With an emphasis on “patient-centered care” and translational research, the three-day symposium will address the current state of both clinical and research efforts in hydrocephalus. We seek to come to a consensus on priorities in hydrocephalus that have the potential to impact patient care in the next five years. Critical long term research and clinical goals will be identified and discussed.
Unlike most conferences, the main objective is NOT to present any one individual’s research, but to frame and summarize the field in its entirety.
Day three of the conference will be an open discussion to set priorities and directions that will culminate in a white-paper summarizing the meeting and providing direction to the NIH and other funding entities.
Welcome to “Opportunities for Hydrocephalus Research: Pathways to Better Outcomes.” What we originally envisioned as a regional meeting has taken shape to become the 3rd NIH-sponsored conference on hydrocephalus. As the program evolved we chose to take a different approach and focus on hydrocephalus from the family/patient’s perspective. This focus created our goals to better understand and share the current state of hydrocephalus and discover what research or interventions might improve treatment in the next five years. To this end, we have asked the renowned list of speakers to forgo the usual didactic lectures focused solely on their clinical or laboratory efforts and instead critically review the state of their field and discuss the critical areas that hold promise for meaningful advances to patient care in the next several years. We want to understand broadly where the field of hydrocephalus has been in the last several years and look forward in an attempt to set priorities for research that have the realistic potential to impact patient lives. We have attempted to bring together noted experts in various fields of hydrocephalus including genetics, pathophysiology, diagnosis, biomarkers, imaging, bioengineering, surgical treatment, neurophysiology and outcome/quality of life to effect these goals. The meeting is meant to be highly interactive with all participants having a voice in discussions and ultimately in the output of the meeting, a white-paper which we hope NIH and other agencies will reference to set funding priorities.
We hope you enjoy the meeting. It is through everyone’s efforts and dedication to hydrocephalus that the field moves forward improving lives and reaches the day when hydrocephalus is relegated to the historical record.
Conference Organizers and Directors
General Meeting Organization & Development:
Samuel R. Browd, M.D., Ph.D.
Pat McAllister, Ph.D.
Amy Anderson, B.S.N., R.N.
Dawn Mancuso, MAM, CAE, FASAE
Gavin Reed, M.P.H.
Esteban Rodriguez, M.D., Ph.D.
Marc R. DelBigio, M.D., Ph.D.
David D. Limbrick, M.D., Ph.D.
Mark Wagshul, Ph.D.
Barry Lutz, Ph.D.
Jay Riva-Cambrin, M.D.
Jack M. Fletcher, Ph.D.
Abhaya V. Kulkarni, M.D., Ph.D.
Event Planning & Assistance:
David Su, M.D.
Carroll Olson, M.D.
Founder & first CEO of Netflix
Santa Cruz, CA
“That will never work”
The role of failure in success – the founding of Netflix
Marc Randolph is a veteran Silicon Valley entrepreneur, angel investor and executive mentor. Most recently, Marc was founder of the online movie service Netflix, serving as their founding CEO, as the executive producer of their web site, and as a member of their board of directors until his retirement in 2004. Prior to founding Netflix, Marc was on the founding team of more than half a dozen other successful start-ups in the e-commerce, media, enterprise software and portable device markets – all of which went on to IPOs or other liquidity events. Since leaving Netflix he has been an active angel investor, executive mentor and consultant. He currently sits on the boards of Rafter, ReadyForce, Getable, and the National Outdoor Leadership School; and is a mentor to the executive teams of numerous other startups.
