, has been with the team since October 2019. Follow him on Twitter 

Marco Meglio

Results from a prospective cohort study conducted at the MS Center Amsterdam revealed that patients with multiple sclerosis (MS) who were depleted of B-cells had lower severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody response.

Lead author Zoe L. E. van Kempen, PhD, department of neurology, Amsterdam University Medical Centers, and colleagues also concluded that the results “hold important consequences for humoral immunity after COVID-19 infection and possibly vaccination.” A total of 546 patients with MS were included in the study, 64 (11.7%) of whom had SARS-CoV-2 antibodies detected. Ongoing treatment with disease-modifying therapy (DMT) was recorded in 405 (74.2%) of the total cohort. Signals of antibodies were quantified as normalized optical density (nOD) units, ranging from low (0.1-1.0 nOD) to high (>1.0 nOD).

Patients treated with ocrelizumab (Ocrevus; Genentech) experienced a lower median SARS-CoV-2 antibody response compared to those treated with other DMTs (0.2 [interquartile range (IQR), 0.1-0.4] nOD vs 2.5 [IQR, 0.6-2.5] nOD; 

<.001). Notably, at a median of 2.5 days (range, 0-41) before the antibody response was measured, all patients treated with ocrelizumab were B-cell depleted.

Using polymerase chain reaction (PCR) testing, researchers observed that 35 patients contracted COVID-19, and 4 of them (11%) tested negative for SARS-CoV-2 antibodies. “Case reports have described patients with MS and neuromyelitis optica treated with anti-CD20 therapies who did not develop detectable SARS-CoV-2 antibodies after PCR-confirmed COVID-19,” van Kempen and colleagues wrote.

The Remaining Necessities for Future Progressive MS Research

The investigators also showed that SARS-CoV-2 antibodies were less prevalent in patients using injectable drugs such as interferon ß-1a and glatiramer acetate than patients on other treatments (3 of 69 [4%] vs 44 of 336 [13.1%]; 

Among those who were antibody positive, 9 patients (14%) did not experience any symptoms suggestive of COVID-19. The loss of taste or smell was the most frequently reported symptom in those positive for SARS-CoV-2 antibodies, found in 30 of 64 patients (47%). In comparison, only 14 of 482 (2.9%) of patients without SARS-CoV-2 antibodies reported these symptoms (

). Van Kempen et al also noted that there were no COVID-19 fatalities in this MS population.

The study included adult patients with a current diagnosis of MS who had visited the MS Center Amsterdam in the past 2 years, beginning on July 31, 2020. The database was closed on December 18, 2020 and the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guideline was followed throughout.

Van Kempen and colleagues noted that the relatively low percentage of patients who were SARS-CoV-2 positive posed as a limitation to the study. Despite this, they were still able to show a lower antibody response in patients depleted of B-cells.

Humoral immunity in patients with MS, previously mentioned by van Kempen et al, was just recently observed in a study published in 

Therapeutic Advances in Neurological Disorders

. Investigators found that cladribine (Mavenclad; EMD Serono) was the only high-efficacy DMT that 

 in patients with MS who received mRNA-COVID-19 vaccines.

The same was not observed for the other DMTs evaluated in the study. Patients treated with fingolimod (n = 26; Gilenya; Novartis) showed no development of a post-vaccination humoral response. Only 1 of 26 patients (3.8%) had an antibody response that, although attenuated, was above the cut-off value for a positive response (

Among 44 patients treated with ocrelizumab, 10 (22.7%) demonstrated a protective antibody titer (

<.0001). Additionally, 42 of 44 (95.5%) patients had lymphocyte counts above 1000 cells/mm3, indicating that the failure to develop humoral response was not related to absolute lymphocyte count.

1. van Kempen ZLE, Strijibs EMM, Al MMC, et al. SARS-CoV-2 antibodies in adult patients with multiple sclerosis in the Amsterdam MS cohort. 

Published online April 30, 2021. doi:10.1001/jamaneurol.2021.1364

2. Achiron A, Mandel M, Dreyer-Alster S, et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. 

. Published online April 22, 2021. doi:10.1177/17562864211012835

Articles

All patients treated with ocrelizumab (Ocrevus; Genentech) were B-cell depleted and had lower SARS-CoV-2 antibody response than any other patients in the study. 

B-Cell Depletion a Factor in SARS-CoV-2 Antibody Response in Multiple Sclerosis

This article was originally published on our sister site, GeneTherapyLive. 

Data from a preclinical study of mouse models presented at 2021 American Society of Gene & Cell Therapy (ASGCT) Annual Meeting, May 12-15, showed that scAAV9 gene therapy could provide a meaningful benefit to patients with SLC13A5 deficiency.

