large vessel occlusion (LVO) stroke. This is the most severe form of stroke, where a large artery in the brain gets suddenly blocked by a clot that either comes from the heart or diseased arteries in the neck, sometimes the arch of the aorta, and results in significant disability, like loss of speech or loss of movement on one side of the body. The standard-of-care approval of this treatment really was a major step forward, not just in stroke, but all of medicine. The reason being that LVO stroke, as we know, accounts for anywhere from 15% to as high as 30% of all strokes, and its contribution to long-term disability burden and death is much higher. Of all stroke-related long-term disability and death, LVO stroke [accounts for] almost three-fifths of that burden. There’s a disproportionate contribution because of how severe these strokes are, and the fact that we now have a treatment that’s overwhelmingly powerful in reversing this is a major, aptly called revolution that has occurred.

When this happened in 2015, we started to think about the implementation and dissemination of this treatment, not just all over the United States, but also globally. In researching that, I realized that the burden of stroke is actually disproportionately higher in low- and middle-income countries, [which] shoulder 80% of all stroke burden, whereas the high-income countries only have about 20% of all stroke. There are about 13.6 million strokes per year, and the vast majority of them are in under-resourced areas. To get mechanical thrombectomy to make a dent in the global stroke burden, we would really have to get this therapy to be available worldwide.

The therapy is effective up to 24 hours after stroke symptoms, so it has to be accessed very urgently. In the early period, it’s very time-sensitive. The earlier you get this treatment, the better the outcomes. That’s putting 2 types of burden on accessing this care. It has to be available widely, but also in a geographically distributed manner so that patients can get it quickly. It’s not a therapy that affords itself to being centralized.

Is mechanical thrombectomy used widely enough in clinical practice where it is available?

It has actually increased quite rapidly, especially in the high-income countries, because it’s so overwhelmingly effective. Almost 50% of treated patients are completely independent at 3 months, which is very powerful compared to any therapy in medicine. But having said that, that rate of exponential increase still leaves a vast gap even in the US. In 2019, the estimate of thrombectomies was right below 40,000, whereas the number of patients who could benefit from thrombectomy was between 200,000 and 350,000. That gap is 5 times wider, or even more, in the low- and middle-income countries. So, while it’s widely practiced, while it’s increasing, the initial baseline gap is so high that even our metric of doubling the rate of thrombectomies every 2 years in a given region could only get us to fill 50% of the gap—we estimate in about 10 to 15 years. But if we didn’t even do public health interventions, it would probably be 30 or 40 years before we get to about 50% or 60% access. The rate is increasing, but it’s not fast enough.

"There are about 13.6 million strokes per year, and the vast majority of them are in under-resourced areas. To get mechanical thrombectomy to make a dent on the global stroke burden, we would really have to get this therapy to be available worldwide."

What factors affect the greater adoption of this more rapidly?

Because of the time-sensitivity and the fact that you need to have a center that’s ready to do this 24/7, this treatment needs a system of care to be in place in a given community. So that places an additional system burden on a community. For something like, let’s say, the treatment of pneumonia, it doesn’t need a system. Because first of all, it’s widely known. Everybody knows it, the antibiotics are widely available, and there is time. You don’t have only 24 hours. You can access it. Then, let’s say that the pneumonia is very complicated. You can transfer to a [more specialized] center. For a condition like LVO stroke, it’s like a cardiac arrest, but of a part of the brain. If you don’t do CPR very quickly, you’re losing that part of the brain. So that need for a system to be in place is such a huge step, that unless this is proactively pursued by communities and by stakeholders, it’s going take a long time to just by itself fall in place.

Is education about mechanical thrombectomy a challenge?

Absolutely. The education around the fact that LVO stroke should be recognized in the field and triaged to the right center is one big educational gap. That’s a prehospital system gap that needs to be addressed in a big way. The US is a vast country, and certainly, globally, we have a lot of area to cover. The second big gap is this understanding that a fair number of resources and thought need to be put into building a strong system of care in our community, and in a hospital, to really make this happen to get the best outcomes. Those are the 2 educational pieces: one is prehospital, and one is the clinicians themselves.

How does MT2020+ plan to help close that gap?

Public health interventions are the approach that MT2020+ is using to achieve our goals. By that what we mean is using upstream strategies—going from a big picture approach, rather than going hospital by hospital, because the efficiency of public health interventions is much higher in increasing access suddenly. Things need to happen from the ground up also, but the health policymakers really need to be fully educated about the benefit of thrombectomy and thrombectomy systems.

The second public health intervention that has a common application is prehospital personnel education of recognizing LVOs. There are very standardized scales now, and the need to bring the patient as rapidly as possible to a thrombectomy center is apparent. The third is certification. To bring someone to a thrombectomy center, that thrombectomy center has to be recognized as such, and without certification, it’s a hit or miss. It’s not publicly known, especially at 3AM when a stroke happens, where to take the patient. I would say there are probably about 10 very intense public health interventions that have an impact. These are the top 3 that I’ve mentioned. But the way we are doing it is we have created regional committees that are headed by a stroke neurologist and an interventionist in 82 regions in the world already. Those regional committees can actually decide what are the top 3 or 4 interventions that will make the most impact in a given year. For example, in low- and middle-income countries, reimbursement for these procedures and having no barrier for a concentration of reimbursement when the [need arises] are big public health interventions that need to be put in place, with either public system funding or some other mechanism of payment. The public interventions vary from region to region in terms of the most impact, but these would be examples of what is being perceived by MT2020+ as effective for any community around the globe.

