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"Mind Moments," a podcast from NeurologyLive, brings you an exclusive interview with David Vossler, MD.

Ep. 18: Preventing Tonic-Clonic Seizures in Refractory Epilepsy

The FDA has sent a complete response letter (CRL) to Aquestive Therapeutics for its new drug application (NDA) for diazepam buccal film (Libervant) for the management of seizure clusters. The agency indicated that certain weight groups in a study that was part of the NDA showed a lower drug exposure level than what was desired.

Aquestive noted in a release that it plans to provide the FDA with additional information on pharmacokinetic modeling in order to demonstrate that the desired levels of exposure can be achieved with dose adjustments. Additionally, the regulatory agency stated that a small number of deviations from protocol were identified in blood draws in 1 of the studies included. No other safety, clinical, or Chemistry, Manufacturing and Control issues were identified in the CRL, and no further clinical studies are anticipated as necessary to complete the resubmission for the therapy. 

“While we are surprised by and disappointed with the Agency’s decision, we remain committed to continuing to work with the FDA toward approval of Libervant to provide epilepsy patients with the first orally-administered treatment for breakthrough and seizure clusters,” said Keith J. Kendall, president and chief executive officer, Aquestive, in a statement. “We look forward to quickly scheduling a meeting with the FDA to solidify Libervant’s path forward and in-turn move toward the NDA resubmission before year’s end. Epilepsy patients have been underserved for some time with little choice beyond device-based products such as rectally administered gels and nasal sprays and Libervant represents a meaningful and improved therapy for patients who can’t or won’t use the alternatives.”

Based on its interactions with the FDA, the company stated that this CRL will not be a barrier to the eventual approval of the therapy. Aquestive added that it plans to request a Type A meeting with the FDA in the coming weeks with plans to resubmit the NDA before the end of 2020, which would result in a new Prescription Drug User Fee Act (PDUFA) action date sometime in the first half of 2021.

The NDA was originally accepted for submission in early February of this year. It was supported by data from a single-dose crossover study (NCT03953820) including adult patients aged 18 to 65 years with epilepsy who were on a stable regimen of ≥1 antiepileptic drug, the data from which were presented at the 2019 Annual Meeting of the American Epilepsy Society (AES). Those patients were randomly assigned to receive a single dose of either diazepam buccal film or diazepam rectal gel separated by a 28-day washout period. Both were administered according to a weight-based regimen—dose range: 12.5–17.5 mg for the buccal film; 12.5–20 mg for rectal gel for 51–111 kg.

In total, 28 patients were included in the final analysis, receiving mean doses of 15.4± -1.9 mg of the diazepam buccal film and 17.1± -3.0 mg of the rectal gel. Mean Cmax values for the buccal film were 204.26 ng/mL compared with 211.22 ng/mL in the rectal gel group, demonstrating comparable but less variable Cmax values with diazepam buccal film versus rectal gel (

 <.0001). Across the different weight categories, mean maximal plasma concentration (Cmax) values were consistently 150 ng/mL in the buccal film group.

The second study, also presented at AES 2019, was a phase 3 safety and tolerability trial (NCT03428360), in which patients aged 2 to 65 years were received diazepam buccal film doses ranging from 5 mg to 17.5 mg. Doses were administered at home by the patient or a caregiver, and could be given for up to 5 seizure episodes per month.

Results of that analysis included data from 72 patients (adults, n = 59; adolescents, n = 7; pediatric, n = 6). Overall, 6.9% (n = 5) of patients reported 7 mild treatment-related AEs over a mean of 192 days of follow-up, with 1 patient reporting mild local buccal discomfort. Thirteen serious, but non-treatment-related AEs were reported; however, no patients discontinued participation due to AEs. The most common treatment-related AEs were somnolence, lethargy, altered state of consciousness, mouth swelling, oral discomfort, gait disturbance, and skin sensitization (all n = 1).

REFERENCES
1. Aquestive Therapeutics Receives Complete Response Letter from FDA for Libervant™ (diazepam) Buccal Film for Management of Seizure Clusters. News release. Aquestive Therapeutics. September 25, 2020. Accessed September 28, 2020. www.globenewswire.com/news-release/2020/09/25/2099499/0/en/Aquestive-Therapeutics-Receives-Complete-Response-Letter-from-FDA-for-Libervant-diazepam-Buccal-Film-for-Management-of-Seizure-Clusters.html
2. Seinfeld S, Gelfand M, Heller AH, Buan C, Slatko G. Safety and tolerability associated with chronic intermittent use of diazepam buccal film in pediatric, adolescent, and adult patients with epilepsy. Presented at: 2019 American Epilepsy Society Annual Meeting. December 6-10, 2019; Baltimore, MD. Abstract 3.444.
3. Rogawski MA, Heller AH, Farrow S, et al. Pharmacokinetics of diazepam buccal film in adult patients with epilepsy: comparison with diazepam rectal gel. Presented at: 2019 American Epilepsy Society Annual Meeting. December 6-10, 2019; Baltimore, MD. Abstract 1.432.

Articles

Aquestive Therapeutics plans to provide the agency with information on pharmacokinetic modeling to demonstrate that the desired levels of diazepam exposure can be achieved with dose adjustments.

FDA Issues CRL for Diazepam Buccal Film for Seizure Cluster Treatment

New study findings from an assessment of artificial intelligence (AI) based deep learning platform, dubbed DystoniaNet, suggest that the platform can accurately identify patients with dystonia within a single second via magnetic resonance imaging (MRI) data. The investigators noted that the tool may help clinicians severely cut down the time to diagnosis in an otherwise challenging condition.

