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Penn Neurosurgery basic science :: transformative care

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who we are At Penn Neurosurgery, we are driven by the knowledge that the brain and nervous system are the foundation of who people are and how they interact with the world. We are neurosurgeons who pioneer new techniques for safely treating brain and nervous system conditions. We are researchers working to unravel the biological and genetic underpinnings of serious brain diseases, so we can improve prevention and detection as well as treatment. We seek to understand the mechanisms of brain and nervous system injury, so we can restore function that otherwise might be permanently lost.

White matter fiber architecture of the brain, as measured by diffusion spectral imaging (DSI). Courtesy of the USC Laboratory of Neuro Imaging and Athinoula A. Martinos Center for Biomedical Imaging, Consortium of the Human Connectome Project • humanconnectomeproject.org

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types of brain tumors.

SPINE SURGERY AND REPAIR Our neurosurgeons offer the most advanced surgeries to treat spinal degeneration, injuries, tumors, and other conditions, even as they pioneer new and better approaches.

PEDIATRIC NEUROSURGERY Neurosurgeons at The Children’s Hospital of Philadelphia and at Penn excel at treating a full range of brain and spinal problems in children.

ADVANCED SURGERY FOR OTHER NEUROLOGICAL ISSUES From aneurysms to Parkinson’s disease to traumatic peripheral nerve injuries, Penn’s neurosurgeons specialize in the latest techniques to restore function.

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Brain injury brain tumor

From bench to bedside, Penn Neurosurgery is advancing treatment for the most challenging

Spine

BRAIN TUMOR TREATMENT

1

pediatric

Our researchers and clinicians are shedding light on the aftermath of brain and nervous system injury and how best to repair it.

OTHER CONDITIONS

brain injury and repair


BRAIN

INJURY and REPAIR


Brain injury

Our researchers and clinicians are shedding light on the aftermath of brain and nervous system injury and how best to repair it.

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Developing a Blood Test for Brain Damage

C

ould a simple blood test one day

determine who is at risk of long-term brain damage after traumatic brain injury? Research Professor of Neurosurgery Robert Siman, Ph.D., thinks so, and he has been working with colleagues at Penn and as far away as Texas and Sweden to build the scientific foundation for such a test. “You can’t even begin to develop treatments for chronic neurodegeneration after brain injury until you know which 150 people out of 1,000 injured will suffer those long-term effects,” Dr. Siman says. “In my view, developing a prognostic blood test first is an absolute requirement.” There are specific proteins that are usually only found inside the brain’s neurons. When head trauma occurs, those neurons can burst and spill their contents. Dr. Siman’s team has discovered that some neuronal proteins can be measured in the cerebrospinal fluid (CSF) and blood in the hours, days, and even weeks after brain injury—making them potential “biomarkers” of the injury’s severity and its long-term consequences. The team began by looking at surgical patients who experienced a different kind of insult to the brain: loss of blood supply to its tissue, either because their hearts were stopped for a cardiovascular procedure or they experienced a subarachnoid hemorrhage (bleeding on the brain). Certain proteins were

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A stained microscopic image shows the neural “signature” of injury in layers of brain tissue (left side).


begin to develop treatments for chronic neurodegeneration after brain injury until you know which 150 people out of 1,000 injured will suffer those long-term effects.” Dr. Robert Siman

Robert Siman, Ph.D. Research Professor of Neurosurgery

An image highlighting dentate granule neurons in the brain.

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Brain injury

“You can’t even


Untangling the Relationship Between Alzheimer’s and Traumatic Brain Injury

present in the CSF and blood at the time of the surgery and in the days and months afterward, with higher levels correlating with a higher risk of problems with brain function. Dr. Siman has since discovered that the same biomarkers are present in animals and humans after traumatic brain injury. Working with Douglas Smith, M.D., director of the Penn Center for Brain Injury and Repair, and researchers at Baylor College of Medicine in Houston, Dr. Siman has zeroed in on one particular protein, known as SNTF (calpain-cleaved all-spectrin N-terminal fragment), as a potential predictor of which concussion victims are at greatest risk. The research has found that in some patients, SNTF levels are elevated after concussion but resolve over time, while in others the high levels can persist for three months or longer and are associated with ongoing cognitive difficulties and structural damage visible on brain imaging studies. This focus on biomarkers has continued with more research that involves blood testing of professional Swedish ice hockey players who suffer concussions.

Although researchers don’t know for sure what causes Alzheimer’s disease, they do know that repeated traumatic brain injury is an important risk factor. Dr. Robert Siman has been recognized by the Alzheimer’s Association for his mouse model of the disease, which recreates its early impact on the neural pathway responsible

“We have found that SNTF accumulates in the white matter tracts of

for short-term memory—unlike other mouse

pigs and humans after injury, and we find it in the blood, so it is tied to

models that have focused on recreating the late

the underlying processes that cause brain damage,” Dr. Siman says.

effects of the disease, such as the appearance

“That is why we are so enthusiastic about it.”

of plaques and tangles. “Unless you understand

This work is building toward the day when an athlete, accident victim, soldier, or other brain injury sufferer could undergo blood tests to predict the severity of the long-term impact—just as we can now correlate a high blood cholesterol level with future cardiac risk, for example, or PSA blood levels with prostate cancer risk. Then physicians would know with greater certainty who stands to benefit from current interventions such as activity restrictions and brain rest. Even more importantly, researchers could identify the best candidates for clinical trials of new medical treatments that might one day halt the damaging aftermath of brain injury.

the progression of the disease, you can’t develop treatment strategies that will have a high likelihood of success,” Dr. Siman says. In addition to using the model to investigate novel treatment approaches, he is now using it in collaboration with Dr. Doug Smith to understand the possible interplay between early-stage Alzheimer’s and traumatic brain injury. Their research is looking at how brain injury might impact Alzheimer’s progression in the mouse model, and in turn how early-stage Alzheimer’s might affect the brain’s response to injury. Untangling this relationship will pave the way toward understanding the relationship between brain injury and Alzheimer’s disease in humans.

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Brain injury

Focusing on Nervous System Pathways to Understand and Repair Damage

Douglas Smith, M.D. Director of the Penn Center for Brain Injury and Repair

E

very day, the Penn Concussion

Clinic sees people who have experienced a mild traumatic brain injury, better known as concussion. Treatment typically consists of “brain rest:” limiting outside stimulation to the brain—work, television, phone use, screen time—until a patient reports improvement in symptoms. Decisions about a safe return to normal activities are based on educated guesses, rather than hard medical evidence, even though experience has shown that one in five people will suffer long-term difficulties with thinking, studying, working, processing information—all of which can be life-altering. Penn Neurosurgery’s Center for Brain Injury and Repair (CBIR), led by Doug Smith, M.D., and drawing on the work of 25 researchers across campus, is a recognized leader in building the evidence base so critically needed to guide decision-making in the aftermath of mild traumatic brain injury (TBI).

