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Tag: American Neurological Association (ANA)

  • Largest Study to Date Results in Simple Genetic Risk Test for Nearly 100 Drugs Linked to Often-Fatal Side Effect in Those Being Treated for MS and Other Conditions

    Largest Study to Date Results in Simple Genetic Risk Test for Nearly 100 Drugs Linked to Often-Fatal Side Effect in Those Being Treated for MS and Other Conditions

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    Key Takeaways: 

    • Researchers have identified 99 drugs used for conditions ranging from multiple sclerosis to blood cancers that may cause a rare but often-fatal condition called Progressive Multifocal Leukoencephalopathy (PML). 
    • People who have one of four recently identified genetic variants are at 10 times the risk of developing PML if they take these drugs. 
    • A simple and free genetics test can identify those who are at higher risk. 
    • Many physicians who treat these patients may be unaware of how many of these commonly prescribed drugs increase the risk of PML, which has no cure. 
    • Drug warning labels should be updated to include genetic testing before prescribing one of these drugs. 

     

    PHILADELPHIA, Sept. 11, 2023 – Nearly 100 drugs for multiple sclerosis (MS), blood cancers, rheumatoid arthritis and other diseases may cause Progressive Multifocal Leukoencephalopathy (PML), a rare but often-fatal condition. A simple genetic test can determine who has a 10-fold higher risk for the condition so they can discuss safer treatment options with their physicians. The largest study to date on drugs that increase the risk for PML and the genetic link to the disease is being presented at the 148th Annual Meeting of the American Neurological Association (ANA). 

    Researchers analyzed the Food and Drug Administration Adverse Event Reporting System (FAERS) and found 81 drugs—plus 18 more not reported to FAERS but in the same drug class as PML-linked drugs—are linked to PML deadly brain disease. Most of them are immunosuppressant disease-modifying therapies. They assessed whether the drug label listed PML risk anywhere on the label and if so, whether it was only listed as a Serious Adverse Event (SAE) or carried a Boxed Warning, the FDA’s strongest drug label warning. They note that the largest number of PML cases have been associated with natalizumab (for MS) and rituximab (for cancer and rheumatoid arthritis), both of which have a Boxed Warning. But they also found two common blood cancer drugs (daratumumab and venetoclax) have no warning on their labels of the risk of developing PML.  

    The researchers recently identified genetic variants in four genes (C8B, FCN2, LY9, STXBP2) that increase by 10-fold a person’s risk of developing PML when taking one of these drugs. ​All four genetic variants play a key role in immune pathways and disorders related to activating the JC virus, which lies dormant in the vast majority of people. Once activated in a person who is immune compromised, the JC virus can infect the brain and cause PML. ​Using a free genetic test, those who are considering taking one of those drugs can learn if they have one of the genetic variants and, if so, may consider alternative treatments that aren’t linked to PML. 

     

    A growing number of PML cases have been reported in patients on therapies for conditions including MS, Crohn’s disease, psoriasis, lupus, blood cancers, and organ transplants heightening the importance of understanding the risk and options to help prevent future cases of this devastating drug-induced side effect. 

     

    “The increased risk of drug-induced PML in patients testing positive is higher than already-known genetic associations that are used to guide treatments, like BRCA1/2 for breast cancer, yet many neurologists and oncologists may have limited awareness of how many drugs have been linked to PML,” said Peggy S. Eis, PhD, lead author of the study and chief technology officer at Population Bio, Inc., New York. “There are no treatments to cure PML, so prevention is the best defense, including knowing your genetic risk. Even though the chance of developing PML is very low for some of these drugs, patients should still be screened given the ease and low cost of doing so relative to the avoidable potential consequences for those who do test positive. Clearly, warning labels on some of these drugs need to be updated and can now include a requirement for genetic testing before these drugs are prescribed.” 

     

    She noted that patients who are currently taking those drugs should also be tested and said surveys have found patients overwhelmingly want to be tested once they know a genetic test is available.  

     

    Those testing positive for one of the genetic variants may want to consider an alternative treatment that has not been associated with PML, such as an interferon-based therapy, glatiramer acetate or teriflunomide in MS patients. In some cases, despite testing positive for one of the genes, patients may choose to stay on PML-linked therapies because they are so effective. But having knowledge of their higher genetic risk, patients and their doctors can monitor more closely for PML, such as with more frequent brain MRIs.  

