Neurological Institute

CLEVELAND CLINIC NEUROLOGICAL INSTITUTE 7WELCOME FROM THE CHAIRMANDear Colleagues,If there’s one thing the past year has made clear,Year in Review publication from our Neurologicalit’s this: Healthcare is changing and will continueInstitute is filled with examples:to change.›Our novel two-stage approach to GammaKnife therapy discussed on page 12 mayIn Cleveland Clinic’s Neurological Institute, westrive to navigate this change by relying on ourrepresent innovation, but it’s innovation bornmantra of “Excellence, Discovery and Innovation.”of a bold, uncompromising commitment toYet in these times when change increasinglyproviding the best possible therapy option tocomes in the form of tightening reimbursements,patients with large brain metastases.it can be tempting to shift greater focus toexcellence at the expense of discovery and›program detailed on page 16 may be primarilyinnovation. After all, the rise of healthcareabout discovery, but the story also notes howconsumerism and hospital rating systemsour clinicians are leveraging this translationalhas made high-volume delivery of excellentinitiative to develop new MRI sequences tocare — in terms of both outcomes and patientbetter manage today’s MS patients.experience — more critical to success than ever.Who can blame patients or staff for wonderingwhether a day spent advancing discovery orinnovation — perhaps in the lab or writing agrant — might not be better spent seeing a fewmore patients and perhaps impacting more lives?It’s an interesting argument, but it’s ultimatelya false choice. For one, neglecting discoveryand innovation would amount to abandoning thefounding mission of Cleveland Clinic. And it wouldshortchange our children and grandchildren byundercutting development of the therapies oftomorrow. If our predecessors had adopted thismindset, how many treatments that we take forgranted today would have never materialized?The multiple sclerosis (MS) rapid autopsy›The population health pilot program featured onpage 14 is more than a trial run of an innovativemodel for managing chronic back pain; it’s alsoa patient-empowering initiative to deliver betterpain outcomes than patients typically achievewith riskier, costlier procedure-driven care.The latter example is a helpful reminder thatinnovation itself can and should extend beyondnew therapies and technologies to encompass caredelivery as well. You’ll find additional examplesthroughout these pages, which I hope you’ll finduseful and of interest.Respectfully,But the strongest argument for not neglectingdiscovery and innovation is that they are so oftenlinked inextricably to excellence in care. ThisAndre Machado, MD, PhDChairman, Cleveland Clinic Neurological Institutemachada@ccf.org

8 YEAR IN REVIEW 2016

CLEVELAND CLINIC NEUROLOGICAL INSTITUTE 92016 HIGHLIGHTFirst-in-Human Trial of DBS for Stroke RecoveryLaunched with NIH BRAIN SupportCan neuromodulation be used effectively to recoverThe study builds on more than a decade ofneurological function, such as in paralysis?Cleveland Clinic preclinical research. “We knowThat’s among the key research questions beingexplored in a Cleveland Clinic first: a new clinicaltrial testing deep brain stimulation (DBS) asrehabilitative therapy for stroke survivors. Thetrial, launched in 2016, was awarded nearly 5 million in funding from the NIH’s Brain Researchthrough Advancing Innovative Neurotechnologies(BRAIN) initiative.“When we use DBS for a movement disorder, we’reattempting to suppress a positive symptom, suchas tremor or rigidity, that’s overlaid on top ofnormal function,” explains lead investigator Andrethat deep cerebellar stimulation promotes motorrecovery in a preclinical model of cortical stroke,”says Kenneth Baker, PhD, of Cleveland Clinic’sDepartment of Neurosciences. “Our goal is toadvance this therapy to promote recovery of motorfunction in humans. This has the potential to bea significant advancement for the field.”Trial enrollment is underway. Candidates arepatients with severe residual hemiparesis froman ischemic stroke 12 to 24 months previouslydespite physical therapy. Primary aims include:›Establishing safety and proof-of-concept dataMachado, MD, PhD. “In contrast, in this trialfor dentate nucleus DBS in this populationwe’re attempting for the first time to use DBS toand defining optimal metrics for further trialshelp recover a function that’s been lost — i.e.,›cortex excitabilitysurvivor’s body.”The study will examine a novel strategy —›dentate nucleus in patients whose leads areto enhance excitability and plasticity in sparedtemporarily externalizedcerebral cortical regions — with the aim of“Our primary hypothesis is that by applying DBSto the connections between the cerebellum andcerebral cortex, we can facilitate the plasticity thatoccurs in the cortex around the stroke and therebypromote recovery of function beyond what physicaltherapy alone can do,” Dr. Machado notes.Characterizing movement-related local fieldpotential changes in the area of the cerebellarstimulation of the dentatothalamocortical pathwaypromoting recovery of motor function.Characterizing acute and chronic effectsof dentate nucleus DBS on cerebralmotor function on the paretic side of a stroke›Characterizing changes in perilesionalcortical maps in response to chronic dentatenucleus DBS“We need more and better options to help the manypatients who remain chronically disabled after astroke,” says Dr. Machado. “The opportunity hereis to explore a new avenue that may improve theirlong-term rehabilitative outcomes.”LEFT — Illustration showing a DBS lead implanted in the cerebellar dentate nucleus for treatment of post-strokemotor deficits. Low-frequency stimulation is predicted to enhance neural activity across the ascending, excitatorydentatothalamic pathways (blue) and, in turn, thalamocortical pathways (red/yellow), thereby increasing cerebralcortical excitability and enhancing functional reorganization across spared perilesional cortex.