Conference Agenda July 9-11, 2012
Opportunities for Hydrocephalus Research:
Pathways to Better Outcomes
Monday, July 9, 2012
07:00 Continental Breakfast and Registration
08:00 Introduction-Sponsor Acknowledgements
Dawn Mancuso, FASAE, CAE, Chief Executive Officer, Hydrocephalus Association
Title: Opening Remarks
08:10 CAUSES OF HYDROCEPHALUS
Directors introduced by Pat McAllister, PhD; Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Utah, Salt Lake City, UT
Plenary Session 1: GENETICS – Directed by Esteban Rodriguez, MD, PhD
Speaker: William B. Dobyns, MD; Seattle Children’s Research Institute & University of Washington, Seattle, WA
Title: The genetic basis of human hydrocephalus: hindbrain development, growth regulation and more
This lecture will review the known genetic causes of hydrocephalus in humans, especially congenital hydrocephalus. Specific disorders to be reviewed will include neural tube malformations (briefly), mid-hindbrain developmental disorders such as congenital aqueductal stenosis, Dandy-Walker malformation and rhombencephalosynapsis, and syndromes with uncertain pathogenesis. The lecture will also review several disorders with abnormally large brain size or megalencephaly and the common neurological complications which include Chiari malformation, syrinx and seizures. Information on the underlying genes in human and mouse hydrocephalus will be presented as well.
Director: Esteban Rodriguez, MD, PhD; Instituto de Histologia y Patología,Universidad Austral de Chile Valdivia, Chile
Present evidence obtained from humans and animal models indicating that the common history of hydrocephalus and brain maldevelopment starts early in the embryonic life with the disruption of the ventricular (VZ) and subventricular (SVZ) zones. A “cell junction pathology” involving adherent and gap junctions appears as the final common outcome of a wide range of gene mutations. Disruption of the VZ of the aqueduct leads to its obliteration and hydrocephalus, while disruption of the VZ of telencephalon implies the loss of neural stem cells (NSCs). NSCs and neural precursor cells (NPCs) can be collected from the CSF of hydrocephalic human foetuses and mutant HTx rats and grow into neurospheres (NE). The cells forming these NEs express pathological features, thus becoming a valuable tool to study cell and molecular defects in animal and human neurogenesis. When NEs obtained from the SVZ of normal HTx are cultured in the presence of CSF from normal and hydrocephalic rats differentiate into neurons and glia, indicating that CSF is a friendly medium for NE cells to differentiate. This is good news for transplantation of normal NEs into the CSF of human and animals with foetal onset hydrocephalus.
Speaker: Antonio J. Jimenez, PhD; Departamento de Biología Celular Genética y Fisiología, University of Malaga, Spain
In congenital hydrocephalus the development of the neuroepithelium/ependyma is affected. Our studies in human fetuses and in an animal model, the hyh mouse, have shown that as a consequence alterations in neurogenesis and cortical development take place. In addition, an astroglial reaction is triggered to replace the absence of ependyma in the ventricle border. This new layer contains astrocytes that share several cytological features with the normal multiciliated ependyma, as well as transport properties with similar paracellular and trans-cellular routes between ventricular CSF and the brain parenchyma. Their role in the production of proinflammatory and neuroprotector factors is currently under study. In the animal model, the reactive astrocytes can be also involved in the production of TNF alpha, which is found correlated with the severity and prognosis of the disease.
Plenary Session 2: PATHOPHYSIOLOGICAL MODIFICATIONS – Directed by Marc R. Del Bigio, MD, PhD
Director: Marc R. Del Bigio, MD, PhD; Department of Pathology & Canada Research Chair in Developmental Neuropathology, University of Manitoba, Winnipeg, Manitoba
Presentation includes a brief overview of the causes of hydrocephalus, including the relationship to intracranial hemorrhage. Details addressing the white matter damage in the brain including the pathology and pathogenesis (mechanical factors + chronic intermittent hypoxia-ischemia). Adverse effects on the developing nervous system including germinal cell insults and oligodendrocyte function will be addressed. A final summary of the experimental work done on pharmacologic interventions to protect the brain, which could be a supplement to shunt therapy.
Speaker: Stephen A. Back, MD, PhD; Departments of Pediatrics and Neurology, Oregon Health & Science University, Portland, OR
Cerebral white matter injury (WMI) is the leading cause of chronic brain injury in infants who survive preterm birth and results in life-long cerebral palsy and cognitive disabilities. Discussion of recent changes in our understanding of cellular and molecular mechanisms related to the pathogenesis of acute and chronic lesions that are initiated by hypoxia-ischemia. Presentation of recent data with high field MRI that have permitted unprecedented resolution of WMI previously not detected clinically at lower field strengths. High field imaging raises the possibility that therapies directed at myelin regeneration and repair could be monitored over time in preterm survivors.
