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Xiaoyao Fan, David W. Roberts, Songbai Ji, Alex Hartov and Keith D. Paulsen

OBJECT

Fiducial-based registration (FBR) is used widely for patient registration in image-guided neurosurgery. The authors of this study have developed an automatic fiducial-less registration (FLR) technique to find the patient-to-image transformation by directly registering 3D ultrasound (3DUS) with MR images without incorporating prior information. The purpose of the study was to evaluate the performance of the FLR technique when used prospectively in the operating room and to compare it with conventional FBR.

METHODS

In 32 surgical patients who underwent conventional FBR, preoperative T1-weighted MR images (pMR) with attached fiducial markers were acquired prior to surgery. After craniotomy but before dural opening, a set of 3DUS images of the brain volume was acquired. A 2-step registration process was executed immediately after image acquisition: 1) the cortical surfaces from pMR and 3DUS were segmented, and a multistart sum-of-squared-intensity-difference registration was executed to find an initial alignment between down-sampled binary pMR and 3DUS volumes; and 2) the alignment was further refined by a mutual information-based registration between full-resolution grayscale pMR and 3DUS images, and a patient-to-image transformation was subsequently extracted.

RESULTS

To assess the accuracy of the FLR technique, the following were quantified: 1) the fiducial distance error (FDE); and 2) the target registration error (TRE) at anterior commissure and posterior commissure locations; these were compared with conventional FBR. The results showed that although the average FDE (6.42 ± 2.05 mm) was higher than the fiducial registration error (FRE) from FBR (3.42 ± 1.37 mm), the overall TRE of FLR (2.51 ± 0.93 mm) was lower than that of FBR (5.48 ± 1.81 mm). The results agreed with the intent of the 2 registration techniques: FBR is designed to minimize the FRE, whereas FLR is designed to optimize feature alignment and hence minimize TRE. The overall computational cost of FLR was approximately 4–5 minutes and minimal user interaction was required.

CONCLUSIONS

Because the FLR method directly registers 3DUS with MR by matching internal image features, it proved to be more accurate than FBR in terms of TRE in the 32 patients evaluated in this study. The overall efficiency of FLR in terms of the time and personnel involved is also improved relative to FBR in the operating room, and the method does not require additional image scans immediately prior to surgery. The performance of FLR and these results suggest potential for broad clinical application.

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Alexander Hartov, Symma D. Eisner, David, W. Roberts, Keith D. Paulsen, Leah A. Platenik and Michael I. Miga

Image-guided neurosurgery that is directed by a preoperative imaging study, such as magnetic resonance (MR) imaging or computerized tomography (CT) scanning, can be very accurate provided no significant changes occur during surgery. A variety of factors known to affect brain tissue movement are not reflected in the preoperative images used for guidance. To update the information on which neuronavigation is based, the authors propose the use of three-dimensional (3-D) ultrasound images in conjunction with a finite-element computational model of the deformation of the brain. The 3-D ultrasound system will provide real-time information on the displacement of deep structures to guide the mathematical model. This paper has two goals: first, to present an outline of steps necessary to compute the location of a feature appearing in an ultrasound image in an arbitrary coordinate system; and second, to present an extensive evaluation of this system's accuracy. The authors have found that by using a stylus rigidly coupled to the 3-D tracker's sensor, they were able to locate a point with an overall error of 1.36 ± 1.67 mm (based on 39 points). When coupling the tracker to an ultrasound scanhead, they found that they could locate features appearing on ultrasound images with an error of 2.96 ± 1.85 mm (total 58 features). They also found that when registering a skull phantom to coordinates that were defined by MR imaging or CT scanning, they could do so with an error of 0.86 ± 0.61 mm (based on 20 coordinates). Based on their previous finding of brain shifts on the order of 1 cm during surgery, the accuracy of their system warrants its use in updating neuronavigation imaging data.

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Pablo A. Valdés, Valerie Jacobs, Brent T. Harris, Brian C. Wilson, Frederic Leblond, Keith D. Paulsen and David W. Roberts

OBJECT

Previous studies in high-grade gliomas (HGGs) have indicated that protoporphyrin IX (PpIX) accumulates in higher concentrations in tumor tissue, and, when used to guide surgery, it has enabled improved resection leading to increased progression-free survival. Despite the benefits of complete resection and the advances in fluorescence-guided surgery, few studies have investigated the use of PpIX in low-grade gliomas (LGGs). Here, the authors describe their initial experience with 5-aminolevulinic acid (ALA)-induced PpIX fluorescence in a series of patients with LGG.

