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OBJECTIVEIn meningiomas involving the orbit and optic canal, surgery is the mainstay of therapy. However, radical resection is often limited to avoid functional damage, so multidisciplinary treatment concepts are implemented. Data on the timing and value of early postoperative radiotherapy (PORT) are scarce. This retrospective study analyzes outcomes in patients who underwent targeted resection alone or in combination with early PORT.METHODSPatients undergoing resection of orbit-associated WHO grade I meningiomas from January 1999 to December 2013 who presented to the authors’ department at least twice for follow-up were included. Clinical and radiological findings were analyzed retrospectively. Patients were stratified into two cohorts: follow-up with MRI scans at regular intervals, i.e., the watch and wait (W&W) group, and a PORT group receiving PORT within 6 months after surgery in addition to MRI follow-up. Patients in the W&W group were scheduled for treatment when tumor progression was detected by imaging.RESULTSOne hundred twenty-two patients were included. The mean follow-up was 70 months. The most common symptoms at presentation were visual disturbances; 87.7% of patients received Simpson grade II–III targeted partial resection. Twenty-three patients received PORT, and 99 patients were regularly observed with MRI scans (W&W group). Tumor recurrence/progression occurred significantly later (76.3 vs 40.7 months) and less frequently in the PORT group (13%) than in the W&W group (46.5%). Cases of recurrence were diagnosed an average of 39 months after initial surgery in both groups. PORT patients demonstrated significantly less visual impairment at last follow-up.CONCLUSIONSThese results indicate that receiving PORT early after targeted partial resection might help to postpone tumor recurrence and the need for additional treatment, while preserving or even improving visual outcome.

Intraspinal epidermoid/dermoid cysts are very rare, benign tumors arising from pathological displacement of epidermal cells into the spinal canal. Literature data about the long-term outcome after microsurgical resection with multimodal intraoperative neurophysiological monitoring (IONM) are lacking. We analyzed one of the largest case series with special regard to intraoperative characteristics and long-term outcome after IONM-aided surgery. All 12 patients (m:f = 1.4:1) who underwent microsurgical tumor resection with multimodal IONM for intraspinal epidermoid/dermoid tumors between 1998 and 2019 in our university hospital were included. We retrospectively investigated the patients’ characteristics, imaging/surgical parameters, and postoperative long-term outcomes. Symptomatic tumor manifestation was seen during adulthood in 4 patients (median age 33.0 years) and during childhood in 8 patients (median age 4.3 years). Spinal dysraphism was the most often comorbidity (75%). The most frequent symptoms at diagnosis were spastic pareses (75%), ataxia (58%), and vegetative disorders (42%). Tumors were most often lumbosacral (L1–L5 42%, L5–S3 50%) and intradural-extramedullary (92%). For microsurgical resection, IONM with EMG, SSEPs, and TcMEPs of the limbs and pudendal nerve/anal sphincter was always applied and feasible; intraoperative corrective actions were initiated in three cases due to transient IONM deterioration. None of the patients showed a postoperative deterioration of the neurological status with a gross total resection rate of 92%. Pain situation, McCormick grade, and mJOA Score were improved at long-term follow-up (median 4.8 years). IONM-aided resection of intraspinal epidermoid/dermoid tumors is feasible both in adult and pediatric cases and enables a satisfying clinical and surgical outcome.

For meningiomas, the 2016 revision of the WHO classification introduced brain invasion per se as a sufficient condition to classify as grade II. We analyzed whether meningiomas previously graded as WHO grade I differ in prognosis depending on the presence of microscopic brain invasion. A consecutive series of patients with intracranial meningioma WHO grade I (± brain invasion) at two neurosurgical departments was analyzed retrospectively. Cox regression models on progression-free survival (PFS) and Kaplan–Meier survival estimates were performed. 875 adult patients were included. Histological diagnosis of brain invasion was confirmed in 28 patients. Median follow-up was 73 months. In univariate and multivariate models, gross total resection gained favorable prognostic influence for PFS (p

Introduction The role of chemotherapy alone in newly diagnosed WHO grade 2 oligodendroglioma after biopsy, incomplete or gross total resection remains controversial. We here analyze the clinical outcome of four patient cohorts being treated with either procarbazine, CCNU and vincristine (PCV) or temozolomide (TMZ) after biopsy, resection only, or wait-and-scan after biopsy. Methods Patients (n = 142) with molecularly defined oligodendroglioma (WHO 2016) were assigned to four cohorts: W&S, wait-and-scan after stereotactic biopsy (n = 59); RES, surgical resection only (n = 27); TMZ, temozolomide after biopsy (n = 26) or PCV (n = 30) after biopsy. Presurgical MRI T2 tumor volumes were obtained by manual segmentation. Progression-free survival (PFS), post-recurrence PFS (PR-PFS) and rate of histological progression to grade 3 were analyzed. Results PFS was longest after PCV (9.1 years), compared to 5.1 years after W&S, 4.4 years after RES and 3.6 years after TMZ. The rate of histological progression from grade 2 to 3 within 10 years was 9% for the PCV, 29% for the W&S, 67% for the RES and 75% for the TMZ group (p = 0.01). In the W&S group, patients treated with PCV at first relapse had a longer PFS from intervention than those treated with TMZ (7.2 vs 4.0 years, p = 0.04). Multivariate analysis identified smaller tumor volume prior to any intervention (p = 0.02) to be prognostic for PFS. Conclusions PCV chemotherapy alone is an effective treatment for WHO grade 2 oligodendroglioma, with long PFS and low rate of histological progression.

