Effects of Alzheimer's disease transgenes on neurochemical expression in the mouse brain determined by ¹H MRS in vitro.

Transgenic models of human disease can be used to understand pathology and to discover biomarkers of disease presence, progression and response to therapy. Here we report a study of longitudinal metabolic differences between TASTPM transgenic Alzheimer's disease (AD) mice and their wild type counterparts using (1)H magnetic resonance spectroscopy (MRS) to look for potential biomarkers for use in AD research and drug discovery. Chloroform methanol extractions were performed on the brains of mice aged between 3 and 18 months. (1)H MR spectra were recorded from the aqueous fractions. Absolute metabolite concentrations, determined from resonance integrals relative to an internal standard, were analysed by 2-way ANOVA (genotype x age). Significant effects of age alone were identified for creatine, glutamine and total choline-containing compounds. There was a marked increase in creatine in the oldest (15-18 mo) TASTPM mice. The increase in creatine was unexpected and may be caused by osmotic stress in older animals as plaque load increases. Care should be taken when using creatine as a reference metabolite during scans of these animals in vivo. A significant effect of genotype alone was identified for myo-inositol (MI), which was higher in TASTPM mice at all ages. Succinate, glycerophosphocholine and choline all showed significant effects of age and genotype. No significant effects were detected in N-acetylaspartate (NAA) levels. Increased MI could be a marker of gliosis or microglial activation in TASTPM mice, but the absence of an age dependence for MI levels means it may be a biomarker of disease, but not of disease progression. Decreased succinate is indicative of disrupted neuronal energy metabolism, an effect that has been seen in human AD.

Radiosurgery for the control of glomus jugulare tumours.

OBJECTIVE: To ascertain the efficacy of stereotactic radiosurgery (gamma knife) for the control of glomus jugulare tumours. METHOD: Between March 1994 and December 1997 we treated eight patients of glomus jugulare tumour with radiosurgery. These patients have been followed for more than four years (range 52 to 97 months). The age of the patients ranged between 32-64 years (mean 53 years). The male: female ratio was 3:5. Three patients had previously undergone surgery and one had unsuccessful embolization. The dose applied to tumour margin ranged between 16-25 Gy (median 25 Gy). Patients were followed up with yearly MRI scans and where possible with cerebral angiography. RESULTS: All patients showed stabilisation of their symptoms following radiosurgery and six improved clinically. Five of these patients showed decrease in the size of lesion seen objectively on radiology, either slight to moderate decrease seen on the MRI scan or reduction in size and vascularity seen on cerebral angiography. The procedure is minimally invasive and none of the patients showed any adverse effect to radiosurgery. CONCLUSION: These results are encouraging but because of its naturally slow growth rate, up to 10 years of follow up will be necessary to establish a cure rate after radiosurgery for these lesions.

Malignancy in a vestibular schwannoma. Report of a case with central neurofibromatosis, treated by both stereotactic radiosurgery and surgical excision, with a review of the literature.

Malignant change in schwannoma is rare. Malignant change in a vestibular schwannoma (acoustic neuroma) is even more rare. This paper presents a case of rapidly growing vestibular schwannoma first treated by radiosurgery whose histopathology after surgical excision 42 months later showed malignant changes. Up to now, eight cases of malignancy in eighth nerve tumours have been reported, four of which, including the present case, had previously been treated with radiosurgery and four cases that had not received radiation. Thus, it would seem, the overall incidence is extremely low. Nevertheless, extreme vigilance and careful reporting continues to be necessary.

Cerebral arteriovenous malformations: comparison of novel magnetic resonance angiographic techniques and conventional catheter angiography.