METHODS

Twelve patients with presumed LGGs underwent resection of their tumors after receiving 20 mg/kg of ALA approximately 3 hours prior to surgery under an institutional review board-approved protocol. Intraoperative assessments of the resulting PpIX emissions using both qualitative, visible fluorescence and quantitative measurements of PpIX concentration were obtained from tissue locations that were subsequently biopsied and evaluated histopathologically. Mixed models for random effects and receiver operating characteristic curve analysis for diagnostic performance were performed on the fluorescence data relative to the gold-standard histopathology.

RESULTS

Five of the 12 LGGs (1 ganglioglioma, 1 oligoastrocytoma, 1 pleomorphic xanthoastrocytoma, 1 oligodendroglioma, and 1 ependymoma) demonstrated at least 1 instance of visible fluorescence during surgery. Visible fluorescence evaluated on a specimen-by-specimen basis yielded a diagnostic accuracy of 38.0% (cutoff threshold: visible fluorescence score ≥ 1, area under the curve = 0.514). Quantitative fluorescence yielded a diagnostic accuracy of 67% (for a cutoff threshold of the concentration of PpIX [CPpIX] > 0.0056 μg/ml, area under the curve = 0.66). The authors found that 45% (9/20) of nonvisibly fluorescent tumor specimens, which would have otherwise gone undetected, accumulated diagnostically significant levels of CPpIX that were detected quantitatively.

CONCLUSIONS

The authors’ initial experience with ALA-induced PpIX fluorescence in LGGs concurs with other literature reports that the resulting visual fluorescence has poor diagnostic accuracy. However, the authors also found that diagnostically significant levels of CPpIX do accumulate in LGGs, and the resulting fluorescence emissions are very often below the detection threshold of current visual fluorescence imaging methods. Indeed, at least in the authors’ initial experience reported here, if quantitative detection methods are deployed, the diagnostic performance of ALA-induced PpIX fluorescence in LGGs approaches the accuracy associated with visual fluorescence in HGGs.

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Xiaoyao Fan, David W. Roberts, Timothy J. Schaewe, Songbai Ji, Leslie H. Holton, David A. Simon and Keith D. Paulsen

OBJECTIVE

Preoperative magnetic resonance images (pMR) are typically coregistered to provide intraoperative navigation, the accuracy of which can be significantly compromised by brain deformation. In this study, the authors generated updated MR images (uMR) in the operating room (OR) to compensate for brain shift due to dural opening, and evaluated the accuracy and computational efficiency of the process.

METHODS

In 20 open cranial neurosurgical cases, a pair of intraoperative stereovision (iSV) images was acquired after dural opening to reconstruct a 3D profile of the exposed cortical surface. The iSV surface was registered with pMR to detect cortical displacements that were assimilated by a biomechanical model to estimate whole-brain nonrigid deformation and produce uMR in the OR. The uMR views were displayed on a commercial navigation system and compared side by side with the corresponding coregistered pMR. A tracked stylus was used to acquire coordinate locations of features on the cortical surface that served as independent positions for calculating target registration errors (TREs) for the coregistered uMR and pMR image volumes.

RESULTS

The uMR views were visually more accurate and well aligned with the iSV surface in terms of both geometry and texture compared with pMR where misalignment was evident. The average misfit between model estimates and measured displacements was 1.80 ± 0.35 mm, compared with the average initial misfit of 7.10 ± 2.78 mm between iSV and pMR, and the average TRE was 1.60 ± 0.43 mm across the 20 patients in the uMR image volume, compared with 7.31 ± 2.82 mm on average in the pMR cases. The iSV also proved to be accurate with an average error of 1.20 ± 0.37 mm. The overall computational time required to generate the uMR views was 7–8 minutes.

CONCLUSIONS

This study compensated for brain deformation caused by intraoperative dural opening using computational model–based assimilation of iSV cortical surface displacements. The uMR proved to be more accurate in terms of model-data misfit and TRE in the 20 patient cases evaluated relative to pMR. The computational time was acceptable (7–8 minutes) and the process caused minimal interruption of surgical workflow.