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“The core of our work has been understanding what happens in the brain at that moment of impact—essentially, what causes the brain to ‘break’—and then what keeps happening afterward in the 20 percent of people who have long-term problems,” says Dr. Smith, who is also the Robert A. Groff Professor and vice chairman of research and education in the Department of Neurosurgery. Dr. Smith and his CBIR colleagues were the first to show that the root cause of concussion is the stretching of the brain’s axons, which are the tiny fibers bundled into nerve tracts that connect neuron to neuron. By using computer and animal models as well as studying humans, the researchers discovered that, when axons are stretched too far, these “train tracks of the brain” can swell and even break apart, causing widespread disruption of normal communication pathways (diffuse axonal injury). In some people, the degeneration continues over time and can produce visible structural changes

Kacy Cullen, Ph.D. Research Assistant Professor of Neurosurgery Images showing successful grafts of neural tissue, which has been engineered from human stem cells, into rodent brains (top right of each panel).

The team is engineering axons in the lab that could potentially replace damaged nerve pathways. Illustration by Jean-Francois Podevin

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Brain injury not unlike those seen with Alzheimer’s disease and other forms of dementia. The key questions then become: Why does this happen? Who is affected? Can it be stopped? “In some patients, there is clearly an ongoing period of vulnerability where they appear to be symptom-free, but they’re really not,” says Dr. Smith. The quest for answers to these questions is a current focus at CBIR, as Dr. Smith and other researchers work to identify biological markers—“biomarkers” for short—that can be measured in the blood, picked up on neurological imaging, or both, to identify patients at risk for long-term consequences. Their studies have found that, when axons rupture, certain proteins normally only found in the brain start showing up in the blood. CBIR research suggests that concussion victims with persistently higher levels of these proteins are more likely to have structural and functional changes detectable on imaging studies (see page 4). This is bringing researchers closer to a more evidence-based approach to concussion treatment, both in terms of identifying those at greatest risk and developing medical treatments that target mechanisms of post-concussion damage. But what if the damage is already done? Once axons are destroyed, they don’t grow back—and this is true not only with traumatic brain injury, but also with degenerative brain diseases such as Alzheimer’s and Parkinson’s. Dr. Smith is working alongside CBIR researchers Kacy Cullen, Ph.D., research assistant professor of neurosurgery, and Isaac Chen, M.D., assistant professor of neurosurgery, to pioneer revolutionary brain repair techniques that involve actually growing new axons outside the body in cell culture. These tiny fibers can then be microsurgically implanted to take over for the missing neural pathways and jumpstart regeneration in the brain—almost like mini-jumper cables. This tissue microengineering approach has already shown promise in rat and pig models.

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The researchers are applying the same principle to other areas of nervous system damage outside the brain, which have a devastating impact on motor control and sensation. Dr. Smith and Dr. Cullen have pioneered a “stretch-growth” process that can quickly grow the much longer axons required to carry nerve signals from the spinal cord to the outer reaches of the body. Their early work suggests that these new axons can be implanted to bridge nerve pathways destroyed by surgery, traumatic injury, or disease. This technique might even be used to connect a high-tech prosthetic limb to the central nervous system, allowing the person to direct the prosthesis with his or her own brain. Dr. Cullen believes that human testing of these implantable neural networks could happen within a few years. “We are working on the next generation of restorative therapies right here and mimicking the anatomy of what is missing to make people whole again,” he says.

The ultimate goal is to have the lab-generated axons serve as a bridge, carrying nerve signals from brain to spine to limb. Illustration by emily cooper

Isaac Chen, M.D. Assistant Professor of Neurosurgery

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“Replacing the substrate of the brain, both its computational centers and its network wiring, has enormous potential for restoring neurological and cognitive function in patients.” Dr. Isaac Chen


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“Patients’ suffering motivates everything we do in the lab. Permanent neurological disability results in lost function, lost productivity, and loss of gainful employment. Today, many patients have little hope of meaningful recovery. We aim to change that.” Dr. Timothy Lucas

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Brain injury

Restoring Communication Between Brain and Body

W

hen the arm or hand is paralyzed,

the chain of nerve signaling from brain to limb and limb to brain has been interrupted—whether due to spinal cord injury, stroke, or another insult. Normal movement becomes difficult or impossible. Signals from the outside world, once effortlessly translated by the brain into conscious perception, can no longer get through. As a result, sensations such as touch, pressure, pain, and temperature are lost. But what if we could somehow “bypass” this interrupted circuitry in paralyzed patients and turn these signals into information their brains can use, while also turning motor signals into information their limbs can use? Penn’s Translational Neuromodulation Laboratory (TNL), led by neurosurgeon Timothy Lucas, M.D., Ph.D., and senior investigative scientist Andrew Richardson, Ph.D., has been working to do just that, paving the way toward more advanced treatments for paralysis. “The goal is to decode thoughts about moving into information that an external device can use, while also encoding sensory information from the outside world into the brain,” Richardson says. “It’s about bridging the interruption and

restoring bidirectional communication.” Working with collaborators in Penn’s College of Engineering, TNL researchers have created a system of small wearable devices that can communicate with each other wirelessly to generate sensations and movements artificially. Electrodes implanted in the brain record motor signals, which are then decoded and used to drive electrical stimulation of paralyzed muscles in the

Timothy Lucas, M.D., Ph.D. Director, Penn Translational Neuromodulation Laboratory

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Restoring Facial Movement

Facial expressions are a defining feature of human identity. Yet no effective treatment exists for conditions that paralyze a portion of the face.

“Our ultimate goal is to close

the loop between input

Just one example is Bell’s palsy, often caused

and output—sensation and

by a viral infection that damages the facial

movement—and link the

nerve on one side and makes the eye and face

two together, essentially

droop uncontrollably. Not only does this affect

reanimating the person’s

the person’s appearance, but it hinders talking,

own limb.”

eating, and normal blinking and can even lead to blindness. Penn’s TNL is pioneering new treatments for facial paralysis using technologies that capitalize on the symmetry of facial movements: If the left eye blinks, so does the right, and if the left side of the smiles, so does the right. TNL researchers have created wireless implantable devices that can record signals from the working side of the face and use them to activate the paralyzed side. While the technology is still in development, the researchers hope to bring it to patients in clinical trials in the near future.

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Dr. Timothy Lucas


Andrew Richardson, Ph.D. (left) Senior Investigative Scientist with Dr. Timothy Lucas The lab is distinguished by being funded from National Institutes of Health, National Science Foundation, and the Department of Defense. A diagram of how the Brain-Machine-Brain Interface works, with implanted electrodes in brain and limb communicating wirelessly to restore motion and sensation.

hand. Wireless sensors on the fingers detect touch sensations and encode them into the brain by stimulating electrodes in the brainstem. The system, known as the Penn Brain-Machine-Brain Interface (PennBMBI), is designed to be low-power, lightweight, biocompatible, and reprogrammable for a variety of tasks. This represents a bold new alternative to current investigational treatments for paralysis, which tend to focus on harnessing brain signals to manipulate external devices such as robotic arms—much too expensive and cumbersome for the average person with paralysis. Penn’s approach is designed to direct motor stimulation to the patient’s own limb. And unlike other treatment approaches, PennBMBI seeks to restore sensation, as we know that motion and sensory perception are closely linked in a feedback loop of information: Think about feeling a pen in your hand and then being able to write with it.

motor interface somatosensory interface

“In medical school I worked with paralyzed patients, and it became obvious

implanted electrodes

to me that most researchers were focused on the effort to try to restore

wearable RF electronics

movement, but movement is only half of the equation,” says Dr. Lucas. “Continuous sensory feedback is necessary to guide accurate movements.”

