Korean J Radiol.  2005 Jun;6(2):64-74. 10.3348/kjr.2005.6.2.64.

Imaging of the Ischemic Penumbra in Acute Stroke

• Lee DH
• Kang DW
• Ahn JS
• Choi CG
• Kim SJ
• Suh DC

• KMID: 1783178
• DOI: http://doi.org/10.3348/kjr.2005.6.2.64

Abstract

One of the main reasons for the soaring interest in acute ischemic stroke among radiologists is the advent of new magnetic resonance techniques such as diffusion-weighted imaging. This new modality has prompted us to seek a better understanding of the pathophysiologic mechanisms of cerebral ischemia/infarction. The ischemic penumbra is an important concept and tissue region because this is the target of various recanalization treatments during the acute phase of stroke. In this context, it is high time for a thorough review of the concept, especially from the imaging point of view.

Keyword

Brain blood flow; Brain perfusion; Brain ischemia; Brain MR; Brain PET; Review

MeSH Terms

Brain/radiography
Cerebrovascular Accident/*diagnosis
Humans
Magnetic Resonance Imaging
Research Support, Non-U.S. Gov't
Tomography, X-Ray Computed

Figure

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  Fig. 1 A schema of the concentric, four-compartment, brain ischemia model. The brain parenchyma affected by hypoperfusion can be compartmentalized by using various physiologic imaging modalities. The ischemic core (4) represents a tissue compartment that is irreversibly damaged or infracted, and it is surrounded, to a various extent, by the ischemic penumbra (3) that is at risk of infarction. Between the unaffected area (1) and the ischemic penumbra, there is an area of benign oligemia (2) that usually survives the ischemic insult, even without prompt reperfusion. The extent of each compartment changes with the passage of time after the initiation of hypoperfusion.

• 

  Fig. 2 Schematic graphs representing the dynamic change of the various hemodynamic or metabolic parameters during the ischemic process of the brain. Each y axis represents the level of those parameters. The x axis is divided into four areas, 1-4, according to the four-compartment concept. Area 1 is the unaffected area (1' is autoregulated), Area 2 is the benign oligemia, Area 3 is the ischemic penumbra and Area 4 is the ischemic core. Rough thresholds are presented at the left side of each graph to help understand those parameters. The reader should refer to the text for the detailed thresholds. If the values are variable, then thick, dotted curves are used. CPP = cerebral perfusion pressure; CBV = cerebral blood volume; CBF = cerebral blood flow; MTT = mean transit time; OEF = oxygen extraction fraction; and CMRO2 = cerebral metabolic rate of oxygen.

• 

  Fig. 3 The initial non-enhanced CT (A), the CT angiography (B), and the CT perfusion maps (C-E) were obtained about one hour after symptom onset in a 63-year-old female patient who presented with right side weakness. Her initial national institutes of health stroke scale score was eight. There is no definable early CT sign on the initial CT scan (A) although a long segment occlusion of the left distal middle cerebral trunk is noted on the slap maximal intensity projection image of CT angiography (B). A large perfusion defect is found in the entire left middle cerebral trunk territory on the mean transit time (C), CBV (D), and CBF (E) maps. On the follow-up CT (F) obtained about 24 hours after the initial imaging, an obvious low density infarction is noted at the area of the initial perfusion abnormality.

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  Fig. 4 The fluid-attenuated inversion recovery image (A) and its corresponding DWI with a b-factor of 1000 sec/mm2 (B) that were obtained during the acute phase. We can assume the diffusion weighted image high signal lesion is the core of the ischemia, and the surrounding parenchyma encompassed with the intravascular high signals (arrows) related with the slow flow is the hypoperfused area. Although the area may contain the ischemic penumbra and the benign oligemia, this area can be the target of prompt recanalization treatment.

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  Fig. 5 The diffusion weighted image (A) and apparent diffusion coefficient map (B) obtained 2 hours after symptom onset in a 70-year-old female who presented with aphasia and right-side weakness. The relative apparent diffusion coefficient of the lesion was about 0.8. She responded to the intravenous thrombolytic treatment that was initiated immediately after MR imaging. The follow-up diffusion weighted image (C) and T2-weighted images (D) show the decrease extent of the initial diffusion weighted image lesion. The difference in the extent of the high signal lesion between the initial diffusion weighted image and the follow-up T2-weighted image can be interpreted and treated as the ischemic penumbra, which would progress to infarction if we failed to perform timely recanalization.

