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(Stroke. 2003;34:2908.)
© 2003 American Heart Association, Inc.

Original Contributions

Extracellular Concentrations of Non–Transmitter Amino Acids in Peri-Infarct Tissue of Patients Predict Malignant Middle Cerebral Artery Infarction

Bert Bosche, MD; Christian Dohmen, MD; Rudolf Graf, PhD; Michael Neveling, MD; Frank Staub, MD; Lutz Kracht, MD; Jan Sobesky, MD; Fritz-Georg Lehnhardt, MD Wolf-Dieter Heiss, MD

From the Max Planck Institute for Neurological Research (B.B., C.D., R.G., L.K., J.S., W-D.H.), Cologne, Germany; and Departments of Neurology (B.B., C.D., M.N., J.S., F-G.L., W-D.H.) and Neurosurgery (F.S.), University of Cologne, Cologne, Germany.

Correspondence to Bert Bosche, MD, Max Planck Institut fuer neurologische Forschung, Gleulerstrasse 50, D-50931 Koeln, Germany. E-mail bbosche{at}pet.mpin-koeln.mpg.de

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose— Space-occupying brain edema is a life-threatening complication in patients with large middle cerebral artery (MCA) infarction. To determine predictors of this detrimental process, we investigated alterations of extracellular non–transmitter amino acid concentrations in peri-infarct tissue.

Methods— Thirty-one patients with infarctions covering >50% of the MCA territory in early cranial CT scans were included in the study. Probes for microdialysis, intracranial pressure, and tissue oxygen pressure were placed into the noninfarcted ipsilateral frontal lobe. Positron emission tomography imaging was performed in 16 of these patients to measure cerebral blood flow in the tissue around the neuromonitoring probes.

Results— Fourteen of the 31 patients developed a malignant MCA infarction, and 17 did not. The patients in the malignant group had significantly lower extracellular concentrations of non–transmitter amino acids than those in the benign group in the first 12 hours of neuromonitoring. At this time, CBF values determined in regions of interest around the probes by positron emission tomography and tissue oxygen pressure showed that the monitored tissues were not yet infarcted, and no differences in transmitter amino acids concentrations were found between the 2 groups. Furthermore, extracellular concentrations of non–transmitter amino acids were negatively correlated with size of infarction.

Conclusions— We assume that reduction of non–transmitter amino acid concentrations reflects an expansion of the extracellular space by vasogenic edema formation in peri-infarct tissue of patients with malignant MCA infarction. Our findings facilitate early prediction of malignant edema formation and may help to increase knowledge of the pathophysiology of the peri-infarct zone of large MCA infarction.

Key Words: amino acids • brain edema • cerebral infarction • middle cerebral artery

	Introduction

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Space-occupying brain edema is a life-threatening complication in patients with large middle cerebral artery (MCA) infarction.¹ Therefore, early identification is essential for timely application of invasive therapies such as hemicraniectomy.² We implemented invasive neuromonitoring comprising measurements of extracellular substrate concentrations by microdialysis, intracranial pressure (ICP), and tissue oxygen partial pressure (PtO₂). In recent studies we have focused on neuromonitoring of neuroactive substances such as transmitter amino acids (TAAs), lactate, pyruvate, and purines in peri-infarct tissue in patients at risk for malignant MCA infarction.^3,4 These investigations were based on the hypothesis that early elevation of neuroactive substances (eg, glutamate) could predict malignant MCA infarction, as had been suggested by other authors.⁵ It was shown, however, that these substances rise only during the later course of malignant infarction at time points that might be too late for implementation of hemicraniectomy. To

See Editorial Comment, page 2914

determine other predictors of malignant MCA infarction, we enlarged the spectrum of the detected substances. Shimada et al⁶ reported alterations of extracellular concentrations of non–transmitter amino acids (non-TAAs) using a cat ischemia model. In the present study we systemically investigated alterations of non-TAAs in patients with large MCA infarction with special emphasis on changes in the first 12 hours after the start of neuromonitoring. Furthermore, positron emission tomography (PET) imaging was performed to measure cerebral blood flow (CBF) in the tissue around neuromonitoring probes. This is the first report on non-TAAs in human stroke.

