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

The vice president of Clinical Research at Eisai provides updates on the MOMENTUM trials which will examine lorcaserin as a potential treatment for patients with Dravet syndrome.

NeuroVoices: Michael Irazarry, PhD, on Lorcaserin for Dravet Syndrome

"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

A new multicenter study that investigated 1-year outcomes of minimally invasive surgical treatment with laser interstitial thermal therapy (LITT) found it to be a safe and effective treatment option for patients with drug resistant epilepsy (DRE), with 64% of patients free of seizures at the end of the study period. 

Additionally, the study assessed quality of life with the Quality of Life (QoL) in Epilepsy questionnaire (QOLIE-31). The median score increased by 14.1 points at 1-year follow up, driven by improvements in seizure worry and social functioning. Although this total score change was not statistically significant, it is still clinically meaningful, according to Patrick Landazuri, MD, associate professor of neurology, University of Kansas Medical Center, and colleagues. 

They examined these 1-year outcomes from patients enrolled in the multicenter, prospective LAANTERN registry (Laser Ablation of Abnormal Neurological Tissue Using Robotic NeuroBlate System; NCT02392078) specifically for epilepsy treatment. They looked at the 60 LITT procedures performed for DRE. Patients with mesial temporal lobe epilepsy/mesial temporal sclerosis (MTLE/MTS) made up the majority of procedures but other etiologies were assessed, too. 

 talked to Landazuri to learn more about the LITT procedure, the advantages of epilepsy surgery for patients, and how it compares to these other procedures.

: Could you give an overview on how the LITT procedure compares to other epilepsy surgeries?

: LITT is also known as selective laser ablation or SLA. The way it's performed is, prior to the surgery itself, the epileptologist and the neurosurgeon both clearly identify the part of the brain that's epileptogenic. That can be done in multiple ways. Sometimes, a preoperative MRI will clearly show an epileptogenic cause. Other times it's more extensive and includes recording EEG from inside someone's brain, often with intracranial electrodes, one method being stereo encephalography, or sEEG. Once that area has been defined, whether by imaging or by electrographic findings, the patient's case is discussed at a surgical conference, which is the standard of care for all surgical centers. When the decision is made to offer LITT as a potential therapy, that's discussed with the patient. When the patient agrees, they are brought to surgery and LITT is done in an MRI scanner. The patient is positioned, and the surgeon will stereotactically plan how to insert essentially a probe inside someone's brain. The surgeon then verifies the probe positioning using the MRI. When the probe is appropriately placed, the neurosurgeon starts the ablation. If it's not, then the surgeon adjusts the location of the probe. Once it's in the position, then they fire the laser into the probe. The surgeon uses the MRI during that period to take real time thermography so that they know exactly what's been heated and so that they're not injuring tissue surrounding the intended target. Then they make sure that the brain tissue that they mean to ablate is ablated to a high enough temperature. Once that's seen on the thermography, the ablation is stopped. If they think they need to get any surrounding area that the initial ablation didn't cover, then they'll move the probe again to cover that region. When they're done the probe is removed. After that it's most typically one or two stitches and then the patient goes to recovery.

Could you outline some of the advantages of LITT over other kinds of epilepsy surgery?

The main advantage of LITT versus resection or open craniotomy is that it's a minimally invasive surgery. Inserting the probe typically requires just one Burr hole, or a 3-millimeter hole for the laser equipment that KU uses, and that's the only entrance into the head. MTLE ablation is the most common ablation surgery, but the most common brain surgery for epilepsy is an anterior temporal lobectomy (ATL). This involves an incision into the skull on the side of the head that is a significantly larger opening compared to the 3-millimeter Burr hole. An ATL is a typical surgery, but what's typical to the surgeons and to the neurologist is not typical to the patient who, hopefully, only does that once. It's a big decision for the patient, and that's the big difference. In our study, we actually captured pain scores. The average pain score was 1.4 out of 10, which is very minimal head pain score at discharge.

How do you think clinicians can mediate these sometimes-disproportionate fears about epilepsy surgery?

One of the main challenges in epilepsy care is the misperception of the efficacy of seizure medicines after a certain time point. So, to be clear, medicines are a very effective treatment for epilepsy — nearly 70% of people will be seizure free on medications. The challenge is that's most typically within the first three medicines that they try. After a third failed medicine, less than 1% of people are seizure free on a long-term basis with medicines alone. So, I think it has to do with the early recognition, and appropriate referral to centers that are able to discuss surgical therapy and evaluate people that would benefit from surgery. Once a patient is at one of those centers, patients can know that our study saw 97% of patients discharged to home with our median length of stay being 32.7 hours. Coupled with the low head pain score on discharge, these findings continue to suggest LITT as a form of epilepsy surgery is a safe and well tolerated procedure.

Transcript edited for clarity. NeurologyLive has previously written about Landazuri and colleagues’ investigation, which you can read more about by clicking 

Landazuri P, Shih J, Leuthardt E, et. al. A prospective multicenter study of laser ablation for drug resistant epilepsy – One year outcomes. 

. 2020; 167. doi: 10.1016/j.eplepsyres.2020.106473

Articles

In this interview, Patrick Landazuri, MD, shares an in-depth look at his investigations into the safety and efficacy of laser ablation. 

