- Department of Surgical Neurology, Research Institute for Brain and Blood Vessels-AKITA, Akita, Japan
Department of Surgical Neurology, Research Institute for Brain and Blood Vessels-AKITA, Akita, Japan
DOI:10.4103/2152-7806.140705Copyright: © 2014 Kobayashi S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
How to cite this article: Kobayashi S, Ishikawa T, Tanabe J, Moroi J, Suzuki A. Quantitative cerebral perfusion assessment using microscope-integrated analysis of intraoperative indocyanine green fluorescence angiography versus positron emission tomography in superficial temporal artery to middle cerebral artery anastomosis. Surg Neurol Int 15-Sep-2014;5:135
How to cite this URL: Kobayashi S, Ishikawa T, Tanabe J, Moroi J, Suzuki A. Quantitative cerebral perfusion assessment using microscope-integrated analysis of intraoperative indocyanine green fluorescence angiography versus positron emission tomography in superficial temporal artery to middle cerebral artery anastomosis. Surg Neurol Int 15-Sep-2014;5:135. Available from: http://sni.wpengine.com/surgicalint_articles/quantitative-cerebral-perfusion-assessment-using-microscope-integrated-analysis-of-intraoperative-indocyanine-green-fluorescence-angiography-versus-positron-emission-tomography-in-superficial-temporal/
Background:Intraoperative qualitative indocyanine green (ICG) angiography has been used in cerebrovascular surgery. Hyperperfusion may lead to neurological complications after superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis. The purpose of this study is to quantitatively evaluate intraoperative cerebral perfusion using microscope-integrated dynamic ICG fluorescence analysis, and to assess whether this value predicts hyperperfusion syndrome (HPS) after STA-MCA anastomosis.
Methods:Ten patients undergoing STA-MCA anastomosis due to unilateral major cerebral artery occlusive disease were included. Ten patients with normal cerebral perfusion served as controls. The ICG transit curve from six regions of interest (ROIs) on the cortex, corresponding to ROIs on positron emission tomography (PET) study, was recorded. Maximum intensity (IMAX), cerebral blood flow index (CBFi), rise time (RT), and time to peak (TTP) were evaluated.
Results:RT/TTP, but not IMAX or CBFi, could differentiate between control and study subjects. RT/TTP correlated (|r| = 0.534-0.807; P P = 0.017). The ratio of TTP was also significantly lower in patients with postoperative HPS than in patients without postoperative HPS (0.64 ± 0.081 and 0.85 ± 0.095, respectively; P = 0.017).
Conclusions:Time-dependent intraoperative parameters from the ICG transit curve provide quantitative information regarding cerebral circulation time with quality and utility comparable to information obtained by PET. These parameters may help predict the occurrence of postoperative HPS.
Keywords: Hyperperfusion syndrome, indocyanine green angiography, positron emission tomography, superficial temporal artery to middle cerebral artery anastomosis
The hemodynamic status of brain tissue can be classified into stage 0 (normal flow state), stage 1 (cerebral autoregulatory vasodilatation to compensate for a decrease in blood flow toward the brain), and stage 2 (autoregulatory failure, with a compensatory rise in oxygen extraction fraction [OEF]).[
Intraoperative indocyanine green (ICG) angiography has been in use for a decade and allows qualitative visualization of arterial, capillary, and venous systems and pathological vascular structures.[
Recent studies have clarified that postoperative hyperperfusion may cause serious neurological complications, such as brain swelling, seizure, and intracerebral hemorrhage, after superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis in patients with severe hemodynamic compromise.[
Therefore, the purpose of this study was to determine whether integrated dynamic ICG fluorescence analysis could accurately detect impaired cerebral perfusion, and to compare the reliability and utility of such measurements with those obtained by PET using oxygen-15-labeled tracers. Further, we evaluated whether integrated dynamic ICG fluorescence analysis could predict onset of postoperative hyperperfusion syndrome (HPS) after STA-MCA anastomosis.
