As we move into the next decade, we asked the editorial board of Neurology Today to reflect back on 2019 to highlight those advanceshowever large, small, or transformationalthat moved neurology and the field forward in the clinic, at the bench, in the therapeutic pipeline, and in areas of policy and practice. Here below they offer their expert picks on the neurology news that mattered in 2019. Look for more in-depth discussion of these picks and reports in NeurologyToday.com.

JAMES C. GROTTA, MD, FAAN

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

Memorial Hermann-Texas Medical Center

Houston, TX

The Pick: Johnston KC, Bruno A, Pauls Q, et al. Intensive vs standard treatment of hyperglycemia and functional outcome in patients with acute ischemic stroke. The SHINE randomized clinical trial. JAMA 2019;322(4):326-335.

The Findings: This trial randomized 1,151 acute ischemic stroke patients with blood glucose>110 mg/dL (or >150 mg/dL if not diabetic) at admission to receive either aggressive blood glucose-lowering using an insulin drip, which achieved a mean glucose level of 118 mg/dL or a conventional insulin sliding scale, which achieved a mean glucose level of 179 mg/dL. Intensive management compared with standard management did not improve functional outcome, and intensive treatment was associated with more symptomatic hypoglycemia.

Why It's Important: Many patients with acute stroke are hyperglycemic on admission and hyperglycemia has been associated with increased brain swelling and bleeding. But it is not known if aggressively lowering elevated blood glucose will result in a better outcome. This study conclusively shows that aggressive reduction of blood glucose in the acute setting is not beneficial.

The Pick: Connolly SJ, Crowther M, Eikelboom JW, et al, for the ANNEXA-4 Investigators. Full study report of andexanet alfa for bleeding associated with factor Xa Inhibitors. N Engl J Med 2019;380(14):1326-1335.

The Findings: Andexanet alfa is a recombinant inactive form of factor Xa developed for reversal of factor Xa inhibitors. A total of 352 patients with acute major bleeding due to a factor Xa inhibitor (64 percent had intracranial hemorrhage) were given a bolus of andexanet followed by a two-hour infusion. Andexanet resulted in 92 percent reduction of factor Xa levels, and excellent or good hemostasis was achieved in 82 percent.

Why It's Important: Factor Xa inhibitors are safer and at least as effective as warfarin, so they are commonly used, including for prevention of stroke in patients with atrial fibrillation. Major bleeding complications including intracranial hemorrhage may occur. Andexanet is the first specific factor Xa inhibitor reversal agent designed to stop such bleeding. The major drawback of andexanet is its cost. Andexanet will likely become more commonly used in selected patients with life-threatening factor Xa-associated acute major bleeding and will provide further support for the use of Xa inhibitors over warfarin.

The Picks: Pan Y, Elm JJ, Easton JD, et al. Outcomes associated with clopidogrel-aspirin use in minor stroke or transient ischemic attack: A pooled analysis of CHANCE and POINT trials. JAMA Neurol 2019; Epub 2019 Aug 19.

Wang Y, Chen W, Lin Y, et al. Ticagrelor plus aspirin versus clopidogrel plus aspirin for platelet reactivity in patients with minor stroke or transient ischemic attack. BMJ 2019;365:12211.

Classens DMF, Vos GJA, Bergmeijer TO, et al. A genotype-guided strategy for oral P2Y12 Inhibitors in primary PCI. N Engl J Med 2019;381:1621-1631.

The Findings: The Pan, et al study pooled data on 10,051 patients from two large studies (CHANCE and POINT), which both showed that in patients with high-risk transient ischemic attack (TIA) or minor stroke, dual antiplatelet therapy (DAT) with clopidogrel plus aspirin resulted in fewer recurrent ischemic events than monotherapy with either aspirin or clopidogrel alone. However, the two studies had differing duration of DAT, and this pooled analysis showed that the benefit occurred with the first 21 days of treatment. After that, the risks of bleeding exceeded the benefit.

