National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome.

OBJECTIVE: To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). METHODS: A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES, April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298). RESULTS: Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features. CONCLUSIONS: New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.

Meeting Proceedings for SCI 2020: Launching a Decade of Disruption in Spinal Cord Injury Research.

The spinal cord injury (SCI) research community has experienced great advances in discovery research, technology development, and promising clinical interventions in the past decade. To build upon these advances and maximize the benefit to persons with SCI, the National Institutes of Health (NIH) hosted a conference February 12-13, 2019 titled "SCI 2020: Launching a Decade of Disruption in Spinal Cord Injury Research." The purpose of the conference was to bring together a broad range of stakeholders, including researchers, clinicians and healthcare professionals, persons with SCI, industry partners, regulators, and funding agency representatives to break down existing communication silos. Invited speakers were asked to summarize the state of the science, assess areas of technological and community readiness, and build collaborations that could change the trajectory of research and clinical options for people with SCI. In this report, we summarize the state of the science in each of five key domains and identify the gaps in the scientific literature that need to be addressed to move the field forward.

Proceedings of the 15th Antiepileptic Drug and Device Trials Meeting: State of the Science.

On May 22-24, 2019, the 15th Antiepileptic Drug and Device (AEDD) Trials Conference was held, which focused on current issues related to AEDD development from preclinical models to clinical prognostication. The conference featured regulatory agencies, academic laboratories, and healthcare companies involved in emerging epilepsy therapies and research. The program included discussions around funding and support for investigations in epilepsy and neurologic research, clinical trial design and integrated outcome measures for people with epilepsy, and drug development and upcoming disease-modifying therapies. Finally, the conference included updates from the preclinical, clinical, and device pipeline. Summaries of the talks are provided in this paper, with the various pipeline therapeutics in the listed tables to be outlined in a subsequent publication.

Redefined Measure of Early Neurological Improvement Shows Treatment Benefit of Alteplase Over Placebo.

Background and Purpose- The first of the 2 NINDS (National Institute of Neurological Disorders and Stroke) Study trials did not show a significant increase in early neurological improvement, defined as National Institutes of Health Stroke Scale (NIHSS) improvement by ≥4, with alteplase treatment. We hypothesized that early neurological improvement defined as a percentage change in NIHSS (percent change NIHSS) at 24 hours is superior to other definitions in predicting 3-month functional outcomes and using this definition there would be treatment benefit of alteplase over placebo at 24 hours. Methods- We analyzed the NINDS rt-PA Stroke Study (Parts 1 and 2) trial data. Percent change NIHSS was defined as ([admission NIHSS score-24-hour NIHSS score]×100/admission NIHSS score] and delta NIHSS as (admission NIHSS score-24-hour NIHSS score). We compared early neurological improvement using these definitions between alteplase versus placebo patients. We also used receiver operating characteristic curve to determine the predictive association of early neurological improvement with excellent 3-month functional outcomes (Barthel Index score of 95-100 and modified Rankin Scale score of 0-1), good 3-month functional outcome (modified Rankin Scale score of 0-2), and 3-month infarct volume. Results- There was a significantly greater improvement in the 24-hour median percent change NIHSS among patients treated with alteplase compared with the placebo group (28% versus 15%; P=0.045) but not median delta NIHSS (3 versus 2; P=0.471). Receiver operating characteristic curve comparison showed that percent change NIHSS (ROCpercent) was better than delta NIHSS (ROCdelta) and admission NIHSS (ROCadmission) with regards to excellent 3-month Barthel Index (ROCpercent, 0.83; ROCdelta, 0.76; ROCadmission, 0.75), excellent 3-month modified Rankin Scale (ROCpercent, 0.83; ROCdelta, 0.74; ROCadmission, 0.78), and good 3-month modified Rankin Scale (ROCpercent, 0.83; ROCdelta, 0.76; ROCadmission, 0.78). Conclusions- In the NINDS rt-PA trial, alteplase was associated with a significant percent change improvement in NIHSS at 24 hours. Percent change in NIHSS may be a better surrogate marker of thrombolytic activity and 3-month outcomes.

Development of Common Data Elements for Use in Chiari Malformation Type I Clinical Research: An NIH/NINDS Project.

