Brain Edema; Subarachnoid Hemorrhage; Trauma, Nervous System; Brain Hemorrhage, Traumatic; Infarction, Middle Cerebral Artery; Brain Infarction
Dr. Sheth's research focuses on the identification and translation of new therapies for patients with acute neurological injury such as stroke, brain hemorrhage, and trauma. The main focus of his group is to further the understanding of inflammation and swelling after acute central nervous system injury. His group is actively involved in developing new methods, including neuroimaging, to detect and follow brain swelling. He is also involved in leading several national clinical trials testing novel therapies directed at brain swelling. Dr. Sheth also studies medical decision making and prognostication in patients with acute neurological injury.
Extensive Research Description
The central mission of my research program is to 1. Improve our understanding of blood brain barrier injury, inflammation, and swelling after acute central nervous system injury and 2. Translate novel therapies to critically ill neurological patients in the hopes of improving what are all too often devastating outcomes.
For the early part of my career, I have partnered with Marc Simard, a vascular neurosurgeon at the University of Maryland, who discovered a new receptor in the brain, SUR1, expressed on all components of the neurovascular unit. Blockade at the capillary level reduces the formation of the space-occupying edema responsible for cell death. Small molecule-based therapy using the well-known and safe drug glyburide is effective in blocking this channel, thereby significantly reducing edema formation following ischemia.
With the direct purpose of translating this therapy using a novel approach in stroke (prevention of swelling), I have formed a research group working toward solving fundamental gaps in knowledge with the ability to reliably measure brain edema. In order to develop this intermediate endpoint, we have recently validated and published unique neuroimaging measures of brain swelling in patients with large stroke. These imaging endpoints now serve as a primary efficacy endpoint in our phase II NINDS submission. In addition, we are exploring how novel therapies like glyburide may attenuate serum markers of injury at the blood-brain barrier. Early work in human patients suggests that MMP-9 levels are reduced in patients treated with glyburide, and this observation is associated with decreased swelling and hemorrhagic transformation. We continue to search for new pharmacodynamics markers of injury. Both areas of inquiry leverage existing collaborations with groups at Massachusetts General Hospital, Stanford University, and other institutions as well as newly developed groups here at Yale.
SUR1 appears to be implicated broadly after CNS injury, and we are now pursuing new directions with my transition to Yale. One new area of inquiry is a potential collaboration with the Yale PET center to develop a carbon labeled version of glyburide so that we may use the drug as a marker of blood brain barrier integrity and injury, both in terms of spatial and temporal resolution of injury. Another new collaboration has formed with Laura Ment in pediatric neurology to explore the role of SUR1 in blood brain barrier breakdown and hemorrhage in the setting of germinal matrix hemorrhage in preterm infants. These projects are under way and serve as the basis for new grant applications.
In terms of clinical translation, I have had the privilege of leading several phase II studies testing glyburide in ischemic stroke patients at high risk for brain swelling. Initial pilot studies have been completed, submitted for publication and highlighted at the NIH Princeton Stroke Conference and the International Stroke Conference, receiving top awards at both meetings. This work has been internationally recognized in the stroke community as an example of translating an exciting basic science discovery (SUR1) to patients, using a novel target (brain swelling) that has required innovation along the way (imaging and serum biomarkers of inflammation and swelling). I now co-lead one 12 center phase II study (GAMES-RP) in the next stage of this program as well as a complementary phase II study (GAMES) which has submitted to NIH. Both studies involve academic-industry partnerships.
Finally, because outcome assessment is a critical component of successful patient-centered translation, a significant aspect of our program, in patients with intracranial hemorrhage, has focused on prognosis and aggressiveness of care. I currently lead a 4-center prospective observational study where we obtain prognosis predictions from nurses and physicians within 24 hours of hospital admission. These individual estimates are compared against proposed prognosis scores such as the ICH Score. This work builds on prior studies where I examined the association of various interventions in ICH, aggressiveness of care, anti-epileptic drug use, and outcome. Preliminary data from this work is now being used to help support career development awards for junior faculty in this section who have specific interests in this area.
My independent research program has been supported by multiple early career development awards, and now serves as the basis for submitted NIH and other applications. The focus on translation of preclinical science to patients as well as patient centered outcomes directly supports a primary mission of the Neurology Department and Yale Medical School, to further the clinical research enterprise. Recognition of this work is evidenced by several invited reviews in malignant edema and leadership roles in multiple international writing groups for the management of brain swelling and palliative care. I am a member of the steering committee of the Neurocritical Care Society (NCS) Clinical Trial Network, have served as the scientific meeting co-chair for NCS, and sit on several editorial boards for leading journals in this field.
Glyburide Against Malignant Edema and Stroke – RP (GAMES-RP) – I am the national co-PI for this phase II double blind randomized controlled trial. The scientific basis for this study, including pre-clinical collaborations, neuroimaging and serum biomarker development, infrastructure and leadership for this clinical study all capture the central thrust of my research program – to understand the mechanisms of brain swelling and inflammation after injury and to develop and translate novel therapies towards its prevention.
a. Sponsor: Remedy Pharmaceuticals, Inc
b. Data Coordinating Center: Medical University of South Carolina (PI: Jordan J. Elm, PhD)
c. Neuro-Imaging Coordinating Center: Yale Medical School (co-PI: Lauren Beslow, MD – Pediatric Neurology; Gordon Sze, MD – Neuroradiology)
d. Co-PI: W. Taylor Kimberly, M.D.; PhD – Massachusetts General Hospital
e. 12 center study; Yale Site PI: David Hwang; MD
A parallel phase II study (NINDS UO1) has been re-submitted to NIH as a $12 million dollar 25 center study. The submitted proposal uses a different clinical endpoint and tests two dose tiers. I am a co-PI along with Barney Stern, M.D. (University of Maryland) and Gregory del Zoppo, M.D. (University of Washington). The proposal is submitted through NINDS NeuroNext Clinical Trials Network in collaboration with Massachusetts General Hospital.
