Diseases and malformations of thebrain’s endovascular system—once treatable only by invasive

and complicated surgical procedures—are increasingly being treated essentiallyfrom within using a procedure known asendovascular surgical neuroradiology.

“We’re brain plumbers,” noted PhilipMeyers, MD. “If the pipes are leaking,we plug the leak; if the pipes areclogged, we unclog them. All jokingaside, endovascular surgical neuroradiol-ogy is a very important and rapidlygrowing specialty in major medical cen-ters across the United States.”

With an array of high-tech tools—glues, coils, tubes, balloons, and eventiny “umbrellas”—researchers atNewYork-Presbyterian Hospital are, asDr. Meyers would say, “plumbing” thedepths of the brain’s blood vessels.Along the way, their innovations andstudies have made them recognizedworld leaders in the treatment of stroke,aneurysms, arteriovenous malforma-tions, and carotid stenting for openingthe neck’s plaque-choked artery.

“One of the biggest and most dramaticthings we do is to take care of intracra-nial aneurysms, ruptured or unrup-tured,” said Howard A. Riina, MD.“The endovascular way of treatinganeurysms is by coiling them.”

Developed in 1990 by Guido Guglielmi,MD, the Guglielmi Detachable Coil is atiny, flexible platinum coil placed into ananeurysm via catheter. By packing theaneurysmal sac, it induces clotting and

NeuroscienceAugust 2003

N E W Y O R K – P R E S B Y T E R I A N

Deep brain stimulation, the pow-erful new modality for treatingthe disabling motor symptoms

of Parkinson’s disease and other move-ment disorders, has become the proce-dure of choice at the Center forMovement Disorders Surgery atColumbia Presbyterian Medical Center,and at the Center for Stereotactic andFunctional Neurosurgery at NewYorkWeill Cornell Medical Center. It haslargely supplanted tissue ablation proce-dures, which had been the standard asrecently as the 1990s.

“We have converted, almost totally,from doing lesions to stimulator

Deep BrainStimulation Surgeryfor Parkinson’s Disease

I N S I D E

Computed Tomography Perfusion

2Engineering advances and continued research

have made CT perfusion scanners better

diagnostic tools for the ER setting

Gene Therapy

4Researchers have launched the first human

clinical study investigating the efficacy of gene

therapy in the treatment of neurologic disorders

Noninvasive Radiotherapy

6Painless and noninvasive radiotherapy is being

explored as an alternative to neurosurgery for

patients with intractable temporal lobe epilepsy

t-PA in Stroke Treatment

7Researchers at NewYork–Presbyterian Hospital are

seeking to expand the window for use of

intravenous tissue plasminogen activator in stroke

Emergency Treatments for Cerebral Hemorrhage

9Studies are revealing opportunities to provide

patients suffering from intracerebral hemmorhage

with more than supportive care in the ER

see Deep Brain Stimulation, page 5

Endovascular SurgeryShows Promising Results

Aneurysm, before and after: The endovascular way of treatinganeurysms involves the GuglielmiDetachable Coil. By packing theaneurysmal sac, the coil induces clotting and scarring to remove theaneurysm from circulation.see Endovascular, page 11

Affiliated with COLUMBIA UNIVERSITY COLLEGE OF PHYSICIANS & SURGEONS and WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY

2

NeuroscienceStroke’s status as the third leading

cause of death in the United Stateshas served to spur researchers to

find safe and effective tools for its diag-nosis and treatment. To some, computedtomography (CT) scans have often beenseen as somewhat of a “down and dirty”radiologic tool when compared topositron emission tomography (PET)scans, single-photon–emission CT scans,and magnetic resonance imaging (MRI).

Thanks to engineering advances andcontinued research, much of which isbeing done at NewYork-PresbyterianHospital, CT perfusion scanners nowshow numerous advantages over otherdiagnostic tools, particularly in thediagnosis and safer treatment of emer-gency room and intensive care unitpatients already in stroke or facingcerebral hemorrhage.

According to Pina C. Sanelli, MD,while PET scans have remained thegold standard for the evaluation of cere-bral blood flow and brain metabolismfor many years, they have often been anonviable option for analyzing thestroke patient in the emergency room orintensive care unit after hours or on theweekend because of their limited avail-ability and the need for prior prepara-tion of the radioactive tracer. Therefore,she said, other modalities such as CTand magnetic resonance perfusion haveemerged as promising tools for physi-cians.“When you’re dealing with some-one connected to multiple lines and/or

on very aggressive drips that can’t beinterrupted, the enclosed MRI tube canpresent a major obstacle,” added IgorOugorets, MD. “By comparison, CTperfusion makes it easier to prepare thepatient and the exam takes about 30 seconds—versus 10 minutes in MRI—to perform. You also have full access tothe patient, so if something happens, thedoctor or the technician can jump in totreat the patient, fix a line, etc. CT perfusion is definitely more user-friendlyfor the critically ill patient.”

Monitoring VasospasmLed by Robert DeLa Paz, MD, neurol-

ogists at Columbia Presbyterian MedicalCenter have discovered 2 increasingly

valuable uses for CT perfusion—acutestroke evaluation in the ER and treat-ment of the post-stroke patient in theintensive care unit.

“CT perfusion changes can be seensooner after stroke onset than CT low-density changes, allowing earlier diagnosisand treatment,” said Dr. DeLa Paz. Headded that the technology is also useful inmonitoring the reduction of blood flow tothe brain that may be produced by pro-gressive vasospasm, which can result fromsubarachnoid hemorrhage.

