Dominique S. Tews

Muscle‐fiber apoptosis in neuromuscular diseases

Muscle‐fiber loss is a characteristic of many progressive neuromuscular disorders. Over the past decade, identification of a growing number of apoptosis‐associated factors and events in pathological skeletal muscle provided increasing evidence that apoptotic cell‐death mechanisms account significantly for muscle‐fiber atrophy and loss in a wide spectrum of neuromuscular disorders. It became obvious that there is not one specific pathway for muscle fibers to undergo apoptotic degradation. In contrast, certain neuromuscular diseases seem to involve characteristic expression patterns of apoptosis‐related factors and pathways. Furthermore, there are some characteristics of muscle‐fiber apoptosis that rely on the muscle fiber itself as an extremely specified cell type. Multinucleated muscle fibers with successive muscle‐fiber segments controlled by individual nuclei display some specifics different from apoptosis of mononucleated cells. This review focuses on the expression patterns of apoptosis‐associated factors in different primary and secondary neuromuscular disorders and gives a synopsis of current knowledge. Muscle Nerve, 2005

Stereotactic Biopsy in Gliomas Guided by 3-Tesla 1H-Chemical-Shift Imaging of Choline

Objective: To investigate chemical-shift imaging (CSI) to guide stereotactic biopsy of the choline ‘hot spot’ in cerebral lesions suggestive of low-grade glioma. Methods: Nine patients with hyperintense lesions on T2-weighted images of standard magnetic resonance imaging without contrast enhancement underwent advanced magnetic resonance studies. These studies included 3-dimensional T1-weighted sequences with contrast enhancement and 2-dimensional 1H-CSI spectroscopy at 3 T. Signal intensity maps with relative signal intensities for choline were generated. The region with the highest choline signal intensity (the hot spot) was chosen as the target for stereotactic biopsy. The histopathological results were correlated with the increase in choline. Results: All spectroscopic data were of sufficient quality. In 5 instances the neuropathological diagnosis was grade II glioma, according to the WHO classification, and in 4 instances it was grade III glioma. According to the CSI criteria, all grade III gliomas and 4 of the 5 grade II gliomas were classified correctly. One grade II glioma was overestimated by CSI as a high-grade glioma. Conclusion:1H-CSI-guided stereotactic biopsy may offer advantages as compared to conventional stereotactic biopsy. The biopsy of the choline hot spot in suggestive low-grade gliomas may help to identify focal points of higher tumor malignancy independent of contrast enhancement.

Expression patterns of initiator and effector caspases in denervated human skeletal muscle

There is evidence that apoptotic cell death contributes to the loss of denervated muscle fibers. In 17 patients with neurogenic muscular atrophy, we studied the expression of the apoptosis mediators APAF‐1/caspase‐9 and degrading caspases‐2, ‐3, and ‐7 by immunohistochemical and western blot analyses. Muscle with neurogenic atrophy showed distinct upregulation of caspase‐9 and ‐7 and no expression for APAF‐1 (apoptosis protease‐activating factor‐1) and caspase‐2 and ‐3. Expression of caspase‐7 was restricted to atrophic fibers, but caspase‐9 was also found in normal‐sized muscle fibers where its expression was often confined to single fiber segments. These findings indicate that upregulated expression of caspase‐9 can initiate the proteolytic cascade involving the downstream executioner caspase‐7, which mediates degradation of denervated muscle fibers. However, apoptotic events may be restricted to single muscle‐fiber segments, where apoptotic cell degradation contributes to the long‐term process of atrophy. Pharmacological inhibition of caspases may be a therapeutic strategy in diminishing muscle atrophy. Muscle Nerve, 2005

Multiple endocrine neoplasia type 1–associated thyrotropin-producing pituitary carcinoma: report of a probable de novo example

Pituitary carcinomas are exceedingly rare. At present, the sole diagnostic criterion is metastatic spread, either craniospinal or systemic. There is no agreement on a histologic, immunohistochemical, and/or ultrastructural definition. We report a clinically and morphologically well-documented example of pituitary thyrotropin cell carcinoma in a man with multiple endocrine neoplasia type 1 syndrome. The tumor produced thyrotropin, alpha-subunit, and prolactin and, through electron microscopy, was found to consist solely of Thyrotroph cells. Over a protracted course, craniospinal and systemic metastases were noted. The primary and metastatic deposits of this aggressive tumor were studied. To our knowledge, this tumor is the first reported case of thyrotropin cell carcinoma occurring in association with the multiple endocrine neoplasia type 1 syndrome. The literature regarding thyrotropin carcinomas is reviewed. Based on the study of several biopsies during disease progression, we believe that the carcinoma originated de novo without an intermediary adenoma phase.

