Neurological Institute

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2016 Year in Review

16-NEU-1727

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Contents Resources for Physicians

3 Neurological Institute Overview

6 Welcome from the Chairman Stay Connected with Cleveland Clinic’s Critical Care Transport Worldwide Neurological Institute 216.448.7000 or 866.547.1467 clevelandclinic.org/criticalcaretransport 2016 Highlights Consult QD – Neurosciences Online insights and perspectives from Cleveland Outcomes Books 8 First-in-Human Trial of DBS for Clinic experts. Visit today: clevelandclinic.org/outcomes Stroke Recovery Launched with consultqd.clevelandclinic.org/neurosciences NIH BRAIN Support CME Opportunities Facebook for Medical Professionals ccfcme.org 10 Sizing Up Ketamine vs. ECT for Facebook.com/CMEClevelandClinic Treatment-Resistant Depression Executive Education Follow us on Twitter clevelandclinic.org/executiveeducation 12 Pioneering Staged Gamma Knife @CleClinicMD for Large Brain Metastases “Cleveland Clinic Way” Book Series Lessons in excellence from one of the world’s leading 14 Remaking the Management Connect with us on LinkedIn healthcare organizations. of Chronic Low Back Pain clevelandclinic.org/MDlinkedin

On the web at The Cleveland Clinic Way 16 Rapid Autopsy Program Speeds www Research Progress in Multiple clevelandclinic.org/neuroscience Toby Cosgrove, MD Sclerosis President and CEO, Cleveland Clinic

18 Dual-Task mTBI Assessment: Communication the Cleveland Clinic Way Out of the Biomechanics Lab, Edited by Adrienne Boissy, MD, MA, 24/7 Referrals Onto the Battlefield and Tim Gilligan, MD, MS Referring Physician Center and Hotline 20 2016 Look-Back in Brain Health: Innovation the Cleveland Clinic Way 855.REFER.123 (855.733.3712) Two Studies with Potential Thomas J. Graham, MD clevelandclinic.org/Refer123 Long-Term Impact Former Chief Innovation Officer, Cleveland Clinic 22 Advanced MRI Complements Physician Referral App Intracranial EEG for Surgical Download today at the Service Fanatics Treatment of a Youth with Epilepsy App Store or Google Play. James Merlino, MD Physician Directory Former Chief Experience Officer, 24 2016 Clinical and clevelandclinic.org/staff Cleveland Clinic Research Achievements Same-Day Appointments IT’s About Patient Care: Transforming 30 Neurological Institute Staff 216.444.CARE (2273) or Healthcare Information Technology the 800.223.CARE (2273) Cleveland Clinic Way 35 Resources for Physicians C. Martin Harris, MD Track Your Patients’ Care Online Secure online DrConnect account at Visit clevelandclinic.org/ClevelandClinicWay clevelandclinic.org/drconnect for details or to order.

About Cleveland Clinic

Cleveland Clinic is an integrated healthcare delivery system with local, national and international reach. At Cleveland Clinic, more than 3,400 physicians and researchers represent 120 medical specialties and subspecialties. We are a main campus, more than 150 northern Ohio outpatient locations (including 18 full-service family health centers and three health and wellness centers), Cleveland Clinic Florida, Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Cleveland Clinic Canada, Sheikh Khalifa Medical City and Cleveland Clinic Abu Dhabi.

In 2016, Cleveland Clinic was ranked the No. 2 hospital in America in U.S. News & World Report’s “Best Hospitals” ON THE COVER — Illustration of a deep brain stimulation lead implanted in the cerebellar dentate nucleus for treatment survey. The survey ranks Cleveland Clinic among the nation’s top 10 hospitals in 13 specialty areas, and the top of post-stroke motor deficits. See story on page 8. hospital in heart care for the 22nd consecutive year.

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THE NEUROLOGICAL INSTITUTE: A Care Model for Transformative Practice

Cleveland Clinic’s multidisciplinary Neurological Institute includes over 300 medical, surgical and research specialists dedicated to the diagnosis, treatment and rehabilitation of adults and children with brain and nervous system disorders. The institute is structured into four departments — Neurology, Neurological Surgery, Physical Medicine and Rehabilitation, and Psychiatry and Psychology — that oversee education/training and coordinate activities across 14 subspecialty centers:

› Center for Behavioral Health › Concussion Center › Neuromuscular Center › Lou Ruvo Center for › Epilepsy Center › Center for Pediatric Brain Health › Mellen Center for MS Neurosciences › Rose Ella Burkhardt Treatment and Research › Center for Regional Brain Tumor and › Center for Neuroimaging Neurosciences Neuro-Oncology Center › Center for Neurological › Sleep Disorders Center › Cerebrovascular Center Restoration › Center for Spine Health

Patients access care through these subspecialty centers, which bring together medical, surgical and rehabilitative experts in a model organized around patients’ diagnostic and management needs rather than a traditional departmental or discipline-based structure.

NEUROLOGICAL INSTITUTE VITAL STATISTICS (2015)

INTEGRATED 230,874 Annual outpatient visits INSTITUTE 16,434 Annual admissions 1 94,829 Annual inpatient days 14,064 Annual surgical/interventional procedures

85,198 Annual neuroimaging studies ORGANIZATIONAL 240 Staff physicians DEPARTMENTS 4 151 Clinical residents and fellows 30 Research fellows SUBSPECIALTY CENTERS NEUROLOGICAL INSTITUTE RESEARCH FUNDING (2015) 14 FOR CARE $20.5M Total grant and contract research funding

59 Federal grants/contracts

236 Nonfederal grants/contracts

300+ 343 Active clinical research projects PROFESSIONAL STAFF 75 New clinical research projects (initiated 2015)

102 Staff leading clinical research projects

7,859 Patients enrolled in clinical research projects

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230,800 A MULTIREGIONAL PATIENT VISITS U.S. PRESENCE Access has become a critical component of U.S. healthcare value, and Cleveland Clinic recognizes its special importance in complex brain and spine diseases. 16,400 Neurological Institute services are available at more than ADMISSIONS two dozen Cleveland Clinic locations across Northeast Ohio, as well as in Weston, Florida, and Las Vegas, Nevada. This network enables patients to access the institute’s specialists within a couple hours’ flight time 14,000 from almost any site in the continental U.S. PROCEDURES

Across its more than 230,800 annual patient visits and 16,400 annual admissions, the Neurological Institute manages the full spectrum of brain and central nervous system disorders. For patients in need of advanced diagnostics and treatment, Neurological Institute physicians and surgeons are at the forefront of practice innovation in areas including: $20.5M

› Epilepsy surgery and monitoring IN RESEARCH GRANTS › Stereotactic radiosurgery 343 › Deep brain stimulation for movement disorders and RESEARCH PROJECTS emerging applications The Neurological Institute’s clinical caregiving is complemented by a robust research program prioritizing › Brain tumor therapeutics collaboration and innovation. In addition to operating 343 clinical research projects, its clinicians team with › Multiple sclerosis therapeutics scientists in Cleveland Clinic’s Lerner Research Institute and disease monitoring to pursue lab-based and translational investigations.

› Use of telemedicine and mobile Program highlights include one of the largest U.S. clinical devices to enhance patient trial programs for neurocognitive diseases, pathbreaking access and experience translational research in multiple sclerosis and other demyelinating diseases, and pioneering work in the simultaneous use of neural stimulation and fMRI to study, diagnose and manipulate diseased brain networks.

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DATA CAPTURE = TRANSFORMED CARE

The Neurological Institute is committed to data-informed practice. Its pioneering Knowledge Program© platform electronically collects and tracks patient-reported outcomes for real-time integration into clinical workflows. The Knowledge Program is customized for a diversity of conditions, leveraging data from millions of patient visits to guide clinical decisions at the point of care.

The institute has applied this ethic of data-driven care to the creation of EMR-embedded care paths and a growing collection of integrated mobile apps for neurological conditions. The aim is to optimize clinical decision-making while informing quality initiatives and identifying key research questions. The result is improved care for populations and individuals alike. This data strategy has put the Neurological Institute on a path toward use of predictive analytics to improve patient outcomes, reduce costs and enhance healthcare value.

