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Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder of unknown etiology, characterized pathologically by α-synuclein aggregates preferentially found in oligodendroglial cells. DNA methylation has emerged as a mechanism of regulation of α-synuclein expression. Reduced 5-methylcytosine (5-mC) DNA methylation of α-synuclein has been found in the brains of patients with Parkinson’s disease (PD). 5-hydroxymethylcytosine (5-hmC) methylation is another epigenetic modification of DNA. It is involved in the de-methylation of DNA, gene regulation, and DNA repair mechanisms. Here, we examined sections of human paraffin-embedded brain tissue from the cerebellum and brain stem, including the substantia nigra pars compacta, of patients with PD (n = 8) and MSA (n = 8) as well as age-matched controls (n = 8). The neocortical tissue of PD patients (n = 10) and controls (n = 10) was also examined. Using immunohistochemistry, we analyzed the expression of 5-mC and 5-hmC with an automatic, rater-independent semi-quantification method. We found a significant upregulation of 5-mC, but not 5-hmC, in cortical sections from PD patients. The brain stem and substantia nigra, and in particular the dopaminergic neurons, showed unchanged levels of both 5-mC- and 5-hmC-immunoreactivity in all groups. In the cerebellum, 5-mC was significantly decreased only in MSA patients in the granule cell layer; in contrast, 5-hmC was significantly upregulated in the cerebellar white matter of both PD and MSA patients. Our study showed different levels of expression of total 5-mC and 5-hmC methylation across different brain regions in PD and for the first time in MSA. Our results indicate that 5-mC may be relevant in MSA. The underlying mechanism of the differential 5-mC and 5-hmC expression remains unclear.

Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity, presence of perivascular pseudo-rosettes, small to medium-sized nuclei with characteristic granular chromatin and strikingly abundant cells with dot-like cytoplasmic expression of epithelial membrane antigen. Eleven cases presented features of anaplasia, corresponding to WHO grade III. MRI showed large supratentorial multinodular tumors with cystic components, heterogeneous contrast enhancement, located in the ventricular or periventricular region. One of two variants of YAP1-MAMLD1 fusions was detected in all cases. The MIP genome profiles showed balanced profiles, with focal alterations of the YAP1 locus at 11q22.1-11q21.2 (7/14), MAMLD1 locus (Xp28) (10/14) and losses of chromosome arm 22q (5/14). Most patients were female (13/15) and younger than 3 years at diagnosis (12/15; median age, 8.2 months). Apart from one patient who died during surgery, all patients are alive without evidence of disease progression after receiving different treatment protocols, three without postoperative further treatment (median follow-up, 4.84 years). In this to date, largest series of ependymomas with YAP1-MAMLD1 fusions we show that they harbor characteristic histopathological, cytogenetic and imaging features, occur mostly in young girls under 3 years and are associated with good outcome. Therefore, this genetically defined neoplasm should be considered a distinct disease entity. The diagnosis should be confirmed by demonstration of the specific fusion. Further studies on large collaborative series are warranted to confirm our findings.

Intracerebral hemorrhage (ICH) is a frequently disabling or fatal disease. The localizationof ICH often allows an etiological association. However, in atypical/lobar ICH, the cause of bleedingis less obvious. Therefore, we present prospective histopathological and radiological studies whichwere conducted within the diagnostic workup to identify causes for lobar ICH other than hypertension.From 2016 to 2018, 198 patients with spontaneous, non-traumatic ICH requiring neurosurgicalmonitoring were enrolled in an institutional prospective patient registry. Patients with deep-seatedICH and/or hemorrhagically transformed cerebral infarcts were excluded from further analysis.Data to evaluate the source of bleeding based on histopathological and/or radiological workup wereprospectively evaluated and analyzed. After applying the inclusion criteria and excluding patientswith incomplete diagnostic workup, a total of 52 consecutive patients with lobar ICH were furtheranalyzed. Macrovascular disease was detected in 14 patients with lobar ICH (27%). In 11 patients,diagnostic workup identified cerebral amyloid angiopathy-related ICH (21%). In addition, five patientswith tumor-related ICH (10%) and six patients with ICH based on infectious pathologies(11%) were identified. In four patients, the cause of bleeding remained unknown despite extensivediagnostic workup (8%). The present prospective registry study demonstrates a higher probabilityto identify a cause of bleeding other than hypertension in patients with lobar ICH. Therefore, athorough diagnostic work-up in patients with ICH is essential to accelerate treatment and furtherimprove outcome or prevent rebleeding

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40years (range 15–61years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.

