Department of Neurology

The CASE Department of Neurology has active clinical, basic, and translational research programs in wide ranging disciplines of neuroscience.

Brain Tumor and Neuro-Oncology

Innovations

• Laser Interstitial Thermotherapy with real-time MRI using the Monteris AutoLitt System

• Brain mapping with functional MRI (fMRI), Diffusion Tensor Imaging (DTI) and/or magnetoencephalography (MEG) to optimize identification of brain tumors and surrounding normal tissues

• Intraoperative MRI to maximize safety and completeness of tumor removal

• New techniques for optical and fluorescence imaging to better identify infiltrating tumor

• Convection Enhanced Delivery (CED): A technology to improve delivery of small anti-tumor molecules and chemotherapy to brain tumors

• Stereotactic Radiosurgery using Gamma Knife or CyberKnife®

Current Clinical Trials:

UH provides both standard and advanced nonoperative treatments for patients with brain tumors through our advanced and extensive clinical trials. Many of these are offered in collaboration with the NCI-funded Adult Brain Tumor Consortium (ABTC), a group of 15 elite “Brain Tumor Centers of Excellence” which collaborate to offer the most innovative treatments to patients with brain tumors. Clinical trial offers change frequently, but current offers include:

• Tumor vaccines (immunotherapy) to teach the patient’s own immune system to fight their tumor

• New drugs specifically targeting brain tumor “stem cells” which are resistant to current therapies

• Gene therapy for brain tumors

• New agents targeting “angio-genesis,” the need for tumors to acquire a new blood supply

• Convection Enhanced Deliver (CED). New ways to deliver drugs and immunotoxins specifically to the tumor while avoiding toxicity from the normal brain.

• Innovative combinations of chemotherapeutic agents which are more powerful together than apart

Specific trials include:

• ABTC 0603 – A Phase I/II Trial of Hydroxychloroquine in conjunction with Radiation therapy and concurrent and Adjuvant Temozolomide in Patients with Newly diagnosed Glioblastoma Multiforme (Version 01/08/09)

• ABTC 0703 – Phase I/II study of the poly (ADP-ribose) polymerase-1(PARP-1) inhibitor BSI-201 in patients with newly diagnosed malignant glioma (version 02/06/09)

• ABTC 0904 – A Biomarker and Phase II Study of GDC-0449 in Patients with Recurrent Glioblastoma Multiforme

• ABTC 0901 – An Open Label, Phase 2 Study Evaluating the Safety and Efficacy of IMC-3G3 or IMC-1121B in Patients with Recurrent Glioblastoma Multiforme

Epilepsy Center

Innovations:

• Cortical stimulation identifies brain areas involved with specific cognitive functions like reading, writing and mathematical calculations, recognition of faces, etc.

• Cortico-cortical evoked potentials uncover brain to brain connections

• Advanced computer programs permit automatic recognition of the interictal and ictal epileptiform activity

• Multiple hippocampal transections reduce seizure activity while preserving memory functions

Current clinical trials:

UH researchers are pioneering advances in the understanding of and causes of seizures through participation in various clinical and surgical studies including:

• A Double-Blind, Randomized Conversion to Monotherapy Study to Evaluate the Efficacy and Safety of Brivaracetam in Subjects With Partial Onset Seizures. Only a limited number of antiepileptic drugs (AEDs) are approved for use as monotherapy. The objective of this study is to evaluate the efficacy of Brivaracetam when changing treatment for patients with partial onset seizures from combination treatment to monotherapy.

• Visual Field Assessment With Subjects Who Receive Either Lyrica Or Sugar Pills. Patients with partial seizures will take either Lyrica 300 mg per day or placebo in addition to their current medication. Visual field tests will be done at the beginning of the study, before Lyrica or placebo is added and at the end of the study. By the end of the treatment the person’s visual field test results will be compared to the tests collected at the beginning, prior to taking the study drug, to see if there are any changes.