Laser Ablation for Drug Resistant Epilepsy: An Effective and Minimally Invasive Surgery

This fall at the Alzheimer’s Drug Discovery Foundation (ADDF) International Conference, Ronald G. Crystal, MD, presented to more than 800 attendees on the current state of gene therapy for 

 influenced Alzheimer disease and other neurodegenerative disorders, detailing ongoing development and the current state of a small trial in patients with Alzheimer.

Crystal, who is the chairman of the Department of Genetic Medicine at Weill Cornell Medicine, urged attendees to watch this therapeutic development closely, noting that the progress of gene therapy after decades of research reveals a promising future. With regard to Alzheimer, the plan is to provide the 

 gene—which literature has suggested may offer a protective effect against Alzheimer disease—to individuals who are 

, Crystal spoke to the takeaways for the clinical community and discussed the current state of that research. He also explained some of the challenges of developing these therapies, specifically as it relates to the differences in approach to intracellular versus extracellular targets.

: What are your thoughts are on the current state of gene therapy development?

 If you take the common neurodegenerative diseases and make a list of them, they have certain things in common despite the fact that they're very different diseases. One of the things that they have in common is that they are chronic diseases, right? They also, obviously, are in the nervous system and they have a therapeutic challenge—the blood-brain barrier. Those are 2 things that are key things that gene therapy can do. You can use gene therapy to have genes put directly into the nervous system, that bypasses the blood-brain barrier problem. Also, with gene therapy—if it works and if it's safe—there's a single administration to cure it forever. That's why so many people are interested, like us and many others.

We’re interested in gene therapy for the central nervous system. Now the issue is what's the state of the art and where are we? It started with us and some others approaching some diffuse diseases, like the lysosomal storage diseases, by taking the affected individuals to the operating room, putting Burr holes in the skull, catheters directly into the brain, and infusing the viruses that we use to carry the gene. But then the investigators start thinking, could you do this intravenously? That would obviously be a lot easier, right? Spinal muscular atrophy (SMA) was a good example of that. But the problem there was that even though it worked and it’s an approved therapy, is that it’s in infants before the blood-brain barrier is fully formed. With the blood-brain barrier fully formed, it's much tougher to use intravenous approaches because you think about how do the viruses get across the blood-brain barrier?

We and many others then started thinking about other strategies to deliver viruses to the brain. One approach was intraventricular: put a burr hole in the skull and a catheter directly into the cerebral spinal fluid in the ventricle. That's one approach. Then we started thinking about using intracisternal or intrathecal approaches, as well. That's evolving more as the favorite approach. Now, that doesn't mean it solves everything. But there's a lot of data in the field by many investigators, including us, that using intracisternal—or perhaps going down a little lower to C1, C2, or going down even lower and threading a catheter up—is another way to do it. If you can do that without toxicity, although there are some issues, you can get widespread expression throughout the brain. So that's been a part of a revolution in gene therapy for the CNS.

With regard to the viruses that are used, we think of those gene therapy terms as serotypes, and what is being used in the field is adeno-associated viruses (AAVs). There are some that are derived from humans, and some that are derived from nonhuman primates, and then there are some that are man-made in the laboratory by taking known ones and modifying the capsid. That’s done by sort of evolutionary techniques or directed techniques where you make specific changes. In the field, people are developing more capsids that may be a little better here and there, but I think in general, we have the capsids right. The strategy now is to use those capsids to choose the gene of interest and then the approach in terms of how we're going to deliver it.

Gene therapy for the CNS has really evolved over the last decade or so, and I think it's now at the point where there is obviously is an approved drug now, and I think you're going to see a number of approved drugs.

For neurodegenerative disease specifically, what are the challenges and what work are you and your colleagues doing?

In terms of the neurodegenerative diseases, the issues are with the hereditary disorders and the nonhereditary disorders and then sort of in-between disorders. The hereditary disorders like the lysosomal storage diseases, or the genetic form of ALS, or frontal temporal dementia, or Parkinson, or Huntington—you know what the target is. There becomes a delivery problem, a safety problem, an efficacy problem because you know you can deliver the gene, but can you accomplish it and do it sufficiently?

Then there's a group of disorders like we're interested in like Alzheimer, where we're taking advantage of the epidemiology that the apolipoprotein (

. Now, 85% of us are APOE3, but then if you're an 

 homozygote, you have a 15- to 20-fold increased risk for the development of Alzheimer, and if you develop it, it's more aggressive and occurs earlier as well. But if you're lucky enough to inherit from your parents 

, you have a decreased risk of Alzheimer, and if you do develop Alzheimer, it's milder and occurs later.

What got us interested in it was the heterozygotes. If you're an 

 takes away most of the risk—not entirely—for 

. APOE is made mostly by glia and astroglia, and the receptors are mostly on neurons. The particles are formed in the extracellular space. So, if you're heterozygote, your extracellular particles are 

heterozygotes. Our whole strategy is to bathe the brain of 

, so that the particles become heterozygote or even more 

. What we're doing is ignoring the pathogenesis of the disease, whether it's its amyloid, phospho-tau, inflammation, or multiple other mechanisms, all of which are being studied. We're proximal to that because we know that 

 affect multiple sites in the pathogenesis. That's the whole strategy. The way we're administering it is that we decided not to go intracisternal, we do it at C1 or C2. There is a sort of argument in the field about what's best. As you probably know, there are some blood vessels that run at the roof of the cisterna magna, so there's a little bit of a risk to going into the cisterna magna, so we decided to do C1 or C2, just below that. It's done under CT scanning, it's an outpatient procedure, and it takes about 25 to 30 minutes to place the needle, and about 5 minutes to administer. So far, we've treated 3 patients and we're looking for more, and we are actively following them.