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  Fig. 6 The MR perfusion maps obtained three hours after symptom onset in a 72-year-old female with global aphasia and right-side weakness. The mean transit time map (A) is regarded as the most sensitive map for perfusion abnormalities while the other maps, such as the cerebral blood volume map (B) and the cerebral blood flow map (C), provide other ancillary information. Area 1 represents normal perfusion status and it has no risk of infarction. Area 2 shows the marked prolongation of the mean transit time with the concomitant decrease of both the cerebral blood volume and cerebral blood flow. This area usually has no chance to survive from infarction. This area eventually showed hemorrhagic infarction on the follow-up gradient echo image (D). Area 3 of moderately prolonged mean transit time shows a slightly increased cerebral blood volume value to maintain the cerebral blood flow. This area often has a benign course and it is salvageable via recanalization treatment.

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  Fig. 7 The diffusion-weighted maps (A) and mean transit time map (B) of a 59-year-old male presenting with left-side weakness two hours prior to imaging. The area of perfusion abnormality is much larger than the area of the high signal lesion on the diffusion weighted image. The mismatched area can be operationally regarded as the ischemic penumbra. Intravenous thrombolytic treatment was initiated after the imaging. A follow-up T2-weighted image (C) obtained five days later shows mild progression of the lesion, but there is sparing of most of the initial penumbra zone.

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  Fig. 8 A modified diagram of the concentric, four-compartment brain ischemia model. The diffusion weighted image lesion extent (orange) is usually larger than that of the ischemic core (red). The perfusion weiguted image lesion extent (light blue) is usually larger than that of the ischemic penumbra (blue).

Reference

1. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995. 333:1581–1587.

2. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999. 282:2003–2011.

3. Baron JC. Mapping the ischemic penumbra with PET: a new approach. Brain. 2001. 124:2–4.

4. Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia - the ischemic penumbra. Stroke. 1981. 12:723–725.

5. Astrup J, Symon L, Branston NM, Lassen NA. Cortical evoked potential and extracellular K⁺ and H⁺ at critical levels of brain ischemia. Stroke. 1977. 8:51–57.

6. Baron JC. Barnett H, Mohr JP, Stein BM, Yatsh FM, editors. Positron Emission Tomography. Stroke: Pathophysiology, Diagnosis, and Management. 1998. Philadelphia: Churchill Livingstone;101–119.

7. Heiss WD. Ischemic penumbra: evidence from functional imaging in man. J Cereb Blood Flow Metab. 2000. 20:1276–1293.

8. Firlik AD, Rubin G, Yonas H, Wechsler LR. Relation between cerebral blood flow and neurologic deficit resolution in acute ischemic stroke. Neurology. 1998. 51:177–182.

9. Schlaug G, Benfield A, Baird AE, Siewert B, Lovblad KO, Parker RA, et al. The ischemic penumbra: operationally defined by diffusion and perfusion MRI. Neurology. 1999. 53:1528–1537.

10. Powers WJ. Cerebral hemodynamics in ischemic cerebrovascular disease. Ann Neurol. 1991. 29:231–240.

11. Sharp FR, Swanson RA, Honkaniemi J, Kogure K, Massa SM. Barnett H, Mohr JP, Stein BM, Yatsh FM, editors. Neurochemistry and Molecular Biology. Stroke: Pathophysiology, Diagnosis, and Management. 1998. Philadelphia: Churchill Livingstone;51–83.

12. Read SJ, Hirano T, Abbott DF, Markus R, Sachinidis JI, Tochon-Danguy HJ, et al. The fate of hypoxic tissue on 18F-fluoromisonidazole positron emission tomography after ischemic stroke. Ann Neurol. 2000. 48:228–235.

13. Warach S. Tissue viability thresholds in acute stroke: the 4-factor model. Stroke. 2001. 32:2460–2461.

14. Tomandl BF, Klotz E, Handschu R, Stemper B, Reinhardt F, Huk WJ, et al. Comprehensive imaging of ischemic stroke with multisection CT. Radiographics. 2003. 23:565–592.

15. von Kummer R, Bourquain H, Bastianello S, Bozzao L, Manelfe C, Meier D, et al. Early prediction of irreversible brain damage after ischemic stroke at CT. Radiology. 2001. 219:95–100.

16. Wintermark M, Bogousslavsky J. Imaging of acute ischemic brain injury: the return of computed tomography. Curr Opin Neurol. 2003. 16:59–63.

17. Mayer TE, Hamann GF, Baranczyk J, Rosengarten B, Klotz E, Wiesmann M, et al. Dynamic CT perfusion imaging of acute stroke. AJNR Am J Neuroradiol. 2000. 21:1441–1449.