	Subjects and Methods

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Patients
We included 31 patients in this study. Neuromonitoring was performed in 34 patients (see Dohmen et al⁴), but in 3 cases the volume of microdialysates was insufficient for further high-performance liquid chromatography (HPLC) analysis. All patients suffered from ischemic infarction that covered >50% of the MCA territory on early cranial CT scans. They showed clinical signs of a severe ischemic MCA syndrome with dense hemiparesis and conjugate gaze palsy. Patients were categorized post hoc into a malignant group or a benign group according to the clinical course. Courses were regarded as malignant when the patients had signs of uncal herniation with a unilaterally fixed and dilated pupil. All patients with malignant course under conservative treatment showed clinical signs of herniation; space-occupying brain edema with a midline shift >2 mm at the level of the septum pellucidum on CT corresponds to >5.54 mm in situ. All patients were admitted to the neurological intensive care unit and treated with antiedematous therapy, including 30° elevation of the upper body and osmotic therapy with mannitol; mean arterial blood pressure was controlled with the use of urapidil or catecholamines. Twenty-seven patients were sedated with fentanyl plus midazolam, intubated, and mechanically ventilated during the neuromonitoring. Four patients were sedated only for probe implantation; thereafter they were conscious and breathed spontaneously. This study was approved by the ethics committee of the medical faculty of the University of Cologne (approval No. 99182).

Neuromonitoring
Probes for microdialysis (CMA 70 custom probe, Axel Semrau GmbH), for ICP measurement (Codman Microsensor, Ethicon GmbH), and for PtO₂ (Licox CC1 SB, Integra Neurosciences) were placed into the noninfarcted frontal lobe of the affected hemisphere by standardized implantation via a 3-channel bolt kit (Licox IM3.S, Integra Neurosciences). Probe locations were evaluated on follow-up CT scans. The mean distance between probes and infarcted tissue was 9±4 mm (malignant group, 8±3; benign group, 10±5; P=NS). The implantation did not harm the patients, and no symptomatic bleeding occurred. ICP and PtO₂ were continuously monitored. The microdialysis probe was perfused continuously at a rate of 0.3 µL/min with a sterile isotonic solution, and samples were collected every 120 minutes. Microdialysates were analyzed for extracellular concentrations of non-TAAs (arginine, asparagine, isoleucine, leucine, methionine, phenylalanine, serine, threonine, valine) and TAAs (glutamate, aspartate, -aminobutyric acid [GABA]) in a post hoc analysis on a HPLC system.

PET and CT Studies
PET studies were performed on an ECAT EXACT HR scanner (Siemens/CTI) in 16 of the 31 patients. A total of 20 mCi (740 MBq) [¹¹C]flumazenil was injected intravenously, and the distribution and accumulation of this tracer were followed by serial scanning. Tracer distribution within 2 minutes after injection allows a semiquantitative measurement of regional CBF, which can be quantified by a reference method described earlier.^4,7 In PET images we formed a 0.51-cm³ volume of interest around the probes, which was identified on coregistered cranial CT scans. Cranial CT scans were performed on admission, at 6 to 12 hours, and at day 5. Scans were scrutinized for probe localization, presence of mass effect, secondary hemorrhagic transformation or bleeding, and size of infarction with the use of an approximate planimetric method according to Hasselblatt et al.⁸

Statistical Analysis
Results are expressed as mean±SD if not otherwise noted. Comparisons between the patient groups were analyzed by Student t test for quantitative variables, by Mann-Whitney U test for ordinal variables, and by ² test for categorical variables. The Spearman coefficient was used to analyze correlations between size of infarction and extracellular non-TAA concentrations. A significance level of P<0.05 was chosen. Discriminatory power and the optimal cutoff values of non-TAAs for differentiation among the patient groups were determined by analysis of the receiver operating characteristic curves. Statistical analysis was performed with the use of SPSS for Windows version 10 (SPSS).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients
Fourteen of the 31 patients included in the study had a malignant course, and 17 had a benign clinical course. On admission there were no significant differences in clinical parameters, ie, sex, affected hemisphere, age, National Institutes of Health Stroke Scale score, leukocyte count, temperature, and mean arterial blood pressure between the 2 groups. The portion of patients treated with intravenous recombinant tissue plasminogen activator thrombolysis did not differ significantly between the malignant and the benign group (Table 1). Values of the modified Rankin Scale, as an indicator of patient’s outcome 3 months after stroke, were significantly lower in the malignant group than in the benign group (malignant group, median score 6; benign group, median score 4; P<0.01; mean scores were 5.5 and 4.2, respectively).

