Clinical ischemic penumbra

The clinical ischemic penumbra was described in a recent review by Moustafa and Baron [1]. They provided three criteria which are listed in Table 9.1. The clinical ischemic penumbra is the hypoperfused, but viable brain that is responsible for neurological deficits that can be reversed with the resumption of normal blood flow. This operational definition has value because it provides a physiologically relevant target for therapy, and the target may be identifiable by methods including CT and MRl as described in prior chapters. An important known property of the ischemic penumbra is that it is dynamic, that is, it becomes smaller with time, and conversely, the irreversibly injured brain (infarct core) grows with time. This is illustrated in Fig. 9.1. The... 

The Clinical Ischemic Penumbra Identified by MR Imaging and Correlated to PET... 

Simple Methods for Identifying Patients with a Significant Clinical Ischemic Penumbra... 

A goal of advanced imaging is to reliably idenfify patients with a clinical ischemic penumbra who could benefit from therapy. The patients most likely to benefit... 

The concept of critical flow thresholds provides the rational basis for attempts to salvage the ischemic penumbra. In the clinical environment, the successful application of thrombolysis in stroke patients (NINDS Study Group 1995) could be shown to be related to this issue fair clinical outcome correlated positively with early recanalization (von Kummer et al. 1995) and even small improvements of local CBF in the 10% range predicted the reversibility of ischemic tissue changes (Butcher et al. 2003). 

The results of the 2008 European Cooperative Acute Stroke Study (ECASS 111) expanded the 3-h time window for IV thrombolysis and revealed that although safe and effective up to 4.5 h after stroke onset, treatment benefits roughly one-half as many patients as those treated within 3 h [2, 158, 159]. Hence, the ratio between the hemorrhagic risk of treatment and the potential clinical benefit of treatment becomes a more critical consideration as the time window for therapy is expanded with newer IV and lA techniques. It is the mismatch between the size of the infarct core (proportional to hemorrhagic risk) and the size of the ischemic penumbra (proportional to potentially salvageable tissue), as determined by CTP, that provides an imaging measure of this risk-to-benefit ratio. Evidence suggests that core/penumbra mismatch may persist up to 24 h in some patients [160,161]. 

Reperfusion as predictor of follow-up infarct volume. Revascularization therapies in acute ischemic stroke patients aim to rescue the ischemic penumbra by restoring the patency of the occluded artery (recanalization) and the downstream capillary blood flow (reperfusion). Although reperfusion and recanalization have been used interchangeably, the terms describe two distinct concepts [236]. Earlier studies supported the benefit of early recanalization in predicting smaller infarct volumes and clinical outcomes [2, 237, 238]. However, more recent studies have shown that recanalization does not always lead to reperfusion [239, 240]. One explanation is that the main clot may be fragmented and occlude smaller, downstream arterial branches, not allowing capillary reperfusion [241]. A second, distinct, but complementary reason is the noreflow phenomenon even if recanalization is achieved, tissue edema may not allow blood flow [242, 243]. 

The concept of the ischemic penumbra has proven to be an extremely valuable construct for both experimental studies of ischemic stroke and for the development of tools for the management of patients with this disorder. Indeed, a major driver in the development of treatments for ischemic stroke is the belief that in many acute stroke patients, there is a region of salvageable brain that is threatened with permanent injury. This region of brain corresponds to the ischemic penumbra originally described in experimental stroke studies. The clinical condition does not strictly meet the criteria as originally defined by experimentalists. Nonetheless, the concept is clinically valuable, and a suitable modification of its definition applicable to the clinical condition is appropriate. 

PET studies have demonstrated the direct relevance of the ischemic penumbra found in experimental animal studies to human stroke patients. These studies have shown the presence of an ischemic penumbra in a significant proportion of patients studied within 24 h of stroke onset [12-15]. The derangements in CBF, CMRO and OEF in stroke patients were similar to baboon stroke models the penumbra was found to have low CBF, relatively normal CMRO, and high OEF, while the core was characterized by a severely rednced CBF and low CMRO and OEF [15]. Together, these studies have demonstrated that patients with stroke have essentially the same cerebral pathophysiology as the nonhuman primate model, and lessons learned from the latter should be applicable to the clinical condition. 

Two clinical examples that illustrate the potential variability of the ischemic penumbra are shown in... 

The concept of the ischemic penumbra arose in experimental stroke studies, and it has proven to be a useful concept in clinical stroke. The clinical ischemic... 

The pial collateral circulation to the MCA territory, primarily from the anterior cerebral artery and to a lesser degree from the posterior cerebral artery, is the main determinant of the degree of CBF impairment, and thus the rate of neuronal loss [40], The strength of the collateral circulation is variable between patients and has been shown to be a significant predictor of clinical outcome and tissue fate [35, 105-107], The presence of a substantial ischemic penumbra (hypoperfused but viable tissue) is a marker of good collaterals, represents a therapeutic target that is tailored to each patient s individual physiology, and supersedes time as the more important parameter for the decision to proceed with lAT. 

As described in the previous chapter on the ischemic penumbra, a patient with significant neurological deficit (NIHSS > 10), the finding of an ICA or proximal MCA occlusion and a small infarct core (<70-100 mL), very likelyhasavolumeofhypoperfused, symptom-producing tissue at risk that is at least 50% greater than the core volume. This concept was initially proposed as the diffusion-clinical mismatch [108, 109], and is based on the fact that the occlusion, core, and penumbra are not independent variables, but are related to each other by the collateral circulation. If one can identify two of the... 

Precise quantification of CBF and ischemic duration is not possible in the clinical setting [110]. Instead, a semi-quantitative approach has been used to estimate the ischemic penumbra. Using perfusion imaging techniques, a... 

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