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Best Advances of 2017: Picks from the Neurology Today Editorial Advisory Board

doi: 10.1097/01.NT.0000530359.19433.76
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What makes a development in the field the very best? Sometimes, it can be a small incremental change; other times, practice-changing. In an age of information overload, it can be difficult to distinguish the hype from what is truly the hope. That is why each year Neurology Today turns to its editorial advisory board — all leaders in their respective fields — to offer guidance on the advances, policies, and professional issues that stood out from the rest during the past 12 months. Here, in the “Best Advances of 2017,” our editorial team sheds light on developments that were both incremental and transformational this past year. Read on to learn more about those advances — and why they are important — in such areas as dementia, epilepsy, professionalism, stroke, and multiple sclerosis, to name a few.

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DEMENTIA

Eric McDade, DO, associate professor of neurology, division of cognitive neurology, Washington University School of Medicine, Saint Louis, MO

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The Pick: DeVos SL, Miller RL, Schoch KM, et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med 2017; 9(374): pii: eaag0481.

The Findings: Using antisense oligonucleotides (ASO) targeting human tau expression, researchers demonstrated that they could decrease the production of tau in mice carrying the P301S MAPT mutation, one of the most common mutations in familial frontotemporal dementia. Importantly, reducing tau expression prevented new tau deposits in young mice and reversed tau pathology in aged mice with established neurofibrillary tau deposits. Lastly, the ASO-related effects on tau resulted in decreased neuronal loss and neuroinflammation; it also lengthened survival and improved behaviors compared to the sham-treated mice.

Why It's Important: This work provides reason to be optimistic about targeting tau pathology by decreasing its expression in the CNS. Importantly, the study suggests that even at the point of well-established tau pathology the neurodegenerative processes can be halted, and possibly reversed, something that has not been clearly identified when targeting amyloid-beta-pathology late in the Alzheimer's disease pathological cascade. Studies in tau-based neurodegenerative diseases are now underway using the intrathecal administration of tau-ASO.

The Pick: Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet 2017:379(10113):2673-2734.

The Findings: The Lancet Commission on Dementia Prevention, Intervention and Care, comprising 24 experts, highlighted the clear evidence that dementia represents a chronic disease that is potentially amenable to disease-modifying measures. By considering potentially reversible factors across the lifespan, the Commission determined that up to one-third of future cases of dementia are preventable.

Why It's Important: Any study using a meta-analysis approach will have its limitations. However, the methods employed in this work were impressive, and importantly, led the Commission to make concrete recommendations that can be started now: improving early-child education, increasing physical activity, treating midlife and late-life hypertension, smoking cessation, preventing obesity and diabetes in midlife, and decreasing depression and social isolation. This work highlights the important role neurologists can play as advocates. Although we have no effective disease-modifying therapies for dementia, we can modify the prevalence of the disease.

The Pick: Donadio V, Incensi A, Rizzo G, et al. A new potential biomarker for dementia with Lewy bodies. Neurology 2017;89(4):318-326.

The Findings: The researchers found phosphorylate alpha-synuclein deposits in 100 percent of the cervical skin biopsies of 18 patients with dementia with Lewy bodies (DLB) compared to 23 non-DLB dementia cases and 25 age-matched controls. No deposits were identified in the comparator groups.

Why It's Important: DLB can be a difficult diagnosis to make, particularly early in the disease. By using a very well characterized cohort with autonomic testing and nigrostriatal dopamine transporter ligand PET scans to confirm the diagnosis, this study suggests that a simple skin biopsy could effectively identify DLB patients in a relatively non-invasive and inexpensive way. If replicated in populations more representative of the typical DLB cases seen in neurology clinics, it could be in highly effective diagnostic tool.

Read the Neurology Today article, “A Potential Skin Biopsy Biomarker for Differentiating DLB from Other Dementias” (September 7, 2017): http://bit.ly/NT-DLB-biopsies.

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NEUROMUSCULAR DISEASE

Norman Latov, MD, PhD, professor of neurology and neuroscience, Weill Medical College of Cornell University, New York, NY

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The Pick: Finkel RS, Mercuri BT, Darras AM, et al. Nusinersen vs sham control in infantile-onset spinal muscular atrophy. N Engl J Med 2017;377:1723-1732.