Allgrove or triple A syndrome is a rare autosomal recessive disorder that can present with a variable range of multi-system manifestations, including optic atrophy, cerebellar ataxia, upper and lower motoneuron signs and various neuropathic abnormalities. These cases are a diagnostic challenge, particularly when the eponymous combination of achalasia, Addisonianism and alacrima is incomplete. Therefore, it is in the differential diagnosis for multisystem conditions and should be known to pathologists who diagnose disorders of skeletal muscle. Here, we describe new findings in skeletal muscle histology from the case of a boy of consanguineous Turkish origin whose achalasia provided the only specific clinical clue to the diagnosis. These include myocyte nuclear abnormalities with partially abnormal anti-lamin A/C immunohistochemistry and altered nuclear ultrastructure but without overt abnormalities of nuclear pore morphology. In this case, the condition was associated with a hitherto unreported c.762delC mutation in the nucleoporin gene AAAS.

Pediatric tumors of the central nervous system composed of oligoid tumor cells showing diffuse leptomeningeal spread without a primary mass lesion seem to represent a novel tumor entity. The terms “diffuse leptomeningeal glioneural tumor” or—preferably—“disseminated oligodendroglial-like leptomeningeal tumor of childhood” (DOGLT) were proposed. Four patients were identified with clinico-neuropathologic findings compatible with DOGLT and a mean follow-up time of 54 months was determined. Seven different biopsies obtained from the four patients were histologically evaluated. Clinical course, diagnostic measures, histopathologic and radiologic features and treatment suggestions were recorded, on the basis of which diagnostic and therapeutic algorithm was proposed. Patients with DOGLT presented with hydrocephalus as first symptom, requiring neurosurgical therapy. Open arachnoid biopsy was necessary to confirm diagnosis. The oligoid cells in a desmoplastic or focally myxoid matrix showed OLIG2-, MAP2-, S-100 and rare HuC/HuD protein-immunopositivity. IDH1 (R132H)- and CD99-immunohistochemistry was negative in all patients. None of the evaluable biopsies of three patients showed chromosome 1p/19q deletion, neither as isolated nor combined allelic loss. Chemotherapy according to the SIOP-LGG 2004 standard induction and consolidation protocol resulted in complete response and partial response, respectively, in 50 % of the patients. However, after discontinuation of chemotherapy, two patients experienced tumor progression and one of them succumbed to the disease after 19 months. Radiological criteria as well as preliminary treatment results are presented after observation of four clinical cases. Prognosis and long-term clinical courses remain to be observed.

Die klinische Diagnose einer lebensbedrohlichen Erkrankung bei mental retardierten Patienten kann aufgrund fehlender oder eingeschrankter Kommunikationsmoglichkeit, physischer Einschrankungen, variabler Schmerztoleranz und dem Einfluss psychotroper Medikamente erheblich erschwert sein. Dies gilt insbesondere dann, wenn andere Erkrankungen die Symptomatik zusatzlich uberlagern.

The original publication contains the following errors: In the title, the words ‘oligodendroglial cell-like’ should read ‘oligodendroglial-like’. (The correct title is shown in this erratum.) The images in Figs. 3 and 4 were incorrect. The correct figures are shown below. All the figure citations except the citation of Fig. 1 were incorrect. All citations of Fig. 2 actually concern Fig. 5, all citations of Fig. 3 actually concern Fig. 6, all citations of Fig. 4 actually concern Fig. 2, all citations of Fig. 5 actually concern Fig. 3 and all citations of Fig. 6 actually concern Fig. 4.

Primary Hodgkin's lymphomas of the central nervous system (CNS) as well as cerebral involvement as the first manifestation of a systemic Hodgkin's disease are very rare. CNS involvement usually occurs in patients with advanced or relapsing systemic disease. Because primary CNS Hodgkin's lymphoma may present unexpected and sometimes misleading clinical and neuroradiological features, the description of unusual cases is important for expanding the awareness of this rare disease of the central nervous system. We describe three cases of primary Hodgkin's lymphoma of the CNS with peculiar features. None of the three patients had a previous clinical history of systemic Hodgkin disease. Case 1 and case 2 presented an unusual localization in the cerebellar hemisphere and in the brainstem, respectively. The third case occurred as a temporal lesion in the settings of a Richter transformation of a chronic lymphocytic leukemia.