     

    The researchers will present updated findings from this largest-ever PML study of its kind, including an analysis of the FAERS data, a breakdown by drug class (such as target and mechanism of action) and indication. For example, 17 of the 99 drugs are used to treat MS. It will also provide further insights into the biology of the four genes linked to PML risk and immune biology regarding how PML infects the brain (all four genes are linked to viral defense mechanisms) as well as how the genes and processes overlap with infections from the Epstein-Barr virus (EBV). For example, the STXBP2 gene (one of the four genes associated with PML) is directly linked to a type of EBV-associated disease called hemophagocytic lymphohistiocytosis.  

     

    The test for the four genetic variants associated with PML is now available free in the U.S. at https://www.pmlrisktest.org/. The test sample can be taken at home and shipped to the lab for analysis.  

     

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    About the American Neurological Association (ANA) 

    From advances in stroke and dementia to movement disorders and epilepsy, the American Neurological Association has been the vanguard of research since 1875 as the premier professional society of academic neurologists and neuroscientists devoted to understanding and treating diseases of the nervous system. Its monthly Annals of Neurology is among the world’s most prestigious medical journals, and the ANA’s Annals of Clinical and Translational Neurology is an online-only, open access journal providing rapid dissemination of high-quality, peer-reviewed research related to all areas of neurology. The acclaimed ANA Annual Meeting draws faculty and trainees from the top academic departments across the U.S. and abroad for groundbreaking research, networking, and career development. For more information, visit www.myana.org or @TheNewANA1   

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  • Sleep Plays a Major Role in Neurological Disorders Getting Good Sleep May Help Reduce Risk

    Sleep Plays a Major Role in Neurological Disorders Getting Good Sleep May Help Reduce Risk

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    Key Takeaways: 

    • Neurological disorders from autism spectrum disorder (ASD) to Alzheimer’s disease cause significant sleep problems. 
    • Good sleep may serve as an armor against neurological disorders. 
    • Good sleep helps children with ASD improve their brain function and behavior. 
    • Too little or too much sleep increases the risk of Alzheimer’s disease-like changes in the brain.  
    • The “glymphatic system” that cleans the brain of waste material only works during sleep. 
    • Genes may help protect “short sleepers” from Alzheimer’s disease.  

     

    PHILADELPHIA, Sept. 10, 2023 – Neurological disorders – including autism spectrum disorder (ASD), Alzheimer’s disease and Parkinson’s disease – cause sleep disturbances that make life extra challenging for people with those conditions. Improving sleep not only helps improve their quality of life, evidence is mounting that good sleep is vital for a healthy brain and may reduce the risk of some neurological disorders, according to neurologists speaking at the Presidential Symposium – Exploring Sleep Disturbances in CNS Disorders plenary session at the 148th Annual Meeting of the American Neurological Association (ANA). 

    “Normal, healthy sleep is under assault by our 21st century environment – from artificial light to massive anxiety to social media – and sleep deprivation can exacerbate an existing neurological condition,” said Frances E. Jensen, MD, FANA, FACP, president of the ANA and Arthur Knight Asbury, MD Professor in Neurology and chair of the Department of Neurology at the Perelman School of Medicine, University of Pennsylvania, Philadelphia. “Anything that affects the brain can affect sleep and vice versa. It’s important to focus on how we can improve sleep at any age because it doesn’t just keep you healthy, it can be a great armor to prevent disease.” 

    Neurological disorders including ASD, Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, REM sleep disorder, epilepsy and traumatic brain injury interfere with sleep, but the mechanism of sleep interruption varies between disorders.  

    Disrupted sleep can, in turn, exacerbate problems associated with the specific condition. Focusing on getting good sleep not only helps people with neurological conditions but may reduce the risk of developing them.  

    Neurologists suggest getting good sleep by: 

    • keeping a regular schedule for going to sleep and waking up; 
    • making sure the bedroom is dark and all the lights are off; 
    • using ear plugs and eye masks, and ensuring the bedding is comfortable; 
    • shunning caffeine after 3 p.m.; 
    • avoiding screens (TV, phone) for at least an hour before bed; 
    • napping no more than 30 minutes a day (if at all); 
    • exercising regularly, but not in the evening; 
    • avoiding eating before bedtime; and 
    • having no more than one alcoholic drink a day.  

    Sleep is Critical for Brain Development and Health in Children with ASD 

    Consistent routines and methods can help children with ASD get better sleep, which improves their executive function (planning, focus, etc.), performance on working memory tasks and daytime behavior so they are less irritable, less aggressive and have fewer meltdowns during therapy, according to information being presented during the sleep symposium. 