Speaker: Jerold Chun, MD, PhD; Department of Molecular Biology, Dorris Neuroscience Center, The Scripps Research Institute (TSRI), La Jolla, CA
Title: Lysophosphatidic acid (LPA) signaling in post-hemorrhagic hydrocephalus
Lysophospholipids are small lipids derived from the cell membrane, which can act as extracellular signals via cognate G protein-coupled receptors. One lysophospholipid form called lysophosphatidic acid (LPA) is prominent during hemorrhage where high concentrations, as well as hypoxia, can over-activate LPA receptors present on prenatal neuroprogenitor cells (NPCs). Animal studies have identified altered LPA signaling that disrupts normal NPC development resulting in hydrocephalus, suggesting that therapeutic intervention targeting LPA receptors could provide medical treatments for some forms of hydrocephalus.
Speaker: J. Gordon McComb, MD; Children’s Hospital of Los Angeles, University Children’s Medical Group, Los Angeles, CA
Title: Funding for promising aspects of hydrocephalus research by the Rudi Schulte Research Institute, Santa Barbara, CA
13:00 KEYNOTE ADDRESS
Speaker: Marc Randolph; founder & first CEO of Netflix, Santa Cruz, CA
Title: “That will never work”: the role of failure in success – the founding of Netflix
13:45 DIAGNOSIS OF HYDROCEPHALUS
Directors introduced by Samuel R. Browd, MD, PhD; Department of Neurological Surgery Seattle Children’s Hospital and the University of Washington, Seattle, WA
Plenary Session 3: BIOMARKERS – Directed by David D. Limbrick, MD, PhD
Director: David D. Limbrick, MD, PhD; St. Louis Children’s Hospital & Washington University School of Medicine, St. Louis, MO
Improving outcomes in hydrocephalus is critically dependent on developing objective metrics to inform clinical treatment decisions. In recent years, technological advances in analytic methodologies and brain imaging have accelerated the discovery of candidate biomarkers with potential clinical utility. The process of biomarker discovery-validation will be discussed both in general terms and in detail using post-hemorrhagic hydrocephalus of prematurity and congenital hydrocephalus as case examples.
Speaker: Laurence Watkins, MD; Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, Queen Square, London
Normal pressure hydrocephalus affects an estimated 1% of the over-65 year-old population, causing loss of mobility, cognitive decline and urinary incontinence. The condition was first reported over 45 years ago, but there are still problems with diagnosis and prediction of outcome from shunting. Biomarkers are measurable characteristics that can be used to track biological processes, both for diagnosis and to indicate response to therapeutic intervention. CSF peptides, neurotransmitters, metabolites, enzymes and other proteins have all been investigated as possible biomarkers for NPH. Tau protein, amyloid beta, tumor necrosis factor, lactate, sulfatide and neurofilament triple protein all show promise.
Speaker: Richard S. Morrison, PhD; Department of Neurological Surgery, Centers on Human Development and Disability & Proteomics, Intellectual and Developmental Disabilities Research Center, University of Washington School of Medicine, Seattle, WA
The continuing expansion of proteomic technology has been fueled by the potential for discovering novel biomarkers that may be used for the early detection of disease. Using a simple separation strategy in conjunction with a novel bioinformatic approach, the protein complement of human ventricular cerebrospinal fluid obtained from patients with hydrocephalus was evaluated. One goal of this study is to identify markers that might predict neuropsychological outcomes in patients with congenital and acquired hydrocephalus.
Plenary Session 4: NEUROIMAGING– Directed by Mark Wagshul, PhD
Speaker: William G. Bradley, MD, PhD; Department of Radiology, University of California, San Diego, CA
Use of MRI-based aqueductal CSF flow quantitation to predict shunt-responsiveness for NPH will be discussed. Evidence that idiopathic NPH is a two-hit disease, ie, benign external hydrocephalus in infancy followed by deep white matter ischemia in late adulthood, will be presented. This includes the findings that NPH patients have larger intracranial volumes than controls and that they have increased apparent diffusion coefficients in the white matter supporting at least partial CSF outflow through the extracellular space of the brain.
