Reperfusion Therapy in Acute and Subacute Stroke: Selection of Candidates Using Magnetic Resonance Perfusion and Diffusion Imaging

Argye E. Hillis, M.D., M.A.

Johns Hopkins University, Baltimore, MD

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

April 2000, for 3 years

Funding Amount:

$100,000

Investigator Biographies

Argye E. Hillis, M.D., M.A.

Professor of Neurology, Johns Hopkins University

Hypothesis

Hypothesis:
Stroke patients who have regions of brain that are hypoperfused (defined by MR perfusion weighted imaging (PWI)), but not yet infracted (on diffusion-weighted imaging (DWI)), and who have functional impairments attributable to the regions of hypoperfusion, are likely to benefit from reperfusion therapies, even one week after post-onset of ischemic symptoms.

Goals:
1. To determine the percentage of all patients presenting to the hospital with large vessel ischemic stroke who have a diffusion-perfusion mismatch on the initial scans done at greater than 24 hours, and in subsequent 24 hour intervals, up to seven days, after onset of initial stroke symptoms.

2. To determine whether currently used types of reperfusion therapy (thrombolysis, vascular surgery, medically-induced hypertension) can result in both functional improvement and reduction of hypoperfused tissue (on post- vs. pre-treatment PWI) in patients with diffusion-perfusion mismatch up to seven days post onset of symptoms.

3. To identify the cognitive and motor impairments that improve when specific regions of the brain are reperfused (as identified on pre-intervention vs. post-intervention PWI).

Methods:
Researchers will identify stroke patients in whom PWI shows larger areas of brain tissue that are receiving poor blow flow, compared to the area of brain tissue that has already died. If they are candidates for thrombolysis or endarterectomy, they will undergo those procedures. The remaining patients will be invited to participate in a randomized trial of induced blood pressure elevation versus conventional management. All subjects will have repeat PWI and DWI and tests of motor and cognitive function before and after treatment, to determine if improved blood flow to a particular region corresponds to improved function.

Follow-on Funding:
7/1/02- 6/30/07 “Neural Basis for Lexical Processes in Hyperacute Stroke”
RO1 DC 5375
Sponsor: NIH/NIDCD
Total direct cost: $1,411,427
Current annual direct cost: $250,025
PI: A.E. Hillis
Role: PI

7/1/04 – 6/30/08 Neural Basis of Unilateral Spatial Neglect
RO1 NS047691
Sponsor: NIH/NINDS
Total direct cost: $1,674,518
Current annual direct cost: $323,196;
PI: A.E. Hillis
Role: Primary Investigator

6/1/03-5/30/07 “Induced Hypertension for Acute Ischemic Stroke”
R01 NS42607-01
Sponsor: NIH/NINDS
Total direct costs: 948,138
Current annual direct cost: $316,046
PI: R. Wityk
Role: Investigator

Findings:
We learned that some patients who have had neurological deficits (language problems or attentional problems or weakness on one side) even for several days can improve in function by improving blood flow, by temporarily increasing blood pressure with medications.

This research has led to additional funding from NIH to (1) further investigate the effectiveness of blood pressure elevation on improving function in acute to subacute stroke in a multi-center trial (PI: R. Wityk) and (2) further investigate the relationship between low blood flow in specific areas of the left side of the brain and language deficits in patients with cerebrovascular disease (PI: A.E. Hillis); (3) further investigate the relationship between low blood flow in specific areas of the left or right side of the brain and spatial processing and attention deficits in patients with cerebrovascular disease (PI: A.E. Hillis).

Selected Publications

Reineck L., Agarwal S., and Hillis A.E. “Diffusion-clinical mismatch” is associated with potential for early recovery of aphasia. Neurology. 2005 Mar 8;64(5):828-33.

Hillis A.E., Newhart M., Heidler J., Barker P.B., Herskovits E., and Degaonkar M. The roles of the “visual word form area” in reading. Neuroimage. 2005 Jan 15;24(2):548-59 .

Hillis A.E. Systemic blood pressure and stroke outcome and recurrence. Curr Atheroscler Rep. 2004 Jul;6(4):274-80.
Reprinted in: Curr Hypertens Rep. 2005 Feb;7(1):72-8 .

Hillis A.E., Chang S., Breese E, and Heidler J. The crucial role of posterior frontal regions in modality specific components of the spelling process. Neurocase. 2004 Apr;10(2):175-87.