All told, when doing a comparison using MRI data from 612 individuals—220 healthy subjects and 392 with 3 types of isolated focal dystonia (laryngeal dystonia, n = 279; cervical dystonia, n = 59; blepharospasm, n = 54)—the DystoniaNet platform diagnosed the condition with 98.8% accuracy in a matter of 0.36 seconds. Specifically, it showed 98.2% accuracy in diagnosing laryngeal dystonia, 100% in diagnosing cervical dystonia, and 98.1% in diagnosing blepharospasm, while referring 3.5% of patients (n = 6) for further examination.

The performance of the platform lends credence to its potential to make an impact in the movement disorder field, as dystonia is an oft-misdiagnosed condition that can take up to a decade for patients to correctly receive.

“We basically leveraged the advances made in deep learning and designed an architecture that was able to look at raw structural MRI and find a biomarker for dystonia that could help with the diagnosis of this disorder,” study author Davide Valeriani, PhD, postdoctoral research fellow in the Dystonia and Speech Motor Control Laboratory at Mass Eye and Ear and Harvard Medical School told 

. “We specifically took an approach that could be easily clinically translated, which is why we used raw structural MRI. This kind of measure is what comes out directly from the scanner and is available to many clinicians in-clinic.”

Valeriani explained that the DystoniaNet platform takes the MRI and learns from the training algorithm developed from one of the largest dystonia datasets, and then uses this data-driven approach to identify the condition. It was developed over the last several years by Valeriani and coauthor Kristina Simonyan, MD, PhD, DrMed, director, Laryngology Research, Mass Eye and Ear; associate neuroscientist, Massachusetts General Hospital; and associate professor, Otolaryngology-Head and Neck Surgery, Harvard Medical School, and was assessed in an analysis-driven marker evaluation previously.

Optimal Management of OFF Episodes in Parkinson's Disease

“[The analysis-driven] results were quite encouraging, where we would have an accuracy between 71% and 81% correctly diagnosing dystonia, and research from other labs also has shown that similar analysis-driven biomarkers can be implemented for diagnosing dystonia” Simonyan said. “However, that was not good enough for us because that type of paradigm has to involve substantial data processing, which has been clinically challenging to do. Us clinicians just don’t have the luxury of several hours per patient to process their data. In a way, our study was designed to lessen the time burden on the clinician and to speed up the diagnosis.”

The performance of the biomarker and its DystoniaNet pipeline was consistently stable independent of the magnetic field strength (accuracy range, 98–100), MRI scanner vendor (accuracy range, 96.9–100), head coil (accuracy range, 95.2–100), T1-weighted image acquisition sequence (accuracy range, 98.3–100), or a data collection site (accuracy range, 97.6–100). The specificity was additionally confirmed with a third and supplementary independent dataset of 1480 healthy controls (accuracy, 96.9%; referral rate, 2.6%).

Simonyan noted that traditionally, this diagnosis is made based on clinical observations, and available literature suggests that that the agreement on dystonia diagnosis between clinicians using purely clinical assessments is as low as 34%, and with roughly 50% of the cases going misdiagnosed or underdiagnosed at a first visit.

It is estimated that 35 of 100,000 individuals have isolated or primary dystonia, though it is believed that this prevalence is underestimated due to the current challenges in diagnosis. Although Parkinson disease or stroke can lead to the development of dystonia, the majority of isolated dystonia cases have no known cause and impact only a single muscle group in the body. Focal dystonia can lead to disability and problems with physical and emotional quality of life.

“In some sense, this provided us an opportunity to train this machine-learning algorithm to diagnose dystonia because we had a large available dataset of neuroimages,” Valeriani said. “But we also made the development of DystoniaNet open to the possibility of extending it to other disorders. For example, we took away all the prognosis that’s required and just stared with raw structural MRI. Every patient could get that, and we have this data for many different disorders. We are currently testing this on some other disorders with very promising results—about 80% accuracy. We want to see how much this architecture will generalize to other disorders.”

REFERENCES
1. New Artificial Intelligence Platform Uses Deep Learning to Diagnose Dystonia with High Accuracy in Less Than One Second. News release. Boston, MA. Mass Eye and Ear. Published September 28, 2020. Accessed September 28, 2020. eurekalert.org/pub_releases/2020-09/meae-aip092320.php
2. Valeriani D, Simonyan K. A novel microstructural neural network biomarker for dystonia diagnosis identified by a DystoniaNet deep learning platform. 

. Published September 28, 2020. doi: 10.1073/pnas.2009165117.

The platform, dubbed DystoniaNet, was able to identify 3 varieties of focal dystonia in a matter of 0.36 seconds with almost 100% accuracy.

Focal Dystonia Accurately Identified by AI-Based Deep Learning Platform

Newly published data from a multicenter cohort study suggest there is an association between previous pregnancies and childbirths and the timing of clinically isolated syndrome (CIS) onset but did not appear to show an association between having more pregnancies or childbirths and later CIS onset.

Ai-Lan Nguyen, MBBS, neurologist, Royal Melbourne Hospital, and colleagues gathered data on gravida, defined as any pregnancy including pregnancy that ended in miscarriage and induced abortion, and parity, defined as childbirth after gestational age of more than 20 weeks, including livebirth and stillbirth in 2557 women before CIS onset.

Of these women, 1188 (46%) had at least 1 pregnancy and 1100 (43%) had at least 1 childbirth. Investigators found that later-onset CIS was more common in women with previous pregnancies and childbirths compared to those who had never been pregnant (hazard risk [HR], 0.68; 95% CI, 0.62–0.75; 

 <.001), with a median delay of 3.3 years (95% CI, 2.5–4.1). Of the 2557 total participants, 71 (3%) had their first demyelinating event during pregnancy.