The US is a leader in mechanical thrombectomy research and implementation, and this is a great opportunity to influence global health in a manner that could affect millions of people. The prevalence of stroke was estimated in 2017 to be over 100 million people. It’s a big burden that the US could influence as a leader by sharing best practices and influencing public policy, not just here, but around the world.

REFERENCES
1. McCarthy DJ, Diaz A, Sheinberg DL, et al. Long-term outcomes of mechanical thrombectomy for stroke: a meta-analysis. 

. 2019:1-9. doi:10.1155/2019/7403104
2. Patil CG, Long EF, Lansberg MG. Cost-effectiveness analysis of mechanical thrombectomy in acute ischemic stroke. 

. 2009;110(3):508-513. doi:10.3171/2008.8.JNS08133
3. A global push to increase awareness, action and access to thrombectomy care for stroke patients is underway. News release. Society of Vascular and Interventional Neurology. October 29, 2020. Accessed November 9, 2020. https://www.prnewswire.com/news-releases/a-global-push-to-increase-awareness-action-and-access-to-thrombectomy-care-for-stroke-patients-is-underway-301162546.html
4. Society of Vascular and Interventional Neurology. Mechanical thrombectomy for acute stroke: building stroke thrombectomy systems of care in your region. October 24, 2020. Accessed November 9, 2020. https://www.svin.org/files/Final_formatted_SVIN_White_paper_2020_updated_references(1).pdf

Articles

Clinical Viewpoint

Increasing the use and accessibility of mechanical thrombectomy may reduce the burden of stroke on a global scale.

The Global Push for Mechanical Thrombectomy in Stroke Care

Multiple sclerosis (MS) is an autoimmune-mediated disorder of the central nervous system (CNS). There is currently no single defined cause of MS development, but the neurological impairments characteristic of the disease are thought to result from auto-immune- or inflammation-mediated axonal demyelination that impedes nerve conduction.1 Drug development for MS has been challenging, in part because a comprehensive treatment should address effects of the disease on both the immune system and CNS. Available treatments, which are largely immunosuppressive, cannot reverse neurological deficits by stimulating remyelination or halting progressive neuronal dysfunction. Thus, concurrent treatment of autoimmune reactions and axonal degeneration has been proposed as a potentially more effective approach to MS therapy.

Repulsive guidance molecule-a (RGMa) is a glycosylphosphatidylinositol-anchored membrane protein that, upon binding its receptor neogenin, inhibits neuronal regeneration and regulates cell death.

 Expression of RGMa is upregulated in the CNS of patients with MS, where RGMa is found in active and chronic lesions, normal-appearing gray and white matter, and meningeal infiltrates.

 In MS, RGMa enhances activation of CD4-positive T cells by dendritic cells presenting myelin sheath self-antigens, initiating an autoimmune response in the white matter of the brain and spinal cord and resulting in axonal demyelination, neurodegeneration, and progressive paralysis.

 The multiple functions of RGMa in the CNS and immune system offer an opportunity to therapeutically and concurrently block the autoimmune reactions and axonal injury observed in neurodegenerative and neuroinflammatory diseases.

Patients with MS have an urgent need for therapies that can reverse neurologic disability by promoting remyelination.

 RGMa- specific monoclonal antibody (mAb) treatment (

) promises to surpass the current standard of care for MS, which primarily relies on disease-modifying therapies and symptom management. Anti-RGMa mAbs have been shown to attenuate the severity of animal models of MS, such as experimental autoimmune encephalomyelitis (EAE), by inhibiting T-cell activation in the CNS

 while promoting neuroprotection and neuroregeneration.

 Along with decreased expression of RGMa in the spinal cord, EAE mouse survival was prolonged, accompanied by suppressed secondary progression of disease.

 In a rat model of spinal cord injury, the beneficial effects of anti-RGMa mAb administration were observed over a period of up to 24 hours post-injury. These benefits included reduced tissue degeneration and promotion of neuronal sparing, axonal plasticity, and functional recovery.

Elezanumab (ABT-555; AbbVie) is a fully-humanized anti-RGMa mAb that has demonstrated promotion of axonal regeneration, neuroprotection, remyelination, and immune modulation in MS-relevant preclinical models. A phase 1, double-blind, placebo-controlled, randomized, escalating 4-dose 29-week study was completed in April 2018 (NCT02601885). The study examined 3 treatment groups (150 mg, 600 mg, and 1800 mg elezanumab via intravenous infusion) and 1 placebo group to determine safety and tolerability in 20 patients with relapsing forms of MS.

 Adverse events (AEs), cerebrospinal fluid (CSF) and plasma biomarker analyses, and Expanded Disability Status Scale (EDSS) scores were assessed. Increasing levels of elezanumab were associated with decreased free soluble RGMa and increased interleukin-10 in CSF. EDSS scores were unchanged. Overall, elezanumab was well tolerated, with the most common AE being headache, and treatment did not consistently result in symptom worsening in patients who received multiple doses up to 1800 mg.

Elezanumab was granted orphan drug and fast track designations by the FDA on September 28, 2020, for treatment of spinal cord injuries.