Patients and subjects
Ten patients undergoing STA-MCA bypass surgery for unilateral major cerebral artery occlusive disease (two women and eight men; mean age, 63.8 years; age range, 45-74 years) who were referred to the Department of Surgical Neurology, Research Institute for Brain and Blood Vessels-AKITA, Japan, between June 2011 and March 2013 were enrolled in this study [
Ten patients (seven women and three men; mean age, 61.3 years; age range, 32-70 years) undergoing craniotomy and clipping surgery for unruptured cerebral aneurysms served as control subjects. These subjects had no steno-occlusive disease, as assessed by intracranial MRA and neck MRA/neck ultrasonography, and these subjects completed the ICG-VA protocol just after fronto-temporal craniotomy.
The institutional medical review board of the Research Institute for Brain and Blood Vessels-AKITA approved the study protocol. All patients provided written informed consent.
Icg-va protocol and analysis
The recommended dose of ICG-VA is 0.1-0.3 mg/kg, and the daily dose should not exceed 5 mg/kg. In this series, all patients completed the ICG-VA study protocol just after fronto-temporal craniotomy, and the patients undergoing bypass surgery completed the same protocol just after bypass procedure. Subjects received a standard dose of 7.5 mg per injection dissolved in 3.0 ml of physiologic saline. The recording was started, and a calculated bolus of ICG was administered by the anesthesiologist at the surgeon's request. The ICG transit curves intensities were recorded by an automatic microscope-integrated algorithm using near-infrared light (λ = 800 nm; OPMI Pentero microscope with infrared fluorescence detection hardware and the Flow 800 software analysis tool; Carl Zeiss Meditec, Oberkochen, Germany). This tool features an algorithm for correcting shading and brain pulsation. Fluorescence intensities were measured in arbitrary intensity units (AIs) that corresponded to the intensity detected by the camera. The additional time needed for ICG angiography was approximately 90 s. The focal length and magnification of the microscope were set at the same level for comparison of flow analysis in all procedures. PaO2, PaCO2 and mean blood pressure were maintained within the normal range. Normal cardiac function (ejection fraction >55%) was also confirmed preoperatively in all patients.
The course of fluorescent intensities was measured by freely definable regions of interest (ROIs). The data from ROIs were exported as a Microsoft Excel file for further processing after surgery. This feature enabled calculation of various hemodynamic parameters. In this study, three facultative ROIs were defined on the superficial brain cortex of the frontal lobe (avoiding vascular structures), and three ROIs were defined on the superficial brain cortex of the temporal lobe in the same manner; thus, a total of six cortex ROIs were used for each patient. These ROIs were representative of the capillary compartment and were chosen for the absence of arterial or venous vessels traversing the respective territory. The following parameters were assessed [
(a) Fluorescence intensity was measured in defined ROIs. Six facultative ROIs were defined on the cortex in the superficial brain tissue, avoiding vascular structures. (b) ICG transit curve showing the different parameters used to estimate perfusion. Parameters included IMAX (maximum intensity); TTP (time to peak); RT (rise time; i.e., the interval between 10% and 90% of maximum signal); and cerebral blood flow index (CBFi; i.e., the ratio of fluorescence intensity to RT: CBFi: Δ fluorescence intensity/RT)
Pet protocol and imaging data analysis
PET was done with a three-dimensional PET scanner (SET-3000GCT/M; Shimadzu Corp., Kyoto, Japan), which provides 59 sections with a center-to-center distance of 2.6 mm. The axial field of view was 156 mm. The intrinsic spatial resolution was 3.5-mm full width at half maximum in-plane and 4.2-mm full width at half maximum axially. Filtered backprojection image reconstruction followed by 3D Gaussian smoothing with 6-mm full width at half maximum resulted in a final in-plane resolution of approximately 7-mm full width at half maximum. Each PET study included a transmission scan for attenuation correction. In our institution, three static emission scans with the inhalation of C15O, the inhalation of 15O2, and the injection of H215O were performed to obtain cerebral blood volume (CBV), cerebral metabolic rate of oxygen, OEF, and CBF maps, respectively, according to the studies of Hatazawa et al.[