EXTREME ACCESS: LEADING THE WAY IN VIRTUAL CARE

The Neurological Institute’s commitment to patient access increasingly extends beyond geographic boundaries through its expanding collection of virtual healthcare offerings and other pacesetting distance health initiatives. These include:

› A mature and expanding › A growing teleneurology › One of the nation’s very ﬁrst telestroke network program offering two-way- mobile stroke treatment providing remote, two-way- video-enabled virtual visits units for management of video-enabled consultation with a Cleveland Clinic suspected acute stroke at the services out of Cleveland neurologist for hospitalized site of symptom onset. Since Clinic’s main campus for patients at external hospitals its launch in July 2014, the patients with acute stroke at that lack 24/7 neurologist unit has been dispatched over 15 facilities in three states. coverage. Conditions 2,600 times, transported managed by the program more than 660 patients and range from seizure disorders delivered IV tPA to over 90 to cranial neuropathy to stroke patients. nontraumatic spine conditions and many others.

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ANDRE MACHADO, MD, PhD CHAIRMAN, CLEVELAND CLINIC NEUROLOGICAL INSTITUTE

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WELCOME FROM THE CHAIRMAN Dear Colleagues,

If there’s one thing the past year has made clear, Year in Review publication from our Neurological it’s this: Healthcare is changing and will continue Institute is filled with examples: to change. › Our novel two-stage approach to Gamma In Cleveland Clinic’s Neurological Institute, we Knife® therapy discussed on page 12 may strive to navigate this change by relying on our represent innovation, but it’s innovation born mantra of “Excellence, Discovery and Innovation.” of a bold, uncompromising commitment to Yet in these times when change increasingly providing the best possible therapy option to comes in the form of tightening reimbursements, patients with large brain metastases. it can be tempting to shift greater focus to › The multiple sclerosis (MS) rapid autopsy excellence at the expense of discovery and program detailed on page 16 may be primarily innovation. After all, the rise of healthcare about discovery, but the story also notes how consumerism and hospital rating systems our clinicians are leveraging this translational has made high-volume delivery of excellent initiative to develop new MRI sequences to care — in terms of both outcomes and patient better manage today’s MS patients. experience — more critical to success than ever. Who can blame patients or staff for wondering › The population health pilot program featured on whether a day spent advancing discovery or page 14 is more than a trial run of an innovative innovation — perhaps in the lab or writing a model for managing chronic back pain; it’s also grant — might not be better spent seeing a few a patient-empowering initiative to deliver better more patients and perhaps impacting more lives? pain outcomes than patients typically achieve with riskier, costlier procedure-driven care. It’s an interesting argument, but it’s ultimately a false choice. For one, neglecting discovery The latter example is a helpful reminder that and innovation would amount to abandoning the innovation itself can and should extend beyond founding mission of Cleveland Clinic. And it would new therapies and technologies to encompass care shortchange our children and grandchildren by delivery as well. You’ll find additional examples undercutting development of the therapies of throughout these pages, which I hope you’ll find tomorrow. If our predecessors had adopted this useful and of interest. mindset, how many treatments that we take for granted today would have never materialized? Respectfully,

But the strongest argument for not neglecting discovery and innovation is that they are so often linked inextricably to excellence in care. This Andre Machado, MD, PhD

Chairman, Cleveland Clinic Neurological Institute [email protected]

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2016 HIGHLIGHT First-in-Human Trial of DBS for Stroke Recovery Launched with NIH BRAIN Support

Can neuromodulation be used effectively to recover The study builds on more than a decade of neurological function, such as in paralysis? Cleveland Clinic preclinical research. “We know that deep cerebellar stimulation promotes motor That’s among the key research questions being recovery in a preclinical model of cortical stroke,” explored in a Cleveland Clinic first: a new clinical says Kenneth Baker, PhD, of Cleveland Clinic’s trial testing deep brain stimulation (DBS) as Department of Neurosciences. “Our goal is to rehabilitative therapy for stroke survivors. The advance this therapy to promote recovery of motor trial, launched in 2016, was awarded nearly function in humans. This has the potential to be $5 million in funding from the NIH’s Brain Research a significant advancement for the field.” through Advancing Innovative Neurotechnologies (BRAIN) initiative. Trial enrollment is underway. Candidates are patients with severe residual hemiparesis from “When we use DBS for a movement disorder, we’re an ischemic stroke 12 to 24 months previously attempting to suppress a positive symptom, such despite physical therapy. Primary aims include: as tremor or rigidity, that’s overlaid on top of normal function,” explains lead investigator Andre › Establishing safety and proof-of-concept data Machado, MD, PhD. “In contrast, in this trial for dentate nucleus DBS in this population we’re attempting for the first time to use DBS to and defining optimal metrics for further trials help recover a function that’s been lost — i.e., › Characterizing acute and chronic effects motor function on the paretic side of a stroke of dentate nucleus DBS on cerebral survivor’s body.” cortex excitability › Characterizing movement-related local field The study will examine a novel strategy — potential changes in the area of the cerebellar stimulation of the dentatothalamocortical pathway dentate nucleus in patients whose leads are to enhance excitability and plasticity in spared temporarily externalized cerebral cortical regions — with the aim of › Characterizing changes in perilesional promoting recovery of motor function. cortical maps in response to chronic dentate “Our primary hypothesis is that by applying DBS nucleus DBS to the connections between the cerebellum and “We need more and better options to help the many cerebral cortex, we can facilitate the plasticity that patients who remain chronically disabled after a occurs in the cortex around the stroke and thereby stroke,” says Dr. Machado. “The opportunity here promote recovery of function beyond what physical is to explore a new avenue that may improve their therapy alone can do,” Dr. Machado notes. long-term rehabilitative outcomes.”

LEFT — Illustration showing a DBS lead implanted in the cerebellar dentate nucleus for treatment of post-stroke motor deficits. Low-frequency stimulation is predicted to enhance neural activity across the ascending, excitatory dentatothalamic pathways (blue) and, in turn, thalamocortical pathways (red/yellow), thereby increasing cerebral cortical excitability and enhancing functional reorganization across spared perilesional cortex.

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2016 HIGHLIGHT Sizing Up Ketamine vs. ECT for Treatment-Resistant Depression

Use of the anesthetic agent ketamine as an other U.S. sites are being randomized to receive alternative to electroconvulsive therapy (ECT) for one of the following for three weeks: treatment-resistant depression has surged over › Multiple infusions of ketamine (at a the past decade and a half. The problem is, no subanesthetic dose) twice a week large-scale trials of ketamine’s safety and efficacy › ECT three times a week in treatment-resistant depression have been conducted, so its use in this setting hasn’t been Changes in depressive symptoms, memory covered by insurers. And patients and clinicians function and quality of life will be assessed through have no direct evidence of how ketamine and patient self-reports and clinician ratings. Following ECT stack up in terms of efficacy, side effects the acute phase of treatment, responders to each and patient quality of life. therapy will be followed up by their usual providers to measure differences in long-term outcomes. A key partner of the federal government is now intent on changing that, by way of an $11.8 Quality of life and relief from depression without million award to fund a Cleveland Clinic-led study significant side effects are key outcomes of comparing ketamine and ECT for patients with interest. Although ECT is highly effective for treatment-resistant depression. The award comes treatment-resistant depression, many patients from the Patient-Centered Outcomes Research find it unsatisfactory because ECT is often Institute (PCORI), which is authorized by Congress associated with memory deficits, is difficult to fund comparative effectiveness research. The and costly to administer, and tends to carry study was one of just three research projects to win a lingering social stigma. PCORI funding in its July 2016 round of awards. “If ketamine is found to be as effective as ECT, it is “This study will fill the evidence gap around likely to be rapidly adopted by patients, providers ketamine versus ECT for treatment-resistant and payers for the acute reversal of treatment- depression,” says the study’s principal investigator, resistant depression,” says Dr. Anand, who notes Amit Anand, MD, Vice Chair for Research in that ketamine has potentially fewer side effects, Cleveland Clinic’s Center for Behavioral Health. is easier to administer and will likely be less Dr. Anand was a member of the 1990s Yale expensive than ECT. University team that first discovered that ketamine For a more detailed version of this article, see could effectively treat severe depression. consultqd.clevelandclinic.org/ketamine. The PCORI-funded study is a five-year investigation in which 400 patients with severe treatment- resistant depression at Cleveland Clinic and three

LEFT — Amit Anand, MD, principal investigator of the Cleveland Clinic-led multicenter study of ketamine versus electroconvulsive therapy for treatment-resistant depression.