The basis of both studies was GAMES-Pilot, a multicenter phase IIa study completed one year ago, for which I received the Robert Siekert Investigator Award from the American Heart Association/American Stroke Association as well as the top prize at the NINDS Princeton Stroke Conference.
Prognosis in Intracerebral Hemorrhage (PICH) – I am the national PI for this 5 center study (University of Cincinnati PI: Daniel Woo; Massachusetts General Hospital PI: Jonathan Rosand; University of Miami PI: Sebastian Koch; University of Maryland PI: Steven Kittner; Duke University: Jessica McFarland) aimed at understanding the ability of physicians and bedside nurses to accurately predict functional outcome in patients with intracerebral hemorrhage against the existing prediction scales that are widely used.
a. Sponsor: American Heart Association
b. Data Coordinating Center: Wake Forest University (PI: Carl Langefeld PhD)
c. Parent Study: ERICH (Ethnic & Racial Variation in Intracerebral Hemorrhage)
New England Perihematoma Edema Study – This is a collaborative study between the neurocritical care divisions at Massachusetts General Hospital (MGH) and Yale Medical School. Our group has identified and obtained CT scans from over 500 subjects at MGH with intracerebral hemorrhage. We are performing quantitative assessments of edema volume around the hemorrhage to understand both the timing of edema formation and its potential impact on clinical outcome.
Ethnic & Racial Variation in Intracerebral Hemorrhage (ERICH) – I am an active member of this NINDS funded UO1 consortium (PI Daniel Woo; University of Cincinnati) examining the epidemiology of intracerebral hemorrhage in a cohort enriched with minority populations. The PICH study (PI: Sheth) is a substudy of ERICH, and independently, I have led several analyses through ERICH, two of which have been oral presentations at international conferences (Anti-Epileptic Drug Use in ICH and Withdrawal of Care in ICH)
Neurologic Emergencies Treatment Trials (NETT) – I am the Yale Co-PI along with Chas Wira (Emergency Medicine) for the Yale NETT, a spoke of the Boston NETT Clinical Trials Group. Dr. Wira and I brought NETT to Yale, which is an NINDS funded phase III clinical trials network for neurological emergencies and represents a broad based collaboration between emergency medicine and neurology. We are currently joining POINT (Anti-platelet study in transient ischemic attack) and PROTECT (Progesterone in the Treatment of Traumatic Brain Injury) to Yale through the NETT.
High Dose Deferoxamine for Intracerebral Hemorrhage (Hi-Def) – This phase II study for which I am the Yale Site PI is a NINDS funded phase II study examine the safety and potential efficacy of deferoxamine against inflammation and swelling after ICH.
Germinal Matrix/Intraventricular Hemorrhage (IVH) in Infants – Abcc8, the gene encoding SUR1, the receptor implicated in brain swelling and hemorrhagic transformation, is also associated with germinal matrix hemorrhage in pre-term infants with IVH. Using their existing NIH funded cohort and genetic profiles of pre-term infants with various grade IVH, I have collaborated with Laura Ment (Pediatric Neurology) and Charles Duncan (Neurosurgery) to examine various SNP’s associated with SUR1. This preliminary data is a component of the submitted grant to the Hartwell Foundation, to examine SUR1 and other potential biomarkers in cord blood. This proposal also involves a collaboration with Michael Paidas in Obstetrics & Gynecology.
Glyburide, SUR1, PET – This early stage collaboration is a new direction for my group’s work in brain edema. I am collaborating with Richard Carson PhD in the Yale PET Center to develop a carbon labeled version of glyburide so that we may potentially use the drug as a marker of blood brain barrier integrity and injury, both in terms of spatial and temporal resolution of injury.
- Sheth KN, Kimberly WT, Elm JJ, Kent TA, Mandava P, Yoo AJ, Thomalla G, Campbell B, Donnan G, Davis SM, Albers GW, Jacobson S, Simard JM, Stern BJ. A pilot study of intravenous glyburide in patients with a large ischemic stroke. Stroke (in press)
- Kimberly WT, Battey T, Pham L, Wu O, Yoo AJ, Furie KL, Singhal AB, Elm JJ, Stern BJ, Sheth KN. Glyburide is associated with attenuated vasogenic edema in stroke patients. Neurocrit Care (in press)
- Tchopev Z, Hiller M, Zhuo J, Betz J, Gullapalli R, Sheth KN. Prediction of Poor Outcomes in Cerebellar Infarction by Diffusion MRI. Neurocrit Care, Epub ahead of print, 2013.
- Sheth KN, Yoo AJ, Kimberly WT, Chaudhry ZA, Elm JJ, Jacobson S, Davis SM, Donnan GA, Albers GW, Stern BJ, Gonzalez RG. Validating Imaging Biomarkers of Cerebral Edema in Patients with Severe Ischemic Stroke. J Stroke Cerebrovasc Dis Epub ahead of print,
- Cronin CA, Shah N, Morovati T, Hermann LD, Sheth KN. No Increased Risk of sICH in tPA Treated Stroke Patients With ECASS Exclusion Criteria. Stroke. 43(6): 1684-6, 2012.
- Sheth KN, Stein DM, Aarabi B, Hu P, Kufera JA, Scalea TM, Hanley DF. Intracranial Pressure Dose and Outcome in Traumatic Brain Injury. NeuroCritical Care. Epub ahead of print, 2012.