A new Gamma Knife radiosurgery paradigm: tomosurgery.

This study proposes and simulates an inverse treatment planning and a continuous dose delivery approach for the Leksell Gamma Knife (LGK, Elekta, Stockholm, Sweden) which we refer to as "Tomosurgery." Tomosurgery uses an isocenter that moves within the irradiation field to continuously deliver the prescribed radiation dose in a raster-scanning format, slice by slice, within an intracranial lesion. Our Tomosurgery automated (inverse) treatment planning algorithm utilizes a two-stage optimization strategy. The first stage reduces the current three-dimensional (3D) treatment planning problem to a series of more easily solved 2D treatment planning subproblems. In the second stage, those 2D treatment plans are assembled to obtain a final 3D treatment plan for the entire lesion. We created Tomosurgery treatment plans for 11 patients who had already received manually-generated LGK treatment plans to treat brain tumors. For the seven cases without critical structures (CS), the Tomosurgery treatment plans showed borderline to significant improvement in within-tumor dose standard deviation (STD) (p <0.058, or p <0.011 excluding case 2) and conformality (p < 0.042), respectively. In three of the four cases that presented CS, the Tomosurgery treatment plans showed no statistically significant improvements in dose conformality (p <0.184), and borderline significance in improving within-tumor dose homogeneity (p <0.054); CS damage measured by V20 or V30 (i.e., irradiated CS volume that receives > or =20% or > or =30% of the maximum dose) showed no significant improvement in the Tomosurgery treatment plans (p<0.345 and p <0.423, respectively). However, the overall CS dose volume histograms were improved in the Tomosurgery treatment plans. In addition, the LGK Tomosurgery inverse treatment planning required less time than standard of care, forward (manual) LGK treatment planning (i.e., 5-35 min vs 1-3 h) for all 11 cases. We expect that LGK Tomosurgery will speed treatment planning and improve treatment quality, especially for large and/or geometrically complex lesions. However, using only 4 mm collimators could greatly increase treatment plan delivery time for a large brain lesion. This issue is subject to further investigation.

Quality of coverage: conformity measures for stereotactic radiosurgery.

In radiosurgery, conformity indices are often used to compare competing plans, evaluate treatment techniques, and assess clinical complications. Several different indices have been reported to measure the conformity of the prescription isodose to the target volume. The PITV recommended in the Radiation Therapy Oncology Group (RTOG) radiosurgery guidelines, defined as the ratio of the prescription isodose volume (PI) over the target volume (TV), is probably the most frequently quoted. However, these currently used conformity indices depend on target size and shape complexity. The objectives of this study are to systematically investigate the influence of target size and shape complexity on existing conformity indices, and to propose a different conformity index-the conformity distance index (CDI). The CDI is defined as the average distance between the target and the prescription isodose line. This study examines five case groups with volumes of 0.3, 1.0, 3.0, 10.0, and 30.0 cm(3). Each case group includes four simulated shapes: a sphere, a moderate ellipsoid, an extreme ellipsoid, and a concave "C" shape. Prescription dose coverages are generated for three simplified clinical scenarios, i.e., the PI completely covers the TV with 1 and 2 mm margins, and the PI over-covers one half of the TV with a 1 mm margin and under-covers the other half with a 1 mm margin. Existing conformity indices and the CDI are calculated for these five case groups as well as seven clinical cases. When these values are compared, the RTOG PITV conformity index and other similar conformity measures have much higher values than the CDI for smaller and more complex shapes. With the same quality of prescription dose coverage, the CDI yields a consistent conformity measure. For the seven clinical cases, we also find that the same PITV values can be associated with very different conformity qualities while the CDI predicts the conformity quality accurately. In summary, the proposed CDI provides more consistent and accurate conformity measurements for all target sizes and shapes studied, and therefore will be a more useful conformity index for irregularly shaped targets.

Low-dose stereotactic radiosurgery is inadequate for medically intractable mesial temporal lobe epilepsy: a case report.