 Two long-term, phase 2 studies are underway to elucidate the efficacy of elezanumab in larger patient populations. The RADIUS-R trial (NCT03737851), which commenced in December 2018, enrolled 208 participants with relapsing forms of MS. The RADIUS-P trial (NCT03737812), which began in February 2019, enrolled 123 participants with progressive forms of MS. Both randomized, double-blind, placebo-controlled, multiple-dose studies are assessing the safety and efficacy of elezanumab when added to standard of care and have an estimated study completion date of October 2021. In both trials, patients are randomly assigned to receive 1 of 2 doses of either elezanumab or placebo by intravenous infusion every 4 weeks for 48 weeks. Improvement in measures of physical disability (EDSS, Timed 25-Foot Walk, and 9-Hole Peg Test scores) is recorded at week 52 as the primary outcome.

Therapeutic antibodies are especially effective for diseases with clearly elucidated molecular mechanisms for which the specific molecules involved in pathogenesis have been identified. Despite its demonstrated efficacy, anti-RGMa mAb therapy does not address some aspects of MS progression, suggesting complexities in the mechanisms of this disease that may not be fully dependent on RGMa. The MS therapeutics market currently has multiple late-stage pipeline products with diverse mechanisms of action (eg, antioxidants; the mAb opicinumab, which inhibits LINGO-1, a negative regulator of axonal myelination

). RGMc-based therapy is also a promising avenue worth exploring. RGMc, a member of the RGM family whose expression is limited to striated muscle and the liver, is downregulated in the sera of mice induced with EAE.

 Treatment with soluble RGMc enhanced the integrity of the blood-brain barrier to significantly delay the onset of EAE and reduce its clinical severity.

 Overall, with each new intervention undergoing development, investigators will gain further insight into the disease process of MS and eventually pinpoint the key molecular drivers of this disease.

REFERENCES
1. Kubo T, Tokita S, Yamashita T. Repulsive guidance molecule-a and demyelination: implications for multiple sclerosis. J Neuroimmune Pharmacol. 2012;7(3):524-528. doi:10.1007/s11481-011-9334-z 2. Demicheva E, Cui Y-F, Bardwell P, et al. Targeting repulsive guidance molecule a to promote regeneration and neuroprotection in multiple sclerosis. 

. 2015;10(11):1887-1898. doi:10.1016/j.celrep.2015.02.048
3. Muramatsu R, Kubo T, Mori M, et al. RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis. 

. 2011;17(4):488-494. doi:10.1038/nm.2321
4. Göttle P, Förster M, Weyers V, et al. An unmet clinical need: roads to remyelination in MS. 

. 2019;1(1):21. doi:10.1186/s42466-019-0026-0
5. Harada K, Fujita Y, Okuno T, et al. Inhibition of RGMa alleviates symptoms in a rat model of neuromyelitis optica. Sci Rep. 2018;8. doi:10.1038/s41598-017-18362-2
6. Tanabe S, Fujita Y, Ikuma K, Yamashita T. Inhibiting repulsive guidance molecule-a suppresses secondary progression in mouse models of multiple sclerosis. 

. 2018;9(11). doi:10.1038/s41419-018-1118-4
7. Mothe AJ, Coelho M, Huang L, et al. Delayed administration of the human anti-RGMa monoclonal anti-body elezanumab promotes functional recovery including spontaneous voiding after spinal cord injury in rats. 

. 2020;143:104995. doi:10.1016/j.nbd.2020.104995
8. Ziemann A, Rosebraugh M, Barger B, Cree B. A phase 1, multiple-dose study of elezanumab (ABT-555) in patients with relapsing forms of multiple sclerosis (S56.001). 

. 2019;92(15 Supplement):S56.001. 
9. AbbVie receives orphan drug and fast track designations from the U.S. Food and Drug Administration for elezanumab, an investigational monoclonal antibody RGMa inhibitor, for the treatment of spinal cord injury. News release. Abbvie. September 28, 2020. Accessed October 30, 2020. https://www.biospace. com/article/releases/abbvie-receives-orphan-drug-and-fast-track-designations-from-the-u-s-food- and-drug-administration-for-elezanumab-an-investigational-monoclonal-antibody-rgma-inhibitor-for- the-treatment-of-spinal-cord-injury/
10. Cree B, Pfleeger K, Schwefel B, Ziemann A. Investigating the safety and efficacy of elezanumab in two phase 2 studies enrolling patients with different disease courses of multiple sclerosis (1219). 

. 2020;94(15 Supplement). Accessed October 27, 2020. https://n.neurology.org/ content/94/15_Supplement/1219
11. Cadavid D, Balcer L, Galetta S, et al; RENEW Study Investigators. Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial. 

. 2017;16(3):189-199. doi:10.1016/S1474-4422(16)30377-5
12. Raftopoulos R, Hickman SJ, Toosy A, et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. 

. 2016;15(3):259-269. doi:10.1016/ S1474-4422(16)00004-1
13. Kuns-Hashimoto R, Kuninger D, Nili M, Rotwein P. Selective binding of RGMc/hemojuvelin, a key protein in systemic iron metabolism, to BMP-2 and neogenin. 

. 2008;294(4):C994-C1003. doi:10.1152/ajpcell.00563.2007
14. Vigouroux RJ. Identifying the role of RGMc in an animal model of Multiple Sclerosis. [master’s thesis]. Toronto, Ontario, Canada: University of Toronto. 2015.

NeuroPathways

Patients with MS have an urgent need for therapies that can reverse neurologic disability by promoting remyelination, and RGMa inhibition may help meet that need.

RGMa Inhibition for Repair and Protection in Multiple Sclerosis

Alzheimer disease (AD) is a leading cause of disability and the fifth leading cause of death in patients age 65 or older.

 As the aging population continues to grow, the incidence of AD also increases, spurring research into innovative ways of detecting, managing, and treating the condition. Digital biomarkers, in particular, have aroused interest from researchers and manufacturers, as they have the potential to provide precise, quantifiable physiological information that can be used as diagnostic and prognostic indicators.

