The latest news and research presented in multiple sclerosis and related disorders.

Live Coverage of MS Virtual 2020: The 8th Joint ECTRIMS-ACTRIMS Meeting

The latest research and news from the International Congress on Parkinson's Disease and Movement Disorders.

Live Coverage of the 2020 MDS Virtual Congress

"Mind Moments," a podcast from NeurologyLive, brings you an exclusive interview with Paul Fisher, MD, and Gerald Grant, MD, FACS.

Episode 22: Capitalizing on Collaboration in Neurology Care

Michael Okun, MD, executive director of the Normal Fixel Institute for Neurological Diseases sat down to discuss his viewpoint paper on changing the approval system for neurotechnological devices in rare diseases.

NeuroVoices: Michael Okun, MD, on Reforming the Device Approval Process

The onset of multiple sclerosis (MS) is commonly seen between age 20 and 40 years, making the millennial generation (aged 24-39 years in 2020) the most likely generation to develop MS in the coming years. As a cohort, millennials manage their health differently from the generations before them and thus will value and expect different things when it comes to their MS care. Furthermore, these differences may create new challenges for the health care team. Current MS practice must adapt to engage this unique generation and create innovative solutions tailored to their specific needs and desires. Doing so could afford this generation better prognostic outcomes as a result of increased engagement and disease management.

The defining quality of the millennial generation is their use of technology, although some may describe it as a dependence. Millennials are digital natives, meaning they are the first generation to grow up with the internet, and they integrate technology throughout multiple aspects of their everyday lives. Ninety-three percent of millennials own a smartphone, and nearly 100% use the internet.

 Furthermore, the millennial generation is the most educated generation yet, with 36% of millennial women and 29% of millennial men holding at least a bachelor’s degree as of 2017.

Their education and tech savviness enable millennials to leverage technology to better manage their health. In fact, 55% of millennials said they believed health-related information on the internet is as reliable as information from medical professionals, more than any other generation.

 Providers should value this personal motivation to seek out health information and continue to encourage patients’ self-learning. The advantages of easily accessing a multitude of information from a wide variety of sources on the internet, however, must be balanced with an understanding of the differing degrees of validity between sources. Less than half of millennials were concerned with finding false or misleading health data on the internet, the lowest percentage among all generations.

 Pointing patients toward trusted sources of information is an important first step to help encourage a credible knowledge source for these patients and to create a shared knowledge base between patient and provider. Equipping millennial patients in this way will emphasize their autonomy and facilitate shared decision-making between the patient and provider.

Building Trust to Enhance Patient Counseling

Current trends demonstrate an overall lack of trust in medical doctors by millennials; less than half of millennials were very satisfied with information from their doctor.

 Additionally, millennials were the least likely generation to respond, “I always listen to my doctor(s)” compared with other generations. Medical providers can build trust by understanding the communication strategies that millennials prefer.

As digital natives, millennials expect easy accessibility, rapid turn-around, and direct communication.

 Easy online appointment scheduling, short wait times, and online patient portals where patients can access their results and communicate directly with providers are examples of baseline logistics that health care providers can implement to start off on the right foot with their millennial patients. Millennials also value medical information directly from their peers: 4 out of 10 millennials trust their peers more than they trust medical professionals when it comes to their health.

 Providers can build off this heightened trust in social circles by utilizing young adult patient support groups to allow millennial patients with MS to share their experiences and learn from their peers. Highly versed in social media platforms, this generation could transform patient advocacy both locally and globally.

Using social media as a way to engage millennial patients with MS can be effective if done correctly. Millennials do, however, have a healthy dose of skepticism when it comes to health information on social media specifically. While 67% of Americans reported seeing health information on social media, only 35% said the information was even “mostly accurate.”

 Curated social media content from providers and clinics should emphasize the validity of the content by referencing studies, citing a trusted school or research organization, or including explanations directly from a medical professional. Consistency in communication style and content is key to bridging the gap between millennial patients and health care providers.

It would be a disservice to all patients not to note the complex impact of race on mistrust in the medical profession specifically.

 Ramifications from historic unjust medical practices continue to influence current medical practice, exemplified by the decreased participation in clinical trials by minorities due to the influence of the US Public Health Service Syphilis Study at Tuskegee (commonly known as the Tuskegee Syphilis Study).

 Because the millennial generation is the most diverse population in America, with minorities making up almost half of the population

 mistrust in medical providers and medical institutions may be heightened within the millennial cohort. It is imperative for providers to understand the history of racism in American medicine and the complex ways in which it influences patients today. Establishing a shared understanding of these health injustices with millennial patients can help rebuild trust one patient at a time.

Millennials are the most cost-conscious generation yet, and understandably so; millennials have higher levels of student loan debt, poverty, and unemployment rates than the 2 previous generations— Generation X and baby boomers—had at the same stage of their life cycles.

 This economic strain leads millennials to often cut corners when it comes to their health care, a dangerous trend when diagnosed with a chronic, progressive disease like MS. More than half of millennials admit to delaying or avoiding medical treatment due to cost.

 It is well known that the cost of MS care is substantial, and MS-specific health care costs have been shown to increase with disease severity. Those with mild to moderate disease severity spent an average of $30,000 on health care costs per year compared with $100,000 per year for those with severe disability.

 Therefore, a key strategy to decreasing overall costs for millennial patients is emphasizing disease prevention. For example, although disease-modifying therapies (DMTs) often account for the majority of MS-related health care costs due to their high price tags, an effective DMT is a patient’s best resource for preventing the frequency and severity of relapses and for slowing disease progression. Emphasizing the cost-saving strategy of disease prevention from the day of diagnosis is important to encourage millennials with MS to invest in their health care. As
new DMTs continue to be developed, often with greater efficacy at the expense of higher costs, it is imperative for providers to navigate costs with millennial patients when making treatment decisions. Treatment plans need to be individualized and align with each patient’s unique values and goals, as well as financial feasibility. These cost conversations should be initiated by providers to demonstrate a common understanding of the immense financial burden that an MS diagnosis entails. There is also a clear, increased need for financial advisers within MS practices to help millennial patients financially plan for lifelong MS health care costs.

