Mark C. Preul

The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma

BackgroundMalignant brain tumors affect people of all ages and are the second leading cause of cancer deaths in children. While current treatments are effective and improve survival, there remains a substantial need for more efficacious therapeutic modalities. The ketogenic diet (KD) - a high-fat, low-carbohydrate treatment for medically refractory epilepsy - has been suggested as an alternative strategy to inhibit tumor growth by altering intrinsic metabolism, especially by inducing glycopenia.MethodsHere, we examined the effects of an experimental KD on a mouse model of glioma, and compared patterns of gene expression in tumors vs. normal brain from animals fed either a KD or a standard diet.ResultsAnimals received intracranial injections of bioluminescent GL261-luc cells and tumor growth was followed in vivo. KD treatment significantly reduced the rate of tumor growth and prolonged survival. Further, the KD reduced reactive oxygen species (ROS) production in tumor cells. Gene expression profiling demonstrated that the KD induces an overall reversion to expression patterns seen in non-tumor specimens. Notably, genes involved in modulating ROS levels and oxidative stress were altered, including those encoding cyclooxygenase 2, glutathione peroxidases 3 and 7, and periredoxin 4.ConclusionsOur data demonstrate that the KD improves survivability in our mouse model of glioma, and suggests that the mechanisms accounting for this protective effect likely involve complex alterations in cellular metabolism beyond simply a reduction in glucose.

The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma.

Introduction The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. KetoCal® (KC) is a nutritionally complete, commercially available 4∶1 (fat∶ carbohydrate+protein) ketogenic formula that is an effective non-pharmacologic treatment for the management of refractory pediatric epilepsy. Diet-induced ketosis causes changes to brain homeostasis that have potential for the treatment of other neurological diseases such as malignant gliomas. Methods We used an intracranial bioluminescent mouse model of malignant glioma. Following implantation animals were maintained on standard diet (SD) or KC. The mice received 2×4 Gy of whole brain radiation and tumor growth was followed by in vivo imaging. Results Animals fed KC had elevated levels of β-hydroxybutyrate (p = 0.0173) and an increased median survival of approximately 5 days relative to animals maintained on SD. KC plus radiation treatment were more than additive, and in 9 of 11 irradiated animals maintained on KC the bioluminescent signal from the tumor cells diminished below the level of detection (p<0.0001). Animals were switched to SD 101 days after implantation and no signs of tumor recurrence were seen for over 200 days. Conclusions KC significantly enhances the anti-tumor effect of radiation. This suggests that cellular metabolic alterations induced through KC may be useful as an adjuvant to the current standard of care for the treatment of human malignant gliomas.

Blood supply and vascular reactivity of the spinal cord under normal and pathological conditions

The authors present a review of spinal cord blood supply, discussing the anatomy of the vascular system and physiological aspects of blood flow regulation in normal and injured spinal cords. Unique anatomical functional properties of vessels and blood supply determine the susceptibility of the spinal cord to damage, especially ischemia. Spinal cord injury (SCI), for example, complicating thoracoabdominal aortic aneurysm repair is associated with ischemic trauma. The rate of this devastating complication has been decreased significantly by instituting physiological methods of protection. Traumatic SCI causes complex changes in spinal cord blood flow, which are closely related to the severity of injury. Manipulating physiological parameters such as mean arterial blood pressure and intrathecal pressure may be beneficial for patients with an SCI. Studying the physiopathological processes of the spinal cord under vascular compromise remains challenging because of its central role in almost all of the bodys hemodynamic and neurofunctional processes.

Magnetic resonance spectroscopy guided brain tumor resection : Differentiation between recurrent glioma and radiation change in two diagnostically difficult cases