Any medical data that are objectively collected through digital technology, such as wearable devices and smartphones, are referred to as “digital biomarkers.” Given that the wearable health care device market is predicted to grow by 20% in the next 5 years,

 digital biomarker are an attractive option within the medical community.

Digital biomarkers show definite promise in detecting AD in its early stages.

“Although the gold standard for diagnosis is an autopsy or positron emission tomography (PET) scan, clinically validated end points for digital biomarkers are on their way,” said Graham Jones, PhD, director of innovation at Novartis. Indeed, over the past few years, much research has focused on the utility of digitally acquired data in detecting AD and predicting cognitive decline.

Based on their method of acquisition, 2 major categories of digital biomarkers are currently being employed for neurologic conditions

Active biomarkers, as the name suggests, require users to be actively involved in recording the parameter being measured. These biomarkers generally assess cognitive function through digitally administered tests or quizzes.

Passively collected data, on the other hand, occurs without active user engagement and results in continuous, real-time data acquisition. For instance, data such as step count, gait symmetry, and clarity of speech can all be recorded during spontaneous activities, and without any engagement on the part of the user.

According to Mircea Balasa, MD, PhD, a neurologist at Hospital Clinic de Barcelona in Spain, innovative digital biomarkers based on cognitive testing are being devised to improve on existing neuropsychological symptom tests, making them more standardized and reliable. One such innovation is using gamified versions of standard memory tests to make it more attractive and increase patient engagement. For example, Balasa and his team have been working on validating the Altoida Neuro Motor Index device, which is based on augmented reality technology and consists of a 10-minute gamified assessment that tests a patient’s functional and cognitive aptitude.

 “At present, the Altoid device shows promise in distinguishing patients with mild cognitive impairment from controls,” Balasa told 

Research has shown that AD presents with a definitive decline in sensory and motor functioning, even before cognitive decline begins.

 These deficits include general visual parameters, such as visual acuity, color perception, contrast sensitivity, and visual integration, all of which are reduced in patients with mild AD.

 Investigators have suggested that passive tests can measure the amount of fixation time on certain graphics that are repeatedly viewed, to quantify visual parameters over time.

 Both peripheral and central auditory system dysfunction occur in the prodromal stages of AD,

 and passively monitoring conversations could be one way of screening for AD. For instance, a study showed that atypical repetitions in 2 conversations that occurred on different days was a strong indicator of AD.

 Reading comprehension can also be evaluated by tracking eye movements.

In addition, slow gait speed is a strong predictive factor for dementia and cognitive decline.

 Measurement of gait speed using an accelerometer or gyroscope sensors has the potential to improve the detection of AD. Also, touchscreen sensors can evaluate fine motor control capabilities such as typing skills, swiping, and other keystroke patterns.

Imaging studies have shown that neuropathological lesions can develop in the autonomic nervous system (ANS) in the earliest stages of AD. “The ANS is fertile ground for diagnosis,” Jones told 

. “The ANS impacts several factors that can be picked up by digital tools—heart rate, reflexes, and respiration, for instance.” Indeed, the earliest stages of AD have been associated with heart rate variability (HRV),

 and mobile devices with built-in electrocardiogram (ECG) capabilities, such as the Apple Watch, can be used to monitor HRV in at-risk patients.

 AD is also associated with disturbed circadian rhythms,

 so devices that have built-in ballistocardiography sensors can be used to monitor sleep patterns.

Determining the Most Accurate Digital Biomarkers

Although investigators have studied a variety of digital biomarkers, very few have dealt with real-world, home-based evaluations. In 2019, Evidation Health set the ball rolling when they partnered with Apple and Eli Lilly and Company for a real-world study that produced around 16 terabytes of digital biomarker data. The investigators were able to establish that specific motor skills, such as reading, typing, and keystroke tasks were performed more slowly in patients who had mild cognitive impairment and dementia.

In 2018, the United Kingdom (UK) Alzheimer’s Society and the University of Oxford’s Big Data Institute launched the GameChanger project, which employs a smartphone app called Mezurio.

 Volunteers across the UK are being recruited to complete activities each day using the app, from which the data collected will be used to study markers of healthy cognition and determine factors that would be affected by cognitive decline.

Another project in the European Union, RADAR-AD, is focused on exploring the potential of mobile technologies in measuring disability progression associated with AD,

 while the US-based Alzheimer’s Drug Discovery Foundation is supporting digital biomarker exploration through its Diagnostics Accelerator.

"There is a very real expectation that digital biomarkers can monitor progression from prodromal to diseased states...[and] some evidence that learned behaviors—such as performing specific functions on tablets—coupled with certain exercise regimens, can delay the onset and severity of diseases like AD."


Digital biomarkers have the potential to advance several stages of the disease process:

 The current standard for diagnosis of AD is through PET molecular imaging, which is expensive and often only available at regional facilities. In contrast, when patients use mobile or wearable devices, there is continuous monitoring of passive biomarkers and data can be compared to the patient’s previous data. This makes it easier to detect any decline in nervous system parameters. “Any deviations from normal biomarker levels can be used as an indication to recommend more specific investigations, such as PET scans,” Jones said.

 Currently, neuropsychological testing is used to monitor cognitive function in high-risk individuals. However, these tests are not always reliable and may fail to detect the earliest stages of cognitive impairment. According to Balasa, active digital biomarkers could be used instead to create prognostic models that can help monitor patients who are at higher risk of developing cognitive decline. “Such individuals do not normally seek medical advice, as they don’t usually have clinically relevant cognitive decline,” he said.

