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The News That Mattered in 2021
Neurology Today Editorial Board Top Picks

Article In Brief

The Neurology Today editorial board highlights the advances that occurred in 2021 across multiple subspecialties and areas of practice.

As 2021 came to a close, studies about COVID-19 continued to dominate across major journals and institutions. But even with another year of the coronavirus and a troubling variant, neurology witnessed the expansion of developments across every subspecialty. The selections of the most important advances in 2021 by members of the Neurology Today editorial board highlighted below are not all game-changers, but whether incremental or transformational, they have all moved the field forward in practice and the care of patients.

ADVANCED PRACTICE PRACTIONERS

JULIE A. GURWELL, PHD, PA-C

Associate Professor, Director of Advanced Practice Providers

University of Kentucky

Louisville, KY

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JULIE A. GURWELL, PHD, PA-C

The Pick: Cook CL, Schwarz HB. Advanced practice clinicians-neurology's underused resource. JAMA Neurol 2021; 78(8):903-904.

Kreimer S. Professionalism: On training and retaining advanced practice clinicians in neurology. Neurol Today 2021;21(15):1,9.

The Findings: These two articles provide an important reminder that advanced practice clinicians can be valued team members of neurology care teams in collaboration with physicians when they are supported and mentored. The articles discuss the intrinsic challenges of training and utilizing advanced practice clinicians, as well as offer insights on ways to onboard and engage advanced practice providers to prevent attrition.

Why It's Important: The demand for neurologic care continues to outpace the availability of neurology clinicians. Advanced practice clinicians can help increase access to neurologic care. Although hiring advanced practice clinician requires a significant financial investment, if integrated strategically, that investment will lead to better provider retention, and subsequent continuity for access to neurology.

CEREBROVASCULAR DISEASE

JAMES C. GROTTA, MD, FAAN

Director of Stroke Research at the Clinical Institute for Research and Innovation

Memorial Hermann-Texas Medical Center, Houston, TX

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JAMES C. GROTTA, MD, FAAN

The Pick: Ebinger M, Siegerink B, Kunz A, et al. Association between dispatch of mobile stroke units and functional outcomes among patients with acute ischemic stroke in Berlin. JAMA 2021;325:454-466.

Grotta JC, Yamal J-M, Parker et al. Prospective, multicenter, controlled trial of mobile stroke units. New Engl J Med 2021;385:971-81.

The Findings: Previous studies had shown that mobile stroke units, specialized ambulances with CT imaging, personnel, and drugs, integrated with emergency medical services systems, can accurately diagnose strokes and speed delivery of tissue plasminogen activator (tPA) treatment into the pre-hospital setting. These two studies from Berlin and seven sites in the US were the first large, controlled trials showing that mobile stroke unit management translates to substantially better clinical outcomes as measured by the modified Rankin scale at 90 days. Better results were driven by more and faster tPA treatment, especially in the first “golden” hour after symptom onset.

Why It's Important: The biggest current challenge in acute stroke treatment is getting appropriate treatment to the patient and getting the patient to the appropriate treatment, and doing this as fast as possible. Mobile stroke units are a way to achieve all this by taking the most widely used effective treatment, intravenous thrombolysis, to the patient immediately following the 911 call, and by triaging patients with large vessel occlusions directly to hospitals that can do thrombectomy.

The Pick: LeCouffe ND, Kappelhof M, Treurniet KM, et al. A randomized trial of intravenous alteplase before endovascular treatment for stroke. New Engl J Med 2021;385:1833-44

Suzuki K, Matsumaru Y, Takeuchi M, et al. The effect of mechanical thrombectomy without vs with intravenous thrombolysis on functional outcome among patients with acute ischemic stroke. JAMA 2021;325(3):244-253.

Zi W, Qiu Z, Li F, et al. Effect of endovascular treatment alone vs intravenous alteplase plus endovascular treatment on functional independence in patients with acute ischemic stroke. JAMA 2021;325(3):234-243.

The Findings: Among patients who qualify for systemic thrombolysis with tPA, about 25 percent harbor clots in the large vessels or large vessel occlusions (LVOs). Endovascular thrombectomy is a powerfully effective treatment for these patients, but tPA usually cannot dissolve these large clots. Consequently, there is uncertainty if tPA should be given or skipped in LVO patients. The LeCouffe study tested non-inferiority and could not exclude that skipping tPA was inferior to giving it. In fact, patients receiving tPA on average had better outcomes than those in whom it was skipped. This was confirmed in a Swiss study, presented but not yet published (SWIFT-DIRECT), and in the Suzuki study from Japan. The Zi study, along with a similar study reported last year, both conducted in China, demonstrated non-inferiority for skipping.

Why It's Important: The preponderance of evidence is that tPA should be given as soon as possible in all patients who qualify, including those who are candidates for endovascular thrombectomy.

The Pick: Halliday A, Bulbulia R, Bonati L, et al. Second asymptomatic carotid surgery trial (ACST-2): A randomised comparison of carotid artery stenting versus carotid endarterectomy. Lancet 2021; 398:1065-1073.

The Findings: Previous studies had suggested that carotid stenting was associated with more risk than endarterectomy. In asymptomatic patients, the benefit of either procedure over medical therapy is still in question, so any increased risk would tip the balance. In this large international randomized study of 3,265 patients, serious complications were similarly uncommon after carotid artery stenting and carotid endarterectomy, and the long-term effects on fatal or disabling stroke were comparable.

Why It's Important: While the benefit of stenting or surgery compared with optimal modern medical therapy for asymptomatic carotid stenosis is currently being re-evaluated, these interventions are still commonly practiced. This study shows that both interventions are associated with low risk in expert hands.

The Pick: de Havenon A, Sheth K, Johnston K, et al. Acute ischemic stroke interventions in the United States and racial, socioeconomic, and geographical disparities. Ann Neurol 2021;97:e2292-2303

The Findings: An analysis of 1,439,295 patients from the National Inpatient Sample with discharge diagnosis of ischemic stroke showed that, between 2016 and 2018, treatment with tPA increased from 8.8 percent to 10.2 percent, and endovascular thrombectomy from 2.8 percent to 4.9 percent. Both treatments, however, were less commonly employed for Black people, patients living in zip codes with low median income, and in rural areas. Contrary to previous reports, there was no difference by sex.

