Can we use gonadotropin plasma concentration as surrogate marker for BMI-related incomplete estrogen suppression in breast cancer patients receiving anastrozole?

BACKGROUND: BMI has been suggested to impact on estrogenic activity in patients receiving anastrozole resulting in a reduced treatment efficacy in obese women. Current evidence in this regard is controversially discussed. Since estradiol is inversely correlated with gonadotropins it can be assumed that an impact of BMI is also reflected by gonadotropin plasma concentrations. We aim at investigating the impact of BMI on the hormonal state of breast cancer (BC) patients receiving anastrozole indicated by LH, FSH and SHBG as well as estradiol. METHODS: We determined gonadotropin-, estradiol- and anastrozole- serum concentrations from postmenopausal, early stage breast cancer patients receiving upfront anastrozole within routine after care. Gonadotropin plasma concentrations were derived from the routine laboratory examination report. A liquid chromatography tandem mass spectrometry method was used for the measurement of anastrozole serum concentrations. BMI was assessed within the routine after-care check-up. RESULTS: The overall sample comprised 135 BC patients with a mean age of 65.3 years. BMI was significantly correlated with LH, FSH and SHBG. This association was neither influenced by age nor by anastrozole serum concentrations according to the regression model. Despite aromatase inhibition 12% of patients had detectable estrogen levels in routine quantification. CONCLUSION: Obese women have an altered hormonal situation compared to normally weight women under the same dose of anastrozole. Our study findings are a further indicator for the relevance of BMI in regard of anastrozole metabolism and possible estrogenic activity indicated by gonadotropin plasma level.

Dysregulation of the (immuno)proteasome pathway in malformations of cortical development.

BACKGROUND: The proteasome is a multisubunit enzyme complex involved in protein degradation, which is essential for many cellular processes. During inflammation, the constitutive subunits are replaced by their inducible counterparts, resulting in the formation of the immunoproteasome. METHODS: We investigated the expression pattern of constitutive (ß1, ß5) and immunoproteasome (ß1i, ß5i) subunits using immunohistochemistry in malformations of cortical development (MCD; focal cortical dysplasia (FCD) IIa and b, cortical tubers from patients with tuberous sclerosis complex (TSC), and mild MCD (mMCD)). Glial cells in culture were used to elucidate the mechanisms regulating immunoproteasome subunit expression. RESULTS: Increased expression was observed in both FCD II and TSC; ß1, ß1i, ß5, and ß5i were detected (within cytosol and nucleus) in dysmorphic neurons, balloon/giant cells, and reactive astrocytes. Glial and neuronal nuclear expression positively correlated with seizure frequency. Positive correlation was also observed between the glial expression of constitutive and immunoproteasome subunits and IL-1ß. Accordingly, the proteasome subunit expression was modulated by IL-1ß in human astrocytes in vitro. Expression of both constitutive and immunoproteasome subunits in FCD II-derived astroglial cultures was negatively regulated by treatment with the immunomodulatory drug rapamycin (inhibitor of the mammalian target of rapamycin (mTOR) pathway, which is activated in both TSC and FCD II). CONCLUSIONS: These observations support the dysregulation of the proteasome system in both FCD and TSC and provide new insights on the mechanism of regulation the (immuno)proteasome in astrocytes and the molecular links between inflammation, mTOR activation, and epilepsy.

[Quality guidelines for presurgical epilepsy diagnosis and operative epilepsy therapy: 1st revised version]. / Qualitätsleitlinien für prächirurgische Epilepsiediagnostik und operative Epilepsietherapie : 1. Neufassung.