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Pablo A. Valdés, Frederic Leblond, Anthony Kim, Brent T. Harris, Brian C. Wilson, Xiaoyao Fan, Tor D. Tosteson, Alex Hartov, Songbai Ji, Kadir Erkmen, Nathan E. Simmons, Keith D. Paulsen and David W. Roberts

Object

Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative fluorescence of protoporphyrin IX (PpIX), synthesized endogenously following δ-aminolevulinic acid (ALA) administration, has been used for this purpose in high-grade glioma (HGG). The authors show that diagnostically significant but visually imperceptible concentrations of PpIX can be quantitatively measured in vivo and used to discriminate normal from neoplastic brain tissue across a range of tumor histologies.

Methods

The authors studied 14 patients with diagnoses of low-grade glioma (LGG), HGG, meningioma, and metastasis under an institutional review board–approved protocol for fluorescence-guided resection. The primary aim of the study was to compare the diagnostic capabilities of a highly sensitive, spectrally resolved quantitative fluorescence approach to conventional fluorescence imaging for detection of neoplastic tissue in vivo.

Results

A significant difference in the quantitative measurements of PpIX concentration occurred in all tumor groups compared with normal brain tissue. Receiver operating characteristic (ROC) curve analysis of PpIX concentration as a diagnostic variable for detection of neoplastic tissue yielded a classification efficiency of 87% (AUC = 0.95, specificity = 92%, sensitivity = 84%) compared with 66% (AUC = 0.73, specificity = 100%, sensitivity = 47%) for conventional fluorescence imaging (p < 0.0001). More than 81% (57 of 70) of the quantitative fluorescence measurements that were below the threshold of the surgeon's visual perception were classified correctly in an analysis of all tumors.

Conclusions

These findings are clinically profound because they demonstrate that ALA-induced PpIX is a targeting biomarker for a variety of intracranial tumors beyond HGGs. This study is the first to measure quantitative ALA-induced PpIX concentrations in vivo, and the results have broad implications for guidance during resection of intracranial tumors.

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Daniel Ikeda and E. Antonio Chiocca

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David W. Roberts, Jonathan D. Olson, Linton T. Evans, Kolbein K. Kolste, Stephen C. Kanick, Xiaoyao Fan, Jaime J. Bravo, Brian C. Wilson, Frederic Leblond, Mikael Marois and Keith D. Paulsen

OBJECTIVE

The objective of this study was to detect 5-aminolevulinic acid (ALA)-induced tumor fluorescence from glioma below the surface of the surgical field by using red-light illumination.

METHODS

To overcome the shallow tissue penetration of blue light, which maximally excites the ALA-induced fluorophore protoporphyrin IX (PpIX) but is also strongly absorbed by hemoglobin and oxyhemoglobin, a system was developed to illuminate the surgical field with red light (620–640 nm) matching a secondary, smaller absorption peak of PpIX and detecting the fluorescence emission through a 650-nm longpass filter. This wide-field spectroscopic imaging system was used in conjunction with conventional blue-light fluorescence for comparison in 29 patients undergoing craniotomy for resection of high-grade glioma, low-grade glioma, meningioma, or metastasis.

RESULTS

Although, as expected, red-light excitation is less sensitive to PpIX in exposed tumor, it did reveal tumor at a depth up to 5 mm below the resection bed in 22 of 24 patients who also exhibited PpIX fluorescence under blue-light excitation during the course of surgery.

CONCLUSIONS

Red-light excitation of tumor-associated PpIX fluorescence below the surface of the surgical field can be achieved intraoperatively and enables detection of subsurface tumor that is not visualized under conventional blue-light excitation.

Clinical trial registration no.: NCT02191488 (clinicaltrials.gov)

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David W. Roberts, Pablo A. Valdés, Brent T. Harris, Kathryn M. Fontaine, Alexander Hartov, Xiaoyao Fan, Songbai Ji, S. Scott Lollis, Brian W. Pogue, Frederic Leblond, Tor D. Tosteson, Brian C. Wilson and Keith D. Paulsen

Object

The aim of this study was to investigate the relationships between intraoperative fluorescence, features on MR imaging, and neuropathological parameters in 11 cases of newly diagnosed glioblastoma multiforme (GBM) treated using protoporphyrin IX (PpIX) fluorescence-guided resection.