The Findings: In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (p<0.001), prompting early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response, and the likelihood of event-free survival was higher in the nusinersen group than in the control group (p=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (p=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.

Why It's Important: The study reports the first effective treatment for SMA, stresses the importance of early intervention, and offers proof of efficacy of gene therapy to correct a neuromuscular disease.

Read the Neurology Today article, “News from the AAN Annual Meeting: In Phase 3 Results, Infants on Nusinersen Survive Longer, Achieve Motor Milestones” (May 18, 2017): http://bit.ly/NT-nusinersendata

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NEUROCRITICAL CARE

Kevin N. Sheth, MD, FAAN, chief, division of neurocritical care and emergency neurology, Yale New Haven Hospital, New Haven, CT

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The Pick: Hanley DF, Lane K, McBee N, et al. Thrombolytic removal of intraventricular haemorrhage treatment of severe stroke: Results of the randomized, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet Neurol 2017;389(10069):603-611.

The Findings: Between September 18, 2009, and January 13, 2015, 249 patients were randomized to alteplase and 251 to saline. The primary efficacy outcome was similar in each group: a good outcome in 48 percent of the alteplase group versus 45 percent in the saline group (p=0.554). Researchers reported a 3.5 percent difference (p=0.420) after adjustment for intraventricular hemorrhage size and thalamic intracerebral hemorrhage. At 180 days, the treatment group had lower case fatality (p=0.006), but a greater proportion had a modified Rankin Scale (mRS) score of 5 (p=0.007). Irrigation with alteplase and a routine extraventricular drain did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Serious adverse events were less frequent with alteplase treatment (p=0.002). Symptomatic bleeding was similar in the alteplase and saline groups (p=0.771).

Why It's Important: This is the first trial on this devastating condition, the study used a very clever design, and it showed that tissue plasminogen activator was safe in this population.

Read the Neurology Today article, “Alteplase for Intraventricular Hemorrhage Is Found to Save Lives, But Not Improve Function” (April 6, 2017): http://bit.ly/NT-alteplase.

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HEADACHE AND PAIN

Jennifer Bickel, MD, FAAN, associate professor of pediatrics, Children's Mercy Hospital, University of Missouri, Kansas City, MO

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The Picks: Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med 2017;377(22):2113-2122.

Goadsby PJ, Reuter U, Hallström Y, et al A controlled trial of erenumab for episodic migraine. N Engl J Med 2017;377(22):2123-2132.

The Findings: With over 1,100 patients enrolled, the study by Silberstein, et al, demonstrated that fremanezumab, a humanized IgG2A monoclonal antibody that selectively binds to calcitonin-gene related peptide (CGRP), was effective over a 12-week trial in decreasing headache days compared to placebo in chronic migraine patients.

The study by Goadsby, et al, of 955 patients showed that erenumab, a fully human monoclonal antibody that inhibits the CGRP receptor, was effective over six months in decreasing headaches days compared to placebo in episodic migraine patients. The rates of adverse events were similar between erenumab and placebo.

Why It's Important: Erenumab and fremanezumab are likely just the beginning of a new class of injectable drugs for migraine prevention. These antibodies offer the ability to target the migraine pathway in ways that we have never done before. Both trials excluded highly refractory patients, so we do not know now if these antibodies will be helpful for those most disabled from migraines; however, the potential is there. In addition to demonstrating efficacy, these antibodies appear well tolerated without the sedation and mood changes that can limit the use of conventional migraine medications. As with all new pharmaceutical developments, these treatments can only improve lives if they are financially accessible to patients. Over the next year, we will likely see these antibodies come to market and witness firsthand how our practices and patients' lives are affected.

Read the Neurology Today article, “News from the American Headache Society Annual Meeting: Positive Trial Results for Anti-migraine Drugs Targeting CGRP Could ‘Change the Way Neurologists Practice,’ Experts Say” (July 6, 2017): http://bit.ly/NT-CGRP.

