Stanford Neurosurgery A continuum of innovation and applications
It is my pleasure to present to you the 2015 Stanford Department of Neurosurgery Book. The members of our department are clinicians and research scientists who are dedicated to join us in our mission of investigating the underlying mechanisms of neurological disease. Together, we are driving forward the most innovative technologies in neurosurgeryâ€”from cutting-edge neuroscience research and clinical trials to the widespread implementation of our resulting innovations. I invite you now to explore the many ways in which Stanford Neurosurgery demonstrates unwavering passion and commitment to performing the very best in neurological disease research, surgery and patient care.
Gary K. Steinberg, MD, PhD Bernard and Ronni Lacroute-William Randolph Hearst Professor in Neurosurgery and the Neurosciences Professor, by courtesy, of Neurology
Table of Contents Neurosurgery Faculty
Neurosurgery Programs Brain Trauma
Cerebrovascular 14 CyberKnife 17 The first hospital in the nation to be verified as a comprehensive Stroke Center by The Joint Commission. This new level of certification recognizes hospitals that have state-of-the-art equipment, infrastructure, staffing and training to diagnose and treat patients with the most complex strokes.
between San Francisco and San Jose, a recognition by the American College of Surgeons of our Emergency Department teamâ€™s ability to treat the most severe and complex cases.
Ischemic Stroke and Postconditioning Treatments
Function and Dysfunction in the Brain
Neurodegenerative Disease: Impact of Gene-Environment Interactions
Neurocognitive Disorders Modeling
Neuronal Mitochondrial Transport and Misregulation
Stereotactic and Functional Neurosurgery
Pediatric Neurosurgery Program
Optogenetic Functional MRI and Brain Network Connectivity
Retinal Neural Circuitry
Stem Cell Transplantation
Spine and Peripheral Nerve
Stem Cellâ€“Based Transplantation for Spinal Cord Injury
The only Level 1 Trauma Center
CyberKnife Treatments: Survival Rates and Outcomes
CD47 Monoclonal Antibody Therapy
Cancer Vaccine for Glioblastoma Multiforme
Medulloblastoma Molecular Characterization
Stroke: Inflammatory Responses and Outcomes 45 Neurosurgery Clinical Trials
Publications 47 Neurosurgery Outreach Clinics
Every day we are inspired to innovate through the stories of our patientsâ€”some who have been devastated by neurological disorders with little or no hope for recovery or function. At Stanford, we feel a responsibility to treat patients with the most difficult and complex problems, actively applying the most advanced care with the latest therapies. â€”Gary Steinberg, MD, PhD
Our multidisciplinary team is at the forefront of emerging breakthroughs in the study and care of neurological disease. We are advancing the way many
therapies and creating stem cell
neurological diseases or injuries,
transplantation therapies to treat the
including stroke, Parkinsonâ€™s
brain following stroke.
disease, moyamoya, epilepsy and brain tumors, are treated. We are restoring function through deep brain stimulation, focused ultrasound, CyberKnife radiosurgery, cellular transplantation, stem cell transplantation and brain-computer interfaces. Significant innovations focused on minimally invasive surgery techniques, from endovascular to
advance, so does our need to rigorously demonstrate that the treatments are effective. Therefore, we have created the new Division of Outcomes Research to help us achieve our goal of providing effective, evidence-based neurosurgery practices.
microscopic surgery, were developed
We adopt both a macroscopic and
a microscopic view to treating our
We continue to be at the forefront of the most exciting clinical trials, some of which are not being performed anywhere else in the world. We are testing vaccines for glioblastomas, developing new anti-tumor CD47
As our technological innovations
patients with neurological diseases, in order to provide the most compreÂ hensive approach. We examine the larger issues of patient health requirements within the community, while simultaneously focusing in
1 FY 2012FY 2010 FY 2013FY 2011 FY 2014FY 2
on individual patient care. Our department has several outreach clinics in the community to provide expert local care and referrals for complex cases. At Stanford Neurosurgery, we
it comes to making a decision about their care providersâ€”they expect and deserve the best. At the intersection of practical science and compassionate care, we are positioned to not only meet, but exceed, all patient expectations.
patients have many choices when
Case Mix Index (severity)
recognize and appreciate that
3 2 1
2010 2011 2012 2013 2014
2010 2011 2012 2013 2014
A relative value assigned to a diagnosis-
The average length of stay for a NeuroÂ
related group of patients in a medical
surgery patient has decreased between
care environment. It has steadily
2010 and 2014 to:
Case Mix Index
3.37 in 5 yrs
Average Length of Stay
STANFORD MEDICINE RESEARCHERS 1.
Marion S. Buckwalter, MD, PhD Assistant Professor, Neurology and Neurosurgery
James R. Doty Professor in Neurosurgery and the Neurosciences, Emeritus
STANFORD MEDICINE PHYSICIANS 1.
Gary Steinberg, MD, PhD, Chairman Bernard and Ronni Lacroute–William Randolph Hearst Professor in Neurosurgery and the Neurosciences and Professor, by courtesy, of Neurology
John Adler, MD
Steven D. Chang, MD
18. Jaimie M. Henderson, MD
Samuel Cheshier, MD, PhD
Bohdan W. Chopko, MD, PhD Clinical Associate Professor, Neurosurgery
Graham H. Creasey, MD Paralyzed Veterans of America Professor, Spinal Cord Injury Medicine
Atman Desai, MD Clinical Assistant Professor, Neurosurgery
Robert L. Dodd, MD, PhD Assistant Professor, Neurosurgery and Radiology
Associate Dean, Post-Graduate Medical Education Professor, Neurosurgery and, by courtesy, of Otolaryngology-Head and Neck Surgery Vice-Chair for Education
17. Melanie Hayden Gephart, MD, MAS
Assistant Professor, Neurosurgery and, by courtesy, of Neurology & Neurological Sciences
16. Griffith Harsh IV, MD, MBA
The Dorothy and Thye King Chan Professor in Neurosurgery, Emeritus
Robert C. and Jeannette Powell Professor in the Neurosciences in the Department of Neurosurgery
James R. Doty, MD, FACS, FICS, FAANS Clinical Professor, Neurosurgery
10. Michael S.B. Edwards, MD, FAANS, FACS, FAAP Lucile Packard Children’s Hospital Professor in Pediatric Neurosurgery and Professor, by courtesy, of Pediatrics
11. Jamshid Ghajar, MD, PhD, FACS Clinical Professor, Neurosurgery
12. Gerald Grant, MD, FACS, FAANS Associate Professor, Neurosurgery and, by courtesy, of Neurology Division Chief, Pediatric Neurosurgery Vice-Chair for Pediatric Neurosurgery
13. Casey H. Halpern, MD Assistant Professor, Neurosurgery and, by courtesy, of Neurology and Psychiatry
14. Ciara D. Harraher, MD, MPH, FRCSC Clinical Assistant Professor, Neurosurgery
15. Odette A. Harris, MD, MPH Associate Professor, Neurosurgery at the Palo Alto Veterans Affairs Health Care System
Pak H. Chan, PhD
Assistant Professor, Neurosurgery
John and Jene Blume–Robert and Ruth Halperin Professor and Professor of Neurosurgery and, by courtesy, of Neurology
19. Laurence Katznelson, MD
Associate Professor, Neurosurgery and Psychiatry and Behavioral Sciences
Chief, Santa Clara Valley Medical Center Clinical Assistant Professor, Neurosurgery
21. Josh Levin, MD Clinical Assistant Professor of PM&R Section, Orthopaedic Surgery and Neurosurgery
22. Gordon Li, MD Assistant Professor, Neurosurgery and, by courtesy, Neurology
23. Jason I. Lifshutz, MD Clinical Associate Professor, Neurosurgery
24. Jon Park, MD, FRCSC Associate Professor, Neurosurgery
25. Randal Peoples, MD, MS Clinical Associate Professor, Neurosurgery
26. John Ratliff, MD, FACS Associate Professor, Neurosurgery Vice-Chair for Clinical Operations and Development
27. Lawrence Shuer, MD Professor, Neurosurgery Vice-Chair for Quality Improvement
28. Harminder Singh, MD Clinical Assistant Professor, Neurosurgery
29. Stephen L. Skirboll, MD Chief, Veteran Affairs Associate Professor, Neurosurgery
30. Suzanne Tharin, MD, PhD Assistant Professor, Neurosurgery
E.J. Chichilnisky, PhD John R. Adler Professor of Neurosurgery
Yoon-Jae Cho, MD Assistant Professor, Neurology and of Neurosurgery
Jun Ding, PhD Assistant Professor, Neurosurgery and, by courtesy, of Neurology
Jin Hyung Lee, PhD Assistant Professor, Neurology, Neurosurgery and Bioengineering and, by courtesy, of Electrical Engineering
Associate Dean, Graduate Medical Education Professor, Neurosurgery and Medicine
20. Marco Lee, MD, PhD
Lu Chen, PhD
Jessica Little, PhD Clinical Assistant Professor, Neurosurgery
Judith Murovic, MD Clinical Assistant Professor, Neurosurgery
10. Theo Palmer, PhD Associate Professor, Neurosurgery Vice-Chair for Basic Research
11. Giles Plant, PhD Associate Professor, Neurosurgery
12. Robert Sapolsky, PhD John A. and Cynthia Fry Gunn Professor and Professor, Neurology and Neurosurgery
13. Gregory Scherrer, PhD Assistant Professor, Anesthesiology, Neurosurgery and, by courtesy, of Molecular and Cellular Physiology
14. Merhdad Shamloo, PhD Associate Professor, Neurosurgery and, by courtesy, of Comparative Medicine and Neurology
15. Ivan Soltesz, PhD Professor, Neurosurgery Vice-Chair for Translational Research
16. Peter Tass, MD, PhD Consulting Professor, Neurosurgery
17. Xinnan Wang, PhD Associate Professor, Neurosurgery
18. Albert Wong, MD Professor, Neurosurgery
19. Heng Zhao, PhD Associate Professor, Neurosurgery
Brain Trauma There's a significant amount of mental resilience that plays into brain injury recovery, and it's something I work on with every one of my patients. I've seen recoveries that are astounding, even though the injuries themselves are devastating. â€”Odette A. Harris, MD, MPH
Nowhere is the continuum of patient care better exemplified than in Stanford’s Brain Trauma Program. Inclusive of clinicians and scientists from Stanford Medicine, Stanford University, and the Veterans Affairs Palo Alto Health Care System (VAPAHCS), this program is dedicated to military and civilian patients with traumatic brain injury (TBI). “TBI is heterogeneous because no two people have the same experience, even
Physician Bios Odette A. Harris, MD, MPH, is an Associate Professor of Neurosurgery and the Director of Brain Injury. She is the Medical Center Associate Chief of Staff of Polytrauma at the VA Palo Alto Health Care System, and Site Director and Principal Investigator of the Defense and Veterans Brain Injury Center Palo Alto. Her clinical focus is neurosurgery, traumatic brain injury and peripheral nerve injuries. Her ongoing research focuses on the epidemiology and outcomes arising from
with what appears to be the same type of injury,” said Director Odette A. Harris,
traumatic brain injury.
MD, MPH. “So there is a focus not only on the quality of individual patient
Jamshid Ghajar, MD, PhD, is a Clinical
care at each stage of treatment, but also a focus on continually assessing and
Professor of Neurosurgery and the Director
streamlining procedures to effectively manage the many complexities of TBI.”
and founder of the Stanford Concussion
An exciting innovation to study concussion was brought to Stanford in 2014 by
the founding member of the Brain Trauma
Jamshid Ghajar, MD, PhD, Director, Stanford Concussion and Brain Performance
Foundation, which is dedicated to improving
Center. Supported by a $21 million Department of Defense grant, Dr. Ghajar and colleagues are testing more than 10,000 subjects in the national EYE-TRAC
and Brain Performance Center. He is also
traumatic brain injury outcomes using best-practice guidelines. Through his clinical research into the full spectrum of brain
Advance study—subjects include athletes and military members at high risk of
trauma, from concussion to coma, he aims
concussion. The EYE-TRAC device is based on several patents that Dr. Ghajar holds
to understand and improve brain health.
and tests attention focus and predictive timing, two traits that can become altered following a concussion. The goal is to employ the eye-tracking device as a key assessment tool in both establishing normal brain attention function and revealing abnormal function in the event of a concussion.