Background Prognostic markers for meningioma recurrence are needed to guide patient management. Apart from rare hereditary syndromes, the impact of a previous unrelated tumor disease on meningioma recurrence has not been described before. Methods We retrospectively searched our database for patients with meningioma WHO grade I and complete resection provided between 2002 and 2016. Demographical, clinical, pathological, and outcome data were recorded. The following covariates were included in the statistical model: age, sex, clinical history of unrelated tumor disease, and localization (skull base vs. convexity). Particular interest was paid to the patients’ past medical history. The study endpoint was date of tumor recurrence on imaging. Prognostic factors were obtained from multivariate proportional hazards models. Results Out of 976 meningioma patients diagnosed with a meningioma WHO grade I, 416 patients fulfilled our inclusion criteria. We encountered 305 women and 111 men with a median age of 57 years (range: 21–89 years). Forty-six patients suffered from a tumor other than meningioma, and no TERT mutation was detected in these patients. There were no differences between patients with and without a positive oncological history in terms of age, tumor localization, or mitotic cell count. Clinical history of prior tumors other than meningioma showed the strongest association with meningioma recurrence (p = 0.004, HR = 3.113, CI = 1.431–6.771) both on uni- and multivariate analysis. Conclusion Past medical history of tumors other than meningioma might be associated with an increased risk of meningioma recurrence. A detailed pre-surgical history might help to identify patients at risk for early recurrence.

BACKGROUND Current treatment guidelines for oligodendrogliomas (OD) recommend watch-and-wait strategies after gross total resection and radiation with subsequent chemotherapy (procarbazine, CCNU and vincristine (PCV)) after incomplete resection. The value of chemotherapy alone as an option to delay the risk of late cognitive deficits is not well defined yet. Here, we retrospectively investigated long-term outcome in OD WHO II with respect to initial therapy and tumor volume in magnetic resonance imaging (MRI). METHODS A total of 142 patients with OD WHO (World Health Organization) II according to WHO 2016 were retrospectively included. Patients either had watch and wait (W&W) after histological sampling through stereotactic biopsy (n=59) or tumor resection (n=27) or else stereotactic biopsy with subsequent temozolomide (TMZ) (n=26) or PCV (n=30). Pre- and post-therapeutic T2 tumor volumes were obtained. Progression-free survival (PFS), post-recurrence PFS (PR-PFS) and rate of secondary malignization after 10 years (MR-10yrs) were correlated with clinical and volumetric data. RESULTS PFS was significantly longer in the PCV cohort compared to TMZ (9.1 vs. 3.6 years, p = 0.04), even after matching patients according to age and initial tumor volume (9.1 vs 4.7 yrs, p = 0.03). PFS in the W&W cohort was 5.1 years and 4.4 years in those receiving tumor resection only. MR-10yrs was 4% in PCV cohort, 18% in the W&W cohort and 52% in the resection only cohort (p = 0.01). In the W&W cohort, patients treated with PCV at first relapse had a longer PR-PFS than those treated with TMZ (in years, 7.2 vs 4.0, p = 0.04). Multivariate analysis confirmed initial PCV therapy (p = 0.01) and initial T2 tumor volume (p = 0.02) to be prognostic. CONCLUSION In oligodendrogliomas WHO II PCV chemotherapy alone is superior in terms of PFS and rate of secondary malignization compared to TMZ chemotherapy alone or tumor resection only.

A 67-year-old man developed gradually worsening left-sided spastic hemiparesis under immunosuppressive therapy with tacrolimus after single lung transplantation. MRI revealed 2 diffusion-restricted, T2-hyperintense lesions without and with partial contrast enhancement, respectively (figure 1). Therefore, differential diagnosis mainly included progressive multifocal leukoencephalopathy, atypical CNS lymphoma, and CNS vasculitis. PET with the novel translocator protein (TSPO) tracer [18F]GE-180 showed high focal tracer uptake in both T2-hyperintense lesions. TSPO is overexpressed in activated micoglia.1 Stereotactic brain biopsy revealed tacrolimus-associated CNS vasculitis with distinct microglia activation, a rarely reported finding2 (figure 2). Our case thus suggests that TSPO PET might be a helpful tool for detection of active CNS inflammation3 in patients with suspected CNS vasculitis.

INTRODUCTION: The revised version of the WHO classification system (2016) introduced molecular markers being of prognostic importance in gliomas. Primary spinal cord astrocytomas are very rare. Aggressive surgical resection is believed to be critical for extending progression free and overall survival. However, the prognostic significance of molecular variables remains unclear for these tumors. Herein we investigate molecular chances of spinal gliomas, which may allow more accurate risk stratification. METHODS: We performed genome sequencing in 10 spinal astrocytomas undergoing surgical resection between 2000 and 2017. These spinal astrocytomas include glioblastomas (WHO grade IV), anaplastic astrocytomas (WHO grade III), diffuse astrocytomas (WHO grade II) and pilocytic astrocytoma (WHO grade I). RESULTS: We identified 5 spinal glioblastomas, 1 anaplastic astrocytoma, 2 diffuse astrocytomas and 2 pilocytic astrocytomas. Median overall survival (OS) was 6 months (range: 2–14 months) for grade IV tumors, 33 months (range: 30–136 months) for grade II and III tumors and 95 months (range: 49–141 months) for grade I tumors, respectively. One grade II and one grade I tumor were carrying the IDH1 and IDH2 mutation, all other tumors were IDH wild type (OS: 93 vs. 10 months). Gross total resection was not achieved in any patient. 9 patients received adjuvant radiotherapy. The most current findings in spinal GBM were H3F3A mutations (5/5) and ATRX mutation (3/5). H3F3A mutation was observed in 1 WHO grade II tumor with a OS of 33 months. Mutation in H3F3A and WHO grade was associated with shortened OS in univariate analysis. WHO grade II tumors were found to have mutations in CCND2, DDX3X, EGFR, HIST1H3B, KIT, MYC, PDGFRA, PTCH2, SMARCA4 and TSC2. CONCLUSION: Genomic analysis of spinal astrocytomas provides an opportunity to identify potential clinically relevant information. These data indicate an association between H3F3A mutation and a shortened overall survival in spinal astrocytomas.

