Published online before print September 18, 2003, doi: 10.1161/01.STR.0000095162.75634.CE
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(Stroke. 2003;34:2434.)
© 2003 American Heart Association, Inc.
Original Contributions |
Editorial Comment—Challenging the Concept of a Dynamic Penumbra in Acute Ischemic Stroke
Department of Neurology, Ev. Krankenhaus Königin Elisabeth Herzberge, Berlin, Germany
Ever since the concept of an ischemic penumbra began receiving wider acceptance in the early 1980s,1 much attention and endeavors has been focused on the demonstration of this "salvageable rim" in order to define the usefulness of acute stroke therapy. Several techniques have been applied to demonstrate the extent of the penumbra in acute stroke in humans. Besides that these techniques are mostly very complex and therefore far from being accessible to a considerable proportion of acute stroke patients, the interpretation and generalization of their results in human stroke are complicated by several factors. First, the ischemic penumbra is considered an unstable, dynamic, and transient condition. Moreover, aside from time since onset, several factors like residual/collateral blood flow, metabolic parameters (eg, glucose), temperature, and the anatomical resolution of the technique applied further contribute to a patient’s "individual" penumbra.2 This is reflected by the fact that, second, flow thresholds for various states of tissue perfusion differ considerably among studies and techniques applied.3 Third, given the complexity and effort associated with the majority of methods capable of measuring penumbral tissue, most of our current knowledge derives from rather small cohorts and may not be applicable to subgroups of ischemic stroke, like lacunar infarction.
On first gaze, the retrospective study by Jovin et al is not much different from former studies, as it applies a very sophisticated technique (xenon-enhanced CT cerebral blood flow [Xe-CT CBF]) to a small cohort (n=36) of severely affected patients (median NIHSS score, 18) with occlusion of the middle cerebral artery (MCA) stem as determined by conventional or CT angiography. Patients were investigated with a median of 4 hours after symptom onset and treatment strategies comprised intravenous/intra-arterial thrombolysis either combined or alone in 72% of subjects. Primary aims of the study were to determine the relative proportions of tissue CBF conditions stratified into core, penumbra, and non-core/non-penumbra (NC/NP) within the cortical MCA territory and whether these proportions predict clinical outcome. In addition, clinical outcome was unblindedly determined by nonstandardized data retrieval from medical records or by telephone interview at 3 to 6 months.
So, this is just another attempt to determine crucial parameters of CBF in a small subgroup of stroke patients, hampered by methodological limitations. While this somewhat provocative resume might be appropriate in several aspects, the article by Jovin et al is of interest not only because it is the first Xe-CT CBF study associating the proportion of ischemic core with clinical outcome; more importantly and perhaps unexpectedly, its results regarding the relation and dynamics of penumbra, core, and NC/NP proportions are rather startling. Regions with CBF values indicating core (0 to 8 mL/100 g per minute) or NC/NP (>20 mL/100 g per minute) were found to be highly variable among individuals, with proportions ranging from 7.6% to 70.5% and 4.7% to 66% of the MCA cortical territory, respectively. This might be due to the many anatomical variants of collateral pathways to the cortex and concurs with recent MRI studies indicating a high variability of areas with specific flow characteristics in MCA stem occlusion.4,5 The core’s extension, however, was inversely correlated with percentage NC/NP tissue, but was neither associated with the time elapsed since symptom onset nor with the percentage of penumbral tissue, which was in fact found to be rather constant (range, 16.2% to 46.9%). In addition, in a subgroup analysis of thrombolyzed patients (n=21), only the mean percentage core but not the status of recanalization or percentage penumbra was associated with patient outcome. Finally, the final infarct size on follow-up imaging was strongly correlated with the percentage of core, while a favorable clinical outcome was associated with lower percentages of core, but was independent from the penumbral proportion.
Currently, the penumbra is conceived as a tissue condition spreading from the center of an ischemic area, thereby shrinking and leaving behind an enlarging ischemic core region when adjacent, formerly penumbral areas undergo irreversible ischemic damage.3,6 Tissue characteristics compatible with penumbra have been demonstrated up to 48 hours after onset of ischemia,7 although recent studies using benzodiazepine receptor ligands as markers for neuronal integrity indicate that major cell damage occurs during the very early phase of ischemic stroke.8,9 Nevertheless, substantial changes of the penumbra have been demonstrated even several hours after onset by various techniques applying serial imaging.10–15 Thus, besides the aforementioned difficulties and variations in determining CBF and cerebral metabolic states in humans, the paradigm of a dynamic penumbra-core interdependence with expansion of the core at the cost of the penumbra over time is still an integral part of our understanding of early ischemic stroke pathophysiology. Furthermore, recanalizing treatment strategies based on this concept have been proven to be effective both in PET studies demonstrating the reversibility of penumbral tissue characteristics by early reperfusion16 and in larger cohorts of patients treated with thrombolysis.17,18 Thus, Jovin et al’s findings of a rather stable penumbra together with the inverse relation between core and NC/NP tissue (and not penumbral tissue) contradict the assumption of a dynamic and interdependent relation between penumbra and core. Therefore, the results presented by Jovin et al have to be viewed with skepticism.
The independence of CBF parameters from time after onset in the presented study may be explained by the merely one-time examination of patients, while serial investigations might have revealed the relation of core and NC/NP as changing over time. Even under this assumption, however, according to the results by Jovin et al, an increase of the core area would occur at the cost of NC/NP area and not the penumbra. Provided NC/NP represents functioning tissue, this should be accompanied by clinical deterioration (or improvement in case of core shrinkage). Unfortunately, neither Jovin et al nor other studies measuring CBF have correlated their findings realtime with clinical changes, since all these studies were focused on long-term clinical outcome.
The results of Jovin et al further suggest that final infarct size and clinical outcome are likely to be determined very early in the course. Other studies applying different methods but with similar mean time intervals between onset and investigation (4 to 5 hours) have also shown an association of early infarct volume with clinical outcome.14,19,20 Transferred to clinical experience, this assumption of a very early defined core even concurs with the results of large-scale trials on systemic thrombolytic therapy, where particularly patients treated within 90 minutes profited from treatment.21
To date, only 3 other Xe-CT CBF studies investigating acute stroke patients were published,22–24 partly with clearly differing results (present study,23). Nevertheless, Xe-CT CBF, despite its methodological limitations and possible side effects of xenon gas inhalation,25 is already considered a reliable tool to measure human CBF with sufficient spatial resolution.3 Thus, more studies applying Xe-CT CBF in early acute ischemic stroke are worthwhile. While not all of the results presented by Jovin et al are compatible with current knowledge and concepts, some of their findings deserve further investigation in order to confirm or refute the hypothesis of a stable penumbra.
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