INFLUENCE OF GENDER ON TBI OUTCOMES Dr. Harris and her team have focused recent research initiatives on the influence of gender on TBI outcomes with a focus on the polytrauma (military) population, as in previous studies women have been significantly underrepresented. In their current work, they found that women had markedly higher depression rates and were more likely to be unemployed, despite higher education levels, following a TBI event. These results will have great impact in shaping care decisions and assessing ongoing community needs for female TBI patients, as well as informing decisions regarding optimal resource allocation. Dr. Harris’s study has already earned national attention, being presented at both the Pentagon and the Department of Labor.
STANFORD BRAIN TRAUMA FACTS & FIGURES
300 patients per year for Dr. Harris at Stanford
as part of the TBI inpatient program.
Dr. Harris has been a member of the Executive Committee of the Congress of Neurological Surgeons since 2004.
$21 million grant
was awarded in 2014 by the Department of Defense to Dr. Ghajar to study concussions.
subjects in the national EYE-TRAC Advance study.
Stanford Concussion and Brain Performance Center Drs. Ghajar and Harris are establishing the Stanford Concussion and Brain Performance Center to focus on brain health in athletes. The goal is to perform standard baseline testing for all high-risk Stanford athletes. In the event of a concussion, innovative protocols and novel rehabilitation methods will be employed. The athlete’s progress and recovery will be measured against baseline levels in order to assess his or her readiness to return to play.
300,000 sports-related traumatic brain injuries (TBIs) of mild to moderate severity, most of which can be classified as concussions, occur in the U.S. each year.
Source: Centers for Disease Control and Prevention (CDC). Sports-related recurrent brain injuries— United States. MMWR Morb Mortal Wkly Rep. 1997;46:224–227.
My goal is for Stanford to become the leading brain trauma center, from concussion to coma, in the world. Stanford's name will be synonymous with brain health by educating the community about monitoring brain health so that we can work together to prevent brain trauma. —Jamshid Ghajar, MD, PhD Only Level 1 Trauma Center between San Francisco and San Jose
Brain Tumor Most brain tumors are benign and potentially curable; there is real hope for the successful treatment of malignant brain tumors as well. At Stanford, we're developing highly promising innovative treatments arising from multidisciplinary and collaborative research efforts for malignant brain tumors. â€”Griffith Harsh IV, MD, MBA
Glioblastoma at high magnification
Stanford Brain Tumor Center’s priority—see all patients within 24 hours
Stanford’s Brain Tumor Center is dedicated to providing patients with coordinated, comprehensive and innovative care for tumors of the brain, skull base, pituitary gland and spine. Directed by Griffith Harsh IV, MD, MBA, one of Stanford’s most accomplished and well-respected neurosurgeons, the Center is often referred the most complex cases. Stanford’s multidisciplinary team of experts offers numerous investigative protocols that combine surgery with various forms of chemotherapy, immunotherapy and radiation therapy. One of the Center’s priorities is seeing all patients within 24 hours—many other centers’ timelines are as long as seven days. “If you’re a patient and you find out you have a brain
In association with neuro-oncologists Lawrence Recht, MD,
tumor, you’re not going to be able to think about much
Seema Nagpal, MD, and Reena Thomas, MD, along with
else until you meet with your surgeon. You want to look
radiation oncologists Iris Gibbs, MD, and Scott Soltys, MD,
your surgeon straight in the eye and get them to tell you
Stanford neurosurgeons are developing and testing novel
the plan of exactly how the tumor’s going to be treated,”
Steven Chang, MD, explains. “That’s what I’m always thinking about when I make my decisions as a surgeon. What would I do, what choices would I make—if I or someone in my family had this tumor?” 12
Stanford is currently one of only a few centers in the U.S. using specialized endoports in surgery. This technology can now access deeper brain tumors and produces less overall damage to brain tissue, reducing the chances of subsequent
neurological deficits. Focused ultrasound, one method of tumor ablation, is also being investigated as a tool to open the
Brain Tumor Support Groups
blood-brain barrier and provide targeted
Part of Stanford’s ongoing commitment for community education
therapeutics directly to the brain.
including Phase III testing of the EGFRvIII
Acoustic Neuroma Support Group Brain Tumor Support Group Neurofibromatosis Support Group Meningioma Support Group
vaccine. Developed by Albert Wong, MD,
All of the above support groups above are led by Steven Chang, MD.
Stanford’s pioneering immunotherapy is now at various stages of clinical trial,
it is an anti-cancer therapy against glioblastomas and diffuse intrinsic pontine gliomas. Another Stanford clinical trial combines hypofractionated
radiotherapy and the FDA-approved drug
temozolomide to treat supratentorial glioblastoma multiforme. As a testament
Dr. Harsh is the Principal Investigator
to the innovations occurring at the
for a Phase I clinical trial examining the
Brain Tumor Center, Stanford currently has 13 other clinical trials open for brain tumors.
administration of Vorinostat, a chemotherapy drug, in parallel with stereotactic radiosurgery for the treatment of brain metastases arising from non-small-cell lung cancer.
Physician Bios Griffith Harsh IV, MD, MBA, is a Professor of Neurosurgery. He is the Associate Dean of Post-Graduate Medical Education, School of Medicine. He is the Director of both the Stanford Brain Tumor Center and Stanford Surgical Neuro-Oncology, as well as the Surgical Director of the Stanford Pituitary Center. Dr. Harsh is also Program Director of the Stanford Neurosurgery Resident Training Program as well as the ViceChair for Education. He is an expert in developing investigative protocols that combine neurosurgery with various forms of chemotherapy, immunotherapy and radiation therapy. Steven D. Chang, MD, is the Robert C. and Jeannette Powell Professor in the Neurosciences in the Department of Neurosurgery. He is the Director of the Stanford Neurogenetics Program and the Stanford Neuromolecular Innovations Program, and a Co-Director of the Stanford CyberKnife Program. His clinical focus includes brain tumors, cerebrovascular disease, stereotactic radiosurgery and neurogenetic disorders. His current research includes the characterization of AVM progenitor cells and examining blood vessel growth in response to radiosurgery. Robert L. Dodd, MD, PhD, is an Assistant Professor of Neurosurgery and Radiology. He is a member of the Stanford Cancer Institute and has been an Educational Council Member at the Massachusetts Institute of Technology (MIT) since 2002. Dr. Dodd was trained uniquely as both a neurosurgeon and an interventional neuroradiologist, and his clinical focus is cerebrovascular disease and stroke. He specializes in the use of minimally invasive endoscopic techniques in the treatment of brain tumors. He also performs research relating to stroke and cerebral blood vessel reactivity. Melanie Hayden Gephart, MD, is an Assistant Professor of Neurosurgery. Her clinical practice focuses on the treatment of patients with tumors of the central nervous system. She is also developing novel therapies for primary and metastatic brain tumors. Gordon Li, MD, is an Assistant Professor of Neurosurgery and, by courtesy, of Neurology & Neurological Sciences. He is a member of the Stanford Brain Tumor Center. His clinical and research focus relates to glioblastomas. Additionally, he specializes in minimally invasive surgical procedures and radiosurgery to treat brain tumors. Lawrence Shuer, MD, is a Professor of Neurosurgery. He is also the Vice-Chair for Quality Improvement. His clinical research interests are in the surgical treatment of epilepsy and new developments in the treatment of craniosynostosis, a congenital abnormality of infants' skulls. 13
The Cerebrovascular Neurosurgery Program is one of the largest nationwide and is a specialist referral center for aneurysms and arteriovenous malformations
Physician Bios Gary Steinberg, MD, PhD, is the Bernard
(AVMs). The Stanford Moyamoya Center and the Stanford Stroke Center are two
and Ronni Lacroute-William Randolph Hearst
recognized Centers of Excellence that form part of this exceptional program.
Professor of Neurosurgery and, by courtesy,
Other specialties include cerebral ischemia, intracranial aneurysms, cavernous
a Professor of Neurology & Neurological
malformations and carotid artery disease. Gary Steinberg, MD, PhD, pioneered the surgical treatment of brainstem and thalamic cavernous malformations at Stanford, using various skull-based approaches coupled with real-time electrophysiological monitoring. He has
Sciences. He is the Chairman of the Department of Neurosurgery and the founder and Co-Director of the Stanford Stroke Center. Dr. Steinberg is recognized internationally as a cerebrovascular neurosurgeon specializing in moyamoya disease (MMD) and occlusive
treated over 240 cases to date. In stroke treatment, new minimally invasive surgical
cerebrovascular disease. His extensive
approaches are also continually evolving, such as the use of pipeline stents for
clinical focus also includes neurological
aneurysms. Stroke patients have a wider range of treatment options than ever before, including stem cell treatments that were first initiated at Stanford. Other
surgery, carotid endarterectomy, intracranial aneurysms, cerebrovascular and spinal vascular surgery, arteriovenous malformations
advanced treatments available include endovascular removal of intracranial artery
(AVMs), and cavernous malformations. His
clots and intravenous tissue plasminogen activator (TPA) therapy.
main research focus areas investigate the
Stanford is constantly striving to develop minimally invasive surgeries across
cell therapy for stroke into the clinical arena.
many of its clinical platforms, particularly in the treatment of intracranial
Steven D. Chang, MD, is the Robert C.
hemorrhages. There are no current effective treatments, and the surgical
and Jeannette Powell Professor in the
options for patients with this condition are extremely high risk.
Neurosciences in the Department of
genetics of MMD and the translation of stem
Neurosurgery. He is the Director of the Stanford Neurogenetics Program and of the Stanford Neuromolecular Innovations Program, and a Co-Director of the Stanford CyberKnife Program. His clinical focus includes brain tumors, cerebrovascular disease, stereotactic radiosurgery and neurogenetic disorders. His current research includes the characÂterization of neural stem cells derived from brain tumors, examining blood vessel growth in response to radiosurgery, and the use of microfluidic biochips as a potential diagnostic tool for neurological conditions. Robert L. Dodd, MD, PhD, is an Assistant Professor of Neurosurgery and Radiology. He is a member of the Stanford Cancer Institute and has been an Educational Council Member at the Massachusetts Institute of Technology (MIT) since 2002. Dr Dodd was trained as both a neurosurgeon and an interventional
Stanford Health Care was the first on the West Coast to build an Endovascular Hybrid Suite, a highly specialized operating room. It allows neurosurgeons and neuroradiologists to work together to perform precisely guided neurosurgery as a
neuroradiologist, Doddâ€™s clinical focus is cerebrovascular disease and stroke. He specializes in the use of minimally invasive endoscopic techniques in the treatment of
result of concurrent navigational 3D imaging. This means shorter operating times
brain tumors and stroke. He also performs
and higher surgery success rates for patients.
research relating to stroke and cerebral blood vessel reactivity. 15
Stanford Aneurysm Cases: 1989–2014
'89-'90 '90-'91 '91-'92 '92-'93 '93-'94 '94-'95 '95-'96 '96-'97 '97-'98 '98-'99 '99-'00 '00-'01 '01-'02 '02-'03 '03-'04 '04-'05 '05-'06 '06-'07 '07-'08 '08-'09 '09-'10 '10-'11 '11-'12 '12-'13 '13-'14
The Cerebrovascular team is part of an exciting international clinical trial now entering Phase III: the Minimally Invasive Surgery plus TPA for Intracranial Hemorrhage (MISTIE). It uses stereotactic CT-guided endoscopic surgery to locate and drain clots, and to deliver TPA directly to the hemorrhage site. Results are showing that patients gain better recovery of function and decreased mortality rates, as compared with traditional surgical approaches. Stanford has been a world leader in treatment of AVMs for over 25 years and is successful due to its multidisciplinary approach. Approximately 2,200 AVM patients have been treated with the many varied modalities available. Approximately half of all AVM cases are now treated with radiosurgery using CyberKnife. Other surgical approaches include microsurgical resection and endovascular embolization. Adjunctive techniques and management include electro physiological monitoring, functional brain mapping, surgical navigation, intraoperative angiography, neuro anesthesia and postoperative neurocritical care.
Patient Success Story A hypertensive patient with a major intracranial hemorrhage bleed was admitted to Stanford Health Care. She was experiencing paralysis and was progressing rapidly to a comatose state. Dr. Dodd performed the same surgery as described for the MISTIE trial (Minimally Invasive Surgery plus TPA). The procedure enabled a recovery that Dr. Dodd calls miraculous. Although one of the patient’s arms is still paralyzed, she can now walk again. FAST FACT: Dr. Dodd is one of the only surgeons in the country qualified as both an interventional neuroradiologist and a neurosurgeon.