Extrapleural solitary fibrous tumors are uncommon mesenchymal neoplasms frequently observed in middle-aged adults and are classified, according to the WHO classification of soft tissue tumors, as part of the hemangiopericytoma tumor group. However, these two entities remain separated in the WHO classification of tumors of the central nervous system. In fact, meningeal solitary fibrous tumors are believed to be benign lesion and only in a minority of cases local relapses have been described, although detailed survival clinical studies on solitary fibrous tumors of meninges are rare. In contrast to hemangiopericytoma, which frequently shows distant extracranial metastases, such an event is exceptional in patients with meningeal solitary fibrous tumors and has been clinically reported in a handful of cases only and their histopathological features have not been investigated in detail. In this report, we describe the detailed clinico-pathological features of a meningeal solitary fibrous tumor presenting during a 17-year follow-up period, multiple intra-, extracranial relapses and lung metastases.

We report on a 7-year-old girl with a phenotype combining mandibuloacral dysplasia (MAD), progeria, and rigid spine muscular dystrophy. Mild proximal weakness, contractures, and rigidity of the spine were the primary findings. Although present since birth, dysmorphic manifestations typical for MAD and progeroid features became more prominent with time, and the full clinical phenotype was recognizable at early school age. Her phenotype was caused by a homozygous mutation in LMNA (c.1411C > T, which predicts p.R471C) inherited from the heterozygous, consanguineous, unaffected parents. This mutation has only been reported in compound heterozygous state and was associated with a milder phenotype. Some LMNA mutations are known to cause MAD and overlapping phenotypes (MAD spectrum) in an autosomal recessive pattern. The p.R471C homozygous LMNA mutation causes a severe phenotype of the MAD spectrum. This case extends the clinical spectrum of MAD and further expands the phenotypic range of lamin A/C associated diseases. © 2008 Wiley-Liss, Inc.

The post-translational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) represents a remarkable example of dynamic modulation of homo- and heterophilic cell interactions by glycosylation. The synthesis of this unique carbohydrate polymer depends on the polysialyltransferases ST8SiaII and ST8SiaIV. Aiming to understand in more detail the contributions of ST8SiaII and ST8SiaIV to polySia biosynthesis in vivo, we used mutant mouse lines that differ in the number of functional polysialyltransferase alleles. The 1,2-diamino-4,5-methylenedioxybenzene method was used to qualitatively and quantitatively assess the polySia patterns. Similar to the wild-type genotype, long polySia chains (>50 residues) were detected in all genotypes expressing at least one functional polysialyltransferase allele. However, variant allelic combinations resulted in distinct alterations in the total amount of poly-Sia; the relative abundance of long, medium, and short polymers; and the ratio of polysialylated to non-polysialylated NCAM. In ST8SiaII-null mice, 45% of the brain NCAM was non-polysialylated, whereas a single functional allele of ST8SiaII was sufficient to polysialylate approximately 90% of the NCAM pool. Our data reveal a complex polysialylation pattern and show that, under in vivo conditions, the coordinated action of ST8SiaII and ST8SiaIV is crucial to fine-tune the amount and structure of polySia on NCAM.

We report anterior segment abnormalities in both eyes of a 33-week-old fetus endorsing the diagnosis of MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome. After abortion, the fetus was examined by a standard pediatric autopsy that included macroscopic and microscopic examination of both eyes. Postmortem findings included craniofacial stigmata (such as hypertelorism, a flat nose and low-set ears) and an agenesis of the corpus callosum. Array comparative genomic hybridization revealed a deletion of the short arm of the X chromosome (region Xp22.2 to p22.32). Ophthalmopathologic examination of the eyes revealed microphthalmia with anterior segment developmental anomalies, in particular sclerocornea and Peters' anomaly, respectively. General pathology findings plus the ocular findings allowed the diagnosis of MIDAS syndrome. A discussion of differential diagnoses is provided. This case report indicates that ophthalmopathologic investigation of fetal eyes can be of great value for the further classification of syndromes.