• Efficacy And Safety Study Of Pregabalin (Lyrica) As Monotherapy In Patients With Partial Seizures. This study will determine the safety and efficacy of pregabalin (Lyrica) when administered by itself (without any other anti-epileptic medication) to epilepsy patients for the treatment of partial seizures.

Additional Areas of Research

• Hippocampal transections in rodents: This project aims at identifying the effect of CA3 cuts in the rat hippocampus on memory and seizure control.

• Hippocampal transection in patients with nonlesional temporal lobe epilepsy: This is a novel, alternative surgical procedure we have been offering to selected patients aims at controlling seizures without interfering with memory function.

• Studying in-hospital mortality and complications of status epilepticus in a pediatric population.

• Studying insular connectivity in patients with implanted intracranial electrodes.

• Studying connectivity of the posterior cingulate cortex in patients with implanted intracranial electrodes.

• Studying interhippocampal connectivity in patients with implanted intracranial electrodes: the role of the dorsal hippocampal commissure.

• Electrical stimulation of the insula.

• Basal temporal reading-related potentials in patients with intracranial electrodes.

• Stimulation of the dorsal hippocampal commissure for treatment of intractable epilepsy.

• Stimulation of the fornix for treatment of intractable epilepsy

Neurocritical Care Center  

A major focus of research in the Neurocritical Care Center is on integrated data acquisition, complex processing, and innovative visualization in the intensive care unit. To achieve these goals we have created the Case Critical Care Bioinformatics Consortium, a tight collaboration between physicians, engineers, computer scientists, experts in informatics and complex biostatistics, and industry.

Established in 2007, the mission of CCCBC is to provide a forum for multidisciplinary collaboration between the computational science and critical care medicine. The potential payoffs are huge: better insight into complex physiology, early detection of secondary insults, reduction in medical errors, improved efficiency, and most importantly, better patient outcomes. We believe that this approach could fundamentally change the way medicine is practiced.

Background

The ICU is a complex, data-intense environment. Physiologic data is acquired, continuously or intermittently, using devices from a variety of different manufacturers. Dozens of systemic parameters are monitored including hemodynamics, blood pressure, heart rate, respiratory rate, and pulse oximetry. Neuromonitoring is superimposed on this systemic monitoring. And while the number of monitors has grown exponentially since the origins of critical care almost forty years ago, the reality is that we look at the data essentially the same way. Standard practice at most institutions simply includes recording and logging the data by hand onto paper medical records.

We believe that the future of intensive care monitoring lies in (1) integration and time-synchronization of multiple channels of physiological data continuously and simultaneously; (2) processing of this data in real- time, using new tools such as multivariate analysis and nonlinear time series analysis to facilitate rapid diagnoses; and (3) presenting the processed information visually in a user-friendly and customizable way to maximize the information available to clinical staff. The combination of all three elements—data integration, processing, and visualization—is far beyond the scope of what is commercially available today.

This is a job beyond clinicians. It is ambitious and the challenges immense. It is like the Apollo Space Mission and requires a coordinated effort involving clinicians, engineers, computer scientists, experts in informatics and complex biostatistics, and industry to truly move this field of “critical care bioinformatics” forward. In 1961, President Kennedy said, “It is time for this nation to take a clearly leading role in space achievement…I believe we possess all the resources and talents necessary. But… we have never made the national decisions or marshaled the national resources required for such leadership. I believe that this nation should commit itself to achieving the goal, before this decade is out, of landing a man on the moon and returning him safely to the earth.” This is our mission at Case Western Reserve University, to bring people together, marshal the resources and talents, and lead in this area.

Brain Health and Memory Center

Innovations:

The Brain Health and Memory Center has established an interdisciplinary care model that has been adopted by neurological institutes nationwide. It has been a leader for research in Alzheimer’s disease and has contributed to studies of the natural history, genetics and behavioral aspects of
Alzheimer’s disease.