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PRACTICE MANAGEMENT/PROFESSIONALISM

Neil A. Busis, MD, FAAN, director of community neurology, University of Pittsburgh Physicians; chief, division of neurology, University of Pittsburgh Medical Center-Shadyside, Pittsburgh, PA

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The Pick: Linzer M, Sinsky CA, Poplau S, et al. Healthy work place investigators. Joy in medical practice: Clinician satisfaction in the healthy work place trial. Health Aff (Millwood) 2017;36(10):1808-1814.

The Findings: Increased clinician satisfaction in the workplace is associated with lower burnout and turnover rates, which other studies have shown are associated with improved patient care.

Why It's Important: A healthy medical workplace leads to improved patient care. As the authors state, “These findings confirm that clinicians' job satisfaction is related to remediable work conditions and suggest that it may be an important metric for clinical practices and practice organizations.”

The Pick: Erickson SM, Rockwern B, Koltov M, McLean RM. Medical Practice and Quality Committee of the American College of Physicians. Putting patients first by reducing administrative tasks in health care: A position paper of the American College of Physicians. Ann Intern Med 2017;166(9):659-661.

The Findings: The authors propose a framework to analyze the many administrative tasks required in health care today. If an administrative task does not improve patient care, it should be revised or eliminated.

The Pick: Noseworthy J, Madara J, Cosgrove D, et al. Physician burnout is a public health crisis: A message to our fellow health care CEOs: Health Affairs Health Care Blog, March 28, 2017. http://bit.ly/healthaffair-blog

The Findings: Eleven chief executive officers of large health care organizations unequivocally state that physician burnout is a public health crisis since it interferes with patient care by detracting from the missions and values of their organizations.

Why It's Important: Many drivers of physician burnout originate at the organization and work-unit levels. The first step to eliminate these drivers is recognizing the problem. This strong statement is one of the most visible and compelling calls to action for health care leaders to recognize, assess, and mitigate physician burnout in their organizations.

Neurology Today has a series of articles on burnout: http://bit.ly/NT-burnoutseries.

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MOVEMENT DISORDERS

Melissa J. Nirenberg, MD, PhD, FAAN, adjunct professor of neurology, NYU School of Medicine; medical director, New York Stem Cell Foundation, New York, NY

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The Pick: Bond AE, Shah BB, Huss DS, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease: A randomized clinical trial. JAMA Neurol 2017:74(12):1412-1418.

The Findings: The authors performed a two-center, double-blinded, sham-controlled, randomized pilot study of unilateral focused ultrasound (FUS) thalamotomy for treatment of medically-refractory tremor in severe, disabling tremor-dominant Parkinson's disease (PD): 20 patients underwent FUS thalamotomy and seven had sham therapy. Three months after the procedure, improvement in the on-medication median hand tremor subscore of the treated hand on the Clinical Rating Scale for Tremor was significantly higher in the FUS thalamotomy group (62%; IQR, 22%-79%) versus the sham therapy group (22%; IQR, -11% to 29%), a statistically significant difference (p=0.04).

Why It's Important: This pilot study shows preliminary evidence that unilateral FUS thalamotomy may be useful for the treatment of refractory hand tremor in PD. It is important to note, however, that FUS thalamotomy is only expected to improve tremor, whereas deep brain stimulation is an established treatment that has a more global benefit on motor function. As in trials of FUS thalamotomy for essential tremor, the procedure was associated with adverse events, some of which may be permanent. The high placebo effect provides further evidence of the importance of sham controls in studies of surgical treatments for PD.

The Pick: Kikuchi T, Morizane A, Doi D, et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model. Nature 2017;548:592-596.

The Findings: In this two-year study, midbrain dopaminergic progenitor cells derived from human induced pluripotent stem cells were grafted into the putamina of primates with MPTP-induced parkinsonism. There was sustained motor benefit, and the transplanted dopaminergic neurons demonstrated long-term survival. Similar results were seen with cells derived from subjects with Parkinson's disease and those from healthy subjects.

Why It's Important: This in vivo, preclinical study shows that human iPS cells can be used to create long-lasting, functional grafts of dopaminergic neurons in an established primate model of PD. The derivation of dopaminergic neurons from human iPS cells circumvents the practical and ethical concerns associated with the use of human embryonic stem cells or fetal transplants. The long-term efficacy of transplantation therapy with cells derived from PD patients suggests that it may be possible to use autologous cell-replacement therapy in clinical applications, thus avoiding the need for immunosuppression.