View this table: [in this window] [in a new window]   TABLE 1. Patient Data of the Malignant (n=14) Versus the Benign (n=17) Group

Neuromonitoring
Neuromonitoring was started at a mean time of 26.7±7.7 hours (malignant group, 29.1±7.9 hours; benign group, 24.6±7.0 hours; P=NS) and ended 118.9±38.9 hours after stroke onset (120.5±33.9 versus 117.6±34.3 hours, respectively; P=NS). All patients were monitored until at least 80 hours after stroke onset. Extracellular concentrations of 9 essential (labeled by asterisk) or nonessential non-TAAs (arginine, asparagine, isoleucine,* leucine,* methionine,* phenylalanine,* serine, threonine,* and valine*) were analyzed, and all of them proved to be significantly lower in the malignant group than in the benign group in the first 12 hours of measurement (Figure 1). In contrast, extracellular concentrations of TAAs (glutamate, aspartate, and GABA) did not differ significantly between the 2 groups. At this time, we did not find hypoxic values of the PtO₂ in peri-infarct tissue in either group (malignant group, 18.9±11.7 mm Hg; benign group, 19.2±5.9 mm Hg; P=NS). ICP tended to be higher in the malignant group, but this difference did not reach statistical significance (malignant group, 13.3±7.8 mm Hg; benign group, 8.5±4.0 mm Hg).

View larger version (24K): [in this window] [in a new window]   Figure 1. Extracellular concentrations of non-TAAs and TAAs expressed as mean±SD of the first 12 hours of microdialysis measurement. Measurements were performed in peri-infarct tissue of patients with large MCA infarction. Patients in the malignant group developed life-threatening edema formation, whereas patients in the benign group did not.

To analyze the discriminatory power of non-TAA concentrations in the first 12 hours of measurement for early differentiation among the patient groups, we created receiver operating characteristic curves (Figure 2). Receiver operating characteristic curves demonstrated optimal cutoff values as well as percentage of subjects who had true-positive (sensitivity) and false-positive (100-specificity) results. Cutoff values found for the individual non-TAA concentrations are designated by an arrow in Figure 2. The areas under the curves indicated diagnostic accuracy (1, optimal test assertion; 0.5, test assertion equal to random). Sensitivity and specificity as well as the area under the curve varied only slightly among analyzed non-TAAs.

View larger version (49K): [in this window] [in a new window]   Figure 2. Receiver operating characteristic curves analyze the discriminatory power of non-TAA concentrations in the first 12 hours of measurement for prediction of patients with life-threatening edema formation. Curves demonstrate the optimal cutoff values as well as the percentage of true-positive (sensitivity) and false-positive (100-specificity) results in tested individuals. The areas under the curves indicate diagnostic accuracy.

Figure 3 shows time courses of non-TAA concentrations related to stroke onset. For better display, only 6 non-TAAs are presented as mean values of the several patients of each group (Figure 3, top). Non-TAA concentrations in the malignant group were lower than in the benign group throughout the whole analyzing period. The order of substance concentrations (with valine highest, leucine second, and asparagine lowest) was the same in both groups. It did not vary over time in either the benign or the malignant group. In the benign group, the concentrations of the several non-TAAs showed a similar pattern of changes over time; this was also valid for the malignant group (Figure 3a and 3b). To demonstrate the uniformity of extracellular non-TAA alterations within 1 group over time, ratios for all pairs of non-TAAs (eg, valine/leucine; the reciprocal values, ie, leucine/valine are not shown) were calculated for corresponding time points (Figure 3c and 3d; ratios were calculated for 15 possible pairs of the 6 non-TAAs in each group). These ratios remained almost constant throughout the observation period, documenting that substrate concentrations changed homogeneously. Thus, only absolute but not relative values of non-TAA concentrations changed over time, and it becomes clear that common mechanisms must be responsible for the observed changes.

View larger version (42K): [in this window] [in a new window]   Figure 3. a, b, Time courses of non-TAA concentrations are shown for malignant and benign groups. Times are related to stroke onset. Only 6 of the 9 non-TAAs are presented as mean for better display. c, d, Ratios for all 15 pairs of individual non-TAAs calculated for corresponding time points.

PET and CT Studies
The mean time from stroke onset to PET imaging was 15.9±6.4 hours (malignant group, 15.2±7.1 hours; benign group, 16.4±6.3 hours; P=NS). PET measurements demonstrated that CBF within the volume of interest around the probes was not at ischemic levels in both groups but was significantly lower in the malignant group than in the benign group (59.5±6.4% versus 89.1±20.5% of mean CBF of contralateral hemisphere [P<0.01], which corresponds to approximately 18 versus 25 mL/100 g per minute; see also Thiel et al⁷).

Negative correlations were found between size of infarction on follow-up CT scan and non-TAA concentrations (Table 2). These correlations reached statistical significance for extracellular concentrations of arginine, asparagine, isoleucine, leucine, methionine, phenylalanine, serine, and valine. Threonine showed the same tendency, but this did not reach statistical significance (P=0.064).