What’s the takeaway for the clinical community from your perspective?

Gene therapy is essentially a drug delivery system. It's not an end-all, but it's a drug delivery system, just like small molecules are and monoclonal antibodies are. Gene therapy is real now. We and others have been working on it for several decades now. We now have approval for 1 drug in the field, and I think that one of the real challenges in neurodegenerative disease is the blood-brain barrier and that we can overcome that with the technology that we have. The questions are: can we do it safely, can we get enough in, and can we design the right targets?

What I'd want people to take away is to pay attention to the space. This is going to be something real, and there'll be select diseases where this will be a therapy that over the next decade will become real for you in terms of treating patients.

Ronald Crystal, MD, chairman, Department of Genetic Medicine, Weill Cornell Medicine, discussed the promise of gene therapy for patients with Alzheimer disease and related disorders.

Gene Therapy for Alzheimer and Neurogenerative Disease

The FDA has accepted the biologics license application (BLA) for avalglucosidase alfa (Sanofi) for long-term enzyme replacement therapy for the treatment of patients with Pompe disease. A prescription drug user fee act (PDUFA) date has been set for May 18, 2021.

Avalglucosidase alfa has received FDA breakthrough therapy and fast track designations for the treatment of people with Pompe disease. The basis for the BLA originates from positive data from both the phase 3 COMET trial (NCT02782741) and the phase 2 mini-COMET trial (NCT03019406), which showed improvements over standard of care.

The investigational enzyme replacement therapy was designed to improve the delivery of acid alpha-glucosidase (GAA) enzyme to muscle cells, in which patients with Pompe disease are deficient. It has approximately a 15-fold increase in mannose-6-phosphate (M6P) content, compared to standard of care alglucosidase alfa, and aims to help improve cellular enzyme uptake and enhance glycogen clearance in target tissues. Sanofi noted that the M6P receptor plays a key role in the transport of GAA.

"The hallmarks of Pompe disease are the relentless and debilitating deterioration of the muscles, which causes decreased respiratory function and mobility,” Karin Knobe, MD, PhD, head of development for rare diseases and rare blood disorders, Sanofi, said in a statement. “Avalglucosidase alfa is specifically designed to deliver more GAA enzyme into the lysosomes of the muscle cells. We have been greatly encouraged by positive clinical trial results in patients with late-onset and infantile-onset Pompe disease.”

READ MORE: Centralizing Neuromuscular Disease Data With the MDA MOVR Database

Data from the double-blind, global comparator-controlled COMET trial showed that 

avalglucosidase alfa met the primary end point

 of the study in demonstrating non-inferiority in improving respiratory function compared to the standard of care with alglucosidase alfa (Lumizyme; Sanofi) in patients with late-onset Pompe disease.

Those treated with the drug showed a 2.43-point greater improvement (95% CI, –0.13 to 4.99) in percent-predicted forced vital capacity (FVC) compared to the standard of care (

 = .0074). All told, those in the avalglucosidase alfa group reported a percent predicted FVC of 2.89 (standard deviation [SD], 0.88) compared to the reported 0.46 (SD, 0.93) with the standard of care group.

The agent, while achieving statistical significance for the primary end point, did not achieve statistical superiority (

= .0626). Due to the hierarchy of the study protocol, Sanofi noted that the formal statistical testing for all secondary end points was not conducted. Although, a key secondary end point measuring mobility was the 6-minute walk test (6MWT), and those treated with avalglucosidase alfa walked 30.01 m farther (95% CI, 1.33–58.69; distance, 32.21 m [SD, 9.93]) than the standard of care group (distance, 2.19 m [SD, 10.40]).

Also assessed were the percent-predicted Maximum Inspiratory Pressure and Maximum Expiratory Pressure. Those in the avalglucosidase alfa group reported percentages of -0.29 (SD, 3.84) and 2.39 (SD, 4.00), respectively, compared to -2.87 (SD, 4.04) and 5.00 (SD, 4.20) with standard of care. Those totaled differences of 2.58 (95% CI, -8.54 to 13.71) for Maximum Inspiratory Pressure and -2.61 (95% CI, -14.22 to 9.00) for Maximum Expiratory Pressure.

Mini-COMET is an ongoing, phase 2, open-label, ascending-dose, 3-cohort study of avalglucosidase alfa in 22 patients under 18 years of age with infantile-onset Pompe disease, who were previously treated with avalglucosidase alfa and showed incomplete treatment response in pre-specified clinical outcomes.

Presented at the WORLDSymposium in February 2020, results showed that treatment with avalglucosidase alfa was well-tolerated at 20mg/kg and 40mg/kg dose every 2 weeks at the 6-month period. The most common adverse events (AEs) reported were all mild to moderate in nature, including vomiting and pyrexia (6 patients each), upper respiratory tract infections (5 patients), and cough and rash (4 patients each). There were no serious or severe treatment-related AEs, including no AEs that resulted in permanent discontinuation or death.