Dr. Sanelli believes that CT perfusionhelps physicians to better “estimate therisk of developing vasospasm andstroke” by providing actual numbers forsuch parameters as cerebral blood flowand mean transit time. She admits thatcatheter angiography is the gold stan-dard for vasospasm evaluations, but it isalso an invasive procedure, which pres-ents increased risks for patients. As aresult, NewYork Weill Cornell MedicalCenter has been involved for more thana year in a new institutional reviewboard–approved protocol to use CTperfusion to “provide us with informa-tion as to when patients are developingvasospasm and need an angio,” notedDr. Sanelli. “We feel that with CT per-fusion we can image areas of the brainthat may be undergoing end-vesselvasospasm.” Historically, this has beendifficult information to obtain, evenwith catheter angiography.

The All-in-One DebateA critical question facing doctors who

treat stroke patients is how much of thebrain has been infarcted and how much isstill treatable ischemic penumbra. “If thediffusion-weighted imaging lesion issmaller than the perfusion-weightedimaging abnormality, there is a potentiallytreatable stroke penumbra,” said Dr. DeLa

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Computed Tomography Perfusion: Improving Stroke Diagnosis and Treatment

N E W Y O R K – P R E S B Y T E R I A N

A CT angiogram shows right middlecerebral artery occlusion with large parietal collaterals.

“CT perfusion changes can be seen sooner after stroke onsetthan computed tomography low-density changes, allowing earlier diagnosis and treatment.”

—Robert DeLa Paz, MD

Paz. “If diffusion-weighted imaging versus per-fusion-weighted imaging is the same or larger,we conclude the tissue’s blood supply has beenreduced too long or that the body has reperfusedthat tissue and we’re too late to do anything.”

Clinical debate in this area has centeredaround whether it is possible for CT perfusionto provide both diffusion-weighted imagingand perfusion-weighted imaging data alone(as postulated by Wintermark et al inSwitzerland [Adv Neurol 2003;92:389-400]).According to Dr. DeLa Paz, researchers atColumbia Presbyterian Medical Center haveused Dr. Wintermark’s methods and failed toobtain “a reliable discrimination between thetwo.” But at NewYork Weill Cornell MedicalCenter, according to Dr. Sanelli, preliminarydata in this area have “demonstrated the relia-bility and reproducibility of CT perfusion”alone for delineating the cerebral infarct core,making it a useful tool in analyzing strokepatients in emergency situations.

It should be noted that the more limitedbrain coverage provided by CT perfusion isanother consideration for making it reliable indiffusion-weighted imaging and/or perfusion-weighted imaging differentiation. “Would Ilike to have an 8-slice image of the brain as Ido with MRI? Yes,” said Dr. Ougorets. “But Inow have 4 slices with the CT perfusionwhere I used to have 1.” That said, Dr.Ougorets added that he has no reason tobelieve that in a few years CT perfusion won’tgive him those 8 slices.

Risking t-PAUsing CT perfusion to determine the viabili-

ty of intra-arterial delivery of tissue plasmino-gen activator (t-PA) is another area researchersat Columbia Presbyterian Medical Centerhave been exploring. The suggested timelinefor safe and effective stroke treatment using t-PA is within the first 3 hours after onset.

3

NewYork-Presbyterian Neuroscience is a publication of the Neuroscience Centers of NewYork-Presbyterian Hospital. The Neuroscience Centers are at the forefront of research and practice inthe diagnosis, treatment, and rehabilitation of neurologic disease. NewYork-Presbyterian Hospitalis located at Columbia Presbyterian Medical Center and NewYork Weill Cornell MedicalCenter. The Neuroscience Centers include the Neurological Institute at Columbia PresbyterianMedical Center and the NewYork Weill Cornell Neuroscience Institute, which are respectivelyaffiliated with Columbia University College of Physicians & Surgeons and the Weill MedicalCollege of Cornell University.

www.nypneuro.org

NewYork-Presbyterian Neuroscience Editorial Board:

M.Flint Beal, MDNeurologist-in-Chief, NewYork-Presbyterian Hospital at NewYork WeillCornell Medical CenterAnne Parrish Titzel Professor of Neurologyand Chairman, Department of Neurology,Weill Medical College of Cornell Universityfbeal@med.cornell.edu

Y. Pierre Gobin, MDDirector, Division of InterventionalNeuroradiology, NewYork-PresbyterianHospital at NewYork Weill Cornell Medical CenterProfessor of Radiology in NeurologicalSurgery, Weill Medical College of Cornell Universityyvg2001@med.cornell.edu

Sean Lavine, MDCo-Director, Neuroendovascular Services,NewYork-Presbyterian Hospital at ColumbiaPresbyterian Medical CenterAssistant Professor of Neurological Surgeryand Radiology, Columbia University Collegeof Physicians & Surgeonssl2081@columbia.edu

James Lieberman, MDPhysiatrist-in-Chief, NewYork-PresbyterianHospital at Columbia Presbyterian Medical CenterH.K. Corning Professor and Chairman,Rehabilitation Medicine, ColumbiaUniversity College of Physicians & Surgeonsjs112@columbia.edu

Philip Meyers, MDCo-Director, Neuroendovascular Services,NewYork-Presbyterian Hospital at ColumbiaPresbyterian Medical CenterAssistant Professor of Neurological Surgeryand Radiology, Columbia University Collegeof Physicians & Surgeonspmm2002@columbia.edu

Michael O’Dell, MDAssociate Chief, Department ofRehabilitation Medicine, NewYork-Presbyterian Hospital at NewYork WeillCornell Medical CenterAssociate Chief and Professor ofRehabilitation Medicine, Weill MedicalCollege of Cornell Universitymio2005@med.cornell.edu

Timothy Pedley, MDNeurologist-in-Chief, NewYork-Presbyterian Hospital at ColumbiaPresbyterian Medical CenterHenry and Lucy Moses Professor ofNeurology and Chairman, Department ofNeurology, Columbia University College ofPhysicians & Surgeonstap2@columbia.edu

Howard Riina, MDAttending Neurosurgeon, NewYork-Presbyterian Hospital at NewYork WeillCornell Medical CenterAssistant Professor of Neurological Surgery,Neurology and Radiology, Weill MedicalCollege of Cornell Universityhar9005@med.cornell.edu

Robert Solomon, MDChairman and Director of Service,Department of Neurological Surgery,NewYork-Presbyterian Hospital atColumbia Presbyterian Medical CenterByron Stookey Professor of NeurologicalSurgery, Columbia University College of Physicians & Surgeonsras5@columbia.edu

Philip Stieg, PhD, MDNeurosurgeon-in-Chief, Department ofNeurological Surgery, NewYork-PresbyterianHospital at NewYork Weill Cornell Medical CenterProfessor and Chairman, Department ofNeurological Surgery Weill Medical Collegeof Cornell Universitypes2008@med.cornell.edu

see CT Perfusion, page 10

Clinical debate has centered around whetherit is possible for CT perfusion to provide bothdiffusion-weighted imaging and perfusion-weighted imaging data.