CyberKnife I think that patients are looking for a personal connection with you as their physician, because they're basically trusting you with their brain. They want to see your philosophy about managing their disease, and that you're interested in their quality of life after the treatment. They want to feel that bond. â€”Steven Chang, MD
Stanford is constantly striving to develop minimally invasive surgeries across many of its clinical platforms, and CyberKnife stereotactic radiosurgery has become an instrumental tool in these advances. The sheer number of neurological disorders that are finding beneficial outcomes from CyberKnife treatment is staggering, and the program, now in its 20th year at Stanford, has treated over 6,500 patients. The technology developed by John Adler, MD, was wholly designed, created and implemented into regular practice at Stanford, and represents one of its greatest innovations to date. In conjunction with advanced 3D imaging, CyberKnife is
cord AVMs using CyberKnife than anywhere else in the
being used to treat disorders ranging from arteriovenous
world. The advantages of using this noninvasive method
malformations (AVM) and acoustic neuromas to skull base
cannot be overestimated, as spinal cord AVMs are very
tumors and trigeminal neuralgia. Griffith Harsh IV, MD,
difficult to remove by traditional surgery, and if located in
MBA, and Robert Dodd, MD, PhD, are leaders in CyberKnife
the high cervical region, they are potentially lethal.
radiosurgery. Harsh treats benign and malignant tumors with CyberKnife, as it has proven particularly effective for elderly patients or those with surgically inaccessible tumors. For metastatic tumors, CyberKnife has become a mainstay of treatment before open surgery, or even in lieu of surgery. He is also currently involved in clinical trials using CyberKnife for brain metastases and lung cancer. Dr. Dodd, together with Steven Chang, MD, Co-Director of the program, uses CyberKnife in the treatment of spinal AVMs. To date, Stanford has treated more patients with spinal
Some of the latest innovations in the program include their partnership with the Interventional Neuroradiology Program, to combine traditional CyberKnife and CT/ MRI imaging with additional 3D cerebral angiography targeting to treat AVMs. Chang, with former Co-Director Iris Gibbs, MD, and colleagues, published a study in the journal Neurosurgery in 2013 describing increased AVM target specificity using this approach, as compared with standard CyberKnife CT/MRI target imaging.
The CyberKnife is also being used to lesion small, selected brain areas in order to treat a range of neurological disorders such as depression, obsessive-compulsive disorder, back pain, hypertension and high blood pressure. Early results are encouraging and could provide patients, especially high-risk surgery candidates, with additional therapy options, as well as reduce the need for ongoing medication treatment. 18
STANFORD CYBERKNIFE FACTS & FIGURES
CyberKnife was invented by Stanford neurosurgeon Dr. John Adler.
Patients treated since 1999, making it the most experienced center in the world.
Steven D. Chang, MD, is the Robert C. CyberKnife can treat diseases and
and Jeannette Powell Professor in the
conditions throughout the body.
Neurosciences in the Department of
BRAIN & SPINE
Neurosurgery. He is the Director of the
• Acoustic Neuroma
Stanford Neurogenetics Program and the
• Anaplastic Astrocytoma • Arteriovenous Malformation (AVMs) • Brain Metastasis
Stanford Neuromolecular Innovations Program, and a Co-Director of the Stanford CyberKnife Program. His clinical focus includes brain tumors, cerebrovascular
disease, stereotactic radiosurgery and
• Gangliocytoma • Germinoma
Scott Soltys, MD, is an Assistant Professor of Radiation Oncology. His clinical and research
• Glioblastoma Multiforme
interests focus on the development of new
radiation techniques involving stereotactic
• Glomus Jugulare Tumor
radiosurgery and radiotherapy for the treat
• Hemangioblastoma • Meningioma
ment of malignant and benign brain and spine tumors, and trigeminal neuralgia.
CYBERKNIFE PROVIDERS AT STANFORD
Steven D. Chang, MD Co-Director CyberKnife Program, Neurosurgery
• Neurofibromatosis • Oligodendroglioma • PNET • Pituitary Adenoma • Schwannoma • Spine Metastases • Trigeminal Neuralgia • Vestibular Schwannoma • Back Pain (on protocol) EXTRACRANIAL SITES • Osteosarcoma • Nasopharyngeal Carcinoma • Squamous Cell Carcinoma • Non-Small Cell Lung Cancer • Small-Cell Lung Cancer • Pancreatic Cancer • Hepatocellular Carcinoma • Prostate Cancer • Renal Cell Carcinoma • Colon Cancer • Ovarian Cancer • Uterine Cancer • Arteriovenous Malformation (AVMs)
Scott Soltys, MD Co-Director CyberKnife Program, Radiation Oncology Nikolas Blevins, MD Otolaryngology–Head & Neck Surgery Mark Buyyounouski, MD Prostate CyberKnife Robert L. Dodd, MD, PhD Neurosurgery and Radiology Michael S.B. Edwards, MD Pediatric Neurosurgery Iris C. Gibbs, MD Radiation Oncology Gerald Grant, MD Pediatric Neurosurgery Steven Hancock, MD Radiation Oncology Griffith Harsh IV, MD, MBA Neurosurgery Robert Jackler, MD Otolaryngology–Head & Neck Surgery John Ratliff, MD Neurosurgery 19
Stereotactic and Functional Neurosurgery
The Stereotactic and Functional Neurosurgery Program has significant expertise in deep brain stimulation for movement disorders and advanced surgical treatments for epilepsy, as well as facial and general pain surgery.
Physician Bios Jaimie M. Henderson, MD, was awarded the prestigious John and Jene Blume–
Some of their newest innovations, translational studies and multicenter
Robert and Ruth Halperin Professorship
clinical trial participations are focused on applying novel therapeutic
in 2014 and is a Professor, by courtesy, of
approaches to the treatment of neurologic and psychiatric disorders and even conditions such as obesity, addiction and depression. Stanford’s program is
Neurology & Neurological Sciences. He directs the Stereotactic and Functional Neurosurgery Program, is the Co-Director
also at the forefront of trialing minimally invasive procedures, such as focused
of the Neural Prosthetics Translational
ultrasound therapy and MRI-guided thermal laser ablation for these disorders.
Laboratory and is also the current
The advanced training offered by this program is accredited by the Society of Neurological Surgeons and is one of only six such programs in North America. Stanford’s functional neurosurgeons utilize deep brain stimulation (DBS) methodologies to improve surgical accuracy, as well as patient comfort and safety, such as frameless techniques and microelectrode mapping procedures. Further innovations are being made with the Radiology Department regarding new imaging techniques, which allow surgeons to refine targeted brain areas intra-operatively.
Director-at-Large of the International Neuromodulation Society. Dr. Henderson is also an Associate Editor of the journals Neuromodulation and Computer Aided Surgery. His clinical focus includes brain computer interfacing, movement disorders and pain. Casey H. Halpern, MD, is an Assistant Professor of Neurosurgery and, by courtesy, of Neurology & Neurological Sciences, and Psychiatry & Behavioral
One of the program’s major goals is to design and implement prosthetic
Sciences. He joined Jaimie Henderson,
systems for patients with paralysis, spinal cord injury and amputations. The
MD, as his partner in Stanford’s
program’s partnership with the Stanford Neural Prosthetics Translational Laboratory has resulted in remarkable progress in the analysis of intracortical readings using surgically implanted silicon electrode arrays. These brain-
Stereotactic and Functional Neurosurgery Program. His clinical focus includes movement disorder surgery, minimally invasive and neuromodulation surgery
computer interfaces (BCI) effectively translate neural activity into control
for epilepsy, and expanding the field of
commands for computer cursors or other prosthetic devices. The team
surgery for psychiatric disorders. His
has already implanted a BCI in a patient with progressive ALS (Lou Gehrig’s disease) as part of the multicenter clinical trial Braingate2: Feasibility Study of
translational research investigates deep brain stimulation techniques in order to ameliorate impulse control disorders
an Intracortical Neural Interface System for Persons with Tetraplegia. One aim
common to multiple neurologic and
of this study is to elucidate the complex differences in the brain’s involvement
psychiatric conditions, with a particular
in neural control (moving computer cursors using only the mind) and motor
focus on obesity and addiction.
control (using a standard computer trackpad). This patient is already showing remarkable and continuing success in using the BCI. She can now type approximately six words per minute and selects targets on a screen with nearly 100 percent accuracy and at twice the speed of previous participants.
FACTS & FIGURES
Dr. Henderson was awarded the prestigious John and Jene Blume–Robert and Ruth Halperin Professorship.
220 100 80
Spinal cord neurostimulation is a treatment treats patients per year implants spinal cord stimulators implants deep brain
not as well known as DBS. It is offered as a treatment at Stanford for nerve-related pain (which can arise from unsuccessful spine surgeries) and complex regional pain syndrome (severe burning, chronic pain).
Interventional Neuroradiology The procedures we use are less invasive and can be more effective than traditional surgical procedures. We continually strive to improve our procedures and tools in order to offer patients the safest and least invasive option for their treatment. â€”Michael Marks, MD
Under the directorship of Michael Marks, MD, the Interventional Neuroradiology Program has made incredible advances in the treatment of vascular disorders in the brain and spine, including aneurysms, carotid stenoses, fistulae and arteriovenous malformations. Treatment options use sophisticated embolization and revascularization procedures. Diagnostic angiography allows the visualization of blood vessels and other anatomy so that accurate diagnoses can be made of the brain, head, neck and spine. Therapeutic angiographic procedures are used to treat aneurysms, vascular malformations and acute stroke. The program has also become a center for vertebroplasty, which is a minimally invasive treatment for spinal compression fractures. The team introduced two new stent devices into
from MRI and CT scanning to help guide interventional
practice in 2012 and 2013, and Stanford Health Care is
procedures. Marks and his team are helping to develop
one of the few institutions that are using both of these
innovative methods to measure cerebral blood flow
devices routinely. The first is a stent retriever that can
directly in the Cath Angio laboratory. Their newest C-Arm
open arteries at the time of acute ischemic stroke.
CT equipment is capable of producing a rotational image
Revascularization rates of occluded arteries in acute
of vascular structures and brain parenchyma at the
stroke have dramatically improved, from 40 percent to
same time as a contrast dye is being injected. Therefore,
over 90 percent. The second device is an intravascular
they can temporally resolve precisely how the contrast
flow-diverting stent that can occlude large and giant
is passing through the brain parenchyma and use that
intracranial aneurysms. These aneurysms previously
information to derive quantitative measures of blood
had no effective therapeutic alternative, and the success
flow. The ultimate goal is to develop a clinical technique
of this treatment is such that approximately half of all
that could eliminate the need for separate blood-flow MRI
aneurysm cases are now being treated endovascularly.
or CT scanning. The exciting potential is that real-time
A key research effort at Stanford has been the use of physiologic information, such as cerebral blood flow
monitoring of therapy administration can occur, helping to inform prognostic and triage decisions during procedures.
FACTS & FIGURES
diagnostic cerebral and spinal angiography cases performed per year.
cases per year in which endovascular techniques are used.
CLINICAL TRIALS HIGHLIGHTS
Interventional neuroradiology is part of the
multicenter SCENT trial, to examine an enhanced endovascular flow diverter for wide neck intra cranial aneurysms that cannot be glued, clipped or coiled using standard methods. The device offers an alternative treatment method for this aneurysm type that carries a high risk of rupture,
47-year-old patient with ophthalmoplegia and a large cavernous aneurysm
failed occlusions and complications during
Upper left: Conventional angiographic picture of the aneurysm. Upper right: 3D image reconstructed from the rotational angiogram. Lower left: The flow diverting device (blue arrow) has been placed. Lower right: The conventional angiogram six months later, after the aneurysm has thrombosed.
endovascular or surgical treatment.
Stanford is home to many trials for acute ischemic stroke. The DEFUSE trials are examining the use of physiologic MRI brain imaging in acute ischemic stroke patients to determine the best candidates for endovascular procedures. Stanford is also participating in the CRISP trial to predict patient response to recanalization using CT-based perfusion imaging.
