Hans Jakob Steiger

Comparison of 18 F-FET PET and 5-ALA fluorescence in cerebral gliomas

PurposeThe aim of the study was to compare presurgical 18F-fluoroethyl-L-tyrosine (18F-FET) uptake and Gd-diethylenetriaminepentaacetic acid (DTPA) enhancement on MRI (Gd) with intraoperative 5-aminolevulinic acid (5-ALA) fluorescence in cerebral gliomas.Methods18F-FET positron emission tomography (PET) was performed in 30 patients with brain lesions suggestive of diffuse WHO grade II or III gliomas on MRI. PET and MRI data were coregistered to guide neuronavigated biopsies before resection. After oral application of 5-ALA, 38 neuronavigated biopsies were taken from predefined tumour areas that were positive or negative for 18F-FET or Gd and checked for 5-ALA fluorescence. 18F-FET uptake with a mean tumour to brain ratio ≥1.6 was rated as positive.ResultsOf 38 biopsies, 21 corresponded to high-grade glioma tissue (HGG) of WHO grade III (n = 19) or IV (n = 2) and 17 biopsies to low-grade glioma tissue (LGG) of WHO grade II. In biopsies corresponding to HGG, 18F-FET PET was positive in 86% (18/21), but 5-ALA and Gd in only 57% (12/21). A mismatch between Gd and 5-ALA was observed in 6 of 21 cases of HGG biopsy samples (3 Gd-positive/5-ALA-negative and 3 Gd-negative/5-ALA-positive). In biopsies corresponding to LGG, 18F-FET was positive in 41% (7/17), while 5-ALA and Gd were negative in all but one instance. All tumour areas with 5-ALA fluorescence were positive on 18F-FET PET.ConclusionThere are differences between 18F-FET and 5-ALA uptake in cerebral gliomas owing to a limited sensitivity of 5-ALA to detect tumour tissue especially in LGG. 18F-FET PET is more sensitive to detect glioma tissue than 5-ALA fluorescence and should be considered as an additional tool in resection planning.

Outcome of aneurysmal subarachnoid hemorrhage in a hospital population: a prospective study including early operation, intravenous nimodipine, and transcranial Doppler ultrasound

A total of 153 consecutive patients with proven aneurysmal subarachnoid hemorrhages (SAHs) admitted immediately after diagnosis regardless of clinical condition were managed according to the same protocol. The initial evaluation included computed tomography (CT), transcranial Doppler ultrasound (TCD), angiography-CT, and/or angiography. Intravenous nimodipine (2 mg/hour) was started after confirmation of the diagnosis. The timing of operation was determined individually according to age, clinical course, and CT and TCD findings. Twenty-one Grade V patients treated with intensive care and ventriculostomy died or did not improve within 24 hours after SAH. Three patients with life-threatening intracerebral hematomas underwent emergency operation. Operation was early in 55 good risk patients and late in 57 patients because of poor initial grade, late admission, or logistic reasons. Seventeen patients had no operation because of old age, persistent poor clinical condition, medical complication, or lethal rebleeding before operation. In the total series, 90 patients (59%) made a full recovery, the overall morbidity rate was 14% (21 of 153 cases), and the mortality rate was 27% (42 of 153). Postoperative mortality including emergency evacuation of hematomas was 7.8% and mortality after elective operation was 6.2%. The causes of disability and death were the initial effect of the hemorrhage in 25 patients (16.3%), rebleeding in 15 (9.8%), delayed cerebral infarction in 8 (5.2%), surgical complications in 7 (4.5%), hydrocephalus in 4 (2.6%), and medical complications in 4 (2.6%).

Clinicopathological relations of cerebral cavernous angiomas: observations in eleven cases.

Eleven cases of cerebral cavernous angiomas (cavernomas) were observed within a period of 3 years. Two patients presented with cerebral hemorrhage, five with epilepsy, three each with a progressive focal neurological deficit, and one with papilledema. The unruptured lesions had a heterogeneous density on computed tomography with relatively little contrast enhancement. Two lesions contained major cysts. In one of these cases, the cyst measured 5.5 cm in diameter, had an enhancing membrane, and was surrounded by brain edema. Angiography did not show hypervascularity in any instance. During exploration and histological processing, special attention was paid to signs of previous silent hemorrhages and to the degree of encapsulation of the lesion. Iron deposits (signs of previous hemorrhages) were seen to varying degrees inside all cavernomas as well as in the surrounding gliotic cerebrum, and a causal relation between iron deposits and epileptic seizures seems likely. Encapsulation was minimal with the ruptured cavernomas and particularly prominent with the cystic lesions. The membrane of the giant cystic lesion with peripheral brain edema had a histological structure similar to that of the membranes of chronic subdural hematomas. It is suggested that continuous growth of cavernoma cysts is the result of recurrent hemorrhages from sinusoids of the malformation and from the neocapillary network of the cyst membranes.