Speaker: Norman Relkin, MD, PhD; Cornell Memory Disorders Program & Departments of Clinical Neurology and Neuroscience, New York Presbyterian Hospital/Weill Cornell Medical College, New York, NY
The diagnosis and treatment of hydrocephalus can be improved by quantitative neuroimaging techniques that permit precise structural and hydrodynamic measurements to be performed on the living human brain. In this presentation, a set of advanced MRI techniques will be described that can assist in the differential diagnosis of idiopathic Normal Pressure Hydrocephalus (iNPH). In addition, a discussion of the feasibility of using brain imaging to guide successful pharmacologic treatment of iNPH.
Director: Mark Wagshul, PhD; Department of Radiology and Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine, Bronx, NY
Title: Mechanisms in hydrocephalus revealed by neuroimaging
There is a critical need for the development and validation of diagnostic and prognostic imaging techniques in both pediatric and adult hydrocephalus. Nonetheless, a key element which is often missing is the link between these techniques and the underlying mechanisms responsible for any imaging changes. In this presentation, we will review various techniques being studied, such as phase contrast, diffusion tensor imaging and MR elastography, and discuss the relationship of these techniques to the disease pathophysiology, and how this information might be used to guide management and development of alternate therapies. We will also review the use of imaging studies in animal models for providing this link and discuss further studies needed to help advance the field of neuroimaging in hydrocephalus.
Tuesday, July 10, 2012
07:00 Continental Breakfast and Registration
08:00 TREATMENT OF HYDROCEPHALUS – Directors introduced by Jill A. Morris, PhD; Program Director in Neurogenetics, NIH/NINDS, Bethesda, MD
Plenary Session 5: BIOENGINEERING ADVANCES– Directed by Samuel R. Browd, MD, PhD and Barry Lutz, PhD
Director: Samuel R. Browd, MD, PhD and Barry Lutz, PhD; Departments of Neurological Surgery and Bioengineering, Seattle Children’s Hospital and the University of Washington, Seattle, WA
The problems with shunts are well known, yet there has been little success in correcting them. In addition, the community has called for advanced shunts with improved control and diagnostics, but we have yet to see one reach the market. We will briefly review how the shunts of today came to be and the critical problems that remain. We will present recent approaches that aim to reduce failure or truly advance shunt technology, including some that have not worked, some that have worked, and some that might work.
Speaker: Thomas J. Clement, MS; Cardiac Insight, Inc./Aqueduct Neurosciences, Inc., Seattle, Washington
The business of developing medical devices for market has many facets, several of which distinguish it from nearly all other business models. This talk will provide a high level overview of the specific areas that leadership in a medical device company need to consider: Intellectual Property, Market Evaluation, Technical Development, Regulatory Path, Reimbursement, Clinical Testing, and Financing.
Speaker: David A. Watson; Dave Watson Engineering, San Jose, California
Title: Risks and misdirection: critical areas to focus shunt technology development
The shunt products on the market are based on technologies that were developed 10 to 30 years ago. Despite the high clinical failure rate of these systems, innovation seems to have stagnated in this market sector. Is that because the market is too small to warrant R&D investments from these large companies that enjoy the current status quo, or is it that there simply are not enough data from which engineers can attempt to design anything better? A discussion of my experiences in developing the highly successful Delta/Strata Valves over 15 years ago in contrast to some recent efforts in trying to advance some other innovations in this field.
Plenary Session 6: SURGICAL TREATMENTS – Directed by Jay Riva-Cambrin, MD
Director: Jay Riva-Cambrin, MD; Primary Children’s Medical Center and the University of Utah, Salt Lake City, UT
Title: Methodology for critical assessment of new techniques, the impact of surgical adjuncts in shunt placement and revisions, and novel advances in infection prevention
This talk will review and highlight recent advances in the surgical management of patients with hydrocephalus with special emphasis on the methodology for critical assessment of new techniques, the impact of surgical adjuncts in shunt placement and revisions, and novel advances in infection prevention.