Methods

In 11 patients with a newly diagnosed GBM, δ-aminolevulinic acid (ALA) was administered to enhance endogenous synthesis of the fluorophore PpIX. The patients then underwent fluorescence-guided resection, coregistered with conventional neuronavigational image guidance. Biopsy specimens were collected at different times during surgery and assigned a fluorescence level of 0–3 (0, no fluorescence; 1, low fluorescence; 2, moderate fluorescence; or 3, high fluorescence). Contrast enhancement on MR imaging was quantified using two image metrics: 1) Gd-enhanced signal intensity (GdE) on T1-weighted subtraction MR image volumes, and 2) normalized contrast ratios (nCRs) in T1-weighted, postGd-injection MR image volumes for each biopsy specimen, using the biopsy-specific image-space coordinate transformation provided by the navigation system. Subsequently, each GdE and nCR value was grouped into one of two fluorescence categories, defined by its corresponding biopsy specimen fluorescence assessment as negative fluorescence (fluorescence level 0) or positive fluorescence (fluorescence level 1, 2, or 3). A single neuropathologist analyzed the H & E–stained tissue slides of each biopsy specimen and measured three neuropathological parameters: 1) histopathological score (0–IV); 2) tumor burden score (0–III); and 3) necrotic burden score (0–III).

Results

Mixed-model analyses with random effects for individuals show a highly statistically significant difference between fluorescing and nonfluorescing tissue in GdE (mean difference 8.33, p = 0.018) and nCRs (mean difference 5.15, p < 0.001). An analysis of association demonstrated a significant relationship between the levels of intraoperative fluorescence and histopathological score (χ2 = 58.8, p < 0.001), between fluorescence levels and tumor burden (χ2 = 42.7, p < 0.001), and between fluorescence levels and necrotic burden (χ2 = 30.9, p < 0.001). The corresponding Spearman rank correlation coefficients were 0.51 (p < 0.001) for fluorescence and histopathological score, and 0.49 (p < 0.001) for fluorescence and tumor burden, suggesting a strongly positive relationship for each of these variables.

Conclusions

These results demonstrate a significant relationship between contrast enhancement on preoperative MR imaging and observable intraoperative PpIX fluorescence. The finding that preoperative MR image signatures are predictive of intraoperative PpIX fluorescence is of practical importance for identifying candidates for the procedure. Furthermore, this study provides evidence that a strong relationship exists between tumor aggressiveness and the degree of tissue fluorescence that is observable intraoperatively, and that observable fluorescence has an excellent positive predictive value but a low negative predictive value.

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Kimon Bekelis, Pablo A. Valdés, Kadir Erkmen, Frederic Leblond, Anthony Kim, Brian C. Wilson, Brent T. Harris, Keith D. Paulsen and David W. Roberts

Object

Complete resection of skull base meningiomas provides patients with the best chance for a cure; however, surgery is frequently difficult given the proximity of lesions to vital structures, such as cranial nerves, major vessels, and venous sinuses. Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative assessment of protoporphyrin IX (PpIX) fluorescence following the exogenous administration of 5-aminolevulinic acid (ALA) has demonstrated utility in malignant glioma resection but limited use in meningiomas. Here the authors demonstrate the use of ALA-induced PpIX fluorescence guidance in resecting a skull base meningioma and elaborate on the advantages and disadvantages provided by both quantitative and qualitative fluorescence methodologies in skull base meningioma resection.

Methods

A 52-year-old patient with a sphenoid wing WHO Grade I meningioma underwent tumor resection as part of an institutional review board–approved prospective study of fluorescence-guided resection. A surgical microscope modified for fluorescence imaging was used for the qualitative assessment of visible fluorescence, and an intraoperative probe for in situ fluorescence detection was utilized for quantitative measurements of PpIX. The authors assessed the detection capabilities of both the qualitative and quantitative fluorescence approaches.

Results

The patient harboring a sphenoid wing meningioma with intraorbital extension underwent radical resection of the tumor with both visibly and nonvisibly fluorescent regions. The patient underwent a complete resection without any complications. Some areas of the tumor demonstrated visible fluorescence. The quantitative probe detected neoplastic tissue better than the qualitative modified surgical microscope. The intraoperative probe was particularly useful in areas that did not reveal visible fluorescence, and tissue from these areas was confirmed as tumor following histopathological analysis.

Conclusions

Fluorescence-guided resection may be a useful adjunct in the resection of skull base meningiomas. The use of a quantitative intraoperative probe to detect PpIX concentration allows more accurate determination of neoplastic tissue in meningiomas than visible fluorescence and is readily applicable in areas, such as the skull base, where complete resection is critical but difficult because of the vital structures surrounding the pathology.