Delayed or late-onset type II glycogenosis with globular inclusions

Three unrelated patients, one girl, one boy, and an adult female, aged 14, 11 and 41 years, respectively, at the time of biopsy, revealed lysosomal glycogen storage, autophagic vacuoles and peculiar globular inclusions of distinct ultrastructure, which were reducing but did not appear like true “reducing bodies” as described in the congenital myopathy “reducing body myopathy”. All three patients had residual activity of acid α-glucosidase in their muscle biopsy samples. Leukocytes in the girl showed normal acid α-glucosidase activity, but in the boy activity was reduced. Molecular genetic analysis of the GAA gene revealed disease-causing mutations in each patient: H568L/R672W, IVS1–13T>G/G615F, and IVS1–13T>G/IVS1–13T>G. Although only one patient with such globular inclusions has been reported up to now, the three patients described here indicate that in the late-onset type of GSD II such inclusions may not be rare.

Diagnostic impact of proton MR-spectroscopy versus image-guided stereotactic biopsy.

SummaryBackground. The aim of this study was to compare the diagnostic accuracy of 1H MR-spectroscopy versus image-guided stereotactic biopsy.Method. A cohort of 83 consecutive patients with a broad spectrum of brain lesions were examined. Prior to stereotactic biopsy, the patients were subjected to 1H MR-spectroscopy examination. Diagnostic accuracy of 1H MR-spectroscopy and image guided stereotactic biopsy was determined for the largest diagnostic subgroups. Each diagnostic procedure was tested for concordance in every subgroup.Findings. The subgroups of patients comprised: low grade glioma, high grade glioma (grades III and IV), lymphoma and metastasis. For the sensitivity of 1H MR-spectroscopy ranged from 87.7 in high grade glioma to 92.3% in metastasis and for specificity from 93.3% for high grade glioma to 100% in low grade glioma. The highest positive predictive value of 100% was reached in the subgroup of low grade glioma. The highest negative predictive value was reached in lymphoma and metastasis, 100%. The kappa values were highly significant for all comparisons (p<0.001). The co-efficient ranged from 0.68 to 0.84. It was lowest in assessing high grade glioma and highest in lymphoma.Conclusion. Compared with each other 1H MR-spectroscopy and image-guided stereotactic biopsy showed a moderate to good, statistically highly significant concordance. In patients in whom operation is at an increased risk e.g., due to severe medical illness, 1H MR-spectroscopy as a noninvasive procedure may be sufficient to assess the diagnosis.

Characterization of initiator and effector caspase expressions in dystrophinopathies

There is evidence that apoptotic cell death mechanisms contribute to muscle fiber loss in dystrophin‐deficient muscle but there is little knowledge about the final degrading events of muscle fiber apoptosis. In muscle biopsy specimens from 14 patients with a dystrophinopathy (10 patients with DMD, two with Becker MD, two DMD carriers), expression of APAF‐1 and caspase‐9, upstream members of the apoptotic protease cascade, as well as of the downstream executioners caspase‐2, ‐6 and ‐7, were studied by immunohistochemistry and Western blots. Besides predominant immunoreactivity in regenerating muscle fibers, which may contribute to apoptotic events during new muscle fiber formation, caspase‐9, ‐6 and ‐7 displayed upregulation in non‐regenerating, light microscopically intact but atrophic muscle fibers. Western blot analyses confirmed the upregulations. These findings indicate that, once activated, caspase‐9 initiates a proteolytic, muscle fiber degrading cascade involving the downstream executioners caspase‐6 and ‐7. However, lacking coexpression of APAF‐1 suggests the existence of other pathways of caspase‐9 activation than through the “apoptosome” in dystrophinopathies.

