Neurosurgery for Brain Tumors: Update on Recent Technical Advances
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- Sherman, J.H., Hoes, K., Marcus, J. et al. Curr Neurol Neurosci Rep (2011) 11: 313. doi:10.1007/s11910-011-0188-9
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Advances in diagnostic imaging modalities and improved access to specialty care have led directly to an increased diagnosis of both metastatic and primary brain tumors. As technology has improved, so has the ability to treat this larger patient population. Diffusion tensor imaging (DTI) has recently shown the potential to aid in histologic diagnosis as well as to identify local brain invasion outside of that readily identifiable by conventional MRI. Similar to DTI, functional MRI provides a noninvasive means of delineating tumor margin from eloquent cortex and aids in preoperative surgical planning. As the literature shows increasing support for the advantages of extensive resection in glioma patients, modalities that aid in this regard are displaying increased importance. Surgeons have recently demonstrated the utility of intraoperative MRI in increasing extent of resection in both low- and high-grade glioma patients. Intraoperative tumor fluorescence provided by the chemical compound 5-aminolevulinic acid assists surgeons in identifying the true tumor margin during resection of glial neoplasms consequently increasing extent of resection. Finally, laser interstitial thermal therapy is an emerging treatment modality allowing surgeons to treat small intracranial lesions with potentially decreased morbidity via this minimally invasive approach. The following review analyzes the recent literature in an effort to describe how these modalities can and should be used in the treatment of patients with intracranial pathology.
KeywordsIntraoperative MRIDiffusion tensor imagingFunctional MRI5-Aminolevulinic acidLaser interstitial thermal therapy
The diagnosis of both primary and metastatic brain tumors has risen over the past 20 to 30 years such that the rate for the former is 6.6 per 100,000 person-years whereas the rate for the latter ranges between 8.3 and 11 per 100,000 person-years [1, 2]. Improved diagnostic modalities and improved access to neurosurgical services are thought have a direct correlation with this increase in tumor diagnosis [3–6]. As these diagnostic techniques have developed, technologic advances have significantly affected the outcome for brain tumor patients in terms of the surgeon’s ability to safely resect lesions in or near eloquent cortex.
Proper characterization of these tumors is critical to defining the appropriate therapeutic management strategy for a particular patient. Although radiographic technology has progressed, true characterization of glial neoplasms hinges upon attainment of specimen. This may consist of either biopsy for confirmation of diagnosis or cytoreductive surgery followed by varying combinations of chemotherapy and/or radiotherapy [7••]. The current paradigm in low-grade glioma (LGG) management is evolving. Although many neurosurgeons may still opt to monitor LGG patients rather than intervene directly with surgical strategies, this “wait-and-see” approach is moving toward one favoring early surgical intervention. . Conversely, where a high-grade glioma (HGG) diagnosis is suspected at initial patient presentation, the primary tenet in management is early surgical intervention for pathologic diagnosis and maximal safe tumor debulking . In addition, patients with brain metastasis causing mass effect, significant peritumoral edema, or isolated intracranial lesions with limited extracranial disease can benefit from upfront surgical resection .
Realizing the inherent limitations in routine preoperative MRI, investigators have evaluated new methodology to minimize the surgical risks to patients. In particular, radiographic innovations such as functional MRI (fMRI), diffusion tensor imaging (DTI), and intraoperative MRI (iMRI) have been studied for their utility in this regard. Moreover, novel surgical advances such as intraoperative tumor fluorescence-guided resection using 5-aminolevulinic acid (5-ALA) as well as laser interstitial thermal therapy (LITT) have become areas of increased interest. In this review we aim to critically analyze the literature to delineate the emerging trends, successes, and shortcomings of these tools for surgical resection of intracranial neoplasms in adult patients with particular emphasis on data published within the past few years.
Preoperative Planning Tools
Diffusion Tensor Imaging
DTI is a form of fMRI used to delineate white matter anatomy. DTI is based on the principle that water preferentially diffuses along the long axis of white matter tracts . There are two values used to quantify water diffusion: apparent diffusion coefficient (ADC), which measures the degree of diffusion, and fractional anisotropy (FA), which measures the directionality. Using these values, water diffusion can be processed via algorithms to reconstruct three-dimensional constructs representing subcortical fiber tracts, a process called tractography [11–13]. Thus, distortions of white matter architecture secondary to a tumor or the edema surrounding a tumor can be mapped in a meaningful way to provide guidance during surgical resection.
