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AAN Annual Meeting

Access daily, concise peer-reviewed reports from the AAN Annual Meeting selected by the Neurology Today editors.

Friday, April 23, 2021

The children of women who took antiseizure medication during pregnancy do not appear to have a different neurodevelopmental trajectory than do children from women who did not have epilepsy while they were pregnant, researchers reported at the 2021 virtual AAN annual meeting.

The findings came from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, a prospective, observational, multicenter investigation of pregnancy outcomes.

In his presentation at the meeting, Kimford Meador, MD, FAAN, professor of neurology and neurosciences at Stanford University, reported, “In these preliminary analyses, neurodevelopmental outcomes did not differ between children of women with epilepsy compared with healthy women, and exposure-dependent antiseizure medication effects were not seen."

The findings were adjusted for maternal IQ, education, and antiseizure medication group.

For the key outcome measure, the mean adjusted Verbal Index scores, there was essentially no statistically significant difference between 275 children born to women with epilepsy and 77 children whose mothers did not have epilepsy (the controls). The Verbal Index score was calculated by averaging the Differential Ability Scales-II (DAS-II) Naming Vocabulary and Verbal Comprehension subtests, Preschool Language Scale-5 Expressive Communication and Auditory Comprehension subscales, and Peabody Picture Vocabulary Test-4.

The research team enrolled women with epilepsy and healthy women who were pregnant.

At enrollment, most pregnant women with epilepsy were being treated with monotherapy. About 77 percent of the women were taking one medication. About 43 percent of the women were taking lamotrigine while another 37 percent were on levetiracetam. If the women were on combination treatment, Dr. Meador reported that treatment with lamotrigine plus levetiracetam was the most popular polytherapy.

In secondary analyses of DAS-II Non-Verbal Index and General Conceptual Ability scores, there was no difference in outcome between the children of women with epilepsy and children of healthy women.

In commenting on the study, Lia Ernst, MD, assistant professor of neurology at the Oregon Health Sciences University Comprehensive Epilepsy Center, told Neurology Today At the Meetings, “Overall the study is reassuring that most women with epilepsy are able to have healthy pregnancies and children of women with epilepsy have normal cognitive outcomes"

Dr. Ernst said that the current trial is a follow-up on the NEAD trial that was conducted from 1999-2004.“In the NEAD study, the antiseizure medications examined were lamotrigine, phenytoin, valproate, and carbamazepine," she said. “In the MONEAD study, most women were taking levetiracetam and/or lamotrigine. This likely represents a shift in practice, given the results of the NEAD study, which showed poorer cognitive outcomes in children of mothers taking valproate.

“Data from previous studies suggests that lamotrigine and levetiracetam are relatively safer medications. Given this shift, I am not surprised that cognitive outcomes appear better in this cohort than the NEAD cohort," Dr. Ernst said.

“The MONEAD study is well designed. “It was a multicenter, prospective study that used multiple outcome measures to determine cognitive outcomes of the children, Dr. Ernst said. “One caveat is that because the majority of women were taking lamotrigine and levetiracetam, the results may be less generalizable to women with epilepsy taking other antiseizure medications or combinations of multiple antiseizure medications."

Dr. Meador has received compensation for travel expenses from Eisai for serving as a lecturer for educational symposium at the European Paediatric Neurology Society. Dr. Ernst disclosed relationships with NeuroPace.

AAN Abstract S1.001: Meador K, Cohen M, Loring D, et al. Fetal antiseizure medication effects on neuropsychological outcomes at age 3 years in the MONEAD study.


Friday, April 23, 2021

A new spinal cord stimulation system appears to markedly suppress pain caused by diabetic neuropathy, researchers reported at the 2021 virtual AAN Annual Meeting.

Patients diagnosed with diabetic neuropathy who were implanted with the 10 kilohertz spinal cord stimulation in the prospective, multicenter, randomized controlled trial (SENZA-PDN) reported that their pain scores decreased from a 7.6 cm on a visual analog scale to 1.7 cm at six months, reported Erika Petersen, MD, professor of neurological surgery and director of functional and restorative neurosurgery at the University of Arkansas for Medical Sciences in Little Rock.

