Skeletal muscle fibers produce B-cell stimulatory factors in chronic myositis.

Introduction: We aimed to identify B-cell-mediated immunomechanisms in inclusion body myositis (IBM) and polymyositis (PM) as part of the complex pathophysiology. Materials and methods: Human primary myotube cultures were derived from orthopedic surgery. Diagnostic biopsy specimens from patients with IBM (n=9) and PM (n=9) were analyzed for markers of B cell activation (BAFF and APRIL) and for chemokines that control the recruitment of B cells (CXCL-12 and CXCL-13). Results were compared to biopsy specimens without myopathic changes (n=9) and hereditary muscular dystrophy (n=9). Results: The mRNA expression of BAFF, APRIL, and CXCL-13 was significantly higher in IBM and PM compared to controls. Patients with IBM displayed the highest number of double positive muscle fibers for BAFF and CXCL-12 (48%) compared to PM (25%), muscular dystrophy (3%), and non-myopathic controls (0%). In vitro, exposure of human myotubes to pro-inflammatory cytokines led to a significant upregulation of BAFF and CXCL-12, but APRIL and CXCL-13 remained unchanged. Conclusion: The results substantiate the hypothesis of an involvement of B cell-associated mechanisms in the pathophysiology of IBM and PM. Muscle fibers themselves seem to contribute to the recruitment of B cells and sustain inflammation.

Early Ectopic Recurrence of Craniopharyngioma in the Cerebellopontine Angle.

Ectopic recurrence of craniopharyngioma in the cerebellopontine angle after surgical resection of a suprasellar craniopharyngioma is rare. Thus, only 5 cases were reported with a delay ranging between 4 and 26 years after removal of the primary tumor. We report a unique case of ectopic recurrence of craniopharyngioma in the cerebellopontine angle, which occurred at only 4 months after surgical resection of the primary tumor. A 24-year-old man underwent resection of a suprasellar craniopharyngioma via a right pterional approach four months earlier. During follow-up, cerebral magnetic resonance imaging (MRI) showed a round homogeneous contrast-enhancing tumor in the right cerebellopontine angle with neither relation to the internal auditory canal nor to the dura mater. After microsurgical resection, histopathological findings revealed ectopic recurrence of craniopharyngioma with similar tumors like the primary tumor. Although infrequent, craniopharyngioma may disseminate via the cerebrospinal fluid during surgical resection and grow in an ectopic place. Early follow-up and MRI scan following resection of a craniopharyngioma is recommended.

Delayed distant spinal metastasis in thymomas.

STUDY DESIGN: A case report. OBJECTIVE: To demonstrate 2 cases of delayed distant spinal metastasis from a thymoma with comprehensive immunohisto-chemical analysis. SUMMARY OF BACKGROUND DATA: Thymoma is a rare slow-growing cancer arising in the mediastinum. Thymomas usually grow invasively into surrounding structures. Distal spinal metastasis is uncommon. To date, only 4 cases with histological verification have been described. METHODS: Patient 1: A 42-year-old female complained about back pain for 4 years. She underwent gross-total resection of a type B2 thymoma 8 years earlier without adjuvant therapy. Neurological examination revealed no deficits. Magnetic resonance imaging demonstrated an intraspinal extradural tumor at the level of L4-S1 with infiltration of vertebral body L5. A nearly total resection was performed via a partial L4 and L5 hemilaminectomy.Patient 2: A 62-year-old female was referred with segmental thoracic pain. She underwent a total of 6 surgical procedures for resection of a thymic carcinoma during a period of 13 years with a subsequently local radiation therapy and various chemotherapy cycles. Magnetic resonance imaging revealed an intraspinal extradural tumor at the level of T9-T10 with infiltration of vertebral body T9-T10. A gross-total tumor resection was performed via a costotransversectomy and facetectomy T9-T10. RESULTS: Patient 1: The tumor cells were strongly positive for AE1/3- and CK5/14-specific antibodies. Most of the immature T-cells expressed CD3. CD1a, CD5, and TdT expression was observed in a smaller portion. The findings were consistent with the diagnosis of a spinal metastasis of the known type B2 thymoma.Patient 2: The tumor cells were CK5/14 and CK19/20 positive. Only the infiltrating lymphocytes were labeled with CD3-specific antibodies. Histopathological findings revealed a metastasis of a previously resected well-differentiated thymus carcinoma. CONCLUSION: We recommend surgical resection because metastasis of thymoma may infiltrate nerve roots and compress the spinal cord. A multidisciplinary approach is required to manage long-term sequelae.