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2016 HIGHLIGHT Pioneering Staged Gamma Knife for Large Brain Metastases: Two Smaller Sequential Doses May Be Better Than One

A novel two-stage approach to Gamma Knife® “This allows us, in most cases, to spare the patient stereotactic radiosurgery is showing improved the risks of open surgery and the toxicity of whole- outcomes for treating large brain metastases, brain radiation therapy that would be standard of and Cleveland Clinic has become the first center care,” Dr. Angelov explains. “It’s a game-changer.” outside Japan to embrace it. By allowing for Encouraging Numbers to Date delivery of an overall higher dose of radiation with minimal toxicity, the strategy represents a potential Among Cleveland Clinic’s first 54 patients — new standard of care for large brain metastases. with a total of 63 brain metastases ≥ 2 cm — treated this way, the local control rate at six The Challenge of Large Tumors months has been 88 percent, up from only 49 Although standard Gamma Knife radiosurgery has percent for similar-sized metastases previously gained favor in recent years as monotherapy for managed with single-stage (standard) Gamma brain metastases, its success has been limited Knife therapy at Cleveland Clinic. Moreover, the in patients with metastases larger than 2 cm. treatment is well tolerated, with only seven instances of adverse radiation effects, which “The question is how to get a large dose to a large were mostly mild and transient. tumor so patients don’t fail therapy,” explains Cleveland Clinic neurosurgeon Lilyana Angelov, MD. Since these initial results, which were submitted for publication in 2016, Dr. Angelov’s team has Two Medium-High Doses a Month Apart used the staged approach for about 150 more In recent years, she and colleagues in Cleveland cases, with continued positive outcomes. Clinic’s Rose Ella Burkhardt Brain Tumor and She expects the approach to ultimately become Neuro-Oncology Center have begun using a novel the standard of care across the country for large approach that could dramatically improve the odds brain metastases: “I see it as a primary modality of a good outcome with large metastases. for treating these patients in a minimally invasive Instead of a single radiation dose limited by manner. I think many patients will be well-served.” the toxicity resulting from treating large tumors, For a more detailed version of this article, see Gamma Knife therapy for large tumors is now consultqd.clevelandclinic.org/stagedgamma. delivered in medium-high doses over two stages about a month apart.

LEFT — MRIs from a patient who underwent staged Gamma Knife therapy. Top images were taken before the first treatment (left) and immediately before the second (staged) treatment (right). Bottom images are from six months (left) and four years (right) after the second treatment, showing significant reduction in the size of the metastases.

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2016 HIGHLIGHT Remaking the Management of Chronic Low Back Pain

Value-based care and the opioid epidemic don’t explains spine neurosurgeon Edward Benzel, MD, usually come up in the same sentence, but they founder of Cleveland Clinic’s Center for Spine have at least one thing in common: Both ranked Health. “We emphasize that surgery is deemed high among 2016’s healthcare headlines. appropriate only after all other relevant and safer treatment strategies have been considered or tried.” Over the past year, Cleveland Clinic’s Neurological Institute has given these issues another point of The program is expected to achieve its primary intersection with a bold new initiative to promote goal of helping patients recover function and value-based care for patients with chronic pain become active again, while also achieving: while also preventing inappropriate opioid use. › Avoidance of opioid prescriptions The initiative, launched in August 2016, is a for chronic pain population health pilot program to treat more than › Greater prudence in prescribing 1,000 patients with chronic low back and leg pain › Greater patient empowerment to self-manage by prioritizing functional outcomes over opioid- or and control pain procedure-based care. If successful, the model can The program is highly interdisciplinary, with be applied to other chronic pain conditions and leadership from the Neurological Institute’s Center perhaps replicated at other institutions. for Spine Health, Department of Physical Medicine Eligible patients are those with low back or leg pain and Rehabilitation, Center for Neurological for more than three months. All undergo combined Restoration and Center for Behavioral Health. physical and behavioral pain rehabilitation as the “The literature supports a collaborative approach first line of care. to these patients,” says Mary Stilphen, PT, DPT, The aim is to promote pain rehabilitation by Senior Director of Rehabilitation and Sports managing the sensory, cognitive and affective Therapy. “Single approaches, used in isolation, domains of pain. The key outcome metric is are often unsuccessful.” restoration of function. “It’s about delivering real “Pain is a multifaceted experience that demands value to patients, with a meaningful transformation interdisciplinary collaboration,” adds Sara Davin, of their lives, rather than hoping for a quick fix,” PsyD, MPH. “Our program differs from others in says Neurological Institute Chair Andre Machado, its interdisciplinary approach to care.” MD, PhD. “This project is made possible by the Neurological Spine medicine physicians and spine surgeons are Institute’s distinctive organizational structure, available throughout patients’ longitudinal care. which breaks down departmental barriers to They manage medications, order tests and provide promote collaboration across subspecialties,” surgical evaluations when appropriate. notes Dr. Machado. “Pulling this off in a traditional “Patients will not be denied surgery, procedures or model would be difficult.” pain medications if the diagnosis calls for such,”

LEFT — A patient undergoes physical therapy as part of Cleveland Clinic’s pilot program for chronic low back pain, which combines physical therapy with behavioral pain rehabilitation as the first line of care.

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2016 HIGHLIGHT Rapid Autopsy Program Speeds Research Progress in Multiple Sclerosis

When Cleveland Clinic’s Bruce Trapp, PhD, created surprises — some MRI changes have been shown one of the first rapid autopsy programs for multiple to not be what we historically thought they were.” sclerosis (MS) back in 1994, he was pioneering Those surprises included the groundbreaking a novel concept — to collect a pre-consented 1998 discovery that transected axons are common patient’s body shortly after death (ideally within in MS lesions and may underlie the disease’s a few hours) for advanced MRI studies followed irreversible neurological impairment, as well as by removal of the brain and spinal cord for the 2002 insight that cells capable of producing pathological analysis. The aim was to study the myelin are present in chronic lesions of MS. effects of MS on the brain in a way impossible with animal models or standard imaging. In parallel with Dr. Trapp’s work, neurologists in Cleveland Clinic’s Mellen Center for Multiple Now, more than two decades later, the program Sclerosis Treatment and Research are using the is the largest of its kind in the world, with over rapid autopsy program in ways that promise more 160 specimens collected, and it’s been central immediate impact for patients: testing new MRI to Cleveland Clinic’s mounting grant funding to sequences and technologies in MS. advance understanding of how MS develops and progresses in the human brain. Three grants were By applying newly developed MRI sequences awarded in 2015-2016 for research that draws to cadavers, Mellen Center researchers get an on the autopsy program: immediate reading on whether the MRI changes observed are suggestive of the underlying brain › $6.97 million from the National Institute of and spinal cord pathology. Once validated in Neurological Disorders and Stroke (NINDS) the postmortem program, the sequences can be to identify new therapeutic targets causing applied as outcome measures in selected clinical axonal and neuronal degeneration trials, with the hope that some can ultimately be › $1.7 million from the NINDS to support brought into clinical practice. work to further reveal factors influencing remyelination “The postmortem program is the perfect place for › $460,000 from the National MS Society incorporating new MRI technologies in MS,” says to investigate differences between primary the rapid autopsy program’s medical director, progressive and secondary progressive MS, Daniel Ontaneda, MD. “We’re directly translating with the goal of aiding therapy development MRI research to pathology, and it accelerates MRI development.” “One of our program’s aims is to correlate MRI changes with pathological changes,” explains For a more detailed version of this article, see Dr. Trapp, now Chairman of Cleveland Clinic’s consultqd.clevelandclinic.org/rapidautopsy. Department of Neurosciences. “We’ve uncovered

LEFT — Pathology images from normal white matter (top) and white matter with an active MS lesion (bottom), with corresponding MRI findings in the insets. Such pathology-MRI correlation is a central objective of Cleveland Clinic’s rapid autopsy program for MS.