Millennials report the worst mental and behavioral health outcomes compared to any prior generation.

 Compounding these trends is the increased prevalence of mental health disorders among the MS population in general. Patients with MS are 3 times more likely to experience anxiety or depression compared with the general population.

 Furthermore, inequity in mental and behavioral health prevalence has been seen among different demographics. In a survey of 1500 individuals, people who identify as LGBTQ+ were 3 times more likely to experience a mental health condition. Black and Hispanic respondents were more likely to experience every mental and behavior symptom assessed in the study compared with the study population as a whole.

Because millennials are the most diverse generation to date, MS providers should understand the increased burden of mental health on this generation as well as the unique experience of specific millennial demographics. Increased collaboration with mental health providers is imperative to providing quality MS care to millennial patients. Incorporating standardized depression and anxiety assessments into clinic workflow can equip providers to track mental health outcomes in their patient populations over time and serve as a launching point for provider-initiated conversations about mental health. Quality MS care must not only treat this unpredictable disease, but also adequately address the multiple disease sequelae experienced by patients, including mental and behavioral health.

Millennials are a technologically savvy, cost-conscious, diverse, and educated population who experience unique financial and mental health burdens compared with previous generations. Their distinctive characteristics drive change across multiple different sectors, including health care, and these changes create ripple effects across all generations. For example, millennial demand for technology has led Generation X and baby boomers to increasingly adopt technological platforms in their own lives.

 Early analysis of the youngest generation, Generation Z (those born after 1996), signal similar preferences to millennials, only heightened.

MS care not only needs to adapt to better serve millennial patients with MS, but to adequately serve
all generations past, present, and future. Innovative solutions geared specifically toward millennials will allow for increased patient engagement now and in the years to come.

1. Vogels EA. Millennials stand out for their technology use, but older generations also embrace digital life. Pew Research Center. September 9, 2019. Accessed October 12, 2020. 

https://www.pewresearch.org/fact-tank/2019/09/09/us-generations-technology-use/

2. Fry R, Igielnik R, Patten E. How millennials today compare with their grandparents 50 years ago. Pew Research Center. March 16, 2018. Accessed October 13, 2020. 

https://www.pewresearch.org/fact-tank/2018/03/16/how-millennials-compare-with-their-grandparents

3. Weber Shandwick and KRC Research. The great American search for healthcare information. November 13, 2018. Accessed October 12, 2020. 

https://www.webershandwick.com/wp-content/uploads/2018/11/Healthcare-Info-Search-Report.pdf

4. Waljee JF, Chopra V, Saint S. Mentoring millennials. JAMA. 2020;323(17):1716-1717. doi:10.1001/jama.2020.3085

5. Sullivan LS. Trust, risk, and race in American medicine. Hastings Cent Rep. 2020;50(1):18-26. doi:10.1002/hast.1080

6. Scharff DP, Mathews KJ, Jackson P, Hoffsuemmer J, Martin E, Edwards D. More than Tuskegee: understanding mistrust about research participation. J Health Care Poor Underserved. 2010;21(3):879-897. doi:10.1353/hpu.0.0323

7. Millennials in adulthood. Pew Research Center. March 7, 2014. Accessed October 13, 2020. 

https://www.pewsocialtrends.org/2014/03/07/millennials-in-adulthood

8. Five ways tech-savvy millennials alter health care landscapes. News release. PNC Healthcare. March 23, 2015. Accessed October 13, 2020. 

https://www.prnewswire.com/news-releases/five-ways-tech-savvy-millennials-alter-health-care-landscape-300054028.html

9. Owens GM. Economic burden of multiple sclerosis and the role of managed care organizations in multiple sclerosis management. Am J Manag Care. 2016;22(suppl 6):s151-s158.

10. APA Stress in America survey: Generation Z stressed about issues in the news but least likely to vote. News release. American Psychological Association. October 30, 2018. Accessed October 13, 2020. 

https://www.apa.org/news/press/releases/2018/10/generation-z-stressed

11. Beier ML. Multiple sclerosis and mental health: 3 common challenges. Johns Hopkins Medicine. Accessed October 13, 2020. 

https://www.hopkinsmedicine.org/health/conditions-and-diseases/multiple-sclerosis-ms/multiple-sclerosis-and-mental-health-3-common-challenges

12. Mind Share Partners. Mental Health at Work 2019 Report. Accessed October 13, 2020. 

https://www.mindsharepartners.org/mentalhealthatworkreport

13. Parker K, Igielnik R. On the cusp of adulthood and facing an uncertain future: what we know about Gen Z so far. Pew Research Center. May 14, 2020. Accessed October 13, 2020. 

https://www.pewsocialtrends.org/essay/on-the-cusp-of-adulthood-and-facing-an-uncertain-future-what-we-know-about-gen-z-so-far/

Articles

Effectively navigating the nuances of this unique patient population will ultimately help drive innovative solutions for this generation and those to come.

Managing MS in Millennials

 found that a ketogenic medium chain triglyceride (kMCT) drink improved executive function, episodic memory, and language by increasing blood ketone levels and brain energy status in patients with evidence of mild cognitive impairment (MCI). These findings reinforce the potential of brain energy rescue as a strategy to reduce cognitive decline in MCI) and Alzheimer Disease (AD).