In CHANCE, Wang, et al had also shown that many patients on DAT continue to have heightened platelet reactivity, in particular those carrying the CYP2C19 loss-of-function allele. Ticagrelor is pharmacologically similar to clopidogrel but its metabolism does not involve the CYP2C19 pathway. Now the same investigators show that substituting ticagrelor for clopidogrel resulted in much more complete suppression of platelet reactivity without increased bleeding risk compared to those just left on clopidogrel plus aspirin.

Supporting this concept, Classens, et al randomized stroke patients with percutaneous coronary intervention (PCI) to receive either ticagrelor or prasugrel versus clopidogrel. Patients in the clopidogrel group who had CYP2C19 loss-of-function alleles were switched to ticagrelor or prasugrel. The genotype-guided group was non-inferior with regard to recurrent ischemic events and had less bleeding.

Why It's Important: Patients with minor stroke and some TIA patients are at high risk of recurrent ischemic events, and based on the CHANCE and POINT studies should be treated with DAT. The Pan, et al pooled analysis conclusively shows that such DAT should be stopped and patients reverted to monotherapy after 21 days. However, even if on DAT, many patients continue to have high platelet reactivity because they harbor the loss-of-function CYP2C19 allele that prevents the conversion of clopidogrel to its active form. Because ticagrelor and prasugrel metabolism do not involve the CYP2C19 pathway, and they are under evaluation to replace clopidogrel, these studies suggest that high-risk patients continued on clopidogrel should be checked for CYP2C19 activity, and ticagrelor substituted if loss-of-function is identified.

ANN TILTON, MD, FAAN

Professor of Neurology and Pediatrics

Louisiana State University Health Sciences Center

New Orleans, LA

The Pick: Kim J, Hu C, Moufawad EA, et al. Patient-customized oligonucleotide therapy for a rare genetic disease. N Engl J Med 2019;381(17):1644-1652.

The Findings: In this N of 1 study, investigators designed, tested, and manufactured milasen, a splice-modulating antisense oligonucleotide (ASO) drug tailored to a particular patient with a rare genetic form of Batten disease. There were no serious adverse events, and treatment was associated with a reduction in seizures (evidenced by EEG and parental reporting). This ability and the development of the ASO drug nusinersen for the treatment of infants and children with spinal muscular atrophy opened up the ability to utilize similar technology in the child in this study who was deteriorating.

Why It's Important: This study provides a proof-of-concept demonstrating an N of 1 studya patient-specific treatmentthat has thus far been safe and has some efficacy. The authors rapidly utilized genomic medicine to further open the door for individualized treatment in the rare disease space.

Read the Neurology Today story, In the Pipeline-An Antisense Oligonucleotide Therapy Looks Promising for a Rare Form of Batten Disease (June 20, 2019).

ERIC M. MCDADE, DO

Associate Professor of Neurology

Washington University at St. Louis

School of Medicine

St. Louis, MO

The Pick: Preische O, Schultz SA, Apel A, et al, for the Dominantly Inherited Alzheimer Network. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Nat Med 2019;25(2):277-283.

The Findings: In this study, researchers studying a group of participants with autosomal dominant Alzheimer's disease (AD), a highly predictable form of the disease, measured serum and CSF neurofilament light chain (NfL)a neurospecific marker that increases with neuronal damage, across the disease spectrum to determine if NfL could provide unique information on disease stage and risk. In doing so, they found that NfL begins to increase between five to 10 years before cognitive decline begins and that the rate of change of serum NfL was a good predictor of cortical atrophy and decline on the Mini-Mental State Exam. These findings suggest that this test may be a marker of the neurodegenerative aspect of the disease in those at a high risk of developing AD.

Why It's Important: Although important advancements have been made in the development of diagnostic tests that are specific to AD and other associated dementias, the long time period from when amyloid-beta pathological changes begin to when cognitive decline starts introduces a large amount of uncertainty in predicting the likelihood of dementia on cognitively normal adults with abnormal AD biomarkers. Furthermore, the most accurate AD diagnostic biomarkers are either PET or cerebrospinal fluid (CSF)-based and therefore limit their use at this time.

As the ability to identify those at risk for AD improves it is important to determine reliable tests for determining those at the greatest risk of developing cognitive decline in the near future. Moreover, NfL has been shown to respond to disease-modifying therapies in multiple sclerosis, suggesting that it might also provide an important outcome measure of the neurodegenerative process in AD clinical trials.