Having 1 (HR, 0.70; 95% CI 0.61–0.79), 2 (HR, 0.67; 95% CI, 0.60–0.76), or 3 or more pregnancies (HR, 0.66; 95% CI, 0.58–0.75) delayed the onset of CIS compared with no pregnancies (

Ponesimod Shows Safe Cardiac Profile in MS

Prior to the study, there was no consensus on whether pregnancy can delay the first episode of demyelination or CIS despite multiple research attempts to unveil this information. Jennifer Graves, MD, PhD, neurologist, associate professor of neurosciences, UC San Diego Health, wrote in a related editorial that “although specific genes on the X chromosome may play a modest role in MS susceptibility and severity, reproductive factors, including sex steroid hormone production and pregnancy, have long been recognized to alter the disease course in MS.”

Reproductive history including duration of each pregnancy, date of delivery, and length of breastfeeding were all incorporated into the study. Researchers also pulled preexisting data such as date of CIS onset, date of birth, sex, date of clinical onset, and Expanded Disability Status Scale (EDSS) score from MSBase.

Nguyen and colleagues also found that having 1 (HR, 0.70; 95% CI, 0.62–0.79), 2 (HR, 0.66; 95% CI, 0.58–0.74), or 3 or more childbirths (HR, 0.69; 95% CI, 0.58–0.81) all delayed the onset of CIS compared with no pregnancies (

The mean age at CIS onset was 31.5 years (standard deviation [SD], 9.7) while the mean age at first pregnancy and first childbirth was 23.3 (SD, 4.5) and 23.8 years (SD, 4.5), respectively.

Graves continued to note that “concern remains that reverse causation could support the association of gravidity and parity status with MS risk, but Nguyen et al. tried to mitigate this issue by using age at onset (not risk) of CIS as the primary outcome measure and to treat pregnancy as a time-dependent variable.”

Three sensitivity analyses were performed. In the first, left censoring occurred at age 18 years instead of 16 years. In the second sensitivity analysis, analyses were stratified according to changing diagnostic criteria for clinically definite multiple sclerosis (CDMS). In the third sensitivity analysis, patients treated with DMT during CIS, before MS diagnosis, were included. All of the sensitivity analysis confirmed the results of the primary analysis. Additionally, a higher gravidity and parity number were no associated with a change in CIS onset.

Investigators noted that further studies are needed to help explain the mechanisms behind the associations between pregnancy and onset of MS.

1. Nguyen A, Vodehnalova K, Klinicik T, et al. Association of pregnancy with the onset of clinically isolated syndrome. 

. Published September 14, 2020. doi: 10.1001/jamaneurol.2020.3324.

2. Graves JS. Do pregnancies forestall the onset of MS? JAMA Neurol. Published September 14, 2020. doi: 10.1001/jamaneurol.2020.3332.

The study investigators noted that a higher gravidity and parity number was not associated with a delay in CIS onset.

Previous Pregnancy May Lead to Later-Onset Clinically Isolated Syndrome

An evaluation of the cardiac safety profile of ponesimod (Janssen Pharmaceutical) showed that treatment with the agent was not associated with an increased risk for major cardiovascular (CV) events such as myocardial infarction (MI), stroke, or CV death when compared to teriflunomide (Aubagio; Sanofi).

The dataset was from the phase 3 OPTIMUM study (NCT02425644) and was presented at 

, the 8th Joint ECTIMS-ACTRIMS meeting, September 11–13, 2020, by Till Sprenger, MD, neurologist, DKD Helios Klinik Wiesbaden.

Researchers found no major CV events (MACE)—defined as CV death, non-fatal MI, and non-fatal stroke—in patients who were treated with ponesimod. In comparison, 3 instances of MACE occurred in the teriflunomide group.

Among a cohort of 1131 patients who received treatment with either ponesimod (n = 565) or teriflunomide (566), cardiac treatment-emergent adverse events (TEAEs) that led to discontinuation occurred in 1 patient (0.2%) on ponesimod (cardiomyopathy) and 2 patients (0.4%) on teriflunomide (1 atrial fibrillation, 1 coronary artery insufficiency).

Patients within the study were between the ages of 18 and 55 years were randomized 1:1 to ponesimod 20 mg or teriflunomide 14 mg for 108 weeks. Those on ponesimod underwent a gradual 14-day titration starting with 2 mg implemented to address first-dose cardia effects. Blood pressure (BP) and 12-lead electrocardiogram (ECG) measurements were used to assess cardiac safety.

Sprenger and colleagues noted that there was no association between clinically significant bradyarrhythmia events and patients who had dosage uptitrated. Additionally, none of those evens were serious or led to discontinuation. No 2nd degree or higher atrioventricular (AV) blocks were reported.

READ MORE: Low-Dose Rituximab Safe, as Effective as High Dose in MS

Hazard risks (HRs) and rhythm TEAEs of special interest (AESIs) were reported in 29 patients (5.1%) on ponesimod compared to 24 patients (4.2%) in the teriflunomide group. On Day 1, the incidence of HR and rhythm AESIs was 2.1% in the ponesimod group and included bradycardia (HR, <50 bpm) in 0.7% and 1st degree AV block in 0.5%. First degree AV block was found in 0.4% of teriflunomide patients.

On Day 1, the max mean reduction in HR from pre- to post-dose at 2 hours was –8.7 bpm for ponesimod and –1.7 bpm for teriflunomide.