The stent devices we're now routinely using are generating very impressive results and shorter operation times. Time is brain— you want to be using devices that are effective and fast to optimize patient outcomes. —Robert L. Dodd, MD, PhD
Physician Bios Michael Marks, MD, is a Professor of Radiology and, by courtesy, of Neurosurgery. He is the Chief of Interventional Neuroradiology in the Department of Radiology and the Director of Neuroradiology at the Stanford Stroke Center. Dr. Marks has been a pioneer in the field of interventional neuroradiology at Stanford for over 25 years. His clinical focus includes cerebrovascular disorders, stroke treatment and imaging, brain aneurysms, cerebral arteriovenous malformations, and diagnostic radiology. He performs ongoing research exploring new ischemic stroke treatments, the endovascular treatment of intracranial atherosclerotic disease, and the management of cerebral arteriovenous malformations. Robert L. Dodd, MD, PhD, is an Assistant Professor of Neurosurgery and Radiology. He is a member of the Stanford Cancer Institute and has been an Educational Council Member at the Massachusetts Institute of Technology (MIT) since 2002. Dr. Dodd was trained uniquely as both a neurosurgeon and an interventional neuroradiologist, and his clinical focus is neurological surgery. He specializes in the use of minimally invasive endoscopic techniques in the treatment of brain tumors. He also performs research relating to stroke and cerebral blood vessel reactivity. Huy M. Do, MD, is a Professor of Radiology and, by courtesy, of Neurosurgery. He has held the position of Fellowship Director for the Neuroradiology Program at Stanford since 2004. Dr. Do is a Professor, by courtesy, of Neurosurgery, as well as an active member of Bio-X. His clinical interests include interventional neuroradiology, endovascular neurosurgery, cerebral aneurysm coiling, brain AVM (arteriovenous malformation) and stroke.
The Stanford Moyamoya Center is a Center of Clinical Excellence and is directed
FACTS & FIGURES
by Gary Steinberg, MD, PhD, who is recognized as the world’s leading expert on moyamoya disease (MMD). He and his team have treated over 1,200 patients with this chronic and progressive disease. Surgical revascularization (direct or indirect) is undertaken once a diagnosis has
Moyamoya means “a hazy puff of smoke” in Japanese
been confirmed via cerebral angiography. In direct vascularization procedures alone, the team has achieved over 98 percent graft patency with excellent long-
term patient outcomes. They have also reduced the five-year risk of recurrent
appearance of the arterial enlargement and
the 17 percent noted in a previous study. Occlusion times during surgery are
profusion of tiny vessels that result from the
being constantly reduced, and procedures can now be performed with bypass
blockage. Patients can suffer multiple strokes,
times from 11 to 22 minutes.
stroke following revascularization to approximately 5.5 percent, a reduction from
Refers to the unusual angiographic
transient ischemic attacks (TIA), hemorrhages, headaches and cognitive decline before an accurate diagnosis is determined.
Intraoperative flow measurements during surgery represent another program innovation. Using this real-time data helps predict graft patency, and also helps
The disease can be associated with many
prevent perioperative complications such as stroke, transient neurologic
other genetic disorders, including sickle cell
deficits and hemorrhage.
anemia, Down syndrome and some types of dwarfism. The team is currently investigating
Significant advances are being made in indirect revascularization, a technique
the genetic basis of moyamoya using
often employed in children younger than five. Laparoscopic omental-cerebral
chromosomal analysis and genome wide sequencing.
transposition is an indirect method that was developed at Stanford. A portion of the omentum is laparoscopically transported to the brain’s surface in order to provide the needed blood flow pathways. Eight of these incredibly complex and delicate procedures have been successfully performed at since 2011, 15 in
DEMOGRAPHICS OF MOYAMOYA PATIENTS TREATED AT STANFORD
total since 2009. Steinberg’s 2014 article published in Neurosurgery details the refined laparoscopic method used to safely and effectively achieve angiographic revascularization and resolution of ischemic symptoms in MMD patients. Hispanic
Steinberg is also researching the neurocognitive and psychological aspects of
MMD in patients where stroke has not yet occurred. Their study in 2012 found
Asian Black Caucasian
a surprisingly high incidence of depression and anxiety among MMD patients, as well as significantly impaired cognitive abilities. Neuropsychological testing revealed that around 23percent of those patients already had significant cognitive impairment. This indicates that the chronic lack of blood flow may in fact be causing problems even before patients experience overt strokes. Additionally, approximately 37 percent of the patients already had significant depression or anxiety. This has led the team to consider the important question of determining whether surgical revascularization in MMD patients can inhibit or even prevent
STANFORD MOYAMOYA FACTS & FIGURES
790+ cases Moyamoya Disease FAQs 1,177 bypass procedures IS MOYAMOYA CURABLE?
Moyamoya is a progressive disease that does not improve without surgical treatment. While moyamoya itself is not curable, surgery to provide alternative blood flow to the brain
of moyamoya disease treated by Dr. Steinberg and his team to date
1991 year of Dr. Steinberg’s first moyamoya disease surgery
prevents the symptoms related to moyamoya and can provide an excellent long-term outcome with significant stroke risk reduction. IS MOYAMOYA DISEASE GENETIC?
Moyamoya disease runs in families approximately 10 to 12 percent of the time in Dr. Steinberg’s series. Although there is no direct genetic link identified, we recommend that if more than one family member has moyamoya, others be tested for the disease, especially if there are symptoms. Screening tests for family members might include an MRI/MRA head scan. WHAT ARE THE MOST COMMON SYMPTOMS WHEN PATIENTS ARE DIAGNOSED WITH MOYAMOYA?
Patients most commonly present with strokes, mini-strokes (TIAs) and/or headaches.
of Stanford’s patients have
Stroke symptoms can include numbness or weakness in the extremities, visual changes
moyamoya in their families
and/or difficulty speaking or understanding words. WHAT IS NEUROPSYCHOLOGICAL ASSESSMENT AND WHY DO IT?
Neuropsychological assessment is an evaluation of your cognitive abilities or thinking skills. Examples of such abilities are memory, planning/organizing and language. Cognition may be changed by moyamoya disease. The assessment helps the team know if any of these abilities have been affected. It also provides documentation or a baseline of cognitive abilities before surgery. This can be compared with the results of a second assessment that is performed after surgery.
We have the largest referral base in the world. We have treated over 790 cases of moyamoya disease from 47 states in the U.S. and treated hundreds of international patients from 16 other countries, including patients from Japan, where the disease was first characterized. —Gary Steinberg, MD, PhD
Annual reunions for Stanford’s moyamoya patients and their families began in 2005. By adding a Facebook group in 2010, Stanford has developed an even larger extended support system for patients and their families.
Pediatric Neurosurgery Program
My approach is to treat each child like my very own. —Gerald Grant, MD
Physician Bios Michael S. B. Edwards, MD, is the Endowed Professor of Neurosurgery and Pediatrics (Lucile Packard Children’s Hospital and Stanford University School of Medicine),
The Pediatric Neurosurgery Program, directed by Gerald Grant, MD, offers
and also, by courtesy, of Pediatrics. He
comprehensive care for the full range of neurosurgical brain, spinal cord
is Co-Director of the Children’s Brain
and peripheral nerve disorders in children. New innovations include a robust endoscopic micro-neurosurgical program in conjunction with Peter
Tumor Center and the Regional Director of Pediatric Neurosurgery. He is a nationally recognized pediatric neurosurgeon who has
Hwang, MD. The team performs complex skull-based surgery via a trans-
been named one of America’s Top Doctors
nasal endoscopic route rather than a formal craniotomy, which is a rarity for
since 2011. His clinical focus is on the
pediatric programs. Grant has provided expert training for the team in complex brain tumors, surgical epilepsy, and minimally invasive endoscopic techniques for the management of hydrocephalus and craniosynostosis. The team is also performing choroid plexus cauterization in combination with endoscopic third ventriculostomy surgeries, as an effective alternative to the traditional shunt procedures used in hydrocephalus cases. Phrenic nerve stimulators are now used in patients with respiratory insuf
microsurgical treatment of central nervous system pediatric tumors. Gerald Grant, MD, is the Division Chief of Pediatric Neurosurgery, and an Associate Professor of Neurosurgery and, by courtesy, of Neurology & Neurological Sciences. He is also the Vice-Chair for Pediatric Neurosurgery. His clinical focus is on pediatric epilepsy surgery, pediatric brain
ficiencies. The devices stimulate the phrenic nerve leading to the diaphragm
tumors, Chiari malformations, endoscopic
and regulate breathing, essentially acting as pacemakers for the lung.
craniofacial surgery and minimally invasive
Significant advances in imaging are also being developed by the team.
investigating the relationships between the
Pediatric neurosurgeon Samuel Cheshier, MD, PhD, and Kristen Yeom, MD, in the Radiology Department, are exploring the nanoparticle Feraheme to visualize (via MRI) tumor-associated macrophages, with the goal of using this as a biomarker for the efficacy of anti-CD47 cancer treatments and also for brain arteriovenous malformation visualization. Cystine-knot miniproteins,
endoscopy procedures. His research is blood-brain barrier and trauma, tumors, and vascular disease. The goal is translating his findings into measurable beneficial improvements for his patients. Samuel Cheshier, MD, PhD, is an Assistant Professor of Neurosurgery and, by courtesy,
or knottins, are currently being investigated in collaboration with Stanford
of Neurology & Neurological Sciences.
bioengineer Jennifer Cochran, PhD, as a targeting device to maximize tumor
He was awarded the prestigious William
resection during surgery. Surgeons can apply or inject fluorescent knottins that are tumor-specific, and therefore have the capacity during surgery to visualize tumor margins for resection with greatly increased specificity. Grant and Cochran were also recently awarded a $1.37 million grant from the Stanford Child Health Research Institute regarding the transportation of an engineered tumor-targeting peptide across the blood-brain barrier. Pediatric epilepsy continues to be a major focus of the program. Grant is now
P. Van Wagenen Fellowship in 2008 and the Tashia and John Morgridge Faculty Scholarship in Pediatric Translational Medicine in 2013. His clinical focus is on pediatric tumors of the brain and spine, and he heads his own research laboratory that primarily investigates changes in cell surface molecules on cancer stem cells derived from malignant pediatric brain tumors.
using Visualase, a novel and minimally invasive MRI-guided laser technology that ablates brain lesions, for selected epilepsy cases. He is also collaborating with the Stanford Comprehensive Epilepsy Program team on a cognitive brainmapping project in order to understand brain network activity in epilepsy.
What's unique about our program at Stanford is that we offer our patients a one-stop shop for the most up-to-date approaches in pituitary disease management. We have a superb team that focuses on combining our clinical research, our surgical advances, and our new drug development trials for the benefit of the patient. —Laurence Katznelson, MD
Physician Bios Griffith Harsh IV, MD, MBA, is a Professor of Neurosurgery and, by courtesy, of Otolaryngology–Head and Neck Surgery. He is the Associate Dean of Post-Graduate Medical Education, School of Medicine. He is the Director of both the Stanford Brain Tumor Center and Stanford Surgical NeuroOncology, as well as the Surgical Director of the Stanford Pituitary Center. Dr. Harsh is also Program Director of the Stanford
The Stanford Pituitary Center specializes in the treatment of pituitary disorders
Neurosurgery Resident Training Program and
including endocrine active and inactive pituitary adenomas and pituitary hormone
Vice-Chair of Education. One of Stanford’s
deficiencies. Its comprehensive program offers diverse treatment options for patients. The program’s Medical Director, Laurence Katznelson, MD, is an endocrinologist
most accomplished neurosurgeons and in practice for nearly 30 years, he is an expert in developing investigative protocols that
specializing in the diagnosis and management of prolactinomas, acromegaly and
combine neurosurgery with various forms
Cushing’s disease, as well as hypopituitarism and growth hormone deficiency.
of chemotherapy, immunotherapy and
Neurosurgeon Griffith Harsh IV, MD, MBA, is the program’s Surgical Director.