Why It's Important: Stroke treatments are effective but employed in only a minority of patients. This is the most accurate assessment of current stroke treatment rates and populations that should be targeted for improving access.

CHILD NEUROLOGY

ANN TILTON, MD, FAAN

Professor of Neurology and Pediatrics

Louisiana State University Health Sciences Center

New Orleans, LA

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ANN TILTON, MD, FAAN

The Pick: Friedman GK, Johnston JM, Bag AK, et al. Oncoloytic HSV-1 G207 immunovirotherapy for pediatric high grade gliomas. N Engl J Med 2021; 28417):16613-1622.

The Findings: Pediatric high-grade gliomas are known to have poor outcomes, with a median overall survival of less than six months. This article describes the use of intratumor HSV-1 G207 as an immunotherapy by converting the high-grade gliomas from predominantly immunologically silent or “cold” tumors to “hot” tumors. A subset of the study patients was additionally treated with radiation. The outcome revealed those treated with intratumor HSV-1 G207, both with and without radiation, had no serious adverse events attributed to the G207, and the median overall survival was improved to 12.2 months.

Why It's Important: This article is impressive in that it offers the hope of turning pediatric high-grade gliomas from a rapidly terminal disorder into a chronic disease.

The Pick: Smith SE, Gannotti M, Hurvitz EA, et al. Adults with cerebral palsy require ongoing neurologic care: A systematic review. Ann Neurol 2021; 899(5):860-871.

The Findings: Smith and colleagues review the predisposition of patients with cerebral palsy (CP) to additional, new neurologic problems as they age and the need for skilled neurologic care throughout their lifetime to address these issues and provide optimal care. The article skillfully presents a systematic review of the current literature pointing out the intersection of the medical problems due to aging with challenges related to the CP diagnosis. The article also provides guidelines for the clinical care of this population.

Why It's Important: The article elucidates multiple medical conditions associated with CP in adulthood. The review clearly outlines how we, as neurologists, can help improve our patient's health and function as they age.

CLINICAL ETHICS/NEUROCRITICAL CARE

MICHAEL A. RUBIN, MD, MA, FAAN

Associate Professor of Neurology and Neurosurgery

UT Southwestern Medical Center Peter J. O'Donnell, Jr. Brain Institute

Dallas, TX

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MICHAEL A. RUBIN, MD, MA, FAAN

The Pick: Chiong W, Tolchin BD, Bonnie RJ, et al, for the Ethics, Law, and Humanities Committee (a joint committee of the AAN, ANA, and CNS). Decisions with patients and families regarding aducanumab in Alzheimer disease, with recommendations for consent: AAN position statement. Neurology 2021: Epub 2021 Nov 17.

The Findings: Winston Chiong and colleagues analyzed and responded to the approval of aducanumab for treatment of Alzheimer's disease by offering both practitioners and families a framework to make ethically appropriate clinical decisions considering the special conditions under which it achieved approval.

Why It's Important: This piece demonstrated the importance of the willingness of professional medical societies to take positions that are not necessarily in line with regulatory agency viewpoints.

The Pick: Kiker WA, Voumard RR, Andrews LIB, et al. Assessment of discordance between physicians and family members regarding prognosis in patients with severe acute brain injury. JAMA Netw Open 2021: 4(10):e2128991.

The Findings: This mixed methods study evaluated perceptions and predictions of families, physicians, and nurses of patients with severe brain injury and found discordant views in 61 percent of the patient groups with a high level of misunderstanding and multifaceted influences.

Why It's Important: This study adds to our understanding of our current poor predictive ability and lack of consensus among clinicians and family regarding patients with severe brain injury. Such studies provide a baseline from which decision-making tools can be tested for efficacy.

COGNITIVE NEUROLOGY/DEMENTIA

ERIC M. MCDADE, DO

Associate Professor Neurology

Washington University at St. Louis School of Medicine

St. Louis, MO

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ERIC M. MCDADE, DO

The Pick: Mesulam MM, Coventry C, Kuang A, et al. Memory resilience in Alzheimer disease with primary progressive aphasia. Neurology 2021;96(6):e916-e925.

The Findings: In primary progressive aphasia in Alzheimer's disease (PPA-AD), episodic memory, tested with nonverbal items, was preserved at the initial testing and showed no decline at retesting nearly 2.5 years later, at which time symptoms had been present for six or more years. In contrast, language functions declined significantly during the same period. In amnestic dementia of the Alzheimer type with AD at autopsy (DAT-AD), both verbal memory and language declined with equal severity. Compared to DAT-AD, however, the PPA-AD group had lower incidence of APOE ε 4 and of mediotemporal TAR DNA-binding protein 43 pathology.

Why It's Important: This paper is a beautiful illustration of how much we still do not understand in our links between the canonical pathologies of Alzheimer disease and clinical expression at the individual level. In spite of having high levels of neurofibrillary tangle pathology in the limbic regions at the time of autopsy, individuals with a language presentation of AD had significantly slower rates of memory loss relative to those with “typical” amnestic Alzheimer disease symptoms.

The Pick: Palmqvist S, Tideman P, Cullen N, et al. Prediction of future Alzheimer's disease dementia using plasma phospho-tau combined with other accessible measures. Nat Med 2021;27(6):1034-1042.

The Findings: Using a rather simple algorithm combining a blood test of phosphorylated tau (either p-T217 or p-T181), limited cognitive tests, and APOE genotype the researchers were able to predict dementia four years later in individuals with subjective or mild cognitive changes. Importantly, the predictability using the blood test was just as good as when using cerebrospinal fluid and was far superior to predictions based on the memory clinicians assessments.

Why It's Important: 2021 may be remembered as the year of plasma diagnostic tests in AD. This paper nicely summarized the state of the field and the not-too-distant future potential of plasma tests. It is highly likely these blood tests will be available soon and understanding their value will be key to their appropriate use.

The Pick: Salloway S, Chalkias S, Barkhof F, et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol 2021:e214161.

