Neurology Today

AN OFFICIAL PUBLICATION OF THE AMERICAN ACADEMY OF NEUROLOGY

APRIL 19, 2012 | VOLUME 12 | ISSUE 8

www.neurotodayonline.com
64th AAN Annual Meeting Ernest N. Morial Convention Center, New Orleans, LA April 21-28, 2012

INSIDE

4/19/12

AD: Debate about e ectiveness of combination therapy . . . 12 DISCLOSING CONFLICTS: The ethical conundrum . . . 18 RETT SYNDROME: Why bone marrow transplants may be the next clinical trial. . . . . . . 30

How Neurology Can Keep Patients Front and Center in Research Outcomes Embracing a National Initiative
BY M A R K M O R A N

WHY THIS NEUROPROTECTIVE STROKE PRIMATE MODEL MAY BE DIFFERENT

BY R I C H A R D R O B I N S O N

C
STROKE: Surgery not more e ective than medication for treating patent foramen ovale 35
See ID Statement on page 6

ommunication with patients and dissemination of evidence-based best practices to facilitate patient

participation in health care decisions one of ve areas designated as research

Continued on page 22

PUBLISHED BY:

A NEW FEDERAL initiative aims to bring patients to the table, so to speak, so they can understand and make informed care decisions based on outcomes research and evidence-based guidelines.

n what one expert called a tour de force, and another probably the best preclinical neuroprotection study Ive ever seen, researchers have shown that inhibition of a glutamate-related signaling receptor can halt brain damage after stroke onset, reducing infarct volume and preserving behavioral function. They did it in macaque monkeys, whose brains are anatomically much more similar to humans than those of rodents or marmosets, the standard subjects of most neuroprotection trials in stroke. And there is an early indication it may work in people as well. The stroke eld has become deeply skeptical of neuroprotection in recent years, as drug after drug has looked solid in the lab, but gone on to fail in the clinic. In retrospect, many stroke researchers think that a chief problem has been that the animal studies have
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Earlier Epilepsy Surgery Recommended in Pharmacoresistant Patients, New Study Finds

S
PERIODICALS

BY T O M VA L E O

Continued on page 32

istockphoto

urgical removal of a portion of the temporal lobe, widely regarded as a last-resort treatment for epilepsy, appears to control seizures so effectively it should be tried as soon as a patient has failed to respond to two antiepileptic medications, according to a new study. This conrms what we have known all along that surgery is a powerfully effective treatment and theres no reason to wait, said Jerome Engel Jr., MD, PhD, lead author the research published in the March 7 issue of the Journal of

the American Medical Association (JAMA). Evidence shows that if patients fail two trials of drugs, their chances of leading a seizure-free life are 3 percent or less. Yet, less than 1 percent of pharmacoresistant epilepsy patients are referred to an epilepsy center where they can be evaluated. Dr. Engel, the Jonathan Sinay Distinguished Professor of Neurology, Neurobiology, and Psychiatry and Biobehavioral Sciences, and director of the Seizure Disorder Center at the David

Credit: istockphoto

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Patient-Centered Outcomes
Continued from page 1