CBF, CBV, and OEF were analyzed with an automated ROI setting method developed by Ogura et al.[
Numerical data are expressed as the mean ± standard deviation. Differences between measures of various parameters were examined by nonparametric tests, because the relatively small sample size undermines the distributional assumptions of a parametric test, such as the t test. Nevertheless, we confirmed that the same pattern of results was obtained when using t tests. The Mann–Whitney U-test was used to identify differences between measures of various ICG-VA parameters in patients with and without major cerebral artery occlusive disease and differences between measures of various PET parameters/ICG-VA parameters in patients with and without postoperative HPS. The Wilcoxon signed ranks test was used to identify differences between measures of various ICG-VA parameters before and after the bypass procedures. Area under the receiver operating characteristic curve (AUC) was also used to evaluate diagnostic accuracy. Correlations between measured values of ICG-VA parameters and of PET parameters were determined by Pearson's correlation coefficient. The degree of agreement between measured values of ICG-VA and PET parameters was estimated by the Bland–Altman graphical procedure.[
Both the ICG-VA protocol and the PET protocol were successfully conducted. During injection of the ICG, systolic arterial blood pressure was maintained between 100 and 120 mmHg, without significant differences before and after the bypass procedure. The mean temporary recipient vessel occlusion time was 25.1 ± 7.9 (range, 15.9–45.5) min. The patency of bypass graft was evaluated during surgery by ICG-VA. Postoperative MRA also confirmed the patency of bypass graft in all cases, and MRI showed that symptomatic cerebral infarction did not occur after surgery in any patient. Three patients were diagnosed with HPS during the week after surgery, based on findings from SPECT and typical symptoms (paresis and dysarthria; aphasia; headache and seizure, respectively). After the diagnosis, systolic arterial blood pressure was more strictly controlled below 120 mmHg. Symptoms were transient and resolved completely in all cases. Average values and ratio of ipsilateral to contralateral side for each PET parameter were not significantly different when comparing patients with and without postoperative HPS [
Comparison of patients with and without major cerebral artery occlusive disease
The results for the entire data set are summarized in
Correlation between hemodynamic parameters of the icg-va and pet protocol
Associations between measures of ICG-VA parameters and of PET parameters were examined using Pearson's correlation coefficient in patients with major cerebral artery occlusive disease [
(a) Correlations between CBFi measured by the ICG-VA protocol and CBF and between CBFi and CBF ratio in 60 regions of interest among 10 patients. (b) Correlations between RT measured by the ICG-VA protocol and MTT, and between RT and MTT ratio, in 60 regions of interest among 10 patients. (c) Correlations between TTP measured by the ICG-VA protocol and MTT and between TTP and MTT ratio in 60 regions of interest among 10 patients. The black line shows the best fit linear regression for eye guide. The Pearson correlation coefficient (r) and p value are shown in each graph
However, because correlation coefficients are measures of the association between two methods but not of the agreement between them, the degree of agreement between RT and MTT and between TTP and MTT were assessed using the Bland–Altman graphical technique.[
(a) Bland–Altman plot of the means of RT and MTT versus the difference between RT and MTT. Each circle represents one region of interest. Mean bias –0.2 s (solid line) with 95% limits of agreement from –0.8 to 0.4 s (dotted line) are shown. (b) Bland–Altman plot of the means of TTP and MTT versus the difference between TTP and MTT. Each diamond represents one region of interest. Mean bias 6.3 s (solid line) with 95% limits of agreement from 1.4 to 11.2 s (dotted line) are shown. The fine black line shows the best fit linear regression
Changes in icg-va parameters before and after bypass procedures
This study showed that cerebral perfusion in the hemodynamically compromised brain was delayed and that time-dependent parameters of the ICG transit curve (RT and TTP) quantitatively correlated with measures obtained by radio-nuclear examination. On the other hand, IMAX and CBFi, which are volume-dependent parameters, were less reliable for quantitative assessment when compared with time-dependent parameters.
