[Neuritis cordis and myocarditis in rabies]. / Neuritis cordis und Myokarditis bei Tollwut.

Once the rabies virus has spread through the central nervous system (CNS), the virus is also transported centrifugally along axons, especially of the autonomic nervous system, to a wide range of organs including the heart. In this case report of a 49-year-old man who had been bitten by a dog in Asia, the rabies infection of cardiac nerves and cardiac muscle fibres is shown by immunohistochemistry. The neuritis cordis and rabies myocarditis can have important clinical effects on the heart rate and myocardial function and lead to blood pressure crises which are typical for the clinical course of rabies in humans.

[The role of diagnostic neuropathology in familial tumour syndromes]. / Die Rolle der Neuropathologie bei familiären Tumorerkrankungen.

Inherited cancer syndromes often involve the central and peripheral nervous system. For the surgical neuropathologist the possibility in individual patients of a familial tumour syndrome needs to be considered in the case of special tumours such as malignant peripheral nerve sheath tumour (MPNST), medulloblastoma with extensive nodularity (MBEN) or even atypical teratoid/rhabdoid tumour (AT/RT) of the brain. Furthermore, tumour location and patient age may point to a familial tumour syndrome as in the case of neurofibromatosis type 2 (NF2) with typical bilateral vestibular schwannoma in young age. This short review discusses some of the diagnostic aspects in this field relating to neurofibromatosis type 1 and 2 (NF1, NF2), as well as the two rare tumors MBEN in Gorlin-Goltz syndrome and AT/RT in particular.

Absence of the interstitial cell of Cajal network in mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal-recessive multisystemic disorder with predominant gastrointestinal involvement, presenting with variable degrees of gut dysmotility up to frank chronic intestinal pseudoobstruction. Despite major advances in understanding its basic molecular pathogenesis in recent years, the distinct mechanisms and pathoanatomical substrate underlying MNGIE-associated gastrointestinal dysmotility are still widely unknown. As yet, though their critical role in proper gastrointestinal transit in terms of spontaneous pacemaker activity and enteric neurotransmission is well established, the population of the interstitial cells of Cajal (ICC) has not been investigated in MNGIE. Therefore, we examined small bowel samples of a well-characterized MNGIE patient by using conventional histology and immunohistochemistry techniques. The ICC network was studied by immunohistochemistry for the tyrosine kinase Kit (CD117), known to reliably detect ICCs, while mucosal mast cells served as an internal and normal small bowel specimen as external controls. At a light microscopic level, no gross structural alteration of the bowel wall composition and its neuromuscular elements was noted. However, a complete absence of Kit immunoreactive cells could be demonstrated in regions where ICCs are normally abundant, while internal and external controls retained strong Kit positivity. In conclusion, our preliminary results provide a first evidence for an alteration of the ICC network in MNGIE, and support the notion that ICC loss might be an early pathogenetic event in MNGIE-associated gut motor dysfunction before significant myopathic and/or neuropathic structural changes occur.

[Meningiomas: multiparametric approach for risk stratification and grading]. / Meningeome: Multiparametrische Risikostratifizierung und Grading.

The prognosis of the generally benign meningiomas is mainly an issue of the likelihood of recurrence, which increases with WHO grade (7-20% in WHO grade I, 29-40% in WHO grade II, and 50-78% in WHO grade III meningiomas). Among clinical parameters the most important prognostic factor is the completeness of neurosurgical tumor resection. Among histopathological prognostic parameters the mitotic activity is the most important one. As the cutoffs of the mitotic index (MI) are defined for each grade by the WHO classification of brain tumors and because the MI can be applied as the sole grading criterion, the reliable and reproducible assessment of the MI is crucial for an appropriate risk stratification. This is provided by immunohistochemical mitosis markers, i.e., phospho-histone H3 (PHH3). The PHH3 method is superior to the conventional mitosis counting method and therefore allows a more reliable risk stratification. The Ki-67 labeling index provides additional prognostic information, especially in prognostically ambiguous meningiomas. Cytogenetically, the deletion of the short arm of one chromosome 1 (1p-) is an unfavorable prognostic parameter and is correlated with a high risk of recurrence. The enzyme reaction for alkaline phosphatase (ALPL) is a fast and efficient screening method, which strongly indicates an intact chromosome 1 in cases with a positive enzyme reaction.