The management of Chiari I malformation (CMI) is controversial because treatment methods vary and treatment decisions rest on incomplete understanding of its complex symptom patterns, etiologies, and natural history. Validity of studies that attempt to compare treatment of CMI has been limited because of variable terminology and methods used to describe study subjects. The goal of this project was to standardize terminology and methods by developing a comprehensive set of Common Data Elements (CDEs), data definitions, case report forms (CRFs), and outcome measure recommendations for use in CMI clinical research, as part of the CDE project at the National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health. A working group, comprising over 30 experts, developed and identified CDEs, template CRFs, data dictionaries, and guidelines to aid investigators starting and conducting CMI clinical research studies. The recommendations were compiled, internally reviewed, and posted online for external public comment. In October 2016, version 1.0 of the CMI CDE recommendations became available on the NINDS CDE website. The recommendations span these domains: Core Demographics/Epidemiology; Presentation/Symptoms; Co-Morbidities/Genetics; Imaging; Treatment; and Outcome. Widespread use of CDEs could facilitate CMI clinical research trial design, data sharing, retrospective analyses, and consistent data sharing between CMI investigators around the world. Updating of CDEs will be necessary to keep them relevant and applicable to evolving research goals for understanding CMI and its treatment.

The CeNGEN Project: The Complete Gene Expression Map of an Entire Nervous System.

Differential gene expression defines individual neuron types and determines how each contributes to circuit physiology and responds to injury and disease. The C. elegans Neuronal Gene Expression Map & Network (CeNGEN) will establish a comprehensive gene expression atlas of an entire nervous system at single-neuron resolution.

The National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP).

For over 40 years, the National Institute of Neurological Disorders and Stroke/National Institutes of Health-funded Anticonvulsant Screening Program has provided a preclinical screening service for participants world-wide that helped identify/characterize new antiseizure compounds, a number of which advanced to the market for the treatment of epilepsy. The newly-renamed Epilepsy Therapy Screening Program (ETSP) has a refocused mission to identify novel agents which will help address the considerable remaining unmet medical needs in epilepsy. These include identifying antiseizure agents for treatment-resistant epilepsy, as well as anti-epileptogenic agents that will prevent the development of epilepsy or disease-modifying agents that will ameliorate or even cure established epilepsy and its comorbidities. This manuscript provides an overview of the ETSP's efforts aimed at identifying the next generation of therapeutic agents to further reduce the suffering from and burden of epilepsy.

The Anticonvulsant Screening Program of the National Institute of Neurological Disorders and Stroke, NIH: History and Contributions to Clinical Care in the Twentieth Century and Beyond.

The anticonvulsant screening program (ASP) of the national institute of neurological disorders and stroke (NINDS), National Institutes of Health has made substantial contributions to the drug armamentarium of the clinical neurologist. This program, originally a part of the overall Drug Development Program of the Epilepsy Branch, has been fortunate to have talented leadership, both at NINDS in Maryland and at the major contract site, the University of Utah-over a remarkable period of more than 40 years. Future discoveries by the ASP (now renamed the Epilepsy Therapy Screening) can be expected to make additional contributions to improving the health of persons with epilepsy.

Bridging the Gap in Neurotherapeutic Discovery and Development: The Role of the National Institute of Neurological Disorders and Stroke in Translational Neuroscience.

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. NINDS supports early- and late-stage therapy development funding programs to accelerate preclinical discovery and the development of new therapeutic interventions for neurological disorders. The NINDS Office of Translational Research facilitates and funds the movement of discoveries from the laboratory to patients. Its grantees include academics, often with partnerships with the private sector, as well as small businesses, which, by Congressional mandate, receive > 3% of the NINDS budget for small business innovation research. This article provides an overview of NINDS-funded therapy development programs offered by the NINDS Office of Translational Research.

Twenty-five years of progress: the view from NIMH and NINDS.

As directors of two NIH institutes supporting neuroscience research, we explore the gap between 25 years of stunning progress in fundamental neuroscience and the persistent needs of those with brain disorders. We conclude that closing this gap will require a more detailed comprehension of brain function, a rethinking of how we approach translational science, a focus on human neurobiology, and a continuing commitment to build a diverse, innovative neuroscience workforce. In contrast to many other areas of medicine, we lack basic knowledge about our organ of interest. The next phase of progress on brain disorders will require a significantly deeper understanding of fundamental neurobiology.

Neuroscience networking: linking discovery to drugs.

Discoveries in the pre-clinical neurosciences have set the stage for bringing new therapies to patients affected by neurological disorders. The National lnstitute of Neurological Disorders and Stroke (NINDS) is dedicated to promoting the development of new therapies through its funding programs that range from basic neuroscience to translational research and finally clinical research to test the most promising new therapies in patients. In an effort to accelerate the translation of new discoveries to clinical practice, NINDS is piloting novel organizational strategies. In translational research, NINDS is taking the lead on the establishment of a 'virtual pharma' structure, through which researchers will partner with the NIH to accelerate the progress of drug development from early hit discovery through phase 1 clinical trials. In clinical research, the new Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) aims to promote the efficient implementation of scientifically sound, biomarker-informed phase 2 clinical trials that can be initiated by academic or industry investigators.