IMAX is easily affected by variables associated with ICG transit curve imaging, such as the focal distance between the microscope and the surface of the brain. It is also affected by light volume in the operating room. As a logical consequence, CBFi is also partially affected by these factors. This may explain why CBFi was not able to discriminate between normal and impaired cerebral perfusion with high accuracy and why it did not strongly correlate CBF/CBF ratio measured from PET. Although CBFi is useful for qualitative evaluation within a single imaging, use of CBFi for quantitative evaluation may be difficult.
RT and TTP were able to discriminate between impaired cerebral perfusion and normal cerebral perfusion with moderate accuracy and strongly correlated with MTT. Bland–Altman analysis showed a wide limit of agreement between RT and MTT (-4.6 s to 4.2 s), and between TTP and MTT (1.4–11.2 s). In addition, between TTP and MTT there was fixed bias and proportional bias. These findings suggest that RT and TTP are not necessarily consistent with MTT (because of random error) and that TTP may overestimate poor perfusion (because of proportional bias). However, even PET, which is the gold standard for quantitative cerebral perfusion analysis, potentially includes random error depending on the individual and the imaging conditions. In fact, the correlation between RT/TTP and MTT ratio was stronger than that between RT/TTP and MTT. These observations suggest that RT and TTP accurately reflect the true MTT. In fact, RT appeared to be the most reliable quantitative parameter among all the ICG-VG parameters examined in this study.
These correlations and degrees of confidence are interesting and noteworthy results to help validate microscope-integrated analysis of intraoperative ICG fluorescence angiography. This study may promote further clinical study on cerebral blood flow and metabolism using ICG-VA. In clinical practice, these time-dependent parameters from the ICG transit curve may help to make better intraoperative decision based on quantitative cerebral circulation time, such as the number of anastomoses, selection of recipient vessels, and so on. Then additional studies are required for understanding the threshold and for assessment how the decision-making improve clinical outcome. In this study, we also assessed whether these parameters predict postoperative HPS. As will be described in next paragraph, the result is interesting in cerebral blood flow and metabolism and be useful in clinical practice.
In a small number of cases, PET parameters were not significantly different when comparing patients with postoperative HPS and those without postoperative HPS. However, CBV/CBV ratio, MTT/MTT ratio, and OEF/OEF ratio were larger and CBF/CBF ratio was smaller in patients with postoperative HPS than in patients without postoperative HPS, all of which is consistent with findings from previous reports. In this case series, 3 of 10 patients developed postoperative HPS, which is a higher rate than that reported recently.[
The present findings should be viewed in the context of several methodological limitations. First, the number of patients in our study was small, and complete blinding was not done. Additional subjects are required to establish a solid conclusion. Second, the study and control subjects were not perfectly matched in terms of potentially confounding factors. Physiological parameters were also different when comparing the PET study and the intraoperative period in the study subjects. Third, patients with occlusive cerebrovascular disease did not reach stage II brain perfusion and were excluded as candidates for extracranial to intracranial bypass; therefore, these patients were not included in this analysis.
This is the significant study to demonstrate that cerebral circulation time can be quantitatively assessed using microscope-integrated analysis of intraoperative ICG fluorescence angiography. In addition, the conclusions of this study were strengthened by the fact that data assessment by PET (i.e. the gold standard of quantitative assessment for cerebral perfusion and metabolism) was used for comparison purposes.
This study showed that cerebral perfusion in the hemodynamically compromised brain was delayed and that some time-dependent parameters of the ICG transit curve (RT and TTP) assessed by microscope-integrated dynamic ICG fluorescence analysis during surgery quantitatively correlated with measures obtained by radio-nuclear examination. Further, analysis of ICG-VA parameters may provide useful information regarding the development of HPS after STA-MCA anastomosis in patients with severe hemodynamic compromise and may contribute to the reduction of serious and persistent complications due to postoperative hyperperfusion.