wireless communication wearable tactile sensors

PennBMBI is still being tested and refined in animal models, but it holds forth the promise of a day when paralyzed people could be treated with small implant devices—in much the same way that someone with an irregular heartbeat can wear a pacemaker that senses when the heart is out of rhythm and sends out electrical signals to correct it. “Our ultimate goal is to close the loop between input and output—sensation and movement—and link the two together, essentially reanimating the person’s own limb,” Lucas says. BRAIN INJURY AND REPAIR :: penn neurosurgery :: 13

Brain injury


“I am driven by understanding how changes in the connections between networks in the brain lead to symptoms after injury, and what we can do to improve the lives of people who are struggling with these conditions—including our veterans returning from recent conflicts overseas.” Dr. John A. Wolf

John A. Wolf, Ph.D. (left) Research Assistant Professor of Neurosurgery and Sean Grady, M.D. Chairman of the Department of Neurosurgery

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Brain injury

Unraveling the Physiology of Traumatic Brain Injury

“I

n a sense, our approach to

concussion reminds me of where medicine was 100 years ago,” says Sean

A key axonal pathway in

Grady, M.D., chairman of the Department of Neurosurgery. “We try different

the brain as visualized by

treatments and see what happens. So we might prescribe cognitive and physical rest for a week or so, ask the patient about their symptoms, and then

an MRI technique known as tractography.

send them back to their sport or other normal activities if they seem ready. Most will do fine. But some will continue to have problems and develop postconcussion syndrome, and we don’t know why.” What’s missing is an understanding of how concussion affects the physiology of the brain. We know the symptoms: headache, dizziness, memory loss, confusion, mood and emotion changes. But what are the mechanisms behind these symptoms? What changes are happening in important cognitive areas of the brain? Why do these problems develop in only a subset of individuals? Can we use this knowledge to predict who is likely to suffer long-term effects, and what treatments might help them? Dr. Grady is working closely with neuroscientist John A. Wolf, Ph.D., to fill in these gaps. To date, most research on the effects of brain injury has looked at its structural impact on the brains of deceased people or animals who sustained repeated head trauma. Tissue analysis has revealed evidence of diffuse axonal injury—injury to the axons, or nerve fibers, that enable commu-

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Injured neurons as shown by a silver-staining technique. Penn researchers are working to protect injured athletes by using biological markers of damage after brain injury.

nication among different areas of the brain.

“Over time, we should have a better grasp of how

Dr. Wolf’s lab is working to develop a deeper

changes in excitability affect neural networks and

understanding of how communication is

how these networks interact across the brain.

disrupted in the living brain after concussion.

“This is the only way we can begin to understand

The researchers are taking advantage of the fact

the disruption that occurs to white matter

that Penn, using pigs, has developed the best

pathways and brain circuitry,” he adds.

animal model of diffuse brain injury in the world, relying on head rotation to simulate the effects of concussion. Post-injury, they can implant electrodes and track activity in different areas of the brain over time. The researchers measure both brain wave activity using EEG (electroencephalography) as well as single-neuron activity. Initially,

The ultimate goal is to unravel the neurophysiology of concussion in humans, so that Dr. Grady and the other physicians can treat patients based on a concrete knowledge of what is happening in their brains, instead of educated guesses that rely on self-reported symptoms.

they are focusing on the hippocampus, the part

“Once we understand the neurophysiology, we can

of the brain that plays a key role in memory and

think about intervening earlier and developing drug

spatial orientation. Early results suggest that the

therapies for post-concussion symptoms in those

circuitry in this area “overreacts” to inputs after a

who suffer from them,” Dr. Grady says.

head injury, which may be the mechanism behind lingering memory issues. “We can already see that, seven days post-injury, the hippocampus is hyperexcitable with even very

Athlete photo by Max Andrews via Wikimedia Commons

low levels of diffuse brain injury,” Dr. Wolf says.

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about intervening earlier and developing drug therapies for post-concussion symptoms in those who suffer from them.” Dr. Sean Grady

Why Do Individual Neurons Fire the Way They Do? Large Data-Gathering Effort Seeks Answers

Every day, patients undergo neurosurgery at Penn

why neurons right next to each other behave

for a wide range of conditions, from epilepsy,

differently even though they look the same.

brain tumors, and aneurysms to normal pressure

Drs. Wolf and Grady are partnering with Penn’s

hydrocephalus, a buildup of fluid on the brain

Department of Pharmacology to gather infor-

that causes dementia. Typically, any brain tissue

mation about neuron type and behavior into a

that is removed would be discarded. But now,

database that does not identify patients, but

as part of a large cooperative project funded by

does include information about their medical

the National Institutes of Health, Dr. Grady and

condition, medications, and overall health. Over

Dr. Wolf are collecting that tissue and analyzing

time, this single-cell mRNA expression data could

how individual neurons express messenger RNA

pave the way toward a better understanding

(mRNA), which plays a key role in the translation

of how specific neurological conditions and

of genes into proteins. Neurons are cells in the

treatments affect how neurons communicate.

brain that transmit and receive electrochemical

The database will be open to the public, which

signals—but there is much to learn about how

makes it a potentially powerful tool for future

individual neurons behave the way they do, and

translational neuroscience research.

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Brain injury

“Once we understand the neurophysiology, we can think


BRAIN TU TREATME From bench to bedside, Penn Neurosurgery is advancing treatment for some of the most challenging types of brain tumors.

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brain tumor

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“For many years in neurosurgery, we have relied on what we can see, but we are experimenting with infrared technology that makes it possible to light up the cancer, in the same way that black light makes something white glow.� Dr. John Y. K. Lee

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brain tumor

Making Surgery Safer, More Effective

W

hether cancerous or not, brain

tumors can be quite challenging to treat, as they nestle in areas of the brain that control some aspect of what we do or who we are. Removing the tumor without damaging adjacent healthy tissue is the ultimate goal. Neurosurgeons with the Penn Brain Tumor Center—including Center co-director and Director of Neurosurgical Oncology Steven Brem, M.D.; Tim Lucas, M.D., Ph.D.; Donald O’Rourke, M.D.; and John Y.K. Lee, M.D.—are using a revolutionary brain mapping technology that can visualize white matter tracts, the bundles of nerve fibers that carry messages throughout the brain. Known as diffusion tensor imaging, or DTI, it works by measuring the direction in which fluid moves within the brain, gathering data to help determine the location and function of different brain fiber clusters. Advanced diffusion tractography software—which Dr. Brem had a hand in creating—then uses that data to produce striking 2-D and 3-D maps of the brain that reveal its internal wiring and, in conjunction with a computer and MRI imaging, can help the neurosurgeon avoid key tracts and keep more brain function intact. This is an improvement over MRI alone, which only allows the surgeon to distinguish white and gray matter from the tumor; in other words, MRI shows structures but not networks, as DTI does. “This is a tremendously historic time for neurosurgery, as we’re not just relying on the naked eye to guide us but using this astounding new technology,” says Dr. Brem. “It is FDA-approved and now standard at Penn Neurosurgery,” DTI mapping is relatively new, so neurosurgeons here are continuing to explore its use and application—all with an eye toward improving patient