SLC13A5 deficiency, an autosomal recessive disorder, is due to mutations in the 

gene, which codes for a plasma membrane sodium-dependent citrate transporter. There are currently no treatments available that target the underlying cause of the disease.

Lead author Rachel Bailey, PhD, assistant professor, University of Texas Southwestern Medical Center, and colleagues compared the efficacy and safety of scAAV9/SLC13A5

a self-complementary vector encoding a codon-optimized human 

gene, delivered intrathecally lumbar puncture (IT) or intra-cisterna magna (ICM) in 

knockout (KO) mice and wild type (WT) littermates.

Both KO mice and WT littermates were treated with the gene therapy through IT delivery or ICM delivery at 10-12 weeks of age and were monitored for weight and survival. At 1-month post-treatment and beyond, KO mice treated with the gene therapy had significantly decreased plasma citrate levels compared to KO mice treated with vehicle which showed sustained, high citrate levels.

In addition to blood collected at baseline and 5 months after first treatment, the mice received telemetry implants to record electroencephalogram (EEG) and electromyography (EMG) activity over 60-hour recording sessions. KO mice treated with vehicle had increased spike train activity and seizure frequency compared to WT littermates and, notably, that the vector treatment reduced this epileptic activity with greater rescue achieved with ICM delivery than IT delivery.

Following the 60-hour recording sessions, mice were tested for susceptibility to seizure induction by pentylenetetrazol (PTZ). KO mice had increased PTZ-induced seizure susceptibility, which was rescued to WT levels with ICM delivery of scAAV9/SLC13A5 and to a lesser extent with IT delivery.

The safety profile of scAAV9/SLC13A5 was robust, with no adverse events on weight, general activity or survival in KO or WT mice with either IT or ICM delivery.

Bailey and colleagues noted that they used KO mice due to their similarities to patients in that they have increased citrate and abnormalities in TCA intermediates despite not having an overt phenotype. They also noted that these mice have low, but increased epileptic activity compared to WT mice.

Bailey RM, Bailey L, Schackmuth M, Garza I. scAAV9 gene replacement therapy for epileptic SLC13A5 deficiency. Presented at 2021 American Society of Gene & Cell Therapy; May 12-15. Abstract 137

The safety profile of the SLC13A5 vector was “excellent” according to study authors, with no adverse effects on weight, general activity, or survival in knockout mice and wild type littermates. 

scAAV9 Gene Therapy Safe, Effective in Preclinical Study in Epileptic SLC13A5 Deficiency

In April, the FDA granted de novo authorization, as well as breakthrough device designation, to the first device leveraging brain-computer interface technology to assist patients with chronic stroke in rehabilitation. Neurolutions’ IpsiHand Upper Extremity Rehabilitation System contains a robotic exoskeleton that is worn over the patient’s hand and wrist, an electroencephalogram (EEG)-based headset, and a tablet.

The device utilizes the uninjured, or ipsilateral, side of the brain to improve arm and hand function and is indicated for patients 18 years and older. The use of brain-computer interface technology has become more relevant in recent years, which Eric Leuthardt, MD, feels is potentially an effect from the improvements made in acute care.

Leuthardt, founder and chief scientific offer of Neurolutions, also serves as the division chief of neurotechnology and neurological surgery professor at the Washington University in St. Louis School of Medicine. On a new edition of NeuroVoices, Leuthardt discussed the makeup of the IpsiHand System, why its home-use feasibility may be a huge advantage, and the reasons behind the sudden movement toward these post-stroke rehab systems.

What are the clinical tools that make up the IpsiHand System?

Fundamentally, the IpsiHand System is a brain computer interface technology that consists of a noninvasive biometric EEG headset, a wearable robotic exoskeleton that consists of a dynamic orthosis that’s worn by the patient, and a tablet used to help guide the therapy. Those 3 critical components make up the system.

The science and motivation behind all of this stems from the fundamental idea that things that fire together, wire together. To enhance rehabilitation, we want to retrain the brain to basically recalibrate circuits to optimize function. One of the things that was classically understood before the IpsiHand was that 1 side of the brain controls the opposite side of the body. That bears itself out in a lot of common experiences. If, for instance, somebody had a stroke on the right side, their left side is paralyzed.

What have you found this system to be capable of?

The interesting thing is that you can have movement intentions, or the movement physiology, where the information is encoded, and movement is still present. We found that physiology is present on the uninjured side of the brain. Now, that gives us an opportunity to use brain computer interface, a device that can pick up signals from the brain and decodes those intentions, as a rehabilitation tool. That is 1 of the fundamental theses of this company early on.

The idea is that if we’re using a brain computer interface to pick up a signal of movement intention, or ipsilateral movement signal, where the uninjured side of the brain is controlling the same side of the body. When the signal fires off, it is controlling that robotic exoskeleton, which is giving sensory feedback to the individual, concurrent with those brain signals, that’s going to fundamentally lead to a rehabilitation effect, to enable the brain to better control that paralyzed hand.