10 YEAR IN REVIEW 2016

CLEVELAND CLINIC NEUROLOGICAL INSTITUTE 112016 HIGHLIGHTSizing Up Ketamine vs. ECT forTreatment-Resistant DepressionUse of the anesthetic agent ketamine as another U.S. sites are being randomized to receivealternative to electroconvulsive therapy (ECT) forone of the following for three weeks:treatment-resistant depression has surged overthe past decade and a half. The problem is, nolarge-scale trials of ketamine’s safety and efficacyin treatment-resistant depression have beenconducted, so its use in this setting hasn’t been›Multiple infusions of ketamine (at asubanesthetic dose) twice a week›ECT three times a weekChanges in depressive symptoms, memorycovered by insurers. And patients and cliniciansfunction and quality of life will be assessed throughhave no direct evidence of how ketamine andpatient self-reports and clinician ratings. FollowingECT stack up in terms of efficacy, side effectsthe acute phase of treatment, responders to eachand patient quality of life.therapy will be followed up by their usual providersA key partner of the federal government is nowto measure differences in long-term outcomes.intent on changing that, by way of an 11.8Quality of life and relief from depression withoutmillion award to fund a Cleveland Clinic-led studysignificant side effects are key outcomes ofcomparing ketamine and ECT for patients withinterest. Although ECT is highly effective fortreatment-resistant depression. The award comestreatment-resistant depression, many patientsfrom the Patient-Centered Outcomes Researchfind it unsatisfactory because ECT is oftenInstitute (PCORI), which is authorized by Congressassociated with memory deficits, is difficultto fund comparative effectiveness research. Theand costly to administer, and tends to carrystudy was one of just three research projects to wina lingering social stigma.PCORI funding in its July 2016 round of awards.“This study will fill the evidence gap around“If ketamine is found to be as effective as ECT, it islikely to be rapidly adopted by patients, providersketamine versus ECT for treatment-resistantand payers for the acute reversal of treatment-depression,” says the study’s principal investigator,resistant depression,” says Dr. Anand, who notesAmit Anand, MD, Vice Chair for Research inthat ketamine has potentially fewer side effects,Cleveland Clinic’s Center for Behavioral Health.is easier to administer and will likely be lessDr. Anand was a member of the 1990s Yaleexpensive than ECT.University team that first discovered that ketaminecould effectively treat severe depression.For a more detailed version of this article, seeconsultqd.clevelandclinic.org/ketamine.The PCORI-funded study is a five-year investigationin which 400 patients with severe treatmentresistant depression at Cleveland Clinic and threeAmit Anand, MD, principal investigator of the Cleveland Clinic-led multicenter study of ketamine versuselectroconvulsive therapy for treatment-resistant depression.LEFT —

