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David W. Roberts, John W. Strohbehn, John F. Hatch, William Murray and Hans Kettenberger

✓ A computer-based system has been developed for the integration and display of computerized tomography (CT) image data in the operating microscope in the correct perspective without requiring a stereotaxic frame. Spatial registration of the CT image data is accomplished by determination of the position of the operating microscope as its focal point is brought to each of three CT-imaged fiducial markers on the scalp. Monitoring of subsequent microscope positions allows appropriate reformatting of CT data into a common coordinate system. The position of the freely moveable microscope is determined by a non-imaging ultrasonic range-finder consisting of three spark gaps attached to the microscope and three microphones on a rigid support in the operating room. Measurement of the acoustic impulse transit times from the spark gaps to the microphones enables calculation of those distances and unique determination of the microscope position. The CT data are reformatted into a plane and orientation corresponding to the microscope's focal plane or to a deeper parallel plane if required. This reformatted information is then projected into the optics of the operating microscope using a miniature cathode ray tube and a beam splitter. The operating surgeon sees the CT information (such as a tumor boundary) superimposed upon the operating field in proper position, orientation, and scale.

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A. David Mendelow, John O. Rowan, Lilian Murray and Audrey E. Kerr

✓ Simultaneous recordings of intracranial pressure (ICP) from a single-lumen subdural screw and a ventricular catheter were compared in 10 patients with severe head injury. Forty-one percent of the readings corresponded within the same 10 mm Hg ranges, while 13% of the screw pressure measurements were higher and 46% were lower than the associated ventricular catheter measurements. In 10 other patients, also with severe head injury, pressure measurements obtained with the Leeds-type screw were similarly compared with ventricular fluid pressure. Fifty-eight percent of the dual pressure readings corresponded, while 15% of the screw measurements were higher and 27% were lower than the ventricular fluid pressure, within 10-mm Hg ranges. It is concluded that subdural screws may give unreliable results, particularly by underestimating the occurrence of high ICP.

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Neil A. Martin, John Bentson, Fernando Viñuela, Grant Hieshima, Murray Reicher, Keith Black, Jacques Dion and Donald Becker

✓ Intraoperative digital subtraction angiography using commercially available equipment was employed to confirm the precision of the surgical result in 105 procedures for intracranial aneurysms or arteriovenous malformations (AVM's). Transfemoral selective arterial catheterization was performed in most of these cases. A radiolucent operating table was used in all cases, and a radiolucent head-holder in most. In five of the 57 aneurysm procedures, clip repositioning was required after intraoperative angiography demonstrated an inadequate result. In five of the 48 AVM procedures, intraoperative angiography demonstrated residual AVM nidus which was then located and resected. In two cases intraoperative angiography failed to identify residual filling of an aneurysm which was seen later on postoperative angiography, and in one case the intraoperative study failed to demonstrate a tiny residual fragment of AVM which was seen on conventional postoperative angiography. Two complications resulted from intraoperative angiography: one patient developed aphasia from cerebral embolization and one patient developed leg ischemia from femoral artery thrombosis. This technique appears to be of particular value in the treatment of complex intracranial aneurysms and vascular malformations.

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Malcolm D. M. Shaw, Marinus Vermeulen, Gordon D. Murray, John D. Pickard, B. Anthony Bell and Graham M. Teasdale

Object. Delayed cerebral ischemia remains an important cause of death and disability in patients who have suffered subarachnoid hemorrhage (SAH). Endothelin (ET) has a potent contractile effect on cerebral arteries and arterioles and has been implicated in vasospasm. The authors administered ETA/B receptor antagonist (TAK-044) to patients suffering from aneurysmal SAH. They then assessed whether this agent reduced the occurrence of delayed cerebral ischemic events and examined its safety profile in this group of patients.

Methods. Four hundred twenty patients who had suffered an SAH were recruited into a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II trial. The primary end point was whether a delayed ischemic event occurred within 3 months after the first dose of the study drug and the secondary end points included determining whether a delayed ischemic event occurred by 10 days after the first dose of the study drug, whether a new cerebral infarct was demonstrated on a computerized tomography scan or at postmortem examination by 3 months after administration of the initial dose, the patient's Glasgow Outcome Scale scores at 3 months after the initial dose, and adverse events.

There was a lower incidence of delayed ischemic events at 3 months in the TAK-044—treated group: 29.5% compared with 36.6% in a group of patients receiving placebo. The estimated relative risk was 0.8 with a 95% confidence interval of 0.61 to 1.06. There were no significant differences in the secondary end points, including clinical outcomes in the placebo—treated and TAK-044—treated groups.