A total of 3 patients in the ponesimod group had post-dose asymptomatic HR ≤40 bpm on Day 1, and all had pre-treatment HR <55 bpm. Furthermore, new electrocardiogram (ECG) findings of sinus bradycardia was 20% in patients at risk for symptomatic bradyarrhythmia, compared to 3.0%, all of which were asymptomatic, in patients who were not at-risk.

 at ECTRIMS 2019. Results showed that ponesimod, an orally active, selective modulator of the sphingosine-1-phosphate receptor 1 (S1P) had a statistically significant 30.5% greater reduction in annualized relapse rate (ARR) compared to teriflunomide. At week 108, the respective ARRs for the ponesimod and teriflunomide groups were 0.202 and 0.290 (

Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS)

—an MS-specific, 20-item patient-reported outcome measure—scores at week 108 suggested statistically significant effects on fatigue symptoms with ponesimod in comparison to teriflunomide, with a mean difference of —3.57 (

Additionally, the cumulative number of combined unique active lesions (CUALs), measured with MRI, showed a 56% reduction (

 <.0001) with ponesimod. Although 12-week confirmed disability accumulation was observed in 10.1% and 12.4% of patients in the ponesimod and teriflunomide arms, respectively, the results were not statistically significant.

The results from this study led Janssen to 

 (NDA) for ponesimod for the treatment of adults with relapsing MS in March. The company did not announce a prescription user drug fee act (PDUFA) date or when they would hear back from the FDA on the NDA.

1. Vaclavkova A, Burcklen M, Freedman M, et al. Cardiac safety of ponesimod in relapsing multiple sclerosis in the randomized, active-controlled, double-blind, parallel-group phase 3 OPTIMUM study. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0194

2. New Head-to-Head Phase 3 Study Data Show Ponesimod Superiority Versus Aubagio® (teriflunomide) 14 mg in Adults with Relapsing Multiple Sclerosis (MS) [press release]. Stockholm, Sweden: Janssen Pharmaceuticals; Published September 11, 2019. Accessed September 25, 2020. prnewswire.com/news-releases/new-head-to-head-phase-3-study-data-show-ponesimod-superiority-versus-aubagio-teriflunomide-14-mg-in-adults-with-relapsing-multiple-sclerosis-ms-300916102.html.

3. Janssen Submits Ponesimod New Drug Application to the U.S. FDA for Treatment of Adults with Relapsing Multiple Sclerosis. News release. Titusville, NJ. The Janssen Pharmaceutical Companies of Johnson & Johnson. Published March 18, 2020. Accessed September 25, 2020. prnewswire.com/news-releases/janssen-submits-ponesimod-new-drug-application-to-the-us-fda-for-treatment-of-adults-with-relapsing-multiple-sclerosis-301026319.html

Researchers concluded that uptitration of ponesimod was not associated with clinically significant bradyarrhythmia events; none were serious or lead to discontinuation.

The treatment landscape for patients with tuberous sclerosis complex (TSC) recently expanded in August, with the FDA approving a 

 ([CBD] Epidiolex; GW Pharmaceuticals) for the treatment of seizures associated with TSC. The oral solution was approved for use in patients age 1 and older with TSC.

Epidiolex’s approval marks only the second FDA-approved treatment for TSC, which is associated with growth of benign tumors in the brain and other organs resulting in seizures, developmental delay, and behavioral problems. Martina Bebin, MD, professor of neurology and pediatrics, University of Alabama at Birmingham Epilepsy Center, understands the magnitude of the approval after practicing in neurology for over 20 years.

 to discuss the approval, challenges patients with TSC face, and the novelty of CBD as a therapeutic. Bebin also touched on the importance of the expanded indication for patients at such an early age, as well as where we currently stand on prevention strategies.

: What impact does the approval of CBD have on the way clinicians care for patients with TSC?

: The FDA approval of Epidiolex last month is very exciting, particularly for clinicians who care for patients with TSC because they have a very high seizure burden. About two-thirds of them develop drug-resistant epilepsy and it can be a very difficult condition to manage. Now, we have Epidiolex approved for TSC in a variety of seizure types, not just the focal seizures that were studied and identified in the trial, but also the researchers looked at generalized seizures and other types of generalized seizures. It’s really nice to have it approved in TSC because it only helps the numerous seizure types that patients with TSC have.

What sorts of challenges do patients with tuberous sclerosis complex face in comparison with other epilepsies?

The first thing is that it’s a genetic condition. In those patients, there’s 2 different genes that cause TSC, either TSC1 or TSC2. Interestingly, those patients with TSC2 have a much higher risk to develop epilepsy. One of the biggest windows of time for having high risk of seizure is within the first 3 years of life, and in particular the first year of life. By the age of 2, more than 80% will start having epilepsy. In tuberous sclerosis, you have tubers in the brain that are the primary generators of the seizures, which is a little bit different than some other types of epilepsies.

Can you discuss the novelty of CBD and the role it plays in the epilepsy community?

It’s been around for a long time now. Of all the compounds we’ve had, there are CBD formulations that you can get that have not taken the FDA route for drug approval process. As a clinician, I have much more confidence in a compound that has gone through the rigor of an FDA process that includes all the bars of safety and efficacy. It provides much more information in terms of guidance on how you can take care of a patient if you want to implement Epidiolex or CBD into their seizure management regimen.

The approval is indicated for those age 1 and older; what is the importance of treating patients with TSC at an early stage?

With Epidiolex being approved down to the age of 1, it can be very advantageous. You have that option to implement that in the regimen in a child that’s as young as a toddler. TSC is in somewhat of a unique position in that it is a genetic disorder. We have the capability to diagnose it prenatally, and that opens the opportunity for the children with TSC to be seen and followed very closely by a neurologist. It’s a very unique position of which, myself, as well as a group of other TSC researchers, are very interested in looking at. We want to identify children, particularly babies, before they even have their first seizure because the ultimate goal is being on the preventative side of epilepsy, which is where we’re headed. For now, it’s so nice to have another option that’s really gone through the rigor of the FDA process.

