Late Secondary Injury May Limit the Effectiveness of Thrombolysis
Abstracts & Commentary
Sources: Kidwell CS, et al. Late secondary ischemic injury in patients receiving intraarterial thrombolysis. Ann Neurol. 2002;52:698-703; Fisher M. Editorial. Reversal of diffusion abnormalities after ischemic stroke: Adding difficulty and complexity to the conundrum of acute stroke imaging. Ann Neurol. 2002;52:695-696.
Within minutes of an acute cerebral ischemic insult, diffusion-weighted magnetic resonance imaging (DWI) demonstrates ischemic regions with a decline in the apparent diffusion coefficient (ADC) of water.1 ADC decline is associated with impaired high-energy metabolism and loss of ion homeostasis. Animal studies and preliminary observations in humans demonstrate that initial DWI and ADC abnormalities are reversible by early reperfusion.2 Additional animal studies indicate that ischemic tissue that undergoes early reversal of DWI abnormalities may manifest either sustained reversal and tissue salvage or only temporary reversal followed by later reappearance of DWI abnormalities, indicating late, secondary injury.3,4
Kidwell and associates studied the phenomenon of late secondary ischemic injury in 18 ischemic stroke patients treated within 6 hours of stroke onset with intraarterial thrombolysis alone (n = 12) or a combination of intravenous and intraarterial thrombolysis (n = 6). Ten patients (56%) demonstrated no reversal in the size of the DWI lesion after treatment. Eight of 18 patients (44%) demonstrated some amount of ADC reversal when DWI was repeated several hours after thrombolysis. At day 7, however, MRI showed that 5 of 8 patients (28%) had partial or complete reappearance of a DWI abnormality that initially had resolved. Three of 8 (17%) had no secondary ADC changes.
There was no significant difference among these 3 groups in age, time to recanalization, time to post-treatment MRI, degree of vessel recanalization, or occurrence of post-ischemic hyperperfusion. None of the patients showing late secondary injury had evidence of vessel reocclusion on perfusion MRI, MRA, or transcranial Doppler examination. Pretreatment ADC values, however, were lowest in tissues without reversal, intermediate in tissues with late injury, and highest in tissues with sustained reversal. This finding suggests that a profound degree of initial ischemia leads to irreversible infarction, intermediate degrees of ischemia permit initial normalization of DWI abnormalities but promote late secondary injury, and modest degrees of ischemia allow sustained reversal of abnormalities and tissue survival.
Clinically, although patients with sustained reversal of DWI abnormalities showed greater improvement in their median NIH stroke scale scores than did patients with no reversal, the difference was not statistically significant.
Commentary
The clinical significance of late secondary injury remains uncertain. Nevertheless, the present study suggests that late secondary injury occurs with intermediate durations of ischemia and can compromise some or all of the initially salvaged brain tissue. Therefore, Kidwell et al have set the stage for additional investigations to determine the mechanisms, frequency, temporal and spatial evolution, and the clinical significance of late secondary injury. Once the mechanism of injury has been determined, neuroprotective agents can be developed that specifically target late secondary injury.
For the present, the suggestion that delayed tissue injury may limit neurological recovery after successful thrombolysis provides a rationale for further stroke treatment trials of combination thrombolytic and neuroprotective treatment strategies. — John J. Caronna
Dr. Caronna is Associate
Editor of Neurology Alert, Vice-Chairman of the Department of Neurology
at Cornell University Medical Center, and Professor of Clinical Neurology at
New York Hospital.
References
1. Baird AE, Warach S. J Cereb Blood Flow Metab. 1998;18:583-609.
2. Kidwell CS, et al. Ann Neurol. 2000;47:462-469.
3. Li F, et al. Stroke. 2000;31:946-954.
4. Van Lookeren Campagne M, et al. J Cereb Blood Flow Metab. 1999;19:1354-1364.
Within minutes of an acute cerebral ischemic insult, diffusion-weighted magnetic resonance imaging (DWI) demonstrates ischemic regions with a decline in the apparent diffusion coefficient (ADC) of water. ADC decline is associated with impaired high-energy metabolism and loss of ion homeostasis. Animal studies and preliminary observations in humans demonstrate that initial DWI and ADC abnormalities are reversible by early reperfusion.
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