The successful surgical treatment of medically refractory epilepsy is based on one of three different principles: (1) elimination of the epileptic focus, (2) interruption of the pathways of neural propagation, and (3) increasing the seizure threshold through cerebral lesions or electrical stimulation. Temporal lobe epilepsy, being the most common focal epilepsy, may ultimately require temporal lobectomy. This is a case report of a 36-year-old male with drug-resistant right mesial temporal lobe epilepsy who failed to obtain seizure control after stereotactic radiosurgery to the seizure focus. Complex-partial seizures occurred 6-7 times monthly, and consisted of a loss of awareness followed by involuntary movements of the right arm. EEG/CC TV monitoring indicated a right mesial temporal lobe focus, which was corroborated by decreased uptake in the right temporal lobe by FDG-PET and by MRI findings of right hippocampal sclerosis. Stereotactic radiosurgery was performed with a 4MV linac, utilizing three isocenters with collimator sizes of 10, 10, and 7 mm respectively. A dose of 1500 cGy (max dose 2535 cGy) was delivered in a single fraction to the patient's right amygdala and hippocampus. There were no acute complications. Following radiosurgery the patient's seizures were improved in both frequency and intensity for approximately 3 months. Antiepileptic medications were continued. Thereafter, seizures increased in both frequency and intensity, occurring 10-20 times monthly. At 1 year post radiosurgery, standard right temporal lobectomy including amygdalohippocampectomy was performed with subsequent resolution of complex-partial seizures. Histopathology of the resected temporal lobe revealed hippocampal cell loss and fibrillary astrocytosis, consistent with hippocampal sclerosis. No radiation-induced histopathologic changes were seen. We conclude that low-dose radiosurgery doses temporarily changed the intensity and character of seizure activity, but actually increased seizure activity long-term. If radiosurgery is to be an effective alternative to temporal lobectomy for medically intractable temporal lobe epilepsy, higher radiosurgery doses will be required. The toxicity and efficacy of higher-dose radiosurgery is currently under investigation.

Fiducial point placement and the accuracy of point-based, rigid body registration.

OBJECTIVE: To demonstrate that the shape of the configuration of fiducial points is an important factor governing target registration error (TRE) in point-based, rigid registration. METHODS: We consider two clinical situations: cranial neurosurgery and pedicle screw placement. For cranial neurosurgery, we apply theoretical results concerning TRE prediction, which we have previously derived and validated, to three hypothetical fiducial marker configurations. We illustrate the profile of expected TRE for each configuration. For pedicle screw placement, we apply the same theory to a common anatomic landmark configuration (tips of spinous and transverse processes) used for pedicle screw placement, and we estimate the error rate expected in placement of the screw. RESULTS: In the cranial neurosurgery example, we demonstrate that relatively small values of TRE may be achieved by using widely spread fiducial markers and/or placing the centroid of the markers near the target. We also demonstrate that near-collinear marker configurations far from the target may result in large TRE values. In the pedicle screw placement example, we demonstrate that the screw must be approximately 4 mm narrower than the pedicle in which it is implanted to minimize the chance of pedicle violation during placement. CONCLUSION: The placement of fiducial points is an important factor in minimizing the error rate for point-based, rigid registration. By using as many points as possible, avoiding near-collinear configurations, and ensuring that the centroid of the fiducial points is as near as possible to the target, TREs can be minimized.

Retrospective intermodality registration techniques for images of the head: surface-based versus volume-based.

The primary objective of this study is to perform a blinded evaluation of two groups of retrospective image registration techniques, using as a gold standard a prospective marker-based registration method, and to compare the performance of one group with the other. These techniques have already been evaluated individually [27]. In this paper, however, we find that by grouping the techniques as volume based or surface based, we can make some interesting conclusions which were not visible in the earlier study. In order to ensure blindness, all retrospective registrations were performed by participants who had no knowledge of the gold-standard results until after their results had been submitted. Image volumes of three modalities: X-ray computed tomography (CT), magnetic resonance (MR), and positron emission tomography (PET) were obtained from patients undergoing neurosurgery at Vanderbilt University Medical Center on whom bone-implanted fiducial markers were mounted. These volumes had all traces of the markers removed and were provided via the Internet to project collaborators outside Vanderbilt, who then performed retrospective registrations on the volumes, calculating transformations from CT to MR and/or from PET to MR. These investigators communicated their transformations, again via the Internet, to Vanderbilt, where the accuracy of each registration was evaluated. In this evaluation, the accuracy is measured at multiple volumes of interest (VOI's). Our results indicate that the volume-based techniques in this study tended to give substantially more accurate and reliable results than the surface-based ones for the CT-to-MR registration tasks, and slightly more accurate results for the PET-to-MR tasks. Analysis of these results revealed that the rotational component of error was more pronounced for the surface-based group. It was also apparent that all of the registration techniques we examined have the potential to produce satisfactory results much of the time, but that visual inspection is necessary to guard against large errors.