Beyond measuring distortions from mass effect, abnormal water diffusion in parenchyma may indicate the presence of tumor and other pathology. Investigators have studied the reliability of DTI for predicting tumor behavior with respect to glioma cell invasion into normal brain parenchyma. Deng et al.  evaluated 20 patients with LGGs and HGGs. Their group demonstrated that in 50% of patients DTI shows an abnormality larger than that demonstrated on conventional MRI. Moreover, there was a demonstrable increasing trend in FA values from the glioma region outward. The ADC values also trended toward increasing from the glioma core outward, although this only seemed to hold true for the immediate peritumoral region. The investigators felt that this data can be interpreted to evaluate the degree of brain invasion .
Several studies have demonstrated the utility of DTI with regard to intraoperative functional mapping and preservation of neurologic function after surgical resection. In a series of 10 patients with LGG, Leclercq et al.  analyzed the role of DTI in predicting the location of language tracts and compared these results with subcortical electric stimulation, the gold standard for intraoperative tract mapping. The patients in this study were subject to preoperative imaging with standard MRI and DTI. Positive stimulations occurred in 21 patients and 81% of this intraoperative mapping was in accord with tractography of either the arcuate fasciculus or the inferior occipitofrontal fasciculus . Similarly, in a study by Awasthi et al.  analyzing 30 patients who underwent resection of biopsy-proven glioblastoma multiforme, DTI was shown to have value in accurately localizing the corticospinal tract within the internal capsule. The authors used numerous MRI metrics such as FA and mean diffusivity along with cerebral blood volume to generate a multivariate logistic regression model to predict improvement in motor strength following surgery, The authors demonstrated that the model could predict the outcome for five of nine patients with improved postoperative motor function and 18 of 21 patients lacking postoperative improvement. FA values for each group were decreased in the affected internal capsule relative to the contralateral internal capsule. The authors hypothesized that the decreased FA values reflected a combination of vasogenic edema and tumor infiltration .
Current data from additional investigators support this finding that DTI cannot always distinguish between fiber tract disruption secondary to vasogenic edema and tumor infiltration. Kinoshita et al.  used DTI for intraoperative neuronavigation in eight patients with the diagnosis of glioma, meningioma, or metastatic tumor. The authors attempted to calculate a predictive index for tumor infiltration. The tumor infiltration index was defined as a mathematical function of projected versus actual FA values. The authors found that DTI failed to reliably distinguish between abnormal diffusion associated with vasogenic edema and that caused by tumor infiltration alone . Similar to the study by Awasthi et al. , the authors speculated that this result is secondary to the coexistence of both vasogenic edema and tumor infiltration within T2-hyperintense areas .
Beyond delineation of white matter tracts and tumor infiltration, some investigators have studied the role of DTI as a diagnostic imaging modality. For instance, DTI has been investigated as an aid in discerning LGG from HGG on preoperative imaging. In a retrospective review of 40 patients, Jakab et al.  found that preoperative DTI could be reliably used for tumor grading. Using postoperative definitive histopathologic diagnosis, the authors demonstrated with 92.5% sensitivity and 88.5% specificity that preoperative DTI could effectively distinguish between LGG and HGG . In a similar study, Ferda et al.  retrospectively reviewed 24 patients and reported 81% sensitivity and 87% specificity distinguishing glioma tumor grade with DTI .
DTI has also been used to distinguish between various intracranial pathologic diagnoses. Xu et al.  prospectively studied 35 glioma patients with initial diagnosis confirmed via either resection or biopsy. In follow-up, 20 patients were diagnosed with recurrent glioma, whereas 15 patients were diagnosed with radiation necrosis; confirmed via histopathologic diagnosis in 23 patients and via clinical/radiographic follow-up in 12 patients. ADC values were lower and FA values were higher in DTI studies for recurrent tumor compared to those with radiation necrosis. The authors determined that DTI could discern tumor recurrence from radiation necrosis with 85% sensitivity and 86.7% specificity . Wang et al.  analyzed a series of 63 patients, 38 with glioblastoma and 25 with solitary metastasis to determine if a significant difference existed between the two categories of tumors with respect to FA. The authors demonstrated that glioblastoma has a 34% higher FA than solitary brain metastases based on preoperative DTI scans compared to histopathologic diagnosis rendered during surgical resection .
fMRI is a noninvasive imaging modality that uses cortical blood flow changes as a surrogate for increased or decreased neuronal activity. Initial animal studies established correlation of cerebral blood flow both with neuronal activation and with certain MRI pulse sequences. The most commonly used MRI technique uses gradient echo to detect the relative difference in magnetic susceptibility between oxy- and deoxyhemoglobin. This blood oxygen level–dependent (BOLD) fMRI signal has been widely used to map task-driven regional cortical activity in patients and normals [20–22]. Several recent studies have evaluated the use of fMRI to obtain both preoperative diagnostic and prognostic information [22–27].