John Y. K. Lee, M.D. Associate Professor of Neurosurgery

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Skull Base Tumors: Pioneering Minimally Invasive Approaches

Benign brain tumors such as neuromas and meningiomas do not invade healthy brain tissue as cancer does, but they cause problems as they grow larger and press on critical brain structures. The traditional approach to surgery involves opening the skull to access the tumor—reasonable if the growth is near the top of the head, but riskier and more complicated when the tumor is closer to ear level or below. Dr. John Y. K. Lee specializes in a minimally invasive approach that removes skull base tumors through the ear, nose, or small one-inch incision above or behind the ear. He first inserts a specialized endoscope to create vivid three-dimensional images of the area and the tumor on a TV screen, and then uses microsurgical instru-

outcomes. Their efforts are directly related to a large-scale federally-funded effort to map the wiring of the live human brain, the Human Connectome Project. All data from the project are publicly available, and the hope is that it will transform our understanding of brain disease development and treatment.

ments to access and remove the tumor

Just as critical as protecting the brain’s delicate

through the small opening or incision.

wiring is making sure that all cancer has been

“This allows me to see panoramic details

removed when a malignant tumor is found. Again,

and figure out how to do the surgery without

the surgeon’s naked eye is only so powerful—it

collateral damage,” says Dr. Lee. “This is still

cannot see microscopic cancer cells that may

a fairly unusual technique, but if we can avoid

be near the original tumor site. John Y.K. Lee,

completely opening the head to access these

M.D., associate professor of neurosurgery at

tumors, it is better for the patient.”

Pennsylvania Hospital and medical director of its Gamma Knife Center, is investigating the use of an injectable fluorescent material that is taken up by cancer cells and renders them visible using an

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Steven Brem, M.D. Penn Brain Tumor Center Co-Director and Director of Neurosurgical Oncology An MRI shows a skull base tumor before

brain tumor

and after complete resection.

Dr. John Y. K. Lee Together, functional MRI and tractography can visualize brain function and neuronal pathways.

infrared camera. He is collaborating on the project with Penn thoracic surgeon Sunil Singhal, M.D., who is exploring its application in lung cancer surgery. Higher-grade brain tumors such as glioblastomas are notorious for spreading throughout the brain even after the tumor is successfully removed, so the hope is that visualizing and then removing the tiniest cancer deposits could make a difference. “For many years in neurosurgery, we have relied on what we can see, but this makes it possible to light up the cancer, in the same way that black light makes something white glow,” Dr. Lee says. “Now you can visualize what you might have left behind by relying on sight alone.” The end goal at Penn Neurosurgery is always to advance surgery in ways that improve patient outcomes while keeping as much of the healthy

“This is a tremendously historic time for neurosurgery, as we’re not just relying on the naked eye to guide us, but using astounding new brain mapping technology that helps us keep critical brain functions intact.” Dr. Steven Brem

brain intact as possible.

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“It’s about utilizing the biology of the cancer for the development of new therapeutics.” Dr. Donald M. O’Rourke

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brain tumor

Developing Targeted Treatments for Aggressive Brain Cancers

T

he highly aggressive, fast-growing

tumor known as glioblastoma multiforme is the most common primary brain cancer in adults. Even with surgery, chemotherapy, and radiation, median survival is 15 months, suggesting the need for new approaches that target the tumor cells more effectively and short-circuit the disease process. One of the first biologically targeted treatments for glioblastoma that has been found to extend survival is Avastin, which targets a chemical growth factor that enables the tumor to grow new blood vessels to increase blood supply; in fact, Steven Brem, M.D., co-director of the Penn Brain Tumor Center and director of Neurosurgical Oncology, was involved in the development of Avastin earlier in his career. To meet the need for new targets and better treatments, Penn Neurosurgery is pulling together his expertise and that of roughly 20 researchers from seven departments to form the Neuro Translational Center of Excellence, or Neuro TCE. “It’s about utilizing the biology of the cancer for the development of new therapeutics,” says neurosurgeon Donald O’Rourke, M.D., whose longstanding interest in better approaches for glioblastoma led him to establish the Penn Brain Tumor Bank over a decade ago, now administered collaboratively with The Children’s Hospital of Philadelphia. The tissue bank is an essential resource for clinicians and researchers seeking new targets for brain cancer treatments. In the case of glioblastoma multiforme, we know there are four genetic subtypes, but we do not yet fully understand the pathways through which the disease develops—but new knowledge is beginning to emerge.

Donald M. O’Rourke, M.D. Director, Human Brain Tumor Tissue Bank, and Associate Professor of Neurosurgery

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Normal vs. Mutated EGFR

Current Clinical Trials Much of Dr. O’Rourke’s research has focused on a specific mutation in the

Deletion Site Mutated Site

epidermal growth factor receptor (EGFR) gene, known as “variant III,” which signals cells to grow out of control. About 30 percent of glioblastoma patients

Ligand binding domain

test positive for EGFRvIII. Dr. O’Rourke is working closely with Carl H. June,

{

M.D., Richard W. Vague Professor in Immunotherapy, on a clinical trial of a new personalized immunotherapy approach that can engineer a patient’s immune system T cells to target EGFRvIII. In 2014, Dr. June and his team demonstrated this approach’s success against acute lymphoblastic leukemia, and it was promptly fast-tracked by the Food and Drug Administration. Penn is also part of another clinical trial for a personalized vaccine therapy called DC-Vax-L, which uses a patient’s own tumor cells to “teach” the dendritic cells—the immune system’s army of circulating defenders—to recognize the cells as a threat and launch an immune response. Wt EGFR

EGFRvIII

The Search for New Targets Still, the search is on for other genetic targets that could become the basis for future treatments. Dr. Steven Brem was part of a research team that has identified an aging-related set of genes that tend to be overexpressed in older people with glioma and suggestive of a higher-grade cancer. “Histologically, you can’t tell the difference between a glioma that develops in a 28-year-old versus an 82-year-old, but these genetic findings pave the way toward understanding the cancer differently and ultimately treating it differently,” says Dr. Brem. He adds that all patients with glioblastoma now have their tumors sampled and genetically analyzed by the Penn Brain Tumor Bank, so that researchers can develop their understanding of the pathways driving the disease process. One of these researchers is Penn Neurosurgery’s Nadia Dahmane, Ph.D., who uses mouse models and human tissue samples to understand the genes and the signaling pathways involved when the brain develops from a single cluster of cells. Understanding how a healthy brain develops is a key step in understanding what goes wrong when its component cells become cancerous, she says. Dr. Dahmane’s lab focuses on glioblastoma as well as medulloblastoma, a form of brain cancer that is more common in children and teens. Like glioblastoma, it is difficult to cure as it often invades the entire brain, and currently available treatment can have a major impact on brain development and cognition in young people.