Meningeal melanocytoma refers to the uncommon clinical appearance of a generally benign tumour deriving from leptomeningeal melanocytes. Meningeal spread of this tumour is very rarely observed. We present the case of a 38-year-old man with meningeal melanocytoma of the cerebello-pontine angle, who showed a biphasic course of this disease, with a stable period followed by a steady progress within few months. After surgical resection of the melancytoma in the left skull base and of a first local recurrence five years later, a second local recurrence occurred 6 years after diagnosis, with intracerebral and spinal meningeal seeding. This tumor did not respond to a combined radiochemotherapy including oral temozolomide, and the patient died 5 months after starting treatment for this relapse. Secondary malignisation of the melancytoma is suggested.

Object. The mismatch repair (MMR) system has previously been implicated in acquired chemoresistance in malignant gliomas in humans. Its impact on the primary chemoresistance in glioblastoma multiforme (GBM) has not been determined in detail, however. Methods. The authors investigated the expression of both the MMR genes (hMSH2, hMLH1, hPMS1, hPMS2, and hMSH6) at the transcriptional level through reverse transcription—polymerase chain reaction and the hMSH2 protein through Western blot and immunohistochemical analysis of tumor tissue and primary cell cultures of 25 in vitro human de novo GBMs without prior experimental treatment. Results of these analyses were compared with data on in vitro chemoresistance to nine drugs that are in general use in glioma therapy. All MMR genes were expressed in the GBMs, with no significant difference among the individual tumors except in one respect; that is, GBMs showed either relatively high levels or barely detectable levels of hMSH2 messenger (m)RNA and protein expression. All multiresistant tumors demonstrated high hMSH2 expression, and all but two of the sensitive tumors exhibited low hMSH2 mRNA levels. Conclusions. Analysis of the data indicates that functional alterations of the MMR system are involved in the primary drug resistance in in vitro human malignant gliomas. Analysis of hMSH2 expression might therefore predict therapeutic responses in humans with GBMs.

Pediatric tumors of the central nervous system composed of oligoid tumor cells showing diffuse leptomeningeal spread without a primary mass lesion seem to represent a novel tumor entity. The terms "diffuse leptomeningeal glioneural tumor" or-preferably-"disseminated oligodendroglial-like leptomeningeal tumor of childhood" (DOGLT) were proposed. Four patients were identified with clinico-neuropathologic findings compatible with DOGLT and a mean follow-up time of 54 months was determined. Seven different biopsies obtained from the four patients were histologically evaluated. Clinical course, diagnostic measures, histopathologic and radiologic features and treatment suggestions were recorded, on the basis of which diagnostic and therapeutic algorithm was proposed. Patients with DOGLT presented with hydrocephalus as first symptom, requiring neurosurgical therapy. Open arachnoid biopsy was necessary to confirm diagnosis. The oligoid cells in a desmoplastic or focally myxoid matrix showed OLIG2-, MAP2-, S-100 and rare HuC/HuD protein-immunopositivity. IDH1 (R132H)- and CD99-immunohistochemistry was negative in all patients. None of the evaluable biopsies of three patients showed chromosome 1p/19q deletion, neither as isolated nor combined allelic loss. Chemotherapy according to the SIOP-LGG 2004 standard induction and consolidation protocol resulted in complete response and partial response, respectively, in 50 % of the patients. However, after discontinuation of chemotherapy, two patients experienced tumor progression and one of them succumbed to the disease after 19 months. Radiological criteria as well as preliminary treatment results are presented after observation of four clinical cases. Prognosis and long-term clinical courses remain to be observed.