Finding the anaplastic focus in diffuse gliomas: the value of Gd-DTPA enhanced MRI, FET-PET, and intraoperative, ALA-derived tissue fluorescence.

OBJECTIVE Diffuse gliomas may harbor anaplastic foci which affect prognosis and determine adjuvant therapies. Such foci are not always detected by contrast-enhancement on MRI. Recently, other modalities have been introduced, such as FET-PET for pre-diagnostic imaging and 5-aminolevulinic derived tumor fluorescence for intraoperative identification of malignant glioma tissue. The relationship between these modalities and their value for guiding biopsies during resection has not yet been elucidated in the group of diffuse gliomas. METHODS FET-PET was performed in 30 consecutive patients with intracerebral lesions suggestive of diffuse gliomas on MRI with or without areas of contrast-enhancement. Prior to surgery patients were given 5-ALA at a dose of 20mg/kg body weight. Areas of FET uptake with a lesion/brain ratio of 1.6 or more were considered indicators of tumor. FET-PET data were corregistered with MRI data before surgery in order to obtain neuronavigated biopsies during resection, which were collected from FET positive and negative areas, analyzed for tumor fluorescence and correlated to contrast-enhancement on MRI. RESULTS 13 of 30 tumors were diagnosed as gliomas WHO Grade II, 15 as gliomas WHO Grade III and 2 as gliomas WHO Grade IV. The mean lesion/brain tissue ratio of FET uptake was significantly greater for high-grade than for low-grade gliomas (averages SD 2.323±0.754 vs. 1.453±0.538 p=0.0014). A match of FET-pos/ALA-pos biopsies was found in 70.6% (12/17) of high-grade gliomas (WHO Grade III/IV) but only in 7.7% (1/13) of low grade gliomas. Gd-neg/FET-neg/ALA-neg biopsies yielded a low-grade tumor in 46.2% (6/13). A mismatch between FET uptake and 5-ALA (FET-pos/ALA-neg) was found in 46.2% (6/13) of the low-grade and in 17.6% (3/17) of the high-grade tumors. The combination of FET-PET- and 5-ALA-positivity yielded a sensitivity for identifying high-grade glioma foci of 70.5% and a specificity of 92.3%. CONCLUSIONS In low grade gliomas 5-ALA fluorescence is the exception and FET PET is more sensitive. High grade areas in diffuse gliomas with anaplastic foci usually fluoresce, if they are FET PET positive. As a result, FET PET appears valuable for pre-operative identification of anaplastic foci and hot spots are strongly predictive for ALA-derived fluorescence, which highlight anaplastic foci during resection.

Ischaemic preconditioning of the brain, mechanisms and applications

SummaryBackground. The concept of ischaemic preconditioning was introduced in the late 1980s. The concept emerged that a brief subcritical ischaemic challenge could mobilize intrinsic protective mechanisms that increased tolerance against subsequent critical ischaemia. Tissues with a high sensitivity against ischaemia, i.e. myocardium and central nervous system, present the most promising targets for therapeutic application of ischaemic preconditioning. During the last years the mechanisms of neuronal preconditioning were systematically studied and a number of molecular regulation pathways were discovered to participate in preconditioning. The purpose of the present review is to survey the actual knowledge on cerebral preconditioning, and to define the practical impact for neurosurgery.Methods. A systematic medline search for the terms preconditioning and postconditioning was filed. Publications related to the nervous system were selected and analysed.Findings. Preconditioning can be subdivided into early and late mechanisms, depending on whether the effect appears immediately after the nonlethal stress or with a delay of some hours or days. In general early effects can be linked to adaptation of membrane receptors whereas late effects are the result of gene up- or downregulation. Not only subcritical ischaemia can trigger preconditioning but also hypoxia, hyperthermia, isoflurane and other chemical substances. Although a vast amount of knowledge has been accumulated regarding neural preconditioning, it is unknown whether the effects can be potentiated by pharmacological or hypothermic neuroprotection during the critical ischaemia. Furthermore, although the practical importance of these findings is obvious, the resulting protective manipulations have so far not been transferred into clinical neurosurgery. Postconditioning and remote ischaemic preconditioning are additional emerging concepts. Postconditioning with a series of mechanical interruptions of reperfusion can apparently reduce ischaemic damage. Remote ischaemic preconditioning refers to the concept that transient ischaemia for example of a limb can lead to protection of the myocardium and possibly the brain.Conclusion. Possible cumulative neuroprotection by preconditioning and pharmacological protection during critical ischaemia should be studied systematically. Easy to apply methods of preconditioning, such as the application of volatile anaesthetics or erythropoietin some hours or days prior to planned temporary ischaemia, should be introduced into the practice of operative neurosurgery.