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MULTIPLE SCLEROSIS

Stephen Krieger, MD, FAAN, associate professor of neurology, The Corinne Goldsmith Dickinson Center for MS, Icahn School of Medicine at Mount Sinai, New York, NY

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The Picks: Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017;376:221-234.

Montalban X, Hauser SL, Kappos L, et al, for the ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017;376:209-220.

The Findings: In two identical phase 3 trials (by Hauser, et al), 821 and 835 patients with relapsing multiple sclerosis were randomized to intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. Among patients with relapsing MS, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks.

In a third phase 3 trial (by Montalban, et al), 732 patients with primary progressive MS were randomized in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary endpoint was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo.

Why It's Important: These phase 3 clinical trials of ocrelizumab established the efficacy of this B-cell depleting agent in both relapsing MS as compared with interferon injections, and in primary progressive MS as compared with placebo. The findings usher this therapeutic strategy into the mainstream of MS therapeutics, leading to the first approved agent for the primary progressive form of the disease. Enormous attention will be paid to both the long-term extensions from these pivotal trials, as well as the real-world safety and efficacy of this agent as it is utilized in both relapsing and progressive patients with MS after US Food and Drug Administration (FDA) approval in March 2017.

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PEDIATRIC NEUROLOGY

Ann Tilton, MD, FAAN, professor of neurology and pediatrics, Louisiana State University Health Sciences Center, chief section of child neurology, New Orleans, LA

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The Pick: Powers SW, Coffey CS, et al, for the CHAMP Investigators. Trial of amitriptyline, topiramate, and placebo for pediatric migraine. N Engl J Med 2017; 376(2):115-124.

The Findings: This randomized, double-blind placebo-controlled study evaluated amitriptyline, topiramate, and placebo in 8- to 17-year-old patients with migraine. The endpoints were a reduction of headache of 50 percent or more in the last four weeks of the 24-week trial compared to baseline (the primary outcome) and secondary outcomes of headache-related disability, headache days, completion of the trial and serious adverse events. The study found no significant difference in the headache frequency or related disability with any of the three arms: 66 percent had a relative reduction of 50 percent or more in the number of headache days with amitriptyline, 71 percent with topiramate, and 68 percent with placebo. Additionally, there were more side effects in the patients that received amitriptyline and topiramate.

Why It's Important: The best medication approach to childhood headache has not been proven. The study evaluated 328 patients in the efficacy analysis. The interim analysis revealed futility when there was no significance between groups in the primary endpoint of 50 percent reduction or greater. Additionally, the other secondary endpoints showed no difference. The medication-treated group had a higher rate of adverse events. Of note, the high placebo rate is well documented in other headache trials and similar in this one. The medications did not separate from the placebo and were considered a null outcome.

THE PICK: Finkel RS, Mercuri BT, Darras AM, et al. Nusinersen vs sham control in infantile-onset spinal muscular atrophy. N Engl J Med 2017;377:1723-1732.

The Findings: See the findings reported under neuromuscular disease.

Why It's Important: This study provided very significant findings supporting the use of nusinersen in infants with SMA. The medication-treated group displayed improved development of milestones as well as event-free survival compared to the untreated group.

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NEUROGENETICS

Brent Fogel, MD, PhD, FAAN, associate professor of neurology and human genetics, David Geffen School of Medicine, University of California, Los Angeles

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The Pick: Mendell JR, Al-Zaidy S, Shell R, Arnold WD, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 2017;377(18):1713-1722.

The Findings: Fifteen patients with spinal muscular atrophy 1 (SMA1) received a single dose of intravenous adeno-associated virus serotype 9 encoding the missing SMN protein, resulting in longer survival, achievement of motor milestones, and improved motor function.

Why It's Important: The study suggests the potential for an effective single-dose IV therapy for SMA, a leading genetic cause of infant death. It also illustrates the potential viability of gene replacement for long-term treatment of neuromuscular disorders.