BACKGROUND: For meningiomas, the 2016 revision of the WHO classification of tumors of the central nervous system introduced brain invasion per se as a sufficient condition to classify as grade II. We analyzed whether meningiomas previously graded as WHO grade I differ in prognosis according to the feature of brain invasion. MATERIAL AND METHODS: All consecutive patients having been operated between 1/2009 and 03/2016 upon a meningioma being diagnosed as WHO grade I according to the previous (2007) WHO classification system were included. The reference point of the study was the date of surgery. Date of last follow up was 11/2017. Study endpoint was the date of tumor progression. Prognostic factors were obtained from multivariate proportional hazards models. RESULTS: 949 adult patients were included. The median follow-up was 43 months (range: 3–78 months). Gross total resection (GTR) was achieved in 719 (75.8%) patients, adjuvant radiotherapy was applied in 91 (9.9%) patients. Brain invasion was diagnosed by histology in 24 (2.5%) patients. Patients with/without brain invasion did not differ in terms of age and extent of resection. Patients with histologically proven brain invasion received more often adjuvant radiotherapy (p=0.008). 88 patients experienced tumor recurrence/ progression, overall survival was not reached in the majority of patients. The overall median PFS for patients with (without) brain invasion was 22 (23) months (p=0.48). In univariate and multivariate models subtotal resection and history of malignancy gained unfavorable prognostic influence for PFS (p

In suspected grade II gliomas, three distinct patterns of time-activity curves (TAC) on O-(2-[(18)F]fluoroethyl)-1-tyrosine ((18)F-FET) positron emission tomography (PET) have been delineated (i) increasing TAC homogeneously throughout the tumor, and decreasing TAC, (ii) either homogeneously throughout the tumor or (iii) only focally within otherwise increasing TAC patterns. Increasing TAC was associated with low-grade histology and decreasing TAC with high-grade histology. This prospective study analyzed whether these patterns correlate with distinct biological tumor subtypes and differential outcome. (18)F-FET PET-guided biopsies were used for stepwise histopathological evaluation. Molecular-genetic evaluation included O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, isocitrate dehydrogenase (IDH1/2) mutational and 1p/19q codeletion status. Progression-free survival (PFS) was estimated with the Kaplan-Meier method. Prognostic factors were obtained from multivariate regression models. 98 adult patients were included. Homogeneous increasing, focal decreasing and homogeneous decreasing TAC were seen in 51, 19 and 28 patients. The corresponding 1-year (2-years) PFS were 92% (85%), 89% (51%) and 50% (28%; p = 0.002). IDH1/2 mutations were more frequent in tumors with homogeneous increasing (90%) and focal decreasing (79%) TAC, but were rare in those exhibiting homogeneous decreasing TAC (25%; p < 0.001). Overall, TAC patterns, IDH1/2 mutational and 1p/19q codeletion status were powerful and independent prognostic factors. Dynamic (18)F-FET PET might be an important and independent imaging biomarker for patients with suspected WHO grade II gliomas and offers perspectives for stratified diagnostic and therapeutic strategies. Tumors with focal decreasing TAC need highly targeted surgical interventions to avoid undergrading and undertreatment.

In gliomas molecular biomarkers are increasingly gaining diagnostic, prognostic and predictive significance. Determination of biomarker status after biopsy is important as not all patients are eligible for open tumor resection. We developed and validated prospectively (6/10–12/11) a protocol allowing for both reliable determination of multiple biomarkers and representative histological diagnoses from small-sized biopsies. All molecular stereotactic biopsies were performed according to a detailed workflow. The selection of specimens best suited for molecular analyses was intra-operatively guided by the attending neuropathologist. Postoperative screening was done by methylation specific PCR using two distinct cryopreserved specimens to test for reproducibility of the findings and to rule out contamination. The DNA of a single best-suited specimen (1 mm3) was subjected to detailed molecular analysis (MGMT promoter methylation, IDH1/2 mutational status, LOH 1p and/or 19q). 159 consecutively enrolled untreated gliomas were analyzed (94 glioblastomas, 2 gliosarcomas, 24 anaplastic astrocytomas, 10 oligo-tumors grade II/III, 20 grade II astrocytomas and 9 pilocytic astrocytomas). Transient morbidity was 2 %. Overall, the drop-out rate due to tissue contamination was 0.4 %. Median time from biopsy to histological and molecular genetic analyses was 3 and 5 days, respectively. Distributions of the respective biomarker status for tumor subgroups were consistent with the literature. The final histological diagnosis was changed/modified in 5/159 patients according to molecular findings. Treatment after molecular biopsy was highly personalized. Molecular stereotactic biopsy is feasible and safe, can be implemented in daily clinical practice, improves diagnostic precision and enables personalized treatment.