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2016 HIGHLIGHT Dual-Task mTBI Assessment: Out of the Biomechanics Lab, Onto the Battlefield

Dual-tasking — simultaneous performance of personnel lack a cohesive system and standard cognitive and motor tasks — is something we all tools. “We hope to come up with simple dual- do hundreds of times daily: Checking the time tasking and vision assessments and standards to while running out the door. Reading while sipping use across their system — to put more science coffee. Chatting while crossing the street. into the art of evaluating and monitoring mTBI,” says Dr. Alberts. So why shouldn’t neurological disorders — including mild traumatic brain injury (mTBI) — be evaluated The basis for his team’s mTBI assessment is in a way that reflects that reality, rather than the Cleveland Clinic-developed C3Logix™ mobile assessing each function individually? app, which is widely used to assess concussion among student athletes. With their new grant, the Currently, dual-task neurological evaluation is team is combining the C3Logix app’s motor and available only at centers with biomechanics labs. cognitive functions into a dual-task assessment and Cleveland Clinic researchers hope to change that by establishing military-specific norms for it. They also bringing dual-task evaluation to the patient — or, in will develop a multicomponent vision assessment. military contexts, the soldier. They’re doing so with help from a three-year, $1.3 million grant from the Phase 1 of the project includes developing dual- U.S. Department of Defense to develop and validate task assessment software and validating it for a dual-task mTBI assessment for the military. civilians. The C3Logix app will be calibrated with the industry’s leading biomechanical assessment Dual-task capability can be a matter of life tool, the CAREN (Computer Assisted Rehabilitation and death for military personnel, who may be Environment) system (photo). “We’ll test gait monitoring data or interpreting radio transmissions and Stroop tasks on CAREN to determine which while performing strenuous activities. The job cognitive challenges have the most valuable effect is even more perilous for personnel with or on biomechanics, such as postural stability,” recovering from mTBI. Dr. Alberts explains. “Then we’ll collect data from “Studies demonstrate that following mTBI, soldiers CAREN and the mobile app simultaneously to often experience declines in postural stability and ensure the app produces accurate data.” oculomotor and visual function,” says Jay Alberts, Phase 2 involves validating dual-task and vision PhD, Director of Cleveland Clinic’s Concussion assessments for military personnel, to set military Center and Vice Chair for Health Technology norms. “We expect initial results in early 2017,” Enablement in the Neurological Institute. These says Dr. Alberts. declines are more pronounced under dual-task conditions, he notes. For a more detailed version of this article, see consultqd.clevelandclinic.org/dualtask. Accurate assessment of a soldier’s mTBI is vital but not always clear-cut. Corps-level medical

LEFT — A subject undergoes testing on the CAREN system being used in the dual-task mTBI research.

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2016 HIGHLIGHT 2016 Look-Back in Brain Health: Two Studies with Potential Long-Term Impact

When a center runs one of the nation’s largest Detecting CTE In Vivo neurocognitive disease clinical trial programs, any Despite the headlines surrounding chronic year may yield notable developments. For Cleveland traumatic encephalopathy (CTE) in athletes, Clinic Lou Ruvo Center for Brain Health, 2016 saw research on the condition has been hampered by at least two such examples, recapped below. the fact that CTE currently can be diagnosed only Bexarotene in BEAT-AD after death.

Ever since reports that the cancer therapy But a multicenter study launched in 2016 aims bexarotene reduced brain amyloid-ß, plaque to change that. The NIH-funded, $16 million load and behavioral deficits in mouse models of DIAGNOSE CTE trial is the largest study to date Alzheimer’s disease (AD), interest in the agent of living former athletes designed to help enable has been keen. That interest led to BEAT-AD, a in vivo detection of CTE. “There’s an urgent need phase 2a trial conducted at the Lou Ruvo Center to develop accurate methods for detecting and for Brain Health among 20 patients with AD diagnosing CTE during life,” notes Dr. Cummings, (confirmed by florbetapir scan) randomized in one of the trial’s four lead investigators. a double-blind fashion to four weeks of placebo DIAGNOSE CTE will seek those methods by or bexarotene 300 mg/day. studying 240 men aged 45 to 74 with differing While the trial was negative for one of its primary exposures to repetitive head impacts (RHI): outcomes — amyloid burden reduction across › 120 former NFL players with and without CTE the overall sample — it found that bexarotene symptoms (high RHI exposure) significantly reduced amyloid burden in the subset › 60 former college football players with of patients who were noncarriers of the ApoE4 allele and without CTE symptoms (medium RHI for AD, another primary prespecified outcome. exposure) Lou Ruvo Center for Brain Health Director Jeffrey › 60 controls with no history of RHI exposure Cummings, MD, ScD, says the study, published in Participants will be monitored for three years Alzheimer’s Research & Therapy (2016;8:4), is via neuroimaging studies (PET, MRI and MR the first time a small-molecule agent has lowered spectroscopy), biofluid analyses, neurological amyloid in a subset of patients in a double-blind, examinations and neuropsychiatric tests. placebo-controlled setting. “This biomarker-based proof-of-concept trial supports a mechanism-based “We hope to be able to detect CTE before brain biological effect of bexarotene on targets relevant damage occurs and discover means of preventing to AD pathogenesis,” notes Dr. Cummings. He it,” says Dr. Cummings. plans a longer phase 2/3 trial of bexarotene in For a more detailed version of this article, see carriers and noncarriers of the ApoE4 allele with consultqd.clevelandclinic.org/lookback. mild to moderate AD.

LEFT — Images showing mean change in amyloid burden from baseline to week 4 among noncarriers of ApoE4 in the BEAT-AD trial’s bexarotene group (top) and placebo group (bottom). The red end of the color spectrum indicates reduced amyloid burden, whereas the blue end indicates increased amyloid burden.

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2016 CASE HIGHLIGHT Advanced MRI Complements Intracranial EEG for Surgical Treatment of a Youth with Epilepsy

Eighteen-year-old “Randy” (not his real name) had After intense multidisciplinary discussion, Epilepsy experienced seizures since age 5 and tried many Center staff designed a combination evaluation antiepileptic medications, without relief. At age with stereotactic depth and subdural electrodes. 12, he underwent extensive testing at an outside Meticulous analysis of this invasive evaluation center, which indicated that the seizure onset zone revealed evidence of high epileptogenicity was overlapping with language function. His family restricted to the dysplastic cortex in the depth of declined resective surgery, concerned that it would the left inferior frontal sulcus. Functional speech result in a speech deficit. cortex was mapped on surface cortex posterior to abnormal sulcus that was not primarily Randy’s seizures increased over time, prompting epileptogenic, delineating a resective surgical him to come to Cleveland Clinic’s Epilepsy Center approach expected to be both effective and safe. in 2016 for consultation and possible epilepsy surgery. He underwent standard presurgical Randy underwent focal resection of the lesion noninvasive evaluation, including repeat MRI, with intraoperative electrocorticography (ECOG) PET, SPECT and MEG. He also participated in guidance under awake conditions. Language an IRB-approved research protocol allowing him function was intact postoperatively, and the active to undergo 7T MRI scanning for comparison with intraoperative ECOG normalized after resection, the standard 3T MRI obtained in clinical practice. showing absence of pathological patterns. Four months after surgery, he had a single cluster of The 7T MRI results were impactful, revealing five seizures on one day, with no further seizures a subtle but clear malformation of cortical after medication adjustment. While long-term development in the depth of the left inferior follow-up will be definitive, Randy’s epilepsy frontal sulcus, with thickened cortex and indistinct appears to have been positively impacted. gray-white junction. The lesion was confirmed by postprocessing of the 7T MRI using a quantitative This case illustrates the benefits of advanced voxel-based morphometry approach — and also neuroimaging with 7T MRI and postprocessing. confirmed with repeat 3T MRI. By rendering lesions more detectable, these techniques can enable precise implantation Results from video-EEG, PET, MEG and ictal of depth and subdural electrodes and then SPECT showed convergent findings, suggesting his development of a strategy for surgery, even seizures arose from the region of the malformation after “nonlesional” findings on standard MRI. in the depth of the left inferior frontal sulcus. Yet the concern about language deficit remained, as For a more detailed version of this case, see the lesion was near the usual location of Broca’s consultqd.clevelandclinic.org/7Tcase. area, which is critical for speech.

LEFT — Images from Randy’s evaluation, including 7T MRIs in the top row and postprocessing studies of the 7T MRIs in the second and third rows (crosshairs show lesion location). Bottom row contains SPECT, PET and MEG images showing convergent lesion findings.