[WHO classification of tumours of the CNS: revised edition of 2007 with critical comments on the typing und grading of common-type diffuse gliomas]. / WHO-Klassifikation der ZNS-Tumoren: Revidierte Fassung von 2007 mit kritischen Anmerkungen zum "Typing" und "Grading" diffuser Gliome.

The fourth edition of the WHO classification of tumours of the CNS was published in 2007. Six new entities were codified: angiocentric glioma (AG); papillary glioneuronal tumour (PGNT); rosette-forming glioneuronal tumour of the fourth ventricle (RGNT); papillary tumour of the pineal region (PTPR); spindle cell oncocytoma of the adenohypophysis (SCO); and pituicytoma. Furthermore, six histological variants of well-known brain tumours have been added, partially because they show different biological behaviour and/or prognosis: pilomyxoid astrocytoma; atypical choroid plexus papilloma; medulloblastoma with extensive nodularity; anaplastic medulloblastoma; extraventricular neurocytoma; non-specific variant of dysembryoplastic neuroepithelial tumour (DNT). The new entities and variants are discussed in this review. Moreover, the typing und grading of common-type diffuse gliomas, as well as the WHO grading system, are critically reviewed, particularly with regard to the prognostically important differential diagnosis of diffuse astrocytomas und oligodendrogliomas.

How a neuropsychiatric brain bank should be run: a consensus paper of Brainnet Europe II.

The development of new molecular and neurobiological methods, computer-assisted quantification techniques and neurobiological investigation methods which can be applied to the human brain, all have evoked an increased demand for post-mortem tissue in research. Psychiatric disorders are considered to be of neurobiological origin. Thus far, however, the etiology and pathophysiology of schizophrenia, depression and dementias are not well understood at the cellular and molecular level. The following will outline the consensus of the working group for neuropsychiatric brain banking organized in the Brainnet Europe II, on ethical guidelines for brain banking, clinical diagnostic criteria, the minimal clinical data set of retrospectively analyzed cases as well as neuropathological standard investigations to perform stageing for neurodegenerative disorders in brain tissue. We will list regions of interest for assessments in psychiatric disorder, propose a dissection scheme and describe preservation and storage conditions of tissue. These guidelines may be of value for future implementations of additional neuropsychiatric brain banks world-wide.

[Histopathology of space-occupying lesions of the spine]. / Histopathologie spinaler Raumforderungen.

The first step in diagnosing spinal lesions is to define the anatomical location, especially via magnetic resonance tomography, which is also helpful for histopathologists. However, definite diagnosis is based on histologic and cytologic examinations especially in the case of fine-needle biopsies. In this short review the principal histopathologic diagnoses of primary and secondary tumors and tumor-like lesions of the spine itself, the epidural space, the spinal meninges and nerve roots, and the spinal cord are addressed. The significance of immunohistochemistry for differential diagnosis or, in cases of spinal metastasis, for determination of the primary is discussed.

Automated nuclear segmentation in the determination of the Ki-67 labeling index in meningiomas.