In patients with pharmacorefractory epilepsy, preoperative epilepsy evaluation and subsequent epilepsy surgery lead to a significant improvement of seizure control, proportion of seizure-free patients, quality of life and social participation. The aims of preoperative epilepsy evaluation are to define the chance of complete seizure freedom and the likelihood of inducing new neurological deficits in a given patient. As epilepsy surgery is an elective procedure quality standards are particularly high. As detailed in the first edition of these practice guidelines, quality control relates to seven different domains: (1) establishing centres with a sufficient number of sufficiently and specifically trained personnel, (2) minimum technical standards and equipment, (3) continuing medical education of employees, (4) surveillance by trained personnel during the video electroencephalography (EEG) monitoring (VEM), (5) systematic acquisition of clinical and outcome data, (6) the minimum number of preoperative evaluations and epilepsy surgery procedures and (7) cooperation of epilepsy centres. In the first edition of these practice guidelines published in 2000 it was defined which standards were desirable and that their implementation should be aimed for. These standards related especially to the certification required for different groups of medical doctors involved and to the minimum numbers of procedures required. In the subsequent decade quite a number of colleagues have been certified by the trinational Working Group (Arbeitsgemeinschaft, AG) for Presurgical Epilepsy Diagnosis and Operative Epilepsy Treatment (http://www.ag-epilepsiechirurgie.de) and therefore, on 8 May 2013 the executive board of the AG decided to now make these standards obligatory.

Voxel-Based Morphometry-from Hype to Hope. A Study on Hippocampal Atrophy in Mesial Temporal Lobe Epilepsy.

BACKGROUND AND PURPOSE: Automated volumetry of the hippocampus is considered useful to assist the diagnosis of hippocampal sclerosis in temporal lobe epilepsy. However, voxel-based morphometry is rarely used for individual subjects because of high rates of false-positives. We investigated whether an approach with high dimensional warping to the template and nonparametric statistics would be useful to detect hippocampal atrophy in patients with hippocampal sclerosis. MATERIALS AND METHODS: We performed single-subject voxel-based morphometry with nonparametric statistics within the framework of Statistical Parametric Mapping to compare MRI from 26 well-characterized patients with temporal lobe epilepsy individually against a group of 110 healthy controls. The following statistical threshold was used: P < .05 corrected for multiple comparisons with family-wise error over the region of interest right and left hippocampus. RESULTS: The sensitivity for the detection of atrophy related to hippocampal sclerosis was 0.92 (95% CI, 0.67-0.99) for the right hippocampus and 0.60 (0.31-0.83) for the left, and the specificity for volume changes was 0.98 (0.93-0.99). All clusters of decreased hippocampal volumes were correctly lateralized to the seizure focus. Hippocampal volume decrease was in accordance with neuronal cell loss on histology reports. CONCLUSIONS: Nonparametric voxel-based morphometry is sensitive and specific for hippocampal atrophy in patients with mesial temporal lobe epilepsy and may be useful in clinical practice.

Lesion-Specific Language Network Alterations in Temporal Lobe Epilepsy.

BACKGROUND AND PURPOSE: Temporal lobe epilepsy, structural or nonlesional, may negatively affect language function. However, little is known about the lesion-specific influence on language networks. We hypothesized that different epileptogenic lesions are related to distinct alterations in the functional language connectome detected by fMRI. MATERIALS AND METHODS: One hundred one patients with epilepsy due to mesiotemporal sclerosis (21 left, 22 right), low-grade mesiotemporal tumors (12 left), or nonlesional temporal lobe epilepsy (22 left, 24 right) and 22 healthy subjects performed 3T task-based language fMRI. Task-based activation maps (laterality indices) and functional connectivity analysis (global and connectivity strengths between language areas) were correlated with language scores. RESULTS: Laterality indices based on fMRI activation maps failed to discriminate among patient groups. Functional connectivity analysis revealed the most extended language network alterations in left mesiotemporal sclerosis (involving the left temporal pole, left inferior frontal gyrus, and bilateral premotor areas). The other patient groups showed less extended but also predominantly ipsilesional network changes compared with healthy controls. Left-to-right hippocampal connectivity strength correlated positively with naming function (P = .01), and connectivity strength between the left Wernicke area and the left hippocampus was linked to verbal fluency scores (P = .01) across all groups. CONCLUSIONS: Different pathologies underlying temporal lobe epilepsy are related to distinct alterations of the functional language connectome visualized by fMRI functional connectivity analysis. Network analysis allows new insights into language organization and provides possible imaging biomarkers for language function. These imaging findings emphasize the importance of a personalized treatment strategy in patients with epilepsy.