Resection of lesions in or encroaching on motor cortex and/or descending corticospinal tracts is often limited by risk of postoperative paresis. The delineation between tumor margin and sensorimotor cortex is important in limiting this risk and is traditionally done intraoperatively by electrophysiologic mapping, which can take considerable time. Li et al.  studied five glioma patients with lesions near the sensorimotor cortex and used preoperative BOLD fMRI to delineate between tumor and sensory cortex. The authors found that the combination of fMRI and intraoperative neuromonitoring led to faster mapping of sensory cortex during resection compared to neuromonitoring alone. In addition, preoperative fMRI compared strongly with intraoperative monitoring findings .
Talacchi et al.  studied 171 HGG patients with either preoperative motor weakness or lesions 1 cm or less from the motor cortex. The authors identified a similar rate of gross total resection (GTR) in those patients with surgical resection using preoperative fMRI and intraoperative neuronavigation (71%) compared to surgical resection using intraoperative neuromonitoring (73%). This rate of GTR was significantly greater than that achieved without either modality (40%, P = 0.02) In addition, patients undergoing surgical resection using either fMRI or intraoperative neuromonitoring displayed a significant improvement in overall survival compared to treatment without these supportive technologies (P < 0.01) .
In an effort to improve the utility of fMRI, Kleiser et al.  studied the combination of fMRI and DTI to accurately reconstruct fiber tracks. The authors analyzed fMRI-based DTI tractography in eight healthy patients and three patients with tumors near the sensorimotor cortex. In these patients, fMRI was used as a starting point for DTI tract reconstruction. This method was shown to be more accurate than DTI tractography based solely on anatomic landmarks . Incorporating BOLD fMRI activation maps with DTI tractography, Pantelis et al.  analyzed four patients with lesions near functionally important cortex receiving stereotactic radiosurgery. The authors displayed an improved ability to identify functional structures using these modalities and consequently limiting high-dose radiation to functional tissue .
Traditional fMRI mapping has required the patient to perform certain tasks to increase oxygenation in specific regions in the brain. However, patients may have a limited ability to perform certain tasks. In addition, impaired patients as well as pediatric patients can have difficulty limiting head movement during the examination. To address these limitations, Zhang et al.  compared resting state with cortical stimulation mapping in localizing sensorimotor areas. The authors assessed 17 healthy controls and four patients with tumors invading the sensorimotor cortex. Resting state mapping compared well with intraoperative cortical stimulation and generated more consistent maps than those formed by traditional task-based fMRI .
Intraoperative Resection Tools
Preoperative MRI in combination with stereotactic guidance can be a valuable tool for intraoperative surgical planning. However, resection is hampered despite using neuronavigation guidance tools due to “brain shift” . Brain shift refers to the secondary intraoperative phenomenon in which changes in tumor volume, cerebrospinal fluid drainage, intracranial pressure, or the use of brain retractors generate intraoperative brain deformation that renders preoperative neuronavigation registration inaccurate . iMRI brings the ability to update the navigational image as necessary and has developed as a valuable tool to maximize surgical resection .
Improved surgical resection after iMRI
Further resection after iMRI, n (%)
Surgical goal achieved, n (%)
Senft et al. 
Maesawa et al. 
Hatiboglu et al. 
Ramina et al. 
Senft et al. 
When evaluating the practicality of iMRI it would be remiss to not comment on the major limitation to this innovation: cost. Currently a dedicated high-field iMRI suite is a stand-alone structure with estimated construction costs at $3 million. However, investigators have demonstrated that beyond initial infrastructure costs inherent to establishing an iMRI suite, future expenditures can be minimized with hybrid work environments. With planning, an MRI scanner may be configured for sharing between two operating rooms in a common suite or even with an outpatient scanning area. In this hybrid environment, the MRI system can be used more frequently in a standard diagnostic capacity, which greatly offsets installation and maintenance costs [34, 35, 36•].
With a need for better intraoperative visualization of glial neoplasms, research primarily directed by Stummer et al. [37, 38] sought to develop a tumor-specific fluorescent marker that would allow more accurate discrimination of infiltrating tumor from normal brain parenchyma, 5-ALA. 5-ALA is a molecule used by human mitochondria during heme synthesis and is a precursor to the production of protoporphyrin IX (PpIX), which accumulates intracellularly and demonstrates red fluorescence under blue light illumination [37–40]. When given orally, 5-ALA has been shown both in vitro and in vivo to produce fluorescence in glial neoplasms [37–43]. In addition, the fluorescence of PpIX is itself cytotoxic and has the potential for use as adjuvant photodynamic therapy for neoplastic tissue that cannot be safely resected [37, 39, 44].