4

NeuroscienceN E W Y O R K – P R E S B Y T E R I A N

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Researchers at NewYork-Presbyterian Hospital havelaunched the first clinical study

investigating the safety and efficacy ofgene therapy in the treatment of neuro-logic disorders in human patients. ThePhase I trials, which involve surgicalinsertion of viral vectors into cells of thesubthalamic nucleus, are targetingpatients suffering from the major motorsymptoms of Parkinson’s disease. If suc-cessful, the therapy has broader implica-tions for other neurologic and brain-related disorders.

For Michael Kaplitt, MD, PhD,co–principal investigator on the study,the trials open a new chapter in his per-sonal research efforts in the area, whichdate from the late 1980s. “The conceptof using gene therapy for Parkinson’sdisease evolved over the course of morethan a decade,” said Dr. Kaplitt.

When he began looking into the con-cept at Rockefeller University in 1989,Dr. Kaplitt and his team—and severalother groups—were seeking to developworkable viral delivery systems that tar-geted the brain. All exploited the natu-ral infectivity of viruses together withrecently developed tools of recombinantDNA research. They found that genesthat produce specific enzymes could beinserted into viruses disposed by natureto integrate cellular DNA.

Adeno-associated virus, which Dr.Kaplitt also studied, was one of a num-ber of candidate vectors in the early1990s. Researchers found it had severaladvantages for gene therapy. A harmlessvirus, adeno-associated virus does notprovoke antibodies or stimulate inflam-mation, and it is able to enter nondivid-ing cells such as neurons. After severalyears of work, Dr. Kaplitt and colleaguesreported the first use of adeno-associat-ed virus in the mammalian brain in

Nature Genetics (1994;8:148-154).Adeno-associated virus subsequentlybecame and remains widely used in genetherapy experiments.

The disabling motor symptoms ofParkinson’s disease arise, it is believed,from excessive neuronal firing in con-sequence of a chemical disturbance inthe brain due, in the last analysis, toloss of dopaminergic neurons. One ofdopamine’s functions is to regulate out-put of the inhibitory neurotransmitterknown as gamma-aminobutyric acid.Dr. Kaplitt and others believed thatrestoring gamma-aminobutyric acid to

specific areas of the basal ganglia could,in principle, reduce the motor symp-toms of Parkinson’s disease, and thatthis plausible long-term solution mightbe implemented by introducing modi-fied recombinant viruses equipped withthe gene that expresses the gamma-aminobutyric acid–producing enzymeglutamic acid decarboxylase.

With this concept firmly in mind, Dr.Kaplitt and colleagues worked to devel-op a stereotactic procedure that woulddeliver these viral vectors specifically tothe basal ganglia cells that could nor-malize the gamma-aminobutyric acidcircuitry. Since the 1980s, neurosur-geons had enjoyed new success both intargeting highly specific areas of thebrain and in treating symptoms byablating tissue or, more recently, byemploying deep brain stimulation.Now, it is hoped that in place of these

procedures, bioengineered cells willrenormalize neurochemical circuitswithout damage to tissue or insertionof an electronic device. A patientundergoes a stereotactic procedure afterextensive imaging and preparation,which leaves within the brain only themodified adeno-associated virus.

Dr. Kaplitt and his colleaguesplanned the surgical intervention indetail and undertook animal studies,the success of which led to efforts togain approval for human trials. Theproposal advanced through theNational Institutes of Health’s

Recombinant DNA AdvisoryCommission, where it gained enthusi-astic support, and the FDA approved itin August 2002. Matthew J. During,MD, co–principal investigator with Dr.Kaplitt and Professor of MolecularMedicine at the University ofAuckland, in New Zealand, empha-sized that these Phase I trials are stillexperimental. “Our primary objectivehas been to stress patient safety aboveall else,” he said. “It is our hope that,with this approach, our trial will helpdemonstrate that gene therapy in thebrain can be both safe and effective.”

Michael Kaplitt, MD, PhD, is SurgicalDirector, Movement Disorders Group,NewYork-Presbyterian Hospital at NewYorkWeill Cornell Medical Center, and isAssistant Professor of Neurological Surgery atWeill Medical College of Cornell University.E-mail: mik2002@med.cornell.edu.

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Studying Gene Therapy in the Treatment of Neurologic Disorders

“The concept of using gene therapy for Parkinson’s diseaseevolved over the course of more than a decade.”

—Michael Kaplitt, MD, PhD

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implants,” according to RobertGoodman, MD.

Michael Kaplitt, MD, PhD, who per-forms the procedure at the Center forStereotactic and Functional Neurosur-gery, added, that “all of our experienceover the past few years indicates thatstimulators are better tolerated thanlesions and have longer-lasting effects.”