View this table: [in this window] [in a new window]   TABLE 2. Correlation Between Size of Infarction on Follow-Up CT and Extracellular Non–Transmitter Amino Acid Concentrations in the First 12 Hours of Measurement (n=31)

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In animal experiments and clinical studies, elevated extracellular concentrations of TAAs such as glutamate indicate not only primary but also secondary ischemic tissue damage.^9–11 We have recently shown that TAAs increase in peri-infarct regions if cerebral perfusion pressure drops below approximately 60 mm Hg.⁴ The time point of this increase, however, is too late for successful intervention with invasive strategies such as hemicraniectomy. To determine other markers and predictors of malignant MCA infarction, we enlarged the spectrum of analyzed substances and systematically investigated non-TAA concentrations, with a special focus on early detection (within 12 hours after the onset of neuromonitoring). In this early time period, differences of TAA concentrations, ie, glutamate, aspartate, and GABA, were small and did not differ significantly between benign and malignant patient groups. These findings can be explained by the fact that PtO₂ values in peri-infarct tissue in the malignant as well as in the benign group were at levels of noninfarcted tissue^4,12, and PtIO₂ did not differ significantly between groups. We therefore assume that microdialysis determinations were performed in both groups in not-yet-infarcted tissue. This assumption is underscored by the PET findings, which revealed normal CBF values in probe regions of all studied patients. One must consider, however, that PET measurements were performed before the onset of neuromonitoring. Since, under the described conditions, release and reuptake mechanisms of TAAs were presumably intact in the investigated peri-infarct tissue, we suppose that TAA concentrations were well controlled, and changes were therefore not detectable.

In contrast to the TAAs, we found lower concentrations of non-TAAs in the first 12 hours of measurement in patients who developed malignant brain edema during the later clinical course compared with the patients who did not. Furthermore, we observed that the proportional composition of the extracellular pool of non-TAAs as well as the concentration ratios among the several non-TAAs did not change over time. From this result, we conclude that decreases of extracellular concentrations of non-TAAs reflect a passive alteration of all non-TAA concentrations, possibly by dilution due to edema formation.

Ischemic brain edema results from cytotoxic edema due to ionic pump failure and from vasogenic edema as a consequence of increased blood vessel permeability.¹³ These 2 types of ischemic brain edema follow a different time course. Cytotoxic edema begins minutes after stroke onset; diffusion-weighted MRI takes advantage of this phenomenon in hyperacute stroke diagnosis.¹⁴ Vasogenic edema appears later than cytotoxic edema in severe ischemic injury.^15,16 It leads to a rise in net water content of the ischemic brain tissue. However, vasogenic edema formation is not restricted to the infarcted tissue but spreads into the extracellular space of the peri-infarct tissue.^13,15,17,18 Such spread has been reported to occur in particular along nerve fibers by bulk flow and diffusion.^17,19 Since our measurements were performed in subcortical white matter of the peri-infarct zone and at a time when vasogenic edema formation predominantly occurs,^20,21 an expansion of the extracellular space and a subsequent dilution effect may not be surprising. In general, the volume of the extracellular space influences substance concentrations detected by microdialysis/HPLC.²² One possible explanation for our findings is that non-TAAs are diluted in the malignant group due to vasogenic edema formation in the infarcted tissue that spreads out into the extracellular space of peri-infarct tissue. The predominantly passive character of the decrease of non-TAA concentrations is supported by the observation that the order of magnitude of individual non-TAA concentrations was exactly the same in patients in the malignant and benign groups (with valine highest, leucine second, and asparagine lowest, as shown in Figure 3). The same order has been found experimentally in cat brain under nonischemic conditions,⁶ and this order remained unaltered through all patients. Even though concentrations changed over time, the order never varied (Figure 3a and 3b), and ratios between concentrations of the all pairs of non-TAAs remained approximately constant (Figure 3c and 3d).

The integrity of neuronal tissue, especially astrocytes, is essential for the function of the blood-brain barrier.^23–25 Consequently, damage of neuronal tissue results in increased blood-brain barrier permeability. Direct ischemic damage of brain vessels¹⁶ may add to the problem, and reperfusion, eg, after thrombolysis, may also exacerbate blood-brain barrier damage.²⁶ The greater the brain tissue and vessel damage, the greater is the water increase in extracellular space of infarction, and because of bulk flow, secondarily of peri-infarct tissue.¹⁷ Accordingly, we expected a negative correlation between size of infarction and non-TAA concentrations. The observation that size of infarction on follow-up CT scans and concentrations of non-TAAs in the peri-infarct tissue were negatively correlated (Table 2) may prove the hypothesis that decreased non-TAA concentrations in patients with malignant infarction result from excessive vasogenic edema formation due to primary or secondary brain vessel damage.