BACKGROUND It is often difficult to differentiate a recurrent glioma from the effects of post-operative radiotherapy by means of conventional neurodiagnostic imaging. Proton magnetic resonance spectroscopic imaging (1H-MRSI), that allows in vivo measurements of the concentration of brain metabolites such as choline-containing phospholipids (Cho), may provide in vivo biochemical information helpful in distinguishing areas of tumor recurrence from areas of radiation effect. PATIENTS AND METHODS Two patients who had undergone resection and post-operative radiotherapy for a cerebral glioma became newly symptomatic. Computed tomographic (CT) and magnetic resonance imaging (MRI) performed after the intravenous infusion of contrast material, and in one case, [18F]fluorodeoxyglucose positron emission tomography (PET), could not differentiate between the possibilities of recurrent glioma and radiation effect. The patients underwent 1H-MRSI prior to reoperation and the 1H-MRSI results were compared to histological findings originating from the same locations. RESULTS A high Cho signal measured by 1H-MRSI was seen in areas of histologically-proven dense tumor recurrence, while low Cho signal was present where radiation changes predominated. CONCLUSIONS The differentiation between the recurrence of a cerebral glioma and the effects of post-operative irradiation was achieved using 1H-MRSI in these two patients whose conventional neurodiagnostic imaging was equivocal for such a distinction. Where these two conditions are present, metabolite images from 1H-MRSI, such as that based on Cho, can be co-registered with other imaging modalities such as MRI and may also be integrated with functional MRI or functional PET within a multimodal imaging-guided surgical navigation system to assure maximal resection of recurrent tumor while minimizing the risk of added neurological damage.

A three-dimensional interactive virtual dissection model to simulate transpetrous surgical avenues.

OBJECTIVEThis project involves the development of a three-dimensional surgical simulator called interactive virtual dissection, which is designed to teach surgeons the visuospatial skills required to navigate through a transpetrosal approach. METHODSA robotically controlled microscope is used for surgical planning and data collection. The spatial anatomic data are recorded from sequentially deeper cadaveric head dissections as a series of superimposed anatomic pictures in stereoscopic digital format. The sequential series of images are then merged to form the final virtual representation. RESULTSThe current three-dimensional virtual reality simulator allows the user to drill the petrous bone progressively deeper and to identify crucial structures much like an experienced surgeon drilling the petrous bone. The program allows surgeons and trainees to manipulate the virtual “surgical field” by interacting with the surgical anatomy. The interactive system functions on a desktop computer. CONCLUSIONThe ability to visualize and understand anatomic spatial relationships is crucial in surgical planning, as is a surgeon’s confidence in performing the surgery. The virtual reality simulator does not replace the need for practicing surgery on cadavers. However, it is designed to facilitate, via stereoscopic projection, learning how to manipulate a drill in complicated or unfamiliar surgical approaches (e.g., a transpetrosal approach).

Trigeminal depressor response during percutaneous microcompression of the trigeminal ganglion for trigeminal neuralgia

Percutaneous microcompression of the trigeminal ganglion for trigeminal neuralgia was performed 23 times on 21 patients. Significant abrupt drops in heart rate and blood pressure (P less than 0.0002) occurred when the needle entered the foramen ovale or upon balloon advancement or inflation. In 16 of 23 (70%) procedures, the heart rate fell abruptly to 60 or less, by a mean of 38%. Mean arterial blood pressure decreased transiently by 31% during 12 of 23 (55%) procedures. Our findings of transient bradycardia and hypotension upon mechanical stimulation or compression of the mandibular nerve or trigeminal ganglion show for the first time the presence of a trigeminal depressor response in humans. We recommend that heart rate and arterial blood pressure be monitored continuously during percutaneous microcompression of the trigeminal ganglion. Intravenous atropine should be available for immediate use, and an external pacemaker should be fitted preoperatively.

An anatomical evaluation of the mini-supraorbital approach and comparison with standard craniotomies.

OBJECTIVE: To compare anatomically the surgical exposure provided by pterional (PT), orbitozygomatic (OZ), and minisupraorbital (SO) craniotomies. METHODS: Seven sides of six fixed cadaver heads injected with silicone were used. The mini-SO craniotomy followed by the PT and OZ approaches were performed sequentially. The bony flaps were attached with miniplates and screws, allowing easy conversion between the approaches. A frameless stereotactic device was used to calculate an area of surgical exposure and the angles of approach for six different anatomic targets. An image guidance system was used to demonstrate the limits of the surgical exposure for each technique. RESULTS: No significant differences were observed in the total area of surgical exposure when comparing the mini-SO (A = 1831.2 ± 415.3 mm2), PT (A = 1860.0 ± 617.2 mm2), and OZ approaches (A = 1843.3 ± 358.1 mm2; P > 0.05). Angular exposure was greater for the OZ and PT approaches than for the mini-SO approach, either in the vertical and horizontal axes, considering all of the six targets studied (P < 0.05). Except for the distal segment of the ipsilateral sylvian fissure, no practical differences in the limits of the exposure were detected. CONCLUSION: The mini-SO approach may offer a similar surgical working area compared with that provided by standard craniotomies and constitutes an excellent alternative to the OZ and PT craniotomies in selected patients. Selection should not be based primarily on the area to be exposed, but rather on the working angles that are anticipated to be required. The key point is to use the most adequate technique for a particular patient, rather than using a one-size-fits-all approach for all patients.