The brain energy rescue process is achieved by offering the brain more ketones to metabolize when brain glucose metabolism decreases, which is a common effect of these disorders. Study author Stephen Cunnane, PhD, Research Center on Aging, Universite de Sherbrooke, and colleagues found that when compared to placebo, the kMCT group scored higher on free and cued recall (

 = .017) after a 6-month randomized, controlled trial.

This study followed up the Brain Energy, Functional Imaging, and Cognition (BENEFIC [NCT02551419]) study that showed a kMCT drink improved brain energy status and aimed to assess the effect of kMCT on cognitive outcomes. To learn more about this new study and how its findings can help benefit those at risk for Alzheimer Disease, 

: Were you surprised to see such significant improvements on these cognitive assessments?

: Yes and no. No because we're not the first to have tried ketogenic interventions in MCI or an Alzheimer's disease, I think the first reports date from 2004, so there was a bit of a trail that had been blazed by other pioneers in this area that encouraged us, but nothing was conclusive. So, we weren’t too surprised, but we were delighted to see an effect in MCI because it's an early stage of the disease. Logically, you would try to slow down the disease at the earliest stage possible. But it's a double-edged sword, because if the problem is quite minor, it's hard to show that you've actually corrected it. In some ways, it would be better to wait until the problem is more severe, and then you have a better chance of seeing an improvement, but that’s not a guarantee. This is the continued dilemma in this field as to when to start, how long to do it, what dose to give. In our case, because we didn't know what amount would be needed to achieve these results, we went with a dose that seemed to be near the upper widely tolerated limit. People do have gastrointestinal side effects, discomfort, stomach discomfort, sometimes diarrhea if they take too much in one shot. There's definitely an upper limit, but everything worked out in the end.

How do you think this study can improve health care for patients suffering from MCI or Alzheimer?

I think the most important thing is that it shows a proof of concept. That is, that you can improve cognitive outcomes in MCI. This is not a dead-end street—it looks like there's a way out, if you start early enough. And if you have something that can effectively help with brain energy status, there may be drugs that would be complimentary, that could help with the neurotransmitters in the brain or within your inflammation in the brain, or with some other aspect, and that would be synergistic. But it seems like dealing with the energy problem is part of the solution. So, it's a proof of concept for scientists and clinicians in this field, and hopefully encouragement for them to go on and do their own studies in their own way and confirm what we've seen. I think it also gives a ray of hope to people for a disease that will strike many of us. But if you take preventive approaches early enough, you can delay it. Well, we're looking to confirm that. This is the next step that we're going do, but we know that we can improve cognitive outcomes in a six-month period. Some people take ketogenic salts, perhaps for this reason or for other reasons. But exercise would also be complimentary. You still need to solve problems like depression, during aging, which contributes markedly to cognitive decline. You need to solve problems of inadequate sleep. social isolation—with COVID these days, that's an even bigger challenge than normally. But remember that there's no single solution. There'll be no miracles. And it's piecing together the parts that will this slow down this disease. That is, I think the only realistic strategy. Prevention strategies have been shown in other studies, as well involving dietary improvements over cardiovascular risk reduction, cognitive stimulation. And I think brain energy rescue is simply part of the package that will help them all become more effective.

1. Fortier M, Castellano CA, Croteau E, et. al. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. 

. 201915(5):625-634. doi: 10.1016/j.jalz.2018.12.017 
2. Fortier M, Castellano CA, St-Pierre V, et. al. A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT. 

. Published online Oct 26, 2020. doi: 10.1002/alz.12206

Stephen Cunnane, PhD, Research Center on Aging, Universite de Sherbrooke, discussed the findings and implications of a recent study of the drink’s effects on patients with mild cognitive impairment.

Improving Cognitive Function With a kMCT Drink

 (ODD) to Seelos Therapeutics’ drug SLS-005 (Trehalose) for the treatment of amyotrophic lateral sclerosis (ALS), or Lou Gehrig disease.

The therapy is believed to impact autophagy through Transcription Factor EB (TFEB), which plays a key role in lysosomal and autophagy gene expression, and thus increase clearance of the protein aggregates that build up in motor neurons of patients with ALS, such as 

"Several preclinical studies have demonstrated the potential of trehalose as a treatment for ALS, demonstrating preservation of motor neurons, motor function and prolonged survival. We are excited to start our clinical program for this devastating disease," said Warren W. Wasiewski, MD, FAAP, chief medical officer, Seelos, addressing planned trials in a statement.

Seelos will conduct a 24-week phase 2b/3 trial of 160 patients with either familial or sporadic ALS in a double blind, placebo-controlled trial. Change will be measured from baseline to 24 weeks using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Slow vital capacity, muscle strength, quality of life measurements, and other signs of disease progression will be studied.

"ALS is a debilitating disease which currently lacks a cure and there is significant evidence suggestive of trehalose having the potential to alter or slow the progression of ALS," said Raj Mehra, PhD, chairman and CEO, Seelos, in a related press release.

 “The FDA signoff to begin this pivotal study allows Seelos to focus on ALS as the lead indication for SLS-005.” 

The agent is a low weight disaccharide that is able to cross the blood-brain barrier. Protein aggregates such as 

 develop as a result of mutations in the 

 genes. Clearing the aggregates has been shown to delay the progression of the disease, preserve motor neurons, and increase muscle fiber size. The activation of TFEB is also beginning to be investigated as a possible mediation of other diseases that involve harmful protein aggregation.

Trehalose has been shown to reduce aggregation of misfolded proteins and harmful detritus in animal studies, however, the effects of trehalose are not conclusive, and its mechanism remains largely theorized. 

He-Jin Lee, PhD, associate professor, Department of Anatomy, Research Institute of Medical Science, Konkuk University, and colleagues reviewed the numerous investigations on trehalose in order to reach a consensus on its actions on the body.