In the conventional medical management group of patients, the baseline pain level on the scale was 7.0 cm, but after six months the average pain score was 6.9 cm—demonstrating almost no difference, she noted.

“SENZA-PDN is the largest randomized clinical trial to date of 10 kHz spinal cord stimulation management of painful diabetic neuropathy," Dr. Petersen told Neurology Today At the Meetings. “Results through six months demonstrate substantial improvements for patients with refractory symptoms that exceed those seen with pharmacotherapy and low-frequency spinal cord stimulation."

“This study shows 10 kHz spinal cord stimulation provides profound, sustained pain relief, improves findings on neurological examination as well as patient-reported dysesthesias, and enhances quality of life," Dr. Petersen said. “For painful diabetic neuropathy patients with inadequate response to conservative care, 10 kHz spinal cord stimulation should be recommended as a treatment option."

“All patients originally randomized to 10 kHz stimulation have completed 12 months of follow up," Dr. Petersen said, “so we have demonstrated that the relief reported in our study after six months in the spinal cord stimulation arm is maintained at nine months and 12 months. Responder rates remain stable up to 12 months as well. The study will follow all patients out to 24 months to show durability of response."

Previously, she reported that the trial met its primary endpoint—the composite of 50 percent or greater pain relief without deterioration of neurological status at three months. Five percent of the 103 patients who were treated with conventional medical management met that endpoint compared with 86 percent of the 113 patients who were treated with spinal stimulation (p<0.001), Dr. Petersen said. The trial was sponsored by Nevro Corp. of Redwood City, CA.

Eligible patients had reported painful diabetic neuropathy for at least 12 months.

Dr. Petersen said there were two infections (2.2. percent) in patients that required device explant. Just 6.3 percent of conventional medical management subjects were deemed responders; 52 percent reported worsening pain, she reported in her poster presentation. In contrast, among patients who recede the implant, 85 percent were considered responders, and 2.3 percent reported worsening pain, she said.

 “I would not consider spinal cord stimulation either a last resort or extreme," Dr. Petersen said. “It is a relatively low risk procedure to implant an epidural stimulator to affect spinal cord transmission of pain signals."

Commenting on the study, Chanë Price, MD, assistant professor of neurology at the University of Miami, said: “I use spinal cord stimulation for these patients after they have failed conservative treatment options. This is not a standard of care yet as many insurance carriers have not accepted this form of treatment for approval."

“Given the evidence from the most recent trials, this will soon be a standard of care, not only for painful diabetic neuropathy but also for other painful peripheral neuropathies such as chemotherapy-induced painful peripheral neuropathies," he said.

Dr. Petersen disclosed relationships with Abbott/St Jude Medical, Medtronic, Neuromodulation, Nevro, Vertos, Boston Scientific, Neuros Medical, ReNeuron, Saluda, and SynerFuse. Dr. Price had no disclosures.

AAN Abstract: Petersen E, Stauss T, Scowcroft J, et al. Sustained benefits for 10 kHZ spinal cord stimulation treatment of painful diabetic neuropathy—six month results from a multicenter randomized controlled trial.​​

Friday, April 23, 2021

Efgartigimod was safe and effective for patients with generalized myasthenia gravis (MG), according to a phase 3, placebo controlled trial, presented at the virtual 2021 AAN Annual Meeting.

Efgartigimod, an investigational antibody fragment, is designed to block the activity of the neonatal Fc receptor, a protein that normally prevents IgG antibodies—including the harmful self-reactive antibodies found in MG patients — from being destroyed.

Efgartigimod was recently assessed in trials for efficacy in myasthenia gravis, said the study's lead author, James F. Howard Jr, MD, FAAN, professor of neurology at the University of North Carolina in Chapel Hill. “We are very excited that this offers a new option for our patients. It is a targeted therapy with a rapid onset of action, reasonable durability, and an acceptable side effect profile.

“The goal with this drug is not only to reduce disease burden, but also treatment burden for the patient, and in doing so, offer them a more normal and acceptable quality of life," he told Neurology Today At the Meetings.

If it meets regulatory approval standards in the US and abroad, this drug has the potential to revolutionize current myasthenia gravis management techniques, said Dr. Howard. “I believe that it will be a substitute for plasma exchange and intravenous immunoglobulin based on the side effect profiles," he said.