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2016 Clinical and Research Achievements

A sampling of notable developments from across Cleveland Clinic’s Neurological Institute

New Use for Cortico-Cortical Evoked Potentials

Cortico-cortical evoked potentials (CCEPs) offer distinct advantages for invasive monitoring of epilepsy surgery patients. Now Cleveland Clinic’s Epilepsy Center is spearheading an NIH-funded project to expand this tool’s utility by developing a brain atlas of CCEP responses from across hundreds of patients who have undergone epilepsy surgery using stereoelectroencephalography.

The research aims to elucidate the complex interactions of brain regions that can be elicited using CCEP studies. Its goal is to find noninvasive strategies 20 IN 10 to identify the cortico-cortical pathways PLACEMENTS PATIENTS that underlie the pathophysiology of intractable epilepsy — and perhaps of other neurological conditions. That’s the cumulative count through November This project to map brain connectivity 2016 for successful placements of the Cleveland was awarded a five-year R01 grant from Multiport Catheter (CMC), a novel convection- the National Institute of Neurological enhanced delivery device for direct administration Disorders and Stroke. Cleveland Clinic of high volumes of chemotherapy to the brain serves as a principal investigative site in patients with high-grade gliomas. The device along with the University of Southern (shown above) was developed by Cleveland California. Clinic experts, and all CMC placements to date have been done at Cleveland Clinic’s Rose Ella For more, see Burkhardt Brain Tumor and Neuro-Oncology consultqd.clevelandclinic.org/ccep. Center. Multicenter efficacy trials of the promising CMC device are being planned.

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Milestones in Data-Informed MS Care

Data-informed care for patients with MS. That’s the raison d’être for two recent initiatives by Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research that grew by leaps and bounds in 2016.

Adolescent Suicide: As of early November, more than 1,600 Search Is On for Objective unique patients had undergone over 2,100 Risk Marker assessments with the Multiple Sclerosis Performance Test (MSPT) suite of iPad® app Objective measures for suicide risk are scarce, modules developed at Cleveland Clinic. By but a Cleveland Clinic team hopes to change enabling patients to efficiently self-report that with a study launched in 2016. Supported MS signs and symptoms as a routine part of by a $400,000 National Institute of Mental each office visit, the MSPT allows providers Health grant, the study is exploring whether to focus on interpreting and acting on data blood levels of the astrocytic protein S100B rather than collecting and entering it.

(molecular model above) and five other The MSPT is now being rolled out to other peripheral inflammatory markers can predict MS centers around the U.S. as part of the suicidal ideation in adolescents following pioneering MS PATHS collaborative led by hospital discharge after a prior suicide attempt. Biogen and Cleveland Clinic. MS PATHS The study, the first longitudinal investigation is a multicenter initiative to use clinical of its kind, will enroll 120 patients and 40 and imaging data from routine office visits controls. Patients are adolescents admitted to to develop better outcome measures and Cleveland Clinic’s psychiatric unit after a suicide improve care for patients with MS. To date, attempt. All will have blood samples taken at over 1,300 patients have authorized use admission, at discharge and at any time they of their clinical data for the initiative at may make another suicide attempt in the year Cleveland Clinic alone.

following discharge. Serum biomarker levels will For more on MS PATHS, see be matched with suicide screening test results consultqd.clevelandclinic.org/mspaths. to assess for correlations.

“About 30 percent of adolescents who attempt suicide will have a relapse of suicidal ideation,” MSPT says lead investigator Tatiana Falcone, MD, of >2,100 ASSESSMENTS the Center for Behavioral Health. “So we want to see if their levels of these inflammatory markers correspond with whether and when CLEVELAND >1,300 CLINIC they may have suicidal thoughts again.” An MS PATHS ultimate goal is a blood test to help predict PARTICIPANTS which patients are at greatest risk of relapse so interventions can be better targeted.

For more, see consultqd.clevelandclinic.org/S100B.

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A Growing Inpatient Rehab Footprint

The past year has seen Cleveland Clinic’s Department of Physical Medicine and Rehabilitation expand its joint venture with rehabilitation services provider Select Medical. First there was the December 2015 opening of a new 60-bed rehabilitation hospital 20 miles west of Cleveland that is operated under the joint venture. Then construction began in 2016 on two similar hospitals at sites east and south of Cleveland, with completion expected by the end of 2017. The result will be a system of state-of-the-art inpatient rehabilitation hospitals across Northeast Ohio operated under the venture.

Pursuing the Promise of Going Mobile for Coordinated Reset DBS Acute Stroke

Researchers in Cleveland Clinic’s Center for Since its launch in July 2014, Cleveland Neurological Restoration and Department of Clinic’s mobile stroke treatment unit (MSTU) Neurosciences are investigating a novel deep has remade the management of acute stroke brain stimulation (DBS) paradigm that holds for thousands of patients in Northeast Ohio, promise for mitigating the risk of stimulation- with over 2,680 dispatches to date through induced side effects. The therapeutic potential October 2016. Here’s a sampling of stats from of the paradigm — known as coordinated reset 2016 alone (annualized based on YTD data DBS — is supported by various theoretical through September): models and now by experimental data from a preclinical parkinsonian model. 1,264 MSTU dispatches

Researcher Kenneth Baker, PhD, published 299 Patient transports data from that model in Brain Stimulation (2016;9:609-617) showing that benefits from 32 IV tPA administrations coordinated reset DBS accumulated over five

days of intermittent therapy and persisted for 8 Endovascular therapy more than a week after therapy cessation, interventions in contrast to limited carryover effects with 52 Minutes, on average, traditional DBS. “Our ongoing work aims to from 911 call to IV tPA realize the translational potential of coordinated administration reset DBS while also elucidating the link between changes in motor circuit neural activity 10 Municipalities now served, and motor sign manifestation in Parkinson’s with > 575,000 population disease,” says Dr. Baker. in total For more, see consultqd.clevelandclinic.org/dbsreset.

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Defining the Demographics of Sports-Related Concussion

Portable yet systematic characterization of sports-related concussion. That’s the impetus behind the five-year-old Cleveland Clinic-developed C3Logix™ mobile app. Now Cleveland Clinic Concussion Center researchers have leveraged the app to characterize triage for suspected concussion in one of the largest observational samples of young athletes reported to date. Spearheading the First Their study, presented at the International Consensus Conference on Concussion in Sport, Dementia with Lewy Bodies held in Berlin in October 2016, reviewed Consortium electronic incident reports completed with the app for suspected concussion among athletes Research into dementia with Lewy bodies (DLB) in the care of Concussion Center clinicians has been hampered by a shortage of biomarkers over a recent 19-month period. The sample and a lack of research consortia to leverage included youth (n = 110), high school resources and patient volumes across multiple (n = 1,175) and college (n = 309) athletes. centers. But now DLB, the second most common Among key findings: dementia in the elderly, is getting its due with

formation of the Dementia with Lewy Bodies › Injuries were most frequent in football Consortium, funded by a $6 million, five-year for males and soccer for females. NIH grant awarded in 2016. › Youth athletes were sent to emergency departments following injury at a fourfold Cleveland Clinic has been designated the higher rate (22 percent) compared with coordinating site for the consortium, which consists high school and college athletes (5 percent) of nine U.S. centers with expertise in Lewy body despite having significantly fewer red-flag disorders. “This consortium brings together a findings. group of investigators who have collaborated › The incidence of injury as a function of extensively on DLB for many years,” says the sport and setting (practice vs. competition) project’s principal investigator, James Leverenz, remained constant across the various age MD, Director of Cleveland Clinic Lou Ruvo Center cohorts of athletes. for Brain Health, Cleveland.

The project aims to emulate consortia for Alzheimer’s and Parkinson’s diseases by creating a foundation for biomarker development through 4-fold enrollment of large numbers of subjects, systematic Increase in the rate of ED referrals assessment of patients, collection of biofluid following suspected concussion among samples and imaging data, and ultimately youth athletes compared with high collection of autopsy specimens. Creation of a school and college athletes sample of patients for translational and therapeutic studies is an expected ancillary benefit.