Two-hour improvement of patients in the National Institute of Neurological Disorders and Stroke trials and prediction of final outcome.

BACKGROUND AND PURPOSE: Ongoing clinical trials are using early response to intravenous tissue-type plasminogen activator (tPA) to stratify patients into endovascular therapies. Little is known about the likelihood of early recovery and its correlation with final stroke outcome. METHODS: We analyzed the National Institute of Neurological Disorders and Stroke tPA dataset for patients with early improvement (EI), a change of ≥4, or score 0 on the 2-hour National Institutes of Health Stroke Scale (NIHSS) to predict good 90-day outcome. We adjusted for multiple confounders and divided the patients by baseline NIHSS score 0 to 10, 11 to 20, >20, and stroke type to analyze if EI predicted good outcome across stroke severities and types. We analyzed different EI thresholds to identify the best level of NIHSS change to predict good 90-day outcome using a receiver-operator characteristic curve. RESULTS: In total, 183 of 624 (29.3%) patients had EI, 112 of 312 (35.9%) in the tPA group had EI, and 71 of 312 (22.7%) in the placebo group had EI (P<0.0001). Smokers (P=0.012) and patients treated in <90 minutes (P=0.008) were more likely to have EI; diabetic patients (P=0.023) were less likely to show EI. The baseline NIHSS (mean±SD) of patients with EI was 16.1±6.5 versus 14.3±7.4 (P=0.001). A 90-day modified Rankin Scale score of 0 to 1 was achieved in 68 of 112 (60.7%) tPA-treated patient with EI and 65 of 200 (32.5%) without (placebo groups 30 of 71 [42.3%] versus 53/241 [22.0%]). The adjusted odds ratio for good outcome was 1.71 (95% confidence interval [CI], 1.1-2.6; P=0.011) for tPA treatment and 7.69 (95% CI, 4.63-12.76; P<0.0001) for early improvement. EI predicted good outcome in patients with cardioembolic (13.6; 95% CI, 3.6-51.5) and small vessel (6.98; 95% CI, 2.86-17.03), but not large vessel stroke (1.82; 95% CI, 0.38-8.59). The receiver-operator characteristic curve showed that a threshold of 4 on the NIHSS for prediction of good outcome had a sensitivity of 84% and 36% specificity. CONCLUSIONS: Early improvement was more common in tPA-treated patients and was associated with good 90-day outcome. Whereas 32.5% of nonresponders after tPA had a good 90-day outcome, the use of EI to predict stroke outcome shows value.

Common data elements in epilepsy research: development and implementation of the NINDS epilepsy CDE project.

The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience-related clinical research. CDEs are intended to standardize aspects of data collection; decrease study start-up time; and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS-funded clinical research, and where appropriate, facilitate the development of evidenced-based guidelines and recommendations. Epilepsy-specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antiepileptic Therapies (AETs), (2) Comorbidities, (3) Electrophysiology, (4) Imaging, (5) Neurological Exam, (6) Neuropsychology, (7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy-specific CDE initiative can be viewed as part of the larger international movement toward "harmonization" of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS.

Incorporation of the International Spinal Cord Injury Data Set elements into the National Institute of Neurological Disorders and Stroke Common Data Elements.

OBJECTIVES: To develop consistent variable names and a common database structure for the data elements in the International Spinal Cord Injury (SCI) Data Sets. SETTING: National Institute of Neurological Disorders and Stroke (NINDS) Common Data Elements (CDE) Project and The Executive Committee of the International SCI Standards and Data Sets committees (ECSCI). METHODS: The NINDS CDE team creates a variable name for each defined data element in the various International SCI Data Sets. Members of the ECSCI review these in an iterative process to make the variable names logical and consistent across the data sets. Following this process, the working group for the particular data set reviews the variable names, and further revisions and adjustments may be made. In addition, a database structure for each data set is developed allowing data to be stored in a uniform way in databases to promote sharing data from different studies. RESULTS: The International SCI Data Sets variable names and database specifications will be available through the web sites of the International Spinal Cord Society (http://www.iscos.org.uk), the American Spinal Injury Association (http://www.asia-spinalinjury.org) and the NINDS CDE project web site (http://www.CommonDataElements.ninds.nih.gov). CONCLUSION: This process will continue as additional International SCI Data Sets fulfill the requirements of the development and approval process and are ready for implementation.