OBJECTIVE: To investigate the potential of novel magnetic resonance (MR) angiographic techniques for the assessment of cerebral arteriovenous malformations. METHODS: Forty patients who were about to undergo stereotactic radiosurgery were prospectively recruited. Three-dimensional, sliding-slab interleaved ky (SLINKY), time-of-flight acquisition was performed, as was a dynamic MR digital subtraction angiography (DSA) procedure in which single thick slices (6-10 cm) were obtained using a radiofrequency spoiled Fourier-acquired steady-state sequence (1 image/s). Sixty images were acquired, in two or three projections, during passage of a 6- to 10-ml bolus of gadolinium chelate. Subtraction and postprocessing were performed, and images were viewed in an inverted cine mode. SLINKY time-of-flight acquisition was repeated after the administration of gadolinium. Routine stereotactic conventional catheter angiography was performed after MR imaging. All images were assessed (in a blinded randomized manner) for Spetzler-Martin grading and determination of associated vascular pathological features. RESULTS: Forty-one arteriovenous malformations were assessed in 40 patients. Contrast-enhanced (CE) SLINKY MR angiography was the most consistent MR imaging technique, yielding a 95% correlation with the Spetzler-Martin classification defined by conventional catheter angiography; MR DSA exhibited 90% agreement, and SLINKY MR angiography exhibited 81% agreement. CE SLINKY MR angiography provided improved nidus delineation, compared with non-CE SLINKY MR angiography. Dynamic information from MR DSA significantly improved the observation of early-draining veins and associated aneurysms. CONCLUSION: CE SLINKY MR angiographic assessment of cerebral arteriovenous malformations offers significant advantages, compared with the use of non-CE SLINKY MR angiography, including improved nidus demonstration. MR DSA shows promise as a noninvasive method for dynamic angiography but is presently restricted by limitations in both temporal and spatial resolution.

Spontaneous obliteration of pial arteriovenous malformations: a review of 27 cases.

BACKGROUND AND PURPOSE: Brain arteriovenous malformations (AVMs) occur in approximately 0.14% of the population. The most common presentations are hemorrhage (50%) and seizures (25%). Although they are congenital abnormalities, their angioarchitecture may vary over time. A rare but well-recognized phenomenon of AVMs is that of spontaneous obliteration. It is not known what factors predispose to spontaneous obliteration. The purpose of our study was to determine whether spontaneous thrombosis of AVMs can be predicted by their angioarchitecture and whether there is any risk of recurrence once obliteration has occurred. METHODS: We retrospectively reviewed the angiographic and cross-sectional imaging data amassed over an 18-year period, including follow-up imaging studies and mail surveys of referring and family physicians. A control group was obtained from contemporaneous AVMs of a similar size. RESULTS: We identified 28 cases of spontaneous obliteration in a series of 2162 patients. The mean time between initial diagnostic angiography and angiographic obliteration was 10 months, during which time there was no intervention and no history of repeat hemorrhage; nor had hemorrhage recurred during the follow-up period (mean, 53 months). Most of the AVMs were deep (22/27) with only one draining vein (21/27) and few feeding arteries. In more than half the cases (15/27) drainage was exclusively into the superficial venous system. CONCLUSION: Spontaneous obliteration is rare (1.3%). Common features include hemorrhagic presentation and few arterial feeding vessels. Although we found no instance of repeat hemorrhage during the follow-up period, AVMs can recanalize, and follow-up is therefore recommended.

Stereotactic radiosurgery and the risk of haemorrhage from cavernous malformations.

Eighteen patients with cerebral cavernous malformations were treated with single dose of cobalt 60 source stereotactic radiosurgery. All had suffered at least one haemorrhage prior to treatment with six suffering 2, four suffering 3 and one suffering 4. Mean follow-up was 4.5 years. A total of 36 pretreatment haemorrhages occurred in 139 patient years. The first haemorrhage each patient suffered was taken as the start of observation and not included in the rehaemorrhage rate calculation. Three posttreatment haemorrhages occurred in 81 patient years of observation. The annual haemorrhage rate thus fell from 13% before to 3.7% after treatment. The odds ratio was thus 0.29 with a 95% confidence interval of (0.08-0.97), but this must be interpreted with caution because of the prereferral selection of this group of patients. Three patients developed complications of radiosurgery, two of them recovered fully.

Ganglioneuroblastoma of the cauda equina.

