Epilepsy is a relatively common seizure disorder, affecting eight or nine out of every 1,000 people. According to Charles Yu Liu, M.D., Ph.D., Associate Professor and holder of the Michael L. J. Apuzzo Professorship for Advanced Neurological Surgery at the Keck School of Medicine of USC, patients fall into three main categories: “There are patients who are amenable to pharmacotherapy and can be managed quite well by experienced neurologists and epileptologists. There are those who do well with surgical ablation if the seizure focus is identified and safe to remove.

“Then there is a third group of treatment-resistant patients that ends up being very challenging. For that third group that doesn’t respond to either drugs or are not candidates for ablative surgery, we have shown that there is hope in a technique called neuromodulation, which involves

the direct electrical stimulation of either the vagus nerve in the neck or the brain itself.”

Established in 1988, the USC Comprehensive Epilepsy Center has had a great deal of experience in the management of epilepsy patients using the neuromodulative technique of Vagus Nerve Stimulation (VNS). In fact, the USC program played a crucial role in clinical trials of VNS for epilepsy and is now one of the largest centers in the United States offering VNS therapy as a treatment for epilepsy. The scope of the program encompasses USC University Hospital, the LAC + USC Medical Center and the Rancho Los Amigos National Rehabilitation Medical Center.

Now the epilepsy team at USC is studying a new neuromodulative therapy, the RNS™ System, which has thus far shown a great deal of promise. Developed by NeuroPace, the RNS System is designed for the treatment of medically refractory partial epilepsy. The RNS neurostimulator is a programmable, battery powered, microprocessor-controlled device that delivers electrical pulses to the brain through implanted leads. When the device detects abnormal electrical activity in the brain, it can then deliver a small amount of electrical stimulation to suppress seizures before symptoms occur.

Neuromodulation Helps Patients With Treatment-Resistant Epilepsy

Charles Yu Liu, MD

Areas of Treatment: Epilepsy, Skull Base

Tumors, Meningioma, Pituitary Adenoma,

Craniopharyngioma, Cavernous

Hemangioma, Subarachnoid Hemorrhage,

Depression, Intracranial Tumors

(Intrinsic and Mets), Arteriovenous

Malformation (AVM), Vagal Nerve

Stimulator Implantation, Temporal

Lobectomy, Craniotomy, Transphenoidal

Craniotomy, Aneurysm Clip Ligation,

Stereotactic Radiosurgery

USC played a crucial role in clinical trials of VNS for epilepsy and is now

one of the largest centers in the United States

offering VNS therapy as a treatment for epilepsy.

The following clinical trials are currently enrolling or are in progress:

• Parkinson’s recovery of brain with exercise

• RhinoChill: A novel hypothermia delivery system

• Gamma Knife radiosurgery in the treatment of temporal lobe epilepsy

• Vagus nerve stimulation vs. medical therapy/outcomes

• Donepezil in the treatment of memory dysfunction of temporal lobe epilepsy

• Neurodevelopmental effects of anti-epileptic drugs

• Progesterone therapy for women with epilepsy

• Pregabalin open-label, follow-on safety trial in patients with refractory epilepsy

• Pregabalin open-label add-on trial: An open-label multicenter follow-on study to determine long-term safety and efficacy in patients with partial seizures

• A multicenter, double-blind, randomized, placebo-controlled, parallel group trial to investigate the efficacy and safety of SPM 927 as adjunctive therapy in subjects with partial seizures with or without secondary generalization

• A multicenter, double-blind, randomized, parallel group evaluation of LAMICTAL extended-release adjunctive therapy in subjects with partial seizures

For information on these or other clinical trials ongoing at USC University Hospital or USC Norris Cancer Hospital, please contact Sandra Oviedo or Guadalupe Corral-Leyva at 323-442-5890.