Additionally, other studies have demonstrated that CSF and serum changes in NfL are highly correlated, indicating that a blood test is likely to be sufficient when using this as a diagnostic measure. Although there is plenty of work to be done, this study has been confirmed in non-familial forms of AD and NfL has become a measure of great focus in AD research and clinical trials.

The Pick: Largent EA, Terrasse M, Harkins K, et al. Attitudes toward physician-assisted death from individuals who learn they have an Alzheimer disease biomarker. JAMA Neurol 2019;76(7):864-866.

The Findings: In this small study of participants participating in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study, a secondary prevention trial testing whether solanezumab can slow cognitive decline in persons with amyloid accumulation, and a related study, participants who had abnormal or normal amyloid PET scans were followed over a 12-month period to assess how knowing whether they have an abnormal amyloid level affected their views on physician-assisted death (PAD). Twelve months after they received the results of their abnormal amyloid PET scans, approximately 20 percent reported that they would consider PAD if they began to develop dementia or consider themselves a burden to others. Importantly, these participants in the study nonetheless endorsed a greater likelihood of planning for the future.

Why It's Important: Given the increasing push for prevention studies in Alzheimer's disease and the development of increasingly accurate and accessible diagnostic tests for AD related biomarkers, it is imperative that we understand the potential benefits and hazards of cognitively-normal adults learning about whether they have abnormal AD pathologies that significantly increase their risk for developing dementia. We have truly entered into a stage in AD research where the neurobiological underpinnings of the disease can be identified prior to the development of clinical impairment. Although this offers the opportunity for greater chances of identifying disease-modifying therapies, until there are effective preventive therapies it is absolutely critical that we understand how this type of information affects our patients.

JACQUELINE A. FRENCH, MD, FAAN

Professor of Neurology

NYU School of Medicine

New York, NY

The Pick: Lagae L, Sullivan J, Knupp K, et al for the FAiRE DS Study Group. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A randomised, double-blind, placebo-controlled trial. Lancet 2019; 394(10216):2243-2254.

The Findings: This is the first randomized, placebo-controlled trial of fenfluramine for Dravet syndrome. A total of 119 children with Dravet syndrome were randomized to high- or low-dose fenfluramine, compared with placebo, and treated for 14 weeks. Convulsive seizures were reduced substantially. The high-dose group (0.7 mg/kg) had 62.3 percent greater reduction in mean monthly convulsive seizure frequency compared with those taking placebo; the low-dose group (0.2 mg/kg per day) showed a 32.4 percent reduction compared with those taking placebo. Half the children in the high-dose group and almost a quarter in the low-dose group had a 75 percent or greater reduction in mean monthly convulsive seizures. The drug was tolerable for most. There were no dropouts in the low-dose group; six dropped out in the high-dose group compared with three in the placebo group.

Why It's Important: There has been a greater focus on treatment of orphan epilepsies over the last decade. Dravet syndrome has been the orphan poster child, with numerous trials underway for the condition. Pharmaceutical-grade cannabidiol (Epidiolex) was the first antiseizure medication approved for Dravet syndrome. Based on the trial above, the US FDA recently granted fenfluramine a priority review. Such reviews are given to drugs that are expected to have a substantial impact on a disease. Fenfluramine is currently undergoing trials in Lennox-Gastaut syndrome, another orphan epilepsy. Safety studies are also ongoing, to ensure that the valve thickening and pulmonary fibrosis seen with Fen-Phenwhich had fenfluramine as a componentdo not occur.

Read the Neurology Today article, In the Pipeline-Oral Fenfluramine Is Promising Therapy for Children with Dravet Syndrome (January 9, 2020).

The Pick: Kapur J, Elm J, Chamberlain JM, et al, for the NETT and PECARN Investigators. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med 2019;381(22):2103-2113.

The Findings: This randomized trial assessed levetiracetam, fosphenytoin, and valproate for the treatment of status epilepticus, which continued after benzodiazepines had failed. The trial was stopped for futility after 384 adults and children were randomized. The endpoint of cessation of clinically-apparent status and improving mental status, without the addition of another medication at 60 minutes, was achieved in 47 percent of patients assigned to levetiracetam, 45 percent assigned to fosphenytoin, and 46 percent assigned to valproate. Adverse effects were similar between the groups.