Speaker: Benjamin Warf, MD; Children’s Hospital Boston, Boston, MA
Title: The expanding role of combined endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC) as the primary treatment for infant hydrocephalus
The majority of infant hydrocephalus can be treated successfully without a shunt. This talk will review what we have learned over the past decade about the burden and causes of infant hydrocephalus in East Africa and its treatment by the technique we developed for combined endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC). The long-term success of this procedure for different types of hydrocephalus will be reviewed, including its impact on cognitive development and childhood mortality, as well as its effect on subsequent shunt survival for those who fail endoscopic treatment. New data on the indications and effectiveness of ETV/CPC as the primary treatment for infant hydrocephalus in the United States will be presented.
Speaker: Richard J. Edwards, MD; Department of Neurosurgery, Frenchay Hospital, Bristol, UK
Title: Strategies to reduce proximal catheter revision rates
Despite numerous advances in shunt technology and adjuncts to shunt surgery over the last few decades, the shunt survival curve has remained steadfast. This talk will highlight the possible use of endoscopic choroid plexus coagulation to reduce catheter occlusion rates and discuss possible future research directions, including catheter design and placement to reduce the incidence of proximal catheter blockage.
13:00 OUTCOME IN HYDROCEPHALUS – directors introduced by Paul Gross; Chairman, Hydrocephalus Association
Plenary Session 7: NEUROPSYCHOLOGICAL OUTCOMES – Directed by Jack M. Fletcher, PhD
Director: Jack M. Fletcher, PhD; Department of Psychology, University of Houston, Houston, TX
Title: Hydrocephalus: Why is there variability in neuropsychological outcomes?
Variability is a hallmark of neuropsychological outcomes in congenital and acquired hydrocephalus. Understanding the sources of this variability is a key to understanding mechanisms that influence outcomes and could be factors in treatment. In addition to the mechanical effects of hydrocephalus on the brain, other sources of variability include the brain disorders that cause hydrocephalus, its treatment, genetic expressions, and a host of environmental factors. As the recently initiated MOMS2 fetal surgery trial follow-up demonstrates, outcome assessments should include traditional neuropsychological assessments as well as interview-based measures of adaptive behavior and rating scales.
Speaker: Andrew Zabel, PhD; Department of Neuropsychology, Kennedy Krieger Institute, Baltimore, MD
Title: Spina bifida and hydrocephalus across the lifespan: Part I – Children
Spina Bifida is an important condition-related variable which influences neuropsychological outcome in children with obstructive hydrocephalus. Neuropsychological research efforts have culminated in the emergence of a cognitive phenotype of spina bifida, with features thought to be attributable to primary and secondary neurologic injury. This talk will review the cognitive phenotype of spina bifida as expressed in childhood, and discuss possible cognitive implications for children with other etiologies of obstructive hydrocephalus.
Speaker: Maureen Dennis, PhD; Program in Neurosciences and Mental Health and Department of Surgery, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario
Title: Spina bifida and hydrocephalus across the lifespan: Part 2 – Adults
Living with congenital brain disorders involving hydrocephalus for 30-50 years involves not only cognitive challenges originating in childhood but also new challenges emerging in adult life. This talk will (1) compare the adult cognitive profile of individuals with spina bifida and hydrocephalus with that of children having the same condition, (2) outline new challenges of adult life for those with spina bifida and hydrocephalus, (3) consider the role of hydrocephalus in spina bifida in adulthood, and (4) discuss the implications for treatment, functional independence, and quality of life.
Speaker: Michael A. Williams, MD; The Sandra and Malcolm Berman Brain & Spine Institute, Sinai Hospital, Baltimore, MD
Title: Redeeming Salomon’s Prophesy – Reversible neuropsychological deficits of INPH
Salomon Hakim saw the diagnosis of NPH as affording the opportunity of “rescuing from oblivion” patients who were labeled with senile dementia, but the early failures of shunting in NPH resulted in a generation of skepticism. This presentation will examine Salomon’s prophesy, the nature of the dementia of INPH, its reversibility, and its implications for the INPH outcomes.