Current clinical trials:

Over the past two decades, our physicians have emerged as leaders in Alzheimer’s disease evaluation and genetic studies. Clinical trials are ongoing to determine the safety and efficacy of pharmaceutical alternatives, including: Studies change frequently, following are those we are currently recruiting for:

• Randomized, Controlled Study Evaluating CERE-110 in Subjects with Mild to Moderate Alzheimer’s Disease. The purpose of this study is to evaluate the potential benefits of CERE-110, an experimental drug that is designed to help nerve cells in the brain function better, in the treatment of Alzheimer’s disease. CERE-110 uses a virus to transfer a gene that makes Nerve Growth Factor (NGF), a protein that may make nerve cells in the brain healthier and protect them from dying.

• A Phase 3 Study Evaluating Safety and Effectiveness of Immune Globulin Intravenous (IGIV 10%) for the Treatment of Mild to Moderate Alzheimer´s Disease. The purpose of this study is to determine whether IGIV administered at two different doses for nine and 18 months results in a significantly slower rate of decline of dementia symptoms in subjects with mild to moderate Alzheimer´s disease.

• Safety and Efficacy Study Evaluating Dimebon in Patients With Mild to Moderate Alzheimer’s Disease on Donepezil (CONCERT). The purpose of this study is to determine if Dimebon is safe and effective in patients with mild to moderate Alzheimer’s disease on Donepezil (Aricept).

• Cataract removal and Alzheimer’s disease. The investigators have designed this study to determine whether or not cataract removal will improve the AD patient’s quality of life, vision and cognition.

• Memantine for the Frontal and Temporal Subtypes of Frontotemporal Dementia. Memantine (Namenda) has been approved for the treatment of Alzheimer’s disease; this study seeks to understand if its use can be applied to Frontotemporal dementia to effectively decrease the rate of behavioral decline in frontotemporal dementia.

Movement Disorders Center

Innovations:

• First in North America to perform DBS of the thalamus to treat symptoms of Tourette syndrome successfully.

• The first group worldwide to complete a prospective randomized double blinded trial of thalamic DBS for Tourette syndrome in a pilot clinical trial of five patients.

• Greatest experience in Ohio with botulinum toxin injections, and uses the procedure for the broadest range of neurological indications.

Current clinical studies:

• Establishment of a CTSC Parkinson’s Disease Phenotypic and Genotypic Registry. The purpose of this research study is to establish a registry of people with Parkinson’s Disease (PD) to examine the effects of genes on PD. Investigators will compare disease features in people with certain gene mutations associated with PD but without those mutations, attempting to identify any distinctive characteristics. Investigators will also try to determine how the mutations contribute to the damage done to nerve cells in PD.

• Assessment of Objective Measures of Motor Impairment in the “On” and “Off” Motor States of Parkinson’s Disease. The purpose of this study is to test a new computer-based device called Quantitative Motor Assessment Tool (QMAT) in people diagnosed with Parkinson’s disease (PD) to measure various tasks reflecting motor performance and compare the results to the Unified Parkinson’s Disease Rating Scale (UPDRS).

• Assessment of Objective Measures of Motor Impairment In Parkinson’s Disease: Evaluation of a Computer-Based Test Battery. This study tests the same new computer-based device as the previous study, the Quantitative Motor Assessment Tool (QMAT). This project involves the measurement of performance of PD subjects at random times, and represents a simpler version of the previous study.

• Genetic and Environmental Risk Factors for Progressive Supranuclear Palsy (PSP): The purpose of this study is to gain a better understanding of the genetic and environmental risk factors associated with the development of PSP. Participating subjects supply information about possible exposure histories by reviewing where they have lived, the diets they have consumed, and the jobs they have held, among other data. Subjects also furnish DNA through a blood draw. Thus the investigators will be able to look at both genetic and environmental risk factors to see if PSP patients share any common threads.