First, we were able to show that patients with stroke could do brain computer interface and control a device with those movement intentions from the uninjured side of the brain. We then pair that with a robotic exoskeleton. That actually did indeed have a rehabilitative effect in patients with chronic stroke, who are at least 6 to 8 months out from their stroke and are at a point where the expectation is that they should not get any meaningful clinical benefit. That’s the thinking behind the device and how it works.

What advantages does this system bring to the post-stroke treatment landscape?

There’s a heterogenous cause for disability post-stroke, as well as heterogenous locations of where that injury can occur, whether it be in the white matter, internal capsule, cortex, or even whole hemispheric. By assessing the uninjured side of the brain, we’re acknowledging that the stroke has left you with a motor disability, but that we’re going to tap into the good part of the brain. We’re basically, in some sense, homogenizing that patient population by tapping into these brain signals from the uninjured side to have an effect on improvement. That provides us with an opportunity.

The other thing that gets us excited is that when we publish these papers on brain computer interfacing, they’re typically done in very rarefied controlled laboratory environments. The expectation was that you’re going to use these types of technology, that they had to be in specialized tertiary environments. We’re doing brain computer interface with patients at home. To me, this is really exciting aspect of this technology

In addition to the fancy science bells and whistles, equally important is a system that we can send home with you. Patients with stroke can dawn and doth independently, put it on, the system will then walk them through it and screen their brain signals. That was 1 of the key early findings that this system can enable home brain computer interfacing and generate a meaningful clinical result as part of that. Having the ability to have this rehabilitation system that goes in a box at home, meets the patient where they are, and is also a real opportunity for improvement for patients with chronic stroke.

What has driven this growing movement towards these post-stroke rehab systems in recent years?

Firstly, there’s a growing movement in the acute care of stroke. There’s some key aspects whether that’s earlier use of TPA or emerging thrombectomy, that show that we’re getting better with acute stroke in terms of improving outcomes. With that said, there’s still a sizeable number of patients that are left with a motor deficit. Around 300,000 to 400,000 patients per year are left with a chronic upper extremity deficit. We’re expanding our perspective in that we’re maturing our technology for acute intervention, but that’s not the whole story.

How do we start making meaningful strides for people who have gotten past that acute phase? What can we do for them to improve their quality of life? A lot of times people are quite simply resigned to the fact that they’ve got a permanent deficit. The focus, historically, has been adaption and how you can best accommodate that deficit. Now we’re starting to see, especially with brain computer interface, that we can perhaps open that window, again, and start to do things. That’s really starting to generate a lot of excitement for adding to the equation of this global ability to care for these patients.

The founder and chief scientific officer of Neurolutions discussed how the company’s newly approved chronic stroke rehabilitation system will provide expanded benefits to post-stroke patients.

NeuroVoices: Eric Leuthardt, MD, on the IpsiHand Stroke Rehab System

Data from an open-label extension trial (NCT02348632) evaluating solriamfetol (Sunosi; Jazz Pharmaceuticals) demonstrated that the treatment is safe and efficacious among patients with 

 (OSA) regardless of adherence to continuous positive airway pressure (CPAP), defined as primary OSA therapy.

 Solriamfetol, a dual-acting dopamine and norepinephrine reuptake inhibitor, received FDA approval for the treatment of 

 (EDS) in adults with narcolepsy or OSA in March 2019.

Lead author of the study Paula K. Schweitzer, PhD, director of research, St. Luke’s Sleep Medicine and Research Center, explained that the clinical need to treat patients who are both adherent and nonadherent to primary OSA therapy is what motivated her to conduct the study. 

Schweitzer and colleagues found that at 40 weeks, mean Epworth Sleepiness Scale (ESS) scores were 6.5 in the adherent group and 6.8 in the nonadherent group. She sat down with 

 to provide more context to the study findings, as well as to discuss the current understanding of residual EDS and where it may stem from. Additionally, she stressed the need to improve awareness of EDS for both patients and clinicians. 

: Sleepiness is common among patients with obstructive sleep apnea. It doesn’t occur with everyone, but it’s fairly common. It persists in approximately 9% to 22% of patients despite adequate treatment for sleep apnea. Additionally, nonadherence to sleep apnea treatment is very common and a lot of people don’t like or can’t use CPAP because they have difficulty sleeping with it. Even those who are using it may not use it all night long, and so they can be sleepy as a result of inadequate treatment, no treatment, or even with adequate treatment. Sleepiness can still persist in those cases.

Because sleepiness has consequences for productivity, potential for accidents, and reduced quality of life, the clinicians who treat this need something to help with those situations. We were looking at solriamfetol as a new treatment for sleepiness in and of itself, and decided to use both patients that were adherent to treatment, as well as those who weren’t, because both types exist. There’s a clinical need for treatment in both situations. 