USC Universi ty Hospital — 888-700-5700 • USC Norris Cancer Hospital — 800-700-3956 • The Doctors of USC — 800-USC-CARENEURoMoDULATIoN CoNT’D oN PAGE 2

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Current Clinical Trials at USC University Hospital

A Publication of The Doctors of USC, USC University Hospital and USC Norris Cancer Hospital

USC CONSULT>

NeUrOSCieNCeS iSSUe, Vol. 3 SUMMER 2009

and technically demanding procedure by neurosurgeons, spine surgeons and orthopedic surgeons. USC is one of only a handful of centers around the country to offer this type of radical treatment for spine tumors.

According to a recent study presented by Dr. Hsieh at several national and international meetings, “An analysis of twenty consecutive patients who underwent radical en bloc excision of sacral chordomas and chondrosarcoma showed that en bloc sacral tumor excision for chordomas and chondrosarcomas can be performed safely with acceptable perioperative morbidity rate and post-surgical functional outcomes.”

He continues, “In this study, we achieved wide or marginal en bloc tumor excisions in 14 out of 20 patients, and patients with wide or marginal excisions had significant increase in disease-free survival than those with contaminated excisions.” The results of the study indicate that en bloc tumor excision with negative tumor margins is the ideal treatment for patients with sacral chordomas and chondrosarcoma, and that wide or marginal en bloc excisions of sacral chordoma and chondrosarcoma result in significant increase in disease-free survival. In addition, en bloc sacral tumor excision for chordomas and chondrosarcomas can be performed safely with acceptable perioperative morbidity rate and post-surgical functional outcomes.

Unlike many other programs, the • USC spine oncology program features neurosurgeons who are fellowship-trained in oncology.

USC University Hospital is one of only • two local centers with the CyberKnife stereotactic radiosurgery system.

En bloc spinal tumor excision may be • the ideal treatment for patients with certain primary spinal malignancies.

RefeRRaL NoTeS

SPINE TUMoRS CoNT’D

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The Doctors of USC is a group of more than 500 physicians and specialists who are full-time faculty members of the world-renowned Keck School of Medicine of the University of Southern California. The Doctors of USC see private patients at facilities all across Los Angeles, including USC University Hospital, one of “America’s Best Hospitals”® in 2008, and USC Norris Cancer Hospital, which provides patient care for the USC Norris Comprehensive Cancer Center, one of only six institutions in California designated by the National Cancer Institute as a Comprehensive Cancer Center. USC Consult is a quarterly newsletter published for physicians throughout Southern California. Health Sciences Public Relations and Marketing • University of Southern California • Keith Administration Building • 1975 Zonal Avenue, Room 400 • Los Angeles, California 90033-9029

USC is one of only two centers in the Los angeles area currently using the CyberKnife™ stereotactic radiosurgery system to treat spine metastases.

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For Christianne N. Heck, M.D., M.M.M., Director, USC Comprehensive Epilepsy Center and Principal Investigator of the RNS trial, the RNS System represents a breakthrough in the treatment of a difficult-to-manage patient population. “The NeuroPace trial has been very exciting. We have ten patients implanted and are looking forward to a long-term treatment protocol for five-year follow-up,” she says. USC is currently the only site in Southern California participating in clinical trials of the RNS System.

But the epilepsy program’s focus doesn’t begin and end with neuromodulation. Dr. Heck says, “Now is a very exciting time for epilepsy study. We’re making great strides, especially in things such as neuro-imaging, where we can now see abnormal structures in the brain that we couldn’t have seen ten years ago, giving us good targets for therapy.”

Dr. Heck and her team, which includes Laura Kalayjian, M.D., Assistant Professor of Neurology, are also focusing on women and epilepsy, including how the disease affects women during the menstrual cycle, pregnancy and menopause. Dr. Kalayjian continues to lead efforts in investigating the impact of hormones on epilepsy as well as the impact of anti-epileptic medications on children exposed to epilepsy medications in the womb.