 Lee and colleagues stated in their paper that “neuroprotective effects of trehalose have been fairly consistent in many different neurodegenerative disease models. It has been hypothesized that trehalose directly acts on neurons and induce autophagy, thereby promoting the clearance of protein aggregates. However, careful examination of the literature raised a question as to whether trehalose can directly induce the autophagic process. A recent paper, indeed, showed that trehalose treatment of neuronal cells hampers the progression of autophagosomes to autolysosomes. Furthermore, it is not clear whether and how much trehalose can be delivered to the brain parenchyma when it is administered to the animals.”

The authors propose that “trehalose intake exerts neuroprotective effects in neurodegenerative disease models through a direct or indirect mechanism, which may involve the gut microbiota.”

Earlier this year, trehalose was also granted ODD for the treatment of patients with Mucopolysaccharidosis type III (MPS III), also known as Sanfilippo syndrome, another rare neurodegenerative disease that involves the accumulation of protein and waste aggregates.

1.Seelos Therapeutics receives US orphan drug designation for SLS-005 (Trehalose) in Amyotrophic Lateral Sclerosis. News release. Seelos Therapeutics. November 19, 2020. Accessed November 24, 2020. 

https://www.prnewswire.com/news-releases/seelos-therapeutics-receives-us-orphan-drug-designation-for-sls-005-trehalose-in-amyotrophic-lateral-sclerosis-301176560.html


2. Seelos Therapeutics Receives FDA May Proceed Notice to Initiate a Phase IIb/III Trial of SLS-005 in Amyotrophic Lateral Sclerosis. News Release. Seelos Therapeutics. August 10, 2020. Assessed November 24, 2020. 

https://www.prnewswire.com/news-releases/seelos-therapeutics-receives-fda-may-proceed-notice-to-initiate-a-phase-iibiii-trial-of-sls-005-in-amyotrophic-lateral-sclerosis-301108763.html


3. Lee H, Yoon Y, Lee S. Mechanism of neuroprotection by trehalose: controversy surrounding autophagy induction. 

. 2018; 9:712. doi: 10.1038/s41419-018-0749-9
4. FDA Grants Orphan Drug Status to SLS-005 for Treating Sanfilippo. News release. Seelos Therapeutics. May 7, 2020. Accessed November 24, 2020. 

https://sanfilipponews.com/2020/05/07/fda-grants-orphan-drug-status-to-sls-005-for-treating-sanfilippo/

Seelos Therapeutics will soon enroll patients in its phase 2b/3 trial of SLS-005 in amyotrophic lateral sclerosis. 

Trehalose Granted Orphan Drug Designation for Treatment of Patients with ALS

that has occurred over the course of the coronavirus disease 2019 (COVID-19) pandemic has shined an even brighter light on the already recognized care access challenges faced by patients with chronic, debilitating diseases such as multiple sclerosis (MS)—one that often requires repeat clinic visits and consults with a large team of health care professionals. With many of those visits now taking place virtually out of necessity, it has added support to the argument that there is a “clear and tremendous” need for more digital and telehealth-based interventions in MS.

This has long been the focus of clinical neuropsychologist Leigh Charvet, PhD, of the division of MS at NYU Langone Health in New York, who told 

that when these digital interventions are brought home to patients, clinicians reach a much broader spectrum of people living with MS—a highly important facet for research. Access to these resources, she said, underscores the demand for symptomatic management and rehabilitation, areas of treatment that often fall second to relapse prevention despite their immense impact on patient quality of life. To learn more about the digital therapeutic landscape and telemedicine’s place in the future treatment of MS, 

: Can you describe the evolution of your research into digital, home-based interventions for patients with MS?

: My entry into this world was with cognitive remediation, which we know that we need a lot of training to do. That’s probably one of the early therapies that has very well designed and accessible computer-based or online-based training. That was really our first entry into this, to send people computers to their home and supervise them remotely to complete our first trial. They did 60 sessions over 12 weeks, so you could just imagine that that wouldn’t have been able to be done if they were coming to clinic. In general, with cognition, we also think of what a lot of times we call the “invisible symptoms” that have such a burden on day-to-day living for so many people. That definitely includes fatigue, and things like pain, and emotional distress is another huge component for many of us. Our approach has been to evaluate computer-based or app-based interventions targeting these symptoms remotely, and we do that because we can reach many more people and provide the adequate number of treatment sessions.

Our particular focus moved from that cognitive rehabilitation trial to evaluating the use of noninvasive brain stimulation, in particular, something called transcranial direct current stimulation (tDCS). That’s in the world of noninvasive brain stimulation therapies, but it can be portable and wearable. We knew that we could reach people in their homes, so we developed a whole protocol where we do live video visits to help people self-administer, with supervision, tDCS. The idea with tDCS is it may be therapeutic on its own. For instance, it is approved in many countries for the treatment of depression, but we’re particularly interested in its ability to boost rehabilitative outcomes. The idea is that pairing the stimulation while you’re doing a training activity may boost the benefit of the training activity. We took our cognitive remediation that we had established and then added tDCS to that.

That also brought us into the world of some motor rehabilitation. For instance, there is an established at-home hand exercise program to strengthen and recover hand function, where we’re actually adding tDCS to that right now in the clinical trial. We’re also very interested in types of exercise, physical therapy, and aerobic exercise at home paired with the brain stimulation to see if we can boost the benefit of that training activity.

We’re interested in its benefits for fatigue, in general. There are a lot of parameters on how to use it, and in our research program, we’re sending it home. And with our absolutely amazing patient participants who are true collaborators, we’ve designed a platform where we can reach people in their homes and have the high volume of sessions and sample sizes needed to really evaluate these emerging therapeutics. In that work, what we’ve seen is that people are able to do what would seem on paper to be very complicated procedures in their homes with supervision. We’ve learned how to take on the technical burden on our side, and then guide people to be able to do these therapies very successfully in their homes.