Classification of tremor and update on treatment.

Tremor is a symptom of many disorders, including Parkinson's disease, essential tremor, orthostatic tremor, cerebellar disease, peripheral neuropathy and alcohol withdrawal. Tremors may be classified as postural, rest or action tremors. Symptomatic treatment is tailored to the tremor type. Combination therapy with carbidopa and levodopa remains the first-line approach for parkinsonian tremor. Essential tremor may be amenable to propranolol or primidone. Propranolol may be useful in treating alcohol withdrawal tremor, and isoniazid may control the cerebellar tremor associated with multiple sclerosis. Clonazepam may relieve orthostatic tremor. Other agents are also available for the treatment of tremor. When medical therapy fails to control the tremor, surgical options such as thalamotomy, pallidotomy and thalamic stimulation should be considered in severe cases. Thalamic stimulation, the most recent of these surgical approaches, offers the advantage over ablative procedures of alleviating tremor without the creation of a permanent lesion.

Measurement of intraoperative brain surface deformation under a craniotomy.

OBJECTIVE: Several causes of spatial inaccuracies in image-guided surgery have been carefully studied and documented for several systems. These include error in identifying the external features used for registration, geometrical distortion in the preoperative images, and error in tracking the surgical instruments. Another potentially important source of error is brain deformation between the time of imaging and the time of surgery or during surgery. In this study, we measured the deformation of the dura and brain surfaces between the time of imaging and the start of surgical resection for 21 patients. METHODS: All patients underwent intraoperative functional mapping, allowing us to measure brain surface motion at two times that were separated by nearly an hour after opening the dura but before performing resection. The positions of the dura and brain surfaces were recorded and transformed to the coordinate space of a preoperative magnetic resonance image, using the Acustar surgical navigation system (manufactured by Johnson & Johnson Professional, Inc., Randolph, MA) (the Acustar trademark and associated intellectual property rights are now owned by Picker International, Highland Heights, OH). This system performs image registration with bone-implanted markers and tracks a surgical probe by optical triangulation. RESULTS: The mean displacements of the dura and the first and second brain surfaces were 1.2, 4.4, and 5.6 mm, respectively, with corresponding mean volume reductions under the craniotomy of 6, 22, and 29 cc. The maximum displacement was greater than 10 mm in approximately one-third of the patients for the first brain surface measurement and one-half of the patients for the second. In all cases, the direction of brain shift corresponded to a "sinking" of the brain intraoperatively, compared with its preoperative position. Analysis of the measurement error revealed that its magnitude was approximately 1 to 2 mm. We observed two different patterns of the brain surface deformation field, depending on the inclination of the craniotomy with respect to gravity. Separate measurements of brain deformation within the closed cranium caused by changes in patient head orientation with respect to gravity suggested that less than 1 mm of the brain shift recorded intraoperatively could have resulted from the change in patient orientation between the time of imaging and the time of surgery. CONCLUSION: These results suggest that intraoperative brain deformation is an important source of error that needs to be considered when using surgical navigation systems.

Sublabial, transseptal, transsphenoidal approach to the pituitary region guided by the ACUSTAR I system.