How far away from true prevention are we?

I’ve been practicing neurology for over 20 years and there has been a notable change in how clinicians’ practice, and it’s certainly within reach. We’re doing it now to be on the preventative side and early identification of patients with TSC. We have to figure out what impact we can have on early treatment. Not only how this impacts seizures, but does it impact their development, mainly because these children are at high risk for intellectual disability and autism. In our mind’s eye, the target is to find a cure. For many of the children I see, I think there’s great interest in their lifetime, probably in the next decade, that we can get there. The researchers in the test community are extremely motivated and creative thinkers are very enthusiastic about collaborating with our researchers and other disciplines. The basis of tuberous sclerosis is the mTOR pathway, which is so pivotal in so many systems within the body.

What are the next steps in treating patients with TSC? What are the current unmet needs?

At this point in time, a lot of emphasis has been placed, and is currently improving, on the early recognition and early identification of not only a patient to have the diagnosis of tuberous sclerosis, but the awareness of their risk for seizures and refractory epilepsy. To have Epidiolex as another option to treat this patient population is wonderful and welcomed. Not just that, but it also gives more options for parents who take care of their children as well.

How do you feel that this CBD product will impact future studies?

I know there’s a lot of enthusiasm and interest in not only how CBD or Epidiolex has impacted seizures, but to better understand its mechanism and what other potential benefits there might be from those CBD compounds. More and more information and better understanding of CBD and its utility in physiology is really emerging. We’re going to learn more and more as each year passes.

There’s been such an interest in the community with this approval. For parents or patients who are interested, definitely talk to your neurologist. Most TSC clinicians are certainly aware of Epidiolex, and it certainly may be an option for those who have not had the opportunity to try it in the past.

Martina Bebin, MD, professor of neurology and pediatrics at the University of Alabama at Birmingham Epilepsy Center, detailed the importance of cannabidiol for treatment of TSC.

Tuberous Sclerosis Complex Takes Major Step With Epidiolex Approval

's Friday 5! Every week, the staff compiles 5 highlights of 

's widespread coverage in neurology, ranging from newsworthy study findings and FDA action to expert interviews and peer-to-peer panel discussions.

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The current perspective on the care of patients and the anticipated developments of the future are detailed by Jessica Ailani, MD, in part 3 of this special 3-part multimedia series on the evolution of migraine care.

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The Latest News and Commentary on the Treatment of Alzheimer Disease

 shared some of the latest clinical developments and thoughts from leaders in the field.

 Podcast: Preventing Tonic-Clonic Seizures in Refractory Epilepsy 

, brings you an exclusive interview with David Vossler, MD.

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Indu Subramanian, MD,  director of the VA Southwest Parkinson’s Disease Research, Education, and Clinical Centers spoke to the importance of patient-focused interventions in PD.

Take 5 minutes to catch up on NeurologyLive's highlights from the week ending September 25, 2020.

NeurologyLive Friday 5 — September 25, 2020

Data from an analysis of the Penn State Adult Cohort suggest that insomnia accompanied by objective short sleep duration is linked to an increased prevalence of cognitive impairment, particularly as it relates to cardiometabolic health.

All told, those who reported poor sleep or chronic insomnia who slept for fewer than 6 hours were twice as likely to have cognitive impairment and possible vascular cognitive impairment compared with those who slept more than 6 hours. The analysis included 1524 adults (mean age, 48.9 years [±13.4]) and was conducted by Julio J. Fernandez-Mendoza, PhD, clinician scientist, Penn State Hershey Sleep Research & Treatment Center, Penn State Health, and colleagues.

“These data are among the first to indicate that patients who complain of insomnia and who sleep objectively short in the lab have a higher prevalence of mild cognitive impairment, particularly that associated with cardiometabolic risk factors,” Fernandez-Mendoza told 

. “From a practice standpoint, patients with insomnia who have cardiometabolic risk factors should be objectively evaluated for their nighttime sleep and cognition, and not just evaluated by self-reports. Conversely, patients with mild cognitive impairment presenting at neurology clinics who complain of insomnia, should undergo a sleep study not only to examine the potential contribution of sleep apnea and other sleep disorders, but also to identify this more severe form of insomnia that may require specific treatment approaches.”

He added that from the treatment standpoint, the data imply these patients might require more targeted therapeutic approaches, such as a combination of cognitive-behavioral and pharmacological therapies, due to this “clustering of highly impairing conditions.”

For this analysis, self-reported sleep difficulty was defined as normal sleep (n = 899), poor sleep (n = 453), and chronic insomnia (n = 172). Objective short sleep duration was defined as less than 6 hours of sleep, which was based on in-lab, 8-hour polysomnography. Cognitive impairment (n = 155) and possible vascular cognitive impairment (n = 122) were determined with a comprehensive neuropsychological battery.

The odds ratios (ORs) for cognitive impairment for those with poor sleep and insomnia with objectively short sleep duration were 2.06 (95% CL, 1.15–3.66) and 2.18 (95% CL, 1.07–4.47), respectively. Likewise, the ORs for possible vascular cognitive impairment for those with poor sleep and insomnia who slept fewer than 6 hours were 1.94 (95% CL, 1.01–3.75) and 2.33 (95% CL, 1.07–5.06), respectively.