Why It's Important: Status epilepticus is a major cause of harm related to seizures and epilepsy. Levetiracetam has increasingly been used in place of the older antiseizure medications phenytoin and valproate due to the perception that it is safer and produces less drug interactions. To date, there has been no rigorous evidence to support its use. This study shows no substantial difference (either in safety or efficacy) when levetiracetam is used, compared with the older drugs. Unfortunately, in the absence of a difference, it is impossible to say if any of the drugs were effective, however there is a reasonable likelihood that the status epilepticus did not stop on its own, considering that median time to seizure cessation after infusion was less than 15 minutes for all three drugs. The study highlights a very significant treatment gap, with fully half of patients inadequately treated with any of the three studied antiseizure medications.

Read the Neurology Today article, For Your Patients-Three Anticonvulsants Are Equally Effective for Status Epilepticus (January 9, 2020).

The Pick: Dubey D, Britton J, McKeon A, et al. Randomized placebo-controlled trial of intravenous immunoglobulin in autoimmune LGI1/CASPR2 epilepsy. Ann Neurol 2019;Epub 2019 Nov 28.

The Findings: Fourteen patients with LGI1- and three with CASPR2-related epilepsy who had two seizures per week were randomized to placebo versus treatment with IVIG added to standard antiseizure medicine. At baseline more than half of the patients were having 10 or more seizures daily. Six of eight patients in the IVIG group were responders (with a 50 percent reduction in seizures from baseline to five weeks), compared with two of nine in the placebo group (p=0.044). Only two patients treated with IVIG were seizure-free by the end of the study. The authors concluded that IVIG combined with antiseizure medicine is more effective than antiseizure medicine alone.

Why It's Important: There has been a great deal of interest in autoimmune epilepsy. When patients present with cognitive disturbance and a high seizure burden, the diagnosis is made more readily, but there may be additional patients who present as more typical focal epilepsy. This study underscores that the diagnosis is important and has treatment implications. While this study provides evidence that IVIG is superior to antiseizure medicines, the role of other standard immunotherapies such as corticosteroids and plasma exchange, either alone or in combination with IVIG, remains to be determined.

SHAWNIQUA WILLIAMS ROBERSON, MD

Assistant Professor of Neurology

Vanderbilt University Medical Center

Nashville, TN

The Pick: Kini LG, Bernabei JM, Mikhail F, et al. Virtual resection predicts surgical outcome for drug-resistant epilepsy. Brain 2019;142(12):3892-3905.

The Findings: This study combined automated processing of neuroimaging and intracranial EEG (iEEG) recordings in 28 patients with drug-resistant epilepsy to determine which specific brain regions, if resected, were most likely to result in seizure freedom. The authors found that decreases in broadband synchronizability of the resection zone at seizure-onset predicted surgical outcome (AUC 0.89, 95% CI 0.76-1.00) and that this information correctly predicts outcomes even when visual inspection of ictal iEEG could not clearly identify the seizure-onset zone. Preictal perilesional synchronizability was higher in nonlesional patients with malformations of cortical development than in those with lesions evident on MRI (rank sum statistic -2.08, p=0.04).

Why It's Important: Selection of surgical resection candidates and precise identification of the optimal extent of resection is the holy grail in the management of drug-resistant focal epilepsy. This study presents an important step forward, validating the previously published virtual resection method in a cohort of patients with and without identifiable MRI lesions and elucidating relationships between network synchronizability and certain clinical characteristics. Additionally, the authors provide a robust pipeline including rigorous clinical marking and validation of electrocorticographic recordings, MRI-based resection zone quantification, and online data-sharing. This open invitation to collaborate sets the stage for further advances to hone our prediction models and improve surgical resection planning for patients with intractable epilepsy.

The Pick: Ghassemi MM, Amorim E, Alhanai T, et al, for the Critical Care Electroencephalogram Monitoring Research Consortium. Quantitative electroencephalogram trends predict recovery in hypoxic-ischemic encephalopathy. Crit Care Med 2019;47(10):1416-1423.