Next to H₂O shifts from intracellular or vascular compartments to the extracellular compartment, other mechanisms that could alter extracellular concentrations of non-TAAs in the peri-infarct tissue must be taken into consideration. It has been suggested that suppression of protein synthesis is already induced at approximately 80% of normal CBF.^27,28 Accordingly, one might expect protein synthesis to be inhibited in peri-infarct tissue of patients with large MCA infarction and extracellular concentrations of non-TAAs to be increased because of continuous protein degradation. One would therefore expect concentrations of non-TAAs in peri-infarct tissue of malignant patients to be higher rather than lower if compared with the same site in benign patients because CBF in the probe region was shown to be lower in the malignant group. In consideration of our findings and the fact that half-life values of brain proteins vary between 3 and 9 days,²⁹ the influence of protein synthesis inhibition on alteration of extracellular non-TAAs, however, may have played a minor role.

Other mechanisms by which extracellular substrate concentrations may be altered include transmembrane transport mechanisms for individual substances. Various transport systems are known for selected non-TAAs in brain cells, predominantly in gray matter regions.³⁰ Several of these transport mechanisms are coupled to ion gradients across cell membranes. Since our measurements were performed in not-yet-ischemic peri-infarct tissue in subcortical white matter, we assume that ion homeostasis was not affected in this compartment, and transport systems should have still worked in physiological conditions. Therefore, changes in transmembrane transport are unlikely to explain the differences found in extracellular concentrations of non-TAAs between malignant and benign patients.

Regarding the usefulness of our findings for prediction of malignant edema formation, the acquired cutoff values permitted good diagnostic accuracy, with sensitivities and specificities of approximately 80% in the first 12 hours of neuromonitoring. The presented data have been acquired by post hoc HPLC analysis. We are currently implementing bedside HPLC to test whether online monitoring of non-TAAs is feasible. The method is not much slower than enzymatic detection by semiautomated commercial analyzers such as those used in the preceding studies^3,4 but is more elaborate and therefore is not suitable for routine use in intensive care stroke units, and it is questionable whether the method can be implemented in more diffused non–intensive care stroke units. Hence, the search for more easily detectable markers of edema formation should be continued. Other approaches for detection of extracellular space alterations should also be considered in this context. First, diffusion-weighted MRI is capable of providing good estimates of extracellular space alterations that derive from cytotoxic or vasogenic edema.^14,31 To provide longitudinal information, however, sequential imaging would be needed, perhaps in combination with neuromonitoring. Other, more quantitative assessments of diffusion conditions in the extracellular space, by using tetramethylammonium ions, for example, have been described,³² but these methods have not been adapted to clinical conditions.

Conclusion
We found significantly lower concentrations of non-TAAs in peri-infarct tissue of patients who developed malignant brain edema than in patients with a benign clinical course. This decrease of non-TAAs may be attributed to a dilution of substances in an expanded extracellular space resulting from vasogenic edema of infarcted tissue. This edema may proceed into the peri-infarct region when the tissue is not yet secondarily ischemic. Our findings may help to predict the malignant progression of edema formation in patients suffering from hemispheric stroke. These results emphasize the relevance of vasogenic edema in the pathophysiology of the peri-infarct zone of malignant MCA infarction.

	Acknowledgments

 
This work was supported by a grant from the Bundesministerium für Bildung und Forschung (Kompetenznetz Schlaganfall) to Dr Graf and Dr Heiss. The authors thank Paula Gabel, Andreas Beyrau, and the staff of the neurological intensive care unit for valuable technical assistance.

Received June 5, 2003; revision received July 28, 2003; accepted July 31, 2003.

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				A. Bhardwaj, B. Bosche, C. Dohmen, and R. Graf In Vivo Regional Neurochemistry in Stroke: Clinical Applications, Limitations, and Future Directions * Cerebral Microdialysis in Stroke Patients: Potentials and Limitations of a Method with Longitudinal Information: Response Stroke, April 1, 2004; 35(4): e74 - e76. [Full Text] [PDF]

				C. Berger and S. Schwab Editorial Comment--"Malignant" or Not: Is There a Role for In Vivo Neurochemistry? Stroke, December 1, 2003; 34(12): 2914 - 2915. [Full Text] [PDF]

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