How easily could these interventions be incorporated into standard care that patients with MS receive?

I think we’re pretty close to that, but there are a lot of these emerging therapeutics—and this is not specific to MS, especially as these things are computer-based—where there’s a disconnect between a provider or therapist telling a patient, “Here’s something that you can access that will help you,” and then the patient actually doing that. We all know that you should go to the gym every day, but if I don’t have a personal trainer or somebody watching me, I’m not going to do it. It’s hard to change the behavior. Because of the brain stimulation part with tDCS, we are live with patients through video visits every time. That’s really helped to have that behavioral adoption of the daily treatments, and I think that is a critical ingredient, that there is this supervised, connected onboarding of these daily therapies. There are all these wonderful tools out there, and many of them need more research, but the uptake is not there yet, and I think that connection is necessary for wider-scale adoption and people truly benefiting from these therapies.

What kind of barriers to adoption of these therapies have you experienced from both patients and the clinical community?

There are 2 types of pushback; 1 is awareness. Raising awareness for your patients of this tool does not mean that they’ll use it and benefit from it. That’s a common experience for a provider. Maybe [the provider] is aware of the tool, they refer their patients who then have the tool, but they hear, “Oh, I looked at it twice, and I didn’t do it.” There’s that critical period of structured onboarding, how to use it, in order to have an adequate evaluation. I think that causes premature dismissal of some things that are actually of great therapeutic benefit. Second, despite moving the dial on the acceptability of telehealth at a lightning rate because of COVID-19, there’s always been the pushback of “people can’t do that.” [Excuses like] my patient isn’t computer or tech savvy, or my patient has too much cognitive involvement or too many motor impairments to be able to do that. However, if you take care of designing the intervention, those are all easily overcome, and that’s what we found in our journey with our program.

Do you anticipate that more MS centers will adopt these interventions for at least some patients as they are validated?

Well, the short answer is absolutely. But I think what you raised is the critical piece, in terms of validation. What happens is, you have a glut of apps and online programs, and some are very science based. They take what we know from in-person therapy and make it into a digital therapeutic for access. Others are very different, and it’s hard for the consumer—it’s hard for the researcher—to tell the difference sometimes between what is what. We need carefully controlled clinical trials to guide our use because nobody wants to tell anybody to use something, to put the time into something, that hasn’t been demonstrated to be worth their time. I don’t think it would replace anything that we do now. We have our provider care, our nursing support, our social worker support, our therapists—physical, occupational, all kinds of therapists that we work with. That’s already comprehensive care on-site, but this would supplement it because we know that so many people in between these visits still have significant burden of disease, primarily with these symptoms for which there aren’t any tools to readily manage them. Therefore, access to these digital therapeutics might fill that need.

How might these digital and telehealth approaches influence data collection for the study of the MS population?

It will absolutely have a positive effect in getting therapies evaluated for what we call pragmatic practical use, so very downstream. For very good reasons, clinical trials have that rigorous enrollment eligibility criteria because it’s a different set of questions. We’re on the total opposite end of the spectrum in that we want to reach as many people living with MS as possible, to have these tools evaluated. Then we can see that maybe there’s a segment or something that wouldn’t benefit from them, but let us find out by including everybody. We’re much more focused on inclusion, and in that, we’ve been able to demonstrate that it’s very important for evaluation of these types of therapies—any kind of tele- or digital therapeutics—to include the broadest spectrum of people living with MS as possible. That’s important for so many reasons. There’s a segment of people living with MS who are left out of a lot of clinical trials right now, and they face even more burden to get to a clinic visit to receive some type of therapy for a trial. We’ve been encouraged by being able to reach so many more people than are typically reached in a clinical trial to evaluate these therapies.

As the adoption of telemedicine rises, the ability to incorporate digital and telehealth-based therapies offers clinicians a unique opportunity to supplement the comprehensive care model.

The Future Is Digital: Telemedicine Is Helping Open Doors to More Comprehensive Care in MS

 by Michael Okun, MD, and James Giordano, PhD, highlighted some of the major flaws with the process in which deep brain stimulation and neurotechnological devices are approved for patients with rare diseases. While the process for requesting orphan drug designation for the use of specific drugs may be more straightforward, neurotechnological devices that are developed and/or can be used for rare diseases do not benefit from the same approval process.

Humanitarian device exemptions (HDEs) have been used as a regulatory pathway for device availability in rare diseases but are slowly being phased out due to industry partner concerns over the costs required to develop and maintain the HDE, as well as limitations of profit, tax exclusivity, lack of incentives, and legal liability. Okun and Giordano touch upon multiple issues within the system, including the barriers set by insurance companies which force patients who seek this selective type of care to pay out-of-pocket costs.

Okun, the executive director of the Norman Fixel Institute for Neurological Diseases, and Adelaid Lackner Professor and chair of neurology at the University of Florida, also serves as the medical director of the Parkinson’s Foundation. He calls for major reform throughout the paper, with an emphasized use of disease-based registries and modifications to the preexisting condition clause of the Patient Protection and Affordable Care Acts.

As part of the NeuroVoices series, Okun sat down to provide in-depth explanation of the flaws of approval system for neurotechnological devices for patients with rare diseases, and why they do not receive the same standardized process that clinical drugs have as they go through the pipeline. He also touched on the issues that stem from insurance companies and why change is only attainable if all levels are engaged at the discussion table.

: Why do neurotechnological devices that are developed for rare diseases not receive the same benefit as other drugs that may receive orphan drug status? Where is the disconnect?