Fully approved by the Food and DrugAdministration (FDA) in 2002 afterconsiderable media coverage in the laypress, deep brain stimulation has rapidlydefined a new standard of care amongParkinson’s disease patients for whommedication has ceased to provide signif-icant relief. Deep brain stimulation isnot a cure, but for the right patients theprocedure can substantially reducemotor symptoms and improve quality oflife. A procedure that can be postopera-tively programmed and adjusted to indi-vidual patients, deep brain stimulationhas quietly and rapidly supplanted thal-amotomy and pallidotomy, 2 sophisti-cated lesion-based techniques that forthe past 2 decades represented state-of-the-art surgery for advanced Parkinson’sdisease. These procedures, althoughquite frequently effective, carry variousdegrees of risk that deep brain stimula-tion largely avoids.

Crucial to the success of deep brainstimulation are comprehensive patientscreening, preparation, education, andpreoperative and postoperative care.Candidates for deep brain stimulationusually suffer from the advanced motorsymptoms of Parkinson’s disease thatarise in most patients within 5 to 10years of initial diagnosis. Although thesepatients are invariably helped at first bylevodopa—still the standard medicationfor Parkinson’s disease—their responseto the drug eventually becomes prob-lematic or unpredictable, and othermedications fail to help. Sometimes adose of levodopa will fail to controlsymptoms or work only intermittently,with spells of “wearing off ” as levodopaceases to work, during which patientsbecome stiff or unable to move. Otherpatients suffer from rapid motor fluctu-ations or from dyskinesias, the most dis-abling of motor symptoms, that involvesinvoluntary muscle contractions in theextremities, head, or trunk. Patients atthis stage of the disease, according to

Blair Ford, MD, can almost always ben-efit from deep brain stimulation if theyare in good general health. Althoughyounger patients tend to have the bestresults, advanced age alone is not a con-traindication to surgery.

Like the lesion-based procedures thatit has largely replaced, deep brain stimu-lation is a stereotactic operation inwhich a coordinate system enables thesurgeon to target a specific location inthe brain with millimeter-by-millimeteraccuracy. However, instead of tissueablation to create lesions that reducemotor symptoms, the surgeon insertselectrodes into the brain through burrholes in the skull. Brain mapping proce-dures to ensure proper placement of thestimulators are performed by neurolo-gists with expertise in this technique. Atthe Center for Stereotactic andFunctional Neurosurgery, this work is

done by Shaik Ubaid, MD. SethPullman, MD, handles the same dutiesat the Center for Movement DisordersSurgery. The surgical procedure itself is

performed by Dr. Goodman or GuyMcKhann, MD, at ColumbiaPresbyterian Medical Center, and by Dr.Kaplitt at NewYork Weill CornellMedical Center.

During deep brain stimulation, thepatient remains awake and helps thesurgical team guide electrode placementby answering various questions con-cerning symptoms and sensations. Forpatients with bilateral symptoms, elec-trode insertion is performed on bothsides of the brain.

Once the electrode is anchored in thebrain, its lead is attached to the insideof the skull, and a connecting wire islaid in behind the ear and neck, leadingto the chest, where a battery-operatedimplantable pulse generator is placed ina surgically created pocket beneath theclavicle. (This can be done on the same

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Deep Brain Stimulationcontinued from page 1

A patient undergoing deep brain stimulation surgery: The surgeon insertselectrodes into the brain through burrholes in the skull. The electrodes reachtheir targets with the help of magneticresonance imaging and brain mappingwith microelectrodes.

Blair Ford, MD, consults with aParkinson’s disease patient: “The care forthese patients needs to be comprehensive,and optimally carried out in a contextwhere there’s an accumulation of expertise, clinical experience, and institutional resources.” see Deep Brain Stimulation, page 12

Candidates for deep brain stimulation usually suffer from theadvanced motor symptoms of Parkinson’s disease that arise inmost patients within 5 to 10 years of initial diagnosis.

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NeuroscienceN E W Y O R K – P R E S B Y T E R I A N

Researchers at NewYork-Presbyterian Hospital’s Centerfor Movement Disorders

Surgery believe painless, noninvasiveradiotherapy can become a viable alter-native to neurosurgery for patients withintractable temporal lobe epilepsy.

“This treatment may prove just aseffective as surgery for at least some ofthe patients that we treat,” says RobertGoodman, MD. Dr. Goodman and hissurgical team are currently participatingin a multicenter study to determine theeffectiveness of gamma knife radio-surgery in temporal lobe epilepsy, withpreliminary results expected within ayear. The research is supported by theNational Institutes of Health.

Surgery remains the accepted treat-ment for patients with refractory tem-poral lobe epilepsy. Dr. Goodman’sstudy offers patients the radiologicoption as an alternative to conventionalsurgery. The larger aim is to discoverwhether and to what extent the gammaknife can effectively eliminate symptomswhile reducing or avoiding the risks offunctional impairment that come withinvasive neurosurgery.

“We might learn we can eliminate theseizure potential without eliminating allof the function in the part of the brainoperated on,” noted Dr. Goodman.

Gamma knife radiosurgery involvesuse of a multi–million-dollar system (itweighs 20 tons) that delivers highlyfocused beams of cobalt-60 radiation to3-dimensional pinpoint targets withinthe brain. Therapeutic benefits accrueover time, presumably due to radiation-induced changes in cell function andmetabolism. Developed in Sweden inthe 1960s, the instrument has beenemployed for years by neurosurgeons—sometimes with outstanding success—to

treat vascular abnormalities and braintumors for which resection is not anoption. With improved understandingof brain structure and neurochemicalinteractions, the gamma knife is cur-rently on track to treat several move-ment disorders, including Parkinson’sdisease. To date, the procedure has beenused to treat temporal lobe epilepsy in asmall number of cases in Europe andthe United States.

Epilepsy affects about 1 million peoplein the United States, an estimated100,000 of whom become candidates forsurgery when medication fails to ade-quately control seizures. Lesionectomyand other operations, ranging from cura-tive to palliative, aim to reduce or elimi-nate seizures. Aided by advances in brainimaging, surgical procedures currentlyenjoy high rates of success overall. Butwith an estimated 1% mortality rate andpostoperative complications as high as10% to 20%, a noninvasive alternativewould be welcome.