Background and Objective Interstitial photodynamic therapy (iPDT) of non-resectable recurrent glioblastoma using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) has shown a promising outcome. It remained unclear, however, to what extent inter- and intra-tumoural differences of PpIX concentrations influence the efficacy of iPDT. In the current pilot study, we analysed PpIX concentrations quantitatively and assessed PpIX induced fluorescence and photobleaching intraoperatively. Materials and Methods Five patients harbouring non-resectable glioblastomas were included. ALA (20 or 30 mg/kg body weight) was given 5–8 hours before treatment. Stereotactic biopsies were taken throughout the tumour volume for both histological analysis and determination of PpIX concentrations, which were measured by chemical extraction. Cylindrical light diffusors were stereotactically implanted. Prior to and after irradiation, fluorescence measurements were performed. Outcome measurement was based on clinical and neuro-radiological follow up. Results In three patients, a strong PpIX fluorescence was seen before treatment, which was completely photobleached after iPDT. High concentrations of PpIX could be detected in viable tumour parts of these patients (mean PpIX uptake per tumour: 1.4–3.0 µM). In the other two patients, however, no or only low PpIX uptake (0–0.6 µM) could be detected. The patients with strong PpIX uptake showed treatment response and long-term clinical stabilisation (no progression in 29, 30 and 36 months), early treatment failure was seen in the remaining two patients (death after 3 and 9 months). Conclusions Intra-tumoural PpIX concentrations exhibited pronounced inter- and intra-tumoural variations in glioblastoma, which are directly linked to variable degrees of fluorescence intensity. High intra-tumoural PpIX concentrations with strong fluorescence intensity and complete photobleaching after iPDT seem to be associated with favourable outcome. Real-time monitoring of PpIX fluorescence intensity and photobleaching turned out to be feasible and safe and might be employed for early treatment prognosis of iPDT. Lasers Surg. Med. 9999:XX–XX, 2013. © 2013 Wiley Periodicals, Inc.

U. Rub, K. Burk, D. Timmann, W. den Dunnen, K. Seidel, K. Farrag, E. Brunt, H. Heinsen, R. Egensperger, A. Bornemann, S. Schwarzacher, H.-W. Korf, L. Schols, J. Bohl and T. Deller (2012) Neuropathology and Applied Neurobiology 38, 665680 Spinocerebellar ataxia type 1 (SCA1): new pathoanatomical and clinico-pathological insights Aims: Spinocerebellar ataxia type 1 (SCA1) represents the first molecular genetically characterized autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG-repeat or polyglutamine diseases. Owing to limited knowledge about SCA1 neuropathology, appropriate pathoanatomical correlates of a large variety of SCA1 disease symptoms are missing and the neuropathological basis for further morphological and experimental SCA1 studies is still fragmentary. Methods: In the present study, we investigated for the first time serial tissue sections through the complete brains of clinically diagnosed and genetically confirmed SCA1 patients. Results: Brain damage in the three SCA1 patients studied went beyond the well-known brain predilection sites of the underlying pathological process. Along with neuronal loss in the primary motor cortex, it included widespread degeneration of gray components of the basal forebrain, thalamus, brainstem and cerebellum, as well as of white matter components in the cerebellum and brainstem. It involved the motor cerebellothalamocortical and basal ganglia-thalamocortical circuits, the visual, auditory, somatosensory, oculomotor, vestibular, ingestion-related, precerebellar, basal forebrain cholinergic and midbrain dopaminergic systems. Conclusions: These findings show for the first time that the extent and severity of brain damage in SCA1 is very similar to that of clinically closely related spinocerebellar ataxias (that is, SCA2, SCA3 and SCA7). They offer suitable explanations for poorly understood SCA1 disease symptoms and will facilitate the interpretation of further morphological and experimental SCA1 studies.

Outcome and toxicity profiles of salvage stereotactic ablative radiation strategies for recurrent pre-irradiated brain metastases are poorly defined. This study compared risk–benefit profiles of upfront and salvage iodine-125 brachytherapy (SBT) for small brain metastases. As the applied SBT treatment algorithm required histologic proof of metastatic brain disease in all patients, we additionally aimed to elucidate the value of biopsy before SBT. Patients with small untreated (n = 20) or pre-irradiated (n =28) suspected metastases intended for upfront or salvage SBT, respectively, were consecutively included. Temporary iodine-125 implants were used (median reference dose: 50 Gy, median dose rate: 15 cGy/h). Cumulative biologically effective doses (BED) were calculated and used for risk assessment. Treatment toxicity was classified according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria. Upfront SBT was initiated in 20 patients and salvage SBT in 23. In 5 patients, salvage SBT was withheld because of proven radiation-induced lesions. Treatment groups exhibited similar epidemiologic data except for tumor size (which was slightly smaller in the salvage group). One-year local/distant tumor control rates after upfront and salvage SBT were similar (94 %/65 % vs. 87 %/57 %, p = 0.45, respectively). Grade I/II toxicity was suffered by 2 patients after salvage SBT (cumulative BED: 192.1 Gy3 and 249.6 Gy3). No toxicity-related risk factors were identified. SBT combines diagnostic yield with effective treatment in selected patients. The low toxicity rate in the salvage group points to protective radiobiologic characteristics of continuous low-dose rate irradiation. Upfront and salvage SBT are similarly effective and safe. Histologic reevaluation should be reconsidered after previous radiotherapy to avoid under- or overtreatment.