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“Ours is a developmental biology approach to understanding brain diseases,“ Dr. Dahmane

brain tumor

says. “What are the mechanisms regulating cell proliferation, differentiation, communication, and migration when the brain first forms? This approach will lead to a better understanding of the biology of brain tumors—in particular, how these tumors start, develop, progress, and invade the nervous system.” A current focus is a protein called RP58, which Dr. Dahmane and her team have found plays a critical role in brain development and neuronal differentiation. Their work suggests that a dysfunction in this protein may lead to a human brain defect called microcephaly, a condition in which the brain does not develop properly, resulting in a smaller-than-normal head. Her team has also shown that this protein appears to inhibit the growth of medulloblastoma and glioma cell lines, indicating that a problem with this pathway may

“What are the mechanisms regulating cell differentiation, communication, and navigation when the brain and nervous system first form? Only then can we understand how these tumors start and invade the nervous system.”

be to blame when cancer develops. The lab

Dr. Nadia Dahmane

continues to investigate how this pathway controls normal brain development, and particularly the process of neuronal differentiation, as key to understanding the development of brain diseases such as microcephaly and aggressive tumors. From basic research to clinical trials, Penn Neurosurgery is playing an important role in advancing the treatment of brain cancer. Forming the Neuro Translational Center of Excellence will help accelerate this work by creating a structure that brings together this department with other Penn experts in imaging, genomics, immunotherapy, proton therapy, and drug discovery and development.

Dr. Steven Brem

Sagittal section of a newborn mouse cerebellum showing the Purkinje neurons (red) and glial cells (green) in the developing brain.

BRAIN TUMOR TREATMENT :: penn neurosurgery :: 27


SPINE SURGERY AND REPAIR Our neurosurgeons offer the most advanced surgeries to treat spinal degeneration, injuries, tumors, and other conditions, even as they pioneer new and better approaches. 28 :: penn neurosurgery :: spine surgery and repair


spine spine surgery and repair :: penn neurosurgery :: 29


“The great promise is that we could treat those four million patients a year who report they are missing work, or missing their kids’ baseball games, or not doing whatever it is they want to do, because of back pain.� Dr. Neil Malhotra

30 :: penn neurosurgery :: spine surgery and repair


spine

Reversing Painful Spinal Disc Degeneration

A

bout 15 million Americans visit

their doctors each year due to back pain. A common cause is spinal disc degeneration: the breakdown of one or more of the rubbery discs that cushion the spaces in between the vertebrae. Most patients eventually get better with treatment for their symptoms. About 500,000 patients per year will need corrective spinal surgery. But as many as four million patients per year will have little to no symptomatic improvement and do not meet rigorous surgical criteria. There is a pressing need for new solutions to back pain that are less invasive than surgery and ideally can normalize the function of the degenerated disc. Neil Malhotra, M.D., assistant professor of neurosurgery, and Lachlan Smith, Ph.D., research assistant professor of neurosurgery, started the Penn Translational Spine Research Lab (TSRL) to tackle this challenge. They are working on a substance that could be injected into the disc through the skin and do three essential things: (1) replace its weakened interior tissue; (2) stop the inflammation that is breaking down the tissue; and (3) deposit cells that could regenerate new healthy tissue over time. It’s a tall order, but the researchers believe the best treatment has to combine all three.

Neil Malhotra, M.D. Assistant Professor of Neurosurgery

spine surgery and repair :: penn neurosurgery :: 31


“The holy grail is delivering cells that could regrow

Finding the best stem cells to use is their current

the disc, but it is a very inhospitable environment,”

challenge, but early results in the lab and large

says Dr. Malhotra. “Without the first two pieces,

animal models are promising. Drs. Malhotra and

it’s unlikely they would survive.”

Smith both envision a day when people with

Dr. Malhotra devoted several years to creating an injectable hydrogel implant that acts like a normal, strong disc center, helping the disc function as it did when it was healthy. Simultaneously, Dr. Smith was working on a new way to deliver anti-

painful spinal disc degeneration have access to a noninvasive, low-risk solution to this vexing problem that affects not only individual sufferers, but their families, workplaces, and the economy at large.

inflammatory drugs that would keep them in one

“The great promise is that we could treat those

place for an extended time period. His solution

four million patients a year who report they are

was medication-containing “microspheres” that

missing work, or missing their kids’ baseball

dissolve slowly to release their contents. Through

games, or not doing whatever it is they want to do,

the Penn TSRL, Drs. Malhotra and Smith are

because of back pain,” Dr. Malhotra says. “And for

working to combine these materials into a viable

those who are now having surgery, it’s much better

solution for disc degeneration, adding stem cells

to give them back a normal functioning joint,

as a third component.

rather than replacing it or altering it permanently.”

“As the implant degrades over time, you want it to be replaced by native tissue which will have long-term efficacy,” Smith notes.

32 :: penn neurosurgery :: spine surgery and repair


Lachlan Smith, Ph.D. Research Assistant Professor of Neurosurgery Microscopic examination of a histological section of intervertebral disc, part of an ongoing study to establish a preclinical large animal model of disc degeneration. The goal is to use this model to evaluate regenerative therapeutics for disc degeneration and low back pain.

Intervertebral disc sample prepared for histological analysis.

Surgical procedure for minimally invasive delivery of injectable therapeutics to the lumbar intervertebral disc in a large animal model.

Delivery of injectable therapeutics to the model under x-ray guidance.

EpiLog: Capturing the Right Data to Improve Patient Outcomes

Most electronic medical record systems (EMR) simply give new form to the work that used to be done by paper charts. Physicians type in narrative comments about the patient’s condition, which actually can impede direct interaction and eye contact. Dr. Neil Malhotra thought there must be a better way for doctors not only to capture the right information, but also use it to individualize recommendations for each patient and improve quality. He is

• Benchmark • Dashboard • Patient Level

leading Penn Neurosurgery’s work on a new system called EpiLog, a clickable interface embedded within the EMR that allows physicians • Hypothesis Research (IRB)

• PQRS, MU2 • Reimbursement • Contracting

to navigate a menu of options to enter information about a patient’s condition, symptoms, treatments, side effects, other medical issues, and/or lifestyle choices. It also can compile and visually present this information over time—so, for instance, a patient could see how

New Patient

his or her pain levels have changed when deciding on treatment, or • Scalable

understand his or her own personal risk of infection after surgery. It also gives physicians a snapshot of their own clinical outcomes and areas where they can improve quality. EpiLog is now in beta testing throughout the Department of Neurosurgery.

• Data Reliability

• All Encounters • Embedded • Compliance

spine surgery and repair :: penn neurosurgery :: 33

spine

lumbar intervertebral disc in a large animal


Penn’s Spine Group: Advanced Treatment for Complex Spine Disorders

P

enn has a team of neurosurgeons

who work closely with specialists throughout Penn Medicine—including neurologists, rheumatologists, oncologists, rehabilitation specialists, physical therapists, radiologists and pain management specialists—to diagnose and treat complex conditions of the spine. These include spinal tumors, traumatic spinal injury, infection, scoliosis, disc degeneration, and other spinal problems that can result from wear-and-tear and aging. When surgery is needed to relieve pain and restore function, our neurosurgeons can offer the most advanced, minimally invasive repair techniques.

William Welch, M.D., FACS, FICS Vice Chair, Department of Neurosurgery, and Chair, Department of Neurosurgery at Pennsylvania Hospital Dr. William Welch has performed over 15,000 spine surgeries, with a special focus on laminectomy (removal of a portion of the vertebrae) to treat spinal stenosis; other forms of spinal decompression surgery to relieve pain; and cervical and spinal fusion procedures to restore stability. Whenever possible, these surgeries are done using minimally invasive techniques under spinal anesthesia, rather than general anesthesia. Dr. Welch and his colleagues also are actively involved in pioneering new approaches to spinal surgery, including bone substitutes, support devices, and bone grafting techniques. They use the most highly specialized surgical tools, such as ultrasonic bone cutters and lasers and intraoperative CT scans. “We are absolutely comprehensive, customized to the individual patient, and as minimally invasive as we can be,” says Dr. Welch.