PCORI: FIVE PRIORITIES FOR RESEARCH

Assessment of Prevention, Diagnosis, and Treatment Options. Research should focus on 1) clinical options with emphasis on patient preferences and decision-making, 2) biological, clinical, social, economic, and geographic factors that may affect patient outcomes. Improving Health Care Systems. Research should focus on 1) ways to improve access to care, receipt of care, coordination of care, self-care, and decision-making, 2) use of non-physician health care providers, such as nurses and physician assistants, and the impact on patient outcomes, 3) system-level changes affecting all populations, diseases, and health conditions. Communication and Dissemination. Research should focus on 1) strategies to improve patient and clinician knowledge about prevention, diagnosis and treatment options, 2) methods to increase patient participation in care and decision-making and the impact on health outcomes, 3) communication tools that enhance decision-making and achieve desired outcomes, 4) ways to use electronic data (e-health records) to support decision-making, 5) best practices for sharing research results. Addressing Disparities. Research should focus on 1) ways to reduce disparities in health outcomes, 2) benets and risks of health care options across populations, 3) strategies to address health care barriers that can affect patient preferences and outcomes. Accelerating Patient-Centered and Methodological Research. Research should focus on 1) ways to improve the quality and usefulness of clinical data in follow-up studies, 2) methods to combine and analyze clinical data that follow patients over time, 3) use of registries and clinical data networks to support research about patient-centered outcomes, including rare diseases, 4) strategies to train researchers and enable patients and caregivers to participate in patientcentered outcomes research. The entire report is online at www.pcori.org. Mark Moran (PCORI) will be a priority for the AAN. In a March 5 letter written in response to the draft priorities for research released in January by PCORI, AAN President Bruce Sigsbee, MD, said that the goal of communication and dissemination, outlined in the PCORI report, is most concordant with the current efforts of the AAN and has the organizations support as a highest priority. This is an area where not only is the gap large, but there are few other federal dollars dedicated to address this priority, Dr. Sigsbee wrote. The private sector is incentivized to address communication and dissemination when there is nancial gain. This is at variance with the comparative effectiveness motivation, which is expected to lead to utilization of the least expensive resources needed to attain effectiveness. PCORI needs to focus on developing usable end products for dissemination and application by clinicians and patients. [For more on the AAN response, see AAN Responds to Mandate from PCORI.]
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DR. RICHARD DUBINSKY:

These are lofty goals that PCORI has set out as their objectives, but this is a eld of medicine that is in its infancy. It is not certain to me how quickly this eld of patient-centered research can mature to achieve these objectives.

goals by a federal initiative, the PatientCentered Outcomes Research Institute

Neuroprotection, Stroke
Continued from page 21

A battery of sensorimotor tasks was administered blindly throughout the follow-up period. Animals receiving active treatment performed signicantly better than those receiving placebo at all time points, and at the end of 30 days, they were only half as behaviorally impaired. Gene expression analysis from the ischemic penumbra in the acute post-stroke period indicated that active treatment was associated with a much smaller perturbation of normal gene expression, including pathways associated with response to ischemia and cell stress. Dr. Tymianski then performed a second trial of severe stroke, but this time with treatment at 60 minutes and reperfusion at 4.5 hours after onset, which he said more closely modeled the typical clinical severe stroke. There were no mortalities. Again, active treatment was superior to placebo over a seven-day follow-up. The results, he said, suggest that early treatment with Tat-NR2B9c may increase the window in which reperfusion may have functional benets, even in severe strokes. Finally, he induced a less severe stroke by occluding the MCA proximal to the

orbito-frontal branch, creating a slowerevolving stroke and a larger penumbra potentially available for neuroprotection. He administered treatment at three hours and reperfusion at 3.5 hours. Here again, despite the prolonged ischemic interval and the delayed treatment with the drug, those receiving active treatment did signicantly better than those receiving placebo, both on imaging and behavioral tests. EXPERTS COMMENT This is not the rst time neuroprotective drugs have been studied in this species, but Ive never seen a study in primates that had such comprehensive assessments. This is a tour de force, said Sean Savitz, MD, a stroke researcher and associate professor of Neurology at the University of Texas Medical School at Houston. I am denitely guardedly optimistic. Weve been sobered by so many of the failures of the past. But this is the closest I think you can get to proving that something is going to have the chance to work in patients without actually doing it in patients. Marc Fisher, MD, professor of neurology at University of Massachusetts

Medical School in Worcester, and editor of the journal Stroke, agreed. Its probably the best preclinical neuroprotection study Ive ever seen. Earlier studies with positive results in rodents or marmosets, including Dr. Fishers own work with a growth factor, have universally failed in the clinic, leading him to doubt the predictive utility of these models. The whole eld of neuroprotection is about to die. If we are going to go forward, we need positive primate data, he said, and in his opinion, this trial meets that standard. For Thomas Carmichael, MD, PhD, professor of neurology at the Brain Research Institute at the University of California, Los Angeles, the studys strength was the great pains it took to use a clinically relevant design. They did a number of things right, he said, including delivering the drug at different time points, and carefully measuring behavioral outcomes as well as tissue outcomes. After all this, it appears ready for clinical trials. And those trials have already begun. After a successful safety study, Dr. Tymianski helped oversee a phase 2 trial in 185 patients receiving endovascular coiling repair for either ruptured or unruptured aneurysms. Such patients