A 39-year-old lady presented with low back pain and neurogenic claudication. Magnetic resonance imagining revealed an intradural neoplasm in the cauda equina region. The patient underwent lumbar laminectomy and total excision of the neoplasm. Biopsy showed it to be a ganglioneuroblastoma, which is rare in the spinal canal and so far does not appear to have been reported in the region of the cauda equina. Its management is discussed.

Distortion in magnetic resonance images obtained for stereotactic localization. Case report.

The purpose of this paper was to note a potential source of error in magnetic resonance (MR) imaging. Magnetic resonance images were acquired for stereotactic planning for GKS of a vestibular schwannoma in a female patient. The images were acquired using three-dimensional sequence, which has been shown to produce minimal distortion effects. The images were transferred to the planning workstation, but the coronal images were rejected. By examination of the raw data and reconstruction of sagittal images through the localizer side plate, it was clearly seen that the image of the square localizer system was grossly distorted. The patient was returned to the MR imager for further studies and a metal clasp on her brassiere was identified as the cause of the distortion.

Development of a relocatable frame technique for gamma knife radiosurgery. Technical note.

OBJECT: One of the limiting factors in gamma knife radiosurgery is the restriction to one treatment imposed by the fixed stereotactic frame. The ability, in selected cases, to remove the frame and replace it on a subsequent occasion in the same location would facilitate fractionated treatments and provide flexibility in the timing of treatment delivery. It is the purpose of this work to investigate techniques for frame fixation and for essential verification of frame position once it has been reapplied. METHODS: A technique is proposed that requires four surgical self-tapping screws to be inserted into the skull. Aluminum pins are inserted through the frame pillars and are tightened against the head of the screws, providing a firm fixation of the frame. Pin lengths are recorded on gauges to ensure reproducibility of the position. In phantom tests, test objects were localized (using the angiographic localizer) before and after each of five frame removal/reapplications to test the reproducibility of frame position. The mean error in the observed target coordinates was 0.3 mm and the maximum error observed was 0.7 mm, indicating that the frame can be reapplied with some confidence. Repetition of bubble skull measurements has been investigated as a means of verifying that the frame was repositioned correctly; however, reproducibility of patient measurements was found to be poor even when no frame movement had occurred. In contrast, the use of a radiotherapy simulator to obtain repeated lateral and anteroposterior projections of the head was shown to be capable of detecting frame movements of as little as 1 mm. CONCLUSIONS: Using this technique of frame application facilitates the reapplication of the frame with an accuracy of plus or minus 0.7 mm. Bubble measurements are inadequate for the detection of frame movement. Simple techniques in which a radiotherapy simulator is used can verify correct frame placement and indicate frame movements of less than 1 mm.

Adult primitive neuroectodermal tumour. A case report and review of the literature.

A 19-year-old woman presented with left-sided sensorineural hearing loss. She was found to have a left cerebellopontine angle tumour, thought to be an acoustic neuroma on MRI, and was treated with radiosurgery. There was no evidence of tumour on MRI at 6 months. After 1 year, she was admitted with further neurological symptoms. Repeat MRI showed multiple craniospinal tumours. Biopsy of the cerebellar tumour revealed it to be a primitive neuroectodermal tumour (PNET). This is a rare tumour in this age group and its management is discussed.

An improved technique for comparing Gamma Knife dose-volume distributions in stereotactic radiosurgery.

A function derived from the geometry of brachytherapy dose distributions is applied to stereotactic radiosurgery and an algorithm for the production of a novel dose-volume histogram, the Anderson inverse-square shifted dose-volume histogram (DVH), is proposed. The expected form of the function to be plotted is checked by calculating its value for single focus exposures, and its application to clinical examples of Gamma Knife treatments described. The technique is shown to provide a valuable tool for assessing the adequacy of radiosurgical plans and comparing and reporting dose distributions.

Gamma Knife radiosurgery for epilepsy associated with cavernous hemangiomas: a retrospective study of 49 cases.