: I would back up first and say that we’re dealing with a system that’s decades old in place, even before the advent of all these new devices and precision medicine. I don’t know that when it was first constructed but people saw these devices, particularly brain and spinal cord, not the way they see them as such transformational therapeutics. You’re dealing with a system that was designed for drug development, which is sometimes way easier. You take a pill, you document what happens with the pill, and decide yes or no. Same way vaccines were developed as well. When you implant a device, there are bumps in the road. When you implant that device in a human, there’s no blood supply, so the device can get infected. Even if you take an antibiotic, you may not be able to clear that section, and the device may have to come out. This can be anything from a pacemaker for the brain, to a spinal cord stimulator. Anything that you can put in has the potential to get infected and come out. There are hardware issues, things can break, there can be fractures, and pieces that need to be replaced. Additionally, there can be updates, software issues, all of which are not seen by pharmaceuticals in general.

The pharmaceutical industry has a heavy lobby, with a lot more money in it. I don’t think we should kid ourselves with that. If you lift the hood of the car, you’ll see that this is a very strong lobby group. I’m not judging that; I’m just stating the facts. But the device industry is expanding. Now you have a situation that nobody really anticipated. Let’s be fair, I don’t think even the smartest among us anticipated a situation where we might have a precision medicine for devices.

What do I mean by precision medicine? You could have a rare or a common disease, like Parkinson disease (PD), with a rare symptom. In that case, you can actually target a specific circuit in the brain and treat that symptom. The brain has added a level of complexity to the conversation. If you’re talking about the gallbladder, not that there’s anything wrong with the gallbladder, but the distributed network of the nervous system is amenable to being targeted by neuromodulation techniques. We can change the way the different areas communicate with each other and thereby, change individual symptoms.

Now we can change the paradigm. Normally, we get a drug, have it approved, and watch it treat the disease to the best it can. Now we have a situation where a device can be applied to a circuit as well which is very different. We have to appreciate the upside of that. The problem is that if we continue to have a process that is streamlined in the same direction as every drug, that leaves rare diseases out of the picture, or lessens their chance of moving forward. We mentioned in the report that if you’re involved in the drug development of rare diseases, you incentivize people to stay in the game. Those aspects don’t exist on the device side. In fact, what happens is that the cost to the manufacturer can be so high and the legal exposure can be at a level that creates an impossibility for a business to want to do business and get involved.

The example I’ve been involved with for many years stems from a grant from the Tourette Association of America. We have a publicly available database that has tracked 320 cases around the world for many years. Tourette still has no approval, but yet we know that our database works. We know that people with Tourette can have these head snapping tics where they can fracture their neck and become quadriplegic. They can have self-injurious behavior, which can lead to severe consequences to school, social isolation, and acceptance. We have a treatment that can suppress the motor and vocal aspects of Tourette by 40% to 50% better in most series with multiple targets, but we can’t apply it.

We’ve written about a bait and switch, which happens when both an insurance company agrees, their medical director agrees, and the conversation leads to confirmation about a patient having surgery. When payment time comes, they don’t pay for the device. They feel as though they aren’t obligated. We must recognize that we have shifted into a new era, and that we have to have a pathway for rare diseases and devices that can be used to treat these rare diseases or rare symptoms of common diseases.

The humanitarian device exemptions (HDEs) are beginning to fall apart as an option because insurance companies can still refuse payment on those. Device manufacturers are beginning to say, “Whoa, we don’t want this. We have legal risk. We have a million or so bucks to spend on someone patrolling this, along with all these complications and regulations. It’s not our core business anyway. Why do we want to bid?” Now I have to hold onto something that can help our kids and adults with Tourette, for example. Even if I can give it to them, the insurance company is going to bait and switch anyway. Our piece addresses the gaps. We have to have a process where we can move this in a different path. It’s reasonable to have data, but there should be a lower standard, especially if the data is done through foundations and universities and is publicly posted.

On the industry side, people should be given a legal break. Not a pass, but there should be breaks and incentives for them to make these devices available which can end up being life changing innovations for these various disorders. If we don’t do that, we’re going to be in trouble or just sitting on a lot of technology that can’t actually get out to these people with rare diseases.

How much blame is on insurance companies? Do you feel as though we are ever going to reach a point where they finally give that right-to-try?

There’s blame to go around all the way. If you give an insurance company an inch on a loophole, they’re going to take it. It’s a business, and we’ve given them a loophole out, so they’re going to exploit it. We haven’t held them accountable. My argument has been that they shouldn’t be able to loophole out of approvals from various things. They’ve loopholed out even when people have HDEs. They haven’t been paying for obsessive compulsive disorder cases, here, at the University of Florida, even with an HDE in place. In other places around the country, even though there’s an HDE, they don’t want to pay when there’s an ID or experimental IDE that’s in place.

They need to be pushed to say, “Yes, you do have that burden.” I would argue this is not necessarily a violation, but a direct conflict to the pre-existing conditions within the Affordable Care Act, because it appears to me that they’re not offering a treatment for a pre-existing condition. They would respond by saying we (clinicians) haven’t established the data and conversed with the regulatory agents, but that just leaves us stuck. You have to fix both parts of the system to get the wheel moving again. Let’s say you do allow people to post their data on public databases, and the FDA agrees there is enough evidence, then they should be held to a pre-existing standard. They shouldn’t be able to try to get out of that. This will probably reduce the long-term morbidity of the cases when its applied in the right situations as well as save these people money within their insurance systems.

There is a method to the madness, but there a few points in this wheel which make it complicated that need addressing. Industry needs to be given more of an incentive to stay in the game. Universities and foundations need to be allowed to track their own data. Remember, you’re going to need industry to submit on all the side effects and the upkeep of all of these things. The FDA is going to want to see that we’re not going to be able to provide on the device that’s being used. There has to be a way to track, and then there has to be a way within the law for us to say to insurance companies, “you can’t just say there’s a carve out or walk away from people with medical diseases.” I think there’s a few touchpoints that we get out with this piece that are very important.