34 :: penn neurosurgery :: spine surgery and repair


spine

“We are absolutely comprehensive, customized to the individual patient, and as minimally invasive as we can be.� Dr. William Welch

spine surgery and repair :: penn neurosurgery :: 35


James Schuster, M.D., Ph.D. Director of Neurotrauma, Associate Professor of Neurosurgery Dr. Schuster has two primary areas of specialty: spinal tumors and traumatic spine injury. He treats tumors that originate in the spine, such as leiomyosarcomas and chondrosarcomas, as well as metastatic tumors that result when other forms of cancer travel there. Dr. Schuster is leading Penn’s involvement in a large-scale study through AOSpine International, which is creating a database of clinical and quality-of-life outcomes for patients with metastatic spinal tumors. He also treats patients with traumatic brain and spinal injuries at Penn’s Trauma Center, which relocated to a new facility at Penn Presbyterian Medical Center in 2015. There he oversees the neurotrauma program and research, including a study of medication called riluzole, which may improve outcomes after neurotrauma. Dr. Schuster also uses minimally invasive techniques and computer-assisted intraoperative spinal navigation. “The tumor care we provide is part of the comprehensive, multi-disciplinary Abramson Cancer Center, which is a great advantage,” he says. “And for neurotrauma, we have a brand new facility that is a highly focused center for all types of trauma, helping patients not just in our area but throughout the region and beyond.”

36 :: penn neurosurgery :: spine surgery and repair


Paul J. Marcotte, M.D. Associate Professor of Neurosurgery “Our goal with spinal surgery is to dispel the myths and the mysteries regarding spinal problems and their treatment. Patients are often hesitant to consent to surgery, but the results of surgery are much improved versus 30 years ago, thanks to our greater understanding of spinal disorders and the technologies and techniques that are out there. There is not a single solution that suits every patient. We can evaluate each individual situation needed to make someone better.”

“Patients are often hesitant to consent to surgery, but the results of surgery are much improved versus 30 years ago.” Dr. Paul J. Marcotte

spine surgery and repair :: penn neurosurgery :: 37

spine

and determine precisely what treatments are


Stephen Dante, M.D. Penn Medicine Clinician

Ali Ozturk, M.D. Assistant Professor of Neurosurgery

“One of the things that brought me to neuro-

Dr. Ali K. Ozturk specializes in disorders of the

surgery was the desire to treat patients with very

spine, with a particular interest in spinal deformity

challenging problems. My patients mainly have

and tumors. The surgeries he performs often

spinal disorders—some that are congenital or

involve major reconstructions of the spine, which

developmental, some spinal tumors, as well as

can have a significant and lasting impact on

conditions that occur later in life, such as arthritic

patients’ quality of life. In collaboration with Dr.

disease and disc problems. The nervous system

Douglas Smith, Dr. Ozturk focuses his research

is quite complex and sometimes the treatment

efforts on spinal cord injury, which affects

options are elaborate. Penn Medicine is focused

thousands of patients worldwide with devastating

on treating patients’ problems, even the most

consequences, often at a young age. His work

complex situations, with cutting-edge, state-of-

is attempting to bridge spinal cord injuries with

the-art treatments that are not available in many

axons that have been stretched in the lab, with the

other places.”

ultimate goal of using them to restore function in paraplegic patients (see page 8).

38 :: penn neurosurgery :: spine surgery and repair


spine

“My philosophy is to treat the patient the way I would want to be treated: with compassion, understanding, and a holistic approach.� Dr. Ali Ozturk

spine surgery and repair :: penn neurosurgery :: 39


PEDIATRIC NEUROSURGERY 40 :: penn neurosurgery :: PEDIATRIC NEUROSURGERY


PEDIATRIC NEUROSURGERY :: penn neurosurgery :: 41

pediatric

Neurosurgeons at the Children’s Hospital of Philadelphia and at Penn excel at treating a full range of brain and spinal problems in children.


42 :: penn neurosurgery :: PEDIATRIC NEUROSURGERY


Pediatric Neurosurgery: Treating the Youngest Patients

P

ediatric brain and spine conditions

that require surgery may be relatively rare, but they are anything but “rare” to the families and children who are affected. Nor do they seem rare to The Children’s Hospital of Philadelphia (CHOP) neurosurgeons Phillip “Jay” Storm, M.D., and Gregory Heuer, M.D., Ph.D., who treat babies and children from all over the nation and the world. Although they collaborate on the most complex cases, Dr. Storm tends to focus on brain tumors, while Dr. Heuer specializes in fetal and postnatal surgery to correct congenital abnormalities of the brain and spine. For many of their cases, they also work closely with colleagues in Penn Medicine’s Department of Neurosurgery.

PEDIATRIC NEUROSURGERY :: penn neurosurgery :: 43

pediatric


Brain and Spinal Tumors As chief of the Division of Neurosurgery at CHOP, Dr. Storm treats children and teens with brain and spine tumors, always with the goal of preserving as much healthy tissue—and normal function—as possible. CHOP is one of the few places that are able to perform complex spine reconstruction after tumor removal. It is also one of the few to offer endoscopic endonasal surgery, which removes skull base tumors through the mouth or nose, replacing the traditional skin incision and craniotomy (removal of the skull) to access the tumor. Dr. Storm has worked closely with John Y. K. Lee, M.D., associate professor of neurosurgery at Pennsylvania Hospital, to develop the program (see page 22). As with adult patients, this approach reduces the risk of complications and longer recovery times that are associated with more invasive surgery. However, any kind of surgery on a still-developing brain or spine poses a certain level of risk, not to mention the long-term side effects of radiation and

“The whole idea of such open access and sharing of data in real-time is transformative— it is a paradigm shift.” Dr. Phillip “Jay” Storm

chemotherapy if a tumor is cancerous. This points to the need for precision medicine: treatments that can target the cell-level changes that initiate and promote tumor growth. A few years ago, Dr. Storm teamed up with Adam Resnick, Ph.D., assistant professor of neurosurgery and CHOP’s director for neurosurgical translational research, to bank every tumor he removed and sequence its genetic makeup. The pair soon realized they would need a larger sample of tumors to produce meaningful data, so CHOP founded the Children’s Brain Tumor Tissue Consortium (CBTTC). Partner institutions include Seattle Children’s; the Ann & Robert H. Lurie Children’s Hospital of Chicago; The Children’s Hospital of Pittsburgh of UPMC; Meyer Children’s Hospital in Florence, Italy; Children’s National Health System in Washington, D.C.; Rutgers Robert Wood Johnson Medical School; Stanford University/ Lucile Packard Children’s Hospital; The University of California San Francisco Benioff Children’s Hospital; and Weill Cornell Pediatrics. All are collecting tumor tissue and uploading the same information to the CHOP database, including the tumor’s genetic profile, other biological characteristics, the treatment plan, and clinical outcomes. The database offers open access for researchers worldwide. “It is really a bench-to-bedside paradigm,” notes Dr. Resnick, who is director of the CBTTC. “Penn is creating the collaborative space for institutions to work together on pediatric brain and spine tumors.” Already, the tissue bank has helped researchers identify a mutation in a gene called BRAF that plays a role in low-grade gliomas in children. Then same mutation is known to play a role in the development of the skin cancer melanoma. The search is under way for compounds that could target

44 :: penn neurosurgery :: PEDIATRIC NEUROSURGERY


this mutation and become the basis for anti-tumor medications. Still, the Consortium’s work is just getting started. “The whole idea of such open access and sharing of data in real-time is transformative—it is a paradigm shift,” says Dr. Storm.