Read the Neurology Today article, “In the Pipeline-Spinal Muscular Atrophy: Gene Therapy Found Effective for Children with SMA” (December 7, 2017): http://bit.ly/2NT-SMA

The Pick: Eichler F, Duncan C, Musolino PL, et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N Engl J Med 2017;377(17):1630-1638.

The Findings: Seventeen boys with cerebral adrenoleukodystrophy were given an infusion of autologous CD34+ cells transduced with a lentiviral vector encoding the adrenoleukodystrophy (ALD) protein. At approximately two years, 15 of the 17 patients were alive and free of major functional disability, with minimal clinical symptoms.

Why It's Important: The cerebral inflammatory form of X-ALD, one of the most common leukodystrophies, often has a poor prognosis and is difficult to treat. Bone marrow transplantation may be helpful early but not always. This study suggests effective treatment of active demyelinating brain lesions in these children may be obtained by transducing autologous blood cells with the ALD gene.

Read the Neurology Today article, “In the Pipeline-Cerebral Adrenoleukodystrophy: Gene Therapy Halts Progression of Cerebral ALD” (November 16, 2017): http://bit.ly/NT-cerebralALD.

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EPILEPSY

Jacqueline A. French, MD, FAAN, professor of neurology, NYU Comprehensive Epilepsy Center, New York, NY

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The Picks: Harden C, Tomson T, Gloss D, et al. Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsy Curr 2017;17(3):180-187.

Sveinsson O, Andersson T, Carlsson S, Tomson T. The incidence of SUDEP: A nationwide population-based cohort study. Neurology 2017;89(2):170-177.

Devinsky O, Friedman D, Cheng JY, et al. Underestimation of sudden deaths among patients with seizures and epilepsy. Neurology 2017;89(9):886-892.

Read the Neurology Today article, “New Practice Guideline Quantifies SUDEP. Incidence Rates and Risk Factors” (May 4, 2017): http://bit.ly/NT-SUDEP-guideline

The Findings: The AAN/American Epilepsy Society guideline provided evidence of SUDEP frequency, suggesting an association between SUDEP and the occurrence and frequency of tonic-clonic convulsions. In addition, the population-based study by Sveinsson, et al, suggests that SUDEP is under-reported in death certificates, and there is a higher occurrence in children (specifically boys) than previously reported. The paper by Devinsky O, et al, provides evidence that medical examiners will under-report SUDEP.

Why It's Important: SUDEP should be discussed with patients early in the relationship with patients, and patients should be counseled on avoidance of tonic-clonic convulsions.

The Picks: Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58(4):512-521.

Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58(4):522-530.

The Findings: The ILAE has developed a new classification system for epileptic seizures and epilepsy. For example, the term “complex partial seizure” has now become “focal seizure with impaired awareness.” And epilepsy is now divided into four categories: focal, generalized, combined focal and generalized, and unknown. The category of “combined focal and generalized” did not exist before, and now will be used for “mixed” syndromes such as Lennox-Gastaut and Dravet syndromes. The terms “symptomatic generalized” and “cryptogenic” are no longer in use.

Why It's Important: Clinicians will need to understand and start to use the new terminology. The revised classification system includes language and concepts that are much more patient-friendly.

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SPORTS NEUROLOGY

Bert B. Vargas, MD, FAHS, FAAN, associate professor of neurology, division of headache medicine, University of Texas Southwestern, Dallas, TX

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The Pick: McCrory P, Meeuwisse W, Dvorak J. et al. Consensus statement on concussion in sport – the 5th international conference on concussion in sport held in Berlin, October 2016. Br J Sports Med 2017;51(11):838-847.

The Findings: This updated consensus statement included modifications to previous definitions of sport-related concussion (SRC) in an effort to develop more rigorous and science-based definitions to guide future study. It also updates our understanding of SRC, including commentary on the recommended evaluation, rehabilitation, prognosis and prevention of SRC.

Why It's Important: Although this document was not meant to be a comprehensive review of concussion science alongside a critical appraisal of levels of evidence, it does serve as a useful clinical guide for the provider caring for athletes with SRC at various ages and levels of competition. It moves the field toward a more uniform approach to the management of SRC and helps establish the framework for future studies while identifying important gaps in the understanding of SRC.