Chordoid glioma of the third ventricle was recently reported as a novel tumor entity of the central nervous system with characteristic clinical and histopathological features (Brat et al., J Neuropathol Exp Neurol 57: 283–290, 1998). Here, we report on a histopathological, immunohistochemical and molecular genetic analysis of five cases of this rare neoplasm. All tumors were immunohistochemically investigated for the expression of various differentiation antigens, the proliferation marker Ki‐67, and a panel of selected proto‐oncogene and tumor suppressor gene products. These studies revealed a strong expression of GFAP, vimentin, and CD34. In addition, most tumors contained small fractions of neoplastic cells immunoreactive for epithelial membrane antigen, S‐100 protein, or cytokeratins. The percentage of Ki‐67 positive cells was generally low (< 5%). All tumors showed immunoreactivity for the epidermal growth factor receptor and schwan‐nomin/merlin. There was no nuclear accumulation of the p53, p21 (Waf‐1) and Mdm2 proteins. To examine genomic alterations associated with the development of chordoid gliomas, we screened 4 tumors by comparative genomic hybridization (CGH) analysis. No chromosomal imbalances were detected. More focussed molecular genetic analyses revealed neither aberrations of the TP53 and CDKN2A tumor suppressor genes nor amplification of the EGFR, CDK4, and M DM2 proto‐oncogenes. Our data strongly support the hypothesis that chordoid glioma of the third ventricle constitutes a novel tumor entity characterized by distinct morphological and immunohistochemical features, as well as a lack of chromosomal and genetic alterations commonly found in other types of gliomas or in meningiomas.

A 37-year-old man exhibited a suprasellar tumor which histologically proved to be a myxopapillary ependymoma. Since these gliomas are virtually restricted to the cauda equina region, magnetic resonance imaging (MRI) was performed which revealed multiple spinal tumors. The present case seems to be the first report on spontaneous intracranial seeding of a spinal myxopapillary ependymoma.

Catalase and ABCD3 are frequently used as markers for the localization of peroxisomes in morphological experiments. Their abundance, however, is highly dependent on metabolic demands, reducing the validity of analyses of peroxisomal abundance and distribution based solely on these proteins. We therefore attempted to find a protein which can be used as an optimal marker for peroxisomes in a variety of species, tissues, cell types and also experimental designs, independently of peroxisomal metabolism. We found that the biogenesis protein peroxin 14 (PEX14) is present in comparable amounts in the membranes of every peroxisome and is optimally suited for immunoblotting, immunohistochemistry, immunofluorescence, and immunoelectron microscopy. Using antibodies against PEX14, we could visualize peroxisomes with almost undetectable catalase content in various mammalian tissue sections (submandibular and adrenal gland, kidney, testis, ovary, brain, and pancreas from mouse, cat, baboon, and human) and cell cultures (primary cells and cell lines). Peroxisome labeling with catalase often showed a similar tissue distribution to the mitochondrial enzyme mitochondrial superoxide dismutase (both responsible for the degradation of reactive oxygen species), whereas ABCD3 exhibited a distinct labeling only in cells involved in lipid metabolism. We increased the sensitivity of our methods by using QuantumDots™, which have higher emission yields compared to classic fluorochromes and are unsusceptible to photobleaching, thereby allowing more exact quantification without artificial mistakes due to heterogeneity of individual peroxisomes. We conclude that PEX14 is indeed the best marker for labeling of peroxisomes in a variety of tissues and cell types in a consistent fashion for comparative morphometry.

Intravascular diffuse large B-cell lymphoma limited to the CNS (cIVL) is a very rare malignant disorder characterized by a selective accumulation of neoplastic lymphocytes (usually B cells) within the lumen of CNS blood vessels but not in the brain parenchyma. In the past, treatment of cIVL with anthracycline-based regimens was unsatisfactory with very short survival times. In the case of cIVL presented here, high-dose methotrexate-based polychemotherapy according to the Bonn protocol plus rituximab therapy was successful and led to a complete clinical and MRI remission which is ongoing 29 months after diagnosis.

Extrapleural solitary fibrous tumors are uncommon mesenchymal neoplasms frequently observed in middle-aged adults and are classified, according to the WHO classification of soft tissue tumors, as part of the hemangiopericytoma tumor group. However, these two entities remain separated in the WHO classification of tumors of the central nervous system. In fact, meningeal solitary fibrous tumors are believed to be benign lesion and only in a minority of cases local relapses have been described, although detailed survival clinical studies on solitary fibrous tumors of meninges are rare. In contrast to hemangiopericytoma, which frequently shows distant extracranial metastases, such an event is exceptional in patients with meningeal solitary fibrous tumors and has been clinically reported in a handful of cases only and their histopathological features have not been investigated in detail. In this report, we describe the detailed clinico-pathological features of a meningeal solitary fibrous tumor presenting during a 17-year follow-up period, multiple intra-, extracranial relapses and lung metastases.