Although painless and bloodless,gamma knife radiosurgery is not with-out risk. While the procedure hasproved safe in other uses, concern forcomplications—including radiationnecrosis and edema, neurologic deficits,

and eventual neoplasms—remains. Inaddition, for reasons that are stillunclear, patients only gradually becomefree of seizures. While the effects ofneurosurgery are immediate, benefitsfrom the gamma knife in epilepsyappear over several months.

Temporal lobe epilepsy patients in thecurrent study, when offered the gammaknife option, still decided on invasivesurgery approximately half the time. “Bythe time they’re being recommended forsurgery, they want to have it yesterday,”said Dr. Goodman. “So if we suggesttreatment with radiation, which takes 9to 10 months, they don’t want thatdelay.” In addition, he added, thesepatients are often relatively young andmay also have concerns about long-termadverse effects of radiation.

Use of the gamma knife for temporallobe epilepsy does not rule out subse-quent neurosurgery if the patient doesnot become seizure-free. As with otherforms of surgery, if successful, thegamma knife may have other advan-tages. A current hypothesis holds thatsurgery may confer a neuroprotectivebenefit, and some evidence suggests thatpatients who become seizure-free at ayoung age avoid a variety of associatedpsychologic and psychosocial problems.If the gamma knife provides these bene-fits without the risks of invasive proce-dures, it may become a widely usedalternative in a rapidly advancing field.

Robert Goodman, MD, is SurgicalDirector, Center for MovementDisorders Surgery, NewYork-Presbyterian Hospital at ColumbiaPresbyterian Medical Center, and isAssistant Professor of NeurologicalSurgery at Columbia University Collegeof Physicians & Surgeons. E-mail:rrg2@columbia.edu.

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Investigating Noninvasive Radiotherapy in Temporal Lobe Epilepsy

A CT scan of a patient with temporallobe epilepsy–induced left medial temporal sclerosis.

7

Neurosurgeons and interventionalneuroradiologists at NewYork-Presbyterian Hospital are at the

forefront of efforts to widen the windowof opportunity for treating strokepatients. The medical treatment current-ly approved by the FDA for hemorrhag-ic stroke—intravenous tissue plasmino-gen activator, or t-PA—can be givenonly within the first 3 hours after theonset of symptoms. As a result, only 2%to 3% of patients who can benefit fromthe treatment actually receive it.

“If we get to them within those first 3hours with intravenous t-PA, there’s a30% improvement in morbidity and mor-tality,” said Sean Lavine, MD. Beyond 3hours, he added, the risk of the drug’scausing a devastating hemorrhage in thebrain outweighs any possible benefit.

The need to find effective interven-tions beyond those first 3 hours couldn’tbe greater. Intracranial hemorrhage isthe third leading cause of death and theprimary cause of adult disability in theUnited States, making it the leadingdiagnosis for patients moving from hos-pitals to nursing homes. The standardstrategy now used at NewYork-Presbyterian Hospital’s advanced treat-ment centers when patients show upwithin 3 to 6 hours after the onset ofsymptoms is the application of t-PA

directly to the site of the clot, via a radi-ologically guided catheter. Intra-arterialt-PA has the added benefit of allowingthe physician to pump higher concen-trations of the drug into the confines ofthe blockage than could ever be safelydelivered to the entire body intra-venously.

“There have also been some prelimi-nary studies on using intra-arterialurokinase,” said Dr. Lavine. The drug,approved by the FDA in October 2002for treating clots in the heart, is already

showing results comparable to thosewith intra-arterial t-PA when used inthe brain, he said. “We’re hoping toimprove the chances of a good outcomeby 30% to 50% when it’s used in that 6-hour time frame,” he added.

Ultimately, though, “you would preferto not give any thrombolytic at all,because even when delivered intra-arte-rially, it still raises the risk of bleeding,”said Y. Pierre Gobin, MD.

To find a better way to clear neurologicemboli, Dr. Gobin invented a device, theConcentric Retriever, that is being exam-ined in the Mechanical EmbolusRemoval in Cerebral Ischemia (MERCI)Trial at NewYork-Presbyterian Hospital.

“It’s much better to open the arterywith a MERCI device,” Dr. Gobinsaid. “When you reopen the arterywith MERCI, there’s almost no risk of hemorrhage.”

To use the mechanical system, neuro-endovascular therapists guide a micro-catheter beyond the site of the clot,

where it deploys a self-expanding coni-cal coil. The coil becomes so enmeshedin the clot that it can be dragged awaywhen the catheter is removed.

The MERCI I trial, involving 50

patients at 7 centers across the UnitedStates, established that the device couldbe safely used up to 8 hours after theonset of symptoms. In 52% of the cases,the clot was successfully retrieved withthe device. Just 2% of patients had amajor complication during the procedure.Now in a Phase II trial at 20 centersacross the United States, the MERCIdevice has been used on 80 patients.

“We are reporting a 55% recanaliza-tion rate of cerebral arteries,” Dr. Gobinsaid. “Half of the patients that wererecanalized have a great recovery and areable to live independently.”

Dr. Lavine, who has been using theMERCI device, added, “I think it’s apromising, excellent idea. This device isone of the very few tools we have.” Onechallenge with using the device, he said,is that the coil needs to be stiff enoughto hang onto the clot yet flexible enoughto negotiate the twists and turns of theneurovasculature. “To be effective, thedevice has to have some stiffness,” Dr.Lavine explained. “But that comes at theexpense of having more difficulty navi-gating to get it where you want it to go.”

As a result, the MERCI device hasevolved as neurosurgeons such as Dr.Lavine, Dr. Gobin, and others havegained experience with it. In the latestincarnation, Dr. Gobin said, “we areusing a nitinol coil, a special metal madeof super-elastic material, to snare andremove the thrombus that is occludingthe artery in the brain.” Nitinol, an alloyof nickel and titanium, is in a unique

Expanding t-PA’s Use in Stroke Treatment

“There have also been some preliminary studies on using intra-arterial urokinase [in stroke treatment.] We’re hoping toimprove the chances of a good outcome by 30% to 50%when it’s used in that 6-hour time frame.”