Objective Cisplatin exerts its cytotoxic effect through distinct DNA lesions, leading to peripheral neuropathy. The risk of sensory neuropathy is a common problem during cancer treatment with cisplatin, leading to somatic hyperalgesia. Yet, data focussing on cisplatin-induced impairment of the autonomic nervous system are limited. The present study was aimed to investigate the effect of recombinant human erythropoietin (rhEPO) on cisplatin-induced visceral hyperalgesia. Methods C57BL/6 mice were treated either with cisplatin (2 mg/kg, once per week) or with cisplatin (2 mg/kg, once per week) plus rhEPO (40 µg/kg, 3 times per week) for 8 weeks. Controls were treated with saline. To quantify the visceromotor response (VMR) at week 9, standardized electrodes were implanted into the external oblique musculature for electromyographic recordings. After that, animals were decapitated and dorsal root ganglia (DRG) was removed for transmission electron microscopy studies. Results Cisplatin-treated mice showed a significant increase of VMR compared to the controls ((7080 ± 969) vs (2864 ± 279); P < 0.001), while rhEPO dramatically counteracted this effect ((2962 ± 336) vs (7080 ± 969); P < 0.001)). Transmission electron microscopy revealed cisplatin-induced structural lesions of nuclear membrane in DRG cells, which could be ameliorated by rhEPO. Conclusion Erythropoietin can significantly ameliorate the cisplatin-induced visceral hyperplasia and DRG nuclear membrane structure damage in mice, indicating a neuroprotective role of erythropoietin.

Contains fulltext : 81519.pdf (Publisher’s version ) (Closed access) AIMS: Spinocerebellar ataxia type 6 (SCA6) is a late onset autosomal dominantly inherited ataxic disorder, which belongs to the group of CAG repeat, or polyglutamine, diseases. Although, it has long been regarded as a 'pure' cerebellar disease, recent clinical studies have demonstrated disease signs challenging the view that neurodegeneration in SCA6 is confined to the well-known lesions in the cerebellum and inferior olive. METHODS: We performed a systematic pathoanatomical study throughout the brains of three clinically diagnosed and genetically confirmed SCA6 patients. RESULTS: This study confirmed that brain damage in SCA6 goes beyond the known brain predilection sites. In all of the SCA6 patients studied loss of cerebellar Purkinje cells and absence of morphologically intact layer V giant Betz pyramidal cells in the primary motor cortex, as well as widespread degeneration of brainstem nuclei was present. Additional damage to the deep cerebellar nuclei was observed in two of three SCA6 patients. CONCLUSIONS: In view of the known functional role of affected central nervous grey components it is likely that their degeneration at least in part is responsible for the occurrence of a variety of SCA6 disease symptoms.

To analyze efficacy, functional outcome, and treatment toxicity of low‐dose rate I‐125 brachytherapy (SBT) alone or in combination with best safe resection (in case of larger tumor volumes) as first‐line treatment for pediatric low‐grade gliomas (PLGGs) not suitable for complete resection. Consecutively treated (2000–2014) complex located circumscribed WHO grade I/II PLGGs were included. For small tumors (≤4 cm in diameter) SBT alone was performed; for larger tumors best safe resection and subsequent SBT was chosen. Temporary Iodine‐125 seeds were used (median reference dose: 54 Gy). Treatment response was estimated with the modified MacDonald criteria. Analysis of functional outcome included ophthalmological, endocrinological and neurological evaluation. Survival was analyzed with the Kaplan–Meier method. Prognostic factors were obtained from proportional hazards models. Toxicity was categorized according to the Common Terminology Criteria for Adverse Events. Fifty‐eight patients were included treated either with SBT alone (n = 39) or with SBT plus microsurgery (n = 19). Five‐year progression‐free survival was 87%. Two patients had died due to tumor progression. Among survivors, improvement/stabilization/deterioration of functional deficits was seen in 20/14/5 patients, respectively. Complete/partial response had beneficial impact on functional scores (P = 0.02). The 5‐year estimated risk to receive adjuvant radiotherapy/chemotherapy was 5.2%. The overall early (delayed) toxicity rate was 8.6% (10.3%), respectively. No permanent morbidity occurred. In complex located PLGGs, early SBT alone or combined with best safe resection preserves/improves functional scores and results in tumor control rates usually achieved with complete resection. Long‐term analysis is necessary for confirmation of these results.

A 67-year-old woman presented with clinical features of hypercortisolism in association with an invasive pituitary macroadenoma. Adrenocorticotropic hormone (ACTH)-dependent Cushing's disease was documented, and the resected tumor was chromophobic, weakly positive with periodic-Schiff reagent, and showed immunostaining for ACTH and beta-endorphin in a minority of adenoma cells. Both luteinizing hormone and alpha-subunit staining were also observed, but no follicle-stimulating hormone reactivity was seen. Ultrastructurally, the tumor showed typical features of a gonadotroph adenoma of female type. Immunoelectron microscopy showed that ACTH was not produced in corticotrophs, but in cells with the characteristic features of gonadotrophs. This represents the second report of a plurihormonal gonadotroph adenoma producing sufficient ACTH to result in pituitary-dependent Cushing's disease.