We wanted to find out if treatment of excessive sleepiness would cause a decrease in the use of CPAP or whatever treatment they were using for sleep apnea. The study shows that it does not, and that's really encouraging because you still want to treat that underlying disorder. That's really important for cardiovascular health and other reasons.

What do we currently know about residual EDS and are there research areas within that which require attention? 

Sleepiness can be caused by a number of things. In a patient with sleep apnea, it can be caused by inadequate treatment. It can also be caused by other things that we can control. For example, insufficient sleep. If you’re only sleeping for 4 hours, you’re going to be sleepy. You want to improve that. Sometimes patients with depression feel sleepy during the daytime. If the depression is inadequately treated, you may want to focus on treating that. 

Sometimes it persists despite all that. Sometimes, as I said before, the patient can’t always optimize treatment for all those conditions because of an unknown reason. We want to be able to handle that. There are animal studies that suggest that intermittent hypoxia or intermittent loss of oxygen, which can occur in sleep apnea, can cause damage to wake-promoting neurons in the brain. It may not happen to all patients and we don’t know why. Those are things that we need to look at in the future. There are also some studies in humans that show white matter structural changes in patients with sleep apnea who have residual sleepiness, but not in patients with sleep apnea who don’t have residual sleepiness. There may be something going on in the brain that is causing this residual sleepiness. 

Is there a lack of awareness of EDS among those who may be eligible for treatment? 

I think that can happen. There are a number of patients with sleep apnea who are not aware that they’re sleepy. If you talk to the spouse, they’ll tell you that he or she falls asleep in front of the TV all the time, whereas the patient doesn’t necessarily perceive that. A lot of people do activities to prevent themselves from falling asleep. Sometimes you have to look a bit deeper in terms of what they’re doing to determine if it’s something that needs to be treated. It’s certainly something that needs to be addressed at clinician visits and asked about, regarding whether sleepiness is persisting. Some patients will complain of it, which is straightforward, but some others don’t. For safety purposes, the clinician does need to evaluate that.

What advantages does solriamfetol bring to the sleep disorder treatment landscape? 

There’s been no head-to-head comparisons of the drug with other drugs in terms of treatment, but solriamfetol definitely increases alertness significantly throughout the day. It appears that it may be better than some of the other drugs that are available to treat sleepiness. However, right now in the US, the only other drugs that are approved by the FDA for treatment of sleepiness in patients with sleep apnea are modafinil (Provigil; Teva) and armodafinil (Nuvigil; Teva), which are similar drugs.

Those drugs are not approved in the European Union as their approvals were withdrawn. Additionally, those drugs may not treat patients as well as we’d like and sometimes require increased dose for treatment. We really don’t have any other drugs to treat residual sleepiness in patients with sleep apnea. We have some stimulants that we could potentially give them [off-label], but they’re not FDA-approved and haven’t been studied in that particular condition. We don’t have the data to indicate that’s what we want to do. 

Are there any plans for future research building on this study? If so, what in particular would you like to examine? 

We do need a better understanding of excessive daytime sleepiness itself—that’s across the board. Patients and clinicians sometimes don’t differentiate between feeling fatigued and having no energy versus actual sleepiness where they can’t stay awake. That may be an important distinction in determining both cause of the complaint, as well as how to treat the complaint. We need to do that. 

We also need a better understanding of obstructive sleep apnea. Sleep apnea is a heterogenous disorder and we’re learning that it has a number of different underlying physiological traits and a number of different phenotypes or clinical manifestations. In order to provide personalized and individualized care for patients, we need to understand those factors.  

1. Schweitzer PK, Strohl KP, Mayer G, et al. Effects of solriamfetol in a long-term trial of participants with obstructive sleep apnea who are adherent or nonadherent to airway therapy. J Clin Sleep Med. Published online February 1, 2021. doi: 10.5664/jcsm.8992

2. Jazz Pharmaceuticals announces US FDA approval of Sunosi (solriamfetol) for excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. News release. Jazz Pharmaceuticals. March 20, 2019. Accessed May 6, 2021. 

https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-sunositm

Paula K. Schweitzer, PhD, discussed her findings on the safety and efficacy of solriamfetol in patients receiving OSA therapy and the need for more research on residual excessive daytime sleepiness.  

Marco Meglio

Articles

B-Cell Depletion a Factor in SARS-CoV-2 Antibody Response in Multiple Sclerosis

scAAV9 Gene Therapy Safe, Effective in Preclinical Study in Epileptic SLC13A5 Deficiency

NeuroVoices: Eric Leuthardt, MD, on the IpsiHand Stroke Rehab System

Solriamfetol and the Impact of Residual Excessive Daytime Sleepiness