The Findings: Findings from two phase 3, randomized clinical trials of aducanumab—EMERGE and ENGAGE—characterized amyloid-related abnormalities (ARIA) that occurred with 10 mg/kg aducanumab, a monoclonal antibody that targets amyloid-beta in patients with mild cognitive impairment due to AD or mild AD dementia. The most common adverse event in the 10-mg/kg group was ARIA, which occurred in 362 of the 1029 patients (35.2 percent) in the 10-mg/kg group with at least one postbaseline MRI scan, with 94 patients (26 percent) experiencing associated symptoms. The most common associated symptom was headache.

Why It's Important: In spite of the level of controversy regarding the approval of aducanumab, it is available for the treatment of people with AD. Therefore, it is critical to understand the risks associated with the use of aducanumab and this publication is a relatively comprehensive analyses of the most common side-effect— ARIA. The authors, including employees of Biogen, which manufactures the drug, provide information on the most important risk factors and timing for ARIA; in doing so, they provide important guidelines for physicians considering the use of this medication. This publication is particularly important as the MRI schedule used in the trial, which identified the ARIA events, was much more frequent than that provided in the drug label provided to prescribers. This is a must-read for those prescribing aducanumab.

EPILEPSY

JACQUELINE A. FRENCH, MD, FAAN

Professor of Neurology

NYU Grossman School of Medicine

Chief Medical-Innovation Officer, Epilepsy Foundation

New York, NY

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JACQUELINE A. FRENCH, MD, FAAN

The Pick: Josephson CB, Wiebe S, Delgado-Garcia G, et al. Association of Enzyme-inducing antiseizure drug use with long-term cardiovascular disease. JAMA Neurol 2021;78(11):1367-1374.

Larsson D, Baftiu A, Johannessen Landmark C, et al. Association between antiseizure drug monotherapy and mortality for patients with poststroke epilepsy. JAMA Neurol 2021; Epub 2021 Dec 13.

French JA, Perucca E, Sander JW, et al. FDA safety warning on the cardiac effects of lamotrigine: An advisory from the ad hoc ILAE/AES task force. Epilepsia Open 2021;6(1):45-48.

The Findings: The studies by Josephson CB and Larsson D suggest that enzyme-inducing antiseizure medications (ASMs) may lead to long-term risk of cardiovascular disease, stroke, and mortality. This is particularly relevant in light of a recent FDA advisory about an in vitro signal of cardiac effects of lamotrigine.

Why It's Important: While it must be used with caution in patients with certain types of known heart disease, lamotrigine and other non-enzyme inducing ASMs may still be a better long-term choice for the majority of patients. Also, the concerns about lamotrigine's impact on the heart are likely shared by other sodium channel blocking agents, and this is currently being investigated.

The Pick: Sivathamboo S, Friedman D, Laze J, et al. Association of short-term heart rate variability and sudden unexpected death in epilepsy. Neurology 2021;97(24):e2357-e2367.

The Findings: Sudden unexplained death in epilepsy (SUDEP) is the number one cause of epilepsy-related death. There is an urgent need for biomarkers to identify patients at risk. This multinational group identified a possible biomarker of risk associated with heart rate variability.

Why It's Important: A measure of heart rate variability may stratify patients in regard to SUDEP risk, and therefore allow us to identify patients who may benefit from increased safeguards from seizure detection wearables and other devices.

EPILEPSY/CLINICAL NEUROPHYSIOLOGY

SHAWNIQUA WILLIAMS ROBERSON, MENG, MD

Assistant Professor of Neurology

Vanderbilt University Medical Center

Nashville, TN

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SHAWNIQUA WILLIAMS ROBERSON, MENG, MD

The Pick: Quraishi IH, Hirsch LJ. Patient-detectable responsive neurostimulation as a seizure warning system. Epilepsia 2021;62:e110-e116.

The Findings: This case series describes a novel use of the responsive neurostimulation system (RNS) device to induce detectable symptoms of stimulation in an effort to provide a seizure warning for RNS patients. Of 18 participants, tolerable symptoms were inducible in 11 and included vision changes, mild sensory disturbances, or eye twitching. One patient, who was otherwise unaware of her seizures, had the seizure warning protocol left in place for several years and noted concomitant improvements in her memory and cognition.

Why It's Important: One of the most debilitating aspects of epilepsy stems from the unpredictable nature of seizures. Some people with epilepsy have auras that give enough warning to allow them to move to a position of safety prior to loss of awareness or motor manifestations. Yet, modern medicine does not provide us with the tools to control whether a patient has auras or not. The technique described in this paper offers the possibility of inducing a “mechanical” aura in RNS recipients, which could make a significant difference in the quality of life of people with intractable epilepsy. Future studies will be needed to identify the most effective approach for targeting location and stimulation parameters, and to examine long-term effects.

The Pick: Lacaux C, Andrillon T, Bastoul C, et al. Sleep onset is a creative sweet spot. Sci Adv 2021:7(50):eabj5866.

The Findings: This study tested 103 healthy participants on a rule-based series of puzzles delivered before and after a 20-minute nap. They monitored participants during the break with video polysomnography (EEG, EOG, and EMG) to identify wakefulness and sleep stages. Participants who attained N1 sleep were more likely to “break the code” and successfully solve the puzzles than those who stayed awake or attained deeper stages of sleep. The authors also identified significant relationships between EEG alpha and delta power during the break period and the probability of subsequent eureka moments, independent of sleep stage attained.

Why It's Important: This intriguing study provides evidence of a “creative sweet spot” associated with specific electrographic patterns of brain activity that are most common during stage 1 sleep. If generalizable across a range of problem types and populations, the findings point to potentially very simple methods of enhancing creativity and productivity. The study also offers insights to the neural signatures that may support such creativity. This begs the question of whether technologies that noninvasively modulate brain oscillatory patterns (for example, transcranial magnetic stimulation or closed-loop neurofeedback training) could be used to positively influence cognitive performance in healthy individuals—or eventually among those with cognitive impairment.

The Pick: Meador KJ, Cohen MJ, Loring DW, et al. Two-year-old cognitive outcomes in children of pregnant women with epilepsy in the maternal outcomes and neurodevelopmental effects of antiepileptic drugs study. JAMA Neurol 2021;78(8):927-936.