Tumour necrosis factor-mediated cell death pathways do not contribute to muscle fibre death in dystrophinopathies.

There is evidence that apoptotic cell death mechanisms contribute to muscle fibre loss in dystrophinopathies, but little knowledge about the activators of the final degrading caspase cascade in muscle fibre apoptosis. As mitochondria-related activation of this caspase cascade, through e.g. APAF-1, could not be proven in dystrophin-deficient muscle, this study searches for other prospective candidates that may directly trigger apoptotic cell degradation by mitochondria-independent pathways involving the interaction of tumour necrosis factor-α (TNF-α) and TRAIL with death receptors and subsequent activation of caspase-8. The expression of TNF-α, TNF-R1, TRAIL, NF-κB and caspase-8 were studied in muscle biopsy specimens from 14 patients with a dystrophinopathy [10 Duchenne muscular dystrophies (DMD), 2 Becker MD, and 2 DMD carriers] by immunohistochemistry and Western blotting. In all types of dystrophinopathies, necrotic muscle fibres undergoing myophagocytosis displayed strong expression of TNF-α, TNF-R1, and TRAIL, which, however, was attributed to phagocytosing cells and not to the muscle fibres themselves. There was no up-regulation in normal-shaped or atrophic non-necrotic muscle fibres, or in intact muscle fibre segments adjacent to segmental necrosis and myophagocytosis. The expression profiles of caspase-8 and NF-κB resembled that of normal control muscle. There were likewise no significant differences in the Western blot analyses between normal control and dystrophin-deficient muscle. Based on these findings, a contribution of TNF-α or TRAIL-mediated cell death pathways to muscle fibre apoptosis or necrosis in dystrophinopathies could not be confirmed.

Gliosarcoma with bone infiltration and extracranial growth: case report and review of literature

Gliosarcoma is a relatively rare and highly malignant brain tumor consisting of both a glioblastoma and a mesenchymal component. Because of the natural barrier of the dura mater, that prevents intra or extradural neoplasm dissemination, cases of penetration of the dura and cranium by gliosarcomas without previous surgery or radiation are very rarely reported. We report an unusual case of gliosarcoma that involved the temporal skull base and the dura without antecedent radiation or surgery, although the lesion traversed the dura without radiologic or gross interruption of the dura. Remarkable in our case is the initial integrity of cerebral parenchyma. Follow-up revealed a tumorous infiltration of the temporal lobe almost one year after initial diagnosis. Thus the origin of the gliosarcoma in our case seemed to be extradural in the temporal skull base. Furthermore, this report demonstrates that extensive multi-modality treatment might be effective in patients with gliosarcomas and poor prognostic factors, for example unmethylated MGMT status.

Intramedullary Solitary Fibrous Tumor—A Benign Form of Hemangiopericytoma? Case Report and Review of the Literature

BACKGROUNDnSolitary fibrous tumors (SFTs) are benign tumors of the soft tissue occurring anywhere in the human body but arise predominantly in the visceral pleura. SFTs of the central nervous system are rare, especially when they occur within the spinal cord.nnnCASE DESCRIPTIONnWe present a case of an 83-year-old female patient presenting with acute spastic paralysis of the lower extremities after a history of progressive weakness and incontinence. Magnetic resonance imaging (MRI) findings were typical for meningioma, but an intradural, mainly intramedullary tumor was found at the first operation. A second operation was performed under neurophysiological monitoring, and complete removal of the tumor was achieved. Neurological conditions improved after the procedure, but the patient remained paraparetic. Histological and immunohistochemical findings revealed an SFT.nnnCONCLUSIONSnThere is evidence that SFTs and hemangiopericytomas (HPCs) are not different entities but should be considered as different graduations of a common spectrum. The extent of resection is a prognostic factor for recurrence-free survival in SFT; therefore we recommend surgery with complete resection whenever possible depending on the results of mandatory intraoperative neurophysiological monitoring in these cases.