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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, May 1, 2020

Prednisone is effective as an initial short-term therapy for episodic cluster headaches, according to results from a prospective, randomized, controlled trial described in an abstract featured as part of the 2020 AAN Science Advances.

The findings could help reassure clinicians and patients on the use of prednisone for these headaches, said Mark Obermann, MD, professor of neurology at Asklepios Hospitals in Seesen, Germany.

"Even though prednisone is widely used, treating physicians were never quite sure on whether it actually works or not, so that some uncertainty always remained, and there was a lively discussion among headache specialists and general physicians on whether prednisone should be used or not in cluster headache," Dr. Obermann said. Patients, not distinguishing between short- and long-term use, can also have major concerns about prednisone's side effects, and these findings could help alleviate those concerns, he said.

Researchers enrolled 118 patients, 18- to 65-years-old; 109 were included in the analysis of intent-to-treat patients. Fifty-three patients were randomized to receive prednisone and 56 to placebo. Patients in the prednisone group received 100 mg of oral prednisone for five  days, and then they were tapered by 20 mg every three days. This was done in parallel with an increasing dose of verapamil for maintenance, starting with 40 mg three times a day.

In the first week, the average number of cluster headache attacks in the prednisone group was 7.1, compared with 9.5 in the placebo group, a significant difference (p=0.02). Researchers found that 17 patients, or 34 percent, in the prednisone group reported a complete cessation of their cluster headaches after the first week, compared to just four (7.4 percent), in the placebo group. The researchers reported a reduction of at least 50 percent in headache attacks in 25 patients (49 percent) who were receiving prednisone, compared with eight (14.5 percent) receiving placebo (p<0.01). Researchers observed no relevant side effects, Dr. Obermann said.

"The main effect is the establishment of treatment certainty for patients as well as for physicians," he said. "This will reassure prednisone as a gold standard for the short-term prevention of episodic cluster headache."

He said a lack of evidence had also led to some "confusion and concern" about the use of prednisone, with fear of side effects without proof of benefit. A major question, he said, was the dosage that is needed and the duration of treatment.

"We tried to solve these uncertainties by introducing a strict dosage regimen, and thus get rid of all the proposed dosages ranging from 100 mg to 1,000 mg per day applied orally or IV," he said.

He said that diabetic patients might need close blood-sugar monitoring during treatment, but beyond that, he doesn't see a need for reservations in treating these patients with prednisone for short-term benefit until preventive treatment becomes effective.

Commenting on the abstract, Matthew S. Robbins, MD, FAAN, associate professor of neurology specializing in headache at Weill Cornell Medicine, said the trial replicated what is done in the real world with respect to using steroids as a kind of bridge therapy before preventive medication begins to work, and produced affirming results, including its findings of no relevant side effects.

"This abstract brings results that reinforce that our longstanding approach in managing patients with cluster headache with a short-term preventive treatment that is valid in a randomized trial," he said.

His group has found that greater occipital nerve injection with steroid is also an effective short-term strategy, although those on oral steroids generally did better. But the injection could be a better option in certain patients, he said.

"Of course, we all worry about rare adverse events with steroid bursts that would take a huge sample size to potentially uncover—such as avascular necrosis of the hip," he said. "Patients who could be at a particular risk of such adverse effects from steroids, such as people with diabetes or osteoporosis, would be better candidates for an alternative treatment like a greater occipital nerve injection with a steroid."

Disclosures: Dr. Obermann has received scientific support, travel support, and/or honoraria from Biogen Idec, Novartis, Sanofi/Genzyme, Pfizer, Teva, Lilly, Schwarz, and Heel. He has received research grants from Allergan, Electrocore, Heel, and the German Ministry for Education and Research. Dr. Robbins had no relevant disclosures.

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AAN Abstract 4645: Obermann M, Holle D. Prednisone in short-term prevention of episodic cluster headache.

Friday, May 1, 2020

Epilepsy patients having seizures may experience cardiac electrical abnormalities that might explain why they have a higher rate of sudden cardiac arrest, according to an abstract featured as part of the 2020 AAN Science Advances.

"Sudden cardiac arrest is three-fold greater in patients with chronic epilepsy than in the general population," said study author Trudy Pang, MD, assistant professor of neurology at Beth Israel Deaconess Medical Center/Harvard Medical School. "We hypothesized that because generalized tonic-clonic seizures are associated with greater disruption of autonomic function as compared with focal seizures and non-epileptic seizures, the ictal impact on cardiac electrical instability would be greatest during these seizures."

Dr. Pang and her colleagues compared the impact of generalized tonic-clonic seizures, focal seizures, and non-epileptic seizures on T-wave alternans, a marker of cardiac electrical instability linked to sudden cardiac death.