The Findings: This multicenter cohort study examined neurodevelopmental outcomes in 2-year-old children of women with epilepsy (WWE), about 70 percent of whom were taking lamotrigine and/or levetiracetam during pregnancy. WWE more often used high dose folic acid and their children were more often White. Using the Bayley Scales of Infant & Toddler Development (BSID-III), no significant differences were found in any cognitive domain between WWE and healthy women. Higher levels of antiseizure medications in the third trimester were associated with lower BSID-III scores in the motor and general adaptive domains.

Why It's Important: It is extraordinarily difficult to generate high-quality data informing pharmacologic management of epilepsy during pregnancy. These interim results from a large, rigorous observational study provide important insights into the long-term neurodevelopmental outcomes of maternal epilepsy in general and of third-trimester ASM levels in particular.

HEADACHE MEDICINE

AMAAL STARLING, MD

Associate Professor of Neurology

Mayo Clinic, Scottsdale, AZ

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AMAAL STARLING, MD

The Pick: Ishii R, Schwedt TJ, Dumkrieger G, et al. Chronic versus episodic migraine: The 15-day threshold does not adequately reflect substantial differences in disability across the full spectrum of headache frequency. Headache 2021;61(7):992-1003.

The Findings: This study used data collected via the American Registry for Migraine Research, a longitudinal database which allows for the study of changes in headache patterns over time. This registry is unique, rich with data, and one of a kind. It includes data from baseline and follow-up questionnaires, a headache diary mobile app, a biobank that can be used for genetic analyses, and neuroimaging.

This specific study challenges the current differentiation between episodic and chronic migraine. Currently, chronic migraine is defined as 15 or more headache days per month with at least eight days with migraine features. However, the current study found that those with eight to 14 headache days per month and 15+ headache days per month had the same amount of disability and treatment needs.

Why It's Important: This study suggests that perhaps the diagnostic criteria for chronic migraine should be re-evaluated and adjusted from a threshold of 15 or more headache days per month to eight or more headache days per month to be more accurate with respect to disability and treatment needs. The number 15 was arbitrarily selected and it may be time to challenge the status quo with data. This would have a major impact on diagnosis, treatment, clinical trial design, and serve as a paradigm shift in the practice of headache medicine.

MOVEMENT DISORDERS

MELISSA J. NIRENBERG, MD, PHD, FAAN

Professor of Neurology

Icahn School of Medicine at Mount Sinai

New York, NY

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MELISSA J. NIRENBERG, MD, PHD, FAAN

The Pick: Chohan H, Senkevich K, Patel RK, et al. Type 2 diabetes as a determinant of Parkinson's disease risk and progression. Mov Disord 2021;36(6):1420-1429.

The Findings: In this study, the authors performed a meta-analysis of observational and genetic summary data to assess a potential relationship between Parkinson's disease and type 2 diabetes. While there have been conflicting findings in the literature, this analysis supports a relationship between type 2 diabetes and both the risk of Parkinson's disease and rate of disease progression. These findings, if confirmed, have significant implications for both Parkinson's disease management and translational research.

Why It's Important: The results of this systematic review and meta-analysis suggest that type 2 diabetes—a common and treatable disorder—is a potentially modifiable risk factor for the development and more rapid progression of Parkinson's disease. Potential explanations for an association between type 2 diabetes and Parkinson's disease may include shared common genetic risk factors, common pathogenic mechanisms (e.g., insulin resistance), or an additive effect of diabetes-related cerebrovascular disease on motor and cognitive decline. Exenatide, a glucagon like peptide-1 receptor agonist approved for treatment of type 2 diabetes, is currently being evaluated in phase 3 clinical trials as a potential disease-modifying therapy for Parkinson's disease.

The Pick: Pringsheim T, Ganos C, McGuire JF, et al. Rapid onset functional tic-like behaviors in young females during the COVID-19 pandemic. Mov Disord 2021;36(12):2707-2713.

The Findings: The authors describe clusters of patients at eight sites in North America, Europe, and Australia who presented with rapid-onset, complex functional motor and phonic tic-like behaviors after observing social media influencers with similar movement disorders. They describe factors that distinguished functional tics from organic tics, included female (versus male) predominance, rapid/explosive (versus gradual) onset, predominance of complex (versus simple) tics, and adolescent/young adult (versus childhood) onset. They explain how the this “pandemic” of patients with functional tic disorders developed in parallel with the globally shared stressor of the COVID-19 pandemic.

Why It's Important: These “TikTok tics” have been previously described as an example of mass sociogenic illness (“mass hysteria”), a phenomenon that can cause significant distress, disability, and unnecessary medical workup and treatment. Prompt recognition is critical, as it can help to minimize stress, healthcare utilization, and facilitate appropriate mental health referral. The study illustrates yet another indirect medical complication of the COVID-19 pandemic and calls to attention the negative mental health effects of social media in adolescents and young adults.

MULTIPLE SCLEROSIS

STEPHEN KRIEGER, MD, FAAN

Associate Professor of Neurology

Icahn School of Medicine at Mount Sinai

New York, NY

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STEPHEN KRIEGER, MD, FAAN

The Pick: Spelman T, Magyari M, Piehl, et al. Treatment escalation vs immediate initiation of highly effective treatment for patients with relapsing-remitting multiple sclerosis: Data from 2 different national strategies. JAMA Neurol 2021:78(10):1997-1204.

The Findings: Using two large national registries in Sweden and Denmark, the study demonstrated differences in clinical outcomes in MS based on the initiation of high- efficacy therapy. This leverages the use of national health systems for large data sources. The impact of high-efficacy MS treatment was again demonstrated.

Why It's Important: Head-to-head trials of high-efficacy agents compared with other MS disease-modifying therapies are lacking, and long-term outcomes comparing these treatment strategies can only be derived from real-world data. These large datasets provide an opportunity to demonstrate the impact of high-efficacy therapy in a way that supplements our clinical trial data.

These data are all the more important in the COVID era when the risks of high- efficacy immune modulation are at the top of mind. As shown in the second article, the risk/benefit ratio of high-efficacy, disease-modifying therapy in COVID needs to be carefully weighed against the efficacy results as shown in this study.

The Pick: Sormani MP, De Rossi N, Schiavetti I, et al. Disease-modifying therapies and coronavirus disease 2019 severity in multiple sclerosis. Ann Neurol 2021;89(4):780-789.