Assessing Corticospinal Tract Asymmetry in Unilateral Polymicrogyria.

BACKGROUND AND PURPOSE: Asymmetry of the corticospinal tract in congenital lesions is a good prognostic marker for preserved motor function after hemispherectomy. This study aimed to assess this marker and provide a clinically feasible approach in selected cases of unilateral polymicrogyria. MATERIALS AND METHODS: Corticospinal tract asymmetry of 9 patients with unilateral polymicrogyria substantially affecting the central region was retrospectively assessed on axial T1WI and DTI. Volumes of the brain stem and thalamus and DTI parameters of the internal capsule were measured. Two neuroradiologists independently rated the right-left asymmetry at 4 levels along the corticospinal tract. DTI tractography was used to determine the motor cortex within polymicrogyria, with task-based functional MR imaging available in 3/9 cases. RESULTS: Visual assessment of the brain stem asymmetry showed excellent correlation with quantitative measures on both T1WI and color-coded DTI maps (P = .007 and P = .023). Interrater reliability regarding structural and DTI-based corticospinal tract asymmetry was best at the midbrain (Cohen κ = 0.77, P = .018). Three patients underwent functional hemispherectomy with postsurgical stable motor function, all showing marked corticospinal tract asymmetry preoperatively. Following the DTI-based corticospinal tract trajectories allowed identifying the presumed primary motor region within the dysplastic cortex in 9/9 patients, confirmed by functional MR imaging in 3/3 cases. CONCLUSIONS: Visual assessment of corticospinal tract asymmetry in unilateral polymicrogyria involving the motor cortex is most reliable with T1WI and color-coded DTI maps at the level of the midbrain. Pronounced asymmetry predicts preserved motor function after hemispherectomy. DTI-based tractography can be used as a guidance tool to the motor cortex within polymicrogyria.

Novel familial mutation of LRP5 causing high bone mass: Genetic analysis, clinical presentation, and characterization of bone matrix mineralization.

The Wnt signalling pathway is a critical regulator of bone mass and quality. Several heterozygous mutations in the LRP5 gene, a Wnt co-receptor, causing high bone mass (LRP5-HBM) have been described to date. The pathogenic mechanism is thought to be a gain-of-function caused by impaired inhibition of the canonical Wnt signalling pathway, thereby leading to increased bone formation. We report the cases of two affected family members, a 53-year-old mother and her 23-year-old daughter, with high bone mass (T-scores mother: lumbar spine 11.4, femoral neck 10.5; T-scores daughter: lumbar spine 5.4, femoral neck 8.7), increased calvarial thickness, and thickened cortices of the long bones but no history of fractures. Whereas the mother did not show any indications of the mutation, the daughter suffered from congenital hearing impairment resulting in cochlear implantation, recurrent facial palsy, and migraine. In addition, she had stenosis of the foramen magnum. In both individuals, we detected a novel heterozygous duplication of six basepairs in the LRP5 gene, resulting in an insertion of two amino acids, very likely associated with a gain-of-function. When the daughter had part of the occipital bone surgically removed, the bone sample was used for the visualization of bone lamellar structure and bone cells as well as the measurement of bone mineralization density distribution (BMDD). The bone sample revealed two distinctly different regions: an intra-cortical region with osteonal remodeling, typical osteonal lamellar orientation, associated with relatively higher heterogeneity of bone matrix mineralization, and another periosteal region devoid of bone remodeling, with parallel bone lamellae and lower heterogeneity of mineralization. In conclusion, we present data on bone tissue and material level from an LRP5-HBM patient with a novel mutation in the LRP5 gene. Our findings indicate normal morphology of osteoclasts and osteoblasts as well as normal mineralization in skull bone in LRP5-HBM.