1. FDA grants priority review for avalglucosidase alfa, a potential new therapy for Pompe disease. News release. Sanofi. November 18, 2020. Accessed November 19, 2020. 

http://www.news.sanofi.us/2020-11-18-FDA-grants-priority-review-for-avalglucosidase-alfa-a-potential-new-therapy-for-Pompe-disease

2. Sanofi’s investigational enzyme replacement therapy shows clinically meaningful improvement in critical manifestations of late-onset Pompe disease. News release. Sanofi. June 16, 2020. Accessed November 19, 2020. https://www.sanofi.com/en/media-room/press-releases/2020/2020-06-16-14-00-00

3. Avalglucosidase alfa showed positive exploratory efficacy and was well-tolerated in phase 2 trials in Pompe disease. News release. February 10, 2020. Accessed November 19, 2020. https://www.sanofigenzyme.com/en/about-us/newsroom/2020/2020-02-10-04-45-00

Evidence from 2 clinical trials were the basis of the biologics license application, with an FDA decision expected to be made by May 18, 2021.

FDA Accepts BLA for Avalglucosidase Alfa for Pompe Disease

 staff prepares this preview of what to expect from our coverage. This week on 

, there are a number of hot topics that we will be posting throughout the week.

The third segment of the "Updates in the Management of Relapsing Multiple Sclerosis" Peer Exchange premieres Monday, November 23, 2020, and focuses on the misdiagnosis of multiple sclerosis. The panelists discussed their clinical workup criteria, including the use of cerebrospinal fluid, to make a more accurate multiple sclerosis diagnosis. They also touch on the importance of misdiagnosis and how it can impact patients if they are recommended the wrong treatments.

Also going live on Tuesday is a piece from our October 2020 special issue titled, "The Future of Multiple Sclerosis Imaging," authored by Pascal Sati, PhD, director, Neuroimaging Program, Department of Neurology, Cedars-Sinai Medical Center. Sati discussed how advanced imaging technology is on a collision course with artificial intelligence, and how that intersection is shaping up to be a revolutionary period for the diagnosis and management of MS.

On Wednesday, November 25, 2020, the latest edition of our NeuroVoices series goes live, this time featuring Michael S. Okun, MD, executive director, Norman Fixel Institute for Neurological Diseases, University of Florida. Okun sat down to discuss his recently published editorial on reforming the process for deep brain stimulation and neurologic device approval in rare diseases. Specifically, he covers the barriers placed by insurance companies, recommendations for more disease-based registries, and his call to action for what needs to change.

A conversation with Steven Arnold, MD, professor of neurology, Harvard Medical School, and managing director, Interdisciplinary Brain Center, Massachusetts General Hospital, will air on 

 channel this Thursday, November 26, 2020. Arnold discussed the latest on the ongoing phase 2 PEGASUS trial of AMX0035 in Alzheimer disease.

Here's what is coming soon to NeurologyLive.

This Week on NeurologyLive — November 23, 2020

This content was originally published on Diagnostic Imaging, a sister publication of NeurologyLive. To view the original post, click 

A new study suggests that COVID-19-positive patients who have hypertension and type 2 diabetes are more likely to experience neurological complications such as intracranial hemorrhage and stroke.

Investigators from the Perelman School of Medicine at the University of Pennsylvania looked at computerized tomography (CT) and magnetic resonance imaging (MRI) images to determine critical neurological findings. They found the most common comorbidities with critical neurological conditions were hypertension (72.2%; n = 13) and type 2 diabetes mellitus (50%; n = 9).

“COVID-19’s effects extend far beyond the chest,” said lead study author Colbey W. Freeman, MD, chief resident, Penn Medicine radiology department, in a statement.

 “While complications in the brain are rare, they are an increasingly reported and potentially devastating consequence of COVID-19 infection.”

Freeman’s team, including Jonathan Masur, MD, Mougnyan Cox, MD, and Suyash Mohan, MD, will present their findings during this year’s upcomcing Radiological Society of North America (RSNA) annual meeting, November 29–December 5, 2020.

Freeman and colleagues examined head CT and/or MRI images for patients positive for the virus who presented to the University of Pennsylvania Health System from January 2020 to April 2020. Of the 1357 COVID-19-positive patients who were admitted, 81 underwent a brain scan prompted by either altered mental state or focal neurological deficits, including speech and vision problems.

James Grotta, MD: The Impact of COVID-19 on Stroke Care

Based on the team’s analysis, 18 patients—slightly more than 20%—had findings that were considered critical, such as strokes, brain bleeds, or blocked blood vessels. The critical group was 50% male with a mean age of 60.5 years (standard deviation, 12.6), and at least half also had a pre-existing history of high blood pressure or type 2 diabetes. Two-thirds of the patients who had critical findings were African American, indicating COVID-19 positive patients in that minority group should be monitored more closely. Three patients in this group died while in the hospital.

“COVID-19 is associated with neurological manifestations, and hypertension and type 2 diabetes mellitus are common in individuals who develop these manifestations,” Freeman said. “These populations may be at higher risk for neurologic complications and should be monitored closely.”

Although this study revealed a role for high blood pressure and type 2 diabetes in the neurological impact of the virus, investigators still do not know exactly what causes those complications. The mechanisms could be multi-factorial, and the generally accepted belief is that infection-associated inflammation is responsible, they said. In this study in particular, blood markers for inflammation were high in patients who had critical results.