Epileptologist David Ko, M.D., Associate Professor of Neurology, continues his efforts in clinical trials of new drug development. David Millett, M.D., Ph.D., another key member of the team, has recently been awarded a G13 NIH grant for authorship of his book Brain Waves: EEG and the History of Clinical Neuroscience, which chronicles the history of epilepsy care. Dr. Millett’s efforts have added significantly to the success of the USC Comprehensive Epilepsy Center by building a pre-surgical epilepsy monitoring unit with video/EEG at Rancho Los Amigos National Rehabilitation Medical Center. The program has been further enhanced with the expansion of the pediatric epilepsy effort by Dr. Arthur Patikian at the LAC + USC Medical Center, and future recruitments are planned.

Neuromodulative therapies such • as Vagus Nerve Stimulation and the RNS System show promise for patients with treatment-resistant epilepsy.

The USC Comprehensive Epilepsy • Center offers unique research-based expertise in a variety of specific areas, including epilepsy and its effects on women.

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Treatment of Primary and Metastatic Spine Tumors

For Thomas Chen, M.D., Associate Professor of Neurological Surgery at the Keck School of Medicine, the primary advantage of the USC spinal oncology program is that its neurosurgeons are not only fellowship-trained in spine surgery, but also have specific interest in oncology.

“Typically, at other facilities, spine surgery that is performed on cancer patients is performed by spine surgeons who are interested in decompressing and restoring the biomechanical stability of the spine but who do not specifically address the cancer.” He goes on, “We take a broader approach. We’re interested in the oncologic piece; we want to work with the referring oncologist to understand what type of chemotherapy the patient is getting, what other treatment modalities are being used, and we use that to inform our approach to surgery.”

As an example of this in practice, Dr. Chen pointed to the referral of a patient who had renal cell carcinoma. This patient needed a resection of a thoracic spine tumor, due to metastasis. “In a case like this,” says Dr. Chen, “you can approach the spine through the chest or through the back. We made our decision on how to do the procedure based on what we knew about the cancer treatments the patient was going through at the time.”

He also points out that USC is one of only two centers in the Los Angeles area currently using the CyberKnife™ stereotactic radiosurgery system to treat spine metastases. The CyberKnife uses robotic technology and advanced image-guidance to track and destroy small lesions through the delivery of large doses of targeted radiation. The treatment is delivered via a beam of high-dose radiation that tracks the cancer in real time with minimal radiation exposure to surrounding healthy tissue. Since there is no open incision or invasive frame, patients typically experience improved comfort. CyberKnife radiosurgery is done on an outpatient basis.

Dr. Chen’s colleague, Patrick Hsieh, M.D., Assistant Professor of Neurological Surgery at the Keck School of Medicine, undertook a spine tumor fellowship at Johns Hopkins University School of Medicine in Baltimore, Maryland. He has extensive experience in treatment of metastatic and primary spinal tumors. Since his arrival at USC, Dr. Hsieh has continued to develop and expand his experience and interest in both primary and metastatic spine tumors and has been involved in clinical trials for radical resection of primary spinal tumors, also known as “en bloc” spine tumor excision. In this procedure, the malignant tissue is removed intact with a small

rim of normal surrounding tissues, with the goal to minimize the possibility of leaving microscopic tumor cells behind. As a result, there is decreased chance for tumor recurrence and the likelihood for long-term survival and achieving a cure is significantly improved. This type of radical surgical removal of tumors in the spine is considered to be the most complex

“When the device detects abnomal electrical activity in the brain, it can then deliver a small amount of electrical stimulation to suppress seizures before symptoms occur.”