18. Hossmann KA. Viability thresholds and the penumbra of focal ischemia. Ann Neurol. 1994. 36:557–565.

19. Wintermark M, Reichhart M, Thiran JP, Maeder P, Chalaron M, Schnyder P, et al. Prognostic accuracy of cerebral blood flow measurement by perfusion computed tomography, at the time of emergency room admission, in acute stroke patients. Ann Neurol. 2002. 51:417–432.

20. Yuh WT, Crain MR, Loes DJ, Greene GM, Ryals TJ, Sato Y. MR imaging of cerebral ischemia: findings in the first 24 hours. AJNR Am J Neuroradiol. 1991. 12:621–629.

21. Bryan RN, Levy LM, Whitlow WD, Killian JM, Preziosi TJ, Rosario JA. Diagnosis of acute cerebral infarction: comparison of CT and MR imaging. AJNR Am J Neuroradiol. 1991. 12:611–620.

22. Brant-Zawadzki M, Atkinson D, Detrick M, Bradley WG, Scidmore G. Fluid-attenuated inversion recovery (FLAIR) for assessment of cerebral infarction. Initial clinical experience in 50 patients. Stroke. 1996. 27:1187–1191.

23. Toyoda K, Ida M, Fukuda K. Fluid-attenuated inversion recovery intraarterial signal: an early sign of hyperacute cerebral ischemia. AJNR Am J Neuroradiol. 2001. 22:1021–1029.

24. Hoehn-Berlage M, Norris DG, Kohno K, Mies G, Leibfritz D, Hossmann KA. Evolution of regional changes in apparent diffusion coefficient during focal ischemia of rat brain: the relationship of quantitative diffusion NMR imaging to reduction in cerebral blood flow and metabolic disturbances. J Cereb Blood Flow Metab. 1995. 15:1002–1011.

25. Beauchamp NJ Jr, Ulug AM, Passe TJ, van Zijl PC. MR diffusion imaging in stroke: review and controversies. Radiographics. 1998. 18:1269–1283. discussion 1283-1285.

26. Li F, Silva MD, Liu KF, Helmer KG, Omae T, Fenstermacher JD, et al. Secondary decline in apparent diffusion coefficient and neurological outcomes after a short period of focal brain ischemia in rats. Ann Neurol. 2000. 48:236–244.

27. Kidwell CS, Saver JL, Mattiello J, Starkman S, Vinuela F, Duckwiler G, et al. Thrombolytic reversal of acute human cerebral ischemic injury shown by diffusion/perfusion magnetic resonance imaging. Ann Neurol. 2000. 47:462–469.

28. Grant PE, He J, Halpern EF, Schaefer PW, Schwamm LH, Sorensen AG, et al. Frequency and clinical context of decreased apparent diffusion coefficient reversal in the human brain. Radiology. 2001. 221:43–50.

29. Fiehler J, Foth M, Kucinski T, Knab R, von Bezold M, Weiller C, et al. Severe ADC decreases do not predict irreversible tissue damage in humans. Stroke. 2002. 33:79–86.

30. Fiehler J, Knudsen K, Kucinski T, Kidwell CS, Alger JR, Thomalla G, et al. Predictors of apparent diffusion coefficient normalization in stroke patients. Stroke. 2004. 35:514–519.

31. Hermier M, Nighoghossian N. Contribution of susceptibility-weighted imaging to acute stroke assessment. Stroke. 2004. 35:1989–1994.

32. Warach S, Li W, Ronthal M, Edelman RR. Acute cerebral ischemia: evaluation with dynamic contrast-enhanced MR imaging and MR angiography. Radiology. 1992. 182:41–47.

33. Maeda M, Itoh S, Ide H, Matsuda T, Kobayashi H, Kubota T, et al. Acute stroke in cats: comparison of dynamic susceptibility-contrast MR imaging with T2- and diffusion-weighted MR imaging. Radiology. 1993. 189:227–232.

34. Grandin CB, Duprez TP, Smith AM, Oppenheim C, Peeters A, Robert AR, et al. Which MR-derived perfusion parameters are the best predictors of infarct growth in hyperacute stroke? Comparative study between relative and quantitative measurements. Radiology. 2002. 223:361–370.

35. Butcher K, Parsons M, Baird T, Barber A, Donnan G, Desmond P, et al. Perfusion thresholds in acute stroke thrombolysis. Stroke. 2003. 34:2159–2164.

36. Kim JH, Shin T, Park JH, Chung SH, Choi NC, Lim BH. Various patterns of perfusion-weighted MR imaging and MR angiographic findings in hyperacute ischemic stroke. AJNR Am J Neuroradiol. 1999. 20:613–620.