    More than half (50% to 80%) of children and adolescents with ASD have significant sleep problems compared to 20% to 30% of neurotypical children.1 Difficulty falling asleep, staying asleep or obstructive sleep apnea disrupt the sleep that is vital for the healthy development of young brains, including memory, learning and social-emotional development. ASD may interrupt sleep by overly arousing the brain and disrupting the normal processing of melatonin (which promotes sleep). Genetics can also play a role, as well as other medical and psychiatric conditions and medications they are taking.  

    “Parents can help their children with ASD get better sleep by ensuring they don’t ingest too much caffeine such as in soda, coffee or tea, get lots of exercise, avoid screens close to bedtime and have a bedtime routine that’s not too early,” said Beth Malow, MD, MS, FANA, who is presenting on “Sleep and Neurodevelopmental Conditions” and is director of the Sleep Division at Vanderbilt University Medical Center, Nashville. “Clinicians should also be sure there isn’t a medical condition that is waking the child. While behavioral methods should be tried first, if they don’t help enough, medications may be tried using those that target a co-occurring condition if possible, starting at a low dose that is relatively safe and effective.” 

    She noted that children with ASD often are prescribed medications for sleep, including gabapentin, alpha-adrenergic agonists, trazadone, hydroxyzine, mirtazapine, tricyclic antidepressants and others, but there is not enough research to show that they have a positive affect without causing other problems. Melatonin has the strongest track record in terms of research, but it is not regulated by the Food and Drug Administration.  

    “We need more studies with parent input to know which medications and behavioral treatments are most successful,” she said. 

    Sleep as a Factor in Alzheimer’s Disease 

    Poor sleep over long periods of time increases the risk of developing Alzheimer’s disease-type changes in the brain, suggests early research being presented during the symposium. These studies show that poor sleep accelerates changes in the brain, such as the buildup of amyloid beta plaques and tau tangles. 

    “Part of the reason that poor sleep might increase the risk of Alzheimer’s disease is related to changes to immune cells in the brain called microglia,” said David Holtzman, MD, FANA, who is presenting on the “Bidirectional Relationship Between Sleep and Alzheimer’s Disease-Related Pathology” and is scientific director of the Hope Center for Neurological Disorders and director of the Knight Alzheimer’s Disease Research Center at Washington University School of Medicine, St. Louis. “These cells are being explored as a potential target for new therapies for the disease.” 

    While researchers don’t know why Alzheimer’s disease disrupts sleep, it appears the underlying pathology affects some brain regions that control sleep. 

    “It has been shown that people who are in late middle age and cognitively normal who get low and high amounts of sleep decline faster than who get the middle ranges of sleep,” he said. “This suggests that there is an optimal range of sleep for each person that is associated with better performance over time.” 

    Sleep is Necessary to Clean the Brain, Reduce Risk of Neurological Disorders 

    The glymphatic system – which cleans the brain of waste products that increase the risk of neurological disorders – only works during sleep, which is why sleep is so important, according to a presentation at the symposium. 

    “Sleep is serious business, likely as important as exercising and avoiding smoking and excess weight gain,” said Maiken Nedergaard, MD, DMSc, who is presenting on “The Glymphatic System – and Relationship to Disorder,” and is co-director of the Center for Translational Neuromedicine, University of Rochester Medical Center, N.Y. “It’s important to develop good sleep habits because poor sleep accelerates neurological diseases and neurological diseases worsen sleep quality.” 

    The glymphatic system provides a basic housekeeping function for the brain by flushing cerebrospinal fluid into the brain during sleep to remove protein waste products, such as tau proteins and amyloid beta.  

    Gene mutations may protect short sleepers against diseases like Alzheimer’s 

    The genetic variants that enable short sleepers (those who get good sleep in four to six hours) may delay the onset and progression of Alzheimer’s-like diseases, and potentially other neurological disorders, suggests early research being presented at the symposium. 

    “The biological need for sleep varies dramatically among people,” said Ying-Hui Fu, PhD, who is presenting “Genetic Sleep Variants Protect Against Alzheimer-Like Diseases,” and is a neurology professor at the University of California at San Francisco Weill institute for Neuroscience. “Our research of familial sleep traits is beginning to shed light on how sleep is regulated and how it contributes to health.” 

    Dr. Fu’s group has identified four genes (DEC2, ADRB1, NPSR1 and GRM1) that are responsible for the ability to sleep for shorter periods of time. “We believe and predict these natural short sleep mutations can potentially protect the mutation carriers from various diseases, although we only have data for Alzheimer’s disease so far,” she said. 