12 YEAR IN REVIEW 2016

CLEVELAND CLINIC NEUROLOGICAL INSTITUTE 132016 HIGHLIGHTPioneering Staged Gamma Knife for LargeBrain Metastases: Two Smaller Sequential DosesMay Be Better Than OneA novel two-stage approach to Gamma Knife “This allows us, in most cases, to spare the patientstereotactic radiosurgery is showing improvedthe risks of open surgery and the toxicity of whole-outcomes for treating large brain metastases,brain radiation therapy that would be standard ofand Cleveland Clinic has become the first centercare,” Dr. Angelov explains. “It’s a game-changer.”outside Japan to embrace it. By allowing fordelivery of an overall higher dose of radiation withEncouraging Numbers to Dateminimal toxicity, the strategy represents a potentialAmong Cleveland Clinic’s first 54 patients —new standard of care for large brain metastases.with a total of 63 brain metastases 2 cm —The Challenge of Large TumorsAlthough standard Gamma Knife radiosurgery hastreated this way, the local control rate at sixmonths has been 88 percent, up from only 49percent for similar-sized metastases previouslygained favor in recent years as monotherapy formanaged with single-stage (standard) Gammabrain metastases, its success has been limitedKnife therapy at Cleveland Clinic. Moreover, thein patients with metastases larger than 2 cm.“The question is how to get a large dose to a largetumor so patients don’t fail therapy,” explainsCleveland Clinic neurosurgeon Lilyana Angelov, MD.Two Medium-High Doses a Month ApartIn recent years, she and colleagues in ClevelandClinic’s Rose Ella Burkhardt Brain Tumor andNeuro-Oncology Center have begun using a novelapproach that could dramatically improve the oddsof a good outcome with large metastases.Instead of a single radiation dose limited bythe toxicity resulting from treating large tumors,Gamma Knife therapy for large tumors is nowdelivered in medium-high doses over two stagestreatment is well tolerated, with only seveninstances of adverse radiation effects, whichwere mostly mild and transient.Since these initial results, which were submittedfor publication in 2016, Dr. Angelov’s team hasused the staged approach for about 150 morecases, with continued positive outcomes.She expects the approach to ultimately becomethe standard of care across the country for largebrain metastases: “I see it as a primary modalityfor treating these patients in a minimally invasivemanner. I think many patients will be well-served.”For a more detailed version of this article, seeconsultqd.clevelandclinic.org/stagedgamma.about a month apart.LEFT — MRIs from a patient who underwent staged Gamma Knife therapy. Top images were taken before the firsttreatment (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.

14 YEAR IN REVIEW 2016

CLEVELAND CLINIC NEUROLOGICAL INSTITUTE 152016 HIGHLIGHTRemaking the Management ofChronic Low Back PainValue-based care and the opioid epidemic don’texplains spine neurosurgeon Edward Benzel, MD,usually come up in the same sentence, but theyfounder of Cleveland Clinic’s Center for Spinehave at least one thing in common: Both rankedHealth. “We emphasize that surgery is deemedhigh among 2016’s healthcare headlines.appropriate only after all other relevant and saferOver the past year, Cleveland Clinic’s Neurologicaltreatment strategies have been considered or tried.”Institute has given these issues another point ofThe program is expected to achieve its primaryintersection with a bold new initiative to promotegoal of helping patients recover function andvalue-based care for patients with chronic painbecome active again, while also achieving:while also preventing inappropriate opioid use.›Avoidance of opioid prescriptionsfor chronic painThe initiative, launched in August 2016, is apopulation health pilot program to treat more than›Greater prudence in prescribing1,000 patients with chronic low back and leg pain›Greater patient empowerment to self-manageby prioritizing functional outcomes over opioid- orprocedure-based care. If successful, the model canbe applied to other chronic pain conditions andperhaps replicated at other institutions.and control painThe program is highly interdisciplinary, withleadership from the Neurological Institute’s Centerfor Spine Health, Department of Physical MedicineEligible patients are those with low back or leg painand Rehabilitation, Center for Neurologicalfor more than three months. All undergo combinedRestoration and Center for Behavioral Health.physical and behavioral pain rehabilitation as thefirst line of care.“The literature supports a collaborative approachto these patients,” says Mary Stilphen, PT, DPT,The aim is to promote pain rehabilitation bySenior Director of Rehabilitation and Sportsmanaging the sensory, cognitive and affectiveTherapy. “Single approaches, used in isolation,domains of pain. The key outcome metric isare often unsuccessful.”restoration of function. “It’s about delivering realvalue to patients, with a meaningful transformationof their lives, rather than hoping for a quick fix,”says Neurological Institute Chair Andre Machado,MD, PhD.Spine medicine physicians and spine surgeons areavailable throughout patients’ longitudinal care.They manage medications, order tests and providesurgical evaluations when appropriate.“Patients will not be denied surgery, procedures or“Pain is a multifaceted experience that demandsinterdisciplinary collaboration,” adds Sara Davin,PsyD, MPH. “Our program differs from others inits interdisciplinary approach to care.”“This project is made possible by the NeurologicalInstitute’s distinctive organizational structure,which breaks down departmental barriers topromote collaboration across subspecialties,”notes Dr. Machado. “Pulling this off in a traditionalmodel would be difficult.”pain medications if the diagnosis calls for such,”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.LEFT —