 Digital biomarkers are a cost-effective solution to collect objective, continuous, quantifiable data in a longitudinal manner. The precision of this data can increase the statistical power of clinical trials.

 In the advanced stages of AD, neurons are destroyed and the opportunity to study disease pathology is limited. By identifying patients in the early stages of the disease via digital biomarkers, researchers can gain a deeper understanding of the pathophysiology of AD, which can help develop novel treatment strategies.

Wearable devices still have a long way to go before they can be reliably used for the diagnosis and management of AD. “The issue for most of these devices is clinical validation with appropriate double-blinded trials,” Jones said. For effective real-world usage, clinical validation needs to be followed by regulatory approval. The Altoida device is currently the only device-specific for AD that has FDA approval and CE marking. While the Apple Watch has FDA approval for fall detection and ECG rhythm monitoring, its AD-specific features still need validation and approval.

Actively measured biomarkers require dedicated engagement on the part of the patient, who must manually enter inputs into the recording device. Lack of interest or even beginning memory loss are some challenges that can prevent the effective use of this kind of biomarker. While passive biomarkers do not face these challenges, the large volumes of data that are acquired create the need for extensive storage systems. Analysis of this data may require complex tools and trained personnel.

In addition to these disadvantages, both kinds of data face another challenge: wearable devices record vast amounts of medical data that must remain confidential. “We need to navigate data privacy and Health Insurance Portability and Accountability Act regulations,” said Jones. Some applications such as Apple Health allow users to access their health care data directly through their own devices, which may increase the need for secure access to such data.

In Jones’ opinion, apart from timely diagnosis, there are 2 future directions that hold promise. The first is monitoring disease progression. “There is a very real expectation that digital biomarkers can monitor progression from prodromal to diseased states,” he said, adding that cognitive performance could also be tracked digitally. Secondly, and more promising, is the possibility of actual treatment using digital tools. “There is some evidence that learned behaviors—such as performing specific functions on tablets—coupled with certain exercise regimens, can delay the onset and severity of diseases like AD,” he said. Of course, these digital forms of treatment need sound exploration and validation before they become a reality.

REFERENCES
1. Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. 

 2020;16(3):391-460. doi:10.1002/alz.12068
2. Wearable healthcare devices market by type (diagnostic (ECG, heart, pulse, BP, sleep), therapeutic (pain, insulin), application (fitness, RPM), product (smartwatch, patch), grade (consumer, clinical), channel (pharmacy, online) - global forecast to 2025. Markets and Markets. May 2020. Accessed November 19, 2020. 

https://www.marketsandmarkets.com/Market-Reports/wearable-medical-device-market-81753973.html


3. Kourtis LC, Regele OB, Wright JM, Jones GB. Digital biomarkers for Alzheimer’s disease: the mobile/wearable devices opportunity. 

. 2019;2:9. doi:10.1038/s41746-019-0084-2
4. Buegler M, Harms R, Balasa M, et al. Digital biomarker-based individualized prognosis for people at risk of dementia. 

. 2020;12(1):e12073. doi:10.1002/dad2.12073
5. Albers MW, Gilmore GC, Kaye J, et al. At the interface of sensory and motor dysfunctions and Alzheimer’s disease. 

. 2015;11(1):70-98. doi:10.1016/j.jalz.2014.04.514
6. Salobrar-García E, de Hoz R, Ramírez AI, et al. Changes in visual function and retinal structure in the progression of Alzheimer’s disease. 

. 2019;14(8):e0220535. doi:10.1371/journal.pone.0220535
7. Swords GM, Nguyen LT, Mudar RA, Llano DA. Auditory system dysfunction in Alzheimer disease and its prodromal states: a review. 

. 2018;44:49-59. doi:10.1016/j.arr.2018.04.001
8. Yamada Y, Shinkawa K, Shimmei K. Atypical repetition in daily conversation on different days for detecting Alzheimer disease: evaluation of phone-call data from regular monitoring service. 

. 2020;7(1):e16790. doi:10.2196/16790
9. Fernández G, Manes F, Politi LE, et al. Patients with mild Alzheimer’s disease fail when using their working memory: evidence from the eye tracking technique. 

. 2016;50(3):827-838. doi:10.3233/JAD-150265
10. Grande G, Triolo F, Nuara A, Welmer A-K, Fratiglioni L, Vetrano DL. Measuring gait speed to better identify prodromal dementia. 

. 2019;124:110625. doi:10.1016/j.exger.2019.05.014
11. Kim MS, Yoon JH, Hong JM. Early differentiation of dementia with Lewy bodies and Alzheimer’s disease: heart rate variability at mild cognitive impairment stage. 

. 2018;129(8):1570-1578. doi:10.1016/j.clinph.2018.05.004
12. Owens AP. The role of heart rate variability in the future of remote digital biomarkers. 

 2020;14:582145. doi:10.3389/fnins.2020.582145
13. Uddin MS, Tewari D, Mamun AA, et al. Circadian and sleep dysfunction in Alzheimer’s disease. 

. 2020;60:101046. doi:10.1016/j.arr.2020.101046
14. Chen R, Jankovic F, Marinsek N, et al. Developing measures of cognitive impairment in the real world from consumer-grade multimodal sensor streams. 