OBJECTIVE: Assessing the Ki-67 labeling index (LI) is laborious and time consuming. Therefore, an automated computer-based method was developed, which is able to identify and analyze immunolabeled and hematoxylin-stained nuclei in digital images of routine immunohistochemical slides. MATERIAL AND METHODS: The method is based on a plugin for the public domain image analysis software ImageJ, which runs on every operating system (free download at http://rsb.info.nih.gov/ij/). Percentage of Ki-67 immunostained nuclei were determined in 5 high power fields (x40) of immunostained slides (DAB detection technique, hematoxylin counterstain) of 20 Grade I, 20 Grade II, and 10 Grade III meningiomas conventionally by two independent investigators and automatically, respectively. The time effort was measured for each counting procedure. RESULTS: Enumerating conventionally or automatically did not reveal any significant differences in the mean labeling indices. Ki-67 LIs discriminated sufficiently between meningiomas of Grade I (median 1.7% Investigator 1 and 1.5% Investigator 2 vs. 1.5% automatically), Grade II (7.6%, 8% vs. 7.3%), and Grade III meningiomas (22%, 21% vs. 22%). The computer-based results correlated very closely with those obtained by manual counting (correlation coefficient = 0.98). The mean time effort for counting procedure per image was 374 s (130 s-435 s) for the conventional and 11 s (7 s-12 s) for the automated method. CONCLUSIONS: The described method can reliably assess the Ki-67 LI much faster than conventional enumerating. The computerized method has the advantages of objectivity, accuracy, repeatability, and ease of use. There is no request for special stains nor special image acquiring systems. The plugin can be downloaded at the "Morphometrie" section of http://www.uniklinikum-saarland.de/neuropathologie.

The value of micro-Doppler in stereotactic brain biopsy.

OBJECTIVE: The aim of this study was to analyse the value of intraoperative micro-Doppler in stereotactic brain biopsy (SBB). So far, only a few studies have reported about the usefulness of micro-Doppler in stereotactic brain biopsy. METHODS: Between 1998 and 2003, 155 SBBs were performed in 153 patients with micro-Doppler (81 males, 72 females, mean age: 59 years). All operations were performed using a ZD-frame and a multiplanar computer tomography-guided trajectory planning system (Leibinger SPP). A 16 MHz micro-Doppler probe (diameter 1 mm, DWL) was used in all cases to explore the area of biopsy before the tissue probes were taken. Serial biopsies (mean, 6 samples) were taken with the Sedan side-cutting cannula (n = 145) or the small forceps (n = 10). We evaluated the number of intraoperative detectable vessel signals by micro-Doppler, intraoperative bleedings as well as bleedings detected by postoperative CT (which was performed in all cases). We compared our results according to bleeding-related complications with the data of stereotactic biopsy series from the recent literature. RESULTS: A conclusive histopathological diagnosis was achieved in 150/153 patients (98 %). A re-biopsy had to be undertaken in 2 cases. In 98 biopsies (63 %), no vessel could be detected with the micro-Doppler. In the remainder, a signal of arterial vessels was detected in 22 (14 %) and a signal of venous vessels in 35 cases (23 %). Detection of a vessel in the micro-Doppler led to a change of the biopsy site in each case within the same trajectory. Biopsy-related bleedings were detected in 4 cases (2.6 %). Among these, the only bleeding which occurred without any signs of vessels in the micro-Doppler happened in a case of a melanoma. The overall biopsy-related permanent morbidity was 0.6 % (n = 1). The biopsy-related mortality was 0. CONCLUSIONS: Despite the overall high security of SBB, the use of intraoperative micro-Doppler may lead to an additional reduction of the risk for a biopsy-related bleeding without enormous expense.

Monostotic lumbar manifestation of fibrous dysplasia--a rare entity.

Monostotic manifestation of fibrous dysplasia in the spine is exceedingly rare. We report the case of a 30 year-old woman suffering from slowly increasing low back pain. Radiologically a polycyclic, slightly gadolinium-enhancing, solitary lesion within the first lumbar vertebral body was detected. The lesion was removed and stabilized with bone marrow transplant. We describe the radiological and histopathological findings.

March 2003: a 41 -year-old female with a solitary lesion in the liver.