16 YEAR IN REVIEW 2016

CLEVELAND CLINIC NEUROLOGICAL INSTITUTE 172016 HIGHLIGHTRapid Autopsy Program Speeds Research Progressin Multiple SclerosisWhen Cleveland Clinic’s Bruce Trapp, PhD, createdsurprises — some MRI changes have been shownone of the first rapid autopsy programs for multipleto not be what we historically thought they were.”sclerosis (MS) back in 1994, he was pioneeringa novel concept — to collect a pre-consentedpatient’s body shortly after death (ideally withina few hours) for advanced MRI studies followedby removal of the brain and spinal cord forpathological analysis. The aim was to study theeffects of MS on the brain in a way impossiblewith animal models or standard imaging.Now, more than two decades later, the programis the largest of its kind in the world, with over160 specimens collected, and it’s been centralto Cleveland Clinic’s mounting grant funding toadvance understanding of how MS develops andThose surprises included the groundbreaking1998 discovery that transected axons are commonin MS lesions and may underlie the disease’sirreversible neurological impairment, as well asthe 2002 insight that cells capable of producingmyelin are present in chronic lesions of MS.In parallel with Dr. Trapp’s work, neurologistsin Cleveland Clinic’s Mellen Center for MultipleSclerosis Treatment and Research are using therapid autopsy program in ways that promise moreimmediate impact for patients: testing new MRIsequences and technologies in MS.progresses in the human brain. Three grants wereBy applying newly developed MRI sequencesawarded in 2015-2016 for research that drawsto cadavers, Mellen Center researchers get anon the autopsy program:› 6.97 million from the National Institute ofNeurological Disorders and Stroke (NINDS)to identify new therapeutic targets causingaxonal and neuronal degeneration› 1.7 million from the NINDS to supportwork to further reveal factors influencingremyelination› 460,000 from the National MS Societyimmediate reading on whether the MRI changesobserved are suggestive of the underlying brainand spinal cord pathology. Once validated inthe postmortem program, the sequences can beapplied as outcome measures in selected clinicaltrials, with the hope that some can ultimately bebrought into clinical practice.“The postmortem program is the perfect place forincorporating new MRI technologies in MS,” saysto investigate differences between primarythe rapid autopsy program’s medical director,progressive and secondary progressive MS,Daniel Ontaneda, MD. “We’re directly translatingwith the goal of aiding therapy developmentMRI research to pathology, and it accelerates“One of our program’s aims is to correlate MRIMRI development.”changes with pathological changes,” explainsFor a more detailed version of this article, seeDr. Trapp, now Chairman of Cleveland sy.Department of Neurosciences. “We’ve uncoveredPathology 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 ClevelandClinic’s rapid autopsy program for MS.LEFT —

18 YEAR IN REVIEW 2016

CLEVELAND CLINIC NEUROLOGICAL INSTITUTE 192016 HIGHLIGHTDual-Task mTBI Assessment: Out of theBiomechanics Lab, Onto the BattlefieldDual-tasking — simultaneous performance ofpersonnel lack a cohesive system and standardcognitive and motor tasks — is something we alltools. “We hope to come up with simple dual-do hundreds of times daily: Checking the timetasking and vision assessments and standards towhile running out the door. Reading while sippinguse across their system — to put more sciencecoffee. Chatting while crossing the street.So why shouldn’t neurological disorders — includingmild traumatic brain injury (mTBI) — be evaluatedinto the art of evaluating and monitoring mTBI,”says Dr. Alberts.The basis for his team’s mTBI assessment isin a way that reflects that reality, rather thanthe Cleveland Clinic-developed C3Logix mobileassessing each function individually?app, which is widely used to assess concussionCurrently, dual-task neurological evaluation isavailable only at centers with biomechanics labs.Cleveland Clinic researchers hope to change that bybringing dual-task evaluation to the patient — or, inmilitary contexts, the soldier. They’re doing so withamong student athletes. With their new grant, theteam is combining the C3Logix app’s motor andcognitive functions into a dual-task assessment andestablishing military-specific norms for it. They alsowill develop a multicomponent vision assessment.help from a three-year, 1.3 million grant from thePhase 1 of the project includes developing dual-U.S. Department of Defense to develop and validatetask assessment software and validating it fora dual-task mTBI assessment for the military.civilians. The C3Logix app will be calibrated withDual-task capability can be a matter of lifeand death for military personnel, who may bemoni

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” survey. The survey ranks Cleveland Clinic among the nat