KDD ‘19: Proceedings of the 25th ACM SIGKDD International Conference on Knowledge Discovery & Data Mining


15. Study information. Game Changer. Accessed November 19, 2020. https://joingamechanger.org/information/
16. Strategy. Radar-AD. Accessed November 19, 2020. https://radar-ad.org/about-us/strategy
17. Diagnostics accelerator: digital biomarkers. Alzheimer’s Drug Discovery Foundation. Accessed November 19, 2020. https://www.alzdiscovery.org/research-and-grants/funding-opportunities/digital-biomarkers

Features

Digital biomarkers offer promise to revolutionize the diagnosis and treatment of Alzheimer disease via our increasing ability to gather active and passive data.

Data Evolution in Alzheimer Disease: Is the Future Digital?

Expectations for acute migraine treatment are increasing due to the recent uptick in both approved and investigational therapies. With more confidence in the ability to effectively treat acute migraine has come an opportunity to reevaluate how success is measured, with more focus on patient-centered outcomes.

Although conversations in this space have been dominated by the progress and success of the calcitonin gene-related peptide (CGRP)–targeted monoclonal antibodies and the small-molecule gepants, more novel therapies are making their way toward regulatory evaluation. As such, headache and migraine specialists are proceeding with enthusiasm, with the hope of maintaining a reflective approach to gain insights into the possibilities of these new therapies.

In a recent NeurologyLive® Peer Exchange, “

Advances in the Management of Acute Treatment of Migraine

,” a panel of experts led by Peter J. Goadsby, MD, PhD, DSc, professor of neurology at the University of California, Los Angeles, Goldberg Migraine Program, discussed the mechanisms of action, efficacy, and safety of therapies in the acute migraine treatment armamentarium.

In October 2019, the United States Food and Drug Administration (FDA) approved the first member of the ditan class, lasmiditan (Reyvow; Eli Lilly), an oral, central nervous system (CNS)–penetrating agent that selectively targets the 5-HT

 receptor. This is in contrast with the triptan class, which targets the serotonin 5-HT1B/1D receptors, though Goadsby noted that some agents, such as naratriptan and sumatriptan, act on the 5-HT

Triptans, which have been available since the early 1990s, can be challenging to use, as they bind to 5-HT

 and blood vessels, causing vasoconstriction. Jelena Pavlovic, MD, PhD, associate professor of neurology at the Albert Einstein College of Medicine and faculty at Montefiore Headache Center, noted that the high selectivity of lasmiditan offers a unique mechanism of action. “It’s the antagonist of 5-HT

, and it has much higher selectivity for that receptor than the triptans have for the 5-HT

. Therefore, it has no vasoconstriction properties, which have been the primary challenge with triptans,” she explained.

 receptors are found at a number of locations in the trigeminovascular system but do not exist on the blood vessels. The current understanding is that they operate on the level of the trigeminal ganglion, trigeminal nucleus caudalis, cerebral vessels, neocortex, and hippocampus—putting forth multiple pathways in the activation of migraine pain.

Although study results showed success with lasmiditan in providing freedom from pain within 2 hours (across 2 clinical trials with the 3 doses of 50 mg, 100 mg, and 200 mg, 28% to 39% of patients achieved complete resolution of migraine pain at 2 hours), the agent’s CNS penetration occasionally leads to adverse effects.

“The FDA required additional studies for lasmiditan for this reason, including a study showing potential for addiction,” Pavlovic said. “They finally awarded a controlled substance Schedule V rating to lasmiditan, so it is a controlled substance at this point. There is an 8-hour driving restriction, given the cognitive impairment seen after dosing. The recommendation is not to drive for 8 hours or operate heavy machinery.”

Goadsby added that having this selectivity over the 5-HT

 receptors has been an extraordinary development in the treatment of migraine. It may not be perfect, he noted, but it certainly offers clinicians an option to avoid the 5-HT

“Let me just add that one of the reasons I like lasmiditan in my practice is that it does have some ability to lower CGRP concentration in the periphery,” Wade M. Cooper, DO, associate professor of neurology at Michigan Medicine Headache & Neuropathic Pain Clinic, said. “There is a peripheral anti-CGRP effect. The effect is not strong, but it’s one of the few FDA-approved medicines for migraine that goes centrally. That’s what defines it and separates it from some of the other agents out there.”

Cooper and Goadsby then turned to the small-molecule CGRP receptor antagonists, focusing on the 2 approved agents, rimegepant (Nurtec ODT; Biohaven) and ubrogepant (Ubrelvy; AbbVie). Cooper described the mechanistic qualities of these therapies, which work mostly in the periphery, blocking the inflammatory signal coming from the pain-sensitive nerves. Both drugs also suppress inflammation of the meninges.

Additionally, these therapies focus on receptors missed by triptans, in similar fashion to the ditans, making them promising treatments for those who cannot be prescribed triptans or do not derive benefit, which Paul G. Mathew, MD, assistant professor of neurology at Brigham and Women’s Hospital and Harvard Medical School, noted earlier in the discussion.

“What’s also cool about these is that they tend to work relatively quickly,” Cooper said. “Most remarkable from my perspective is their almost complete lack of adverse effects. When you compare the gepants class medicines with the triptan adverse effects, it’s quite phenomenal. Nausea seems to be a reported adverse effect in the clinical trials. I’ve had 1 or 2 people with some pretty severe nausea from it, but as a whole, it’s really well tolerated.”

"These are complex [processes] with many neurotransmitters involved, and when someone knows a bit of what is going on, they’re going to be more comfortable [with their treatment]."