The Findings: The authors compared several prediction models for prognostication of neurologic outcome (Cerebral Performance Category) at six months after cardiac arrest in a series of 438 patients across four institutions. They found that a model using time-varying quantitative EEG features collected over 72 hours outperformed a time-invariant model (p< 0.05) and other models, including a clinical prediction model and a random forest model.

Why It's Important: Accurate prognostication of outcomes after cardiac arrest remains an important and unsolved challenge for neurologists. This study introduces a novel methodologic approach to optimizing prognostication by capitalizing on the time-varying nature of quantitative EEG characteristics to optimize the weighting of each feature and timepoint in the model. This approach outperforms current state-of-the-art models, which use only static features, demonstrating that the statistical association between quantitative EEG features and neurologic outcome changes over time. This study paves the way for development of a risk score that further improves prognostication by incorporating both clinical and EEG features in a time-sensitive manner.

The Pick: Fultz NE, Bonmassar G, Setsompop K, et al. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science 2019;366(6465):628-631.

The Findings: This study investigated EEG, BOLD hemodynamics and CSF oscillations in the fourth ventricle during sleep in a series of 13 participants. They found a large amplitude, pulsatile flow of CSF at 0.05 Hz during non-REM sleep (5.52dB increase, 95%CI 2.33-7.67dB) and observed a strong anticorrelation between this signal and gray matter BOLD oscillations (r= -0.48 at lag 2s, p<0.001). They also found that the CSF pulsations were entrained to fluctuations in amplitude of the slow-delta EEG waves of non-REM sleep (peak amplitude=21%, p<0.001, shuffling).

Why It's Important: The mechanisms by which sleep can be restorative are poorly understood. CSF flow is thought to play a role by facilitating clearance of waste products during sleep. This study demonstrates that CSF flow is entrained by slow waves during non-REM sleep and suggests that the electrophysiological signatures of sleep may drive its physiologically-restorative effects. The study opens the way to further assessment of whether impaired CSF flow dynamics linked to slow-wave sleep lead to neurodegeneration, and whether strategies to preserve slow-wave sleep can rescue brain function.

Read the Neurology Today article, Disease Mechanisms-Slow Waves of CSF During Sleep Clear Toxins Linked to Neurodegenerative Conditions (December 5, 2019).

MICHAEL A. RUBIN, MD, MA, FAAN

Associate Professor of Neurology and Neurotherapeutics

UT Southwestern Medical Center

Dallas, TX

The Pick: Russell JA, Epstein LG, Greer DM, et al. Brain death, the determination of brain death, and member guidance for brain death accommodation requests: AAN position statement. Neurology 2019; Epub 2019 Jan 2.

The Findings: Through this position statement, the AAN endorses the Uniform Determination of Death Act that brain death occurs when, among other factors, the irreversible loss of all functions of the entire brain, including the brainstem, has been demonstrated by complete loss of consciousness (coma), brainstem reflexes, and the independent capacity for ventilatory drive (apnea), in the absence of any factors that imply possible reversibility. The statement helps provide guidance to AAN members who encounter resistance to brain death, its determination, or requests for accommodation, including continued use of organ support technology despite neurologic determination of death.

Why It's Important: The frequency of controversial cases in determination of death by neurologic criteria has accelerated in the last few years. This paper is a first step in not only reiterating established criteria, but also offering Academy members advice in how to navigate the complex landscape that is developing nationally.

Read the Neurology Today story, Policy and Practice-Dead in California, Alive in New Jersey. Neurologists Seek Nationwide Consistency in Policies for Determining Brain Death (January 9, 2020).

The Pick: Vrselija Z, Daniele SG, Silbereis J, et al. Restoration of brain circulation and cellular functions hours post-mortem. Nature 2019; 568:336-343.

The Findings: The study described the restoration and maintenance of microcirculation and molecular and cellular functions of the intact pig brain under ex vivo normothermic conditions up to four hours post-mortem.

Why It's Important: This groundbreaking paper shows that interruption in blood flow and delivery of oxygen to an animal model brain for several hours may not lead to complete loss of cellular function of brain tissue, but likely still leads to loss of tissue and organ function. These data suggest that efforts for brain resuscitation ought to be continued in the acute setting of an injury before a definitive prognosis is determined.