The Pick: Mez J, Daneshvar DH, Kiernan PT, et al. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA 2017;318(4):360-370.

The Findings: In this study, the authors describe pathological findings consistent with chronic traumatic encephalopathy (CTE) in 177 of 202 football players including 110 of 111 who had played in the National Football League (NFL). The severity of CTE pathology was found to correlate to level of play; most collegiate, semi-professional, and professional players had the most severe findings. Most of the players with severe CTE pathology exhibited premortem signs of behavioral, mood, and cognitive symptoms, as well as signs of dementia. The authors concluded that the high proportion of CTE pathology in this case series of football players suggests a correlation with participation in football.

Why It's Important: This study represented the largest case series to date of former football players with CTE pathology and became widely publicized within the scientific and lay media. Although the authors noted several potential weaknesses within the study, including the significant degree of selection bias in the cohort of individuals who were studied, these data contribute to the national debate about the safety of American football and the risks of developing conditions such as CTE. The study also advances current knowledge of the clinical signs and symptoms associated with CTE pathology and emphasizes the need for further studies to better elucidate the natural history of CTE, its clinical spectrum, and the degree of contribution from participation in American football.

Read the Neurology Today article, “Brain Bank Study of Football Players Finds Pervasive CTE, but True Prevalence Remains Unknown” (September 7, 2017): http://bit.ly/NT-CTE-football.

The Pick: Manning KY, Schranz A, Bartha R, et al. Multiparametric MRI changes persist beyond recovery in concussed adolescent hockey players. Neurology 2017;89:2157-2166.

The Findings: A cohort of concussed youth hockey players with a history of concussion were assessed at 24-48 hours and at three months after injury; they were found to have abnormalities on resting-state fMRI, diffusion tensor imaging, and magnetic resonance spectroscopy compared to age-matched non-concussed controls at all time points. Importantly, the imaging abnormalities persisted beyond symptom resolution and return to play in the cohort with a history of concussion.

Why It's Important: Among a cohort of concussed youth hockey players, this study shows evidence that structural and metabolic abnormalities may persist beyond symptom recovery and return to play. Many clinicians must make return-to-play decisions based entirely on subjective reporting of symptoms and performance on neurologic and neurocognitive exams – frequently without baseline data for comparison. These data suggest that the developing brains of youth athletes may be more susceptible to disruptions in cerebral structure and function after concussion and may require more a prolonged rehabilitation and return to play. The dissociation between these abnormal imaging findings and symptom severity underscore the need to further investigate whether more objective indicators of injury and recovery are more accurate than subjective measures at making safe return-to-play decisions and preventing further injury.

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STROKE

James C. Grotta, MD, FAAN, director of stroke research and the mobile stroke program at the Memorial Hermann Hospital, Houston TX

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The Pick: Nogueira RG, Jadhav AP, Haussen DC et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Eng J Med 2017; Epub 2017 Nov 11.

The Findings: The researchers randomized 206 patients with acute ischemic stroke randomized between six and 24 hours from symptom onset to best medical treatment with or without thrombectomy. Patients had to have a severe neurologic deficit and at the same time meet strict imaging criteria demonstrating a large artery occlusion amenable to thrombectomy and a relatively small amount of infarcted brain tissue. The thrombectomy arm did substantially better. Functional independence was 49 percent with thrombectomy compared with 13 percent without, and there was no increased risk.

Why It's Important: Most stroke patients, including those who awaken with their strokes or have unwitnessed onset, present for treatment beyond six hours — the time window in which thrombectomy was found superior to the newer stent-retriever devices in patients with large artery occlusion in five transformative trials in 2015. CT and MR perfusion imaging has shown that patients can vary in their collateral flow, and that in some of these “late” patients, there may be an opportunity to salvage a good outcome. That hypothesis was proven resoundingly correct in this study, which now opens a highly effective therapeutic option for a substantial group of severe stroke patients who previously had no therapeutic options. The study will stimulate further trials investigating reperfusion therapies in the late time window using imaging based selection.

The Picks: Mas J-L, Derumeaux G, Guillon B, et al. Patent foramen ovale closure or anticoagulation vs antiplatelets after stroke. N Engl J Med 2017;377:1011-1121.