We report a 52-year-old woman who underwent otoneurosurgery to resect acoustic neurinoma. Bone reconstruction was performed with an aluminium (Al)-containing cement. Six weeks later the patient suffered from loss of consciousness, myoclonic jerks, and persistent grand mal seizures, clinical symptoms that resembled those of lethal dialysis encephalopathy of the 1960s and 1970s. She died 6 months later because of septic complications. Light- and electron-microscopic investigation of the central nervous system (CNS) showed pathognomonic Al-containing intracytoplasmic argyrophilic inclusions in choroid plexus epithelia, neurons, and cortical glia. These changes are characteristics of dialysis-associated encephalopathy (DAE), induced nowadays by long-term ingestion of Al-containing drugs (and with benign clinical courses). Atomic absorption spectrometry showed an increase of mean bulk Al concentration of the cortex and subcortex up to 9.3 microg/g (normal range

An increased frequency of the A-allele of the alpha-antichymotrypsin (ACT) gene has been recently described in Japanese patients suffering from Parkinson disease (PD). In the present study, we have analyzed 62 German PD patients with regard to their ACT and APOE genotypes and compared them to 53 controls without clinical or pathological evidence of neurodegenerative disease. The A-allele frequency was 47% in PD patients compared to 54% in control cases excluding ACT as a major susceptibility factor for PD in the Caucasian population. Yet, ACT-A allele frequencies were significantly different (p0.001) between Japanese and German controls. Therefore, although our data do not suggest that the alpha1-ACT polymorphism is a significant risk factor for the development of PD, a consideration of differences in genetic background seems warranted when evaluating susceptibility factors for neurodegenerative disease.

Strong genetic evidence has been accumulated in favor of a central role of beta-amyloid precursor protein (APP) and beta-amyloid peptide (betaA4) in the pathogenesis of Alzheimer's disease (AD). We employed four newly developed APP and betaA4 antibodies and performed a comparative neuropathological study of patients with Down's syndrome (DS), early-onset familial AD and sporadic AD to investigate the distribution of APP and betaA4 plaque densities in the cerebral cortex of these disorders. Quantitative analysis of APP versus betaA4 plaques revealed that brains with early-onset familial AD and sporadic AD showed significantly more betaA4 plaques than brains with DS (P < 0.05). In contrast, APP plaques were more abundant in DS cerebral cortex (P < 0.02). These observations suggest that the development of pathological changes in DS brains does not parallel that observed in AD, which might be attributable to different causes in the pathogenesis of betaA4 formation. A comparison of these disorders may be useful to further complement our knowledge of the mechanisms leading to plaque development.

Apolipoprotein E (apoE) genotypes were analyzed in a subset of demented very old patients who share a uniform neuropathological picture consisting of various numbers of neurofibrillary tangles (NFT) in allocortical areas of the inferomedial temporal lobe without significant numbers of either diffuse amyloid or neuritic plaques. Among 18 patients with this condition referred to as NFT-predominant senile dementia (average age at death 87 +/- 4.7 years), we found allele frequencies of 0.11 epsilon 2, 0.86 epsilon 3 and 0.03 epsilon 4, which are significantly different from allele frequencies reported in Alzheimer's disease (0.04 epsilon 2, 0.59 epsilon 3 and 0.38 epsilon 4). The low prevalence of the apoE epsilon 4 allele in this subset of patients is striking and suggests that NFT-predominant senile dementia is a dementing neurodegenerative disease in which the deposition of A beta-amyloid did not occur, possibly due to protective effects of epsilon 2 and/or epsilon 3 alleles or lack of a promoting effect of apoE epsilon 4 on amyloidogenesis. We propose that NFT-predominant dementia is a variant of Alzheimer's disease occurring in the very old.

Six cases of middle cerebral artery occlusion are presented in which the cellular changes accompanying descending degeneration of the lateral corticospinal tract were studied at different time points (5 days–10 years) following the insult. Microglia and perivascular cells were found to ingest large amounts of myelin degradation products, while expressing high levels of major histocompatibility complex (MHC) class II molecules. Activation of perivascular macrophages, as indicated by increased class II expression, lasted for many years and appeared to follow down-regulation of both phagocytic activity and class II expression on parenchymal microglia. TUNEL labeling was absent from both microglia and perivascular cells at all time points investigated. Indirect evidence is presented that microglia may transfer myelin degradation products to the perivascular space. Perivascular cells which express MHC class II molecules constitutively do not appear to leave the perivascular compartment in large numbers and could release myelin degradation products into the cerebrospinal fluid. The possible immunological consequences of these findings are discussed with respect to their possible relevance for antigen presentation and autoimmune central nervous system disease.

In 1911, Alois Alzheimer published a detailed report (Zbl. ges. Neurol. Psych. 4: 356-385) on a peculiar case of the disease that had been named after him by Emil Kraepelin in 1910. Alzheimer describes a 56-year-old male patient (Johann F.) who suffered from presenile dementia and who was hospitalized in Kraepelin's clinic for more than 3 years. Post-mortem examination of the patient's brain revealed numerous amyloid plaques but no neurofibrillary tangles in the cerebral cortex, corresponding to a less common form of Alzheimer disease which may be referred to as 'plaque only'. We have identified well-preserved histological sections of this case and performed mutational screening of exon 17 of the amyloid precursor protein gene and genotyping for apolipoprotein E alleles. The patient was shown to be homozygous for apolipoprotein allele epsilon3 and lacked APP mutations at codons 692, 693, 713 and 717. This case is of historical importance as it may have convinced Kraepelin to name the disease after his co-worker, Alois Alzheimer.