• Functional Magnetic Resonance Imaging (fMRI) Investigations of the Pathophysiology and effects of Deep Brain Stimulation in Dystonia: This NIH-sponsored study aims to reveal changes in the integration of brain sensory and motor systems in patients with dystonia using advanced imaging techniques and to also use these techniques in patients undergoing Deep Brain Stimulation to understand how the integration of these systems change as dystonia improves. This information will lead to understanding into both the pathophysiology of dystonia, and the mechanism by which DBS produced its improvement. This may furthermore be used to advance the treatment of dystonia by improving the location or method by which DBS is delivered and through the development of new therapeutic approaches.

• Functional Magnetic Resonance Imaging (fMRI) Investigations of the Pathophysiology of Parkinson’s disease: This pilot study aims to understand brain network changes involved in changes in the handling and perception of proprioceptive information in patients with Parkinson’s disease. Information gained from this study may be used to develop functional markers for progression of Parkinson’s disease and may reveal the neural circuitry involved in the alterations of perception of scale in patients with Parkinson’s disease.

Neuromuscular Center

Current clinical trials:

Research is a cornerstone in the treatment options Neuromuscular Center physicians offer to patients. Our physicians and scientists contribute to:

• Use of thymectomy vs. no thymectomy for myasthenia gravis

• Safety and Efficacy Study of Eculizumab in Patients With Refractory Generalized Myasthenia Gravis – The purpose of this study is to determine whether eculizumab is safe and effective in the treatment of patients with generalized myasthenia gravis, despite treatment with currently available immunosuppressants.

• ICEPAC NIH Grant: (Interstitial Cystitis Evaluation of Psychophysiologic and Autonomic Characteristics) – to understand the role of the nervous system in this debilitating chronic pain disorder, as well as in another pelvic pain disorder called myofascial pelvic pain syndrome.

• CRPS Bakken Grant (Complex regional pain syndrome) – to determine if CRPS affects just the involved body part or the entire body, and to what extent.

Rainbow Neurologic Center

Current clinical trials:

The Rainbow Neurological Center leads in the field of research related to fetal and neonatal neurology, neuro-intensive care and pediatric epilepsy. Center physicians and scientists are
involved in multiple NIH-funded research projects including:

• Designing new technologies for bedside continuous brain monitoring in the intensive care setting for the diagnosis and assessment of children at high risk for neurological sequelae after brain disorders.

• Drug and surgical outcomes research for pediatric epilepsy.

• Developmental care in the neonatal nursery and the impact of specific nursing care practices on the development of the brain. These studies culminate in evaluation for development neural plasticity concentrating primarily on high-risk preterm populations.

Stroke and Cerebrovascular Center

Care at the Stroke & Cerebrovascular Center is always shaped by the most innovative medical and surgical therapies because our experts continuously engage in research. A connection with the Case Western Reserve University School of Medicine allows basic science research to be quickly translated to findings that will improve patient care. Over the past several years, the Stroke & Cerebrovascular Center has secured over $2,000,000 in clinical research funding, the majority from the National Institutes of Health (NIH).

Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS)

The purpose of this NIH-funded study is to compare the safety and effectiveness of either intensive medical therapy plus stenting or intensive medical therapy only in preventing stroke, heart attacks or death.

Insulin Resistance Intervention After Stroke Trial (IRIS)

The purpose of this NIH-funded study is to determine if pioglitazone is effective in preventing future strokes or heart attacks among non-diabetic persons who have had a recent ischemic stroke.

Secondary Prevention of Small Subcortical Strokes Trial (SPS3)

The goal of this NIH-funded study is to learn if combination antiplatelet therapy (aspirin and clopidogrel) is more effective than aspirin alone for the prevention of recurrent stroke and cognitive decline, and if intensive blood pressure control is associated with fewer recurrent strokes and cognitive decline.
PFO Closure in Cryptogenic Stroke (RESPECT) The goal of this industry-sponsored study was to determine if PFO closure with the AMPLATZER PFO Occluder was superior to the current medical standard of care in the prevention or recurrent embolic stroke in patients with a cryptogenic stroke due to presumed paradoxical embolism.