Diagnostic Performance of 18F-FET PET in Newly Diagnosed Cerebral Lesions Suggestive of Glioma

The aim of this study was to assess the clinical value of O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET in the initial diagnosis of cerebral lesions suggestive of glioma. Methods: In a retrospective study, we analyzed the clinical, radiologic, and neuropathologic data of 174 patients (77 women and 97 men; mean age, 45 ± 15 y) who had been referred for neurosurgical assessment of unclear brain lesions and had undergone 18F-FET PET. Initial histology (n = 168, confirmed after surgery or biopsy) and the clinical course and follow-up MR imaging in 2 patients revealed 66 high-grade gliomas (HGG), 77 low-grade gliomas (LGG), 2 lymphomas, and 25 nonneoplastic lesions (NNL). In a further 4 patients, initial histology was unspecific, but during the course of the disease all patients developed an HGG. The diagnostic value of maximum and mean tumor-to-brain ratios (TBRmax/TBRmean) of 18F-FET uptake was assessed using receiver-operating-characteristic (ROC) curve analyses to differentiate between neoplastic lesions and NNL, between HGG and LGG, and between high-grade tumor (HGG or lymphoma) and LGG or NNL. Results: Neoplastic lesions showed significantly higher 18F-FET uptake than NNL (TBRmax, 3.0 ± 1.3 vs. 1.8 ± 0.5; P < 0.001). ROC analysis yielded an optimal cutoff of 2.5 for TBRmax to differentiate between neoplastic lesions and NNLs (sensitivity, 57%; specificity, 92%; accuracy, 62%; area under the curve [AUC], 0.76; 95% confidence interval [CI], 0.68–0.84). The positive predictive value (PPV) was 98%, and the negative predictive value (NPV) was 27%. ROC analysis for differentiation between HGG and LGG (TBRmax, 3.6 ± 1.4 vs. 2.4 ± 1.0; P < 0.001) yielded an optimal cutoff of 2.5 for TBRmax (sensitivity, 80%; specificity, 65%; accuracy, 72%; AUC, 0.77; PPV, 66%; NPV, 79%; 95% CI, 0.68–0.84). Best differentiation between high-grade tumors (HGG or lymphoma) and both NNL and LGG was achieved with a TBRmax cutoff of 2.5 (sensitivity, 79%; specificity, 72%; accuracy, 75%; AUC, 0.79; PPV, 65%; NPV, 84%; 95% CI, 0.71–0.86). The results for TBRmean were similar with a cutoff of 1.9. Conclusion: 18F-FET uptake ratios provide valuable additional information for the differentiation of cerebral lesions and the grading of gliomas. TBRmax of 18F-FET uptake beyond the threshold of 2.5 has a high PPV for detection of a neoplastic lesion and supports the necessity of an invasive procedure, for example, biopsy or surgical resection. Low 18F-FET uptake (TBRmax < 2.5) excludes a high-grade tumor with high probability.

Haemodynamic stress in lateral saccular aneurysms: An experimental study

SummaryThe flow velocities in lateral glass and silastic aneurysm models were quantitatively measured with the non-invasive laser Doppler method. The influences of the elasticity of the wall, the pulse wave and the properties of the perfusion medium on the intra-aneurysmal circulation were investigated. As shown previously, the inflow into the aneurysm arose from the downstream lip and was directed toward the centre of the fundus. Backflow to the parent vessel took place along the walls of the fundus. With non-pulsatile perfusion, flow velocities in the centre of the standardized aneurysms varied between 0.4 and 2% of the maximum velocity in the parent vessel. With pulsatile perfusion, flow velocities in the centre of the fundus ranged between 8 and 13% of the flow velocity in the axis of the parent vessel. Flow velocities in the aneurysms were slower with a macromolecular perfusion medium with blood like properties compared to a glycerol/water solution. Flow velocity measurements near the aneurysmal wall allowed the estimation of the shear stresses at critical locations. The maximum shear stresses at the downstream lip of the aneurysm were in the range of the stresses measured at the flow divider of an arterial bifurcation. The present results suggest that in human saccular aneurysms intra-aneurysmal flow and shear stress on the wall are directly related to the pulsatility of perfusion,i.e. the systolic/diastolic pressure difference and that the tendency to spontaneous thrombosis depends on the viscoelastic properties of the blood, namely the haematocrit.