The March COM. A 41-year-old woman presented in 1997 with diffuse abdominal pain, meteorism and intermittent diarrhea. Imaging studies revealed a focal rounded lesion in the liver. Although there was no history of progesterone or estrogen therapy, the radiographic appearance was considered to be suggestive of adenoma. The lesion was monitored by ultrasound until October 2000 when a resection was performed because of the presumed risk of a malignant transformation. H&E stained sections revealed an ectopic ependymoma that was strongly positive for GFAP. The surrounding hepatic tissue was negative for GFAP. An extensive search for a CNS manifestation or any other extraspinal localization was unrevealing. We believe we have encountered the first case of an ectopic ependymoma presenting as a solitary hepatic lesion in the absence of CNS disease. Ependymomas generally arise in the CNS in relation to the ventricular system. Extraneural metastasis from ependymomas may occasionally occur even years after detection and treatment of the primary lesion and have been the subject of several reports. In contrast, there are only anecdotal reports of primary extraneural "ectopic" ependymomas. So far those rare cases have only been found in close vicinity to the neural axis, eg, in the sacrococcygeal region, the posterior mediastinum or the ovaries and are there thought to originate from embryonic remnant cells around the neural tube. Distant metastases of ependymomas invading or arising within the extraneural lumbosacral soft tissue may occur in this situation. Here, we report what appears to be the first case of a primary ectopic ependymoma originating in the liver, with no signs of CNS or other systemic involvement.

Paragangliomas of the parasellar region.

Parasellar paragangliomas are rare tumors. As far as we know, only ten cases are described in the literature. Their clinical, pathological, and radiological features and possible origin are discussed in this article and a review of the literature is given. Additionally, we report a new case of a 51-year-old woman with paraganglioma growing in the anterior, middle, and posterior cranial fossa with extended destruction of the skull base. The patient had been suffering from long-standing headaches and facial nerve paresis. Preoperatively, this tumor was suspected to be a meningioma.

[Primary CNS lymphomas. Morphology and diagnosis]. / Primäre ZNS-Lymphome. Morphologie und Diagnostik.

Diagnostically primary central nervous system lymphomas (PCNSL) have to be differentiated from glioblastoma and brain metastases. Histologically the overwhelming majority of PCNSL is represented by diffuse large B-cell lymphomas, in this series with a BCL6 expression in 80% of the cases detected by immunohistochemistry. Stereotactic biopsy is the method of choice in establishing the definite diagnosis and intraoperative smear cytology will detect the lymphoid blasts. To confirm the B-cell lineage, immunohistochemistry is needed (CD20, CD79a). Small reactive T-lymphocytes and monohistiocytic cells and activated "microglia" are found within and at the periphery of PCNSL foci. The infiltrated brain tissue shows partially pleomorphic reactive astrocytes that can be confused with neoplastic astrocytes, especially in small specimens. In contrast to high-grade gliomas, however, PCNSLs do not show endothelial proliferations. Subtypes or variants of diffuse large B-cell lymphomas can also be observed in cases of PCNSL: the anaplastic variant with large multinucleated tumour cells resembling Reed-Sternberg cells, T-cell rich B-cell lymphoma and intravascular B-cell lymphoma with primary manifestation within the brain or the spinal cord. HIV/AIDS-associated PCNSLs are characterised by large plasmoblastic or small Burkitt-like cells and tumour necrosis. Primary leptomeningeal large B-cell lymphomas do occur very rarely and are diagnosed by cerebrospinal fluid cytology.

[Diagnostic value of the monoclonal antibody to thyroid transcription factor -1(TTF-1) in CNS metastases. An immunohistochemical study of 65 cases]. / Diagnostischer Wert des monoklonalen Antikörpers TTF-1 bei ZNS-Metastasen. Immunhistochemische Studie an 65 Fällen.