Targeted Management Intervention for African-American Men with TIA or Stroke (TEAM)

This goal of this NIH- funded study is to determine barriers and facilitators to post-stroke care with the purpose of developing a behavioral intervention to improve adherence with preventive therapies.

Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-III)

This goal of this NIH-funded study is to determine if intraventricular tPA is superior to the current standard of care in the resolution of intraventricular hemorrhage and improving outcomes after hemorrhagic stroke.
 

MultiStem Therapy for Stroke

The purpose of this industry-sponsored study is to determine the safety and efficacy of MultiStem (stem cell therapy) in patients with ischemic stroke within 24-36 hours.

Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II)

The purpose of this NIH-funded study is to determine which of two blood pressure targets is superior in reducing hematoma expansion and improving outcomes after acute intracerebral hemorrhage.

Stenting & Angioplasty with Protection in Patients at High Risk for Endarterectomy – Sapphire Registry

This industry sponsored registry will determine risks of major adverse events in the treatment of carotid occlusive disease with the Cordis PRECISE® Nitinol Stent System and Cordis ANGIOGUARD™ XP/RX Emboli Capture Guidewire.
Carotid Revascularization with ev3 Arterial Technology Evolution (CREATE). This industry sponsored registry will evaluate the efficacy and safety of the ev3's Protege(R) Nitinol Self-Expanding Stent with the company's SPIDER(TM) Embolic Protection Device in the treatment of carotid occlusive disease.

“Wake up” Stroke Study

The purpose of this IRB-approved UHCMC study is to investigate the feasibility of Intra-arterial therapy (IAT) in acute ischemic stroke (AIS) patients with unknown time-of-onset by employing Magnetic Resonance Imaging (MRI)-based diffusion-perfusion mismatch criteria for selection of patient candidates.

Minimally Invasive Surgery plus rt=PA for Intracerebral Hemorrhage Evaluation (MISTIE-ICES)

The purpose of this NIH-funded study is to determine if minimally invasive hematoma evacuation is superior to the current medical standard of care in improving outcomes after hemorrhagic stroke.

“Non-invasive Brain-Signal Training to Induce Motor Control Recovery After Stroke”

Janis J. Daly, PhD, associate professor of neurology at Case Western Reserve University School of Medicine, was awarded a $1 million EUREKA grant from the National Institutes of Health (NIH) to investigate the feasibility of using Electroencephalography (EEG) signals to direct brain retraining following stroke.

Use of Diabetic Medications to Reduce Injury During Stroke

Sophia Sundararajan, MD PhD demonstrated that Thiazolidindiones (TZDs), which bind to and activate peroxisome proliferator-activated receptor-gamma (PPARgamma), suppress the brain’s inflammatory response to stroke. Animals treated with TZDs have smaller strokes and preform better on behavioral assessments.

Interventional Management of Stroke (IMS) III Trial (IMS III)

The purpose of this NIH-funded study was to compare two different treatment approaches—combined intravenous and intra-arterial recombinant tissue plasminogen activator (rt-PA) and standard intravenous (IV) rt-PA—to restoring blood flow to the brain.

Carotid Occlusion Surgery Study (COSS)

The purpose of this NIH-funded study was to determine if extracranial-intracranial bypass surgery, when added to best medical therapy can reduce the subsequent risk of ipsilateral stroke in high-risk patients with recently symptomatic carotid occlusion and increased cerebral oxygen extraction fraction measured by PET.