Intramedullary glioma are rare and their biological behaviour can differ from their cerebral counterparts. Pilomyxoid astrocytoma (PMA, WHO grade II), predominantly occur in the hypothalamic/chiasmatic region of infants and children. The few reported cases of pediatric intramedullary PMA displayed a particularly aggressive behavior. Here, we report a diagnostically challenging case of a five year old female patient presenting with intramedullary glioma and local tumor recurrence three years later. Twelve years after the initial manifestation, a second tumor was found intracerebrally. We performed a comprehensive histological, molecular pathological and imaging analysis of the tumors from both localizations. The results revealed a metastasizing PMA with unique histological and genetic features. Our study indicates that PMA comprise a heterogeneous group including aggressive subtypes which may not be compatible with the current classification according to WHO grade II. Furthermore, the case emphasizes the increasing relevance of molecular pathological markers complementing classic histo-logical diagnosis.

α-Internexin (INA) has been proposed to be a surrogate marker for the 1p/19q codeletion in oligodendroglial tumors (OTs). We analyzed INA expression in 83 glioma and 21 oligodendroglial phenotype-mimicking tumors (OMT) to assess its usefulness in differential diagnosis and its correlation with 1p/19q status; in particular, INA expression in gliomas with isolated/partial 1p or 19q deletions was assessed. α-Internexin expression and 1p/19q codeletion were present in 92% (34/37) of codeleted tumors (p < 0.0001). By contrast, INA was found in only 20% of cases with isolated/partial 1p aberrations and 36% of cases without 1p/19q deletions; it was also foundin 63% (10/16) of cases with isolated/partial 19q aberrations. α-Internexin expression was more specific in high-grade than in low-grade gliomas (66% vs 31%). Notably, a subset of tumors (10/83) displayed a biphasic INA expression pattern that was significantly associated with proliferation rate, whereas all areas harbored the 1p/19q codeletion. Only no or weak INA expression was seen in OMTs. In summary, INA is a useful marker to differentiate OTs from astrocytic tumors and OMTs, but INA expression is not exclusively linked to OTs harboring the 1p/19q codeletion. Moreover, it can sometimes be heterogeneously distributed within tumors, which emphasizes the need for 1p/19q analysis by molecular genetic techniques for diagnosis.

Molecular imaging studies have recently found inter- and intratumoral heterogeneity in World Health Organization (WHO) grade II gliomas. A correlative analysis with tumor histology, however, is still lacking. For elucidation we conducted the current prospective study. Fifty-five adult patients with an MRI-based suspicion of a WHO grade II glioma were included. [F-18]Fluoroethyltyrosine ((18)FET) uptake kinetic studies were combined with frame-based stereotactic localization techniques and used as a guide for stepwise (1-mm steps) histopathological evaluation throughout the tumor space. In tumors with heterogeneous PET findings, the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and expression of mutated protein isocitrate dehydrogenase variant R132H (IDH1) were determined inside and outside of hot spot volumes. Metabolic imaging revealed 3 subgroups: the homogeneous WHO grade II glioma group (30 patients), the homogeneous malignant glioma group (10 patients), and the heterogeneous group exhibiting both low- and high-grade characteristics at different sites (15 patients). Stepwise evaluation of 373 biopsy samples indicated a strong correlation with analyses of uptake kinetics (p < 0.0001). A homogeneous pattern of uptake kinetics was linked to homogeneous histopathological findings, whereas a heterogeneous pattern was associated with histopathological heterogeneity; hot spots exhibiting malignant glioma characteristics covered 4-44% of the entire tumor volumes. Both MGMT and IDH1 status were identical at different tumor sites and not influenced by heterogeneity. Maps of (18)FET uptake kinetics strongly correlated with histopathology in suspected grade II gliomas. Anaplastic foci can be accurately identified, and this finding has implications for prognostic evaluation and treatment planning.

The lysosomal protease cathepsin D is likely involved in beta-amyloidogenesis in Alzheimer's disease (AD). There is evidence for a single nucleotide polymorphism (rs17571) of the cathepsin D gene to be associated with increased AD risk. However, little is known about gender-specific differences. Therefore, we performed a genetic association study focusing on gender-specific differences in 434 participants (219 AD and 215 controls). Screening of the rs17571 shows a significantly higher proportion of T-allele carriers among male Alzheimer patients (28.5%) when compared with male controls (13.8%, p = .013, p(corr) = .039). The odds ratio was 2.48 (95% confidence interval: 1.14-5.58). There was no significant difference in the T-allele distribution in women. Including APOE4 status and age did not have an additional effect on the morbidity risk. Thus, our results support the idea that rs17571 confers an increased risk for AD in men but not in women. Further investigation should substantiate the role of gender for AD risk of rs17571.

Apolipoprotein E (ApoE) genotypes were analyzed in 35 subjects with argyrophilic grain diseases (AgD). Neuropathologically, all cases were characterized by abundant argyrophilic grains in the hippocampus and in the entorhinal or parahippocampal cortex. We found an ApoE epsilon4 allele frequency of 0.007 in AgD patients, which is significantly different from the epsilon4 allele frequencies reported in age-matched Alzheimer's disease (AD) patients (0.24), but not from age-matched controls (0.09). We conclude that the ApoE epsilon4 allele does not constitute a risk factor for the development of AgD. Our results further suggest that AgD is a progressive disorder differentiated from AD by morphological and genetic criteria.