—Sean Lavine, MD

Y. Pierre Gobin, MD, has developed the Concentric Retriever toclear neurologic emboli. To use the system, neuroendovasculartherapists guide a microcatheter beyond the site of the clot,where it deploys a self-expanding conical coil. The coil becomesso enmeshed in the clot that it can be dragged away when thecatheter is removed. Says Dr. Gobin, “When you reopen theartery this way, there’s almost no risk of hemorrhage.”

see t-PA, page 10

Intracerebral hemorrhage represents15% of all strokes in the UnitedStates. It is also among the deadliest

and most disabling forms of stroke.More than 40% of intracerebral hemor-rhage patients die within 6 months orsuffer devastating impairment.

Unfortunately, there are still no effec-tive treatments—including surgery—forintracerebral hemorrhage or other formsof cerebral hemorrhage. Nevertheless,researchers at NewYork-PresbyterianHospital say, studies are revealingopportunities for physicians to providetheir patients with more than just sup-portive care.

“It’s about pushing the envelope, find-ing better ways to treat the patients,”said Stephan A. Mayer, MD. “We’relooking for the cutting-edge protocols.”

Dr. Mayer points to 2 ongoing trialsexploring therapies to help patients copewith hemorrhage. Physicians at ColumbiaPresbyterian Medical Center are lookingat recombinant factor VIIa as a possibilityfor arresting ongoing bleeding in intrac-erebral hemorrhage emergency roompatients. In fact, Columbia PresbyterianMedical Center is part of a worldwide,multicenter trial testing the potential effi-cacy of recombinant human coagulationfactor VIIa as an ultra-early hemostatictherapy for brain hemorrhage.

The preliminary dose escalation safetystudy, which treated 86 patients, offered“some indication of efficacy,” said Dr.Mayer. Because of those results, thedepartment has initiated a proof-of-concept trial with a target enrollment of240 (it now has 186). That trial startedin January.

Researchers at Columbia PresbyterianMedical Center are also exploringoptions for treating a subset of intra-cerebral hemorrhage patients: patientswith intraventricular hemorrhage.Current procedure calls for inserting aventricular catheter, noted Dr. Mayer,but physicians in the NeurologicalIntensive Care Unit recognize that“simply placing a catheter may be life-saving, but otherwise doesn’t appear tosubstantially benefit patients.”

That’s why, in conjunction with other

centers, Dr. Mayer and his colleagueshave been involved in a Phase II studyenrolling 46 patients. The study’s pur-pose is to evaluate the risks and benefitsof a combination therapy: placing thecatheter and “examining the potentialefficacy of direct intraventricular throm-bolytic therapy using tissue plasminogenactivator.” Because there is overwhelm-ing evidence that clotted blood can betoxic, he added, “the hope is that byeffectively lysing the clot and promotingits clearance, patients will suffer lessdamage due to reduced duration of con-tact with potential toxic blood elements(e.g., hemoglobin and thrombin).”

Only Preliminary ResultsAt NewYork Weill Cornell Medical

Center, Igor Ougorets, MD, is currentlyusing a treatment method that involvescontrolling hyperglycemia in hispatients. “Some animal studies haveindicated that hyperglycemia producesmore neuro-injury in ischemic tissue,”he explained. “The problem is that in allthese areas all we have is preliminarydata. We don’t yet have the study thattakes neuro-injured patients on a tightlycontrolled glucose level and comparesthem with a group that was not con-trolled to see if the glucose controlchanges the neurological outcome.”

To date, according to Dr. Ougorets,treatment protocols for hemorrhagehave not been based on the results ofrandomized trials but on the personalexperience of neurologists in the field.All the researchers hope to change that,however, with their recent efforts.

Looking at Body Temperature“Everyone agrees that overall tempera-

ture control has to be done,” said Dr.Ougorets. “The problem is that we don’thave clear-cut trials showing that itactually makes a difference in the out-come of our patients.”

Another critical issue is the treatmentof fever in patients with hemorrhagicstroke, according to Dr. Mayer. “Bodytemperature elevations are independentlycorrelated with death and poor functionaloutcomes after both intracerebral hemor-

rhage and subarachnoid hemorrhage,”he said, adding that conventional coolingblankets have been shown to be ineffec-tive in reducing fever for these patients.

Dr. Mayer and his colleagues are cur-rently conducting a clinical trial of theMedivance Arctic Sun Cooling System.The device seems to normalize body tem-perature more effectively than conven-tional cooling blankets. A hydrogel poly-mer provides enhanced contact with thepatient’s skin, allowing the water-circulat-ing blankets to stick to the body and thusmaintaining the cooling process moreeffectively than conventional means.

“Using regular cooling blankets,patients’ body temperature remains over101°F,” said Dr. Mayer. “With this sys-tem, they go right down to normal, andstay there.” The unexpected benefit ofthe system, he added, seems to be that“effective treatment of fever can produceclear and dramatic improvements inintracranial pressure levels, and inpatients’ levels of consciousness.”

Stephan A. Mayer, MD, is Director of theNeurological Intensive Care Unit, NewYork-Presbyterian Hospital at ColumbiaPresbyterian Medical Center, and is AssistantProfessor of Neurological Surgery atColumbia University College of Physicians& Surgeons. E-mail: sam14@columbia.edu.

Igor Ougorets, MD, is Director of theNeurological Intensive Care Unit, NewYork-Presbyterian Hospital at NewYork WeillCornell Medical Center, and is AssistantProfessor of Neurological Surgery at WeillMedical College of Cornell University.E-mail: igo9001@med.cornell.edu.