“When your body is in an inflammatory state, it produces all these molecules called cytokines to help recruit the immune system to perform its function,” Freeman said. “Unfortunately, if cytokines are over-produced, the immune response actually starts doing damage.”

Using data from this study, the team is also looking at the how frequently COVID-19-positive patients on extracorporeal membrane oxygenation (ECMO)—a pump system that circulates and replenishes oxygen in the blood – experience neurological complications. Many patients included in this study required ECMO during hospitalization.

The authors plan to later pursue a larger prospective study to investigate delayed, long-term, and chronic neurologic manifestations that have not currently been identified but that might manifest later.

This work is among a growing set of literature highlighting the neurologic complications of the disease. Additional, unrelated but recent research from northern Italy has suggested that there is an increased incidence of 

Guillain-Barré syndrome (GBS) during the COVID-19 outbreak

, supporting the hypothesis of a pathogenic link.1 The study consisted of GBS cases diagnosed in 12 referral hospitals in March and April 2020 that were retrospectively collected and compared with a control population of GBS cases diagnosed in March and April 2019 within the same hospitals.

The findings revealed an incidence of GBS in March and April 2020 of 0.202 per 100,000/month (estimated rate, 2.43 per 100,000/year) with 34 cases compared to 0.077 per 100,000/month (estimated rate 0.93 per 100,000/year) and 13 cases in the same months of 2019, equating to a 2.6-fold increase. The 30 COVID-19 positive patients with GBS (88%) represented 0.178 per 100,000 (estimated rate, 2.14 per 100,000/year), while patients who tested negative for COVID-19 with GBS (4 cases) represented 0.024 per 100,000/month (estimated 0.29 per 100,000/year).3

1. Diabetes, hypertension may increase risk of COVID-19 brain complications. News release. RSNA. November 18, 2020. Accessed November 20, 2020. 

https://press.rsna.org/timssnet/media/pressreleases/14_pr_target.cfm?ID=2226


2. Freeman CW, Masur J, Cox M, Mohan S. Coronavirus Disease in the Brain: Incidence of Neurologic Complications of COVID-19 and Its Supportive Treatments. Presented at: RSNA annual meeting; November 29–December 5, 2020. Poster NR-1A-53.
3. Filosto M, Piccinelli SC, Gazzina S, et al. Guillain-Barre syndrome and COVID-19: an observational multicentre study from 2 Italian hotspot regions. 

. Published online November 6, 2020. doi: 10.1136/jnnp-2020-324837

Two-thirds of patients with critical results were African American, demonstrating an additional need to explore associations between ethnicity and COVID-19. 

COVID-19 Neurological Complications More Likely in Those with Hypertension, Diabetes

"One of the biggest concerns is that it puts them at a very high risk to have refractory seizures, or seizures that do not respond to medication.”

Infantile spasms are seizures that typically begin in infants between 3 and 8 months of age, characterized by a sudden stiffening followed by knees pulling up and the body bending forward. These seizures can last for a few seconds, but usually occur close together in a series. Babies who are diagnosed with this condition often will have their development slowed, and potentially lose skills such as sitting, rolling over, or babbling.

These spasms usually will stop by 2 to 4 years of age but can still develop into other types of epilepsies. Treating these seizures early and appropriately can be critical to maximizing the child’s developmental potential, according to Martina Bebin, MD, MPA. Bebin, a professor of neurology and pediatrics at the University of Alabama at Birmingham Epilepsy Center, has been ingrained in the epilepsy community for over 30 years, and understands the attention that children with infantile spasms deserve.

to discuss some of the challenges these patients with infantile spasms face and how those issues can lead to greater developmental concerns as they continue to grow.

Videos

The professor of neurology and pediatrics at the University of Alabama at Birmingham Epilepsy Center detailed challenges faced by children with infantile spasms and how the spasms evolve later in life.

Martina Bebin, MD, MPA: Challenges Associated With Infantile Spasms

'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.

 Podcast: Capitalizing on Collaboration in Neurology Care

, brings you an exclusive interview with Paul Fisher, MD, and Gerald Grant, MD, FACS, on 

how their team at the center is bolstering the use of multidisciplinary care and harnessing advances in science to improve the care of children with neurologic disease.

Tweet Chat Highlights: Epilepsy Awareness Month

Dravet Syndrome Foundation, Lennox-Gastaut Syndrome Foundation, and the Tuberous Sclerosis Alliance, and

 honoring National Epilepsy Awareness Month, featuring highlighted contributions from the medical community.

Use of MRI in Diagnosing Multiple Sclerosis

In this episode, the panel of Fred Lublin, MD; Patricia K. Coyle, MD; Scott Newsome, DO, MSCS, FAAN; and Mark Freedman, MD,

 outline the importance of the use of MRI in the diagnosis of multiple sclerosis.

Stephen Cunnane, PhD: The Potential for Brain Energy Rescue in Mild Cognitive Impairment

The professor from the Universite de Sherbrooke discusses how b

rain energy rescue is emerging as a promising strategy to early combat neurodegenerative disorders before significant impairment occurs, and

 other factors that increase cognitive decline in patients with MCI

Take 5 minutes to catch up on NeurologyLive's highlights from the week ending November 20, 2020.