Plenary Session 8: NEUROLOGICAL OUTCOMES AND QUALITY OF LIFE – Directed by Abhaya V. Kulkarni, MD, PhD
Director: Abhaya V. Kulkarni, MD, PhD; Departments of Neurosurgery and Neurology, Toronto Hospital for Sick Children, Toronto, Ontario,
Title: Quality of life in children with hydrocephalus
This talk will review general concepts of measuring health-related outcomes in children, with a focus on the specific challenges in improving these outcomes in pediatric hydrocephalus.
Speaker: Paige T. Church; MD, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, Ontario,
Title: Troubled waters: hydrocephalus and the preterm infant
Preterm birth interrupts normal brain development, resulting in “encephalopathy of the preterm” and a unique neurodevelopmental phenotype of prematurity. This talk will review the potential additional damage of hydrocephalus to the developing brain as well as the impact of hydrocephalus on neurodevelopmental outcomes of the preterm infant, focusing on functional outcomes.
Speaker: Mohit Bhandari, MD; Canada Research Chair, Department of Surgery and Clinical Epidemiology, McMaster University, Hamilton, Ontario
Title: Advantages of evidence-based treatments: changing the philosophy of a field and identifying good research
Evidence-based medicine has recently been termed one of the top 10 discoveries in medicine. Changing the paradigm from ‘eminence-based’ to ‘evidence-based’ care requires a focus on the value of high quality evidence and its impact on patient care. This talk will highlight the advantages of EBM, the challenges of conducting high quality research, and the opportunities for surgeons and researchers to lead a major shift in paradigm in Neurosurgery.
18:00 – 19:00 Reception in the Pine Room, Westin Seattle
Wednesday, July 11, 2012
07:00 Continental Breakfast
08:00 Closing Day Welcome
Dr. Richard G. Ellenbogen M.D, Professor and Chair of Neurological Surgery, Theodore S. Roberts Endowed Chair of Pediatric Neurological Surgery, University of Washington
08:05 HYDROCEPHALUS ASSOCIATION LECTURE
Speaker: Paul Gross; Chair, Board of Directors, Hydrocephalus Association
Title: Insights into NIH funding
These sessions are intended to provide a consensus on each of the main focus areas with substantial audience interaction. Initial emphasis will be on the critical issues facing future research as identified in the plenary sessions.
08:45 CAUSES OF HYDROCEPHALUS
Moderator: Pat McAllister, PhD; Primary Children’s Medical Center and the University of Utah, Salt Lake City, UT
Panelists: Esteban Rodriguez, MD, PhD; William Dobyns, MD;
Antonio Jimenez, PhD; Marc Del Bigio, MD, PhD;
Stephen Back, MD, PhD; Jerold Chun, PhD
10:00 DIAGNOSIS OF HYDROCEPHALUS
Moderator: Norman Relkin, MD, PhD; Department of Neurology, Weill Cornell Medical College, New York, NY
Panelists: David Limbrick, MD, PhD; Laurence Watkins, MD;
Richard Morrison, PhD; Mark Wagshul, PhD; William Bradley, MD, PhD
11:00 TREATMENT OF HYDROCEPHALUS
Moderator: Marion (Jack) Walker, MD; Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Utah, Salt Lake City, UT
Panelists: Sam Browd, MD, PhD; Tom Clement; David Watson;
Jay Riva-Cambrin, MD; Benjamin Warf, MD; Richard Edwards, MD;
Richard G. Ellenbogen, M.D.
13:00 OUTCOME IN HYDROCEPHALUS
Moderator: Michael A. Williams, MD; The Sandra and Malcolm Berman Brain & Spine Institute, Sinai Hospital, Baltimore, MD
Panelists: Jack Fletcher, PhD; Andrew Zabel, PhD; Maureen Dennis, PhD; Abhaya Kulkarni, MD, PhD; Paige Church, MD
14:00 CRITICAL SUMMARY OF THE SYMPOSIUM and WHERE WE SHOULD BE IN 3 YEARS
Pat McAllister, PhD; Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Utah, Salt Lake City, UT
Samuel R. Browd, MD, PhD; Department of Neurological Surgery,
Seattle Children’s Hospital and the University of Washington, Seattle, WA
John R.W. Kestle, MD, MSc; Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Utah, Salt Lake City, UT
14:45 Closing Remarks – Paul Gross