Michael Okun, MD, executive director of the Norman Fixel Institute for Neurological Diseases sat down to discuss his viewpoint paper on changing the approval system for neurotechnological devices in rare diseases.

Brain imaging research in multiple sclerosis (MS) is experiencing an acceleration of technological progress. Fueled by the relentless pace of innovation in magnetic resonance imaging (MRI) and the recent outburst of artificial intelligence (AI), these advances are the crest of a new wave of scientific tools for the MS clinic.

Since its introduction nearly 3 decades ago, 2-dimensional (2D) multislice brain MRI sequences—such as proton-density, T2, fluid-attenuated inversion recovery (FLAIR), and T1 scans—have become the workhorses of any diagnostic or follow-up brain MRI exams for MS. The longevity of these scans, often referred to as conventional MRI, is explained by their high sensitivity in the detection of white matter lesions (WMLs) of the brain (represented as hyper- or hypointense focal areas) and their robust imaging on any 1.5-T and 3-T clinical scanners. However, recent advances in ultra-fast MRI sequences are about to completely transform the way these conventional brain scans are routinely acquired in hospitals and medical imaging centers.

Advances in Image Acquisition and Analysis

One of these new MRI sequences is simultaneous multislice (SMS), which collects multiple imaging slices concurrently.

 SMS can cut the scan time of conventional 2D multislice scans by a factor of 2 without degradation of image quality.

 Another technique, compressed sensing, collects and utilizes heavily undersampled data; this can reduce the scan time of any 2D or 3D anatomical scans by 20% to 50% while maintaining virtually equivalent image quality.

 Wave–controlled aliasing in parallel imaging is another technical breakthrough that combines an undersampling strategy with an efficient 3D encoding; this technique can massively accelerate any 3D T2, FLAIR, and T1 brain scan to reduce scan times to 1 to 2 minutes.

 Finally, AI-based image reconstruction techniques can improve the image quality of undersampled data, thus enabling shorter scans.

 This significant reduction in scan time will provide crucial benefits. First and foremost, patients will experience less discomfort as a result of a much shorter MRI exam, possibly as short as 10 minutes or even less. Second, a scan will be quickly repeated if motion affects image quality, enabling radiologists and neurologists to evaluate their patients’ images more consistently. Last, high-resolution 3D brain scans will replace conventional 2D brain scans, which produce thick-slice images, often containing large gaps between each slice. These important innovations will pave the way for widespread adoption of automated image analysis tools that provide invaluable information about MS disease activity.

Over the past decade, a multitude of image analysis techniques have been developed to automatically segment brain tissues and lesions using high-resolution 3D anatomical scans. These techniques rely on various approaches, including statistical methods (Method for Inter-Modal Segmentation Analysis

), machine-learning classifiers (Classification using DErivative-based Features

), and deep- learning algorithms (3D U-Net

). Currently, fully automated image analysis solutions powered by AI, including those from CorTechs Labs,

 Icometrix, and Quantib, are even offered as products that are approved for clinical use. Therefore, a flurry of imaging-based measures could be factored into the routine evaluation of patients with MS, including longitudinal volume changes of brain tissues, total/regional lesion load, and individual lesions.

Brain volume changes—which include whole-brain atrophy and regional brain atrophy (eg, cortical atrophy, thalamic atrophy)—are particularly useful as a measurement of brain tissue loss and have become widely accepted measures of neurodegeneration

; they are among the best predictors of physical and cognitive disability. Clinical trials evaluating new disease-modifying therapies (DMTs) for MS already incorporate brain atrophy measures as critical end points in their cohort studies. Further, ongoing efforts to improve the accuracy and reliability of these measures and build large normative reference data sets using cloud computing platforms will allow the ability to track brain atrophy routinely in individual patients. Tracking individual lesions, particularly the formation of new WMLs, is also useful to assess the biological response of a patient to DMTs targeting MS inflammatory activity. By automatically comparing a baseline 3D scan to a follow-up 3D scan, reliable detection of new lesions is now possible without using T1-enhancing lesions,

 thus preventing the repetitive use of macrocyclic and linear gadolinium-based contrast agents, a clinical practice that is being intensively debated because of possible safety concerns.

Additionally, monitoring persistent WMLs will become clinically relevant as some of the chronic lesions slowly expand over time. These slowly expanding lesions are in the spot- light of MS investigators, as they are believed to reflect the demyelination and axonal loss as a result of a smoldering inflammation behind an intact blood-brain barrier.

 Investigators suspect that this chronic inflammation drives the disease worsening observed in patients with progressive MS.

 For this reason, an ongoing race exists in the MS pharmaceutical industry to deliver the first brain-penetrant therapy that could stop this smoldering inflammation.

Other features of MS lesions may also have clinical significance. Specific lesion morphological characteristics, such as shape and surface features extracted from high-resolution 3D brain MRI scans, could help differentiate MS lesions from nonspecific WMLs.

 Additionally, lesion phenotyping based on 3D morphology may open new avenues for developing outcome measures, which would reflect the biological activity of MS lesions such as myelin repair.

Another feature, lesion intensity, is now assessed qualitatively in the clinic. As an example, chronic black holes that are known to be areas of permanent tissue destruction are defined as severely hypointense lesions on T1-weighted scans; however, depending on the type of MRI sequence and parameters of the T1 scan, the level of hypointensity can significantly change, thus hampering the proper identification of these black holes. A quantitative measure of the
T1 signal, referred to as T1 relaxation time, would provide a standardized metric of black holes, enabling their robust discrimination in the clinic.

 Initially dedicated to research, quantitative MRI techniques measuring T1 and T2 relaxation times have been significantly improved in terms of accuracy, reproducibility, and overall workflow. Some of these techniques, such as MAGnetic resonance image Compilation (MAGiC),

 2 inversion-contrast magnetization-prepared rapid gradient echo (MP2RAGE),

 are moving into the realm of clinical imaging. These techniques may even become the future workhorses of clinical MS brain protocols thanks in part to their additional capability of synthesizing multiple image contrasts simultaneously.