NeurologyLive Friday 5 — November 20, 2020

An interim, 12-month analysis from the ongoing open-label extension study (NCT02510261) of patisiran (Onpattro; Alnylam) suggest that the therapy maintains its efficacy and an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis (hATTR) with polyneuropathy.

After the 12-month open-label period, those treated with patisiran from the phase 3 APOLLO (NCT01960348) and phase 2 open-label (NCT01961921) parent studies maintained their improvements on the modified Neuropathy Impairment Score +7 (mNIS+7), with mean changes of -4.0 (95% CI, -7.7 to -0.3) and -4.7 (95% CI, - 11.9 to 2.4), respectively. For those who were on placebo in APOLLO that switched in the open-label extension, the mean change from global OLE enrollment was -1.4 (95% CI -6.2 to 3.5).

The study was conducted by David Adams, MD, PhD, Head, French National Reference Centre for Familial Amyloidotic Polyneuropathy, and head, Department of Neurology Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris Sud, and a number of colleagues. “Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran,” they wrote.

Data from this extension were also presented at the 2018 AANEM Annual Meeting. The study includes 211 of 212 eligible patients enrolled between July 13, 2015, and August 21, 2017. In total, 137 were enrolled from the APOLLO patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. The data cutoff was September 24, 2018, at which time 126 (92%) from the APOLLO-patisiran group, 38 (78%) from the APOLLO-placebo group, and 25 (100%) from the phase 2 OLE patisiran group had completed 12-month assessments.

Centralizing Neuromuscular Disease Data With the MDA MOVR Database

“The global open-label extension is ongoing with no new enrollment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff,” Adams et al. wrote.

As for safety, 204 (97%) of the overall cohort reported adverse events (AEs), and the most common treatment-related AE reported was mild or moderate infusion-related reactions.

There were 82 (39%) patients who reported a serious AE, and 23 (11%) deaths. The APOLLO placebo group experienced a higher frequency of serious AEs (28 of 49; 57%) than the APOLLO patisiran group (48 of 137; 35%) or the phase 2 open-label extension group (6 of 25; 24%). The frequency of deaths in the global cohort was higher in the APOLLO-placebo group (13 of 49; 27%), who had a higher disease burden than the APOLLO-patisiran (10 of 137; 7%) and phase 2 OLE patisiran (0 of 25; 0%) groups.

The median age of patients in the extension trial was 64 years, and 74% were male. The mean time since hATTR amyloidosis diagnosis to first patisiran dose was 2.9 years. Overall, 54% of patients had a non-V30M transthyretin (TTR) genotype and 52% were enrolled in Western Europe. The most common polyneuropathy disability scores were II (27%) and IIIA/B (41%). The mean baseline mNIS+7 was 77, which was driven primary by those enrolling from the placebo arm of the APOLLO study who entered with an mNIS+7 of 101.

Patients switching from placebo to patisiran experienced robust reductions in serum TTR levels. By week 6 of the extension studies, mean serum TTR levels had decline by 79% for patients receiving patisiran for the first time. TTR levels were maintained in the extension study for those treated with the RNA inhibitor in the phase II trial and APOLLO, even out to 4 years, showing the durability of benefit.

In the APOLLO study, which led to the FDA approval of patisiran for hATTR amyloidosis in August 2018, the least mean square change in mNIS+7 from baseline for those treated with patisiran was -6.0 (±1.7) versus 28.0 (±2.6) with placebo.

 Following 52 weeks of treatment with patisiran in the extension study, patients originally treated with the RNA inhibitor had sustained improvements in neuropathy, and those initially receiving placebo experienced a rapid halting disease progression.

REFERENCE
1. Adams D, Polydefkis M, González-Duarte A, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Published online November 16, 2020. doi: 10.1016/S1474-4422(20)30368-9
2. Gonzalez-Duarte A, Coelho T, Adams D, et al. Long-term use of patisiran, an investigational RNAi therapeutic, in patients with hereditary transthyretin-mediated amyloidosis: 12 month efficacy and safety from global open-label extension study. Presented at: 2018 AANEM Annual Meeting, National Harbor, MD, October 10-13, 2018. Abstract 10
3. Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. 

After the 12-month open-label period, those treated with patisiran from the phase 3 APOLLO and phase 2 open-label parent studies maintained their improvements on the modified Neuropathy Impairment Score +7.

Patisiran Shows Sustained Long-Term Efficacy in Patients With hATTR

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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 22, "Capitalizing on Collaboration in Neurology Care," features an interview with Paul Fisher, MD, professor of neurology, and chief of child neurology, and Gerald Grant, MD, FACS, endowed professor of neurosurgery, and chief of pediatric neurosurgery, both of the Brain and Behavior Center at Stanford Children’s Health. The pair discussed how their team at the center is bolstering the use of multidisciplinary care and harnessing advances in science to improve the care of children with neurologic disease. Specifically, they spoke to how Stanford Children's Health collaborates across departments and specialties—from neurology to neurosurgery, radiology, nursing, and pathology, among others—as well as its utilization of the technology, talent, and expertise available from the neighboring Stanford Health Care and Stanford University School of Medicine. The model, they noted, is designed in both actions and geography to do pediatrically what Stanford routinely offers for adults.

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 (ML) models used to predict delayed ischemic stroke (DIC) and functional outcomes significantly outperformed standard models (SMs) when used in subarachnoid hemorrhage (SAH) care.