37. Sorensen AG, Buonanno FS, Gonzalez RG, Schwamm LH, Lev MH, Huang-Hellinger FR, et al. Hyperacute stroke: evaluation with combined multisection diffusion-weighted and hemodynamically weighted echo-planar MR imaging. Radiology. 1996. 199:391–401.

38. Abe O, Aoki S, Shirouzu I, Kunimatsu A, Hayashi N, Masumoto T, et al. MR imaging of ischemic penumbra. Eur J Radiol. 2003. 46:67–78.

39. Castillo M, Kwock L, Mukherji SK. Clinical applications of proton MR spectroscopy. AJNR Am J Neuroradiol. 1996. 17:1–15.

40. Sager TN, Laursen H, Hansen AJ. Changes in N-acetylaspartate content during focal and global brain ischemia of the rat. J Cereb Blood Flow Metab. 1995. 15:639–646.

41. Higuchi T, Fernandez EJ, Maudsley AA, Shimizu H, Weiner MW, Weinstein PR. Mapping of lactate and N-acetyl-L-aspartate predicts infarction during acute focal ischemia: in vivo 1H magnetic resonance spectroscopy in rats. Neurosurgery. 1996. 38:121–129. discussion 129-130.

42. Barker PB, Gillard JH, van Zijl PC, Soher BJ, Hanley DF, Agildere AM, et al. Acute stroke: evaluation with serial proton MR spectroscopic imaging. Radiology. 1994. 192:723–732.

43. Walker PM, Ben Salem D, Lalande A, Giroud M, Brunotte F. Time course of NAA T2 and ADC(w) in ischemic stroke patients: 1H MRS imaging and diffusion-weighted MRI. J Neurol Sci. 2004. 220:23–28.

44. Grohn OH, Lukkarinen JA, Oja JM, van Zijl PC, Ulatowski JA, Traystman JA, et al. Noninvasive detection of cerebral hypoperfusion and reversible ischemia from reductions in the magnetic resonance imaging relaxation time, T2. J Cereb Blood Flow Metab. 1998. 18:911–920.

45. Lee JM, Vo KD, An H, Celik A, Lee Y, Hsu CY, et al. Magnetic resonance cerebral metabolic rate of oxygen utilization in hyperacute stroke patients. Ann Neurol. 2003. 53:227–232.

46. An H, Lin W. Quantitative measurements of cerebral blood oxygen saturation using magnetic resonance imaging. J Cereb Blood Flow Metab. 2000. 20:1225–1236.

47. An H, Lin W, Celik A, Lee YZ. Quantitative measurements of cerebral metabolic rate of oxygen utilization using MRI: a volunteer study. NMR Biomed. 2001. 14:441–447.

48. Roussel SA, van Bruggen N, King MD, Gadian DG. Identification of collaterally perfused areas following focal cerebral ischemia in the rat by comparison of gradient echo and diffusion-weighted MRI. J Cereb Blood Flow Metab. 1995. 15:578–586.

49. Baron JC. Mapping the ischemic penumbra with PET: implications for acute stroke treatment. Cerebrovasc Dis. 1999. 9:193–201.

50. Heiss WD. Imaging the ischemic penumbra and treatment effects by PET. Keio J Med. 2001. 50:249–256.

51. Baron JC, Bousser MG, Rey A, Guillard A, Comar D, Castaigne P. Reversal of focal "misery-perfusion" syndrome by extra-intracranial arterial bypass in hemodynamic cerebral ischemia. A case study with ¹⁵O positron emission tomography. Stroke. 1981. 12:454–459.

52. Marchal G, Beaudouin V, Rioux P, de la Sayette , le Doze F, Viader F, et al. Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke: a correlative PET-CT study with voxel-based data analysis. Stroke. 1996. 27:599–606.

53. Heiss WD, Huber M, Fink GR, Herholz K, Pietrzyk U, Wagner R, et al. Progressive derangement of periinfarct viable tissue in ischemic stroke. J Cereb Blood Flow Metab. 1992. 12:193–203.

54. Heiss WD, Kracht L, Grond M, Rudolf J, Bauer B, Wienhard K, et al. Early [¹¹C]Flumazenil/H₂O positron emission tomography predicts irreversible ischemic cortical damage in stroke patients receiving acute thrombolytic therapy. Stroke. 2000. 31:366–369.

55. Read SJ, Hirano T, Abbott DF, Sachindis JI, Tochon-Danguy HJ, Chan JG, et al. Identifying hypoxic tissue after acute ischemic stroke using PET and 18F-fluoromisonidazole. Neurology. 1998. 51:1617–1621.