OBJECTIVE: Advances in imaging resolution have resulted in superior visualization of intracranial anatomy. Because of the inherent complexity of the surgical exposure of these lesions, intraoperative localizing techniques are required. Currently, C-arm fluoroscopy provides only two-dimensional localization for these anatomic structures. The recently described ACUSTAR I system, developed in conjunction with Codman and Shurtleff, Inc. (Randolph, Mass.), is an interactive, image-guided device that allows three-dimensional localization with a degree of accuracy previously unattainable. We assessed the clinical utility of the ACUSTAR I system for intraoperative spatial confirmation during transsphenoidal approaches to pituitary lesions. METHODS: Eight patients underwent transsphenoidal approaches to pituitary lesions with the assistance of the ACUSTAR I system. The spatial relationships were clinically judged intraoperatively by the surgeon and by use of traditional C-arm fluoroscopy and then were compared with the ACUSTAR I system results. RESULTS: In all eight patients, the ACUSTAR I system correctly displayed the surgical orientation and provided localization to within less than 1 mm. In two patients, this facilitated the redirection of an errant approach. No complications were associated with the use of this image-guided device. CONCLUSIONS: The ACUSTAR I system is useful in displaying accurate, three-dimensional anatomic relationships during transsphenoidal approaches to pituitary lesions. This system provides critical information intraoperatively to redirect errant approaches and prevent significant morbidity.

Registration of head CT images to physical space using a weighted combination of points and surfaces.

Most previously reported registration techniques that align three-dimensional image volumes by matching geometrical features such as points or surfaces use a single type of feature. We recently reported a hybrid registration technique that uses a weighted combination of multiple geometrical feature shapes. In this study we use the weighted geometrical feature (WGF) algorithm to register computed tomography (CT) images of the head to physical space using the skin surface only, the bone surface only, and various weighted combinations of these surfaces and one fiducial point (centroid of a bone-implanted marker). We use data acquired from 12 patients that underwent temporal lobe craniotomies for the resection of cerebral lesions. We evaluate and compare the accuracy of the registrations obtained using these various approaches by using as a reference gold standard the registration obtained using three bone-implanted markers. The results demonstrate that a combination of geometrical features can improve the accuracy of CT-to-physical space registration. Point-based registration requires a minimum of three noncolinear points. The position of a bone-implanted marker can be determined much more accurately than that of a skin-affixed marker or an anatomic landmark. A major disadvantage of using bone-implanted markers is that an invasive procedure is required to implant each marker. By combining surface information, the WGF algorithm allows registration to be performed using only one or two such markers. One important finding is that the use of a single very accurate point (a bone-implanted marker) allows very accurate surface-based registration to be achieved using very few surface points. Finally, the WGF algorithm, which not only allows the combination of multiple types of geometrical information but also handles point-based and surface-based registration as degenerate cases, could form the foundation of a "flexible" surgical navigation system that allows the surgeon to use what he considers the method most appropriate for an individual clinical situation.

Registration of head volume images using implantable fiducial markers.

In this paper, we describe an extrinsic-point-based, interactive image-guided neurosurgical system designed at Vanderbilt University, Nashville, TN, as part of a collaborative effort among the Departments of Neurological Surgery, Computer Science, and Biomedical Engineering. Multimodal image-to-image (II) and image-to-physical (IP) registration is accomplished using implantable markers. Physical space tracking is accomplished with optical triangulation. We investigate the theoretical accuracy of point-based registration using numerical simulations, the experimental accuracy of our system using data obtained with a phantom, and the clinical accuracy of our system using data acquired in a prospective clinical trial by six neurosurgeons at four medical centers from 158 patients undergoing craniotomies to resect cerebral lesions. We can determine the position of our markers with an error of approximately 0.4 mm in X-ray computed tomography (CT) and magnetic resonance (MR) images and 0.3 mm in physical space. The theoretical registration error using four such markers distributed around the head in a configuration that is clinically practical is approximately 0.5-0.6 mm. The mean CT-physical registration error for the phantom experiments is 0.5 mm and for the clinical data obtained with rigid head fixation during scanning is 0.7 mm. The mean CT-MR registration error for the clinical data obtained without rigid head fixation during scanning is 1.4 mm, which is the highest mean error that we observed. These theoretical and experimental findings indicate that this system is an accurate navigational aid that can provide real-time feedback to the surgeon about anatomical structures encountered in the surgical field.

Comparison and evaluation of retrospective intermodality brain image registration techniques.