The advances discussed so far rely on MRI techniques that produce conventional image contrasts (eg, proton-density, T1, T2, and FLAIR). Unfortunately, these types of contrasts lack specificity regarding the underlying pathological mechanisms involved in the development of MS lesions. This poor specificity frequently complicates the evaluation of patients suffering from radiological mimics of MS, putting these patients at risk of receiving a misdiagnosis when there is an overreliance on MRI findings. Brain lesions related to comorbidities in patients with MS could be falsely interpreted as MS lesions and mislead treatment decisions. Therefore, a crucial need exists for MRI techniques to deliver biomarkers specific to MS pathology; currently, 2 extremely promising imaging biomarkers are in the research pipe- line to help address this issue of specificity (

The first and most mature biomarker is the central vein sign (CVS),

 which corresponds to the presence of a small vein running centrally through a focal lesion. The perivenular formation of MS lesions is a well-known biological phenomenon initiated by the breakdown of the blood-brain barrier, which releases inflammatory cells that radially diffuse from the inflamed vein into the surrounding brain tissue leading to focal demyelination. Advanced MRI techniques sensitive
to the magnetic properties of the brain can image these small veins thanks to the difference in magnetic susceptibility between venous blood and parenchymal tissue. One such technique is susceptibility-weighted imaging (SWI), which was initially developed to perform cerebral venograms. However, SWI scans acquire thick-slice images that do not allow adequate visualization of central veins running in a multitude of directions. For a more sensitive and robust detection of the CVS, optimized susceptibility-based techniques can be used instead. Indeed, T2*-weighted 3D echo-planar imaging (or T2*-3DEPI) and FLAIR* (a combination of FLAIR and T2*) produce high-isotropic-resolution 3D images that facilitate the identification of brain lesions with central veins.

 From a clinical perspective, CVS will be helpful for the differential diagnosis of MS. Multiple clinical studies have recently demonstrated that patients with MS have a significantly higher proportion of brain lesions with CVS than patients with migraine,

 Encouraged by these results, an ongoing multicenter study is investigating the diagnostic potential of CVS in undiagnosed patients with typical or atypical onset. By comparing the current diagnostic criteria against the prediction based on CVS detection, this large-scale prospective study could demonstrate a significant gain in speed and accuracy of MS diagnosis.

 Another potential benefit of CVS could be the detection of the disease even before its clinical manifestation. Indeed, patients with radiological findings but without any history of clinical symptoms can have a significant proportion of their brain lesions with CVS, suggestive of subclinical MS disease.

The second biomarker is the so-called paramagnetic rim lesions (PRLs). Using the susceptibility-based MRI techniques introduced above, along with advanced quantitative susceptibility mapping post-processing techniques, investigators very recently demonstrated that some MS lesions possess a paramagnetic rim located at their edges.

 This rim appears to correspond to the accumulation of iron-laden macrophages or microglia, which are thought to be the generation of the smoldering inflammation discussed previously. Although not all patients with MS have PRLs, those with PRLs clearly experience a more aggressive disease.

 These findings point to the potential value of PRLs as a prognostic biomarker. In addition, PRLs appear to be very specific to MS lesions

 and may be a complementary biomarker for MS diagnosis. To prepare for future clinical use of these biomarkers, automated solutions for the detection of CVS and PRLs are already in development using probabilistic methods,

 as well as deep-learning algorithms (CVSnet

Although imaging WMLs is the bread and butter of clinical MRI, cortical lesions are seen with increasing clinical importance and will become important radiological findings for predicting disease progression as well as evaluating new therapies for neuroprotection. Because of their specificity regarding MS pathology, cortical lesions are now part of the MRI diagnostic criteria for MS. However, in practice, these lesions remain difficult to detect reliably using conventional MRI scans. Newer techniques such as phase-sensitive inversion recovery

 and the very recent inversion-recovery susceptibility-weighted imaging with enhanced T2 weighting

 can improve the visualization of cortical lesions on 3T scanners, especially the detection of subpial lesions associated with cognitive decline and disease progression. Meanwhile, another powerful strategy for imaging cortical lesions with high sensitivity utilizes scanners with a stronger magnetic field, such as the 7-T scanner.

Seven-tesla MRI produces exquisite images of the human brain by achieving very high spatial resolution—on the order of hundreds of micrometers. This high-end imaging device has been intensively used in clinical research over the past 10 years to noninvasively investigate MS pathology developing in patients’ brains.

 This sustained research effort has brought new insights into the understanding of cortical and white matter MS lesions

 and sparked the discoveries of the CVS and PRLs. The recent FDA approval of the first 7-T MRI for clinical use is another major step forward for MS imaging, as it will enrich the clinician’s toolbox for diagnosing MS43 and speed up the clinical translation of future imaging biomarkers yet to be discovered with this cutting-edge imaging technology.

Without a doubt, MS imaging is set to undergo an exciting technological transformation. The next-generation MRI techniques discussed here will provide clinicians with an unprecedented wealth of information about this complex and multifaceted disease. By fully embracing these technological and scientific shifts on the horizon, neurologists will enhance their ability to diagnose earlier and more accurately, identify and anticipate the trajectory of the disease, and adapt treatment strategies to keep the irreversible progression of the disease at bay. Lastly, integrating rapidly innovative imaging biomarkers into the clinical trials of emerging drugs—especially those promoting neuroprotection and neurorepair—will help finally turn the tables on this debilitating disease. All in all, the future of MS imaging is very bright.

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Advanced imaging technology collides with artificial intelligence in what is shaping up to be a revolutionary period for the diagnosis and management of MS.

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