He and Robert Dodd, MD, PhD, specialize in minimally invasive endoscopic
Laurence Katznelson, MD, is a Professor
surgical treatment of pituitary tumors. Harsh is also an expert in stereotactic
of Neurosurgery and of Medicine—
radiosurgery of tumors in the region of the pituitary gland. The program’s advances in endoscopic techniques have allowed the team to manage increasingly complex pathologies. Anterior skull-based pathologies, such as very large meningiomas and esthesioneuroblastomas that traditionally could be treated only via a craniotomy, can now be removed endonasally. Many trigeminal schwannomas, another benign skull base tumor traditionally
Endocrinology, Gerontology & Metabolism. He is the Medical Director of the Stanford Pituitary Center. He has been consistently named one of the Best Doctors in America since 2005. His clinical focus includes endocrine disorders and pituitary tumors. Robert L. Dodd, MD, PhD, is an Assistant Professor of Neurosurgery and Radiology.
treated by craniotomy, can now be successfully treated with endoscopic
He is a member of the Stanford Cancer
surgery at Stanford. CyberKnife stereotactic radiosurgery is frequently used to
Institute and has been an Educational
treat lesions located in areas that cannot be safely accessed by the endoscopic approach alone. It is also used as an adjunct to treat aggressive pathologies such as chordomas and chondrosarcomas metastases that can have a high recurrence rate even if fully resected.
Council Member at the Massachusetts Institute of Technology (MIT) since 2002. He is trained uniquely as both a neurosurgeon and an interventional neuroradiologist, and his clinical focus is pituitary tumors. He specializes in the use of minimally invasive
Drs. Katznelson, Harsh, Dodd and colleagues published a study in 2014
endoscopic techniques in the treatment
in the journal Endocrine Practice describing the utility of monitoring
of pituitary tumors and stroke. He also
adrenocorticotropic hormone (ACTH) levels following transsphenoidal surgery for Cushing’s disease patients. They showed that if ACTH levels are significantly
performs research relating to stroke and cerebral blood vessel reactivity.
lowered following surgery, the tumor is much less likely to recur. The clinical benefits of monitoring ACTH measurements postoperatively are twofold. Elevated ACTH levels can indicate that the tumor may not have been completely resected, and the patient may need to be readmitted for further surgery. Conversely, a stable decrease in ACTH levels is indicative that the tumor has likely been fully resected. Further research is being performed with the goal of establishing ACTH measurements as a standard postoperative monitoring tool. 31
Stem Cell Transplantation
Sonia Olea, 31, suffered a severe stroke and has regained her life with the help of stem cell therapy treatments at Stanford.
The results we're seeing from the stem cell therapy stroke trial are actually changing our whole idea of recovery. We thought it was going to be impossible for circuits we presumed dead to work again after a stroke, but in fact our results are showing that it may actually be possible to resurrect these circuits. That's very exciting for us and for stroke victims. â€”Gary Steinberg, MD, PhD 32
The Stem Cell Transplantation Program is a cross-disciplinary program making incredible advances in research and pre-clinical treatments for over 15 years at Stanford. The overarching goal is to investigate promising cellular transplantation therapies for neurological injury or disease and cancer. In addition, drugs, proteins and other novel molecules are being explored as potential concurrent therapies to enhance the efficacy and survival of transplanted stem cells. A $20 million Disease Team Research Grant from the
Translation of basic research findings to safe cell-based
California Institute of Regenerative Medicine was awarded
therapies that can be tested in clinical trials is a major
to study the use of human embryonic-derived neural stem
focus. The team has participated in two major clinical
cells (NR1) in the treatment of motor deficits following
trials that are generating encouraging preliminary results.
ischemic stroke. This five-year grant is exploring preclinical mechanisms, pharmacology, and toxicology questions associated with NR1 cells. Significant pre-clinical outcomes, such as motor function improvements and attenuation of post-stroke inflammation and vascular leakage, are encouraging toward the translation of this product into clinical trials for subacute and chronic stroke victims.
The first was the Geron Phase I multicenter clinical trial studying the effects of embryonic-derived stem oligodendrocyte precursors (GRNOPC1) in spinal cord injury patients. Proof of concept studies show that GRNOPC1 has the ability to produce neurotrophic factors, remyelinate denuded axons and improve locomotor recovery. Results from the trial thus far have shown the
Figures: Images of human neural stem calls in culture.
Highlights for the FUTURE OF STEM CELL USE AT STANFORD Program Director Gary Steinberg, MD, PhD, has recruited faculty including Giles Plant, PhD, Theo Palmer, PhD, and Samuel Cheshier, MD, PhD, whose research holds great promise for successful stem cell transÂ plantation strategies for spinal cord injury, autism spectrum disorders and brain tumors. The Stem Cell Transplantation Program is truly cross-disciplinary, bringing together clinicians and researchers from departments including Neuroscience, Engineering, Physics, Material Sciences and Genetics. CELL LINE NR1 Stem cell therapy for stroke is an upcoming and exciting reality. The programâ€™s research is focusing on the cell line NR1, derived from the embryonic stem cell line H9. Currently, it is the only non-genetically modified, allogeneic neural stem cell intended for chronic stroke treatment. STROKE Cell transplantation therapy for stroke and other neurological diseases holds great promise. Stanford is committed to resolving many of the fundamental issues surrounding
treatment to be safe and feasible. Other stem cell transplant trials for spinal cord injured patients are currently being initiated at Stanford. Stanford was the major site participating in the first North American clinical trial investigating intraparenchymal stem cell transplantation therapy, for
stem cell therapies by prioritizing their
patients with persistent disability following ischemic stroke. In conjunction
pre-clinical studies, in order to ensure that
with SanBio, the company producing the modified adult bone marrow
potential future treatments are feasible and safe for patients.
stromal cells (SB263), this Phase 1/2A study enrolled 18 patients to study the cells' safety and to ascertain motor, sensory, and cognitive ability following transplantation. Early and encouraging results show that patients have significant recovery in motor and language function when examined at six months, and sustained improvement at one year. Plans are currently
$20 million grant
A Disease Team Research I Grant from the California Institute of Regenerative Medicine was
underway to conduct additional trials with larger patient cohorts.
Stanford, from the beginning, has been involved in a lot of the early
awarded to study the use of human embryonic-
preclinical studies in animal models showing the benefits of stem cell
derived neural stem cells (NR1) in the treatment
transplantation for various diseases. What's really exciting now is
of motor deficits following ischemic stroke.
taking those next steps in developing stem cell therapies and bringing them to clinical trials. â€”Gary Steinberg, MD, PhD
Spine and Peripheral Nerve
Physician Bios John Ratliff, MD, is an Associate Professor of Neurosurgery. He is the Co-Director of the Division of Spine and Peripheral Nerve Surgery and the Vice-Chair for Clinical Operations and
The more quality information I have available to me through our new data capture process, the better decisions I'm going to make as a clinician for the best care of my patients. —John Ratliff, MD
Development. He also directs the Stanford Joint Neurosurgery/Orthopaedic Spine
Co-directed by Jon Park, MD, and John Ratliff, MD, the Division of Spine
Surgery Spine Fellowship Program. Ratliff’s
and Peripheral Nerve Surgery is a leader in evidence-based neurosurgery
clinical focus includes minimally invasive surgical techniques for laminectomies,
and outcomes research. Thousands of spinal and peripheral nerve injury
spinal metastases and interbody fusions. His
conditions are treated each year using minimally invasive surgical methods,
research interests include the development
interventional spine services and established conservative therapy methods.
of patient tools and databases to effectively
Increasingly sophisticated methods are being offered, including CyberKnife
predict adverse risk events in spinal surgery. Ratliff is also committed to developing online
radiosurgery and magnetic resonance neurography. The team was also
teaching resources for both spine and
accredited in 2012 by the Society of Neurological Neurosurgeons for the
peripheral nerve surgery.
Joint Neurosurgery/Orthopaedic Spine Surgery Spine Fellowship and is
Jon Park, MD, is an Associate Professor of Neurosurgery and Chief of Spine Neurosurgery. Park has served as Director for the Compre hensive Spine Neurosurgery Program and
indicative of Stanford’s commitment to providing comprehensive training to its residents.
With Stanford University’s strengths in biostatistics, computer modeling
Spine Fellowship and Spine Research Programs
and basic science, surgeons and scientists are collaborating on translational
at Stanford Medical School. His clinical interests
research projects dedicated to improving patient outcomes and achieving
include minimally invasive spine surgery, spine
the best possible care. Since Dr. Ratliff joined Stanford Health Care in 2011, his
trauma, CyberKnife for spine tumors, spine tumor surgery, spine deformity surgery and
research goal has been one of continuous quality improvement in the areas of
spine and peripheral nerve surgery.
Atman Desai, MD, is a Clinical Assistant
He has introduced a sophisticated system to capture quality-of-life metrics.
Professor of Neurosurgery. Desai specializes
Through an electronic data entry system, patients fill out baseline quality-of-
in the minimally invasive surgical treatment of complex spinal conditions including tumor
life questionnaires at their initial consultation and postoperative follow-ups.
degenerational spine diseases, spinal trauma
Ease of accessibility is vital to the collection of high-quality data. Stanford
patients log directly into their medical records—the very same records that
Josh Levin, MD, is a Clinical Assistant
their physicians access—using iPhone or iPad apps to enter their information
Professor of PM&R Section, Orthopaedic
easily. Stanford is the first in the nation to seamlessly integrate these quality-
Surgery and Neurosurgery. He is a triple board
of-life outcomes directly into patient medical records.
certified physiatrist who specializes in the diagnosis and nonsurgical treatment of spine
This enhanced data assists in informing individual surgery choices and day-
to-day patient care, and also contributes to the larger goal of accurately evaluating adverse-event risks. Database modeling is a key focus of the program. Collaborating with the Health and Research Policy and Biostatistics Departments enables the team to use large database mining to develop specific algorithms and models of risk prediction. Data generated includes output aggregate risk of adverse events, and risks of specific adverse events based on a patient’s co-morbidities and diagnosis. Therefore, knowledge of complications or adverse-event occurrence in spine surgery will greatly enhance the quality of care for patients.
Translational Research The Department of Neurosurgery is a world leader in the fast-paced environment of innovative research translation. The rich intellectual environment at Stanford, paired with our accessibility to the most advanced technology, is unmatched and ensures the rapid translation of pioneering laboratory research into life-saving clinical therapies for our patients. Our research scientists have been awarded millions of dollars in grants from prestigious funding bodies, such as the National Institutes of Health (NIH), the California Institute for Regenerative Medicine (CIRM) and the Department of Defense (DOD). Thanks to this critical funding, rapid progress is being made as our research scientists tackle the most complex neurological disease questions in the neurodegenerative and neuroregenerative fields today. In this section, we highlight some of our departmentâ€™s most talented scientists and their translational research endeavors, from anti-cancer therapies and stem cell transplantation therapies for spinal cord injury to the elucidation of retinal neural circuitry and gene-environment interactions in fetal development. 37
Basal Ganglia Effects on Motor Behavior and Disorders Jun Ding, PhD, researches interconnected relationships between the motor cortex, sensory cortex, thalamus and basal ganglia. By elucidating how basal ganglia guide motor behavior, he seeks to construct detailed psychomotor disorder circuit diagrams. These will help to inform
up-state down-state 5 mV
the pathophysiological changes in movement disorders, such as Parkinson’s disease (PD) and Huntington’s disease. He is also examining brain circuitry related to habit learning in the context of compulsive drug and alcohol addiction. Dr. Ding’s alcohol addiction research has revealed a specific protein mutation linked to alcoholism
in certain human populations. He has shown that this protein is directly linked to neurotransmitter
mutation can, therefore, increase susceptibility to compulsive alcoholism. His goal is to develop
release mediated by midbrain dopamine neurons, and that alcohol can inhibit this pathway. This a therapeutic targeted toward this protein mutation. He is also collaborating with Nicholas Melosh, PhD, in the Department of Materials Science and Engineering in developing a deep brain stimulation (DBS) tool using nanofiber bundles. Multiple
stimulation points can be applied simultaneously to create different spatial and temporal patterns that ameliorate the motor symptoms observed in PD for laboratory research. This also has exciting clinical implications, in that brain area targeting during PD treatments could be achieved with greater specificity, therefore increasing the efficacy of DBS treatment overall for patients.
Jun Ding, PhD, is an Assistant Professor of Neurosurgery and, by courtesy, of Neurology. His research
centers on understanding the connections between cellular events and circuit mechanisms under
lying motor behavior by studying basal ganglia processes. His laboratory uses advanced 2-photon microscopy imaging techniques together with electrophysiological, optogenetic and genetic tools. Left image: Dendritic spike generated by local stimulation revealed by calcium imaging. (A) A striatal neuron loaded with Alexa 594 showing position of stimulated dendrite and stimulating theta electrode. (B) Somatic voltage recording in response to stimulation. (C) Image of stimulated dendrites filled with Fluo4 at baseline (D-E) location of calcium hot spot during local stimulation at down- (D) and up-state (E). Arrows show Ca2+ hot spots.