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Viral Immunotherapy Shows Promise in High-Grade Glioma

For the first time, clinical data have shown that treatment with the retroviral replicating vector Toca 511, when used in combination with an antifungal agent, kills high-grade glioma cells and appears to activate the immune system against them while sparing healthy cells. So demonstrated a phase 1 multicenter study of the therapy co-directed by Cleveland Clinic and published in June 2016 in Science Translational Medicine. Taking on Confusion Around The study assessed the combination of Toca Spine Fusion 511 plus Toca FC (flucytosine) among 45 patients with recurrent or progressive high- Should we add spinal fusion for patients grade glioma. Median overall survival was 13.6 undergoing laminectomy for lumbar spinal months and was statistically improved relative stenosis? That was the question tackled by a to an external control group. Tolerability was pair of studies published in the New England excellent. “These encouraging survival and Journal of Medicine in April — the first major safety results support the ongoing randomized randomized, prospective trials on this question. phase 2/3 trial of this immunotherapy and The studies were from the U.S. and Sweden, offer hope for a new treatment option in brain and Cleveland Clinic was one of the lead cancer,” says senior author Michael Vogelbaum, centers in the U.S. study, known as the SLIP MD, PhD, of Cleveland Clinic’s Rose Ella trial, which involved patients with stenosis Burkhardt Brain Tumor and Neuro-Oncology and spondylolisthesis. This study found that Center. Cleveland Clinic is participating in the adding lumbar spinal fusion to laminectomy phase 2/3 trial, known as Toca 5. was associated with slightly greater but clinically meaningful improvement in overall health-related quality of life compared with laminectomy alone. In contrast, the Swedish study found no difference in outcomes.

“This is a very common operation in the U.S.,” says SLIP trial co-author Edward Benzel, MD, a neurosurgeon in Cleveland Clinic’s Center for Spine Health. “The message to glean from our study is that fusion is appropriate in selected cases. The decision depends on symptoms and the imaging findings. This is not yet the final word.”

For more, see consultqd.clevelandclinic.org/fusion.

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Getting to the Core of PD Progression

In February 2016, the Michael J. Fox Foundation selected Cleveland Clinic Lou Ruvo Center for Brain Health to serve as the pathology core for the Parkinson’s Progression Marker Initiative (PPMI). PPMI is a large multinational clinical research study that aims to identify and develop disease biomarkers (blood or spinal fluid tests) in people with Parkinson’s disease (PD) and those at risk for developing it.

The pathology core is creating a brain and tissue bank to collect and store postmortem brain tissue donated by PPMI participants. The goal is to help researchers correlate the brain On the Trail of changes that take place in PD with the motor, cognitive and behavioral changes observed Autism’s First Objective throughout participation in the PPMI study Diagnostic Tool and with the blood and spinal fluid biomarkers The first objective tool for use in diagnosing developed during the study. autism may be at hand, thanks to work reported by Cleveland Clinic autism specialists and pediatric neurologists in the Journal of the American Academy of Child and Adolescent Psychiatry (2016;55:301-309). The team >400 developed an autism risk index (ARI) based on a composite of measurements of remote eye That’s the number of former pro football gaze tracking in response to established social players who’ve been assessed by Cleveland and nonsocial visual stimuli (example shown Clinic to date as part of its participation in above). Initial and replication testing of the ARI The Trust collaboration with the NFL Players found it to be highly accurate in distinguishing Association — more than for any other children with autism spectrum disorder (ASD) participating center. Under The Trust, former from those with non-ASD developmental players undergo a comprehensive brain- disorders, as detailed in the above paper. body health evaluation to characterize their Although further replication of the findings neurocognitive health status and identify in larger samples is warranted, the ARI holds opportunities for early intervention, if indicated. promise as an objective tool to supplement In 2016, Cleveland Clinic also integrated clinical observation for ASD symptom screening for sleep disorders into its assessment — and potentially to help evaluations for The Trust. Former players who measure treatment response. screen positive undergo sleep studies and are For more, see offered specialized treatment as needed. consultqd.clevelandclinic.org/ari.

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Cleveland Clinic Neurological Institute Staff

LEADERSHIP CENTERS AND Emad Estemalik, MD Kathryn Muzina, MD DEPARTMENTS Tatiana Falcone, MD Richard Naugle, PhD Andre Machado, MD, PhD Chairman, Neurological Center for Lara Feldman, DO Michael Parsons, PhD Institute Behavioral Health Darlene Floden, PhD Jeff Plas, MD Donald A. Malone Jr., MD William Bingaman, MD Kathleen Franco, MD Leopoldo Pozuelo, MD Institute Vice Chairman, Director; also President, Clinical Operations Lutheran Hospital Harold Goforth, MD Ted Raddell, PhD

Veena Ahuja, MD Lilian Gonsalves, MD Laurel Ralston, DO Jay Alberts, PhD Institute Vice Chairman, Susan Albers-Bowling, PsyD Justin Havemann, MD Stephen Rao, PhD, Health Technology Murat Altinay, MD ABPP/CN Enablement Leslie Heinberg, PhD Julie Merrell Rish, PhD Amit Anand, MD Raul Hizon, MD Stephen Samples, MD Aaron Ritter, MD Institute Vice Chairman, Kathleen Ashton, PhD Kelly Huffman, PhD Regional Neurosciences Joseph Rock, PsyD Joseph M. Austerman, DO Karen Hurley, PhD Michael Rosas, MD Robert Fox, MD Florian Bahr, MD Karen Jacobs, DO Institute Vice Chairman, Matthew Sacco, PhD Research Sarah Banks, PhD, Vrashali Jain, MD ABPP/CN Judith Scheman, PhD Joseph W. Janesz, PhD, Imad Najm, MD Joseph Baskin, MD Institute Vice Chairman, LICDC Isabel Schuermeyer, MD Strategy and Development Scott Bea, PsyD Amir Jassani, PhD Cynthia Seng, MD

Michael Steinmetz, MD Aaron Bonner-Jackson, PhD Jason Jerry, MD Jean Simmons, PhD Chairman, Department of Adam Borland, PsyD Xavier Jimenez, MD Barry Simon, DO Neurological Surgery Minnie Bowers-Smith, MD Daniel Jones, PhD Christopher Sola, DO Kerry Levin, MD Chairman, Department Dana Brendza, PsyD Regina Josell, PsyD Catherine Stenroos, PhD of Neurology Karen Broer, PhD Elias Khawam, MD Mirica Stevens, DO

Frederick Frost, MD Robyn Busch, PhD Naveed Khokhar, MD David Streem, MD Chairman, Department Jessica Caldwell, PhD of Physical Medicine Patricia Klaas, PhD Amy Sullivan, PsyD and Rehabilitation Kathy Coffman, MD Steven Krause, PhD, MBA Giries Sweis, PsyD

Donald A. Malone Jr., MD Horia Craciun, MD Cynthia S. Kubu, PhD, George E. Tesar, MD Chairman, Department of ABPP/CN Roman Dale, MD Becky Bikat Tilahun, PhD Psychiatry and Psychology Jess Levy, MD Syma Dar, MD Mackenzie Varkula, DO Thomas Masaryk, MD Richard Lightbody, MD Chairman, Department Kelly Davidson, MD Mohsen Vazirian, MD of Diagnostic Radiology Diana Lorenzo, MD Sara Davin, PsyD, MPH Adele Viguera, MD, MPH Shila Mathew, MD Bruce Trapp, PhD Ketan Deoras, MD John Vitkus, PhD Chairman, Department Beth Dixon, PsyD Douglas McLaughlin, DO of Neurosciences Kelly Wadeson, PhD Elizabeth Menefee, MD Judy Dodds, PhD Cynthia White, PsyD Steven Shook, MD Justin Miller, PhD, Institute Quality Ralph Downey, PhD Molly Wimbiscus, MD ABPP/CN Improvement Officer Michelle Drerup, PsyD Amy Windover, PhD Gene Morris, PhD Adrienne Boissy, MD Jung El-Mallawany, MD Dylan Wint, MD Institute Patient Douglas Moul, MD, MPH Experience Officer Donna Munic-Miller, PhD

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Lou Ruvo Center for Erin Murphy, MD Concussion Center Stephen Hantus, MD Brain Health Michael Parsons, PhD Jay Alberts, PhD Lara Jehi, MD Jeffrey Cummings, MD, ScD Director Director David Peereboom, MD Stephen E. Jones, MD, PhD Richard Figler, MD Pablo Recinos, MD Patricia Klaas, PhD James Leverenz, MD Co-Medical Director Director, Cleveland Violette Recinos, MD Andrew Russman, DO Prakash Kotagal, MD Co-Medical Director Sarah Banks, PhD, Jeremy Rich, MD Chetan Malpe, MD ABPP/CN Steven Rosenfeld, MD, PhD Adam Bartsch, PhD John Mosher, PhD