typically suffer very small strokes as a result of treatment, and the trial was designed to assess the ability of the drug to reduce stroke burden on MRI. The drug was effective in doing so, he said. Complete details will be forthcoming in a paper later this year. We now have data to show that this monkey business does translate to humans who have similar demographics to stroke victims and have veriable strokes. We are trying to forge a path that has failed every single time it has been trodden before, but its a great adventure and we plan to take it all the way. REFERENCES: Cook DJ, Teves L, Tymianski M. Treatment of stroke with a PSD95 inhibitor in the gyrencephalic primate brain. Nature 2012;483(7388):213-7. Evaluating Neuroprotection in Aneurysm Coiling Therapy (ENACT): http://1.usa.gov/Hbd6zm Stroke Therapy Academic Industry Roundtable. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999:30:2752-2758.

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Patient-Centered Outcomes
Continued from page 22

Act. The initiative intends to encourage research that provide patients with a better understanding of the prevention, treatment and care options available, and the science that supports those options. In its January report, the PCORI outlined national research priorities including ve broad areas about which it is seeking public comment the assessment of prevention, diagnosis, and treatment options; improving health care systems; communication and dissemination; addressing disparities; and accelerating patient-centered and methodological research. (For a summary of the ve priority areas see PCORI: Five Priorities for Research.) THE CHALLENGES In an interview with Neurology Today, Richard Dubinsky, MD, chair of the Practice Improvement Subcommittee of the AAN Practice Committee, said dissemination of recommended best practices has been a continuing challenge. This is an important gap identied by PCORI that needs to be addressed, he said. It appears that many health care providers are slow to adopt recommendations in our practice parameters unless they are encouraged to do so by nancial incentives or disincentives that are part of reporting systems. But we would rather have buy-in from clinicians based on the science behind our recommendations than have external factors inuencing clinical practice.

Dr. Dubinsky also highlighted, as especially important for neurology, PCORIs fth priority area accelerating patient-centered and methodological research. In studies of neurological treatment, outcomes have been fairly simplistic and not always patient-oriented, he told Neurology Today.

offered to all the people who would benet while others are receiving it who shouldnt. Understanding attitudes about risk and also predictors of stroke risk with and without treatment could allow us to make better recommendations, he said. Similarly, treatments for unruptured

DR. BARBARA VICKREY: There is an enormous potential opportunity through PCORI for research to address disparities in health and health care for neurological conditions, but for many neurologic conditions, we need the surveillance and mechanisms research for investigators to be able to show the need for studies that PCORI might rate as a high priority. PCORI was established as part of the Patient Protection and Affordable Care

It appears that many health care providers are slow to adopt recommendations in our practice parameters unless they are encouraged to do so by nancial incentives or disincentives that are part of reporting systems. But we would rather have buy-in from clinicians based on the science behind our recommendations than have external factors inuencing clinical practice.

AAN RESPONDS TO MANDATE FROM PCORI

n the March 5 letter to the Patient Centered Outcomes Research Institute (PCORI), AAN President Bruce Sigsbee, MD, urged that funding of PCORI priorities avoid duplication of existing efforts in both research and infrastructure. For example, where adequate alternative funding sources are available, such as for developing options for prevention, diagnosis, and treatment, PCORI should support the utilization of existing sources and focus its unique funds on its other priorities, he wrote. And he emphasized that PCORI needs to have an ongoing evaluation plan to measure how it is meeting its goals. Dr. Sigsbee also proposed that the following items be incorporated into its ve priority areas: Quality of care in smaller, rural hospitals versus tertiary care large hospitals from the perspective of stakeholders (patients, providers, insurers). Value of high-priced interventions in health care from the perspective of stakeholders, especially patients and caregivers. Denition of outcomes and determination of how selected outcomes apply to specic diseases, patient populations, provider type, and structure. Emphasis on improved communication between health care providers and patients/caregivers. Payment and reimbursement structures and strategies to ensure that physicians and other health care providers are not dis-incentivized to participate in patient- and outcome-oriented practice. PCORI must ensure that clinicians are not alienated or ignored and that patient-physician communication research agendas support this fundamental concept.