CD47 Monoclonal Antibody Therapy: Treating Brain Malignancies Research in the laboratory of Samuel Cheshier, MD, PhD, isolates stem
types of malignant brain tumors have been successfully eradicated with anti-
cells and progenitors from normal brain and brain tumor samples, in
CD47 therapy, and significantly, normal brain cells are not affected.
order to determine the genetic and epigenetic events that differentiate these cells from normal neural stem cells. By understanding these critical differences, the team aims to develop targeted therapies against many brain malignancies, including medulloblastomas, pediatric glioblastomas and diffuse intrinsic pontine gliomas. Dr. Cheshier has been at the forefront of Stanford Health Care and University’s most exciting cancer research to date in conjunction with Irving Weissman, MD. He is targeting a cell surface molecule, CD47, which is overexpressed on tumor cells. CD47 stops the clearance of the tumor cells by the immune system and therefore allows them to propagate. This finding has been pivotal to creating a CD47 monoclonal antibody therapy, in a truly collaborative project between scientists and clinicians and performed wholly at Stanford. Laboratory results from their animal studies are striking. Several 38
Anti-CD47 therapy also has great potential as an adjunct to surgery in that it may decrease the need for radiation and/or chemotherapy following primary tumor resection, and also as an adjunct treatment to enhance existing cancer immune therapies.
Samuel Cheshier, MD, PhD, is an Assistant Professor of Neurosurgery and, by courtesy, of Neurology & Neurological Sciences. He was awarded the prestigious William P. Van Wagenen Fellowship in 2008 and the Tashia and John Morgridge Faculty Scholarship in Pediatric Translational Medicine in 2013. His clinical focus is on pediatric tumors of the brain and spine, and he heads his own research laboratory that primarily investigates changes in cell surface molecules on neural stem cells derived from malignant pediatric brain tumors.
Cancer Vaccine for Glioblastoma Multiforme His key discovery began with the identification of a genetic variant of the normal EGF receptor,
Medulloblastoma Molecular Characterization
called EGFRvIII, which is expressed only on tumor cells. Dr. Wong designed a vaccine that targets
Yoon-Jae Cho, MD, is a clinician-scientist
EGFRvIII without affecting normal cells. Animal modeling has shown that the vaccine, now called
whose detailed molecular characterization
Rindopepimut, can induce regression of existing tumors and prevent formation of new tumors.
of childhood brain tumors is helping not
Albert Wong, MD, has been engaged for over 25 years in developing one of the most promising cancer vaccines to date against glioblastoma multiforme, the most aggressive type of brain tumor.
This has led to Phase I and Phase II clinical trials of the vaccine in glioblastoma patients. The trials have produced consistent data showing an excellent safety profile and significant increases in patient median survival. In conjunction with Celldex Therapeutics, a multicenter international Phase III clinical trial is now underway with multiple participating sites in the U.S., including Stanford. The study aims to establish Rindopepimut’s efficacy, when administered in conjunction with the standard radiation therapy/temozolomide regimen for glioblastomas. He is also investigating the importance of EGFRvIII’s role in maintaining glioblastoma cancer stem cell populations. In 2014, he published with colleagues a study in the journal Cancer Research showing that within glioblastoma stem cell populations, a subpopulation of those cells expressing EGFRvIII and CD133 had the highest degree of self-renewal and tumor-imitating ability. This subpopulation therefore may represent the most specific target for drug therapy to eliminate this cancer.
only to inform their diagnosis and prognosis, but also to improve on current available therapies. Dr. Cho actively participates in several national clinical trials. He co-chairs the Biology Committee of the Pediatric Brain Tumor Consortium, the largest consortium solely dedicated to conducting early phase clinical trials for children with brain tumors. He is also a member of the CNS committee of the national Children’s Oncology Group. Seminal work published by Dr. Cho in 2010 identified distinct molecular subtypes of medulloblastoma—the most common malig nant brain tumor in children—and described their association with patient outcomes. These findings have had significant clinical relevance, allowing clinicians to better predict a patient’s clinical course and to modify treatment based on their tumor’s molecular profile. In 2012, Dr. Cho and colleagues also published three landmark back-to-back articles in Nature, the first publications describing whole genome sequencing of medulloblastomas. His current research employs sophisticated genomic assays and screening techniques to understand the behavior of medulloblastomas and pediatric high-grade gliomas. This form of functional genomics aims specifically to identify genes essential to these cancers’ survival, which also represent novel targets for therapy.
Cancer stem cells derived from a glioblastoma patient that were labeled for the presence of EGFRvIII (green) and normal EGF receptor (red). Yellow is seen if cells have the presence of both proteins. Nuclei of cells are stained with DAPI (blue).
Yoon-Jae Cho, MD, is an Assistant Professor of Neurology and of Neurosurgery. He focuses on child neurology and neuro-oncology in his clinical practice, and is also the
Albert Wong, MD is a Professor of Neurosurgery and a member of the Stanford Cancer Institute. His research is focused on the development of potential cancer therapeutics by investigating the signal transduction proteins and associated pathways of tumor cells. Dr. Wong discovered, and continues to refine, an effective peptide vaccine as a treatment for glioblastoma multiforme and its potential as a
Principal Investigator of his own laboratory. He seeks to genetically characterize and understand medulloblastomas and high grade pediatric gliomas.
treatment for lung, breast, ovarian and prostate cancers. 39
CyberKnife Treatments: Survival Rates and Outcomes Judith Murovic, MD, is a Stanford neurosurgeon with extensive oncological
Performing a detailed comparison of overall survival rates will determine
neurosurgery experience. A member of the CyberKnife radiosurgery team
the outcomes of that treatment form in both patient groups. The study
for over three years, she oversees all aspects of this treatment form. This
contains both retrospective and prospective patient cohorts, in order to
includes the contouring of treatment targets that requires intricately
gain the best possible survival rate determinations. The study will also
detailed mapping based on fused computerized tomographic (CT) and
characterize the types and relative sizes of primary tumors and their
magnetic resonance imaging (MRI) scans.
relationship to the number of brain metastases that develop.
She is co-investigator in an upcoming Phase I clinical trial with Steven
Dr. Murovic is also the primary author of several comprehensive World
Chang, MD, and Iris Gibbs, MD, that will compare survival rates of patients
Neurosurgery Perspective reviews, on topics including meningioma
with one to three brain metastases versus four or more metastases,
genetic aberrations affecting stereotactic radiosurgery outcomes and
following treatment of these lesions with CyberKnife radiosurgery.
laser interstitial thermal therapy in radiation necrosis. Her ongoing research in the Neurosurgery Spine laboratory involves spinal adjacent segment disease. Judith Murovic, MD, is a Clinical Assistant Professor of Neurosurgery and is a member of the Stanford University Medical Center CyberKnife Radiosurgery (CK RS) Treatment Center. In addition to coordinating CK RS treatments, she has clinical interests in neurosurgery and reconstructive
This is the physics isodose plan of a patient who underwent CyberKnife radiosurgery treatment for two non-small cell lung adenocarcinoma brain metastases to the left high parietal and left high frontal lobes.
peripheral nerve surgery. As part of her work at the Neurosurgery Spine laboratory, Murovic also investigates spinal adjacent segment disease, a disorder arising from cervical spinal fusion surgery.
Ischemic Stroke and Postconditioning Treatments Heng Zhao, PhD, explores the benefits of ischemic postconditioning in stroke events. Postconditioning is a phenomenon first described by Zhao’s laboratory, where they noted that reduced levels of infarction post-stroke could be achieved if the early hyperemic response after reperfusion was interrupted. Dr. Zhao’s finding has important clinical relevance, as postconditioning can be performed immediately following reperfusion in order to reduce tissue damage. Significantly, his laboratory was also the first to show that remote conditioning—interrupting blood flow in remote organs pre- or post-stroke—generates brain protection. This finding suggests a linked network between the brain and peripheral organs, and could provide further insights into the pathological mechanisms of stroke-induced brain injury. This strategy is now in clinical trial for stroke treatment in a number of research hospitals worldwide. Dr. Zhao is currently studying how macrophages of the immune system contribute to brain injury and also to the protective effects of pre-, post- and remote conditioning. Macrophages produce a plethora of pro- and anti-inflammatory cytokines, some of which cause nonspecific brain injury and some that promote brain recovery. They are using advanced techniques to identify and reduce harmful inflammatory macrophages (and their associated pathological pathways) and to promote and sustain favorable inflammatory macrophages capable of repair. His goal is to develop strategies that will have great potential for clinical translation to treat stroke patients. Heng Zhao, PhD, is an Associate Professor of Neurosurgery. His research examines the efficacy of neuroprotection methods against stroke. Dr. Zhao’s laboratory described for the first time the strategy of post-conditioning, and remote pre- and post-conditioning, as a treatment to reduce stroke-induced brain injury. Zhao is using advanced techniques to distinguish the differential effects of monocyte-derived macrophages and microglia-derived macrophages. 40
In the ischemic mouse brain, monocyte-derived macrophages (MoMΦs) are labeled as red (RFP) and microglia-derived macrophages (MiMΦs) as green (GFP). Three days after stroke, brain slices are examined by confocal microscopy. MoMΦs are detected in the blood vessels as stained by CD31 (white, A). Both MoMΦs and MiMΦs are recruited into the ischemic brain (B) and transform into MΦs, as seen by CD68 protein expression (white, C and D). Scale bar: 50 µM.
Function and Dysfunction in the Brain: Retinoic Acid’s Role The research performed by Lu Chen, PhD, explores how synaptic and
neurons in the Fragile-X brain lack the ability to homeostatically adjust
circuit dysfunction in the brain underlies neurological diseases. Her
synaptic strength, which could contribute to the pathophysiology of the
laboratory investigates the molecular basis of activity-dependent
disease. Her team is now actively investigating RA signaling in neurons
synaptic modification, the role of dendritic protein translation, and the
derived from human patient iPS cells. Research in the Chen laboratory
impairment of synaptic function in disorders, such as Fragile-X syndrome.
has important potential for clinical translation, as treatments based on her
Dr. Chen’s novel research centers on all-trans retinoic acid (RA), a
research could be designed to restore some levels of function to patients.
morphogen that controls gene transcription in the developing brain. Her research discovered that RA plays a central role in the mature brain through
Lu Chen, PhD, is an Associate Professor of Neurosurgery, and of
a transcription-independent mechanism, to regulate synaptic transmission
Psychiatry and Behavioral Sciences, and a member of the Center for
in response to synaptic activity history; she also showed that defective RA
Interdisciplinary Brain Sciences Research. Her research examines the
signaling may significantly alter behavior and cognition.
mechanisms controlling neural circuit function and how they regulate
Dr. Chen’s team is part of a Stanford research group investigating the pathophysiology of Fragile-X syndrome. Her research found that in animal models of Fragile-X syndrome, synaptic RA signaling is absent. As a result,
synaptic transmission and information processing. Her discovery of all-trans retinoic acid’s role in regulating synaptic strength has led to continuing research in exploring its potentially larger role as a universal regulator of synaptic transmission.
A model for RA-mediated regulation of synaptic strength. (A) Normal excitatory synaptic transmission maintains dendritic calcium levels above a critical threshold, which, through a mechanism yet to be worked out, inhibits RA synthesis. (B) During synaptic inactivity (1), reduced dendritic calcium levels enable RA synthesis (2). Binding of RA to RARα de-represses mRNA translation and allows dendritic protein synthesis to occur locally (3). Newly synthesized calciumpermeable homomeric AMPA receptors are inserted into local synapses (4), leading to increased excitatory synaptic strength. This process of RA-regulated protein synthesis is largely compromised in the animal model of Fragile X Syndrome.