The Findings: COVID-19 related risks associated with high efficacy and requested therapies has been the subject of great debate over the past two years. In this study by Sormani and colleagues, a large Italian cohort was analyzed to further clarify the extent to which COVID-19 outcomes are influenced by a range of MS therapies. The researchers found subtle differences in COVID severity and mortality outcomes in MS patients treated with B-cell depleting agents.

Why It's Important: While the efficacy advantage of these agents has been shown in multiple studies, including the other pick for 2021, COVID-19 has altered that risk- benefit analysis, particularly in patients with other comorbidities known to affect COVID outcomes.

NEUROCRITICAL CARE

SACHIN AGARWAL, MD, MPH

Assistant Professor of Neurocritical Care

Columbia University Irving Medical Center

New York, NY

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SACHIN AGARWAL, MD, MPH

The Pick: Murthy SB, Zhang C, Diaz I, et al. Association between intracerebral hemorrhage and subsequent arterial ischemic events in participants from 4 population-based cohort studies. JAMA Neurol 2021; 78(7):809-816.

The Findings: In a pooled analysis of four large population-based studies with approximately 50,000 participants, intracerebral hemorrhage was associated with an increased risk of subsequent arterial ischemic events. The association was observed for both ischemic stroke and myocardial infarction. The study found that the degree of increased risk occurred across all patient subgroups and persisted after adjustment for basic demographic characteristics and traditional vascular risk factors.

Why It's Important: These findings suggest that intracerebral hemorrhage may be a novel risk marker for arterial ischemic events. The study findings will give rise to future studies assessing the net clinical benefit of validated treatments for ischemic stroke such as antithrombotic therapy and/or statin medications in this population at high-risk for intracerebral hemorrhage.

The Pick: Dankiewicz J, Cronberg T, Lilja G, et al, for the TTM2 Trial Investigators. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med 2021;384:2283-2294.

The Findings: In an open-label trial with blinded assessment of outcomes, 1,900 adults with coma due to an out-of-hospital cardiac arrest were randomly assigned to either targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). Targeted hypothermia did not lead to a lower incidence of death or functional outcome by six months than targeted normothermia.

Why It's Important: Targeted hypothermia is the standard of care after an out-of-hospital cardiac arrest. The findings of these studies question the efficacy of this intervention in a group of participants recruited primarily from Europe, who were receiving significantly higher rates of pre-hospital care, for example, bystander-witnessed events and CPR, and overall survival rates in both groups. The study highlights the need for additional public health campaigns and/or studies to implement such practices in the diverse US population.

NEUROGENETICS

BRENT FOGEL, MD, PHD, FAAN

Associate Professor of Neurology and Human Genetics

David Geffen School of Medicine, UCLA

Los Angeles, CA

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BRENT FOGEL, MD, PHD, FAAN

The Pick: Smedley D, Smith KR, Martin A, et al, for the 100,000 Genomes Project Pilot Investigators.100,000 genomes pilot on rare-disease diagnosis in health care— preliminary report. N Engl J Med 2021;385(20):1868-1880.

The Findings: This work outlines the UK 100,000 Genomes Project pilot study to assess the benefit of whole genome sequencing (WGS) in establishing a genetic diagnosis in patients with previously undiagnosed rare diseases despite all usual standards of care. Over 2,100 patients, predominantly adults (74 percent), and their families underwent WGS utilizing an automated diagnostic pipeline to prioritize potentially diagnostic genetic variations in the context of clinical phenotype and, in some cases, correlated with subsequent research investigations (14 percent of the diagnoses). Nearly half the patients had primary phenotypes associated with disorders of the nervous system and ultimately 25 percent of the participants were diagnosed. The greatest yields were seen among neurologically-associated diseases (30 percent or better) with the highest percentages seen for intellectual disability, hearing disorders, and vision disorders (40 to 55 percent). Three newly discovered disease genes were identified, two of these related to neurological phenotypes. Finally, the authors speculated resource cost savings of as much as $122 million with 25 percent of the diagnoses resulting in changes to clinical management.

Why It's Important: Rare disease continues to present significant diagnostic challenges and can result in detailed and extensive resource-intensive clinical evaluations. Previous work, such as the findings of the NIH-sponsored Undiagnosed Diseases Network, have reported high diagnostic yields and clinical benefits in this population using genomic testing. This study applies this to the UK national health care system and shows a similar large increase in diagnosis, providing further support for the use of WGS in conjunction with advances in the clinical application of computational genomics and bioinformatics. Important takeaways for this study include the observation that, of the patients diagnosed, the authors suggest that 15 percent of the diagnostic findings would be unlikely to be detected via exome sequencing, the current most commonly utilized genomic test. The consequent findings of significant clinical cost savings and changes to clinical management are important observations as US payers continue to deny patient authorizations for such testing based on a supposed lack of clinical benefit and/or designation as experimental testing.

The Pick: Gillmore JD, Gane E, Taubel J, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med 2021;385(6):493-502.

The Findings: Transthyretin amyloidosis, caused by mutation of the TTR gene, is most commonly characterized by amyloid polyneuropathy, cardiomyopathy, or both in combination. The disease is progressive and can result in death, most commonly due to cardiovascular events. Among current treatments are recently introduced gene therapies, which silence gene expression using either a small interfering RNA- or antisense oligonucleotide-mediated strategy (patisiran or inotersen, respectively), which require continued delivery to maintain efficacy. To achieve sustained elimination of gene expression, the authors utilized the gene-editing CRISPR-Cas9 methodology to develop a novel therapeutic, NTLA-2001. Given by IV, a single dose of NTLA-2001 alters expression of TTR in target hepatocytes to permanently reduce protein levels. This article describes the resulting preclinical studies of this drug and a limited phase 1 clinical trial of six patients. The animal data suggests a permanent and almost full reduction of protein expression with a single dose. The investigators reported a dose-dependent serum protein reduction between 52 to 87 percent in the human patients.

Why It's Important: This work highlights the potential use of CRISPR-Cas9 in vivo gene editing in efforts to achieve single-dose permanent treatment effects in human neurogenetic disease. If effective, such a strategy could be adapted to treatments for other rare disorders. However, long-term follow-up study for continued efficacy as well as off-target and other adverse effects will still be needed.