Thyroid transcription factor-1 (TTF-1) is used as an immunohistochemical marker for the identification of the lungs or thyroid gland as the site of origin in patients with metastatic disease and unknown primary tumor. In this study the reliability of anti-TTF-1 was assessed in 65 metastases of the central nervous system (CNS), among which there were also small stereotactic biopsies (n = 22) and poorly preserved specimens. Eight out of nine CNS metastases of patients with known adenocarcinoma of the lungs, as well as seven adenocarcinoma metastases of patients with radiologically detected or anamnestically presumed pulmonary carcinoma, expressed TTF-1 immunohistochemically. One CNS metastasis from a follicular thyroid carcinoma was positive and one from an anaplastic thyroid carcinoma was negative. All CNS metastases from patients with known primary tumors outside the lungs or thyroid gland were negative. TTF-1 is a sensitive (up to 90%) and specific (100%) immunohistochemical marker for CNS metastases of adenocarcinomas of the lungs and also functions reliably on small or stereotactic biopsies and poorly preserved samples.

[Human prion diseases]. / Prionkrankheiten des Menschen.

Prion diseases are rare neurodegenerative transmissible fatal diseases affecting humans and mammals. The causative agent is a novel pathogen termed the prion. Unlike classical infectious agents such as bacteria or viruses, prions lack an independent genome and consist largely of an abnormal form of the host-encoded prion protein. Creutzfeldt-Jakob disease (CJD) is the main representative of human prion diseases that may be sporadic in most cases, hereditary, or acquired. Clinical examination yields only a suspected diagnosis with formal criteria for probable or possible. Definite diagnosis relies on autopsy and neuropathology findings. This is also true for the new variant CJD (vCJD), a previously unknown prion disease of humans that is connected with the same strain of prions as found in bovine spongiform encephalopathy (BSE). The autopsy and handling of laboratory material for histopathological examination requires specific precautionary measures and decontamination. For definite histopathological diagnosis of a human prion disease, immunohistochemical detection of the prion protein deposits is the gold standard. Furthermore, molecular and genetic investigations are necessary for classification because a close correlation could be established between distinct CJD phenotypes, codon 129 genotypes of the prion protein gene, and the prion protein type.

Initial evaluation of the feasibility of single photon emission tomography with p-[123 I]iodo-L-phenylalanine for routine brain tumour imaging.

p-[123I]iodo-L-phenylalanine (IPA) is a recently described radiopharmaceutical which is highly accumulated in gliomas. The present investigation was designed to evaluate the feasibility of single photon emission tomography (SPET) with IPA to image brain tumours under routine clinical conditions. Using a dual- and a triple-headed SPET camera, whole-body kinetic and brain SPET, as well as plasma, urinary and dosimetric analysis were determined in four patients with gliomas after intravenous injection of IPA. Results obtained by IPA SPET were retrospectively compared with histopathology, magnetic resonance imaging and positron emission tomography with [18F]fluorodeoxyglucose. Tumour lesions were clearly demonstrated by IPA SPET at 30 min, 1h and 4.5h post-injection, even in patients with low grade gliomas. In patients with glioblastoma, excellent visualization of the tumour was possible even at 7h p.i., indicative of the high retention of the radiopharmaceutical in cerebral gliomas. Analysis of the radioactivity in plasma and urine attested to the high in vivo stability of IPA. Blood clearance was rapid (> 65% after 10 min) and IPA was excreted predominantly by the kidneys, the urinary radioactivity excretion ranging from 27% at 1h to 54% of injected doses at 5h p.i. The average effective dose for adults was estimated to be 0.0152mSv*MBq(-1), leading to an effective dose of 3.8mSv in a typical brain SPET investigation with 250 MBq IPA. This result strongly suggests that IPA is a potentially valuable brain tumour imaging agent for widespread clinical studies with SPET. Its high specific tumour uptake and retention even in low grade gliomas represent a major advantage compared to presently available SPET radiopharmaceuticals. Moreover, the radiation dose estimates indicate that clinical use of IPA will result in acceptable radiation dose levels in humans.