A case of a glioblastoma multiforme is presented. Craniotomy was performed with total resection of the right temporal tumor. Postoperatively, the patient received adjuvant radiotherapy, but 6 months after therapy he developed severe nausea and weight loss. Recurrence of an intracranial tumor in the right temporal region with nodules in the liver and spleen were detected by CT scan. Fine-needle biopsies of the liver confirmed the diagnosis of a glioblastoma metastasis with characteristic immunohistochemical staining for glial fibrillary acidic protein. This rare case of an intracerebral glioblastoma metastasizing to liver and spleen was managed by systemic chemotherapy.

Argyrophilic grain disease constitutes one cause of late-onset dementia. Its classification among dementia disorders is still unclear because most of the reported argyrophilic grain disease cases are associated with neurofibrillary lesions (e.g. neurofibrillary tangles) which are also typical of Alzheimer's disease. In the present study we determine whether argyrophilic grain disease is associated with the senile plaques of Alzheimer's disease. The distribution and density of senile plaques was systematically investigated in 11 demented argyrophilic grain disease cases using Abeta immunohistochemistry and stereological techniques, and the results were compared with 11 Alzheimer's disease cases. All subjects with argyrophilic grain disease exhibited neurofibrillary changes corresponding to Braak stages I-III. Three of the 11 argyrophilic grain disease cases (27%) were completely devoid of Abeta deposits. In argyrophilic grain disease cases with senile plaques, the average total plaque-load was significantly lower (1%) than in Alzheimer's disease (3.1%) (P

Recent in vitro experiments suggest that neurotoxicity of the prion protein is dependent on the presence of microglia. We have studied 11 cases of Creutzfeldt-Jakob disease (CJD) using immunocytochemistry in combination with computerized image analysis to clarify the relationship between spongiform change and microglial activation. MHC class II-positive microglia were almost exclusively confined to cortical gray matter where the neuropil area occupied by these cells exceeded that of controls more than 350-fold. In cortical regions with a bimodal distribution of spongiform degeneration, the presence of class II-positive microglia correlated well with the presence of vacuolation in layer V, but significantly less with spongiform change in layers II and III. In areas where spongiform degeneration affected the entire depth of the cortex, activated microglia were predominantly located in the inner one-half of the cortex or were evenly distributed throughout all cortical laminae. Here, microglia exhibited atypical, tortuous cell processes and occasionally intracytoplasmic vacuoles, suggesting that microglia themselves may become a disease target. Taken together, our results provide indirect evidence against an early causative involvement of microglia in the development of spongiform change. At later stages, however, diseased microglia could produce harmful factors which mediate both astrogliosis and neuronal injury.

To evaluate the influence of the apolipoprotein E (ApoE) epsilon4 allele on the age at which Alzheimer-like lesions appear in the brain, we analyzed the degree of cerebral beta-amyloidosis and neurofibrillary tangle formation in the hippocampal formation and adjacent cortical areas 28, 27, and 36 of persons who had died between the ages of 50 and 93 years and who had shown no signs of clinical dementia. The occurrence of the three common polymorphisms of the ApoE gene in this sample of 147 routine autopsy cases from eastern Germany was comparable to previously reported values in European and North American populations: ApoEepsilon2/2, 0.7%; ApoEepsilon2/3, 14.3%; ApoEepsilon2/4, 4.1%; ApoEepsilon3/3, 56.5%; ApoEepsilon3/4, 22.4%; and ApoEepsilon4/4, 2.0%. Nondemented persons carrying the ApoEepsilon4 allele were significantly more likely to have senile plaques, diffuse amyloid deposits, cerebrovascular amyloid, and neurofibrillary tangles than were those lacking E4. Comparing the two largest ApoE subgroups, ApoEepsilon3/3 and ApoEepsilon3/4, the relative increase in the occurrence of beta-amyloid in the epsilon3/4 group was evident by the mid-60s, with the relative increase in neurofibrillary tangles in this group emerging slightly earlier. The ApoEepsilon2 allele appears to delay the appearance of the lesions somewhat. We conclude that ApoEepsilon4 promotes the early appearance of beta-amyloid and neurofibrillary tangles in the elderly and that the increased frequency of these lesions is related to the higher risk of Alzheimer disease in persons bearing the ApoEepsilon4 allele.

Many studies have demonstrated an association between the apolipoprotein E (apoE) epsilon 4 allele and Alzheimer's disease (AD).The present study is concerned with the relationship between the apoE epsilon 4 allele and the progression of symptoms in AD. We determined rates of cognitive decline and deterioration in everyday performance prospectively over 3 years in 64 patients with clinically diagnosed AD using the Cambridge Cognitive Examination (CAMCOG), the Mini-Mental State Examination (MMSE), and the Dementia Scale (DS) included in the Cambridge Mental Disorders of the Elderly Examination (CAMDEX). Carriers and noncarriers of the epsilon 4 allele did not significantly differ in cognitive functioning and everyday performance at baseline measurements. The time that had elapsed since the estimated onset of symptoms was also not different between the two groups. This suggested that the clinical progression of AD was not associated with the epsilon 4 status before the patients entered the study. On prospective observation, the rate of cognitive decline assessed with the CAMCOG and the MMSE and the rate of deterioration in everyday performance rated with the DS were also not different between carriers and noncarriers of the epsilon 4 allele. We conclude that the clinical course of AD is independent of the apoE epsilon 4 allele.NEUROLOGY 1996;47: 440-443

A method is described to visualize rhodamine-labelled microspheres (RLM) at the electron microscopic level using potassium permanganate for negative contrast. Retrogradely labelled nerve cells in the thalamus of the rat and in tissue culture are examined. In addition, it is demonstrated that single beads as small as 50 nm in diameter can be identified with the fluorescent microscope.