Several investigators have recently demonstrated the feasibility of fluorescence-guided resection of patients with HGG. Stummer et al.  performed a randomized controlled trial where they compared 176 patients with tumor resection using 5-ALA with 173 patients treated with conventional white light in an intention-to-treat analysis. In this analysis, the authors identified a lower incidence of repeat surgery with 5-ALA (P = 0.03). In addition, patients with incomplete resection were found to display a faster onset of neurologic deficits (P = 0.036) . Widhalm et al.  administered 20 mg/kg of 5-ALA to 17 patients with contrast-enhancing diffusely infiltrating gliomas. Using MRI, DTI, and positron emission tomography scans as the basis of their neuronavigation, these investigators used both white light and violet blue light for surgical resection. For all samples verified by histopathology to contain World Health Organization grade III tissue, the positive predictive value (PPV) of positive 5-ALA focal fluorescence was 100% with 89% sensitivity .
Nabavi et al.  displayed similar success in obtaining fluorescence-guided biopsies of 36 patients with recurrent HGG. Tissue suspicious for glioma was resected under white light guidance. When the margins of tumor were encountered and the tissue appeared normal under white light illumination, the surgical field was directly illuminated via violet-blue light. Biopsies were then obtained from areas that weakly and strongly fluoresced. On histopathologic analysis of these biopsies, all samples regardless of the strength of fluorescence were positive for tumor cells with a PPV of 97.2% .
There exist certain inherent limitations in using 5-ALA during surgical resection. For instance, depth of penetration of blue light is limited to a few millimeters and is obscured by blood products. Also, nonenhancing tumors do not fluoresce well . And there exists a negative feedback loop as 5-ALA is converted to PpIX that can limit the degree of fluorescence in certain portions of the tumor margin. However, iron chelation strategies can increase intracellular accumulation of iron chelators such as CP94 or deferoxamine and allow for the production of PpIX from 5-ALA to be pushed past negative feedback. This approach serves to increase the PpIX levels available within glial tissue and thus prolong the time that the tissue is able to fluoresce [39, 40]. A second limitation to 5-ALA use is that of the photobleaching effect. Under light exposure the intensity of PpIX fluorescence begins to wane. This is especially problematic in that sources of ambient light such as operating room lighting and that of the operative microscope cannot be fully removed. To circumvent this shortcoming, Haj-Hosseini et al.  describe the use of an optical touch pointer for applications in fluorescence-guided resection. This system is a handheld pointer instrument able to generate pulses of excitatory wavelengths and register fluorescence with an onboard spectrometer. The signals captured can then be displayed on a monitor for real-time feedback regarding presence or absence of PpIX-positive tissue .
Laser Interstitial Thermal Therapy
In considering various treatment options for intracranial lesions, minimally invasive modalities that offer effective treatment with decreased morbidity are of interest to clinicians. These modalities include such techniques as LITT, cryoablation, and radiofrequency ablation [47–51]. LITT has recently seen resurgence with regard to the clinical utility of this technique secondary to advances in MRI thermometry. In particular, LITT may be a treatment option for patients not healthy enough for open surgical resection, for small surgically inaccessible lesions, or for lesions refractory to prior conventional radiation or radiosurgery.
Carpentier et al.  recently reported the successful treatment of six patients with metastatic intracranial lesions. The primary tumor origin was breast carcinoma in five patients and lung carcinoma in one patient, and all lesions were less than 2.5 cm. The patients underwent between one to three treatment doses providing a thermal ablation zone to treat the lesion. Postoperative MRI confirmed adequate treatment of the lesion in all patients without increase in peritumoral edema .
The technical advances that have allowed the clinician to better diagnose intracranial lesions have also provided better treatment of these lesions. Preoperative planning tools such as fMRI and DTI allow surgeons to better assess the relationship between the tumor and functional tissue. In addition, DTI can provide insight into tumor diagnosis prior to obtaining tumor specimen. Intraoperative resection tools such as iMRI and 5-ALA provide real-time feedback to the surgeon in determining the location of residual tumor and consequently increased extent of resection. In addition, the use of minimally invasive techniques such as LITT can provide adequate treatment to a subset of patients with potentially decreased operative morbidity. As the true role of these modalities is better understood, the advantages in combining these modalities during treatment will continue to emerge. These advantages will ideally include not only decreased morbidity and mortality but also improved progression-free and overall survival.
No potential conflicts of interest relevant to this article were reported.