Diagnostic Imaging
December 1999

Neuroradiology:
Imaging helps identify who benefits from stroke intervention

By William T.C. Yuh, M.D., Toshiaki Taoka, M.D., Toshihiro Ueda, M.D., and John C. Chaloupka, M.D.

Advances in imaging techniques and reperfusion therapies have given victims of acute stroke a realistic chance to benefit from early diagnosis and intervention. It is said that “time is brain,” and that a positive outcome can only be achieved when a medical response is initiated within three to six hours of the onset of symptoms.

Unfortunately, the benefit of tPA in stroke therapy has been minimal in the U.S. since the drug was approved in 1996.¹ There are two primary reasons for this. First, there is relatively low recruitment of eligible patients due to the fairly short therapeutic windows for both intravenous and intra-arterial thrombolysis. Second, there is a low rate of therapeutic efficacy (12%), owing to the absence of an effective means for selecting patients.^1,2 Despite the potential of intravenous tPA and intra-arterial thrombolysis, only 3.6% of patients are eligible for treatment within the three-hour time period typically observed, and only 16% are eligible for treatment within six hours.

The average delay in seeking medical attention after the onset of stroke symptoms is about 13 hours. This means that most patients have no chance to benefit from thrombolytic therapy. The Stroke Council of the American Heart Association is attempting to educate the public to recognize early signs and symptoms of acute stroke, and to seek immediate medical help. The goal is to increase the number of potentially eligible patients to 20%.³ Although the AHA expects the average time it takes patients to seek attention to decline, most victims will not be eligible for revascularization unless some means of extending the therapeutic window is achieved. Using noninvasive imaging, it may become possible to better identify patients at risk for reperfusion hemorrhage or who are likely to benefit from arterial reperfusion within or beyond the traditional time frame for therapy.

Interval Debated

These studies are consistent with animal experiments that sought to measure the relationship between the severity and duration of ischemia. Interestingly, our study suggested that within five hours of the onset of symptoms, the therapeutic outcome seemed to be dependent on the severity and duration of ischemia. We also found, however, that residual cerebral blood flow appeared to be the only determinant of therapeutic outcome after the five-hour period of ischemia.

Despite these findings, several groups (including our own) have suggested that therapy can be effectively applied up to 36 hours after the onset of symptoms.^7-11 It is particularly well known that the therapeutic window for revascularization of posterior circulation of ischemia is often longer than for anterior circulation.^12,13 Conversely, some researchers have found that both IV and IA thrombolytic therapy may not always be satisfactory despite successful recanalization within the conventional three- to six-hour period. This is often attributable to hemorrhagic complications or a probable lack of response to therapy (reversibility) of the affected ischemic brain tissue.

Cerebral blood flow (CBF) of the normal brain ranges from 45 to 110 mL per minute per 100 g of tissue, varying in both time and location within the same person.^14-17 Below-normal CBF may be broadly defined as hypoperfusion, which includes a range of values that have been arbitrarily defined as oligoemic and ischemic. Cerebral oligemia is considered underperfused brain parenchyma that will spontaneously recover, and is more likely to not be associated with overt neurologic symptoms. In contrast, ischemic range reduction of CBF is typically symptomatic and at risk for irreversible infarction if revascularization does not occur. This includes both the core region of CBF reduction and the larger surrounding area of so-called “penumbra.”

It is believed that the ischemic penumbra constitutes a potentially reversible volume of cerebral tissue that has CBF between the ischemic and infarction thresholds mentioned above.^{16, 18-20} This ischemic penumbra has been proposed by perfusion and/or diffusion imaging studies performed in untreated patients.^21-23 Without timely recanalization, however, the penumbra eventually progresses to irreversible infarction and therefore cannot be differentiated from core areas of ischemia detected in earlier phases of the stroke.