Congenital Abnormalities of the Brain and Spine, Epilepsy Dr. Gregory Heuer operates on some of CHOP’s tiniest patients, performing both fetal and postnatal surgery for spine abnormalities discovered before birth, including lipomyelomeningoceles, meningoceles, and myelomeningoceles. Meningoceles occur when the meninges, or membranes covering the spine, protrude through an opening in the backbone. Dr. Heuer and his team are able to treat myelomeningoceles even before birth, which is proven to offer superior outcomes over post-natal surgery. With many conditions, including other spinal problems, brain malformations and hydrocephalus (the collection of cerebrospinal fluid around the brain), he typically counsels the family before

Phillip “Jay” Storm, M.D. Chief of the Division of Neurosurgery at CHOP

birth and then performs surgical correction soon after the infant is born. Dr. Heuer also repairs birth-related injuries to the brachial plexus, the network of nerves connecting the spinal cord to the arms, hands, and shoulders. For these surgeries, he works closely with Eric Zager, M.D., Neurosurgical Professor in Academic Excellence, who treats the same type of traumatic injury in adults

Adam Resnick, Ph.D. Assistant Professor of Neurosurgery at CHOP

(see page 53).

disorders as part of CHOP’s Pediatric Regional Epilepsy Program. He uses both magnetic imaging and surgical techniques to map the areas of the brain where unusual activity is giving rise to seizures. Dr. Heuer also performs

Gregory Heuer, M.D., Ph.D. Attending Neurosurgeon in the Division of Neurosurgery at CHOP pediatric

Dr. Heuer treats older children and teens who have epilepsy and other seizure

surgery to treat epilepsy, either by removing selected portions of the brain tissue or implanting nerve stimulators to normalize brain activity. In the future, he plans to begin banking any tissue that is removed in order to generate genetic and clinical data that can improve our understanding of pediatric epilepsy. He is also working with Gordon Baltuch, M.D., professor of neurosurgery and director of Penn Medicine’s Center for Functional and Restorative Neurosurgery, to explore the use of deep brain stimulation as a treatment for seizure disorders in children (see page 51). The great advantage of being at CHOP, Dr. Heuer says, is its role as a center for babies and children with central nervous system problems, which leads to high patient volumes: “Patients seek us out, not only from the region and nation but the world, so we can really focus on making them better while also making the treatments better and understanding these conditions in ways that wouldn’t be possible otherwise.”

PEDIATRIC NEUROSURGERY :: penn neurosurgery :: 45


ADVANCED SURGERY

FOR OTHER NEUROLOGICAL ISSUES From aneurysms to Parkinson’s disease to traumatic peripheral nerve injuries, Penn’s neurosurgeons specialize in the latest techniques to restore function.

46 :: penn neurosurgery :: ADVANCED SURGERY FOR OTHER NEUROLOGICAL ISSUES


OTHER CONDITIONS ADVANCED SURGERY FOR OTHER NEUROLOGICAL ISSUES :: penn neurosurgery :: 47


Endovascular Neurosurgery: Correcting Blood Vessel Problems in the Brain without Open Surgery

A

host of blood vessel problems

affecting the brain—all included under the umbrella term “cerebrovascular disease”—can prevent the tissue from getting its usual blood supply, leading to brain damage and even death. They include conditions that block or narrow the blood vessels, such as strokes and carotid and intracranial stenosis; others characterized by an unusual formation of blood vessels, such as arteriovenous malformations and fistulas (AVMs and AVFs); and still others that result in the weakening, ballooning out, and possible rupture of the blood vessel walls, such as aneurysms and hemorrhages. In some cases, these conditions are treated with craniotomy (opening of the skull) followed by microsurgery, in which the neurosurgeon uses a highly specialized microscope and surgical instruments to identify the problematic vessel (or vessels) and correct it.

48 :: penn neurosurgery :: ADVANCED SURGERY FOR OTHER NEUROLOGICAL ISSUES

CT angiography creates a three-dimensional image of the brain’s vascular system.


“The endovascular approach is becoming more popular because it is always getting safer and better, and avoiding cranial surgery can lead to a better immediate David Kung, M.D., assistant professor of neuro-

outcome for the patient.”

Dr. David K. Kung

surgery at the Hospital of the University of Pennsylvania, offers this option but is also trained to offer a newer technique that does not require opening the skull: endovascular neurosurgery.

David K. Kung, M.D. Assistant Professor of Neurosurgery

Working closely with Penn’s interventional radiologists, he can insert a microcatheter through a small incision in the femoral artery in the leg, or the brachial artery in the arm, and then thread it into the brain to access and treat the vessel problem or malformation. For example, with aneurysms, AVMs, and AVFs, he often uses a technique called embolization to block the blood supply into a malformed vessel using tiny coils or a mesh cylinder. This bypasses the problem area and restores normal blood flow in the brain. For eligible patients, endovascular neurosurgery offers the benefit of avoiding a craniotomy, thereby reducing many cases, patients can go home the next day. Dr. Kung, who arrived at Penn in 2014, is part of the newer generation of neurosurgeons who are being trained to offer both open and endovascular techniques. “To some degree the surgical approach comes down to patient preference, but it also depends on what I am treating—the shape, the size, and how sick the patient is,” says Dr. Kung. “The endovascular approach is becoming more popular because it is always getting safer and better, and avoiding cranial surgery can lead to a better immediate outcome for the patient.”

of the brain accessible. Surgeons can now treat parts of the brain that were too dangerous to approach before, meaning that patients who might have been untreatable five or ten years ago can sometimes be cured. Dr. Kung is involved in research to improve the treatment of cerebrovascular conditions. His primary interest is in understanding the mechanisms of aneurysm rupture so that neurosurgeons can better predict which ones are most dangerous. As more aneurysms are being picked up incidentally on MRI scans done for other reasons, says Dr. Kung, the need to distinguish non-threatening aneurysms from

The other great benefit is that endovascular

those likely to rupture—and therefore in need

techniques can make previously inaccessible areas

of treatment—becomes more pressing.

ADVANCED SURGERY FOR OTHER NEUROLOGICAL ISSUES :: penn neurosurgery :: 49

OTHER CONDITIONS

recovery time and the risk of complications. In


“The wires are tiny, and we’re using MRIs to achieve new levels of accuracy in running wire leads on a precise path around healthy tissue and into a part of the brain that’s about the size of a Rice Krispy.”

Dr. Gordon H. Baltuch

50 :: penn neurosurgery :: ADVANCED SURGERY FOR OTHER NEUROLOGICAL ISSUES


Deep Brain Stimulation: An “Electrical Medicine” for Parkinson’s Disease and Other Neurological Conditions

“A

pacemaker for the brain.”