As for dosing, rimegepant has a set dose of 75 mg while ubrogepant is available in a small range of doses. Pavlovic noted that rimegepant, which comes as an orally disintegrating tablet, provides an appealing ease of administration. Due to the tolerability of these therapies, Cooper noted that he begins dosing at the upper end of the dose range, aiming for the highest efficacy. In comparison, as Pavlovic noted, lasmiditan dosing often requires a “go low, start slow” approach.

“I start at 50 mg in patients who feel relief and may have a lower adverse-effect profile. If they can’t achieve pain freedom completely, then because there is an additive effect to a higher dose, I will increase the dose at that point,” she explained.

Mathew concurred, noting that if a patient easily tolerates 50-mg lasmiditan, he’ll suggest they take a double dose before prescribing 100 mg. “I will do the same thing with ubrogepant, with the instructions that if they tolerate the 50 mg just fine and find it partially effective, try taking 2 of them, then let my office know, and I’ll call in a refill for the 100 mg of that medication as well,” he said.

In addition to the ditans and gepants, there has recently been an attempt to reformulate dihydroergotamine (DHE), a therapy that has been in use since the 1940s. It exists in a number of available formulations, including intravenous, intramuscular, subcutaneous, and inhaled. Mathew noted that DHE causes significant nausea, so it often has to be codosed with an antiemetic, giving it a bit of a “bad name.”

“The 2 newer forms of DHE are both intranasal,” he explained. “One of them is a proprietary pump, which squirts the DHE into a particular part of the nose where it’s able to get absorbed much more consistently. It’s still in liquid formulation. The other is a small vial; you squeeze it, and a powder form of DHE is injected into the nose.”

Mathew noted that these delivery systems are encouraging, in part because of their ability to reach plasma levels lower than the inject-able formulations, which helps to avoid some of the associated adverse effects while maintaining a consistent dose.

“Nerve blocks are something you can consider in the office, urgent care, or emergency department,” Mathew said. “But if either of these formulations gets approved, there may potentially be a DHE protocol in which you give the patient a prescription and they can take 1 of these 2 intranasal formulations for a few days. That’s going to be potentially useful for when someone has status migrainosus [and] nothing else is working.”

Dawn C. Buse, PhD, clinical professor of neurology at Albert Einstein College of Medicine, inquired about the potential of DHE as a therapy for women of child-bearing age, and if extra education and caution is required in that population.

“Regarding pregnancy, the advice I give many of my patients is that—this is just my view—getting pregnant can take weeks, months, or even years,” Mathew said. “To discontinue someone’s medications because they’re trying to get pregnant can really limit their ability to get pregnant and can lead to a lot of migraines and unnecessary suffering. My advice to these patients is, the minute you become pregnant, call your doctor. We’ll rapidly wean you off everything.”

Buse noted that in the CaMEO study, investigators found that 10% of women with chronic migraine chose not to have children or delayed having children because of concerns associated with their migraine care—either that they would pass on their disease, that they would have to stop their medications, or that their migraine would get worse.

“Anything we can do to treat them as well as possible, keep them comfortable, and allow them to make those lifestyle choices— including reproductive choices, which are core to being human— is important,” she explained. “We also need to think about how, as women age out of childbearing age and get older, their risk for cardiac events might increase again. We may need to think about a woman who’s maybe been on a triptan for decades, since she was a teen or a young adult. It may be time to reconsider her options as she ages into the postmenopausal age bracket.”

Pavlovic noted that, similar to triptans, registries accounting for the use of the new medications during pregnancy are needed to help build our understanding. “We know that women will inadvertently use them in early pregnancy before awareness that they are pregnant. These medications will be used, and having registries that are active and already started will be very helpful,” she said.

Goadsby then probed the group about their views of the adverse-effect profiles of these agents, as well as compared with those for older medications. Mathew noted that if the patient is taking a CGRP monoclonal antibody, he may be swayed toward prescribing a ditan over a gepant due to its different mechanism of action.

“It’s certainly mechanistically attractive to think that if you have a CGRP blockade, the ditan will come along and block other things that are prejunctionally and presynaptically released,” Goadsby said. “Glutamate is the obvious thing, and perhaps it blocks other peptides. The multi- mechanistic side is useful. Colleagues are also finding that there’s room still to push on the CGRP mechanism, even in people taking monoclonal antibodies. We have a lot of things to learn practically.”

Mathew noted that he offers this simplified description of that process to his patients: The antibody is lowering the overall level of CGRP, so if they happen to experience a migraine, they will have an episodic burst of CGRP, which the gepant can then suppress. He suggested that giving the patient a better understanding of these processes can also improve adherence to treatment, with which Buse agreed.

“These are complex [processes] with many neurotransmitters involved, and when someone knows a bit of what is going on, they’re going to be more comfortable,” Buse said. “They’re going to tolerate any adverse effects that might arise early a bit better, and they’re going to tend to be more adherent. They’re also going to have more comfort with their provider when they’re told in advance what to expect.”

REFERENCE
1. Wietecha L, Kuca B, Asafu-Adjei J, et al. Phase 3 Studies (SAMURAI, SPARTAN) of Lasmiditan Compared to Placebo for Acute Treatment of Migraine (S50.008). Neurology. 2018;90(suppl 15). http://n.neurology.org/ content/90/15_Supplement/S50.008.

NeurologyLive Peer Exchange

In a NeurologyLive® Peer Exchange, a panel of migraine specialists discussed the novel therapies in development and those entering the market for the treatment of acute migraine.