Histopathological prognostic factors in medulloblastoma: high expression of survivin is related to unfavourable outcome.

Standard postoperative treatment of medulloblastoma consists of craniospinal irradiation and chemotherapy. Currently, only clinical factors are used for therapy stratification. To optimise treatment and patient outcome, biological prognostic markers are needed. In the present study we tested the prognostic influence of four histopathological parameters considered in recent publications as prognostic factors in medulloblastoma. We analysed a series of 82 Austrian medulloblastoma patients who were treated according to the consecutive HIT protocols for medulloblastoma conducted by the German Society of Paediatric Haematology and Oncology. Histological subtype and immunohistochemical expression of erbB-2, TRKC, and survivin were determined on paraffin embedded tumour tissue and correlated with patient outcome. Statistical analysis showed a significant correlation of high expression levels of survivin with decreased survival. None of the other investigated histopathological factors correlated significantly with patient outcome. Our data indicate that high survivin expression is related to unfavourable clinical outcome in medulloblastoma patients.

Fast analysis of 4-tertoctylphenol, pentachlorophenol and 4-nonylphenol in river sediments by QuEChERS extraction procedure combined with GC-QqQ-MS/MS.

A quick, easy, cheap, effective, rugged and safe (QuEChERS)-based extraction method has been optimized for the determination of pentachlorophenol, 4-tertoctylphenol and 4-nonylphenol in river sediments. The extraction method was followed by gas chromatography-triple quadrupole tandem mass spectrometry (GC-QqQ-MS/MS) analysis, which ensures the reliable identification of the target compounds. The proposed method has been validated allowing the successful determination of the selected compounds, with recoveries ranging from 72 to 96%, when three concentration levels were evaluated (10, 50 and 100µgkg(-1)) and inter-day and intra-day precision, expressed as relative standard deviation (RSD), were lower than 20%. The method showed limits of detection (LODs) and limits of quantification (LOQs) ranging from 0.1 to 2.0µgkg(-1) and from 0.5 to 5.0µgkg(-1), respectively. Finally, 25 real samples from Poland have been analyzed, and only 4-tertoctylphenol was detected at concentrations up to 8.9µgkg(-1) of soil dry weight.

Plasticity of Y1 and Y2 receptors and neuropeptide Y fibers in patients with temporal lobe epilepsy.

Marked expression of neuropeptide Y (NPY) and its Y2 receptors in hippocampal mossy fibers has been reported in animal models of epilepsy. Because NPY can suppress glutamate release by activating presynaptic Y2 receptors, these changes have been proposed as an endogenous protective mechanism. Therefore, we investigated whether similar changes in the NPY system may also take place in human epilepsy. We investigated Y1 and Y2 receptor binding and NPY immunoreactivity in hippocampal specimens that were obtained at surgery from patients with temporal lobe epilepsy and in autopsy controls. Significant increases in Y2 receptor binding (by 43-48%) were observed in the dentate hilus, sectors CA1 to CA3, and subiculum of specimens with, but not in those without, hippocampal sclerosis. On the other hand, Y1 receptor binding was significantly reduced (by 62%) in the dentate molecular layer of sclerotic specimens. In the same patients, the total lengths of NPY immunoreactive (NPY-IR) fibers was markedly increased (by 115-958%) in the dentate molecular layer and hilus, in the stratum lucidum of CA3, and throughout sectors CA1 to CA3 and the subiculum, as compared with autopsies. In nonsclerotic specimens, increases in lengths of NPY-IR fibers were more moderate and statistically not significant. NPY mRNA was increased threefold in hilar interneurons of sclerotic and nonsclerotic specimens. It is suggested that abundant sprouting of NPY fibers, concomitant upregulation of Y2 receptors, and downregulation of Y1 receptors in the hippocampus of patients with Ammon's horn sclerosis may be endogenous anticonvulsant mechanisms.

Growth hormone-prolactin-thyrotropin-secreting pituitary adenoma in atypical McCune-Albright syndrome with functionally normal Gs alpha protein.