Hillis, A.E., Work, M., Breese, E.L., Barker, P.B., Jacobs, M.A. & Maurer, K. Re-examining the brain regions crucial for orchestrating speech articulation. Brain. 2004 Jul;127(Pt 7):1479-87 .

Hillis A.E., Barker P.B., Wityk R.J., Aldrich E., Restrepo L., Breese E.L. and Work M. Variability in subcortical aphasia is due to variable sites of cortical hypoperfusion. Brain Lang. 2004 Jun;89(3):524-30 .

Breese, E.L. & Hillis, A.E. Auditory comprehension: is multiple choice really good enough? Brain Lang. 2004 Apr;89(1):3-8 .

Hillis A.E., Wityk R.J., Ulatowski J.A., Beauchamp N., Jacobs M., and Barker P.B. MR perfusion weighted imaging as a marker of treatment response in acute and subacute stroke. Neuroradiology. 2004 Jan;46(1):31-9 .

Hillis A.E., Wityk R.J., Barker P.B., Ulatowski J.A., and Jacobs M.A. Change in perfusion in acute nondominant hemisphere stroke may be better estimated by tests of hemispatial neglect than by the National Institutes of Health Stroke Scale. Stroke. 2003 Oct;34(10):2392-6 .

Hillis A.E., Ulatowski J.A., Barker P.B., Torbey M., Ziai W., Beauchamp N., Oh S., and Wityk R. A pilot randomized trial of induced blood pressure elevation: Effects on function and focal perfusion in acute and subacute stroke. Cerebrovasc Dis. 2003;16(3):236-46 .

Hillis A.E., Wityk R., Barker P.B., and Caramazza A. Neural regions essential for writing verbs. Nat Neurosci. 2003 Jan;6(1):19-20 .

Hillis A.E., Tuffiash E., Wityk R.J., and Barker P.B. (2002) Regions of neural dysfunction associated with impaired naming of actions and objects in acute stroke. Cognitive Neuropsychology 19, 523-534.

Hillis, A.E. & Heidler, J. (2002). Mechanisms of early aphasia recovery: evidence from MR perfusion imaging. Aphasiology, 16, 885-896.

Hillis, A.E., Kane, A., Tuffiash, E., Beauchamp, N., Barker, P.B , Jacobs, M.A., Wityk, R. (2002). Neural substrates of the cognitive processes underlying spelling: Evidence from MR diffusion and perfusion imaging. Aphasiology, 16, 425-438.

Hillis A.E., Wityk R.J., Barker P.B., Beauchamp N.J., Gailloud P., Murphy K., Cooper O., and Metter E.J. Subcortical aphasia and neglect in acute stroke: the role of cortical hypoperfusion, Brain. 2002 May;125(Pt 5):1094-104 .

Hillis A.E., Kane A., Tuffiash E., Ulatowski J.A., Barker P., Beauchamp N., and Wityk R. Reperfusion of specific brain regions by raising blood pressure restores selective language functions in subacute stroke. Brain Lang. 2001 Dec;79(3):495-510 .

Hillis A.E., Wityk R.J., Tuffiash E., Beauchamp N.J., Jacobs M.A., Barker P.B., and Selnes O.A. Hypoperfusion of Wernicke’s area predicts severity of semantic deficit in acute stroke. Ann Neurol. 2001 Nov;50(5):561-6.

Chapters that review studies supported by the Dana Foundation:

Hillis, A.E., & Breese, E. L. (2003). Aphasia recovery: stages and mechanisms. In A. Freddi (ed.) Stroke Today. Rome: San Raffaele Termini, pp. 288 297.

Hillis, A.E. (2005). Application of magnetic resonance perfusion and diffusion imaging to the study of linguistics. In K. Brown (Ed.), Encyclopedia of Language and Linguistics, 2nd Edition. Oxford: Elsevier, pp. 469-470.

Hillis, A.E. (2005). Acute ischemic stroke. In RT Johnson, J Griffin & J McArthur (eds). Current Therapy in Neurologic Disease (7th edition). St. Louis, MO: Mosby. pp. 213-217.

Rosenberg, J.D., Gottesman, R. & Hillis, A.E. (2006). General medical management of stroke. In R. Wityk & R. Llinas (eds.), Diagnosis and Treatment of Stroke. American College of Physicians.