A retrospective multicenter study was performed to evaluate the effectiveness of Gamma Knife radiosurgery (GKRS) in the treatment of drug resistant epilepsy associated with cavernous hemangiomas (CH). The mean duration of epilepsy before GKRS was 7.5 ¿ 9.3 years. The mean frequency of seizures was 6.9 ¿ 14/month. The mean marginal dose was 19.2 ¿ 4.4 Gy (range 11.3 to 36 Gy). The mean follow up was 23.7 ¿ 13 months. At the most recent follow-up examination, 26 (53%) patients were seizure-free (Engel s class I) including 24 in class IA (49%) and two (4%) patients with occasional auras (class IB, 4%). A highly significant decrease in the number of seizures was achieved in 10 (20%) patients, which is class lIB. The remaining 13 (2.6%) patients showed little or no improvement. A medial temporal location was associated with a higher risk of failure. In contrast, all patients with central region CH were seizure free. Two severe but transient complications were observed. There was hemorrhage in one patient and another patient suffered from radio-induced edema with transient aphasia. This series is the first demonstrating that GKRS can be used safely and efficiently to treat epilepsy associated to CH. Seizure control can be reached when a good electro-clinical correlation exists between CH location and epileptogenic zone. Our findings suggest that GKRS can be used to treat epilepsy for CH located in highly functional areas, particularly the central region.

Proximal aneurysms in association with arteriovenous malformations: do they resolve following obliteration of the malformation with stereotactic radiosurgery?

One-hundred consecutive patients were identified who had arteriovenous malformations (AVMs) treated by stereotactic radiosurgery (STRS) which were totally obliterated as shown by follow-up angiography. Of these cases, seven had intracerebral aneurysms at initial angiography, two of which were multiple. Five patients had saccular aneurysms at commonly recognized sites on the circle of Willis or main proximal cerebral arteries, while two patients had aneurysms on distal AVM feeder arteries in atypical sites (one saccular, one fusiform). Saccular aneurysms at typical sites were found to be unchanged in size following AVM obliteration. The significance of this finding in the management of patients who present with subarachnoid haemorrhage and who have both aneurysms and AVMs is discussed.

Stereotactic localization with magnetic resonance imaging: a phantom study to compare the accuracy obtained using two-dimensional and three-dimensional data acquisitions.

OBJECTIVE: To compare the accuracy of stereotactic localization using magnetic resonance imaging (Siemens 1.5-T Magnetom; Siemens, Erlangen, Germany) with two-dimensional and three-dimensional data acquisition techniques. METHODS: A phantom study was performed in which the coordinates of an array of rods were determined from images in both two-dimensional and three-dimensional studies and compared with measured values in a series of transverse, coronal, and sagittal images. RESULTS: The results demonstrated a distinct advantage in using three-dimensional acquisition; an error greater than 2 mm was identified in only 0.8% of the imaged volume, compared with 12% of the imaged volume in the two-dimensional study. CONCLUSION: The results indicated that more accurate stereotactic localization is achieved with a three-dimensional acquisition.

The potential role of myofibroblasts in the obliteration of arteriovenous malformations after radiosurgery.

OBJECTIVES: To examine the structural changes in arteriovenous malformations (AVMs) after stereotactic radiosurgery and to identify the cytoskeletal antigen phenotype of the proliferating cells to gain information about the possible mechanism of obliteration. METHODS: We conducted immunohistochemical and electromicroscopic investigations of surgical material that was removed from seven patients. The patients were harboring cerebral AVMs that had been previously treated with gamma knife irradiation, and they experienced subsequent bleeding 10 to 52 months after treatment. RESULTS: Light microscopy revealed spindle-shaped cell proliferation in the connective tissue stroma and in the subendothelial region of the vessels. The ultrastructural and immunohistochemical characteristics of these spindle cells were identical to those designated as myofibroblasts in wound healing processes and pathological fibromatoses. Whereas in nonirradiated specimens of AVMs, similar cells expressed vimentin and desmin positivity, in irradiated cases, alpha-smooth muscle actin activity was also observed. CONCLUSION: In view of the contractile activity of myofibroblasts, the proliferation generated by irradiation and the transformation of the resting cells into an activated form could be relevant to the shrinking process and eventual occlusion of AVMs after radiosurgery.