Christianne N. Heck, MD

Areas of Treatment: Epilepsy

Thomas Chen, MD

Areas of Treatment: Primary Brain Tumor,

Metastatic Brain Tumor, Glioma, Glioblastoma

Multiforme, Astrocytoma, oligodendroglioma

PNET, Spinal Disc Herniation, Chronic

Back Pain, Spinal Stenosis, Spine Tumor,

Craniotomy for Mass Resection and Neuro-

oncology, Microdiscectomy, Lumbar

Fusion, Instrumentation, Pedicle Screws,

Laminectomy

3Article 2: Primary and Metastatic Spine Tumors2 Article 1: Neruromodulation for Epiliepsy Patients To refer a patient to USC University Hospital, call 1-888-700-5700.

“We want to work with the referring oncologist to understand what type of chemotherapy the

patient is getting and what other treatment modalities are being used. We use that to

inform our approach to surgery.”

SPINE TUMoRS CoNT’D oN PAGE 8

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Bergey, GB, et.al., Implementation of an external responsive neurostimulator system (eRNS) in patients with intractable epilepsy undergoing intracranial seizure monitoring. Epilepsia Vol 43, Suppl 7, 2002

“We’re not sitting around waiting for these patients to have a stroke. We’re stabilizing their arteries, reducing the chance of a stroke ever occurring.”

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According to the American Heart Association (AHA), stroke is the third leading cause of death – and the leading cause of disability – in the United States. Many of these patients may be treated in a community hospital setting. But for certain patients, such as those with unstable intracranial plaque, increased intracranial pressure and multiple co-morbidities, treatment at an academic stroke center may be required.

The USC Comprehensive Stroke Center offers a wide range of services that employ advanced medical, surgical and interventional techniques. The program draws upon expertise from multiple disciplines, from interventional neuroradiology and vascular surgery to neuropsychology and rehabilitation medicine, and a deep commitment to breakthrough research and education.

Though many centers claim to employ a multidisciplinary approach, at USC University Hospital, specialists from all across the discipline of neuroscience convene to bring the most targeted therapies and approaches to each patient’s unique situation. Donald W. Larsen, M.D., M.B.A., Interventional Neuroradiologist and Chief Medical officer for the USC hospitals, gives an example.

“The Division of Endovascular Neurosurgery is embedded in the Department of Neurosurgery, so we’re a one-stop shop for neurovascular disease. That means we take a collaborative approach to patient care, with an emphasis on optimizing the outcome of treatment,” he explains.

onyx® HD-500 Liquid embolic System and VISSIT Trial

As an interventional neuroradiologist, Dr. Larsen is currently involved in carotid angioplasty and stenting, which he has been performing since 1994, and aneurysm embolization. Recently, Dr. Larsen has been researching the use of the onyx liquid embolic system for wide-necked aneurysms where embolic coils may not be sufficient. The system consists of an artificial material used to block blood flow into aneurysms by filling the aneurysm space, preventing rupture or growth. Dr. Larsen, along with his colleagues Gene Y. Sung, M.D., Steven L. Giannotta, M.D., and Arun Amar, M.D., were on the FDA advisory team when the system was in the early stages of FDA approval. Embolization using onyx is currently available for qualified patients, pending IRB approval.

USC University Hospital is the only West Coast site for the Vitesse Intracranial Stent Study for Ischemic Therapy (VISSIT), which is a randomized trial comparing clinical outcomes between patients treated with the Vitesse™ Balloon Expandable Stent and the current best medical practice such as treatment with aspirin or Plavix (clopidogrel bisulfate). Dr. Larsen and his partner, Arun Amar, M.D., are currently enrolling patients in this trial who have had a stroke or transient ischemic attack (TIA) within 30 days and exhibit high-grade stenosis (70-99%) in an intracranial artery. The VISSIT trial is reimbursable by Medicare.