Charles Bernick, MD, MPH Isabel Schuermeyer, MD Edward C. Benzel, MD Ahsan Moosa Naduvil Valappil, MD Brent Bluett, DO Glen Stevens, DO, PhD Neil Cherian, MD Dileep Nair, MD Aaron Bonner-Jackson, PhD John Suh, MD Carly Day, MD Richard Naugle, PhD Jessica Caldwell, PhD Tanya Tekautz, MD Jason Genin, DO Silvia Neme-Mercante, MD Dietmar Cordes, PhD Michael Vogelbaum, MD, Kim Gladden, MD Nestor Galvez-Jimenez, MD PhD Laura Goldberg, MD Elia Pestana Knight, MD

Carrie Hersh, DO, MS Jennifer Yu, MD, PhD Benjamin Katholi, MD Vineet Punia, MD, MS

Anne Rex, DO Adriana Rodriguez, MD Le Hua, MD Cerebrovascular Center Paul Ruggieri, MD Gabriel Léger, MD, CM, M. Shazam Hussain, MD Kelly Richter, MD FRCPC Interim Director Ellen Rome, MD Andrey Stojic, MD, PhD Ramon Lugo-Sanchez, MD Samer Abubakr, MD Alan Rosenthal, MD George E. Tesar, MD Justin Miller, PhD, Mark Bain, MD A. David Rothner, MD Becky Bikat Tilahun, PhD ABPP/CN Dhimant Dani, MD Richard So, MD Guiyun Wu, MD Donna Munic-Miller, PhD Mohamed Elgabaly, MD Tom Waters, MD Elaine Wyllie, MD Jagan Pillai, MD, PhD Neil Friedman, MBChB Zhong Ying, MD, PhD Alexander Rae-Grant, MD Epilepsy Center Pravin George, DO Stephen Rao, PhD, Imad Najm, MD General Adult Neurology Joao Gomes, MD ABPP/CN Director Stephen Samples, MD Director, Schey Center for Stephen Hantus, MD Badih Adada, MD Institute Vice Chairman, Cognitive Neuroimaging Regional Neurosciences Irene Katzan, MD, MS Andreas Alexopoulos, MD, Aaron Ritter, MD Thomas E. Gretter, MD Zeshaun Khawaja, MD MPH Kasia Rothenberg, MD, PhD Kuruvilla John, MD Ajit Krishnaney, MD Jocelyn Bautista, MD Rawan Tarawneh, MD Richard Lederman, MD, Varun Kshettry, MD William Bingaman, MD Babak Tousi, MD PhD John Lee, MD Juan Bulacio, MD Po Heng Tsai, MD Robert Wilson, DO Mei Lu, MD, PhD Richard Burgess, MD, PhD Dylan Wint, MD Mellen Center for Gwendolyn Lynch, MD Robyn Busch, PhD Multiple Sclerosis Rose Ella Burkhardt Thomas Masaryk, MD Patrick Chauvel, MD Treatment and Research Brain Tumor and Peter Rasmussen, MD Tatiana Falcone, MD Jeffrey Cohen, MD Neuro-Oncology Center Director Nancy Foldvary-Schaefer, Gene Barnett, MD, MBA Andrew Russman, DO DO, MS Robert Bermel, MD Director Susan Samuel, MD Paul Ford, PhD Francois Bethoux, MD Manmeet Ahluwalia, MD Jayashree Sundararajan, MD Camilo Garcia, MD Adrienne Boissy, MD Lilyana Angelov, MD Ather Taqui, MD Jorge Gonzalez-Martinez, Devon Conway, MD Samuel Chao, MD Gabor Toth, MD MD, PhD Varun Kshettry, MD Ken Uchino, MD Ajay Gupta, MD Alireza Mohammadi, MD Dolora Wisco, MD

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Robert Fox, MD Alison Smith, MD Neuromuscular Center Prakash Kotagal, MD

Carrie Hersh, DO, MS Todd Stultz, DDS, MD Kerry Levin, MD Ahsan Moosa Naduvil Director Valappil, MD Le Hua, MD Andrew Tievsky, MD Neil Friedman, MBChB Elia Pestana Knight, MD Keith McKee, MD Jawad Tsay, MD Rebecca Kuenzler, MD Elaine Wyllie, MD Deborah Miller, PhD Center for Neurological Yuebing Li, MD, PhD Karen Nater Pineiro, MD Restoration Neuro-Oncology/Brain Mei Lu, MD, PhD Tumor Daniel Ontaneda, MD Hubert Fernandez, MD Director Manikum Moodley, MBChB, Erin Murphy, MD Sarah Planchon Pope, PhD FCP, FRCP Anwar Ahmed, MD Tanya Tekautz, MD Alexander Rae-Grant, MD John Morren, MD Jay Alberts, PhD Mary Rensel, MD Neuro-Ophthalmology Erik Pioro, MD, PhD Kristin Appleby, MD Matthew Sacco, PhD Gregory Kosmorsky, DO David Polston, MD Eric Baron, DO Lael Stone, MD Lisa Lystad, MD Watcharasarn Brent Bluett, DO Amy Sullivan, PsyD Rattananan, MD Neuropsychology Neil Cherian, MD Mary Alissa Willis, MD Steven Shook, MD Patricia Klaas, PhD Sarah Davin, PsyD Payam Soltanzadeh, MD Neuroradiology Center for Neuroimaging Emad Estemalik, MD Jinny Tavee, MD Paul Ruggieri, MD Paul Ruggieri, MD Darlene Floden, PhD, Director Nimish Thakore, MD Director, Center for ABPP/CN Neuroimaging Aliye Bricker, MD Julia Zhu, MD Paul Ford, PhD Stephen E. Jones, MD, PhD Marina Doliner, MD Harold Goforth, MD Pediatric Neurosciences Brooke Lampl, DO Todd M. Emch, MD Neurology Michal Gostkowski, DO Ihsan Mamoun, MD Ramin Hamidi, DO Neil Friedman, MBChB Kelly Huffman, PhD Director Doksu Moon, MD Virginia Hill, MD Ilia Itin, MD Mohammed Aldosari, MD Ellen Park, MD Stephen E. Jones, MD, PhD Steven Krause, PhD, MBA Gary Hsich, MD Esben Vogelius, MD Brooke Lampl, DO Jennifer Kriegler, MD Sudeshna Mitra, MD Mykol Larvie, MD, PhD Cerebrovascular and Cynthia S. Kubu, PhD, Manikum Moodley, MBChB, Endovascular Neurosurgery Daniel Lockwood, MD ABPP/CN FCP, FRCP Mark Bain, MD Mark Lowe, PhD Richard Lederman, MD, Sumit Parikh, MD Peter Rasmussen, MD PhD Ihsan Mamoun, MD A. David Rothner, MD Darlene A. Lobel, MD Michael Martinez, MD Child and Adolescent Indu Sivaraman, MD Psychiatry Andre Machado, MD, PhD Thomas Masaryk, MD Joseph Austerman, DO Jahangir Maleki, MD, PhD Neurosurgery Parvez Masood, MD Section Head Donald A. Malone Jr., MD Violette Recinos, MD Manoj Massand, MD Section Head Veena Ahuja, MD MaryAnn Mays, MD Michael T. Modic, MD William Bingaman, MD Kelly Davidson, MD Chief Clinical Sean Nagel, MD Tatiana Falcone, MD Transformation Officer Jorge Gonzalez-Martinez, Ela B. Plow, PhD, PT MD, PhD Jess Levy, MD Doksu Moon, MD Sarah Rispinto, MD Kaine Onwuzulike, MD, PhD Elizabeth Menefee, MD Melissa Myers, MD Joseph Rudolph, MD Barry Simon, DO Ellen Park, MD Epilepsy Taylor Rush, PhD Mackenzie Varkula, MD Michael Phillips, MD Ajay Gupta, MD Section Head, Mark Stillman, MD Section Head Molly Wimbiscus, MD Imaging Sciences Giries W. Sweis, PsyD

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Developmental-Behavioral Department of Physical A. Romeo Craciun, MD Megan Lavery, PsyD Pediatrics & Physical Medicine and Megan Donnelly, DO Kar-Ming Lo, MD Medicine and Rehabilitation Rehabilitation