In the study, the area under the receiver operating curve (AUC) was 0.75 (standard deviation [SD], 0.07; 95% CI, 0.64–0.84) for ML model predictions of DCI outcome, 0.85 (SD, 0.05; 95% CI, 0.75–0.92) for discharge outcome, and 0.89 (SD, 0.03; 95% CI, 0.81–0.94) for 3-month outcome. The ML model outperformed the SM in AUC by 0.20 (95% CI; -0.02 to 0.4) for DCI, 0.07 (SD, 0.03; 95% CI, 0.0018–0.14) for discharge outcomes, and by 0.14 (95% CI, 0.03–0.24) for 3-month outcomes. Additionally, ML models matched physician performance in predicting 3-month outcomes.

Principal author of the study Jude Savarraj, PhD, research scientist, Department of Neurosurgery, The University of Texas Medical School at Houston, and colleagues stated in their paper that “unlike EEG [electroencephalogram] and TCD [transcranial doppler], the ML approach uses only routine clinical variables (which are already available as part of standard care); it avoids the need for expensive instrumentation (as in the case of EEG and TCD). The output of the ML model (which is simply a probabilistic score between 0–1), is easily translatable in most settings since unlike EEG and TCD expertise of trained technicians is not required.”

Of the 451 patients who participated in the study, 64% (n = 290) were female and the mean age was 54 years (interquartile range [IQR], 45–63). Some participants had histories of hypertension (60%; n = 223), hyperlipidemia (17%; n = 60), or diabetes (12%; n = 44). The median Hunt-Hess (HH) scale score was 3 (IQR, 2–3) and the median modified Fisher scale (mFS) score was 3 (IQR, 3–3). Intraventricular hemorrhage (IVH) was present in 66% (n = 240) of participants upon admission and 21% (n = 88) of participants developed DCI. The mean modified Rankin scale (mRS) score was 3 (IQR, 1–4) on discharge and 1 (IQR, 0–4) after 3 months.

Tranexamic Acid Not Effective as Intracerebral Hemorrhage Treatment

Of the ML models, the artificial neural network model (ANN) performed the best against the standard model (

 = .08). At a determined optimal cutoff threshold, the ML model assessments (sensitivity, 0.75; specificity, 0.87) were significantly better than SM assessments (sensitivity, 0.58; specificity, 0.90; 

 <.05) when assessed with the McNemar test. AAN models are difficult to interpret, so gradient boost and random forest models were also used for analysis.

Savarraj and colleagues used the ML models to rank 31 variables from the EMR based on relative importance in outcome and found the most important variables to include sodium, white blood cells, and neutrophils. These variables have previously been shown to be associated with DCI and discharge outcomes.

ML models performed best when they used clinician-determined HH score in addition to standard electronic medical record (EMR) variables (AUC, 0.85; SD, 0.05; 95% CI, 0.75–0.92) when compared to only using EMR data (AUC, 0.81; SD, 0.05; 95% CI, 0.71–0.89; 

Savarraj and colleagues also found that in clinical teams, the attending physician (sensitivity, 0.88; specificity, 0.95) outperformed the nurse (sensitivity, 0.86; specificity, 0.85) and the fellow (sensitivity, 0.81; specificity, 0.75) in predicting outcomes. When compared against the physician’s predictions, the ML model insignificantly performed slightly worse (sensitivity, 0.91; specificity, 0.64; 

The authors also noted that “ML can offer unique perspective on the patient’s condition and can serve as a decision support tool in the management of SAH. However, clinical judgement is necessary to interpret the ML results and implement a corresponding plan of action.”

Savarraj JP, Hergenroeder GW, Zhu L, Chang T, et al. Machine learning to predict delayed cerebral ischemia and outcomes in subarachnoid hemorrhage. 

. Published online November 12, 2020. doi: 10.1212/WNL.0000000000011211

Machine learning models analyze routine clinical variables to determine the risk of delayed ischemic stroke and other outcomes. 

Machine Learning Models Accurately Predict Outcomes in Subarachnoid Hemorrhages

 partnered with the Dravet Syndrome Foundation, Lennox-Gastaut Syndrome Foundation, and the Tuberous Sclerosis Alliance for a chat on Twitter to discuss and raise awareness towards epilepsy, a disorder with many variations that affects nearly 3.5 million people each year.

Topics of the night included barriers in epilepsy care, recommended resources for patients with epilepsy and their caregivers, improving education on managing a patient’s daily activities, and how family members and siblings can help better understand an epileptic condition.

There was also an increased effort to discuss the role that advocacy organizations play within the community. That being said, all 3 of the previously mentioned co-hosts are leading advocacy groups whose drive to create change and raise awareness helped fuel the tweet chat idea.

Throughout the night, participants chimed in with responses while co-hosts of the chat provided helpful links and resources to the overall community.

When discussing the ways that we can better educate people on seizure first aid and how to handle a critical situation, Wendy Fry, director of Family and Caregiver Engagement, Dravet Syndrome Foundation, stressed the role schools can play in assisting this change.

The importance of advocacy organizations and the benefits they bring to patients with epilepsy was echoed through multiple tweets, including this thread from the TS Alliance. Embedded below, the TS Alliance provided a multitude of links and resources they offer patients with tuberous sclerosis complex.