Neurodegenerative Disease: Impact of Gene-Environment Interactions Theo Palmer, PhD, seeks to understand how genetic and environmental factors interact to cause neurological disease in the developing and adult brain. His team has discovered that certain genetic risk factors can dramatically increase the impact of a mild maternal illness on the developing fetal brain. In extreme cases, illnesses deregulate neural stem cell activity, leading to deficits in brain anatomy, cognition and social behavior. Current research is testing the hypothesis that many diseases, even those detected in the last decades of life, may be caused by gene-environment interactions during fetal brain development. Investigating the impact of immune signaling on development has also provided unusual insight into the therapeutic use of stem cells to treat central nervous system disorders. The team has discovered that the same signals influencing the formation of brain circuitry during development are also critical to adult stem cell–mediated circuit repair. Using stem cells obtained from Parkinson’s disease patients, Palmer has found that abnormal immune signaling in the degenerating brain can cause defects in circuit formation and function similar to those seen as a consequence of elevated immune signaling during fetal brain development. He is devising promising interventions to protect against neurodegeneration by targeting and attenuating the damaging immune signaling cascades. Theo Palmer, PhD, is an Associate Professor of Neurosurgery and Vice-Chair of Basic Research and Director of Fundamental Neurosurgery Research. He is a Founding Member of the Stem Cell Advisors Group, a Scientific Advisory Board Member of the Children’s Neurobiological Solutions Group and a Member of the Working Group in Parkinson’s Disease at Stanford University. Dr. Palmer researches the mechanisms that control neural stem cells in the developing and adult brain.
Human induced pluripotent stem cells form neural rosettes in culture. The radial arrangement of neural stem cells (purple with pale blue nuclei) around a central molecular signaling hub (red and green) is identical to the hub and spoke arrangement of neural stem and progenitor cells that form during the earliest stages of fetal brain development. Our studies are showing that alterations in stem cell activity at this very early stage lead to autism-like features in mice. The human stem cell rosettes are being used to identify molecular mechanisms that may underlie human neurodevelopmental disorders.
Neurocognitive Disorders Modeling Mehrdad Shamloo, PhD, is an expert in behavioral pharmacology and animal modeling who aims to elucidate the pathways of neurological disease. His current translational research projects investigate useful pharmacological interventions to stimulate recovery of function postinjury such as stroke, or in neurocognitive disorders such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD). He is evaluating the ß1 adrenergic signaling cascade—a system related to learning, memory and social discrimination—that is significantly altered in AD states. Dr. Shamloo pubished his novel findings in 2014 showing that activation of the ß1 adrenergic receptor enhances memory in AD models. Two patents are being licensed from this research, and a Phase IIA clinical trial is planned for 2015. Another major project focuses on cysteine protease Cathepsin S (CatS), important in the regulation of MHC Class II antigen presentation and neuroinflammation. Overexpression of CatS and membrane-bound fractalkine are both key hallmarks of AD. Dr. Shamloo is investigating a selective CatS inhibitor as a novel therapeutic target, and results thus far A working model showing the β1-Adernergic receptor and its role in neurocognitive disorders. Chronic or acute treatment with a partial agonist of β1-Adernergic receptor, Xamoterol, induces the phagocytic activity of microglia and restoration of cognitive and synaptic function along with a delay of the neurodegeneration in experimental models of Alzheimer’s disease.
show a significant improvement in working memory and fear condition ing in AD models. Shamloo is also participating in multiple preclinical proof of concept trials for other novel AD therapeutics, such as TPI287, currently in a Phase II trial investigating its effect on modulation of tau hyperphosphorylation and microtubule stabilization in AD and FTD states.
Mehrdad Shamloo, PhD is an Associate Professor of Neurosurgery and, by courtesy, of Comparative Medicine and Neurology. He is also the Director of the Stanford Behavioral and Functional Neuroscience Laboratory (SBFNL). He has an extensive background in CNS drug discovery and preclinical development. His aim is to understand normal and pathological brain function in neurodegenerative diseases and to develop novel therapeutic approaches for treatment of these disorders
Neuronal Mitochondrial Transport and Misregulation Xinnan Wang, PhD, is a pioneer in neuronal mitochondrial transport biology
Parkinsonian neurodegeneration. Using induced pluripotent stem
research. Her work examines whether misregulation of neuronal mitochondrial
cells (iPS) from PD patients, she is investigating whether the cells'
trafficking, clearance and function contribute to neurodegenerative diseases
failure to clear toxins (reactive oxygen species) released by unhealthy
such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).
mitochondria from the iPS-derived neurons is a contributing factor to
Her research has provided a fundamental new understanding of
PD neurodegeneration. By developing a protein or gene target towards
mitochondria’s role in healthy neuronal function through the study of their regulatory factors. In particular, she has been investigating the relationship of two proteins encoded by two PD-associated genes, PINK1
regulating mitochondrial function, Dr. Wang hopes to devise a clinical therapy for patients with PD, AD and other diseases such as chronic fatigue syndrome and fibromyalgia.
and Parkin, to regulation of axonal mitochondrial motility. She is one of the only researchers in this field of study nationwide, and one of the
Xinnan Wang, PhD, is an Assistant Professor of Neurosurgery. Her research
few at Stanford to specialize in Drosophila modeling and genetics. In
examines the means by which neuronal mitochondria are transported,
collaboration with Theo Palmer, PhD, Wang is also examining the role of
and their impact on neurons if those processes are misregulated. She
leucine-rich repeat kinase 2 (LRRK2)—a well-known contributor to PD
is investigating mitochondrial misregulation as a contributing cause
pathology—in mitochondrial regulation.
of several neurodegenerative diseases. Dr. Wang is the recipient of
Dr. Wang was recently awarded a $1.1 million California Institute of Regenerative Medicine grant to study misregulated mitophagy in
distinguished awards including the William and Bernice E. Bumpus Foundation Innovation Award, the Alfred P. Sloan Research Fellowship and the Klingenstein Fellowship in Neuroscience. 43
Optogenetic Functional MRI and Brain Network Connectivity The fascinating research performed by Jin Hyung Lee, PhD, centers around novel optogenetic functional magnetic resonance imaging (ofMRI) technology she developed at Stanford, in order to four-dimensionally examine the connectivity and functioning of the brain as a network. Very little is known about how each cellular population within the brain interacts with other parts of the brain, and a greater understanding of this communication has significant benefits both for understanding neuro degenerative disease and for surgical techniques used to treat them, such as deep brain stimulation (DBS). Having a comprehensive knowledge of cell type specificity using ofMRI leads to more accurate targeting and control of brain stimulation, while simultaneously producing a very high-resolution fullbrain image in order to monitor how these circuit elements are interacting. Dr. Lee’s technique has wide-ranging applicability to study many neuro logical diseases. She is currently collaborating with Gary K. Steinberg, MD, PhD, to map neural circuit reorganization following a stroke event with ofMRI. Accurately understanding how the brain can be rewired will help design highly specific interventions with drugs or surgery. She collaborates with Frank Longo, MD, PhD, to study how Alzheimer’s disease alters brain function. Dr. Lee is also designing therapies addressing brain function degeneration. Her work with Robert Fisher, MD, PhD, examines hippocampal signaling during epileptic seizures to better understand the
We use new tools at the interface of neuroscience and engineering to directly visualize the function of brain circuits and quantify their dynamics. Optical stimulation is used to selectively and precisely manipulate neural circuit elements, while the global brain function is measured using fast, high-resolution magnetic resonance imaging. neural pathways being engaged and, therefore, develop DBS therapies capable of precisely interrupting the seizure circuits. Jin Hyung Lee, PhD, is an Assistant Professor of Neurology, Neurosurgery, and Bioengineering and, by courtesy, of Electrical Engineering. She is an electrical engineer who developed the optogenetic functional magnetic resonance imaging technique (ofMRI) for in vivo visualization and control of neural circuitry. She applies this methodology to investigate global network function of the brain in neurodegenerative disease states.
Retinal Neural Circuitry: Visual Perception and Behavior E.J. Chichilnisky, PhD, investigates the functional neural circuitry of the retina. He seeks to understand how visual information is processed to give rise to visual perception and behavior, and how this knowledge can be used in the treatment of vision loss. Dr. Chichilnisky’s laboratory examines the activity patterns in retinal ganglion cells (RGC) produced by different types of visual stimulation, and how such patterns could be reproduced in an artificial retina using electrical stimulation. Together with physicists Alan Litke, PhD, and Wladek Dabrowski, PhD, Dr. Chichilnisky designed and applied the first large-scale multielectrode system that is capable of recording and stimulating the activity of hundreds of RGCs of different types simultaneously. The results show that it is feasible to create interfaces to the retinal circuitry at its natural spatial and temporal resolution—that is, to talk to the retina in its own language. These findings may have exciting implications for the development of future brain-computer interfaces. Dr. Chichilnisky is collaborating with Jaimie Henderson, MD, Krishna Shenoy, PhD, and Daniel Palanker, PhD, to work toward the long-term goal of developing such interfaces. He is currently serving as a consultant and advisory board member with a private company developing visual prostheses. These implants will ideally provide 44
This image shows a multi-electrode array (black traces leading to black circles) positioned against the retina for recording and electrical stimulation. Retinal ganglion cell bodies are shown in blue, with a single cell and its processes highlighted in yellow. artificial vision to patients with untreatable vision loss arising from diseases such as retinitis pigmentosa and age-related macular degeneration. E.J. Chichilnisky, PhD, is a John R. Adler Professor of Neurosurgery and of Ophthalmology. He is a systems neurobiologist whose primary research is focused on elucidating the functional circuitry of the retina, and on the design of retinal prostheses and implants for patients with vision loss.
Stem Cell–Based Transplantation for Spinal Cord Injury
Stroke: Inflammatory Responses and Outcomes Marion S. Buckwalter, MD, PhD, is board certified in both neurology and neurocritical care and a member of the Stanford Stroke Center. She is a neurointensivist who has specialized in managing acute neurological injury patients in the intensive care unit for over 10 years, and one of the few in the world who is also a research scientist. Her research is primarily focused on improving outcomes for stroke patients. Her team is investigating the compromised neurological recovery that occurs due to inflammatory responses in the post-stroke brain. In animal models, Dr. Buckwalter has shown that chronic autoimmune responses after stroke cause neurodegeneration and dementia. Clinical
A section of contused cervical spinal cord eight weeks post injection of human neural stem cells (NSCs) engineered to express green fluorescent protein (green). Host astrocytes are stained with glial fibrillary acidic protein (red), proliferating cells are labeled with EDU (pink), and spinal cord cells are labeled with Hoechst nuclear dye (blue).
observations show that stroke survivors have twice the risk of developing dementia, and she is collaborating with Maarten Lansberg, MD, PhD, to assess if those same inflammatory responses seen in animal models are related to the cognitive impairment observed in patients.
Giles Plant, PhD, is an Associate Professor of Neurosurgery and has specialized expertise in spinal cord injury (SCI) research with a focus on cellbased transplantation therapies. He is also Basic Science Director of the Stanford Partnership for Spinal Cord Injury and Repair. Dr. Plant’s laboratory is using advanced techniques to assess outcomes from stem and glial cell spinal transplantation. One exciting research avenue is the generation of induced pluripotent stem cells (iPSCs) isolated from individual patients to form corticospinal motor neurons (CSMNs). Two prestigious international grants were recently awarded to study the efficacy and repair potential of human CSMNs following their transplantation into a cervical SCI model. Dr. Plant’s dedication to finding rapid, reproducible and effective means of clinical translation for SCI therapies has led him to collaborate with Sarah Heilshorn, PhD, in Materials Science. A Wallace H. Coulter Translational Research Grant was co-awarded in 2014 for the investigation of injectable hydrogels for glial cell delivery directly into the injured spinal cord, a method holding great promise to preserve cell integrity, survival and efficacy.
Genetically engineered astrocytes in a mouse brain (green). By engineering these cells to respond differently to inflammation, the Buckwalter laboratory is able to uncover how inflammation alters outcomes after stroke. Other research projects include the role of TGFß signaling pathways in astrocytes following brain injury. In articles published in Glia and the Journal of Immunology in 2014, she showed that reduced TGFß signaling in astrocytes caused an increased inflammatory response in stroke models
Dr. Plant also established Stanford’s first SCI Core Facility, a resource for SCI
and brain infection models respectively. Therefore, identifying potential
modeling, in 2013. In addition to providing highly specialized equipment
small molecule targets to upregulate TGFß is of great interest, as they could
and behavioral apparatus, the Core offers expert advice on the selection
decrease inflammation and subsequent neurological damage to the patient.
of appropriate injury models, targeted behavioral analyses, and the strict animal ethics regulations relating to SCI. Giles Plant, PhD, is an Associate Professor of Neurosurgery and the Basic Science Director for the Stanford Partnership for Spinal Cord Injury and Repair. He also directs the Stanford Spinal Cord Injury Core Facility. His primary research goals are to repair mammalian spinal cord injuries using adult stem cells and glial cell transplantation, and to develop neuroprotective and regenerative translational protocols for human clinical treatments.