NEUROMUSCULAR DISORDERS

DIANNA QUAN, MD, FAAN

Professor of Neurology

University of Colorado Denver

Aurora, CO

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DIANNA QUAN, MD, FAAN

The Pick: Gillmore JD, Gane E, Taubel J, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med 2021;385(6):493-502.

The Findings: This paper by Gilmore and colleagues describes the first use of CRISPR-Cas9 technology to treat six patients with transthyretin amyloidosis. The study evaluated the safety and pharmacodynamic effects of single doses of an experimental in vivo gene-editing agent NTLA-2001 in six patients with hereditary ATTR amyloid polyneuropathy. Two doses of 0.1 mg/kg and 0.3 mg/kg were tested and showed 52 percent and 87 percent respective mean reduction from the baseline of serum TTR protein concentration at day 28. Adverse effects were mild.

Why It's Important: In the last few years, Neurology Today has highlighted the emergence of groundbreaking new therapies for hereditary ATTR amyloid polyneuropathy, but all require ongoing lifelong treatment. This highly innovative work harnessing the potential of CRISPR-Cas9 technology represents a critical first step toward curing a formerly deadly neurologic disease with a single infusion. Although it is a small preliminary study, the initial positive results of this approach in human subjects may have profound implications for the future treatment and cure of hereditary ATTR amyloid polyneuropathy and many other devastating hereditary diseases.

The Pick: Howard JF Jr, Bril V, Vu T, et al, for the ADAPT Investigator Study Group. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol 2021;20(7):526-536.

The Findings: This phase 3 study describes the use of efgartigimod, a human IgG1 antibody Fc fragment designed to decrease pathogenic IgG autoantibody levels in patients with generalized myasthenia gravis. The adaptive, patient-friendly design of four weekly infusions followed by as-needed dosing based on clinical response resulted in 68 percent of efgartigimod patients having ≥ 2-point improvement in MG-ADL scores after the initial four-week treatment compared with 30 percent in the placebo group.

Why It's Important: We are on the cusp of a new era in myasthenia gravis treatment. As our understanding of the pathophysiology of myasthenia evolves, the next few years will likely bring numerous new innovative options for managing this disease. This study is part of the tip of the iceberg. [The US Food and Drug Administration approved efgartigimod in December based on these and other data.] Stay tuned!

NEURO-ONCOLOGY

AMY A. PRUITT, MD, FAAN

William N. Kelley Professor of Neurology

University of Pennsylvania

Philadelphia, PA

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AMY A. PRUITT, MD, FAAN

The Pick: Louis DN, et al. The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol 2021;23(8):1231-1251.

The Findings: The classification of central nervous system (CNS) tumors historically has been based on tumor histology, but this has often proved inaccurate. One consequence of reliance on histology is that a potentially heterogeneous group of tumors could be included in clinical trials, rendering potentially erroneous conclusions on which to base prognosis and therapeutic decisions. The molecular provenance of CNS tumors was included with histology for the first time in the 2016 WHO CNS tumor update to give an “integrated diagnosis.” In only five years, further revisions have been made through the work of Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO. In 2021, the fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS5) was published and is usefully summarized by Louis and colleagues.

The classification of gliomas is the most important change in WHO CNS5, differentiating gliomas that occur primarily in adults from those that occur mainly in children.

Why It's Important: Overall, the changes represent a major improvement in the diagnosis of CNS tumors and will require that laboratories have the adequate technologies for subtyping tumors. This will allow patients to receive more personalized therapies and produce homogeneous populations of patients to be enrolled into clinical trials.

The Pick: Van den Bent MJ, Tesileanu CMS, Wick W, et al. Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC 26053-22054): Second interim analysis of a randomised, open-label, phase 3 study. Lancet Oncol 2021;22(6):813-823.

The Findings: This large phase 3 study included 751 patients assigned to four treatment arms, to determine if temozolomide in various sequencing (concomitant or adjuvant) added to radiation therapy improved overall survival in patients with what the WHO legacy term would be grade III anaplastic astrocytoma. The findings were unexpected: No benefit from concurrent temozolomide was seen in the entire study population in every analyzed molecular subgroup.

Why It's Important: The study and its controversial reception by neuro-oncologists illustrates both the utility and the flaws of the prior grading system. IDH status was not included in the stratification of these patients, but it was considered in a companion paper. In most glioblastoma trials, temozolomide is used both adjuvantly and concomitantly, the latter as a probable radiosensitizer. Therefore, the lack of survival benefit from concomitant temozolomide is surely a substantially surprising summation from this study. The neuro-oncologic community is divided on how this will affect the clinical recommendation for standard glioblastoma care.

The Pick: Gu W, Rauschecker AM, Hsu E, et al. Detection of neoplasms by metagenomic next-generation sequencing of cerebrospinal fluid. JAMA Neurol 2021;78(11):1355-1366.

The Findings: Michael Wilson and colleagues at the University of California, San Francisco (UCSF) have reported on a new application of metagenomics next-generation sequencing (mNGS) already useful in cerebrospinal fluid (CSF) infections, to identify aneuploidy, a hallmark of CNS malignancy. Two case-control studies were performed.

The primary outcome measures were the sensitivity and specificity of aneuploidy detection by CSF mNGS. The two studies included 130 participants. The sensitivity of the CSF mNGS assay was 75 percent, and the specificity was 100 percent. Aneuploidy was detected in 64 percent of the patients in the test performance study with non-diagnostic cytologic testing and/or flow cytometry, and in 55 percent of patients in the neuro-inflammatory disease study who were ultimately diagnosed with a CNS malignant neoplasm.

Why It's Important: CSF cytologic testing and flow cytometry are insensitive for diagnosing neoplasms of the CNS. Some clinical phenotypes can mimic infectious and autoimmune causes of meningoencephalitis. Thus, there is increasing interest in cell-free DNA from CSF for detection of malignancy and follow-up of therapeutic interventions. This case-controlled study showed that CSF mNGS, which has low specimen volume requirements, does not require the preservation of cell integrity and can detect genetic evidence of a CNS malignant neoplasm in patients in whom CSF cytologic testing and/or flow cytometry yielded negative results with a low risk of false-positive results. The technique has potential for diagnosing tumors earlier without additional invasive testing.