Clazosentan in Reducing Vasospasm-Related Morbidity and All-Cause Mortality in Adult Patients With Aneurysmal Subarachnoid Hemorrhage Treated by Surgical Clipping (CONSCIOUS-2)

The aim of this industry-sponsored study was to demonstrate that clazosentan, administered as a continuous intravenous infusion at 5 mg/h until Day 14 post aneurysmal subarachnoid hemorrhage (aSAH), reduces the incidence of cerebral vasospasm-related morbidity and all-cause mortality within 6 weeks post-aSAH treated by surgical clipping.

Clinical Outcome in Acute Stroke Treatment After Image Guided Patient Selection for Interventional Revascularization Therapy (START)

This industry-sponsored study was designed to assess the safety and effectiveness of the Penumbra System in a stroke cohort with a known core infarct volume derived from imaging at admission.

Translational Neurosciences Center

Innovations:

The Translational Neurosciences Center is funded by a variety of extramural sources including the NIH and other health care agencies, as well as grants and contracts from corporate and philanthropic organizations. Research is currently being conducted in the following areas:

• In models of stroke, researchers have identified new molecules in the brain that have a neuroprotective function. These, or related molecules, may prove useful in future
stroke treatment.

• Researchers have discovered that drugs used for other treatments stop the growth of some brain tumor cells. These drugs are now being tested in neurological clinical trials.

• Investigators in the center are developing new insights into how to maintain viable neurons after ischemic insults. Several new targets have been identified and will be developed to determine whether they are drug-treatable.

• A novel project defining the responses of the embryonic and newborn brain to inflammation, prematurity and ischemia is identifying new strategies for treating babies with these problems.

• Stem cell therapies for multiple sclerosis and stroke are in development. Our research efforts coordinate with or are parallel to many NIH studies. We welcome inquiries from potential collaborators.

Current clinical trials:

Center investigators use genetic, cellular and molecular analyses to investigate the ways in which the nervous system processes information and which dysfunctions lead to the many kinds of neurological diseases and conditions, including, Stroke, Brain tumors, Multiple sclerosis, Spinal cord injury and Alzheimer’s disease.

Rehabilitation

Cleveland boasts the largest and most successful program in functional electrical stimulation (FES Center), led by Dr. Hunter Peckham and carried out at several institutions. Dr. Robert Ruff is the Medical Director of the FES Center Dr. Ruff is heading an a novel research program that will likely start recruiting subjects in 2011. This program evaluates the utility of a brain-computer interface device to enable people with advanced amyotrophic lateral sclerosis (ALS) to be able to communicate when they can no longer speak or write. Dr. Stephen Selkirk is involved with both clinical and basic research related to multiple sclerosis (MS). Traumatic brain injury (TBI) is a frequent injury among soldiers who have served in Iraq or Afghanistan. The Cleveland VA Medical Center is the Ohio hub for treating veterans with traumatic brain injury. Dr. Ronald Riechers directs the clinical and research activities related to TBI. Dr. Mark Walker is conducting interesting research on the effect of TBI on balance and strategies for improving balance after TBI.

Sleep Medicine

 One main area of interest is restless legs syndrome (RLS). Currently we are carrying out genetic work to see if RLS is associated with mutation in the melanocortin-1-receptor. We are also conducting an epidemiologic study to see if RLS and more specifically periodic limb movements during sleep are associated with incident cardiovascular disease including myocardial infarction and stroke.

Another area of focus is among the disorders of breathing in sleep. We are currently studying breathing patterns in a mouse model of stroke and have found that animals have a pattern of breathing similar to Cheyne-Stokes. We plan to extend on this model, looking at mortality and possible drug therapies.

Additionally, we are investigating REM-related sleep disordered breathing and have found that this entity occurs more commonly in women and more so in younger women, irrespective of obesity.

Ocular Control

Three closely coordinated laboratories have studied control of extraocular movements in patients, headed by Dr. R. John Leigh, Dr. John Stahl, and Dr. Louis Dell’Osso. These laboratories have attained nationally and internationally recognized expertise in the clinical and laboratory evaluation of patients with abnormalities of eye movements. Extramural support includes funding from the NIH and the VA.