9

Emergency Treatments for Cerebral Hemorrhage

A head CT scan demonstrating a left-sidedbasal ganglia hemorrhage (left). A follow-up CT obtained after the patient furtherdeteriorated (right) shows significantenlargement of the hematoma.

10

class of materials known as shape memo-ry alloys. After being heat treated whilein a particular position, it can be bentand distorted, then reheated to regain itsoriginal shape. Thus, the device can beadvanced within a microcatheter insidethe cerebral artery occluded by the clot.

“On the engineering side, it can bevery exciting to work with smart materi-als like that,” Dr. Lavine said.

Both he and Dr. Gobin emphasizedthat the procedure remains experimental.But Dr. Gobin predicted that it willeventually become the treatment ofchoice at hospitals specializing in thetreatment of stroke. “Most treatmentsfor stroke will be mechanical, with aMERCI device,” he said. If this is true,

the result will one day mean a revolutionin the treatment of cerebral infarction.That day can’t come soon enough for theestimated 750,000 people in the UnitedStates who suffer a stroke each year.

Y. Pierre Gobin, MD, is Director of theDivision of Interventional Neuroradiology,NewYork-Presbyterian Hospital at NewYorkWeill Cornell Medical Center, and isProfessor of Radiology in NeurologicalSurgery at Weill Medical College of CornellUniversity. Email: yvg2001@med.cornell.edu.

Sean Lavine, MD, is Co-Director ofNeuroendovascular Services, NewYork-Presbyterian Hospital at ColumbiaPresbyterian Medical Center, and isAssistant Professor of Neurological Surgery,and is Radiology at Columbia UniversityCollege of Physicians & Surgeons. E-mail:sl2081@columbia.edu.

t-PAcontinued from page 7

Delivery even 5 or 6 hours out escalatesthe risk of hemorrhage dramatically,from 5% to as much as 30% or 40%.

Having served on some of the safetycommittees analyzing the 3-hour“deadline,” Dr. DeLa Paz believes thisto be an artificial timeline that can beexpanded. The key is using intra-arteri-al administration of t-PA versus intra-venous delivery. Using an intra-arterialcatheter, he explained, “the lysis ofoccluding thrombus in the cerebral ves-sels and reconstitution of blood flow tothe ischemic brain” may be achieved inonly 20 or 30 minutes. That, he says,means that intra-arterial delivery of t-PAcould begin as much as 4 or 5 hoursafter onset and still provide effectiveresults with a low risk of hemorrhage.

However, intra-arterial delivery of t-PAcarries a much higher risk of hemor-rhage than intravenous delivery if it is

not correlated with a measure of poten-tially salvageable tissue. Using CT per-fusion to determine how much viablebrain exists and to generate constructivemaps of cerebral blood flow, blood vol-ume, and mean transit time is a boon todoctors treating stroke patients.

“Clinical science will only get you sofar,” said Dr. Ougorets. “You need addi-tional information to appreciate what’shappening to the brain tissue.”

Robert DeLa Paz, MD, is Director ofNeuroradiology, NewYork-PresbyterianHospital at Columbia PresbyterianMedical Center, and is Professor ofRadiology at Columbia UniversityCollege of Physicians & Surgeons.E-mail: rld17@columbia.edu.

Igor Ougorets, MD, is Director of theNeurological Intensive Care Unit,NewYork-Presbyterian Hospital atNewYork Weill Cornell MedicalCenter, and is Assistant Professor ofNeurological Surgery at Weill MedicalCollege of Cornell University. E-mail:igo9001@med.cornell.edu.

Pina C. Sanelli, MD, is AssistantAttending Physician, NewYork-Presbyterian Hospital at NewYork WeillCornell Medical Center, and isAssistant Professor of Radiology,Neuroradiology Division at WeillMedical College of Cornell University.E-mail: pcs9001@cornell.med.edu.

CT Perfusioncontinued from page 3

“Would I like to have an8-slice image of the brainas I do with MRI? Yes. ButI now have 4 slices withthe computed tomographywhere I used to have 1.”

—Igor Ougorets, MD

Current work at NewYork-Presbyterian Hospital could one daymean a revolution in the treatment of cerebral infarction. Thatday can’t come soon enough for the estimated 750,000 people in the United States who suffer a stroke each year.

NeuroscienceN E W Y O R K – P R E S B Y T E R I A N

11

scarring to remove the aneurysm from cir-culation. Research has shown that, com-pared with surgery, the GuglielmiDetachable Coil treatment significantlylowers the risk of subsequent severe dis-ability or death from a ruptured aneurysm.

“The study was so overwhelmingly infavor of coiling that the safety commit-tee of the trial stopped enrolling newpatients,” said Y. Pierre Gobin, MD.

Dr. Gobin, who worked for 10 yearswith Dr. Guglielmi at the UniversityCalifornia at Los Angeles, noted thatnew designs and materials for the coilare constantly being tested—including,most recently, special coatings designedto speed the development of ananeurysm-shutting clot.

Another new technique for treatinganeurysms involves the use of theNeuroform stent. “With certain com-plex aneurysms, the GuglielmiDetachable Coil alone may not be ade-

quate,” said Dr. Meyers. “TheNeuroform stent is a self-expandingtube designed specifically for use in thebrain to treat complex aneurysms in away never possible before. Aneurysmcoils can then be safely placed into theaneurysm without jeopardizing theintegrity of the main blood vessels.”

For the treatment of arteriovenousmalformations, Dr. Meyers added,NewYork-Presbyterian Hospital is “oneof the largest treatment centers in theUnited States. It’s been one of the hos-pital’s strengths for many years.”