Longitudinal Sleep Problems in Children Linked With Negative Well-Being

In contrast, participants who slept objectively more than 6 hours did not have significantly increased odds of cognitive impairment when they reported either poor sleep (OR, 0.72; 95% CL, 0.30–1.76) or chronic insomnia (OR, 0.75; 95% CL, 0.21–2.71). Possible vascular cognitive impairment increased odds for those with poor sleep (OR, 1.08; 95% CL, 0.42–2.74) or insomnia (OR, 0.76; 95% CL, 0.16– 3.57) were also not significantly increased with more than 6 hours of sleep.

Furthermore, those who reported normal sleep and slept objectively less than 6 hours were also not associated with significantly increased odds of cognitive impairment (OR, 1.48; 95% CL, 0.86–2.55) or probable vascular cognitive impairment (OR, 1.23; 95% CL, 0.66–2.32) when compared with the reference group of participants who reported normal sleep and slept objectively more than 6 hours.

The association of insomnia with short sleep duration and cognitive impairment “is particularly strong for possible vascular cognitive impairment, as identified by the coexistence of cardiometabolic conditions and cognitive impairment in this study,” the investigators noted. They noted that a variety of literature point to the association of short-sleep insomnia with physiologic hyperarousal, including hyperactivity of the hypothalamic-pituitary-adrenal and sympatho-adrenal-medullary axes and impaired cardiac autonomic modulation, in addition to a greater risk of adverse cardiometabolic health outcomes.

Additionally, Fernandez-Mendoza et al. noted that 2 studies have shown that insomnia with objective short sleep duration is linked to altered brain-based biomarkers: glutamate metabolites and brain-derived neurotrophic factor.

“Taken together, these data can lead us to surmise that the etiology of cognitive impairment in middle-aged adults with insomnia with objective short sleep duration may be more likely related to dysfunction of the neurovascular unit and microvascular brain damage, such as asymptomatic deep brain infarction, white matter hyperintensities, and accelerated brain atrophy,” they wrote, noting that with older-adult-age follow-up, the cognitive impairment will likely ultimately result from a mixture of cerebral amyloid angiopathy and microinfarction, microhemorrhage, and macrohemorrhage, which typically underlie vascular pathology.

“We need longitudinal studies that follow large groups of good sleeping and poor sleeping young and middle-aged adults for enough years to ascertain whether insomnia with objective short sleep duration is a predictor of cognitive decline and future development of cognitive impairment and dementia,” Fernandez-Mendoz explained. “We also need these studies to include neuroimaging and biomarker data so that the underlying etiology of the cognitive impairment observed in individuals with this type of more biologically severe insomnia can be truly disentangled.”

REFERENCES
1. Fernandez-Mendoza J, He F, Puzino K, et al. Insomnia with objective short sleep duration is associated with cognitive impairment: a first look at cardiometabolic contributors to brain health. 

. Published online September 24, 2020. doi: 10.1093/sleep/zsaa150
2. Fan TT, Chen WH, Shi L, et al. Objective sleep duration is associated with cognitive deficits in primary insomnia: BDNF may play a role. 

. 2019; 42(1): doi: 10.1093/sleep/zsy192
3. Miller CB, Bartlett DJ, Mullins AE, et al. Clusters of insomnia disorder: an exploratory cluster analysis of objective sleep parameters reveals differences in neurocognitive functioning, quantitative EEG, and heart rate variability. 

. 2016;39(11):1993–2004. doi: 10.5665/sleep.6230

The findings suggest that this insomnia phenotype is a more biologically severe form of the disorder associated with cardiovascular, cerebrovascular, and neurocognitive morbidity.

Short-Sleep Duration, Insomnia Linked to Doubled Risk for Cognitive Impairment

Based on findings from an analysis of stroke treatment times, investigators suggest that healthcare policies to implement efficient pre-hospital triage and accelerate in-hospital workflow may be needed after they found that any time delay to endovascular therapy (EVT) reduced quality-adjusted life years (QALY) and decreased the economic value of care provided by this intervention.

Markov model analysis showed an average gain of 39 days (95% prediction interval, 23–53 days) of disability-free life for every 10 minutes of earlier treatment with EVT.

For each 10-minute interval, the net monetary benefit (NMB) increased by $10,593 (95% prediction interval, $5549–$14,847) and by $10,915 (95% prediction interval, $5928–$15,356) from health care and societal perspectives, respectively. The researchers combined weighted QALYs and costs into 1 composite outcome, NMB.

The study concluded 849 patients with a large vessel occlusion (LVO) stroke at 65 years of age who were among participants in intervention arms across 7 EVT trials. Wolfgang G. Kunz, MD, associate professor of radiology, Ludwig-Maximilians-University of Munich, and the HERMES collaborators were among those who conducted the study.

READ MORE: SSRIs Have Mixed Risks, Benefits in Post-Stroke Recovery

Patients also gained an estimated 106 additional days of life in functional independence (95% prediction interval, 64–144 days) when EVT treatment was expedited by 10 minutes. Gained days of life in functional independence represented the additional cumulative time the simulated patient spent in the health states modified Rankin Scale (mRS) score 0–2 across the lifetime projection.

The similar accumulation of costs over time with later treatment were explained by the higher mortality rates, which resulted in proportionally lower acute costs within 90 days, thus equating a shorter overall life expectancy to overall lower long-term costs.

For early treatment within 60 to 119 minutes, EVT led to an average NMB of $425,738 from the health care perspective, adding on average more than $300,000 in care value compared to treatment within 360 to 419 minutes.

Kunz and colleagues also looked at the data from a nationwide perspective for the United States. They found that a median reduction of treatment time by 10 minutes was estimated to grant the annual patients with stroke treated with EVT 2440 additional QALYs (95% prediction interval, 1464–3316). Faster treatment by 10 minutes would increase the NMB of EVT by an estimated $242 million per year from a healthcare perspective (95% prediction interval, $127M–$339M) and $249 million from a societal perspective (95% prediction interval, $135M–$351M).