From Hypothermia to New Embolic Agents, USC Offers Promising Treatment for Difficult Stroke

Hypothermia May Improve Patient outcomes after acute Ischemic events

Gene Sung, M.D., Associate Professor of Neurology and Chief, USC Division of Stroke and Critical Care Neurology, has been researching the effect of cooling the brain after an acute ischemic event using the new RhinoChill system. Developed by BeneChill, the RhinoChill device delivers an inert liquid coolant directly to the nasal sinus cavity, cooling the vascular supply in that region through evaporation. The area’s close proximity to the brain means the brain is cooled rapidly and safely – the device’s two main selling points. According to Dr. Sung, “There were studies that showed that cooling the body with simple devices such as ice bags and blankets helped prevent brain damage after heart attack. So the idea was to cool the brain quicker by using this nasal device to cool the blood supply to the brain.” He continues, “At the moment, we’re the only center in Southern California using the RhinoChill system to improve outcomes after acute stroke.”

Stroke Prevention and other Neurovascular activities

Nerses Sanossian, M.D., Assistant Professor of Neurology, Keck School of Medicine, specializes in the diagnosis and management of stroke. Board-certified in Neurology, Vascular Neurology, Neuroimaging and Neurosonology (neurovascular ultrasound), Dr. Sanossian has been studying the anti-inflammatory role of high-density lipoprotein (HDL) cholesterol in cerebral atherosclerosis. As an investigator in a current trial studying a novel cholesterol-modifying agent that acts by blocking the protein ACAT-1, Dr. Sanossian is attempting to demonstrate benefits in reducing arterial narrowing over six months through high resolution carotid plaque MRI. As Dr. Sanossian puts it, “We’re not sitting around waiting for these patients to have a stroke. We’re stabilizing their arteries, reducing the chance of a stroke ever occurring.” The primary inclusion criterion is a narrowing of the carotid artery of between 15 and 70 percent.

Donald W. Larsen, MD, MBa

Areas of Treatment: Stroke Treatment and

Prevention, Brain Aneurysm Embolization,

Carotid Angioplasty and Stenting, Spinal

Injections for Pain Management, Cerebral

Aneurysm, Cerebral Stenosis, Carotid

Stenosis, Stroke, Degenerative Spine Pain,

Vertebral Fracture, Arteriovenous Fistula,

Endovascular Coiling, Endovascular

Stenting, Cerebral Angioplasty,

Intra Arterial TPA, Epidural Steroid

Injections, Vertebroplasty, Kyphoplasty

Clinical trials offer innovative • treatments for stroke patients or those at risk for acute ischemic events.

The USC Stroke Program’s • collaborative approach translates to improved patient care.

Physicians interested in patient • referrals to the stroke program may contact Jennifer Hagemann at (323) 224-5138.

RefeRRaL NoTeS

5Article 3: Promising Treatment for Difficult Stroke4 Article 3: Promising Treatment for Difficult Stroke To refer a patient to USC University Hospital, call 1-888-700-5700.

USC Welcomes New Neurosurgeon,

arun Paul amar, M.D.

Dr. Amar recently joined the USC Department

of Neurosurgery, coming here from the

University of California, San Francisco, where

he was an assistant clinical professor in the

UCSF Department of Neurosurgery. After

receiving his undergraduate degree from Yale

University and his medical degree from the

University of California, San Francisco,

Dr. Amar completed his internship and

residency in the departments of surgery and

neurosurgery, respectively, at USC. He is also a

graduate of the Ph.D. program of the USC Dept.

of Physiology and Biophysics. Dr. Amar is the

founder and current president of the Society of

Endovascular Neurosurgeons.

The RhinoChill device delivers an inert perfluorocarbon gas directly to the nasal sinus cavity, cooling the vacular supply in that region through evaporation.

Image courtesy of BeneChill.

Parkinson’s disease affects one percent of the population over age 60 and is the second most common neurode-generative disease behind Alzheimer’s. Another movement disorder, essential tremor, is even more common, affect-ing four percent of the population over 40 and a much higher percentage of the population over 60. other movement disorders, such as dystonia, may be less common but are equally debilitating.