Studies of multiple sclerosis, for instance, have traditionally looked at the number of new lesions over a period of time with the assumption that the number of lesions correlates with disease burden, he said. But a functional outcome measure based on patient and family member input might have more validity than simply counting lesions. Similarly, in headache research there has been a tendency to simply count the number of headaches without incorporating the fact that there can be tremendous variability in how disabling headaches can be for different patients. These are lofty goals that PCORI has set out as their objectives, but this is a eld of medicine that is in its infancy, Dr. Dubinsky continued. It is not certain to me how quickly this eld of patient-centered research can mature to achieve these objectives. He noted that at this stage PCORI is seeking public comment on how best to allocate their rst round of grant dollars to best pursue the large research objectives set out in its report. ATTITUDES TOWARD STROKE RISK Neurologists who spoke with Neurology Today agreed that the research priorities outlined by PCORI are largely non-controversial and that all of them are relevant to neurology. For example, with regard to prevention of stroke, S. Claiborne Johnston, MD, said that carotid endarterectomy is probably not

aneurysms could be applied much more rationally. Dr. Johnston, director of the Clinical and Translational Science Institute and associate vice chancellor of research at the University of California, San Francisco, added: We also denitely need to work on better care coordination

attitudes about risk and also predictors of stroke risk with and without treatment could allow us to make better recommendations. Similarly, treatments for unruptured aneurysms could be applied much more rationally.

DR. S. CLAIBORNE JOHNSTON: Understanding

APRIL 19, 2012 | NEUROLOGY TODAY | 27

ARTICLE IN BRIEF

The AAN and its members discuss ways in which neurology can embrace a federal initiative to focus on patient-centered research and outcomes.

models. There are lots of chronic and debilitating diseases in the neurosciences and traditional physician-centric models of care are not necessarily the best. Some models for care of dementia are pretty remarkable, relying much more heavily on nurses and training of patients families and other caregivers. Neurological diseases are increasingly burdening society so we need to be front and center in studying better ways of caring for our patients not just when they are acutely ill. DISPARITIES RESEARCH Barbara Vickrey, MD, MPH, professor and vice chair of the department of neurology at the University of California, Los Angeles (UCLA), noted that increasing attention is being paid to health disparities. There is a lot of interest in the use of new technology to improve delivery of health care services and to give individuals tools to help manage their own chronic condition or to use in health promotion, for example, the application of handheld mobile devices to help people with medication reminders or to track their activity level, she told Neurology Today. Yet, some groups may be disadvantaged in being able to access and use this technology due to low income or to language or cultural barriers. So, comparative effectiveness research that compares these new health technology strategies to usual care must include these disadvantaged populations, or else health disparities might be aggravated because of lack of access to or applicability of technologies found effective in more educated or wealthy groups. She noted that there are four stages of research on disparities: surveillance; research on causal or contributing factors; testing interventions; and dissemination of effective interventions. In neurology, with a few exceptions, we are still at the rst and second stages of disparities research, in which there may be anecdotal evidence of the existence of disparities but little data on the extent or on contributing factors, which are typically needed to base applications that fall within PCORIs mission, she said. The most outstanding exception, she said, is stroke, for which it is well-documented that there are substantial differences in the occurrence and outcomes of stroke across minority groups relative to whites, and at least a partial body

of knowledge on mechanisms driving these differences. Dr. Vickrey cited as an important example of disparities research a 2010 study in the journal Neurology showing a much higher age of death from muscular dystrophy for whites compared to blacks in the US. These ndings were not anticipated by many advocates and researchers in

this area, and the data are now driving further research to gure out what are the determinants of this problem, and research on how to redress it, she said. There is an enormous potential opportunity through PCORI for research to address disparities in health and health care for neurological conditions, but for many neurologic conditions, we need the surveillance and mechanisms

research for investigators to be able to show the need for studies that PCORI might rate as a high priority. REFERENCE: Kenneson A, Vatave A, Finkel R. Widening gap in age at muscular dystrophyassociated death between blacks and whites, 1986 2005. Neurology 2010; 75:982-989.