The McCune-Albright syndrome (MAS) comprises a triad of physical signs: localized bone lesions termed polyostotic fibrous dysplasia, café-au-lait pigmentation of the skin, and autonomous hyperfunction of multiple endocrine systems, including overproduction of GH and T4. A somatic activating point mutation in the gene for the alpha-subunit of the G-protein (Gs alpha) in the affected tissue has been claimed to be the underlying defect. A 29-yr-old patient with MAS, showing polyostotic fibrous dysplasia associated with acromegalic features, underwent endocrinological studies, including oral glucose tolerance test and pituitary stimulation test, and magnetic resonance imaging, revealing elevated plasma concentrations of GH, PRL, and secondary hyperthyroidism due to pituitary macroadenoma infiltrating the sphenoid cavity and extending to the suprasellar space. Subsequently, reduction of tumor mass by a transsphenoidal and a subsequent subfrontal operation led to only marginal amelioration of the excessive hormone production. Postsurgery octreotide and bromocriptine therapy induced near-normalization of hormone concentrations. Immunohistochemistry of tumor tissue confirmed the plurihormonal character, but DNA sequence analysis did not detect any of the two known activating mutations in the Gs alpha gene. Furthermore, biochemical tests revealed normal Gs alpha function, ruling out other mutations that lead to constitutive Gs alpha activation. Our study documents that MAS is a heterogeneous disease. Some, but clearly not all, patients have oncogenic mutations of the gene coding for Gs alpha. Any gene acting down-stream of Gs can theoretically be predicted to result in the same phenotype. In addition, hyperthyroidism of MAS may be secondary to a TSH-producing pituitary macroadenoma.

Intra-arterial thrombolysis for the treatment of perioperative childhood cardioembolic stroke.

Local intra-arterial lysis using recombinant tissue plasminogen activator (rTPA) was performed in a 6 and 2/3-year-old patient with major cardioembolic ischemic stroke 48 hours after intracardiac surgery. Selective application of 2.5 mg rTPA (0.11 mg/kg body weight) resulted in recanalization of the occluded cerebral vasculature with good neurologic recovery.

Propagation of interictal epileptic activity in temporal lobe epilepsy.

We recorded interictal spikes with closely spaced scalp electrodes and sphenoidal electrodes in four patients with temporal lobe epilepsy. We used multiple dipole modeling to study the number, three-dimensional intracerebral location, time activity, and functional relationship of the neuronal sources underlying the epileptic spike complexes. In all patients, we found two significant sources generating the interictal spikes which showed considerable overlap in both space and time. Source 1 was located in the mesiobasal temporal lobe and generated a restricted negativity at the ipsilateral sphenoidal electrode and a widespread positivity over the vertex. Source 2 could be attributed to the lateral temporal neocortex and was associated with a relatively restricted negativity at the ipsilateral temporal electrodes and a more widespread positivity over the contralateral hemisphere. The sources were well separated in space, with an average distance of 45 mm between them. The time activities of both sources showed similar biphasic patterns, with the mesial source leading the lateral source by approximately 40 msec, suggesting propagation of interictal epileptic activity from the mesiobasal to the lateral temporal lobe.

Genital automatisms in complex partial seizures.

OBJECTIVE: To determine which brain region is responsible for the generation of sexual automatisms. METHODS: Ninety consecutive patients with medically refractory focal epilepsy (74 with temporal lobe and 16 with frontal lobe epilepsy) referred to an epilepsy monitoring unit were studied. The occurrence of the following sexual automatisms was assessed during prolonged video-EEG monitoring: 1) repeatedly grabbing or fondling the genitals and 2) pelvic or truncal thrusting or similar movements. RESULTS: Five patients repeatedly fondled or grabbed their genitals during or immediately after some of their seizures. All five had temporal lobe epilepsy, as evidenced from prolonged video-EEG monitoring, high-resolution MRI, and good to excellent outcome after epilepsy surgery. Sexual automatisms did not occur with frontal lobe epilepsy. CONCLUSION: Sexual automatisms cannot be related exclusively to frontal lobe seizures. As previously proposed, apparently sexual hypermotoric pelvic or truncal movements are common in frontal lobe seizures, but this study suggests that discrete genital automatisms, like fondling and grabbing the genitals, are more common in seizures evolving from the temporal lobe.