Patients with epilepsy often face a number of barriers that can impede on their quality of life, including finding an expert suited for their needs. The Dravet Syndrome Foundation laid out the multi-step process when trying to find a doctor or institution that specializes in their rare disease.

 has been committed to contributing socially and raising awareness to neurological disorders and the impact they have on their communities. Stay on the lookout for future events and tweet chats that highlight these issues.

An overview of the NeurologyLive tweet chat honoring National Epilepsy Awareness Month, featuring highlighted contributions from the medical community.

Sodium oxybate (SO), a first-line treatment of type 1 narcolepsy (NT1), has the ability to improve nocturnal rapid eye movement (REM) sleep behavior disorder (RBD) and REM sleep without atonia (RSWA) in patients with NT1, according to a newly published study.

The study evaluated 19 children and adolescents with NT1 (mean age, 12.5 [±2.7] years; mean disease duration, 3.4 [±1.6] years) who underwent 3 months of stable treatment with SO. RSWA, automatically computed by means of the validated REM sleep atonia index (RAI) was significantly improved (

 <.05) in patients who received the drug compared to baseline.

Study author Giuseppe Plazzi, MD, director, Sleep Laboratory, Department of Neurological Sciences, University of Bologna, and colleagues noted that the treatment “remarkably” reduced complex movements during REM sleep. They wrote that the improvements on RBD and RSWA point to a direct role of the drug in modulating motor control.

"In our cohort, the significant increase of RAI implies that the decrease of motor episodes during REM sleep cannot be only ascribed to the reduction of the amount of REM sleep and the increase of deep sleep, but reflects a direct effect of SO in improving and stabilizing muscle atonia during REM sleep,” Antelmi et al concluded.

READ MORE: Digital Cognitive Behavioral Therapy Proves Cost-Effective for Insomnia

Compared to baseline, children who received the drug improved in clinical complaints, as well as showed a decrease of the Epworth Sleepiness Scale (ESS) score (14.4 [±9.01] vs 3.25 [±4.87]; 

The treatment also had an effect on the different distribution of sleep stages. Compared to baseline, there was a decrease of the percentage of non-REM (NREM) sleep stage 1 (14.2 [±9.01] vs 3.25 [±4.87]; 

 <.0005) and of REM sleep (23.1 [±7] vs 13.1 [±6.45]; 

 <.0001), and an increase of NREM sleep stage 3 (11.1 [±10.13] vs 53.9 [±17.96]; 

Patients within the study underwent neurological investigations and video-polysomnography (v-PSG) at baseline and after 3 months of stable treatment with SO. In order to properly rate RBD episodes, v-PSG was independently analyzed by 2 sleep experts. The v-PSG included at least 3 electroencephalography (EEG) channels (frontal, central, and occipital leads, referred to the contralateral mastoid), bilateral electrooculogram, submentalis and anterior tibialis electromyography, respiratory parameters, and electrocardiogram.

Antelmi and colleagues noted, “this study offers class IV evidence of the positive effect of SO on modulation of muscle atonia during REM sleep in NT1 children, because of the absence of a control group.”

The investigators also noted that future studies are needed to confirm the findings in adults with NT1 and in patients with idiopathic RBD (iRBD).

In 2002, the original formulation of SO was approved as a central nervous system (CNS) depressant, marketed as Xyrem, to treat symptoms of narcolepsy in adults. The drug was only available through a risk evaluation and mitigation strategy (REMS) program mandated by the FDA. Additionally, it was approved with a black box warning because of its ability to potentially cause depression, seizures, coma, or death, especially in combination with other CNS depressants.

In January 2017, the FDA approved the first generic version of sodium oxybate oral solution, for the treatment of both cataplexy and excessive daytime sleepiness in narcolepsy in adult patients. The treatment’s label was also expanded in October 2018, to include an indication to treat cataplexy or excessive daytime sleepiness in patients with narcolepsy ages 7 and older.

1. Antelmi E, Filardi M, Pizza F, et al. REM sleep behavior disorder in children with type 1 narcolepsy treated with sodium oxybate. 

. Published online November 11, 2020. doi: 10.1212/WNL.0000000000011157

2. Xyrem (sodium oxybate) information. FDA.gov. 

https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/xyrem-sodium-oxybate-information

. Updated January 1, 2017. Accessed November 18, 2020.

3. Jazz Pharmaceuticals announces FDA approval of Xyrem (sodium oxybate) for the treatment of cataplexy or excessive daytime sleepiness in pediatric narcolepsy patients. News release. Jazz Pharmaceuticals. October 29, 2018. Accessed November 18, 2020. 

https://www.prnewswire.com/news-releases/jazz-pharmaceuticals-announces-fda-approval-of-xyrem-sodium-oxybate-for-the-treatment-of-cataplexy-or-excessive-daytime-sleepiness-in-pediatric-narcolepsy-patients-300739288.html

The GABAergic mechanism of sodium oxybate was able to increase simple movements in non-rapid eye movement sleep.

Sodium Oxybate Improves Nocturnal RBD and REM Sleep Without Atonia in Narcolepsy

"What’s more efficient is to be able to offer widespread genetic testing now. As soon as these clinical trials become available to individuals, they already have that answer.”

The chief scientific officer of the Parkinson’s Foundation detailed the benefits expanded access to genetic testing for patients with Parkinson disease would bring to the research setting.

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