CBF Measures

Hemorrhagic complications associated with both spontaneous and therapeutic arterial revascularization in the setting of acute stroke are believed to be related to reperfusion injury within the microvascular bed of nonviable brain tissue (Figures 1 and 2E-F). Theoretically, ischemic brain that has adequate collateral circulation may remain viable long enough so that revascularization will not result in reperfusion injury and consequent hemorrhagic complication. Ischemic brain that remains viable at the time of revascularization may be salvageable if successful and timely reperfusion is achieved (Figures 2A-B). It is also possible, however, that brain that is viable at the time of attempted revascularization may have actually suffered an irreversible ischemic injury that will progress to infarction. In this setting, early reperfusion is associated with low risk of hemorrhage despite the progression to infarction (Figures 2C-D).

The concepts of temporal viability and reversibility of ischemia can only be properly assessed in a setting of demonstrated early recanalization, such as that commonly achieved with thrombolysis. But most prior studies have evaluated only untreated patients. We have assessed the relative differences in residual CBF using single-photon emission computed tomography with technetium-99m HMPO. Our preliminary data suggest that in patients who have undergone successful recanalization, the CBF threshold for viability and reversibility is about 35% and 55%, respectively, when compared to normal brain parenchyma⁷ (Figure 2). Our study also found that most hemorrhages (71%) occur during early therapeutic intervention (three to five hours) in patients with low residual CBF (below 35%).

These findings indicate that the conventional time window alone cannot differentiate those at high risk for reperfusion hemorrhage. Instead, it appears that the pretreatment residual CBF may differentiate three categories of treatment outcomes for ischemic lesions: hemorrhage, infarction, and reversible ischemia. Another interesting observation from our preliminary data is that certain ischemic insults with relatively high residual CBF may be successfully salvaged up to 12 hours after the onset of symptoms. Finally, it should be noted that the viability threshold of CBF reduction found by SPECT is similar to findings our group published using perfusion MRI in untreated patients with acute stroke.²⁶

Neuroimaging techniques have made considerable improvements in stroke imaging, particularly for early detection and delineation of acute ischemia. This has been almost exclusively based on untreated patients.^21,27-42 There is no reliable and definitive means prior to treatment for identifying individuals at risk for hemorrhagic complications, nor those who will potentially benefit from early restoration of CBF.¹

Dwi’s Potential

The efficacy of DWI in assessing tissue viability and reversibility, particularly for considering early intervention, has not been established.^25,26,43-46 Abnormal diffusion measurements in patients with acute stroke may consist of early intracellular and extracellular changes in water distribution associated with both reversible and irreversible cerebral ischemia.⁴⁶

Ischemic lesion volume and ADC values measured by MR diffusion imaging may have predictive value for clinical outcome in untreated patients.^48,49 Baird and Warach,⁴⁷ however, have argued that there is no absolute threshold of apparent diffusion coefficient (ADC) decrease that predicts evolution to infarction. Furthermore, it has been shown that diffusion abnormalities in acute stroke may be reversible if early reperfusion occurs.^{21,29,43,44,50} It is likely that DWI only indirectly reflects the severity of hypoperfusion, as supported by the lack of a linear relationship between the magnitude of ADC reduction and residual CBF.^50,51

Furthermore, the apparent threshold of CBF reduction needed to produce abnormalities on DWI has been reported to be higher than the experimentally defined ischemic and infarction thresholds.^52,53 Diffusion abnormalities are likely to represent a summation of changes from cellular dysfunction over time.^53,54 This suggests that DWI is sensitive in detecting ischemia but may not be as specific as perfusion imaging for assessing viability and reversibility.^43,44,55,56

Perfusion MRI provides more direct information on aberrations in regional CBF that may better reflect the primary underlying pathophysiology of an acute ischemic insult (Figures 3 and 4). Although perfusion MRI cannot produce absolute values of CBF, it is capable of making semiquantitative estimates of relative mean transition time (rMTT), relative cerebral blood volume (rCBV), and regional CBF (rCBF) that can be mapped to the cerebral anatomy. These maps can be generated quickly, having been proved feasible and valuable in prompt decision-making for acute stroke intervention.^26,45,57

Based on the dynamic contrast enhancement curve, a flow-related map can be generated by various parameters such as mean transient time, peak time, etc., and a blood volume map can be estimated. The relationship between the CBF, MTT, and CBV can be expressed as: rCBF= rCBV/ rMTT. The increase in signal intensity on the flow-related maps such as the rMTT map is equivalent to an increase in vascular resistance as seen in Ohm’s law (V= IR), where the relative CBF is equivalent to the current (I) and rCBV is equivalent to voltage (V). Therefore, an increase of signal intensity on the rMTT map may not indicate ischemia or infarction, as seen in patients with asymptomatic carotid stenosis or occlusion (Figure 4). Hyperintensity on flow-related maps may only suggest increased vascular resistance,^58-60 making them less ideal than the rCBV and relative CBF maps for assessing ischemic viability and reversibility.