Radiosurgery: a minimally interventional alternative to microsurgery in the management of acoustic neuroma.

We report the results of treatment with radiosurgery of 29 tumours in 27 patients with acoustic neuromas between 1986 and 1989. The median follow-up was 6.6 years. The treatment appears to be an effective alternative to surgery for patients with tumours of 3 cm diameter or less. The mortality and morbidity of the treatment and the presentation of cranial nerve function is comparable to the very best surgical results. Every patient with an acoustic neuroma should be informed about this alternative to direct surgery.

In vitro contractility studies of the rat middle cerebral artery after stereotactic Gamma Knife radiosurgery.

The middle cerebral artery (MCA) was irradiated in 94 rats using the Gamma Knife. The vessels receiving 20, 50, 80 and 200 Gy were removed 24 h later and mounted on a myograph. Contractility responses to potassium and prostaglandin (PG) F2 alpha were tested. After precontraction with PGF2 alpha, the relaxant effects of histamine, papaverine, L-arginine and sodium nitroprusside were examined. Other vessels were preincubated with ouabain or N omega-nitro-L-arginine methyl ester before testing with the relaxant agents. After irradiation, the contractile response to maximal potassium and PGF concentrations was diminished, suggesting dose-dependent radiation damage to the contractile mechanism. The normal MCA shows an initial relaxation in the presence of a low K+ concentration, which is Na+, K(+)-ATPase dependent. According to this study, the endothelium-derived relaxation function was suppressed by radiation, suggesting that there is an early change in irradiated vessels, demonstrable by functional studies, which affects both the smooth muscle and endothelial layers.

Accuracy of stereotactic localisation using magnetic resonance imaging: a comparison between two- and three-dimensional studies.

The accuracy of stereotactic localisation using magnetic resonance (MR) imaging has been assessed in a phantom study. Parallel studies compared the accuracy obtained. First, a series of two-dimensional (2D) MR slices (transverse, coronal, and sagittal) was acquired sequentially to image the three-dimensional (3D) volume of the phantom. Then, the same volume was imaged in a 3D MR study in which the entire volume was excited simultaneously and 2D slices in transverse, coronal, and sagittal planes were then reconstructed from the 3D data set. The results showed that the 3D acquisition gave superior results in all three planes, and overall it was found that only 1% of the phantom volume was affected by an error greater than 2 mm, compared with 11% for the 2D study. New facilities for image quality assurance provided in GammaPlan version 3.0 have been tested against images from the 2D study with known distortion and consequent localisation errors and successfully identified all images in which the localisation errors were likely to be greater than 3.7 mm.

A phantom study to assess the accuracy of stereotactic localization, using T1-weighted magnetic resonance imaging with the Leksell stereotactic system.

This phantom study assesses the accuracy of stereotactic localization using the Leksell G frame (Elekta Instruments AB, Stockholm, Sweden) with T1-weighted magnetic resonance imaging (Siemens 1.5 T Magnetom; Erlangen, Germany). The coordinates of an array of solid perspex rods were determined and compared with measured values in a series of transverse, coronal, and sagittal images. The maximum absolute errors observed (X = 2.7 mm, Y = 7.0 mm, Z = 8.0 mm) were discouraging. However, the more reasonable mean errors (X = 0.4 mm, Y = 0.7 mm, Z = 1.3 mm) reflect considerable variation in accuracy throughout the volume assessed and limitation of maximum errors to specific areas. We present details of the spatial variation and discuss possible mechanisms for improving accuracy. The overall results are of direct relevance only to the scanner used. These results are, however, an indication of the need to approach with caution stereotactic localization using magnetic resonance imaging and to emphasize the requirement for quality assurance and for a comprehensive study of the scanner's characteristics.