The authors thank Masanobu Ibaraki, Kyoko Nishino, Keita Narita, and Tomomi Ohmura for their invaluable support in the radionuclide study and acquisition of intraoperative data.
1. Belayev L, Zhao W, Busto R, Ginsberg MD. Transient middle cerebral artery occlusion by intraluminal suture: I. Three-dimensional autoradiographic image-analysis of local cerebral glucose metabolism-blood flow interrelationships during ischemia and early recirculation. J Cereb Blood Flow Metab. 1997. 17: 1266-80
2. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986. 1: 307-10
3. Bruneau M, Sauvageau E, Nakaji P, Vandesteene A, Lubicz B, Chang SW. Preliminary personal experiences with the application of near-infrared indocyanine green videoangiography in extracranial vertebral artery surgery. Neurosurgery. 2010. 66: 305-11
4. Czabanka M, Pena-Tapia P, Schubert GA, Woitzik J, Vajkoczy P, Schmiedek P. Characterization of cortical microvascularization in adult moyamoya disease. Stroke. 2008. 39: 1703-9
5. De Oliveira JG, Beck J, Seifert V, Teixeira MJ, Raabe A. Assessment of flow in perforating arteries during intracranial aneurysm surgery using intraoperative near-infrared indocyanine green videoangiography. Neurosurgery. 2007. 61: S63-72
6. Derdeyn CP, Grubb RL, Powers WJ. Cerebral hemodynamic impairment: Methods of measurement and association with stroke risk. Neurology. 1999. 53: 251-9
7. Derdeyn CP, Videen TO, Yundt KD, Fritsch SM, Carpenter DA, Grubb RL. Variability of cerebral blood volume and oxygen extraction: Stages of cerebral haemodynamic impairment revisited. Brain. 2002. 125: 595-607
8. Ferroli P, Acerbi F, Tringali G, Albanese E, Broggi M, Franzini A. Venous sacrifice in neurosurgery: New insights from venous indocyanine green videoangiography. J Neurosurg. 2011. 115: 18-23
9. Ferroli P, Tringali G, Albanese E, Broggi G. Developmental venous anomaly of petrous veins: Intraoperative findings and indocyanine green video angiographic study. Neurosurgery. 2008. 62: ONS418-21
10. Ginsberg MD. Adventures in the pathophysiology of brain ischemia: Penumbra, gene expression, neuroprotection: The 2002 Thomas Willis Lecture. Stroke. 2003. 34: 214-23
11. Hanel RA, Nakaji P, Spetzler RF. Use of microscope-integrated near-infrared indocyanine green videoangiography in the surgical treatment of spinal dural arteriovenous fistulae. Neurosurgery. 2010. 66: 978-84
12. Hatazawa J, Fujita H, Kanno I, Satoh T, Iida H, Miura S. Regional cerebral blood flow, blood volume, oxygen extraction fraction, and oxygen utilization rate in normal volunteers measured by the autoradiographic technique and the single breath inhalation method. Ann Nucl Med. 1995. 9: 15-21
13. Heros RC, Scott RM, Kistler JP, Ackerman RH, Conner ES. Temporary neurological deterioration after extracranial-intracranial bypass. Neurosurgery. 1984. 15: 178-85
14. Ibaraki M, Miura S, Shimosegawa E, Sugawara S, Mizuta T, Ishikawa A. Quantification of cerebral blood flow and oxygen metabolism with 3-dimensional PET and 15O: Validation by comparison with 2-dimensional PET. J Nucl Med. 2008. 49: 50-9
15. Imizu S, Kato Y, Sangli A, Oguri D, Sano H. Assessment of incomplete clipping of aneurysms intraoperatively by a near-infrared indocyanine green-video angiography (Niicg-Va) integrated microscope. Minim Invasive Neurosurg. 2008. 51: 199-203