The Pick: Tawbi HA, Forsyth PA, Stephen-Hodi F, et al. et al. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): Final results of an open-label, multicentre, phase 2 study. Lancet Oncol 2021;22(12)1692-1704.

The Findings: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed lower efficacy in patients with symptomatic MBM (who required steroids). The final three-year follow-up data from this open-label, multicenter, phase 2 study (CheckMate 204) showed that in asymptomatic patients (cohort A), the intracranial progression-free survival (PFS) at three years was 54 percent and overall survival was 72 percent. For cohort B (the symptomatic cohort), the intracranial PFS at three years was 19 percent with an overall survival of 37 percent. Both groups represent significant improvement over a decade ago when survival would have been on the order of six months.

Why It's Important: Now that there are alternatives to whole brain radiation therapy, neurologic consultants must be aware of the efficacy and complications of rapidly evolving treatment strategies. On the other hand, the study generated debate about eliminating the role of stereotactic radiosurgery in selected patients, potentially to their survival detriment. Larger phase 2 trials are necessary.

The Pick: Marini A, Bernardini A, Gigli GL, et al. et al. Neurologic adverse events of immune checkpoint Inhibitors: A systematic review. Neurology 2021;96:754-766.

Placais L, Michot JM, Champiat S, et al. Neurological complications induced by immune checkpoint inhibitors: a comprehensive descriptive case-series unravelling high risk of long-term sequelae. Brain Commun 2021; 3(4):fab220.

The Findings: The Marini paper is a meta-analysis of immune checkpoint inhibitor (ICI) adverse effects. Both studies emphasize the rarity, but severity of neurologic ICI complications. In the Placais study, 40 patients presenting with 51 distinct neurological immune-related adverse events were included. Clinical neurological presentations were peripheral (48 percent), central (35 percent), or mixed (18 percent). Corticosteroid treatment led to neurological recovery in 74 percent. Long-term follow-up highlighted that 53 percent of patients experienced long-term neurological sequelae. Five patients were re-challenged by programmed-cell death 1 monotherapy without recurrence of their neurological immune-related adverse event(s). The mortality rate was 8 percent and long-term sequelae occurred in 53 percent of patients.

Why It's Important: In the rapidly evolving world of neuro-oncologic therapeutics, keeping up is an essential requirement for consulting neurologists. These two reviews will help keep clinicians updated. Neurological immune-related adverse events are complications of ICI therapies and can be life threatening, often leading to anticancer immunotherapy withdrawal.

PEDIATRIC NEUROLOGY/SLEEP/EPILEPSY

TEMITAYO OYEGBILE-CHIDI, MD, PHD

Associate Professor of Neurology

University of California, Davis

Sacramento, CA

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TEMITAYO OYEGBILE-CHIDI, MD, PHD

The Pick: Louis S, Rabah N, Rammo R, Bingaman, et al. Disparities in the nationwide distribution of epilepsy centers. Epilepsy Behav 2021;125:108409.

The Findings: The study authors created heat maps of the United States to visualize geographical locations of level IV epilepsy centers in relation to the 2015 statewide epilepsy prevalence and 2017 countywide Area Deprivation index scores, a composite measure of socioeconomic disadvantage. They tested for associations between the presence or absence of epilepsy centers and socioeconomic disadvantage. There are several disadvantaged communities where level IV epilepsy centers are not available nearby. Specifically, eight states do not have level IV epilepsy centers. Many of these states have a high population of people who are American Indian/Native American. These populations may be more likely to have more comorbidities and worse health care outcomes compared to populations where adequate epilepsy care is readily available.

Why It's Important: The COVID-19 pandemic has laid bare the disparities that exist not only in terms of access to care but also treatment outcomes. This study looks at the issue as it relates to access to epilepsy care. As this study makes clear, historically, access to care has not been equitable across all populations, and some of that relates to the availability of level IV epilepsy centers. It is important that we highlight some of these disparities in specific neurology fields. Epilepsy is an area where we are beginning to become aware of these disparities and addressing potential solutions.

POLICY AND PRACTICE

NEIL A. BUSIS, MD, FAAN

Associate Chair, Technology and Innovation

Department of Neurology, NYU Langone Health

New York, NY

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NEIL A. BUSIS, MD, FAAN

The Pick: Samson LW, Tarazi W, Turrini G, Sheingold S, for the Department of Health and Human Services secretary for planning and evaluation office of health policy. Medicare beneficiaries' use of telehealth in 2020: Trends by beneficiary characteristics and location. https://bit.ly/3ElH2Li. Accessed December 23, 2021.

The Findings: The number of Medicare telehealth visits increased 63-fold in 2020, and most (92 percent) received telehealth visits from their home. Telehealth increased to 8 percent of primary care visits, while specialty care had a smaller shift towards telehealth (3 percent of specialist visits). Black and rural beneficiaries had lower use of telehealth compared with White and urban beneficiaries, respectively. And telehealth use varied by state, with higher use in the Northeast and West, and lower use in the Midwest and South.

Why It's Important: Policy makers are most likely to use evidence from their own studies. This report comes from the Office of Health Policy of the Department of Health and Human Services. It confirms the marked increase in telehealth visits. Before the pandemic, telehealth encounters were not permitted to originate from patients' homes. Since most patients received their telehealth visits at home, this should be supported by the future telehealth policies. The smaller shift toward telehealth for specialist visits compared with primary care visits suggests the need for more evidence to support the effectiveness of telehealth in medical specialties.

The pandemic made us aware more than ever that socioeconomic factors have a major impact on patients' health care. The demographic assessment of telehealth use raises questions whether current models of telehealth may decrease access to care for certain populations rather than increase it. If this is supported by further evidence, future policies need to address this disparity.

The Pick: Albritton J, Ortiz A, Wines R, et al. Video teleconferencing for disease prevention, diagnosis, and treatment: A rapid review. Ann Intern Med 2021; Epub 2021 Dec 7.

The Findings: This rigorous review, which was sponsored by the Patient-Centered Outcomes Research Institute, identified seven different types of bias, and many studies were rejected due to bias. Replacing or augmenting aspects of usual care with audio-video telehealth encounters generally resulted in similar clinical effectiveness, health care use, patient satisfaction, and quality of life. However, included trials were limited to a handful of disease categories, with patients seeking care for a limited set of purposes. The only neurologic conditions with suitable studies were headache and Parkinson's disease.