The sensitivity analyses confirmed that each later treatment has an annual continuous effect on QALYs, the percentage of patients living with functional independence, and the cumulative mortality.

Investigators used the age-specific annual death rate of the general population drawn from the United States Life Table. Hazard rate ratios by mRS health states reported by contemporary cohort studies were used to calculate the excess death rate of stroke survivors.

Understanding the outcomes of EVT has been continually examined within the stroke research community. A case-control study published in August indicated that patients with anterior circulation LVO presenting very late (>16 hours to 10 days) from their last well known (LKW) time 

, despite notions that the therapy can only be effective in a window less than 16 to 24 hours from LKW.

Age can also play a factor in outcomes of EVT. In Kunz et al, investigators performed an analysis on patients with a stroke onset at the age of 65. Recently published data from the MR CLEAN registry revealed that 

older age is associated with an increased absolute risk of poor clinical outcome

 in patients with acute ischemic stroke (AIS) treated with EVT, while the relative benefit of successful reperfusion seems to be high.

1. Kunz WG, Hunink MG, Almekhlafi MA, et al. Public health and cost consequences of time delays to thrombectomy for acute ischemic stroke. 

. Published online September 17, 2020. doi: 10.1212/WNL.0000000000010867

2. Kim BJ, Menon BK, Kim JY, et al. Endovascular treatment after stroke due to large vessel occlusion for patients presenting very late from time last known well. 

. Published August 10, 2020. doi: 10.1001/jamaneurol.2020.2804

3. Groot AE, Treurniet KM, Jansen IGH, et al. Endovascular treatment in older adults with acute ischemic stroke in the MR CLEAN registry. 

. Published online June 11, 2020. doi: 10/1212/WNL.0000000000009764

Markov model analysis showed an average gain of 39 days of disability-free life for every 10 minutes of earlier treatment with EVT.

Late Intervention With Endovascular Therapy Decreases Economic Value of Care

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The Mind Moments podcast features exclusive interviews with leaders in the field discussing the latest research and disease management strategies across the breadth of neurology, including epilepsy, multiple sclerosis, Parkinson disease, dementia, sleep disorders, and more.

Episode 18, "Preventing Tonic-Clonic Seizures in Refractory Epilepsy," features an interview with David Vossler, MD, professor, and medical director, The Neuroscience Institute, UW Medicine Valley Medical Center. He discussed the findings of a recently published phase 3 dataset on lacosamide, also known as Vimpat, and its effects on reducing genetic generalized onset tonic-clonic seizures (previously known as primary generalized tonic clonic seizures).

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Episode 18: Preventing Tonic-Clonic Seizures in Refractory Epilepsy

Results from a 2-center ambispective study presented at 

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, demonstrated that low doses of rituximab (Rituxan; Genentech/Biogen) seem to offer similar effectiveness with better safety profile than high doses when treating multiple sclerosis (MS).

Presented by Luciana Midaglia, MD, neurologist, Vall Hebron University Hospital, and the Multiple Sclerosis Centre of Catalonia, the study compared patients in the Barcelona center (BC; n = 249) who were administered 2 g of rituximab intravenously (IV) during at least 3 cycles, followed by 1 g every 6 months to those in the Girona center (GC; n = 54). In that cohort, 2 g rituximab was administered for at least the first cycle, followed by 500 mg every 6 months.

At baseline, mean annualized relapse rate (ARR) was 0.37 (±0.6) for those in the BC and 0.33 (±0.5) in the GC. At Year 1, ARR decreased to 0.05 (87.5%; 

Remaining stable or improvements on the Expanded Disability Status Scale (EDSS) score was found in 79.4% and 71.4% of progressive MS phenotypes in BC and GC, respectively. Median EDSS at baseline was 5.5 (BC: range, 1–9.0) versus 6.0 (GC: range, 1–8.0).

At Year 1, 2.7% of the BC population had contrast-enhancing lesions (CELs) and 19% reported with new T2 lesions. In comparison, 8% of those in the GC had CELs while 16% had new T2 lesions. At third year, 0% of the GC population documented CELs or new T2 lesions, whereas 12% of the BC reported CELs. Notably, there were 0 cases of CELs reported in the BC at third year.

In the BC, adverse events (AEs) occurred in 14.8% of patients during the first year compared to 4.1% at third year. Researchers noted that there was no difference in the dynamics of CD19% lymphocytes, while immunoglobulin (IgG) values in serum decreased significantly in the BC cohort throughout the first 3 years.

Rituximab, an anit-CD20 monoclonal antibody, has been widely used as an off-label treatment for MS, but has not received FDA approval for this indication. It was first approved in November 1997 and has been indicated for the treatment of chronic lymphocytic leukemia, rheumatoid arthritis, Non-Hodgkin’s lymphoma, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus.

The agent has been often linked in use to treat other MS phenotypes such as myasthenia gravis and neuromyelitis optica spectrum disorder (NMOSD). A study published in May showed that treatment with 

rituximab performs better if initiated earlier

 after the onset of generalized symptoms in those with myasthenia gravis.

 Results from another study of patients with NMOSD suggest that first-line treatment with 

rituximab is more effective in suppressing clinical activity

, independent of the antibody status, compared with mycophenolate mofetil (MMF) and other first-line immunosuppressants.

1. Midaglia L, Alvarez GB, Cedeno RR, et al. Rituximab treatment for MS: an observational multicentric dose comparison. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract PS01.05

2. Stewart J. Rituxan FDA approval history. Drugs.com. drugs.com/history/rituxan.html. Updated September 30, 2019. Accessed Thursday September 24, 2020.