Monitoring Efficacy

This approach has theoretical limitations, however, that will require further evaluation and proper validation when applied to an appropriate patient population. There are several reasons for this. First, the observations of these studies are mostly based on an “untreated” population in whom the viability and reversibility of ischemia cannot be adequately assessed. Second, these studies used rMTT mapping, which is highly sensitive to any hemodynamic compromise that produces a state of hypoperfusion. As stated earlier, however, increased rMTT can be likened to a relative increase in vascular resistance, which can occur in various settings of acute-subacute ischemia or chronic oligemia (Figures 3 and 4).⁶² Therefore, this type of perfusion mapping cannot differentiate the chronicity or functional significance of a given rMTT abnormality, which in our experience is not always indicative for ischemia (Figure 3). Third, the size and magnitude of hyperintensity in rMTT maps is highly dependent on the proximity and severity of vascular narrowing, respectively, which again does not always translate to actual ischemia.

Nuclear Perfusion

Shimosegawa et al⁶⁸ showed that these ratios could estimate the infarction (viability) threshold in an untreated group of patients imaged within six hours after onset of symptoms, which was reported to be 0.48 ± 0.14. In another study, reperfusion occurring within about seven hours of the onset of symptoms substantially reduced the development of infarction (reversibility) with an R/CE ratio (the ratio of ischemic regional activity to cerebellar activity) between 0.55 and 0.75.⁶⁹ Others found that so-called moderate ischemia with residual relative CBF ratios between 0.35 and 0.70 might be suitable for intra-arterial thrombolysis.⁷⁰

Our data show that the pretreatment CBF judged by SPECT in patients with complete recanalization is significantly different among reversible ischemia, infarction, and hemorrhage (Figure 2).⁷ The risk of hemorrhagic transformation in acute stroke treated by IA thrombolytic therapy after five hours primarily depended on residual CBF of ischemic tissue judged by pretreatment SPECT (35%). Within five hours of the onset of symptoms, the development of infarction or hemorrhage appeared to depend on both the residual CBF and the duration of ischemia. Beyond five hours, the residual CBF was the only parameter that appeared to be predictive of treatment outcome.

It must be stressed that our data is unique in that we specifically evaluated the link between relative reductions in rCBF during an acute stroke and the neurological outcome in the setting of acute therapeutic intervention, supporting the notion that such perfusion measurements can provide important information that could be used for optimizing patient selection. This predictability included both overall neurological outcome and risk of hemorrhagic conversion for a spectrum of time intervals from symptom onset, including some cases that were well beyond the conventional six-hour therapeutic window used for intra-arterial thrombolysis.^7,71 Elapsed time alone, therefore, cannot readily determine those patients who could benefit and those at risk for hemorrhage.

Imaging’s Evolving Role

Traditional efforts to obtain absolute measurements of various putative predictive parameters may detract from the more important goal of finding prompt and practical assessments that can rapidly facilitate triage of acute stroke patients. This need may favor use of somewhat more simplistic and semiquantitative methodologies. Cerebral perfusion imaging using SPECT or MRI appears able to provide this type of information because it is most closely tied into the primary underlying pathophysiology—hypoperfusion. We believe that further efforts should be made to apply these modalities prospectively to improve treatment eligibility and effectiveness.

DR. YUH is director of MR and neuroradiology, Dr. Taoka Is a visiting scientist, Dr. Ueda Is a visiting assistant professor, and Dr. Chaloupka Is director of neuroradiology, all in the radiology department at the University of Iowa in Iowa City.

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