Marion S. Buckwalter, MD, PhD, is an Assistant Professor in the Departments of Neurology and Neurosurgery, and a member of the Stanford Stroke Center. Her clinical focus is on neurology and neurocritical care. She is also the Principal Investigator of her own research laboratory, which aims to improve recovery of function for stroke patients. Current research is investigating the changes in inflammatory pathways that occur following a stroke, and the development of appropriate drug targets to mediate inflammatory responses. 45
Neurosurgery Clinical Trials ADULT NEUROSURGERY
Braingate2: Feasability Study of Intracortical
Expression of EGFRvII and other proteins in
The interaction of genotype on outcome in
Neural System for Persons with Tetraplegia
recurrent gliomas and other brain neoplasms
patients with cerebrovascular disease
PI: Jaimie Henderson
PI: Stephen Skirboll
PI: Steven Chang
A Phase 1/2A study of the safety and efficacy
North American Clinical Trials Network for
HDE application for low profile visualized
of Modified SB623 in patients with stable
the treatment of spinal cord injury
intraluminal support device
PI: Graham Creasey
PI: Michael Marks
PI: Gary K. Steinberg
A randomized concurrent controlled trial
SCENT: A multicenter prospective
to asess the safety and effectiveness of the
Understanding moyamoya disease through
nonrandomized trial to evaluate the safety
seperator 3D as a component of the penumbra
multiple scientific perspectives
and effectiveness of the surpass flow diverter
system in the revascularization of large vessel
PI: Gary K. Steinberg
system compared to hisorical control in the
occlusion in acute ischemic stroke
treatment of large or giant neck intracranial
PI: Michael Marks
PI: Robert Dodd
A multicenter prospective randomized
PI: Gary K. Steinberg
controlled clinical trial comparing the safety
(NCT01716117) A feasability study to evaluate the safety
and effectiveness of the Mobi0C prothesis
and initial effectiveness of MR guided
to conventional anterior cervical disectomy
high Intensity focused ultrasound in the
and fusion in the treatment of symptomatic
treatment of facetogenic lumbar back pain
degenerative disc disease in the cervical spine
PI: Pejman Ghanouni
PI: Jungsoo Park
Developing a patient-centered clinical tool
A pivotal study to evaluate the effectiveness
for assessment of risk of perioperative
and safety of ExABlate transcranial MRgHIFE
complications in spine surgery procedures
thalamotomy treatment of medication
PI: John Ratliff
refractory essential tremor subjects PI: Pejman Ghanouni (NCT01827904) A continued access study to evaluate the effectiveness and safety of ExABlate transcranial MRgHIFE thalamotomy treatment of medication refractory essential tremor subjects PI: Pejman Ghanouni (NCT02289560) A Phase I trial of vornistate concurrent with stereotactic radiotherapy in treatment of brain metastases from non-small cell lung cancer PI: Griffith Harsh (NCT00946673) The Neuroscience Brain Bank Collection of Neurosurgical Tissue for research PI: Griffith Harsh 46
DuraSeal™ Exact Spine Sealant System PostApproval Study PI: John Ratliff (NCT01410864) CAMPER: The Canadian Multicenter CSF Pressure Monitoring and Biomarker Study PI: John Ratliff (NCT01279811) Prospective, concurrently controlled, multi center study to evaluate the safety and effectiveness of Spinal Kinetics M6-C artificial cervical disc compared to anterior cervical discectomy and fusion (ACDF) for the treatment of symptomatic cervical ridiculopathy PI: Lawrence Shuer (NCT01609374)
A Phase 1/2A dose escalation study of ASTOPC1 in subjects with cervical sensorimotor complete spinal cord injury
A long-term follow-up study of cervical spinal cord injuries who received AST-OPC1 in Protocol AST-OPC1-01 PI: Gary K. Steinberg A Phase 1 safety study of GRNOPC1 in patients with neurologically complete subacute spinal cord injury PI: Gary K. Steinberg (NCT01217008) Long-term follow-up of subjects who received GRNOPC1 PI: Gary K. Steinberg Quantifying collateral perfusion in cerebrovascular disease PI: Greg Zaharchuk (NCT01419275)
Publications PEDIATRIC NEUROSURGERY
Anisotropic diffusion in the white matter
Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III.
of premature infants with and without
Cancer Res. 2014 Feb 15;74(4):1238-49. doi: 10.1158/0008-5472.CAN-13-1407. Epub 2013 Dec 23.
Emlet DR, Gupta P, Holgado-Madruga M, Del Vecchio CA, Mitra SS, Han SY, Li G, Jensen KC, Vogel
PI: Michael Edwards
H, Xu LW, Skirboll SS, Wong AJ.
Advancing Treatment for Pediatric
Improved capture of adverse events after spinal surgery procedures with a longitudinal
Craniopharyngioma: Prospective Pilot Study
administrative database. J Neurosurg Spine. 2015 Jun 12:1-9. Veeravagu A, Cole TS, Azad TD,
Indentifying Clinically Relevant Biological
Targets for Medical Therapy
Optogenetic neuronal stimulation promotes functional recovery after stroke. Proc Natl
PI: Gerald Grant
Acad Sci U S A. 2014 Sep 2;111(35):12913-8. doi: 10.1073/pnas.1404109111. Cheng MY, Wang EH,
The Park-Reevs Syringomyelia Research
Woodson WJ, Wang S, Sun G, Lee AG, Arac A, Fenno LE, Deisseroth K, Steinberg GK.
Therapeutic strategies to improve drug delivery across the blood-brain barrier. Neurosurg
PI: Gerald Grant
Focus. 2015 Mar;38(3):E9. doi: 10.3171/2014.12.FOCUS14758. Azad TD, Pan J, Connolly ID,
Re-MATCH: Recurrent medulloblastoma
Remington A, Wilson CM, Grant GA.
and primitive neuroectodermal tumor
Îł-Glutamyl transferase 7 is a novel regulator of glioblastoma growth. J Neurooncol. 2015
adoptive T cell therapy during recovery from myeloblative chemotherapy and hematopoietic stem cell transplantation PI: Sonia Partap (NCT01326104) Surgical resection in the treatment of intraceable epilepsy PI: Michael Edwards
Jun 5. BMC Cancer. 2015 Apr 7;15:225. doi: 10.1186/s12885-015-1232-y. Bui TT, Nitta RT, Kahn SA, Razavi SM, Agarwal M, Aujla P, Gholamin S, Recht L, Li G. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014 Nov;99(11):3933-51. doi: 10.1210/jc.2014-2700. Epub 2014 Oct 30. Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, Wass JA; Endocrine Society. Prediction of neurosurgical intervention after mild traumatic brain injury using the national trauma data bank. World J Emerg Surg. 2015 Jun 6;10:23. doi: 10.1186/s13017-015-00176. eCollection 2015. Sweeney TE, Salles A, Harris OA, Spain DA, Staudenmayer KL. Deep brain stimulation surgical techniques. Handb Clin Neurol. 2013;116:27-37. doi: 10.1016/ B978-0-444-53497-2.00003-6. Khan FR, Henderson JM. Carbon dioxide laser for corpus callosotomy in the pediatric population. J Neurosurg Pediatr. 2015 Mar;15(3):321-7. doi: 10.3171/2014.10.PEDS13498. Epub 2014 Dec 19. Choudhri O, Lober RM, Camara-Quintana J, Yeom KW, Guzman R, Edwards MS. Tissue sparing, behavioral recovery, supraspinal axonal sparing/regeneration following sub-acute glial transplantation in a model of spinal cord contusion. BMC Neurosci. 2013 Sep 27;14:106. doi: 10.1186/1471-2202-14-106. Barbour HR, Plant CD, Harvey AR, Plant GW. The role of radiosurgery for infratentorial arteriovenous malformations. World Neurosurg. 2014 Jul-Aug;82(1-2):e85-6. doi: 10.1016/j.wneu.2014.05.002. Epub 2014 May 9. Iyer A, Chang SD. High-fidelity reproduction of spatiotemporal visual signals for retinal prosthesis. Neuron. 2014 Jul 2;83(1):87-92. doi: 10.1016/j.neuron.2014.04.044. Epub 2014 Jun 5. Jepson LH, Hottowy P, Weiner GA, Dabrowski W, Litke AM, Chichilnisky EJ.
Stanford Neuroscience Health Center OPENING E ARLY 2016
The Stanford Neuroscience Health Center is expanding in order to support the growing need for specialized outpatient neurological care, allow for advancements in neurological research and deliver innovative new treatments to the community. The new five-story, 92,000-square-foot Neuroscience Health Center will open its dedicated location in early 2016 at the Stanford Hoover Campus in Palo Alto. The building offers neuroscience patients a one-stop destination, including centralized patient check-ins for all services to increase convenience
• ~$80 million project • Flexible design to allow for advancements in technology • 40 exam rooms and space for clinical research and faculty offices • Dedicated procedure and
and efficiency. Virtually every aspect of the facility has been designed and built
treatment areas as well as Pre-
by feedback from physicians and a neuroscience patient advisory board.
Op Clinic and Autonomic Lab • Soothing design palette with dimmable lights to better support neuroscience patient needs • Coordinated visits and testing available under one roof • Space designed to facilitate multi disciplinary coordinated visits • Supportive services area including multipurpose group space for patient exercise classes and lectures
All imaging will be located on the Ground Floor of the building, including positron emission tomography (PET), magnetic resonance Imaging (MRI), one of the worldâ€™s first combined PET-MRI scanners, CT, fluoroscopy, general radiography and ultrasound. FIRST FLOOR
The First Floor will serve as the main entrance to the building and will include the lobby, central check-in, visitor seating and a coffee bar. This level will include the Central Core Clinic with 10 exam rooms; Rehab, Balance and Gait; as well as Supportive Patient Services. On the First Floor, there will be a multiuse room for restorative patient classes (such as yoga and dance) as well as educational lectures. SECOND FLOOR
The Second Floor will primarily be dedicated to the Neurodiagnostic Lab, the Autonomic Lab (including four EEGs, two EMGs, EKG, TCD, ultrasound, autonomic and two tilt rooms) as well as a procedure and treatment area (including infusion stations, infusion rooms and two procedure rooms). The second floor will also include a pre-op clinic (two exam rooms, blood draw and EKG) and a reception area for patients and visitors. THIRD FLOOR
The Third Floor will include 30 clinic exam rooms, a reception area for visitor seating, and surgery schedulers. Several large multipurpose conference rooms will be located on the Third Floor, as well as staff break areas. FOURTH FLOOR
The Fourth Floor will include physician, administration and neuropsychology offices, as well as space for School of Medicine research and clinical trial studies. There will be eight Neuropsychology testing rooms, a Clinical Research Lab, and administration and staffing space, as well as an outdoor patio for staff to enjoy.
To lead in caring for people with neurological disorders and translating innovations into cures. 49
Neurosurgery Outreach PLEASANT HILL
San Francisco Bay
UNION CITY FREMONT
NEWARK REDWOOD CITY
HALF MOON BAY
WOODSIDE PORTOLA VALLEY
Bohdan Chopko, MD, PhD; Randal Peoples, MD, MS PALO ALTO
James R. Doty, MD, FACS, FICS, FAANS MOUNTAIN VIEW
24/7 Neurosurgery call coverage
Marco Lee, MD, PhD; Jason Lifshutz, MD; SUNNYVALE
SAN Harminder Singh, MD SANTA CLARA
LOMA MAR LOS GATOS
Gordon Li, MD; Melanie Hayden Gephart, MD, MAS
Ciara Harraher, MD
St. Rose Dominican Hospital 3001 St. Rose Parkway Trail Henderson, NV 89052
Stanford Cancer Center South Bay
2589 Samaritan Drive
1555 Soquel Drive
170 Alameda de las Pulgas
San Jose, CA 95124
Santa Cruz, CA 95065
Redwood City, CA 94062
El Camino Hospital
Santa Clara Valley
2500 Grant Road
Mountain View, CA 94040
751 South Bascom Avenue San Jose, CA 95128
To lead in caring for people with neurological disorders and translating innovations into cures. stanfordhealthcare.org/neuro | 300 Pasteur Drive â€˘ Stanford, CA 94305