The study team assessed 38 patients who were AChR-antibody-negative (AChR-Ab-) and 129 who were AChR-Ab-positive (AChR+). Both groups were randomly assigned to either receive a placebo or an initial therapy cycle of four weekly 10 mg/kg infusions of efgartigimod. The researchers used a patient's Myasthenia Gravis Activities of Daily Living  (MG-DAL) score to determine subsequent therapy cycles.

About 68 percent of AChR-Ab+ patients were considered MG-DAL responders, meaning they had a two or more point improvement for four or more weeks following the first treatment cycle. This compared with only 29.7 percent of responders in patients receiving placebo.

Moreover, 63.1 percent of AChR-Ab+ treated patients were Quantitative Myasthenia Gravis (QMG) responders—meaning they had a three or more point improvement for four weeks or longer with the first treatment cycle—compared with 14.1 percent of placebo patients. 

The drug was also effective for 82.9 percent of QMG responders within the first two weeks and 84.1 percent of MG-ADL responders. Patients also had significant improvements in quality of life.

In AChR-Ab- patients, 21.1 percent of patients receiving placebo and 47.4 percent on efgartigimod reached both QMG and MG-ADL responder status.

Most adverse events were mild or moderate, and only a few cases were considered grade 3 severity.

“I'm not sure at this point whether it will play a role in myasthenic crisis for those who are hospitalized. We need further study for that," Dr. Howard said.

There are not many treatment options for myasthenia gravis, so it is very encouraging to have another alternative, said Alejandro Tobon, MD, chief of neurology at South Texas Veterans Healthcare System in San Antonio, who was not involved in the study. “The safety profile is going to be really important because the other available therapies have significant side effects, so more details looking into safety are key."

“Another aspect that is important to highlight is the quick response time [of this therapy], as some treatments for myasthenia may take months, especially the oral treatments. Having therapies that improve symptoms in two to four weeks is very promising," Dr. Tobon told Neurology Today At the Meetings.

“This is one of many FcRn receptor blockers that have been studied recently," added Michael H. Rivner, MD, FAAN, Charbonnier Professor Emeritus of Neurology at Augusta University in Georgia, who was not involved in the research. “This drug class is exciting because of the role played by FcRn receptors in recycling IgG."

Dr. Rivner said that other studies have considered a three-point increase in the MG-ADL to be significant. “So I wonder about the two-point increase used as their primary endpoint and would like to see their other results," Dr. Rivner told Neurology Today At the Meetings.

“This is an important class of drugs. It has the advantage of not being a blood product and probably will be superior to IVIg, but we will need more clinical experience to be certain," he added.

Dr. Howard has received personal compensation for serving as a consultant for Alexion Pharmaceuticals and Regeneron Pharmaceuticals. Dr. Tobon did not report any disclosures. Dr. Rivner disclosed receiving an honorarium from Allergan and Alexion Pharmaceuticals. ​

Link Up for More Information

AAN Abstract. Howard J, Bril V, Vu T, et al. Efficacy, safety, and tolerability of efgartigimod in patients With generalized myasthenia gravis: Analysis of the phase 3 ADAPT study.


Friday, April 23, 2021

Cenobamate leads to sustained, long-term seizure freedom from focal epilepsy in many patients who were refractory to other treatments, according to post-hoc phase 3 findings presented at the 2021 virtual AAN Annual Meeting.

“We know that once two drugs have failed, the likelihood of other drugs working is extremely low," said Michael Sperling, MD, FAAN, professor of neurology at Thomas Jefferson University and lead investigator of the study. “This drug worked in some people who had already failed multiple drugs. So I think it will probably be justifiable to consider using this as drug number three in people with focal epilepsy once we've got some more safety data."

The findings were based on a post-hoc analysis of an open-label, phase 3 study of cenobamate. Phase 2 findings covered just 12 weeks and, as Dr. Sperling noted, “epilepsy is not a 12-week disease."

Cenobamate reduces repetitive neuronal firing by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium current. It also modulates the GABA-A ion channel. It was approved by the FDA in November 2019.

A subset of patients continuing cenobamate after a 12-week titration period were included in the analysis. At baseline, the patients had an average of 18.1 seizures; the median was 2.8 seizures per 28 days.