Neuroendovascular specialists at

NewYork-Presbyterian Hospital caneither cauterize the abnormal tangle ofblood vessels, or deploy the new glueNeuracryl M that hardens slowly andsmoothly. One of the hottest areas ofresearch is the endoscopic widening ofa plaque-clogged carotid artery, withthe use of a stent to keep the arteryclear. Until recently, the endovascularmethod was used only for patients toosick to undergo surgery, because whenperformed from within, the procedurecan dislodge plaque that would thentravel up the bloodstream into thebrain, where it could cause a stroke. Buta new invention offers the possibility ofrevolutionary new safety: a tiny filterthat opens like an umbrella downstreamfrom the stent to safely block any debrisbefore it reaches the brain, while allow-ing blood to flow normally.

“It’s like a coffee filter for the blood,flowing into the brain when you’rereopening an artery in the neck,” Dr.Meyers said. “The filter catches anydebris generated during revasculariza-tion of the brain’s arteries. The early

evidence suggests that stent-supportedangioplasty with filter protection of thebrain’s blood supply may become a pre-ferred method of treatment over stan-dard surgical endarterectomy.”

Researchers at NewYork-PresbyterianHospital are among the lead investiga-tors in a multicenter trial of the proce-dure, called Carotid Revascularization:Endarterectomy versus Stent Trial(CREST). In the early phases of thestudy, “the complication rate with pro-tection is 2% for asymptomatic patients,and 6% for patients with symptomaticstenosis,” said Dr. Gobin, the principal

investigator. Those numbers, he added,“look as good as surgery, maybe evenbetter, without having to perform sur-gery.” Other studies of similar debris-catching devices include the Acculinkfor Revascularization of Carotids inHigh-Risk patients (ARCHeR) and theBoston Scientific EPI: A CarotidStenting Trial for High-Risk SurgicalPatients (BEACH).

According to Sean Lavine, MD, it’sstill too early to tell which of the deviceswill eventually be most effective—oreven whether any of them will ultimate-ly prove safer than surgery. There are“data on both sides,” Dr. Lavine said.“Some say using the devices increasesthe risk of embolic events; others saythat it has dramatically reduced morbid-ity. We are currently investigating thebenefit of these devices with active par-ticipation in trials such as ARCHeR,BEACH, and CREST.”

Y. Pierre Gobin, MD, is Director of theDivision of Interventional Neuroradiology,NewYork-Presbyterian Hospital at NewYorkWeill Cornell Medical Center, and is Professorof Radiology in Neurological Surgery at WeillMedical College of Cornell University. Email:yvg2001@med.cornell.edu.

Sean Lavine, MD, is Co-Director ofNeuroendovascular Services, NewYork-Presbyterian Hospital at ColumbiaPresbyterian Medical Center, and is AssistantProfessor of Neurological Surgery andRadiology at Columbia University College ofPhysicians & Surgeons. E-mail:sl2081@columbia.edu.

Philip Meyers, MD, is Co-Director ofNeuroendovascular Services, NewYork-Presbyterian Hospital at ColumbiaPresbyterian Medical Center, and is AssistantProfessor of Neurological Surgery andRadiology at Columbia University College ofPhysicians & Surgeons. E-mail:pmm2002@columbia.edu.

Howard A. Riina, MD, is AttendingNeurosurgeon, NewYork-PresbyterianHospital at NewYork Weill Cornell MedicalCenter, and is Assistant Professor ofNeurological Surgery, Neurology andRadiology at Weill Medical College ofCornell University. E-mail:har9005@med.cornell.edu.

Endovascularcontinued from page 1

“The Neuroform stent is a self-expanding tube designed specifically for use in the brain to treat complex aneurysms in away that was never possible before. Aneurysm coils can thenbe safely placed into the aneurysm without jeopardizing theintegrity of the main blood vessels.”

—Philip Meyers, MD

day as the electrode surgery, or some-what later.) For bilateral operations, 2implantable pulse generators areinstalled. Three types of deep brainstimulation can be performed: thalamicstimulation, subthalamic nucleus stimu-lation, and globus pallidus stimulation.Each type corresponds to a differentarea in the brain where the stimulator isplaced, and each tends to alleviate spe-cific symptom formations. Beginning inApril 2003, Medicare agreed to covereach of the 3 deep brain stimulationprocedures for patients who fulfill diag-nostic conditions.

Postoperative care after deep brainstimulation forms a crucial part of theentire procedure because it involves

turning on and adjusting the deep brainstimulator. Frequency, polarity, pulsewidth, and voltage may all be adjusted.This process may take several visits overweeks or even months. It is another rea-son why Dr. Ford comes out strongly infavor of a comprehensive program likethat at Columbia Presbyterian MedicalCenter. “The care for these patientsneeds to be comprehensive,” he main-tained, “and optimally carried out in acontext where there’s an accumulation ofexpertise, clinical experience, and insti-tutional resources.”

Dr. Kaplitt, MD, PhD, agreed withDr. Ford on the importance of compre-hensive expertise and training for deepbrain stimulation. He emphasized thetime and teamwork expended on eachpatient in deciding whether a candidateis suitable for surgery and in planningthe procedure. “Collectively, it takes anenormous amount of experience in orderto get it right,” said Dr. Kaplitt.

Blair Ford, MD, is Medical Director at the Center for Movement DisordersSurgery, NewYork-PresbyterianHospital at Columbia PresbyterianMedical Center, and is AssociateProfessor of Clinical Neurology atColumbia University College ofPhysicians & Surgeons. He is also a scientific advisor to the Parkinson’sDisease Foundation. E-mail:ford@movdis.cis.columbia.edu.

Robert Goodman, MD, is Surgical Director,Center for Movement Disorders Surgery,NewYork-Presbyterian Hospital at ColumbiaPresbyterian Medical Center, and is AssistantProfessor of Neurological Surgery atColumbia University College of Physicians &Surgeons. E-mail: rrg2@columbia.edu.

Michael Kaplitt, MD, PhD, is SurgicalDirector, Movement Disorders Group,NewYork-Presbyterian Hospital at NewYorkWeill Cornell Medical Center, and isAssistant Professor of Neurological Surgery atWeill Medical College of Cornell University.E-mail: mik2002@med.cornell.edu.

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