Douglas Henry, MD Frederick Frost, MD Naila Goenka, MD Reena Mehra, MD, MS Director Chairman; also Joshua Gordon, MD Douglas Moul, MD, MPH Executive Director, Carol Delahunty, MD Cleveland Clinic Kuruvilla John, MD Silvia Neme-Mercante, MD Benjamin Katholi, MD Rehabilitation and Robert Kosmides, MD Carlos Rodriguez, MD Sports Therapy Pediatric Behavioral Health Don K. Moore, MD Frederick Royce Jr., MD Richard Aguilera, MD Michael Manos, PhD Shnehal Patel, MD Raymond Salomone, MD Jay Alberts, PhD Director Sheila Rubin, MD Vaishal Shah, MD, MPH Sree Battu, MD Gerard Banez, PhD Joseph Rudolph, MD Laurence Smolley, MD Juliet Hou, MD Ethan Benore, PhD, BCB, Norman Sese, MD Jessica Vensel Rundo, MD, ABPP Lynn Jedlicka, MD MS Payam Soltanzadeh, MD Cara Cuddy, PhD John Lee, MD Harneet Walia, MD Yonatan Spotler, MD Wendy Cunningham, PsyD Zong-Ming Li, PhD Tina Waters, MD Andrey Stojic, MD, PhD Kristen Eastman, PsyD Ching-Yi Lin, PhD Jayashree Sundararajan, Center for Spine Health Kate Eshleman, PsyD Vernon Lin, MD, PhD MD Director, Rehabilitation Thomas Mroz, MD Thomas Frazier, PhD Research Ather Taqui, MD Director Catherine Gaw, PsyD Jane Manno, PsyD Nimish Thakore, MD Michael Steinmetz, MD Vanessa Jensen, PsyD Chairman, Department of Carey Miklavcic, DO Pedro Torrico, MD Neurological Surgery Eileen Kennedy, PhD Erin Murdock, MD Jennifer Ui, MD Jeremy Amps, MD Kathleen Laing, PhD Evan Peck, MD Roya Vakili, MD Lilyana Angelov, MD Katherine Lamparyk, PsyD Ela B. Plow, PhD, PT Simona Velicu, MD Edward C. Benzel, MD Amy Lee, PhD Anantha Reddy, MD Robert Wilson, DO William Bingaman, MD Leslie Markowitz, PsyD Michael Schaefer, MD Joseph Zayat, MD John Butler, MD Beth Anne Martin, PhD Patrick Schmitt, DO Julia Zhu, MD Marzena Buzanowska, MD Alison Moses, PhD Dan Shamir, MD Russell DeMicco, DO Pamela Senders, PhD Sleep Disorders Center Patrick Shaughnessy, MD Nancy Foldvary-Schaefer, Frederick Frost, MD Leslie Speer, PhD Yana Shumyatcher, MD DO, MS Kush Goyal, MD Shawn Sullivan, PhD Jeffrey Thompson, MD Director Garett Helber, DO Loutfi Aboussouan, MD Sleep Medicine Kelly Wadeson, PhD Augusto Hsia Jr., MD Sally Ibrahim, MD Charles Bae, MD Center for Regional Iain Kalfas, MD David Berzon, MD Frederick Royce Jr., MD Neurosciences Tagreed Khalaf, MD Vaishal Shah, MD Stephen Samples, MD A. Romeo Craciun, MD Ajit Krishnaney, MD Institute Vice Chairman, Ketan Deoras, MD Regional Neurosciences Andre Machado, MD, PhD Ralph Downey III, PhD Toomas Anton, MD Jahangir Maleki, MD, PhD Michelle Drerup, PsyD Kristin Appleby, MD E. Kano Mayer, MD Samuel Gurevich, MD Peter Bambakidis, MD R. Douglas Orr, MD Anas Hadeh, MD Dina Boutros, MD Anantha Reddy, MD Sally Ibrahim, MD Luzma Cardoma, MD Teresa Ruch, MD Alan Kominsky, MD

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Jason Savage, MD Tara DeSilva, PhD Department of Anatomic CLEVELAND CLINIC Pathology, Pathology & Richard Schlenk, MD Ranjan Dutta, PhD NEVADA Laboratory Medicine Gandhivarma James Kaltenbach, PhD Institute Jeffrey Cummings, MD, ScD Director, Lou Ruvo Center Subramaniam, MD Yu-Shang Lee, PhD Richard Prayson, MD for Brain Health Santhosh Thomas, DO, Andre Machado, MD, PhD Susan Staugaitis, MD, PhD Sarah Banks, PhD, ABPP/CN MBA Sanjay W. Pimplikar, PhD Gabrielle Yeaney, MD Charles Bernick, MD, MPH Deborah Venesy, MD Brent Bluett, DO Dawn Taylor, PhD Sarel Vorster, MD Jessica Caldwell, PhD Riqiang Yan, PhD CLEVELAND CLINIC Fredrick Wilson, DO FLORIDA Dietmar Cordes, PhD Adrian Zachary, DO, MPH Carrie Hersh, DO, MS Department of Biomedical Nestor Galvez-Jimenez, MD, Engineering, Lerner MSc, MS (HSA) Le Hua, MD Research Institute Director, Pauline M. Gabriel Léger, MD, CM, COLLABORATIVE Jay Alberts, PhD Braathen Neurosciences FRCPC DEPARTMENTS Center Gregory Clement, PhD Justin Miller, PhD Badih Adada, MD Donna Munic-Miller, PhD Section for Neurosurgical Aaron Fleischman, PhD Neuroscience Institute Anesthesia, Department of Aaron Ritter, MD Zong-Ming Li, PhD Center Director; also General Anesthesiology, Chairman, Department Dylan Wint, MD Anesthesiology Institute Paul Marasco, PhD of Neurosurgery

David Traul, MD, PhD Ela B. Plow, PhD, PT Ketan Deoras, MD Section Head Michelle Dompenciel, MD Rafi Avitsian, MD Department of Cancer Biology, Lerner Camilo Garcia, MD Sekar Bhavani, MD Research Institute Daniel Grobman, DO Zeyd Ebrahim, MD Candece Gladson, MD Samuel Gurevich, MD Ehab Farag, MD Steven Rosenfeld, MD, PhD Anas Hadeh, MD Samuel Irefin, MD Department of Cellular Danita Jones, DO Sandra Machado, MD and Molecular Medicine, Tarannum Khan, MD Editorial and Art Staff Mariel Manlapaz, MD Lerner Research Institute Managing Editor Ramon Lugo-Sanchez, MD Marco Maurtua, MD Justin Lathia, PhD Glenn R. Campbell Chetan Malpe, MD Art Director Shobana Rajan, MD Genomic Medicine Anne Drago Angelie Mascarinas, MD Institute, Lerner Stacy Ritzman, MD Photography/Illustration Research Institute Karen Nater Pineiro, MD Hui Yang, MD Russell Lee Lynn Bekris, PhD John O’Connell, MD Mark Sabo Guangxiang Yu, MD Steve Travarca Michal Obrzut, MD Department of Stem Cell For address changes: Department of Biology and Regenerative Scott Robertson, MD Cleveland Clinic Neurosciences, Lerner Medicine, Lerner 9500 Euclid Ave. / AC311 Adriana Rodriguez, MD Cleveland, OH 44195 Research Institute Research Institute 216.448.1022 [email protected] Bruce Trapp, PhD Shideng Bao, PhD Richard Roski, MD Chairman Year in Review is written for Jeongwu Lee, PhD Efrain Salgado, MD physicians and should be relied Kenneth Baker, PhD on for medical education Jeremy Rich, MD Laurence Smolley, MD purposes only. It does not provide a complete overview of Selva Baltan, MD, PhD Hoonkyo Suh, PhD Alexandra Soriano the topics covered and should not replace the independent Cornelia Bergmann, PhD Caminero, MD Jennifer Yu, MD, PhD judgment of a physician about the appropriateness or risks of a Jianguo Cheng, MD, PhD Mark Todd, PhD procedure for a given patient.

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Contents Resources for Physicians

3 Neurological Institute Overview

About Cleveland Clinic

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The Cleveland Clinic Foundation O G I

9500 Euclid Ave. / AC311 C A Cleveland, OH 44195 L I N S T I T U T E | 2 0 1 6 Y E A R I N R E V I E W

Neurological Institute

2016 Year in Review

16-NEU-1727

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