Researchers found that, at their last visit, 25.8 percent of the 240 patients were free of seizures at 12 months, 35 percent at six months or longer, and 44.6 percent at three months or longer. Thirty-six percent had gone for a period of 12 months or longer with no seizures at one point, Dr. Sperling said.

As part of cenobamate's development program, three participants developed drug reaction eosinophilia and systemic symptoms (DRESS), but no cases have been seen in patients treated with the “start low, go slow" approach that has been adopted since then. Patients start at 12.5 mg a day for the first two weeks and move to 25 mg a day for the next two weeks until reaching 200 mg a day at weeks 11 and 12. During the maintenance phase, up to 400 mg per day was allowed, reached at biweekly increases of 50 mg per day.

The most common treatment-emergent adverse events were fatigue (34.6 percent), dizziness (32.1 percent), and excessive sleepiness (29.6 percent). Dr. Sperling said that most of these issues were transient. Researchers reported that 20.8 percent of participants experienced serious treatment-emergent adverse events.

Patients had responses across all seizure types: 88.5 percent of those with focal aware motor seizures had at least a 50 percent seizure reduction and 23.1 percent had a 100 percent reduction; 77.9 percent of those with focal impaired awareness seizures had at least a 50 percent response rate, and 19.1 percent had a 100 percent reduction; and 85.4 percent of those with focal to bilateral tonic-clonic seizures had a reduction of at least 50 percent, with 35.4 percent having a 100 percent reduction.

Dr. Sperling said the drug could potentially alter the way surgery is considered in epilepsy patients.

“Should we make sure a patient's had the chance to try this drug before we operate on them?" he asked. “It's one of the things we'll have to think about for the future."

Shawniqua Williams Roberson, MEng, MD, assistant professor of neurology at Vanderbilt University Medical Center, said that “the idea that such a robust percentage of patients with refractory epilepsy can go from a median of two to three seizures per month to complete seizure freedom for over a year is quite encouraging."

Dr. Williams Roberson, whose division chief is one of the study authors, said she wondered what drove the study withdrawals and the loss to follow-up and what clinical characteristics might serve as predictors of success or of intolerable adverse effects.

“This would help to more precisely target the patient population that would be most likely to benefit from this medication," she said.

Alexis Boro, MD, coordinator of the epilepsy surgery program at Montefiore Medical Center and principal investigator of one of the cenobamate trial sites, said the high rates of seizure freedom are welcome.

“They tend to confirm what was seen in previous blinded trials with this drug—these results are unusual in that seizure-freedom rates like this are not expected with medical management alone in the medically refractory patients," he said. “Cenobamate is an important addition to the neurologist's toolbox."

But he said cenobamate is “not the easiest drug to use" due to remaining concerns about DRESS, the need for meticulous screening for a history of cutaneous drug reactions, and the slow titration that is necessary.

“Sedation is often an issue as the dose is increased. Interactions with other antiseizure medications are often an issue and can complicate dose titration further. In some patients, the option of a trial of cenobamate can make decision-making more complex," he said. “Which patients should undergo a trial of cenobamate versus referral for a palliative implanted device such as responsive neurostimulation? But this is a welcome complication. This is an exciting time in epilepsy."

Dr. Sperling has received personal compensation for serving on a speakers bureau for Eisai and Medscape. Dr. Williams Roberson has no disclosures.

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AAN Abstract S1.002: Sperling MR, Abou-Khalil B, Aboumatar S, et al. Efficacy of cenobamate for uncontrolled focal seizures: Post-hoc analysis of a phase 3, multicenter, open-label study.

Neurology Today Video. Cenobamate Shows Long-Term Benefits for Focal Seizures.

Friday, April 23, 2021

A drug that was initially rejected for its failure to distinguish itself from placebo in a pivotal trial for spinocerebellar ataxia (SCA) is being reconsidered, researchers reported at the virtual 2021 AAN Annual Meeting.

Treatment with troriluzole is being studied after a three-year open-label trial appears to show a stabilization of the degenerative balance disorder, said Melissa Beiner, MD, director of research and development at Biohaven Pharmaceuticals in Madison, CT.

Troriluzole is a glutamate-modulating agent with some pleiotropic effects, such as potential activation of some calcium-activated channels.