Es werden die wesentlichen Zellen des Nervensystems (Neurone, Astrozyten, Oligodendrozyten, Ependymzellen, Plexuszellen, Tanyzyten, NG2-Zellen, Mikrogliazellen, meningeale und vaskulare Zellen) sowie deren Reaktionsformen einschlieslich verschiedener zellularer Einschlusse besprochen.

Fryns anophthalmia-plus syndrome is a very rare condition initially described by Fryns and colleagues in 1995 in a pair of siblings of nonconsanguineous parents. Since that time, only a few cases have been reported, most of them in newborns and young children. Clinical presentation is variable and includes anophthalmia/microphthalmia, cleft lip/palate, and other facial deformities. Furthermore, skeletal, central nervous system, and endocrine anomalies have been described. We report the case of a male fetus of 18 weeks of gestation with normal karyotype and findings matching Fryns anophthalmia-plus syndrome. Pregnancy was terminated because of sonographically proven facial midline defects and a marked cerebral ventriculomegaly. Macroscopic and histological findings obtained at autopsy showed extreme bilateral microphthalmia, unilateral cleft palate, unilateral nasal deformity, and low-set ears. Skeletal anomalies included 13 pairs of ribs, premature ossification of the calcaneus, and talipes.

The development of an acardiac twin in a monochorionic multiple pregnancy is a rare and severe complication of abnormal placental vascular anastomoses. These malformed fetuses present with a very bizarre morphology and a plethora of different malformations. However, all acardiac twins show either a complete absence or an anlage of the heart. Cerebral development is usually poor. We report, according to our review of the literature, for the first time, a very unusual case of acardius with features of acardius amorphus and acormus (fused head and malformed axial skeleton without macroscopically detectable internal organs) with lobar holoprosencephaly and intracerebral pigmented retina-like tissue.

Ependymomas are rare brain tumors representing about 3% of all intra-cerebral and spinal neoplasms. The WHO classification recognizes various rare histological ependymoma variants (i.e., lipidized ependymoma, giant cell ependymoma, etc.). However, a detailed analysis of a larger series of such cases is still lacking. We analyzed 13 case of ependymoma presenting unusual histological features. The data analysis of our series and its comparison to the cases published in literature did not reveal any close association between these features and the clinical parameters (such as age or localization). Moreover, some of these features can be found combined in individual tumors, suggesting that these variants may represent a spectrum of differentiation rather than true specific entities. However, awareness on these rare histological patterns in ependymomas is necessary in the differential diagnosis with other primary or secondary brain tumors.

Three cases of neuroradiologically diagnosed "leucoencephalopathy" are reported. Histopathological examination disclosed Binswanger's encephalopathy in Case 1, congophilic angiopathy with secondary leucoencephalopathy in Case 2, and HIV encephalopathy with secondary white matter changes in Case 3. These three cases demonstrate the unspecificity of neuroradiological findings in "leucoencephalopathy".

Epithelial differentiation in glioblastomas (GBM) may be associated with circumscribed growth and focal keratin expression resembling carcinoma metastasis. Therefore these rare lesions can pose a diagnostic problem suggesting coincidental occurrence of two separate neoplasms. However molecular analysis should succeed in establishing a common origin of seemingly unrelated tumor samples. Five GBMs exhibiting epithelial differentiation were microdissected and analyzed for mutations in the TP53 gene. SSCP analysis of exons 5-8 was followed by direct sequencing of aberrantly migrating fragments. TP53 mutations were identified in tumors from two of five patients. A G--T transversion in codon 176 was detected in a tumor, initially diagnosed as metastases of unknown origin, however, a later autopsy revealed GBM. In this lesion, the mutation was observed in both, areas of astrocytic differentiation and areas of epithelial differentiation. One tumor diagnosed as GBM with epithelial differentiation carried C--T transition in codon 211 in both, areas of astrocytic and epithelial differentiation. Thus, molecular analysis proved clonality in two GBMs with epithelial differentiation, thereby excluding a collision tumor. The present data support the concept of clonal origin of these morphologically heterogeneous lesions.