In seven patients who experienced focal seizures, the researchers observed significant increases in T-waves alternans—an increase from two to 30 µV ictally (p<0.0001)—but the maximum T-wave alternans levels did not exceed the cutpoint for cardiac abnormalities.

Dr. Pang said, however, that in five patients who had generalized tonic-clonic seizures, they observed a marked increase in T-wave alternans from two to 70 µV (p<0.0001), which exceeded the threshold—a 60-µV cutpoint—for severe abnormality in every patient.

The T-wave alternans increased modestly in three patients who had non-epileptic seizures, she reported.

Dr. Pang and colleagues also observed that heart rate increases during generalized tonic-clonic seizures rose from an average of 62 beats per minute to 134 beats per minute during the event. The increase of 72 beats per minute was significantly greater (p=0.014) than during focal seizures. In the focal seizures patients, heart rates rose from an average of 70 beats per minute to 118 beats per minute, or an increase of 48 beats per minute, Dr. Pang reported.

"The associated increases in heart rate likely reflect the reciprocal increase in sympathetic activity and decrease in cardiac vagal tone, factors known to increase T-wave alternans," Dr. Pang suggested.

"This is the first study to demonstrate that generalized tonic-clonic seizures provoke highly significant ictal increases in T-wave alternans," Dr. Pang said. "Further, the levels observed have been associated with heightened risk for sudden cardiac death in other populations. By comparison, focal seizures induced moderate increases in T-wave alternans ictally, whereas effects on T-wave alternans during non-epileptic seizures were only mild despite concurrent heart rate increases."

Dr. Pang and her colleagues suggested that T-wave alternans may represent an important marker to identify patients at high risk for significant cardiac arrhythmias.

Dr. Pang added: "Our study further contributes to our understanding of the risk factors for sudden cardiac death in patients with epilepsy. Routine cardiac evaluation in epilepsy patients is not currently a standard of care. We propose that patients with refractory seizures, particularly generalized tonic-clonic seizures, may be considered for further cardiac evaluation, especially those with additional cardiovascular risk factors."

Determining cardiac risk will not only play an important role in the epilepsy monitoring unit to improve patient safety, she said, but it will also guide the long-term comprehensive management of patients with refractory epilepsy. "Interventions to modify these cardiac markers to confer cardiac protection and reduce the risk of sudden death in patients with epilepsy is an important area of study in the future."

Commenting on the study, David C. Spencer, MD, FAAN, professor of neurology, and director of the Oregon Health and Sciences University Epilepsy Center in Portland, told Neurology Today, "These measures are not routinely checked in people with epilepsy. At present, it is done on a research basis, but if it is shown to be an important marker for cardiac problems or sudden death in people with epilepsy, it could be done more routinely as part of clinical practice."

Dr. Spencer said that more research is needed, however. "The abstract reports findings from a small number of subjects. It would be important to replicate the findings and see if they reflect a general finding in all or most people with epilepsy," he said. "It would also be important to establish the link with cardiac problems or sudden death, if there is one. In other words, is this just an interesting finding on ECG that shows how seizures stress the heart, or does it reflect an underlying process that determines risk for sudden death or severe cardiac problems in people with epilepsy?" he said.

Disclosures: Drs. Pang and Spencer disclosed no relevant relationships with industry.

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AAN 1493: Pang T, Nearing B, Olin B, et al. Comparative acute impact of focal and generalized tonic-clonic seizures on cardiac electrical instability in the epilepsy monitoring unit.

Friday, May 1, 2020

An exercise program that relies on non-contact boxing exercises appears to improve non-motor symptoms and other aspects of life for patients with Parkinson's disease (PD), researchers reported in an abstract featured as part of the 2020 AAN Science Advances.

Seventy percent of 1,709 PD participants surveyed about the program called Rock Steady Boxing said they observed improvements in their social, reported Danielle Larson, MD, a movement disorders fellow at Northwestern Memorial Hospital in Chicago.

Sixty-two percent of the participants said they experienced improvements in fatigue, less fear of falling (61 percent), less depression (60 percent), and anxiety (58 percent).

The subjects in the study were more likely to be retired, were 64- to 74-years-old; more than half were men and 96 percent were white. Dr. Lawson also reported that current participants had better outcomes as assessed by the quality of life PDQ-39 questionnaire (p<0.01).

"This is the largest analysis of Rock Steady Boxing use in Parkinson's disease, and demonstrates that Rock Steady Boxing participants have improvement in non-motor symptoms of Parkinson's disease, and compared to non-participants have significantly better quality of life and exercise self-efficiency," she reported.

Approximately 43,000 people participate in the boxing program at 871 sites worldwide, she said.

Commenting on the study, Brian D. Berman, MD, MS, FAAN, associate professor of neurology,  psychiatry, and radiology and associate director of research at the Movement Disorders Center at the University of Colorado Anschutz Medical Campus in Aurora, said he has patients who participate in boxing programs similar to Rock Steady Boxing.