Cerebral cavernous malformations: from genes to proteins to disease

Over the past half century molecular biology has led to great advances in our understanding of angio- and vasculogenesis and in the treatment of malformations resulting from these processes gone awry. Given their sporadic and familial distribution, their developmental and pathological link to capillary telangiectasias, and their observed chromosomal abnormalities, cerebral cavernous malformations (CCMs) are regarded as akin to cancerous growths. Although the exact pathological mechanisms involved in the formation of CCMs are still not well understood, the identification of 3 genetic loci has begun to shed light on key developmental pathways involved in CCM pathogenesis. Cavernous malformations can occur sporadically or in an autosomal dominant fashion. Familial forms of CCMs have been attributed to mutations at 3 different loci implicated in regulating important processes such as proliferation and differentiation of angiogenic precursors and members of the apoptotic machinery. These processes are important for the generation, maintenance, and pruning of every vessel in the body. In this review the authors highlight the latest discoveries pertaining to the molecular genetics of CCMs, highlighting potential new therapeutic targets for the treatment of these lesions.

Intraoperative Confocal Microscopy for Brain Tumors: A Feasibility Analysis in Humans

BACKGROUND: The ability to diagnose brain tumors intraoperatively and identify tumor margins during resection could maximize resection and minimize morbidity. Advances in optical imaging enabled production of a handheld intraoperative confocal microscope. OBJECTIVE: To present a feasibility analysis of the intraoperative confocal microscope for brain tumor resection. METHODS: Thirty-three patients with brain tumor treated at Barrow Neurological Institute were examined. All patients received an intravenous bolus of sodium fluorescein before confocal imaging with the Optiscan FIVE 1 system probe. Optical biopsies were obtained within each tumor and along the tumor-brain interfaces. Corresponding pathologic specimens were then excised and processed. These data was compared by a neuropathologist to identify the concordance for tumor histology, grade, and margins. RESULTS: Thirty-one of 33 lesions were tumors (93.9%) and 2 cases were identified as radiation necrosis (6.1%). Of the former, 25 (80.6%) were intra-axial and 6 (19.4%) were extra-axial. Intra-axial tumors were most commonly gliomas and metastases, while all extra-axial tumors were meningiomas. Among high-grade gliomas, vascular neoproliferation, as well as tumor margins, were identifiable using confocal imaging. Meningothelial and fibrous meningiomas were distinct on confocal microcopy-the latter featured spindle-shaped cells distinguishable from adjacent parenchyma. Other tumor histologies correlated well with standard neuropathology tissue preparations. CONCLUSION: Intraoperative confocal microscopy is a practicable technology for the resection of human brain tumors. Preliminary analysis demonstrates reliability for a variety of lesions in identifying tumor cells and the tumor-brain interface. Further refinement of this technology depends upon the approval of tumor-specific fluorescent contrast agents for human use.

The minipterional craniotomy: technical description and anatomic assessment.

OBJECTIVE To describe a modification of the pterional approach (PT), the minipterional craniotomy (MPT), and compare the anatomic exposure provided by these two approaches. METHODS The anatomic exposure offered by the MPT and PT were compared in eight sides of cadaver heads using a computerized tracking system, a robotic microscope, and an image-guidance system. The area of surgical exposure, angular exposure, and anatomic limits of each craniotomy were evaluated. Three recently operated clinical cases (EGF) are also reported. RESULTS There were no statistical differences in the total area of surgical exposure between the two craniotomies (PT, 1524.7 ± 305 mm2; MPT, 1469.7 ± 380.3 mm2; P > 0.05) or among the ipsilateral, middle, and contralateral components of the area (P > 0.05). There were no differences in angular exposure along the longitudinal and transverse axis angles for the three selected targets, the bifurcations of internal carotid and middle cerebral arteries, and the anterior communicating artery (P > 0.05). Except for the distal portion of the operculoinsular compartment of the sylvian fissure, no significant differences in the limits of the surgical exposure through the PT and MPT were apparent on the image-guidance system. CONCLUSION The MPT craniotomy provides comparable surgical exposure to that offered by the PT. The advantages of the MPT include reduction of tissue trauma and bony removal, a decrease in surgical time, and improved cosmetic outcomes.