To present 58 cystic space-occupying formations of the spinal canal in 53 cases; these formations are called “juxtafacet cysts”. Fifty-Three patients (33 women and 20 men, with an average age of 60.8 years) were evaluated retrospectively by neurosurgery. All of the patients had received simple X-P, computed tomography (CT) and magnetic resonance imaging (MRI) before surgery. The neurological findings were evaluated on admission and in a follow-up review. Surgical intervention was performed on all patients and they underwent gross-total cyst removal. During surgery, the origin of a cyst was well observed. Follow-up data ranged from 6 to 46 months. Patient outcome was graded on a scale of excellent, good, or poor. Histological findings were evaluated. In 53 patients 58 cysts were identified. Four of the patients had multiple cysts. All cysts were associated with mobile spine. Fifty-five cysts were found in the lumbo-sacral region, two cysts were found in the cervico-thoracic region and one cyst in the thoracic region. Forty-two patients presented back pain and 52 patients presented radicular pain. Four patients had a cauda equina syndrome. Sensory disturbance was observed in 24 cases and motor weakness was observed in 21 cases. Claudication was observed in 19 cases. All cases with cervico-thoracic or thoracic cysts presented myelopathy. The duration of these clinical symptoms ranged from 10 days to 10 years. After surgery there was no case of a recurrent cyst during the follow-up period. Thirty-four cases had an excellent outcome, 18 a good outcome, and one a poor outcome. Out of 58 cysts 32 were joint cysts (11 synovial cysts, 21 ganglion cysts). A further 19 were flavum cysts, one was a posterior longitudinal ligament (PLL) cyst and six others were unknown pseudo cysts. In 34 of the cysts we found hemosiderin deposits and in eight amyloid deposits. Present investigation and findings in literature show a clear comparison of these cystic formations and the mobile part of the spine. An anatomical relation to a vertebral joint (“facet”) is only found in some of the cases (32 of 58). Further to that, the name “cyst” is not correct either, because most of the cystic formations are presented without a cell lining on their internal wall and therefore they are pseudo-cystic. We think that these cystic formations should be called “cystic formations of mobile spine” (CYFMOS) rather than “juxtafacet cysts”. A surgical intervention is the best treatment for these cysts if they cause a compression of nerve roots or/and of the spinal cord.

OBJECTIVE: The causes of cerebral sinus and vein occlusion and the accompanying parenchymal changes remain largely unexplained. The clinical variability and low incidence of the disease complicate systematic clinical investigations. Animal studies are indispensable; however, existing animal models of sinus thrombosis do not allow for long-term follow-up studies and are not suitable for pharmacological recanalization because sinus thrombosis is induced by ligation and injection of thrombogenic substances and does not resemble sinus thrombosis in humans. METHODS: We induced thrombosis of the superior sagittal sinus (SSS) by careful topical application of ferric chloride onto the SSS of rats, leading to highly reproducible occlusions. Magnetic resonance imaging was performed immediately after initiation of thrombosis and on postoperative Days 1, 2, and 7. Diffusion- and T2-weighted images allowed for calculation of the apparent diffusion coefficient and T2 relaxation time. Vascular status was assessed by venous magnetic resonance angiography. Neurological deficits were assessed with the rotarod test. RESULTS: Seven days after induction of thrombosis, partial recanalization (50.7% of the SSS remaining occluded) was accompanied by a resolution of early generalized changes of the apparent diffusion coefficient and of T2 relaxation time, indicating edema of the entire brain parenchyma. Compared with sham-treated animals, clinical skills in the experimental group improved over time, which was statistically independent from the degree of recanalization. Histopathological analysis revealed no signs of cerebral infarction. CONCLUSION: This is the first animal model of SSS thrombosis that offers the possibility to investigate pathophysiological aspects of the disease as well as the influence of therapy on the nature of disease progression.

CASE OF THE MONTH: ABSTRACT April 2004: A 53-year-old woman presented with a large club-shaped intra- and extraspinal tumor of the C6 nerve root which had intradurally grown through the enlarged C5–6 neural foramen and focally infiltrated the dura mater. Microscopy revealed a melanin-pigmented tumor with spindle-shaped and epithelioid cells and scattered psammoma bodies, a so-called psammomatous melanotic schwannoma (PMS). More than half of the patients with PMS have Carney complex, a genetically heterogeneous multiple neoplasia syndrome of autosomal-dominant inheritance, which in our patient, however, could not be detected unequivocally. Prognosis of all melanotic schwannomas (MSs) is not good with local recurrences or metastases in over 40% of cases. In our case, frequent versicular nuclei with distinct nucleoli, occasional mitoses and apoptoses and increased focal MIB-1 labeling indices prompted us to diagnose a malignant PMS. However, histologic criteria for malignancy in MSs are not clearly defined and there is no reliable histopathological indicator of malignant clinical behavior in MSs. Therefore, designation of “PMS with malignant histologic features” may be more appropriate. Since tumor recurrences and metastases im MSs may occur after more than 5 years, long-term follow-up of affected patients is required. One year after operation our patient showed no signs of tumor recurrence or metastases.