Deep Brain Stimulation Shows Promise for Patients With Drug-Resistant Tremor

Many patients with movement disorders suffer from disabling symptoms despite the use of medications. For them, sur-gical intervention such as deep brain stimulation (DBS) may offer new hope. For Mark Liker, M.D., Director of the USC Neurosurgery Deep Brain Stimula-tion Program, DBS represents a modern, less invasive alternative to the tradition-al thalamotomy. When speaking to a lay audience, he explains DBS thusly: “It’s like a pacemaker for the brain.”

DBS involves the use of an implanted electrode, which is surgically inserted under stereotactic guidance into the desired target area of the brain through a small burr hole. This electrode place-ment is performed under local anesthe-sia, with the patient awake and alert. Continuous, high frequency electrical stimulation, similar to a heart pacemak-er, is then delivered to either the thala-mus, globus pallidus (GPi) or to the subthalamic nucleus (STN) – all parts of the brain that control movement.

Although the basic mechanisms of DBS are not well understood, it is believed that these electrical impulses can help to interfere with the abnormal electrical signals that cause uncontrollable move-ments associated with movement disor-ders. Liker comments, “Even though it’s technically ‘brain surgery,’ it’s a pretty safe procedure; the risks are pretty well understood and controlled.” He con-tinues, “As with any surgery, there is a small risk of infection. There is also a small risk of hemorrhage, but it is low – less than one percent.”

The surgery is a two-part procedure con-sisting of the craniotomy and electrode implantation, which typically involves just an overnight stay, and the connec-tion of the battery, which typically takes place a few days later.

For some patients who have had the system implanted, DBS has helped to alleviate symptoms, improving their ability to participate in everyday activi-ties, drastically improving their quality of life.

Dr. Liker says that DBS shows promise for other maladies, too.

“It’s a really exciting field. DBS has just been indicated for treatment of obsessive-compulsive disorder (oCD), and there have been a number of small studies involving the use of DBS for de-pression. It’s also had limited success in treating Tourette syndrome.”

Deep brain stimulation shows • a great deal of promise in the treatment of drug-resistant tremor in patients suffering from movement disorders.

Intense exercise may improve • motor function in patients with recently diagnosed Parkinson’s disease.

RefeRRaL NoTeS

Advances in the Treatment of Movement Disorders

exercise May elicit Improved Motor Performance in

Parkinson’s Patients

Parkinson’s disease is caused by the death or impairment of certain nerve cells in the midbrain that produce dopamine, a chemical messenger that transmits signals that allow for coordinated movement. When these dopamine-secreting cells die, the other movement control centers in the brain become unregulated. Giselle M. Petzinger, M.D., Assistant Professor of Neurology at the Keck School of Medicine, is studying the relationship between exercise and dopamine receptors to find out if exercise can modify the disease.

Dr. Petzinger is enrolling patients in a clinical trial to study the effects of in-tense exercise on activity-dependent neuroplasticity (changes that occur in the organization of the brain as a result of experience) in recently diagnosed Parkinson’s patients. The hypothesis is that promoting neuroplasticity through intense exercise will elicit improved mo-tor performance in Parkinson’s patients. USC is the only center in the country currently participating in this trial. Dr. Petzinger doesn’t mince words when it comes to her preliminary findings. “It’s definitely a breakthrough,” she says.

DBS involves the use of an implanted electrode, which is surgically inserted under stereotactic guidance into the desired target area of the brain through a small burr hole.

7Article 4:Treatment of Movement Disorders6 Article 4: Treatment of Movement Disorders To refer a patient to USC University Hospital, call 1-888-700-5700

The Libra® deep brain stimulation (DBS) system is approved in Europe for treating the symptoms of Parkinson’s disease and is being evaluated in U.S. clinical trials for Parkinson’s disease and essential tremor. Image courtesy of St. Jude Medical.

The hypothesis is that promoting neuroplasticity through intense exercise will elicit improved motor performance in Parkinson’s patients.

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