Strength, elasticity and viscoelastic properties of cerebral aneurysms

SummaryTissue strength and stiffness of cerebral aneurysm walls obtained intraoperatively or at autopsy were evaluated by uniaxial strain/stress measurements. For comparison, corresponding measurements were also made on autopsy specimens of intracranial arteries. The maximum stress that the aneurysm tissue could tolerate, the yield stress, was found to be slightly lower than in arteries, which is likely due to the content of immature forms of collagen. The material stiffness, as determined by division of the yield stress by the corresponding strain, was also smaller in aneurysms than in arteries. The stress resistance of aneurysms and arterial tissue decreased over a period of several hours. The relaxation curves were found to be identical in aneurysms and arteries. The stress tolerated by aneurysm walls was found to be in the range of the stress that is imposed in vivo by the blood pressure. Arteries resisted stresses corresponding to pressures 5–10 times higher than physiological values. It is suggested that the balance of tissue strength and the stress imposed by the blood pressure is causally related to aneurysm growth.

Basic flow structure in saccular aneurysms: a flow visualization study

SummaryBasic flow patterns were investigated in a set of glass aneurysm models by means of flow visualization methods. Dye injection and streaming double refraction were used to visualize flow. The circulation inside lateral aneurysms arising at a 90° angle from a straight parent conduit could not be visualized by the dye-injection technique but could be demonstrated by streaming double refraction. The inflow was seen to arise from the downstream lip of the orifice and to project to the dome of the aneurysm. Backflow to the parent conduit took place along the walls of the aneurysm. In aneurysms located at bifurcations, flow characteristics depended on the geometry of the bifurcation and the flow ratio between the branches. Relatively little intra-aneurysmal flow was demonstrated in side branch-related aneurysms arising distal to an asymmetric 90° bifurcation of the type encountered at the junction of the internal carotid and posterior communicating arteries. Stagnation of flow at the neck and little intra-aneurysmal circulation were found with terminal aneurysms of the basilar bifurcation type if the outflow through the branches was symmetric. With asymmetric outflow, however, or if the axis of the aneurysm did not coincide with that of the afferent vessel, an active rotation developed in these aneurysms. The size of the aneurysm had no influence on the basic pattern of intra-aneurysmal circulation. The use of pulsatile perfusion did not significantly alter the basic flow patterns observed with steady flow. Locally disturbed laminar flow was observed in certain models at physiological Reynolds numbers, but there were no signs of fully developed turbulence.

Hemodynamic stress in terminal saccular aneurysms: A laser-doppler study

SummaryThe flow conditions and the related stresses in glass and silastic model aneurysms located at bifurcations were quantitatively determined by means of laser-Doppler-anemometry. The flow velocities in straight terminal models with the aneurysm forming an extension of the afferent vessel were unstable if the outflow through the branches of the bifurcation was balanced. Average flow velocities in the fundus were small, but irregular flow fluctuations of high amplitudes were observed. Asymmetrical outflow through the branches of the bifurcation induced a rotatory intra-aneurysmal circulation from the dominant to the subordinate branch. The circulation in angled terminal aneurysms with the aneurysmal axis at a 45° angle to the plane of the bifurcation was a vortex caused by the eccentric inflow from the afferent vessel. Maximum flow velocities measured in the center plane of the angled terminal aneurysms were in the range 50%–80% of the axial velocity in the afferent vessel. The present results indicate that the geometrical relation between aneurysm and parent vessels is the primary factor governing the intra-aneurysmal flow pattern. The elasticity of the models did not affect the average flow velocities, but the intra-aneurysmal pulse wave was damped in elastic models. On the basis of the measured velocity gradients near the walls, maximum shear stresses on the wall of a typical human terminal aneurysm were estimated to be in the order of 50 dyne/cm2 (5 Pascal), a value that is similar to the shear stresses that occur at the flow divider of a cerebral artery bifurcation. This is based on absolute flow velocity measurements in patients [8, 13].