DNA topoisomerase IIalpha expression in optic pathway gliomas of childhood.

DNA topoisomerase IIalpha (Topo IIalpha) is linked to tumour cell growth and chemoresistance. We examined immunohistochemically Topo IIalpha expression levels in a series of 36 consecutive paediatric optic pathway glioma (OPG) patients. Topo IIalpha labelling index (LI) ranged from 0.0 to 11.6 and was significantly associated with patient age, with higher levels of Topo IIalpha in children < or = 3 years (P=0.031). Topo IIalpha expression did not correlate with patient survival. Topo IIalpha LI was not significantly increased in specimens of repeat surgery. Topo IIalpha LI closely correlated with MIB-1 LI (R=0.781, P<0.001). We conclude that Topo IIalpha expression correlates with tumour cell proliferation in paediatric OPGs. Assessment of cell proliferation, however, does not assist in refining prognostic predictions. Enhanced Topo IIalpha expression in children < or = 3.0 years suggests that Topo IIalpha-interfering anticancer compounds for adjuvant treatment of OPGs may be of particular benefit to young children.

Altered expression of voltage-dependent calcium channel alpha(1) subunits in temporal lobe epilepsy with Ammon's horn sclerosis.

Voltage-dependent calcium channels, the initial components in the calcium signalling cascade, are increasingly being recognised as relevant factors in the pathology of epilepsy. To further characterise their role in temporal lobe epilepsy associated with Ammon's horn sclerosis, we investigated the immunohistochemical distribution of five different voltage-dependent calcium channel alpha(1) subunits (alpha(1A), alpha(1B), alpha(1C), alpha(1D), alpha(1E)) in 14 hippocampal specimens of patients with Ammon's horn sclerosis in comparison with eight autopsy control cases. In epilepsy specimens an increased immunoreactivity was observed for alpha(1A), alpha(1B), alpha(1D) and alpha(1E) in the neuropil of the dentate gyrus molecular layer. Dentate gyrus granule cells and residual CA3 pyramidal neurones showed enhanced immunoreactivity for alpha(1A), while labelling of these neurones was decreased for alpha(1C). Astrocytes in Ammon's horn sclerosis specimens were strongly immunoreactive for the alpha(1C) subunit contrasting with an absent astrocytic alpha(1C) labelling in controls. Our results suggest that the expression of calcium channels in neurones and glial cells is dynamically regulated in temporal lobe epilepsy, supporting the relevance of calcium signalling pathways for this disease.

Dopamine D2 receptor imaging in pituitary adenomas using iodine-123-epidepride and SPECT.

UNLABELLED: Epidepride is a novel benzamide derivative with high affinity for D2 receptors. Epidepride, in its 123I-labeled form, can be used for SPECT imaging of striatal and extrastriatal dopamine D2 receptors. The present study evaluated the usefulness of epidepride and SPECT for in vivo imaging of dopamine receptors in pituitary adenomas. METHODS: SPECT imaging was performed in 19 patients with pituitary adenomas (among them 9 patients had prolactinoma, 4 acromegaly, 4 clinically nonfunctioning pituitary adenoma, 1 Cushing's disease and 1 Nelson's syndrome) and 7 control subjects 180 min after intravenous bolus injection of 3.9 +/- 1.1 mCi [123I]epidepride. The ratio target/cerebellum minus 1, reflecting specific/ nonspecific binding was used as semiquantitative measure of D2 receptor binding. RESULTS: Eight of nine prolactinoma patients demonstrated specific binding within the adenoma. The adenoma/ cerebellum ratio 3 hr p.i. showed a wide variation with values from 2.5-33. In three prolactinomas, binding was higher than in the striatum. Specific binding within the lower range of prolactinomas (adenoma/cerebellum ratios 2 and 4.8) could be demonstrated in two of four GH-secreting adenomas. All four nonfunctioning tumors showed specific binding. The adenoma/cerebellum ratio was within the lower range of prolactinomas (5.2-7.5) in three of these patients but extremely high in one (52.3). No specific tracer uptake could be demonstrated in patients with Cushing's disease or Nelson's syndrome. The striatum/cerebellum ratio 3 hr p.i. in pituitary adenoma patients was not significantly different from control subjects (17.3 +/- 5.5 versus 17.8 +/- 6.6; patients versus control subjects). CONCLUSION: Epidepride appears to be an excellent ligand for in vivo imaging of dopamine D2 receptors in pituitary adenomas. Epidepride SPECT could serve as a predictor for response to dopamine agonist treatment.