    # # # 

    1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8848524/#:~:text=Sleep%20disturbances%20are%20some%20of,NT)%20children4-7‘ 

     

    About the American Neurological Association (ANA) 

    From advances in stroke and dementia to movement disorders and epilepsy, the American Neurological Association has been the vanguard of research since 1875 as the premier professional society of academic neurologists and neuroscientists devoted to understanding and treating diseases of the nervous system. Its monthly Annals of Neurology is among the world’s most prestigious medical journals, and the ANA’s Annals of Clinical and Translational Neurology is an online-only, open access journal providing rapid dissemination of high-quality, peer-reviewed research related to all areas of neurology. The acclaimed ANA Annual Meeting draws faculty and trainees from the top academic departments across the U.S. and abroad for groundbreaking research, networking, and career development. For more information, visit www.myana.org or @TheNewANA1. 

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  • Aerobic Exercise May Help More than Balance Training to Hold Off Symptoms of Cerebellar Ataxia

    Aerobic Exercise May Help More than Balance Training to Hold Off Symptoms of Cerebellar Ataxia

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    Currently, no medications exist to combat spinocerebellar ataxias, debilitating neurodegenerative diseases that cause loss of balance and coordination. Physicians recommend balance training to improve symptoms, but a new study suggests that rigorous aerobic exercise may provide greater benefit for adults with cerebellar ataxia. Patients were able to safely undergo six months of aerobic training five times a week. Their ataxia symptoms improved significantly, by an average of 1.9 points on the Scale for Assessment and Rating of Ataxia, compared with control patients who did balance training (who saw improvement of 0.6 SARA points). Although some balance-specific measures showed better results with balance training and studies of less-rigorous aerobic training showed little benefit, intense aerobic activity appears to be a promising therapeutic avenue for ataxia, and demonstrates important connections between nervous system health and aerobic activity.

    Full abstract, to be presented at the American Neurological Association 2022 Annual Meeting, October 22-25, 2022 in Chicago, and published in Annals of Neurology:

     

    Home Aerobic Versus Balance Training In Cerebellar Ataxias

    Scott Barbuto, MD, PhD, Columbia University Medical Center

    Coauthors: Sheng-Han Kuo, MD,  Lauren Winterbottom, OTR, Yaakov Stern, PhD, Joel Stein, MD

    Spinocerebellar ataxias are a group of disorders that result from cerebellar degeneration and cause balance and coordination loss. The diseases are devastatingly debilitating with many individuals requiring wheelchairs for mobility within ten years from initial diagnoses. With no disease modifying medications currently available, most guidelines recommend individuals with cerebellar ataxia to perform balance training to maintain functional abilities. Although conflicting results have been reported, most studies indicate that balance training can help improve symptoms of ataxia if the training is adequately challenging. The benefits of aerobic training for cerebellar ataxia have been less well-studied. After promising results in animals, the first study examining aerobic training in humans with cerebellar degeneration showed minimal benefits. However, participants were not provided a structured exercise program, and the training was limited to three, fifteen-minute sessions per week for one month. Hypothesizing that a larger dose of training could be beneficial, our research group conducted a pilot study having individuals with cerebellar degeneration perform one month of rigorous aerobic training, defined as thirty-minutes sessions, five times per week at 65–80% of their maximum heart rate. Our results indicated that individuals with cerebellar ataxias were able to safely perform rigorous aerobic exercise and that a phase II study comparing balance and aerobic training was feasible. After completion of the pilot study, we conducted a single center, assessor-blinded, randomized controlled phase II trial. Individuals with cerebellar ataxia were assigned (1:1) to either home aerobic or balance training for 6-months. The primary outcome was improvement in ataxia severity as measured by the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes included safety, training adherence, and balance improvements. Nineteen subjects were randomized to aerobic training and 17 subjects to balance training. There were no differences between groups at baseline. Thirty-one participants completed the trial, and there were no training-related serious adverse events. Compliance to training was over 70%. There was a mean improvement in ataxia severity of 1.9 SARA points (SD 1.62) in the aerobic group compared to an improvement of 0.6 points (SD 1.34) in the balance group. Although two other measures of balance were equivocal between groups, one measure of balance showed greater improvement with balance training compared to aerobic training.

    Overall, this 6-month trial comparing home aerobic versus balance training in individuals with cerebellar ataxia had excellent retention and adherence to training. There was a significant improvement in ataxia severity with aerobic training compared to balance training, and a phase III trial will be conducted.

     

    All abstracts from ANA2022 will be available in Annals of Neurology starting at 3:01 p.m. U.S. Eastern Time on October 14. This research is under embargo until that time. Contact Katherine Pflaumer ([email protected]) for additional highlighted abstracts, full meeting abstracts, and call-in information for the ANA2022 Media Roundtable (Oct. 25, 11 a.m. U.S. Central).

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