"My patients nearly universally report that they really enjoy the exercise classes and feel it helps their balance and mobility as well as other motor functions such as hand-eye coordination," Dr. Berman told Neurology Today. "Many of my patients also report that their boxing exercises help their energy, thinking, and mood."

"Over the last decade non-contact boxing exercise programs for persons with Parkinson disease have rapidly expanded and are now available in every state," he noted. "As prescribing exercise for patients with Parkinson disease has increasingly become the standard of care, I think most neurologists have at least heard about boxing classes. Patient support groups across the country have also played a big role in getting the word out to persons with Parkinson disease."

Dr. Berman acknowledged that boxing programs as a treatment for Parkinson's disease might seem incongruous since boxing has been linked to parkinsonism symptoms. "At first blush it seems counterintuitive that someone with Parkinson disease should engage in boxing, but the keyword is 'non-contact'," he said. "Aside from its propensity to cause brain injury, something most neurologists certainly would oppose, boxing is an activity that mixes both aerobic and strength training and engages the upper and lower body as well as the mind," he said.

"While presently we do not have evidence that one form of physical exercise is better than another to treat the symptoms of PD, non-contact boxing exercise has been shown in a number of small studies to improve balance, gait and quality of life.

"An additional insight from the study I found interesting and informative was the enhanced exercise self-efficacy reported by participants as this a good indicator of whether patients will continue to adhere to a prescription of exercise."

Disclosures: Dr. Larson disclosed no relevant relationships with industry. Dr. Berman disclosed relevant relationships with Tools4Patient.

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AAN Abstract 1210: Larson D, Yeh C, Rafferty M, et al. Rock Steady Boxing (RSB) participants with Parkinson's disease have better quality of life and lower burden of non-motor symptoms than non-participants.

Friday, May 1, 2020

Losmapimod, an investigational small molecule drug designed to reduce expression of a transcription factor thought to cause facioscapulohumeral muscular dystrophy (FSHD), had favorable safety, tolerability, and pharmacokinetic profiles, according to an abstract featured as part of the 2020 AAN Science Advances.

In addition, the drug achieved target engagement in blood and muscle, the study authors of the phase 1 study reported.

There are no approved disease-modifying drugs for FSHD, a genetic disease that typically first affects the face and proximal arms and progresses over time to affect the legs and trunk. FSHD is caused by aberrant expression of the DUX4 transcription factor, which leads to oxidative stress, cell death, and inhibition of new muscle cell generation. Losmapimod inhibits p38, a protein kinase hypothesized to be involved in DUX4 expression.

Researchers conducted the phase 1 clinical trial in three parts. In segment one, 10 healthy volunteers were randomized to receive a single oral dose of losmapimod (7.5 mg and then 15 mg after a week of washout) or placebo. In the second part, 15 FSHD1 patients were randomized to receive losmapimod or placebo: six received 7.5 mg of losmapimod; six,15 mg of losmapimod, and three received placebo twice daily for 14 days. The third segment was an open label cohort of five FSHD1 patients who received 15 mg of losmapimod twice daily for 14 days, according to Michelle Mellion, MD, senior medical director at Fulcrum Therapeutics.

In the second segment, muscle biopsies were taken from normal-appearing muscle at baseline and during treatment. The researchers biopsied muscle affected by the disease, which was confirmed by MRI. They found dose-dependent concentrations in muscle and in blood, with "robust and sustained target engagement" at the 15 mg dose.

Concentrations in both plasma and muscle reached levels that correlate with reduction of aberrant DUX4-driven gene expression based on observations in preclinical models, Dr. Mellion said.

"We noted in our preclinical research that as we increased target engagement, there was decreased DUX4 -driven gene expression," Dr. Mellion said. This reduction in DUX4-driven gene expression could have a therapeutic benefit for patients in FSHD, in that muscles may be preserved, or the decline of muscle function may be slowed."

"Obviously we will learn more from our ongoing phase 2 trials," she added.

Commenting on the abstract, Kathryn R. Wagner, MD, PhD, director of the Center for Genetic Muscle Disorders at the Kennedy Krieger Institute and professor of neurology and neuroscience at the Johns Hopkins School of Medicine, said treatments for FSHD now are very limited.

"Currently, treatment of FSHD is supportive only with interventions involving bracing and physical therapy," said Dr. Wagner, who is a site investigator for losmapimod's ongoing trial but was not involved with the current analysis. "A novel therapeutic which directly addresses the pathophysiology of the disease would fill a large unmet medical need."

The phase 1 results are a good step forward for losmapimod, she said, showing safety, tolerability, and good target engagement in skeletal muscle. She added that a safe, oral drug directly countering the muscle pathology would be a "welcome contribution" for patients.