“Electrical medicine.” These are the terms in which Gordon Baltuch, M.D., Director of the Center for Functional and Restorative Neurosurgery, describes deep-brain stimulation (DBS) therapy, which he first learned two decades ago from the European physician who pioneered it. DBS is most often used to treat the motor symptoms of advanced Parkinson’s disease when medications alone are no longer sufficient. Parkinson’s is a degenerative disorder of the central nervous system that causes dopamine-generating brain cells to die, resulting in shaking, tremors, rigidity, stiffness, and other movement problems. With deep-brain stimulation, small electrodes are implanted in the distressed areas of the brain and attached to tiny insulated When the brain’s electrical circuitry goes haywire, the pacemaker can correct it, greatly improving motor symptoms. The treatment has to be individualized for each patient, which is why Dr. Baltuch calls it “both science and an art form:” He and his colleagues map the problem areas of the brain to determine placement of the electrodes and wires, and then program the device to deliver just the right amount of electrical stimulation to block aberrant signals. For many people with Parkinson’s, DBS is life-changing. “These are patients with chronic, advanced Parkinson’s who in spite of the best medical therapy are starting to experience a roller coaster ride of unpre-

Gordon H. Baltuch, M.D., Ph.D. Director, Center for Functional and Restorative Neurosurgery and Professor of Neurosurgery

ADVANCED SURGERY FOR OTHER NEUROLOGICAL ISSUES :: penn neurosurgery :: 51

OTHER CONDITIONS

wires, which in turn are connected to a pacemaker-like device in the chest.


dictable, fluctuating symptoms,” says Dr. Baltuch.

that can last up to nine years, which is a major

“Sometimes they are ‘on’ and appear fine, and then

improvement over their previous three- to five-year

they experience abnormal movements such as

shelf life.

slowing, rigidness, an uneven gait. This might be anywhere from seven to ten to 20 years after initial diagnosis.”

cure, nor does it improve the non-motor symptoms of Parkinson’s such as cognitive decline and mood

Today’s patients benefit from the advances that

changes. But videos of patients before and after

have been made in the procedure over more than

the procedure show the incredible difference it

two decades. Dr. Baltuch notes that only dime-sized

can make. “We can restore a basically normal

openings in the skull are required, and he and his

lifestyle for people whose lives have been physically

team are skilled at minimizing impact on healthy

compromised for years,” he says.

brain tissue.

Now he is heavily involved in studying the potential

“The wires are tiny, and we’re using MRIs to achieve

use of DBS as a treatment for other neurological

new levels of accuracy in running wire leads on a

conditions, including severe epilepsy, treatment-

precise path around healthy tissue and into a part

resistant depression, and early Alzheimer’s disease.

of the brain that’s about the size of a Rice Krispy,” he says. If implants are needed on both sides of the An MRI shows the location

Dr. Baltuch is quick to point out that DBS is not a

brain, he can accomplish this in a single surgery,

of the deep-brain stimulation

which is not the case at all institutions. In addition,

electrodes.

the pacemakers now have rechargeable batteries

52 :: penn neurosurgery :: ADVANCED SURGERY FOR OTHER NEUROLOGICAL ISSUES


From Brain to Spine to Nerves: Correcting Problems throughout the Nervous System, with a Focus on Peripheral Nerves

F

or Eric Zager, M.D., FACS, FAANS,

Neurosurgical Professor in Academic Excellence, the major benefit of being at Penn Medicine is that he is not forced to specialize in one or two areas. Rather, he uses advanced microsurgical techniques to correct problems throughout the entire nervous system, often collaborating with colleagues in the Department of Neurosurgery and The Children’s Hospital of Philadelphia. He removes tumors from the brain, spine, and nerves in both adult and pediatric patients. He corrects cranial nerve issues that lead to facial spasms or intense nerve pain. Dr. Zager works as part of the spine surgery team to fix spinal stenosis and other degenerative spine disorders. He also corrects problems in the blood vessels that feed the brain, such as carotid stenosis, aneurysms, and arteriovenous malformations (AVMs). Even as he does all this, Dr. Zager has developed advanced expertise in surgical procedures involving the peripheral nerves: the extensive and delicate system of nerves that carry signals from the brain and spinal cord to rest of the body. He removes tumors from the these, extricating them as carefully as possible to keep the nerves intact. Dr. Zager corrects painful conditions caused by compression of the nerves, such as carpal tunnel syndrome, ulnar on the peripheral nerves after traumatic injuries caused by falls or vehicle accidents or, for newborn infants, the birthing process. Often these injuries involve the brachial plexus, a group of nerves that travel from the spinal cord into the neck down the arm, where they control muscle function and sensation. Surgery typically involves nerve repair or a nerve graft or transfer, which uses healthy nerve tissue to replace the damaged portion.

ADVANCED SURGERY FOR OTHER NEUROLOGICAL ISSUES :: penn neurosurgery :: 53

OTHER CONDITIONS

entrapment neuropathy, and thoracic outlet syndrome. He also operates


Eric Zager, M.D., FACS, FAANS, Neurosurgical Professor in Academic Excellence and Attending Physician

In all types of peripheral nerve surgery, says Dr.

forms of nerve damage our patients present with,

Zager, the goal is to preserve as much nerve

and then the team can develop research models

function as possible or restore it, so that people

to address it. One major challenge we face with

can resume their lives with motor function and

patients with major injuries involving the brachial

sensation intact. Fully restoring nerve function after

plexus is that the hand often remains paralyzed.

the most serious injuries, such as to the brachial plexus, can be extremely difficult, though. Together with Penn’s orthopedic team, Dr. Zager has worked on cases where a healthy muscle can be taken from the leg and used to replace a severely damaged

“Our goal ultimately is to take this basic research into the clinic and enhance our ability to regenerate patients’ nerves,” he adds. “This technology could allow us to restore full function.”

muscle in the arm, with him then performing microvascular nerve repair to restore elbow flexion. But surgery isn’t always a perfect solution. Dr. Zager is collaborating with Penn Neurosurgery colleagues Dr. Doug Smith, Dr. Kacy Cullen, and Dr. Isaac Chen on research into nerve regeneration— that is, growing healthy replacement axons in cell culture, elongating them through a specialized “stretch-growth” process, and then implanting them to replace peripheral nerves lost to traumatic

“Our goal ultimately is to take this basic research into the clinic and enhance our

injury (see page 7).

ability to regenerate patients’ nerves.

“What works so well here at Penn is that the

This technology could allow us to restore

research is informed by our clinical challenges,” Dr. Zager says. “We share information about the

full function.”

54 :: penn neurosurgery :: ADVANCED SURGERY FOR OTHER NEUROLOGICAL ISSUES

Dr. Eric Zager


t e k c o p ” 4 O P F


Penn neurosurgery One of the first neurosurgery programs in the country, Penn Neurosurgery provides comprehensive surgical management of disorders of the brain, spinal cord, and peripheral nervous system. Penn Medicine is committed to translating cutting-edge research into improved patient care. Penn Neurosurgery 3400 Spruce Street 3rd Floor Silverstein Building Philadelphia, PA 19104 pennmedicine.org/neurosurgery 800-789-PENN


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