Conclusions. The TAK-044 was well tolerated by patients who had suffered an SAH, even though hypotension and headache—side effects compatible with the drug's vasodilatory properties—occurred. It would be valuable to proceed to a fully powered phase III trial of an ET receptor antagonist in treating aneurysmal SAH.

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Ingrid Kieran, Zaitun Zakaria, Chandrasekaran Kaliaperumal, Declan O'Rourke, Alan O'Hare, Eoghan Laffan, John Caird, Mary D. King and Dylan J. Murray

The authors describe the case of a 3-year-old boy with a giant congenital vertex hemangioma who underwent presurgical embolization with Onyx (ethylene-vinyl alcohol copolymer dissolved in dimethyl sulfoxide) and Glubran (N-butyl-2-cyanoacrylate). This vascular tumor had no intracranial vascular communication as assessed by pre-embolization MRI and catheter angiography. All embolizations were performed by direct percutaneous injection. One week following the last embolization procedure the child presented with a 24-hour history of ataxia and extrapyramidal tremor. He was diagnosed with a possible immune-mediated reaction to Onyx or Glubran, which was treated with an urgent surgical excision of the hemangioma followed by intravenous administration of immunoglobulin and steroids. To the authors' knowledge, this is the first case of possible immune-mediated toxicity secondary to either Onyx or Glubran administration. This case highlights the need for awareness of potential toxic reactions to these embolic agents in the treatment of hemangiomas in the pediatric patient.

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The role of photodynamic therapy in posterior fossa brain tumors

A preclinical study in a canine glioma model

Harry T. Whelan, Meic H. Schmidt, Annette D. Segura, Timothy L. McAuliffe, Dawn M. Bajic, Kevin J. Murray, John E. Moulder, Douglas R. Strother, James P. Thomas and Glenn A. Meyer

✓ Photodynamic therapy was studied in dogs with and without posterior fossa glioblastomas. This mode of therapy consisted of intravenous administration of Photofrin-II at doses ranging from 0.75 to 4 mg/kg 24 hours prior to laser light irradiation in the posterior fossa. Tissue levels of Photofrin-II were four times greater in the tumor than in the surrounding normal brain. Irradiation was performed using 1 hour of 500 mW laser light at a wavelength of 630 nm delivered through a fiberoptic catheter directly into the tumor bed via a burr hole. All animals receiving a high dose (4 or 2 mg/kg) of Photofrin-II developed serious brain-stem neurotoxicity resulting in death or significant residual neurological deficits. A lower dose (0.75 mg/kg) of Photofrin-II produced tumor kill without significant permanent brain-stem toxicity in either the control animals or the animals with cerebellar brain tumors receiving photodynamic therapy.

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John H. Chi, Amith Panner, Kristine Cachola, Courtney A. Crane, Joseph Murray, Russell O. Pieper, C. David James and Andrew T. Parsa

Object

Despite recent advances in cancer immunotherapy, cellular mechanisms controlling expression of tumor-associated antigens are poorly understood. Mutations in cancer cells, such as loss of PTEN, may increase expression of tumor-associated antigens. The authors investigated the relationship between PTEN status and the expression of a glioma-associated antigen, adenosine diphosphate–ribosylation factor 4–like (ARF4L) protein.

Methods

Human glioma cell lines with confirmed PTEN status were examined by Northern blot analysis and quantitative polymerase chain reaction. Western blot analysis was used to measure ARF4L protein levels across multiple cell lines.

Results

The loss of PTEN was shown to lead to increased levels of ARF4L protein but no change in transcript levels. Cell lines with serial mutations, including activation of Ras and Akt pathways, also demonstrated increased levels of ARF4L protein, which decreased after treatment with rapamycin. The ARF4L transcript preferentially localized to the polysomal compartment after PTEN loss in glioma or activation of Akt in human astrocytes.

Conclusions

Expression of ARF4L is controlled by the activated Akt/mTOR pathway, which is a downstream effect of the loss of PTEN function. Mutations leading to oncogenesis may impact the regulation and expression of tumor specific antigens. Screening of mutation status in glioma may be helpful in selecting patients for immunotherapy trials in the future.