Why It's Important: It's reassuring that the included telehealth studies lead to generally comparable outcomes compared to in-person visits. However, this paper illustrates how meager the current evidence is regarding the effectiveness of telehealth for many conditions. The study methods raise the bar for future design of telehealth effectiveness studies.

The Pick: Predmore ZS, Roth E, Breslau J, et al. Assessment of patient preferences for telehealth in post-COVID-19 pandemic health care. JAMA Netw Open 2021;4(12):e2136405.

The Findings: This study, which used a nationally representative sample of adult members of the RAND American Life Panel, found respondents were generally willing to use video visits but preferred in-person care. Those who preferred video visits were more sensitive to paying out-of-pocket cost. Age, race/ethnicity, educational level, and income were correlated with preference for video visits versus in-person visits.

Why It's Important: Patient preferences are an important determinant of telehealth usage when patients have a choice. The preponderance of telehealth visits during the public health emergency does not predict future telehealth usage, because patients had no choice in many instances. Despite what some industry sponsored studies say, in-person care is still more popular than telehealth care in many circumstances. Several low-usage groups identified in the Health and Human Services study may have had lower telehealth use not due to the digital divide, but rather because they preferred in-person visits. It's uncertain whether their preferences would shift if they had equal access to telehealth technologies or if they had further education regarding the nature and potential benefits of telehealth visits.

The Pick: Thomas-Jacques T, Jamieson T, Shaw J. Telephone, video, equity, and access in virtual care. NPJ Digit Med 2021;4(1):159.

The Findings: There has been much public debate about the benefits of audio-only visits and what their proper roles are and should be. CMS currently supports audio-only encounters for behavioral health indications. Prior to the pandemic, payers rarely covered audio-only visits. As new telehealth policies are being developed, simple technological solutions that provide access to care must continue to be supported along with more advanced telehealth modalities.

Why It's Important: This is a very cogent discussion of the need for audio-only encounters and their proper position along the spectrum of telehealth modalities. It explains why deploying only complex telehealth technologies risks exacerbating health disparities by widening the digital divide for marginalized populations.

PROFESSIONAL WELL-BEING

JENNIFER BICKEL, MD, FAAN

Chief Wellness Officer

Senior Member, Department of Neuro-oncology

Professor of Oncologic Sciences

University of South Florida Morsani School of Medicine

Tampa, FL

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JENNIFER BICKEL, MD, FAAN

The Pick: With the endorsement of the AAN, Congress passed the Dr. Lorna Breen Health Care Provider Protection Act to address wellbeing and burnout among health care providers.

The Findings: The Dr. Lorna Breen Health Care Provider Protection Act aims to reduce and prevent suicide and burnout, among health care professionals. It authorizes grants to create programs that offer behavioral health services for front-line health care workers. Dr. Breen was a New York City emergency department physician who died by suicide in April of 2020 in the midst of the COVID-19 onslaught. Her family founded the Dr. Lorna Breen Heroes' Foundation, which has become a force for wellbeing advocacy.

The American Rescue Plan includes over $100 million in funds for the US Health Resources & Services Administration to support the “implementation of evidence-informed strategies to help organizations and providers respond to stressful situations, endure hardships, avoid burnout and foster healthy workplace environments that promote mental health and resiliency.”

Why It's Important: Clinician burnout was a problem before the pandemic and with wave upon wave of COVID surges, it's not clear how we will weather this long storm. National legislative prioritization of clinician wellbeing is an essential step to not just help health care workers but also keep our country as healthy as possible. This funding is a step in the right direction during a time when relief can't come soon enough. However, it will be imperative that these well intended initiatives don't become yet another hospital mandatory module to demonstrate compliance.

The Pick: We Are All Perfectly Fine: A Memoir of Love, Healing and Medicine by Jillian Horton, MD (Harper-Collins)

The Findings: Dr. Horton's inspiring and at time humorous narrative reflects so much of what I've heard in my hundreds of hours of listening to doctors and their teams about professional wellbeing and burnout.

Why It's Important: Dr. Horton's memoir illustrates the complex interplay between us as individuals, the potentially toxic culture of medicine, and the sustained damaged caused by moral injuries within dysfunctional systems. Her story provides the opportunity to engage those outside of medicine to advocate for clinician wellbeing in a way that statistics alone cannot do.

SLEEP NEUROLOGY

CHARLENE GAMALDO, MD, PHD, FAAN, FAASM

Medical Director, Johns Hopkins Center for Sleep

Associate Professor of Neurology, Psychiatry, Nursing, Anesthesia,

Public Health

Johns Hopkins University

Baltimore, MD

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CHARLENE GAMALDO, MD, PHD, FAAN, FAASM

The Pick: The US FDA approval of the oral solution Xywav (calcium, magnesium, potassium, and sodium oxybates) for idiopathic hypersomnia.

The Findings: The medication, manufactured by Jazz Pharmaceuticals, was approved for the treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy. It was approved for idiopathic hypersomnia in adults in August.

Why It's Important: Idiopathic hypersomnia is an often debilitating neurologic sleep disorder that is characterized by excessive daytime sleepiness that is not caused by other medical, behavioral, or psychiatric conditions. This is the first FDA approved medication indicated for treatment of adults with idiopathy hypersomnia.

The Pick: In June, Phillips issued an announcement of a voluntary recall of select models of their BiLevel PAP, CPAP devices, and mechanical ventilators in the United States.

The Findings: Phillips communicated that the issue was related to a potential breakdown of the polyester-based foam insulation that could result in the inhalation of toxic particles and/or off-gas chemicals that can be inhaled by the user. Phillips has created a website to report affected machines for replacement and remediation and is currently working in cooperation with the FDA for approval of a replacement foam. To date, Phillips has reported replacement of 750,000 machines.

Why It's Important: Phillips is one of two primary manufacturers of PAP and home ventilators in the country. PAP therapy remains one of the primary therapeutic approaches for sleep apnea, which is estimated to affect 18 million Americans. On top of issues related to supply chain, the recall created an additional strain on therapeutic delivery over the last year that is projected to be an issue well into 2022. Additional therapeutic options that include oral appliance therapy and surgical therapy will likely take on greater importance and attention as a result of this shortage.