Read the Neurology Today story, At the Bench-What the Post-Mortem Pig Brain Study Really Says About Brain Death (June 6, 2019).

JENNIFER BICKEL, MD, FAAN

Professor of Pediatrics

Children's Mercy Hospital

University of Missouri-Kansas City

Kansas City, MO

The Picks: Seng EK, Singer AB, Metts C, et al. Does mindfulness-based cognitive therapy for migraine reduce migraine-related disability in people with episodic and chronic migraine? A phase 2b pilot randomized clinical trial. Headache 2019; 59(9):1448-1467.

Dodick DW, Lipton RB, Ailani J, et al. Ubrogepant for the treatment of migraine. N Engl J Med 2019;381(23)2230-2241.

Lipton RB, Croop R, Stock EG, et al. Rimegepant, an oral calcitonin gene-related peptide receptor antagonist for migraine. N Engl J Med 2019;381(2):142-149.

Goadsby PJ, Wietecha LA, Dennehy EB, et al. Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine. Brain 2019;142(7):1894-1904.

The Findings: In the Headache trial, 60 patients who had six to 30 headache days per month were randomized to either eight weekly individual mindfulness-based interventionsmindfulness mediation and cognitive-behavioral skillsor eight weeks of waitlist/treatment as usual. The mindfulness-based cognitive therapy effectively reduced headache-related disability and attack-level migraine related disability.

In the New England Journal of Medicine study on rimegepant, 1,672 participants were randomized to placebo and/or 50 mg of ubrogepant and 100 mg of ubrogepant. A higher percentage of participants who received ubrogepant had freedom from pain and absence of the most bothersome symptomnausea, somnolence, and dry mouthat two hours after the dose.

The New England Journal of Medicine study of lasmiditan randomized 1,186 patients to rimegepant or placebo; the percentage of patients who were free from their most bothersome symptom was 37.6 percent for the rimegepant group compared with 25.2 percent in the placebo group (p<0.001).

The Brain study reported that in a prospective, double-blind, phase 3 multicenter study, lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine. A total of 3,005 patients with migraine were randomized to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Lasmiditan was associated with significantly more pain freedom at two hours200 mg (p<0.001); 100 mg (p<0.001); 50 mg (p=0.003) versus placebo.

Why It's Important: 2019 was another great year for advances in headache management. We have seen FDA approval for novel pharmaceutical options, including ubrogepant and lasmiditan, as well as for additional neurostimulator options. In addition, research continues to indicate that non-pharmaceutical treatments such as mindfulness-based cognitive therapy can significantly reduce migraine related disability. As a Headache Section Chief, I have overseen the care of tens of thousands of patients with refractory, disabling headaches. Never before have we headache specialists had so many options to offer our patients. It's truly exciting to see how far the field has come since I entered practice almost 15 years ago.

Read the Neurology Today article, In the Pipeline-Rimegepant Is Effective for Acute Migraine Pain at 2 Hours, Study Finds (August 8, 2019).

The Pick:The National Academy of Medicine Action Collaborative on Clinician Well-Being and Resilience

The Finding: The NAM Collaborative on Clinician Well-Being and Resilience has brought together a network of 60 organizations to raise the visibility of clinician anxiety, burnout, depression, stress and suicide; improve baseline understanding of challenges to clinician well-being; and advance evidence-based, multidisciplinary solutions to improve patient care by caring for the caregiver. Neil A. Busis, MD, FAAN, a member of the Neurology Today editorial board, represents neurology in this ambitious initiative. The collaborative has sponsored initiatives around wellness, including several that have been featured in Neurology Today this year.

Why It's Important: New FDA approvals like those featured above for migraine are not enough to help our patients and our field. We need major changes in our field to return to the core values of humanism and professionalism in medicine. The National Academy of Medicine Action Collaborative on Clinician Well-being is playing a major role in supporting that goal.

Read the Neurology Today article, Wellness: A National Initiative to Build a Hub for Wellness Resources (March 7, 2019).

MELISSA J. NIRENBERG, MD, PHD, FAAN

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