PURPOSE: The primary objective of this study is to perform a blinded evaluation of a group of retrospective image registration techniques using as a gold standard a prospective, marker-based registration method. To ensure blindedness, all retrospective registrations were performed by participants who had no knowledge of the gold standard results until after their results had been submitted. A secondary goal of the project is to evaluate the importance of correcting geometrical distortion in MR images by comparing the retrospective registration error in the rectified images, i.e., those that have had the distortion correction applied, with that of the same images before rectification. METHOD: Image volumes of three modalities (CT, MR, and PET) were obtained from patients undergoing neurosurgery at Vanderbilt University Medical Center on whom bone-implanted fiducial markers were mounted. These volumes had all traces of the markers removed and were provided via the Internet to project collaborators outside Vanderbilt, who then performed retrospective registrations on the volumes, calculating transformations from CT to MR and/ or from PET to MR. These investigators communicated their transformations again via the Internet to Vanderbilt, where the accuracy of each registration was evaluated. In this evaluation, the accuracy is measured at multiple volumes of interest (VOIs), i.e., areas in the brain that would commonly be areas of neurological interest. A VOI is defined in the MR image and its centroid c is determined. Then, the prospective registration is used to obtain the corresponding point c' in CT or PET. To this point, the retrospective registration is then applied, producing c" in MR. Statistics are gathered on the target registration error (TRE), which is the distance between the original point c and its corresponding point c". RESULTS: This article presents statistics on the TRE calculated for each registration technique in this study and provides a brief description of each technique and an estimate of both preparation and execution time needed to perform the registration. CONCLUSION: Our results indicate that retrospective techniques have the potential to produce satisfactory results much of the time, but that visual inspection is necessary to guard against large errors.

Transforming growth factor beta as a potential tumor progression factor among hyperdiploid glioblastoma cultures: evidence for the role of platelet-derived growth factor.

Among early-passage, near-diploid gliomas in vitro, transforming growth factor type beta (TGF beta) has been previously shown to be an autocrine growth inhibitor. In contrast, hyperdiploid (> or = 57 chromosomes/metaphase) glioblastoma multiforme (HD-GM) cultures were autocrinely stimulated by the TGF beta. The mechanism of this 'conversion' from autocrine inhibitor to mitogen is not understood; previous studies have suggested that platelet-derived growth factor (PDGF) might be modulated by TGF beta. The similar expression of TGF beta types 1-3, PDGF-AA; -BB, as well as the PDGF receptor alpha and beta subunits (a/beta PDGFR) between biopsies of the HD-GM and near-diploid, TGF beta-inhibited glioblastomas (GM) by immunohistochemistry did not explain the discrepancy in their regulatory responses. Flow cytometry demonstrated that TGF beta's mitogenic effect was selective for the aneuploid subpopulations of two of three selected HD-GM cultures, while the diploid cells were inhibited. Among the HD-GM, TGF beta 1 induced the RNA of PDGF-A, c-sis and TGF beta 1. The amount of PDGF-AA secreted following TGF beta treatment was sufficient to stimulate the proliferation of a HD-GM culture. Antibodies against PDGF-AA, -BB, -AB, alpha PDGFR and/or beta PDGFR subunits effectively neutralized TGF beta's induction of DNA synthesis among the HD-GM cell lines, indicating that PDGF served as the principal mediator of TGF beta's growth stimulatory effect. By comparison, TGF beta induced only the RNA of PDGF-A and TGF beta 1 among the near-diploid GM, c-sis was not expressed at all. However, the amount of PDGF-A which was secreted in response to TGF beta 1 was insufficient to prevent TGF beta's arrest of the near-diploid cultures in G1 phase. Thus, the emergence of hyperdiploidy was associated with qualitative and quantitative differences in TGF beta's modulation of PDGF-A and c-sis, which provided a mechanism by which the aneuploid glioma cells might achieve 'clonal dominance'. We hypothesize that TGF beta may serve as an autocrine promoter of GM progression by providing a selective advantage to the hyperdiploid subpopulation through the loss of a tumor suppressor gene which mediates TGF beta's inhibitory effect.

Effect of geometrical distortion correction in MR on image registration accuracy.