"These are very promising results that have encouraged a randomized, double-blind, placebo-controlled, phase 2 trial of losmapimod in FSHD that is ongoing," she said. "One of the main questions to be answered, however, is whether inhibiting DUX4 expression, which is at a very low level in FSHD myocytes, will be enough to result in improved function in FSHD patients.  The ongoing, 24-week phase 2 trial will address this question."

Disclosures: Dr. Mellion disclosed relationships with Fulcrum Therapeutics and Vertex Pharmaceutical. Dr. Wagner has received research funding from Catabasis, Fulcrum, Roche, and Sarepta. She has received honoraria from AskBio, Santhera, Casma and Fibrogen. 

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AAN Abstract 1557: Mellion M, Ronco L, Thompson L, et al. Phase 1 clinical trial of losmapimod in facioscapulohumeral muscular dystrophy (FSHD): Safety, tolerability, and target engagement.

Friday, May 1, 2020

Combining onabotulinumtoxinA (BoNT-A) and atogepant—a calcitonin-related gene peptide–receptor (CRGP) antagonist—subdued cortical spreading depression (CSD) in an animal model of chronic migraine, according to an abstract featured as part of the 2020 AAN Science Advances.

The results suggest that the combination therapy could potentially be an effective target therapy for chronic migraine, the researchers suggested.

Previous research found that CSD activates two trigeminovascular pathways—one consisting of peripheral A-delta nociceptors and central high-threshold neurons that can be blocked by CGRP monoclonal antibodies, and another consisting of peripheral C-fiber and central wide-dynamic-range neurons that can be blocked by BoNT-A.

Researchers studied how dura-sensitive neurons in animals responded to a single wave of CSD after injection with BoNT-A and atogepant, or a placebo. They studied 11 high-threshold neurons and 11 wide-dynamic-range neurons, said the researchers, led by Agustin Melo-Carrillo, MD, PhD, instructor in anesthesia at Beth Israel Deaconess Medical Center in collaboration with Allergan, which manufactures the drugs.

In an analysis of all of the neurons, a single wave of CSD activated 70 percent of the central trigeminovascular neurons among the controls, while in the BoNT-A and atogepant group, only 8.3 percent were activated (p=0.002). The average firing of neurons increased by more than 230 percent in the control group at one and two hours, but was unchanged after CSD in the treatment group.

In their analysis of high-threshold neurons, the CSD wave activated 80 percent of the neurons in the control group, and 16.6 percent in the BoNT-A and atogepant group (p=0.035). In the control arm, average firing of these neurons increased 162 percent after one hour and 251 percent after two hours but was unchanged in the treatment group.

Among the wide-dynamic-range neurons, CSD activated 60 percent of the control neurons and none of the neurons assessed in the treatment group (p=0.026). Average firing increased 543 percent at one hour and 199 percent at two hours after the CSD wave in the control arm and remained unchanged in the BoNT-A and atogepant group.

"The findings," researchers wrote, "raise the possibility that chronic migraine patients may benefit from a treatment approach that combines drugs that block the trigeminovascular A-delta-HT pathway—such as atogepant or another modulator of CGRP—and the C-WDR pathway," such as BoNT-A.

Commenting on the abstract, Teshamae Monteith, MD, FAAN, chief of the headache division at the University of Miami Health System, said that the combination of BoNT-A and anti-CGRP drugs has been attractive to clinicians treating chronic migraine. But, she said, some insurance companies have denied coverage of the combined therapy. This research is a further sign that combination therapy could be of value, she added.

"Clinicians should be encouraged by these experiments because of the profound reduction in activation of central trigeminovascular neurons by differing pathways as compared with control groups," she said. But she said these animal studies still need to be translated into human studies, and it remains to be seen whether the combination has a preventive role that beyond the benefit of BoNT-A alone.

In her experience, she said, the combination of BoNT-A injections and CGRP monoclonal antibodies has been life-saving for some patients on monotherapy.

"The biggest pitfall of this study is that the study was designed as a combination approach versus controls," Dr. Monteith said. "Also, although CSD models provide information about potential aspects of migraine, CSD may not be the underlying process of chronic migraine. Lastly, the study provides an important biological snapshot; however, the persistent benefits needed for adequate prophylaxis needs to be established."  

Disclosures: Dr. Mello-Carrillo disclosed no relevant disclosures. Dr. Monteith has served on the scientific advisory boards of Alder Pharmaceuticals, Biohaven, and Allergan. She is principal investigator for industry trials by Novartis, Amgen, Teva, and Electrocore. Dr.Monteith had no disclosures.

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AAN Abstract 4287: Melo-Carrillo A, Strassman A, Schain A, et al. Extracranial injections of onabotulinumtoxinA in combination with intravenous injection of atogepant attenuates activation and sensitization of HT and WDR neurons by CSD.