3. Brauner S, Eriksson-Dufva A, Hietala MA, Frisell T, Press R, Piehl F. Comparison Between Rituximab Treatment for New-Onset Generalized Myasthenia Gravis and Refractory Generalized Myasthenia Gravis. 

Published online May 4, 2020. doi: 10.1001/jamaneurol.2020.0851

4. Poupart J, Gioivannelli J, Deschamps R, et al. Evaluation of efficacy and tolerability of first-line therapies in NMOSD. Neurology. 2020;94:1-12. doi:10.1212/WNL.0000000000009245.

In the third year of treatment, both dose cohorts did not experience any contrast-enhancing lesions, and only a small population in the Barcelona center showed new T2 lesions.

Low-Dose Rituximab Safe, as Effective as High Dose in MS

A cross-sectional analysis examining the use of midazolam (Nayzilam; UCB) by an emergency medical services (EMS) agency for treatment of adults with status epilepticus showed a significant deviation from evidence-based benzodiazepine use, contributing to the need for rescue therapy and respiratory support.

In total, 2494 cases of status epilepticus in adults were included in the analysis, with 1537 patients given midazolam at any dose (39.4% given 5 mg or more), yielding an administration rate of 62%.

Led by Elan L. Guterman, MD, neurologist, University of California San Francisco, the data showed that undertreatment with midazolam was associated with an increased need for rescue therapy, with 282 (18%) patients needing a second dose.

Those who received rescue therapy were less likely to have received an initial midazolam dose of 5 mg or more, were more frequently tachycardic, had lower Glasgow Coma Scale (GCS) scores, and were evaluated by providers who had seen a higher number of patients with status epilepticus during the study period.

National guidelines state that first-line, evidence-based treatment with midazolam requires administering the medication intramuscularly as a single 10-mg dose, and does not recommend the intranasal, intravenous, or intraosseous route of administration. Notably, no patients included in the study received the guideline-based dose of 10 mg; only 5 patients actually received a dose greater than 5 mg. Intranasal and intravenous injection accounted for 47% and 38.3% of midazolam administration, followed by intramuscular (13.7%) and intraosseous (1%).

Guterman and colleagues wrote that “this finding identifies an important gap in the treatment of status epilepticus and carries important clinical implications if EMS agencies nationally parallel this single site experience. The next challenge will be evaluating the true scope of the problem and identifying effective interventions to correct it.”

Higher midazolam doses were associated with lower odds of needing rescue therapy (odds ratio [OR], 0.8; 95% CI, 0.7–0.9) and were not associated with increased respiratory support, the primary and secondary end point of the study, respectively. In fact, higher doses of midazolam were associated with decreased need for respiratory support after adjustment (OR, 0.9; 95% CI, 0.8–1.0). Notably, receiving a midazolam dose of 5 mg or more was associated with lower odds of needing respiratory support (OR, 0.8; 95% CI, 0.7–1.0).

Respiratory support was ultimately required by 678 of the 1537 (44.1%) patients who received any dose of midazolam, with 517 (33.6%) patients requiring ventilatory support. Those who required respiratory support were more likely to be male, have comorbid alcohol and drug use, were tachycardic, had lower oxygen saturation, had lower GCS scores, and were evaluated by providers who had seen a higher number of total seizure and status epilepticus patients during the study period.

Univariate and multiple logistic regression analysis showed that patients with epilepsy (OR, 1.4; 95% CI, 1.2–1.7) and with a lower GCS score (GCS 8–12: OR, 0.7; 95% CI, 0.5–0.9; GCS 13–15: OR, 0.3; 95% CI 0.2–0.3) were more likely to receive midazolam.

intranasal treatment for acute  intermittent, stereotypic episodes of frequent seizure activity that are distinct from usual seizure pattern in patients with epilepsy 12 years of age and older.

The benzodiazepine, which may be administered in the outpatient setting by a non-healthcare professional in patients actively seizing and where a seizure cluster occurs, is supplied as 2 single-use nasal spray units, each containing a 5-mg dose of midazolam in 0.1-mL solution.

1. Guterman EL, Sanford JK, Betjemann JP, et al. Prehospital midazolam use and outcomes among patients with out-of-hospital status epilepticus. 

Published online September 17, 2020. doi: 10.1212/WNL.0000000000010913

2. UCB announces NAYZILAM® (midazolam) nasal spray now approved by FDA to treat intermittent, stereotypic episodes of frequent seizure activity in people living with epilepsy in the U.S. News release.  UCB. May 20, 2019. Accessed September 23, 2020. https://ucb.com/stories-media/Press-Releases/article/UCB-announces-NAYZILAM-midazolam-nasal-spray-now-approved-by-FDA-to-treat-intermittent-stereotypic-episodes-of-frequent-seizure-activity-in-people-living-with-epilepsy-in-the-U-S

Notably, no patients received a dose and route consistent with national guidelines.

Midazolam for Status Epilepticus Underutilized in EMS Setting Despite High Efficacy

This is the first of a 2-part interview. For part 2, 

A number of data sets examining the efficacy and safety of ocrelizumab (Ocrevus; Genentech) in real-world and long-term populations of patients with multiple sclerosis (MS) were presented at 

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020.

All told, the data included findings from a number of studies focused on patients who were exposed to prior disease-modifying therapy (DMT) as well as those who were initially treated with the humanized anti-CD20 monoclonal antibody. Ultimately, the range of posters showed the agent held benefit for those with a prior suboptimal response, and improved symptoms and rates of no evidence of disease activity (NEDA), among other conclusions.

The medical director manager of neuroscience at Genentech discussed the swath of data presented on the humanized anti-CD20 monoclonal antibody at MS Virtual.

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