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Casey H. Halpern, John A. Wolf, Tracy L. Bale, Albert J. Stunkard, Shabbar F. Danish, Murray Grossman, Jurg L. Jaggi, M. Sean Grady and Gordon H. Baltuch

Obesity is a growing global health problem frequently intractable to current treatment options. Recent evidence suggests that deep brain stimulation (DBS) may be effective and safe in the management of various, refractory neuropsychiatric disorders, including obesity. The authors review the literature implicating various neural regions in the pathophysiology of obesity, as well as the evidence supporting these regions as targets for DBS, in order to explore the therapeutic promise of DBS in obesity.

The lateral hypothalamus and ventromedial hypothalamus are the appetite and satiety centers in the brain, respectively. Substantial data support targeting these regions with DBS for the purpose of appetite suppression and weight loss. However, reward sensation associated with highly caloric food has been implicated in overconsumption as well as obesity, and may in part explain the failure rates of conservative management and bariatric surgery. Thus, regions of the brain's reward circuitry, such as the nucleus accumbens, are promising alternatives for DBS in obesity control.

The authors conclude that deep brain stimulation should be strongly considered as a promising therapeutic option for patients suffering from refractory obesity.

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A. David Mendelow, Graham M. Teasdale, Thomas Russell, John Flood, James Patterson and Gordon D. Murray

✓ Patients with severe head injury frequently have evidence of elevated intracranial pressure (ICP) and ischemic neuronal damage at autopsy. Mannitol has been used clinically to reduce ICP with varying success, and it is possible that it is more effective in some types of head injury than in others. The aim of the present study was to determine the effect of mannitol on ICP, cerebral perfusion pressure (CPP), and cerebral blood flow (CBF) in patients with severe head injury, and to discover if these effects differed in different types of injury. Measurements of CPP, ICP, and CBF were made in 55 patients with severe head injury. In general, the resting level of CBF was higher in patients with diffuse injury (mean 50.2 ml/100 gm/min) than in those with focal injury (mean 39.8 ml/100 gm/min). Mannitol consistently reduced ICP and increased CPP and CBF by 10 to 20 minutes after infusion. The lowest flows (31.8 ml/100 gm/min) were recorded from the most damaged hemispheres of patients with focal injuries and elevated ICP. The baseline levels of flow did not correlate with ICP, CPP, Glasgow Coma Scale score, or outcome. Only four of the 55 patients had a CBF of less than 20 ml/100 gm/min in either or both hemispheres. The few low CBF's in this and other studies may reflect the steady-state conditions under which measurements are made in intensive care units, and that these patients have entered a phase of reperfusion.

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Omar K. Bangash, Arosha S. Dissanayake, Shirley Knight, John Murray, Megan Thorburn, Nova Thani, Arul Bala, Rick Stell and Christopher R. P. Lind

OBJECTIVE

Posterior subthalamic area (PSA) deep brain stimulation (DBS) targeting the zona incerta (ZI) is an emerging treatment for tremor syndromes, including Parkinson’s disease (PD) and essential tremor (ET). Evidence from animal studies has indicated that the ZI may play a role in saccadic eye movements via pathways between the ZI and superior colliculus (incerto-collicular pathways). PSA DBS permitted testing this hypothesis in humans.

METHODS

Sixteen patients (12 with PD and 4 with ET) underwent DBS using the MRI-directed implantable guide tube technique. Active electrode positions were confirmed at the caudal ZI. Eye movements were tested using direct current electrooculography (EOG) in the medicated state pre- and postoperatively on a horizontal predictive task subtending 30°. Postoperative assessments consisted of stimulation-off, constituting a microlesion (ML) condition, and high-frequency stimulation (HFS; frequency = 130 Hz) up to 3 V.

RESULTS

With PSA HFS, the first saccade amplitude was significantly reduced by 10.4% (95% CI 8.68%–12.2%) and 12.6% (95% CI 10.0%–15.9%) in the PD and ET groups, respectively. With HFS, peak velocity was reduced by 14.7% (95% CI 11.7%–17.6%) in the PD group and 27.7% (95% CI 23.7%–31.7%) in the ET group. HFS led to PD patients performing 21% (95% CI 16%–26%) and ET patients 31% (95% CI 19%–38%) more saccadic steps to reach the target.

CONCLUSIONS

PSA DBS in patients with PD and ET leads to hypometric, slowed saccades with an increase in the number of steps taken to reach the target. These effects contrast with the saccadometric findings observed with subthalamic nucleus DBS. Given the location of the active contacts, incerto-collicular pathways are likely responsible. Whether the acute finding of saccadic impairment persists with chronic PSA stimulation is unknown.