In this article we investigate the effect of geometrical distortion correction in MR images on the accuracy of the registration of X-ray CT and MR head images for both a fiducial marker (extrinsic point) method and a surface-matching technique. We use CT and T2-weighted MR image volumes acquired from seven patients who underwent craniotomies in a stereotactic neurosurgical clinical trial. Each patient had four external markers attached to transcutaneous posts screwed into the outer table of the skull. The MR images are corrected for static field inhomogeneity by using an image rectification technique and corrected for scale distortion (gradient magnitude uncertainty) by using an attached stereotactic frame as an object of known shape and size. We define target registration error (TRE) as the distance between corresponding marker positions after registration and transformation. The accuracy of the fiducial marker method is determined by using each combination of three markers to estimate the transformation and the remaining marker to calculate registration error. Surface-based registration is accomplished by fitting MR contours corresponding to the CSF-dura interface to CT contours derived from the inner surface of the skull. The mean point-based TRE using three noncollinear fiducials improved 34%-from 1.15 to 0.76 mm-after correcting for both static field inhomogeneity and scale distortion. The mean surface-based TRE improved 46%-from 2.20 to 1.19 mm. Correction of geometrical distortion in MR images can significantly improve the accuracy of point-based and surface-based registration of CT and MR head images. Distortion correction can be important in clinical situations such as stereotactic and functional neurosurgery where 1 to 2 mm accuracy is required.

An automatic technique for finding and localizing externally attached markers in CT and MR volume images of the head.

An image processing technique is presented for finding and localizing the centroids of cylindrical markers externally attached to the human head in computed tomography (CT) and magnetic resonance (MR) image volumes. The centroids can be used as control points for image registration. The technique, which is fast, automatic, and knowledge-based, has two major steps. First, it searches the entire image volume to find one voxel inside each marker-like object. We call this voxel a "candidate" voxel, and we call the object a candidate marker. Second, it classifies the voxels in a region surrounding the candidate voxel as marker or nonmarker voxels using knowledge-based rules and calculates an intensity-weighted centroid for each true marker. We call this final centroid the "fiducial" point of the marker. The technique was developed on 42 scans of six patients-one CT and six MR scans per patient. There are four markers attached to each patient for a total of 168 marker images. For the CT images the false marker rate was zero. For MR the false marker rate was 1.4% (Two out of 144 markers). To evaluate the accuracy of the fiducial points, CT-MR registration was performed after correcting the MR images for geometrical distortion. The fiducial registration accuracy averaged 0.4 mm and was better than 0.6 mm for each of the eighteen image pairs.

A technique for interactive image-guided neurosurgical intervention in primary brain tumors.

Interactive image-guided neurosurgical techniques allow safer and more complete cytoreduction of gliomas. This is most significant for low-grade tumors, whose configurations and margins are perhaps better appreciated by reference to registered MR images rather than by reliance on direct visualization using microscopic illumination. Spatially registered electro-physiologic recordings of intraoperative cortical stimulation to map language and motor function can increase the margin of safety for performing radical resections. By individualizing approaches and optimizing results, these technologies promise a new degree of standardization of outcome after resective surgery for all glial tumors.

A universal method for geometric correction of magnetic resonance images for stereotactic neurosurgery.

Accurate stereotactic navigation depends strongly upon the spatial fidelity of the image used for registration. Clinically significant levels of geometric distortion are present in standard MR images, limiting their utility. A technique for correction of all geometric distortions in spine echo MR images was assessed in a prospective clinical trial of 19 stereotactic craniotomies. The Euclidean error in target registration between CT and MR was significantly reduced, from 3.833 +/- 0.992 to 1.986 +/- 0.605 mm. The results of this clinical trial support the incorporation of this MR image rectification protocol into standard clinical practice.

Registration of 3-D images using weighted geometrical features.

The authors present a weighted geometrical feature (WGF) registration algorithm. Its efficacy is demonstrated by combining points and a surface. The technique is an extension of Besl and McKay's (1992) iterative closest point (ICP) algorithm. The authors use the WGF algorithm to register X-ray computed tomography (CT) and T2-weighted magnetic resonance (MR) volume head images acquired from eleven patients that underwent craniotomies in a neurosurgical clinical trial. Each patient had five external markers attached to transcutaneous posts screwed into the outer table of the skull. The authors define registration error as the distance between positions of corresponding markers that are not used for registration. The CT and MR images are registered using fiducial paints (marker positions) only, a surface only, and various weighted combinations of points and a surface. The CT surface is derived from contours corresponding to the inner surface of the skull. The MR surface is derived from contours corresponding to the cerebrospinal fluid (CSF)-dura interface. Registration using points and a surface is found to be significantly more accurate then registration using only points or a surface.