Saver JL, Carroll JD, Thaler DE, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017;377:1022-1032.

Sondergaard L, Kasner SE, Rhodes JF et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 2017;377:1033-1042.

The Findings: Three studies randomized patients with cryptogenic stroke and PFO to medical therapy with or without percutaneous patient foramen ovale (PFO) closure. All three showed similar results; the rates of subsequent strokes in the PFO closure group were low (about 1.0 percent per year), and about half as high as in the non-closure group. There was an increased risk of post-closure atrial fibrillation as well as deep vein thrombosis in the PFO closure patients.

Why It's Important: About 25 percent of strokes are “cryptogenic,” and many such patients are found to harbor a PFO. Though there is a statistical association between PFO and stroke, previous studies were inconclusive about the benefit of PFO closure for secondary stroke prevention. These three studies, which were published simultaneously, convincingly demonstrate that PFO closure should be considered in patients who have no other cause for their stroke, are relatively young (< 60 years old and therefore with at least 10 years at risk), and have either a large PFO or associated atrial septal aneurysm.

Read the Neurology Today article, “In the Clinic-Patent Foramen Ovale Closure and Stroke: PFO Closure Associated with Fewer Recurrent Ischemic Strokes Compared to Medical Therapy” (November 2, 2017): http://bit.ly/NT-PFO.

The Pick: Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischemic stroke (NOR-TEST): A phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol 2017;16:781-788.

The Findings: 1,100 patients presenting within 4.5 hours of acute ischemic stroke were randomized to tissue plasminogen activator (tPA) or tenecteplase (TNK). The median NIH Stroke Scale score was 4, indicating relatively mild strokes. There was no difference between the groups in the rate of good outcome or complications such as bleeding.

Why It's Important: tPA remains the only proven effective and approved medical therapy for stroke patients. TNK has certain theoretical and practical advantages: It has higher fibrin specificity, and it is given as a single bolus not requiring subsequent infusion. In the US, it costs less than tPA. This study did not show superiority of TNK but further study is needed to extend to patients with more moderately severe strokes who might harbor larger clots. Furthermore, if TNK is proven equivalent to tPA, it might be preferable for practical reasons.

The Pick: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Amer Coll Cardiol 2017; Epub 2017 Nov 7.

The Findings: The consensus statement from relevant professional societies is based on a study of 9,000 people (SPRINT trial) showing that reducing systolic blood pressure (BP) from 130 to 120 could reduce the risk of heart attack and stroke. The main resultant guideline change is that the “normal” goal BP is set at 120/80, and the definition of “hypertension” is reduced from the previous threshold of 140/90 to 130/80 based on ≥ 2 readings on ≥ 2 occasions. That means that 46 percent of US adults have hypertension and a 45-year-old adult has a greater than 80 percent chance of developing hypertension over the next 40 years.

Why It's Important: Blood pressure is measured during every office visit, and is the single most important modifiable risk factor for vascular disease, including stroke. Every neurologist should be aware of these guidelines and check the BP of their patients. If the pressure is > 130/80, they should recommend rechecking outside of the doctor's office, and if it is still elevated, lifestyle changes and possible pharmacotherapy should be prescribed as outlined in this guideline statement.

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NEURO-ONCOLOGY

Teri Kreisl, MD, associate professor of neurology, division of neuro-oncology, Columbia University Medical Center, New York, NY

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The Pick: Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA 2017;318(23):2306-2316.

The Findings: This study randomized 695 glioblastoma patients at a 2:1 ratio to tumor-treating fields (TTFields) plus maintenance temozolomide chemotherapy or temozolomide alone. The TTFields consisted of low-intensity alternating electric fields delivered via arrays on the shaved scalp connected to a portable device. The researchers reported that median progression-free survival was statistically significant for the TTFields-temozolomide group (at 6.7 months) compared with four months in the temozolomide-alone group (p<0.001). Median overall survival was 20.9 months in the TTFields-temozolomide group versus 16 months in the temozolomide-alone group (p<0.001).

Why It's Important: The study is meaningful because it demonstrates a significant survival benefit in a lethal disease with a paucity of treatment options.

© 2018 American Academy of Neurology