Updates in Approaches to Acute Migraine Care

Insomnia is the complaint of dissatisfaction with sleep quantity or quality associated with an inability to fall or stay asleep or early-morning awakening.1 Considerable changes have occurred in our understanding of insomnia over the past few decades.

 Whereas it was once thought to be an uncommon malady, we now know that it is highly prevalent in clinical settings; after pain, it represents the second-most commonly expressed clinical complaint.

 In community settings, an astounding 35% of the adult population experiences insomnia during the course of 1 year, and that half experiences the problem as severe. Literature suggests 20.1% of adults are dissatisfied with their sleep or take medication for sleeping difficulties.

 Insomnia is also an emerging problem in children and adolescents; an estimated 4% of children complain of insomnia at least 3 times per week over the course of a year.

Although it was once regarded as a benign condition, insomnia is now also known to be associated with a variety of health risks and consequences. Insomniacs suffer from greater functional impairments, cognitive deficits, work-related impairments and absenteeism, social upheaval, and mood impairments than do good sleepers.

 They also exhibit greater cognitive deficits, especially when responding to challenging reaction time tasks.

 Insomnia also contributes to the development of new cardiovascular and metabolic abnormalities such as hypertension, heart failure, and glucose intolerance.

Difficulty falling asleep, frequent nocturnal awakenings, early- morning awakening, nonrestorative sleep, decreased total sleep, and disturbing dreams are commonly reported by patients with major depression.

 However, persistent insomnia, even in the absence of current mood or other disorders, confers an increased future risk of the development of depression and other new psychiatric disorders over the course of the ensuing year, a risk that diminishes if the insomnia resolves and after direct management of insomnia.

 Insomnia also contributes to suicidal ideation and behavior, and direct management of insomnia diminishes suicidal ideation.28 There may, therefore, exist a bidirectional relationship between insomnia and various psychiatric disorders including depression.

Earlier formulations into the pathophysiology of insomnia were based on the notion that insomnia represented a failure of the normal process of dreaming, leading to anxiety resulting in awakenings.

Later formulations focused on cognitive and behavioral principles; insomniacs were theorized to have an exaggerated emotional reaction to everyday stressors, compounded by distorted and negative beliefs about sleep that led to a cycle of catastrophizing apprehension and worry.

 More recent research has implicated the role of an overly active physiological arousal system, both during sleep and wakefulness. Insomniacs are so aroused that they have a decreased ability to fall asleep during daytime nap tests,

 display increased high-frequency beta electroencephalogram power across the entire night,

 and have an increase in positron emission tomography global glucose metabolic rates during both wakefulness and sleep compared with healthy controls.

 Insomniacs also exhibit an increase in heart rate and an increase in whole-body metabolic rate.

The current view of insomnia, which supports the possibility of its existence as an autonomous disorder, is reflected in the 

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

The primary insomnia diagnosis that appeared in prior versions is eliminated, in favor of insomnia disorder, and secondary insomnia conditions are eliminated altogether, in favor of insomnia disorder with concurrent specification of clinically comorbid medical and psychiatric conditions.

We now recognize that the complex nature of insomnia necessitates a systematic evaluation prior to proceeding with treatment, as noted in a number of recently published guidelines.

 The Insomnia Severity Index is a useful clinical tool for identifying insomnia and measuring severity.

 Digital sleep diaries now afford patients the opportunity to display sleep-wake patterns over time and assist in clinical diagnosis. An actigraph, through a device resembling a wristwatch, records movement and ambient light levels and can be useful for the assessment of sleep patterns and the response to behavioral or pharmacological treatments.

Cognitive-behavioral therapy for insomnia (CBT-I) remains the gold standard for insomnia treatment, with proven techniques such as sleep hygiene education, stimulus control therapy, relaxation therapies, restriction of time in bed, cognitive therapy, and paradoxical intention.

 Limitations in availability of CBT-I are now being addressed by the introduction of unguided online and smartphone CBT-I modules and techniques that can be delivered over 4 weeks. Significant advances have also been made in the pharmacological management of insomnia, which had, over the past few decades, relied on older benzodiazepine receptor agonists. More recently, a melatonin receptor agonist, a histamine-1 receptor antagonist, and 2 orexin receptor antagonists have been introduced, and more are being developed. With the increase in the array of available hypnotics, each with identifiable clinical effects, clinicians can now select hypnotic agents based on specific clinical and disease characteristics, such as age, specific insomnia type (initiation vs maintenance insomnia), presence of respiratory comorbidities (chronic obstructive pulmonary disease, sleep apnea), and a history of substance use/abuse.

In conclusion, decades of research confirms that insomnia is a highly prevalent condition with a variety of health risks and clinical consequences. Neurophysiological studies indicate that it is likely a disturbance of central nervous system hyperarousal with far-reaching effects throughout the body. In addition, it is now viewed as an autonomous disorder that is capable of interacting with comorbid disorders in a bidirectional fashion. A plethora of cognitive/behavioral and pharmacological treatments are also available to the clinician to address the specific clinical needs of the patient with insomnia.

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15. Vgontzas AN, Liao D, Bixler EO, Chrousos GP, Vela-Bueno A. Insomnia with objective short sleep duration is associated with a high risk for hypertension. 

Guest Editor-in-Chief Karl Doghramji, MD, FAASM, DFAPA, discusses the recent steps forward that have been made in the care of patients with insomnia.

December 2020

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Recent Advances in the Understanding of Insomnia

Eisai Targets Dravet Syndrome Indication for Lorcaserin With Multifaceted Study Design

A Team Approach to Asleep Deep Brain Stimulation

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