“Even though this isn't a really good comparison with a natural history cohort, we were encouraged by the 96-week outcomes because, at the very least, we think we are seeing disease attenuation in this population with troriluzole," said Dr. Beiner in her oral presentation.

There are no US Food and Drug Administration-approved treatments for SCAs, a group of rare neurodegenerative disorders that can present with balance and gait abnormalities, incoordination of limbs, and dysarthria, as well as cognitive dysfunction, dysphagia, and motor pathology, Dr. Beiner said. Most treatments used are palliative, she added.

In the phase 2/3 double-blind, placebo-controlled trial of troriluzole in adult subjects with SCA, the researchers used preclinical data and two early- stage trials from Italy, which suggested that glutamate modulation had a role in SCA. After a screening period, the study had an eight-week randomization phase, followed by a 48-week open-label phase.

“At the end of our randomization phase we did not hit our primary endpoint, which was the change in the Scale for the Assessment and Rating of Ataxia [SARA] score from baseline to the end of the eight weeks," Dr. Beiner said. 

“In hindsight, the study suffered from a very high placebo performance and the eight-week period was not enough to see a difference. Our patients then proceeded into the open-label [phase]. At the end of the open-label [period], we started hearing from our investigators that an overwhelming number of patients felt that they were declining while they were coming off troriluzole," she said. “The patients felt that they had been more stable on the drug and we were getting request after request for patients to remain on it."

The company re-booted the trial. “We looked at our 48-week data in comparison to an unmatched natural history cohort," she said. “We matched patients from our cohort with the genotype, age, sex, severity of disease, and the baseline SARA score with those in the natural history cohort. After one year, the 81 patients in the troriluzole arm had a change in their SARA score of -0.34 points versus an increase in SARA at 48 weeks among the 112 patients in the natural history cohort, which had an increase of about one point. The difference was 1.41 points which was statistically significant (p=0.0007), she said.

“This gave us the information we needed to start another open-label phase for 96 weeks within the same study to look at this drug over a longer period of time," she said.

“When patients were on the drug, their SARA scores improved by about a point and then were stable until they came off the drug, and their scores increased," Dr. Beiner said. “When they were back on the drug their score stabilized again about at a level of 0.5 points above their original baseline. We would have expected patients at two years, without drug, to have declined two to four points. The patients who were off the drug for less than 180 days had about a 0.5 point increase above baseline, but in those who had a gap of more than 180 days their SARA score was about .75 points above baseline."

Based on the results, Dr. Beiner said the company has launched another phase 3 trial, but this time the randomization phase will last 48 weeks, followed by an open-label phase of another 48 weeks. The outcome measure will use a modified SARA score to try to tease out more functional aspects of the disorder.

“Typically, when you have a negative outcome measure, you will believe the medication is not going to be beneficial," said Deborah Hall, MD, PhD, FAAN, professor of neurological sciences at Rush University in Chicago. “But this study's data suggest that either the patients need longer duration of treatment, the drug is slowing progression, or that there is an impact on participant quality of life that needs to be a primary outcome measure."

“We do need another placebo-controlled study with modification of the protocol to account for findings in the first study, and we need to see the troriluzole data published after peer review," she said. “Stabilization may be the more accurate description for what this drug is doing in patients with SCA if the follow-up studies confirm this study's findings."

Albert La Spada, MD, PhD, Distinguished Professor of Neurology, Pathology & Laboratory Medicine, and Biological Chemistry at University of California, Irvine School of Medicine, agreed that although the findings are promising, it would be “premature to draw definitive conclusions from an open-label trial. However, as many SCA patients show disease progression over time, this initial study is encouraging and now requires that a comprehensive placebo-controlled clinical trial be pursued."

Dr. Beiner is an employee of Biohaven. Dr. Hall, who is an associate editor of Neurology Today, disclosed relationships with Biohaven, CHDI

AAN Abstract S3.002: Beiner M, Wirtz V, L'Italien G, et al. Analysis of 96 week, long-term open label extension phase of study BHV4157-201: A phase IIb/III, randomized, double-blind, placebo-controlled trial of the safety and efficacy of troriluzole in adult subjects with spinocerebellar ataxia.