16. Killory BD, Nakaji P, Gonzales LF, Ponce FA, Wait SD, Spetzler RF. Prospective evaluation of surgical microscope-integrated intraoperative near-infrared indocyanine green angiography during cerebral arteriovenous malformation surgery. Neurosurgery. 2009. 65: 456-62
17. Kuebler WM, Sckell A, Habler O, Kleen M, Kuhnle GE, Welte M. Noninvasive measurement of regional cerebral blood flow by near-infrared spectroscopy and indocyanine green. J Cereb Blood Flow Metab. 1998. 18: 445-56
18. Kuroda S, Kamiyama H, Abe H, Asaoka K, Mitsumori K. Temporary neurological deterioration caused by hyperperfusion after extracranial-intracranial bypass-case report and study of cerebral hemodynamics. Neurol Med Chir (Tokyo). 1994. 34: 15-9
19. Meier P, Zierler KL. On the theory of the indicator-dilution method for measurement of blood flow and volume. J Appl Physiol. 1954. 6: 731-44
20. Minoshima S, Berger KL, Lee KS, Mintun MA. An automated method for rotational correction and centering of three-dimensional functional brain images. J Nucl Med. 1992. 33: 1579-85
21. Minoshima S, Koeppe RA, Frey KA, Kuhl DE. Anatomic standardization: Linear scaling and nonlinear warping of functional brain images. J Nucl Med. 1994. 35: 1528-37
22. Ogasawara K, Ogawa A. JET study (Japanese EC-IC Bypass Trial). Nihon Rinsho. 2006. p. 524-7
23. Ogura T, Hida K, Masuzuka T, Saito H, Minoshima S, Nishikawa K. An automated ROI setting method using NEUROSTAT on cerebral blood flow SPECT images. Ann Nucl Med. 2009. 23: 33-41
24. Pena-Tapia PG, Kemmling A, Czabanka M, Vajkoczy P, Schmiedek P. Identification of the optimal cortical target point for extracranial-intracranial bypass surgery in patients with hemodynamic cerebrovascular insufficiency. J Neurosurg. 2008. 108: 655-61
25. Raabe A, Beck J, Gerlach R, Zimmermann M, Seifert V. Near-infrared indocyanine green video angiography: A new method for intraoperative assessment of vascular flow. Neurosurgery. 2003. 52: 132-9
26. Raabe A, Nakaji P, Beck J, Kim LJ, Hsu FP, Kamerman JD. Prospective evaluation of surgical microscope-integrated intraoperative near-infrared indocyanine green videoangiography during aneurysm surgery. J Neurosurg. 2005. 103: 982-9
27. Terborg C, Birkner T, Schack B, Weiller C, Rother J. Noninvasive monitoring of cerebral oxygenation during vasomotor reactivity tests by a new near-infrared spectroscopy device. Cerebrovasc Dis. 2003. 16: 36-41
28. Uchino H, Nakamura T, Houkin K, Murata J, Saito H, Kuroda S. Semiquantitative analysis of indocyanine green videoangiography for cortical perfusion assessment in superficial temporal artery to middle cerebral artery anastomosis. Acta Neurochir (Wien). 2013. 155: 599-605
29. Woitzik J, Horn P, Vajkoczy P, Schmiedek P. Intraoperative control of extracranial-intracranial bypass patency by near-infrared indocyanine green videoangiography. J Neurosurg. 2005. 102: 692-8
30. Woitzik J, Pena-Tapia PG, Schneider UC, Vajkoczy P, Thome C. Cortical perfusion measurement by indocyanine-green videoangiography in patients undergoing hemicraniectomy for malignant stroke. Stroke. 2006. 37: 1549-51
31. Yamaguchi K, Kawamata T, Kawashima A, Hori T, Okada Y. Incidence and predictive factors of cerebral hyperperfusion after extracranial-intracranial bypass for occlusive cerebrovascular diseases. Neurosurgery. 2010. 67: 1548-54