Preictal SPECT in temporal lobe epilepsy: regional cerebral blood flow is increased prior to electroencephalography-seizure onset.

UNLABELLED: Peri-ictal SPECT provides unique information on the dynamic changes in regional cerebral blood flow (rCBF) that occur during seizure evolution and, thus, could be useful in clarifying the poorly understood interplay of the interictal and ictal states in human focal epilepsy. The regional hyperperfusion observed on ictal SPECT is generally believed to be a consequence of electrical seizure activity. However, recent studies using invasive long-term cortical CBF monitoring have demonstrated that rCBF changes occur up to 20 min prior to ictal electroencephalography (EEG) onset. Because of apparent technical difficulties, no preictal SPECT studies have been reported so far. Therefore, we present our results on two patients with temporal lobe epilepsy in whom preictal SPECT scans were performed fortuitously under continuous video-EEG monitoring control. METHODS: Technetium-99m-hexamethyl propyleneamine oxime was injected 11 min (Patient 1) and 12 min (Patient 2) before clinical and EEG seizure onset, as documented from simultaneous video-EEG monitoring in two patients with temporal lobe epilepsy. We obtained accurate anatomical reference of CBF changes visible on SPECT by a special coregistration technique of MRI and SPECT. RESULTS: Whereas interictal SPECT showed a hypoperfusion of the temporal lobe ipsilateral to the seizure focus, on preictal SPECT, a significant increase in rCBF in the epileptic temporal lobe could be observed. These rCBF changes were not accompanied by any significant changes of the ongoing EEG. CONCLUSION: Our study provides evidence that rCBF is increased in the epileptic temporal lobe several minutes before EEG seizure onset. Thus, rCBF changes observed on peri-ictal SPECT scan cannot be considered a mere consequence of EEG seizure activity but may rather reflect a change in neuronal activity precipitating the transition from the interictal to the ictal state.

Hyaluronidase additional to standard chemotherapy improves outcome for children with malignant brain tumors.

Ex vivo experiments with vital brain tumor samples show that hyaluronidase enhances the permeation of carboplatin into tumor tissue with a matrix rich in hyaluronic acid. We achieved long-lasting second remissions for children with relapsed malignant brain tumors treated with carboplatin, etoposide and this enzyme. Thereafter, we initiated a pilot study where we added hyaluronidase to the first line standard therapy to prevent the deadly relapses right from the beginning. All 19 patients with malignant brain tumors admitted to our pediatric neurooncological center from 1992 to 1994 were included in the study. Kaplan-Meier estimation of event-free survival and overall survival after 3 years follow-up indicates a significantly better outcome for the hyaluronidase-treated group. The children receiving supportive hyaluronidase suffered significantly less relapses (P = 0.034) and had a significantly better chance for survival (P = 0.045) compared to the historical control of 21 children treated with the same standard regimen but without supportive hyaluronidase (product limit analysis and the log-rank test, P < 0.05). Children aged >3 years receiving hyaluronidase together with primary treatment seemed to gain the most benefit.