BACKGROUND: The aim of this study was to investigate the potential of dynamic O-(2-[(18)F]fluoroethyl)-L-tyrosine ((18)F-FET) PET for differentiating local recurrent brain metastasis from radiation injury after radiotherapy since contrast-enhanced MRI often remains inconclusive.METHODS: Sixty-two patients (mean age, 55 ± 11 y) with single or multiple contrast-enhancing brain lesions (n = 76) on MRI after radiotherapy of brain metastases (predominantly stereotactic radiosurgery) were investigated with dynamic (18)F-FET PET. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) of (18)F-FET uptake were determined (20-40 min postinjection) as well as tracer uptake kinetics (ie, time-to-peak and slope of time-activity curves). Diagnoses were confirmed histologically (34%; 26 lesions in 25 patients) or by clinical follow-up (66%; 50 lesions in 37 patients). Diagnostic accuracies of PET parameters for the correct identification of recurrent brain metastasis were evaluated by receiver-operating-characteristic analyses or the chi-square test.RESULTS: TBRs were significantly higher in recurrent metastases (n = 36) than in radiation injuries (n = 40) (TBRmax 3.3 ± 1.0 vs 2.2 ± 0.4, P < .001; TBRmean 2.2 ± 0.4 vs 1.7 ± 0.3, P < .001). The highest accuracy (88%) for diagnosing local recurrent metastasis could be obtained with TBRs in combination with the slope of time-activity curves (P < .001).CONCLUSIONS: The results of this study confirm previous preliminary observations that the combined evaluation of the TBRs of (18)F-FET uptake and the slope of time-activity curves can differentiate local brain metastasis recurrence from radiation-induced changes with high accuracy. (18)F-FET PET may thus contribute significantly to the management of patients with brain metastases.

The arterial vascular wall contains a non-neuronal intrinsic cholinergic system. The rate-limiting step in acetylcholine (ACh) synthesis is choline uptake. A high-affinity choline transporter, CHT1, has recently been cloned from neural tissue and has been identified in epithelial cholinergic cells. Here we investigated its presence in rat and human arteries and in primary cell cultures of rat vascular cells (endothelial cells, smooth muscle cells, fibroblasts). CHT1-mRNA was detected in the arterial wall and in all isolated cell types by RT-PCR using five different CHT1-specific primer pairs. Antisera raised against amino acids 29-40 of the rat sequence labeled a single band (50 kD) in Western blots of rat aorta, and an additional higher molecular weight band appeared in the hippocampus. Immunohistochemistry demonstrated CHT1 immunoreactivity in endothelial and smooth muscle cells in situ and in all cultured cell types. A high-affinity [3H]-choline uptake mechanism sharing characteristics with neuronal high-affinity choline uptake, i.e., sensitivity to hemicholinium-3 and dependence on sodium, was demonstrated in rat thoracic aortic segments by microimager autoradiography. Expression of the high-affinity choline transporter CHT1 is a novel component of the intrinsic non-neuronal cholinergic system of the arterial vascular wall, predominantly in the intimal and medial layers.

BACKGROUND: Fusobacterium nucleatum is a strict anaerobic microorganism that causes disease entities such as periodontal and soft tissue abscesses, pulmonary and intraabdominal infections and very rarely intracerebral infections. CASE PRESENTATION: Here, we report the rare case of a previously healthy 25-year-old German man with a cerebellar abscess caused by Fusobacterium nucleatum that resulted in rapid brain death. Toxicological screening showed positivity for amphetamines and cannabis. The diagnosis was obtained by polymerase chain reaction amplification of bacterial deoxyribonucleic acid in cerebrospinal fluid. CONCLUSIONS: In drug users clinicians should think about rare causes of brain abscesses/meningitis. Early diagnosis is necessary and justifies the use of molecular techniques.