Outcome of surgical decompression of spinal mass lesions in non-Hodgkin's lymphoma and plasmacytoma.

OBJECTIVE: Surgical treatment for spinal mass lesions due to non-Hodgkin's lymphoma (NHL) or plasmacytoma is necessary only in rare instances. The purpose of this study was to investigate long-term outcome and quality of life of surgery combined with postoperative chemotherapy or radiochemotherapy. METHODS: The data of patients, who underwent spinal surgery for mass lesions in a 10-year periods were reviewed, identifying 10 patients with a histopathological diagnosis of NHL or plasmacytoma. Functional outcome were assessed by the Karnofsky Performance Score (KPS), quality of life by the Short Form-36 (SF-36) Health Survey Questionnaire, and pain by the Visual Analog Scale (VAS). RESULTS: Clinical presentations included pain (n=10), paresis (n=5), and sensory deficits (n=5). Surgical treatment included removal of the mass lesion (total, n=5; subtotal, n=5) for decompression, interbody fusion (n=3), and corporectomy followed by stabilization (n=1). Histopathological findings revealed NHL in five patients and plasmacytoma/multiple myeloma in five other patients. Postoperatively, all patients underwent chemotherapy or radiochemotherapy. Mean follow-up time was 38 months. At the last follow-up, 2 patients had succumbed to progression of disease. Pain intensity remained significantly reduced as compared to preoperatively (p=0.049). The KPS was 90-100% in five patients still alive, 70% in two, and 60% in one. SF-36 subscores were lower as compared to age-matched healthy controls. CONCLUSIONS: This retrospective study shows that surgical decompression of spinal mass lesions is a valuable option in selected patients with NHL or plasmacytoma to improve neurological deficits and control pain. Long-term outcome after postoperative adjuvant therapy confirms prolonged stability of quality of life.

Mitogen-activated protein kinase-activated protein kinases 2 and 3 regulate SERCA2a expression and fiber type composition to modulate skeletal muscle and cardiomyocyte function.

The mitogen-activated protein kinase (MAPK)-activated protein kinases 2 and 3 (MK2/3) represent protein kinases downstream of the p38 MAPK. Using MK2/3 double-knockout (MK2/3(-/-)) mice, we analyzed the role of MK2/3 in cross-striated muscle by transcriptome and proteome analyses and by histology. We demonstrated enhanced expression of the slow oxidative skeletal muscle myofiber gene program, including the peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α). Using reporter gene and electrophoretic gel mobility shift assays, we demonstrated that MK2 catalytic activity directly regulated the promoters of the fast fiber-specific myosin heavy-chain IId/x and the slow fiber-specific sarco/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) gene. Elevated SERCA2a gene expression caused by a decreased ratio of transcription factor Egr-1 to Sp1 was associated with accelerated relaxation and enhanced contractility in MK2/3(-/-) cardiomyocytes, concomitant with improved force parameters in MK2/3(-/-) soleus muscle. These results link MK2/3 to the regulation of calcium dynamics and identify enzymatic activity of MK2/3 as a critical factor for modulating cross-striated muscle function by generating a unique muscle phenotype exhibiting both reduced fatigability and enhanced force in MK2/3(-/-) mice. Hence, the p38-MK2/3 axis may represent a novel target for the design of therapeutic strategies for diseases related to fiber type changes or impaired SERCA2 function.

Familial hypertrophic cardiomyopathy: functional effects of myosin mutation R723G in cardiomyocytes.

Familial Hypertrophic Cardiomyopathy (FHC) is frequently caused by mutations in the ß-cardiac myosin heavy chain (ß-MyHC). To identify changes in sarcomeric function triggered by such mutations, distinguishing mutation effects from other functional alterations of the myocardium is essential. We previously identified a direct effect of mutation R723G (MyHC723) on myosin function in slow Musculus soleus fibers. Here we investigate contractile features of left ventricular cardiomyocytes of FHC-patients with the same MyHC723-mutation and compare these to the soleus data. In mechanically isolated, triton-permeabilized MyHC723-cardiomyocytes, maximum force was significantly lower but calcium-sensitivity was unchanged compared to donor. Conversely, MyHC723-soleus fibers showed significantly higher maximum force and reduced calcium-sensitivity compared to controls. Protein phosphorylation, a potential myocardium specific modifying mechanism, might account for differences compared to soleus fibers. Analysis revealed reduced phosphorylation of troponin I and T, myosin-binding-protein C, and myosin-light-chain 2 in MyHC723-myocardium compared to donor. Saturation of protein-kinaseA phospho-sites led to comparable, i.e., reduced MyHC723-calcium-sensitivity in cardiomyocytes as in M. soleus fibers, while maximum force remained reduced. Myofibrillar disarray and lower density of myofibrils, however, largely account for reduced maximum force in MyHC723-cardiomyocytes. The changes seen when phosphorylation of sarcomeric proteins in myocardium of affected patients is matched to control tissue suggest that the R723G mutation causes reduced Ca(++)-sensitivity in both cardiomyocytes and M. soleus fibers. In MyHC723-myocardium, however, hypophosphorylation can compensate for the reduced calcium-sensitivity, while maximum force generation, lowered by myofibrillar deficiency and disarray, remains impaired, and may only be compensated by hypertrophy.

Pipestem capillaries in necrotizing myopathy revisited.

Pipestem-capillaries in necrotizing myopathy, have been reported as a feature of a distinct type of myopathy. Here, we analyze four muscle biopsy specimens from patients exhibiting endomysial fibrosis associated with pipestem capillaries using histological and electronmicroscopic techniques. However, only one case displayed all of the originally described features, including necrotic fibres, capillary thickening and lack of a significant lymphocytic inflammation, while one case exhibited striking capillary pathology with minimal necrosis and absence of inflammation, and the other two cases were accompanied by additional pathological features. These data support the existence of a microangiopathy with pipestem capillaries as a characteristic and distinct histopathological pattern, and indicate that it occurs in the context of a variety of muscular disorders broader than initially suspected. Furthermore, we show that the pipestem-capillary associated decrease in fibre size is at least in part a result of hypoxic changes.

Circulating endothelial cells as potential diagnostic biomarkers in primary central nervous system vasculitis.

OBJECTIVE: Histological evidence is considered the only proof of primary central nervous system vasculitis (PCNSV). However, brain biopsy is often omitted or delayed because of the invasiveness and possible complications of the procedure. Circulating endothelial cells (CEC) were shown to be elevated in patients with active antineutrophil cytoplasmic antibody-associated vasculitis. We hypothesise that CEC are also elevated in patients with active PCNSV and may contribute to the diagnosis. METHODS: CEC were assessed in 18 patients, 3 of whom had biopsy-proven PCNSV and 15 clinical, cerebrospinal fluid and imaging data, highly suggestive of PCNSV. In 3 of these 15 patients CEC assessment was performed after initiation of successful immunosuppressive therapy. CEC numbers of all patients were compared to those of 16 healthy volunteers and 123 subjects with cerebrovascular risk factors and/or ischaemic stroke, who had been studied in our group before. CEC were assessed by immunomagnetic isolation from peripheral blood. RESULTS: In patients with proven and suspected active PCNSV, CEC were extremely elevated (>400 cells/ml in most of the patients) and significantly higher than in healthy and disease controls (p≤0.01 for each group). CEC significantly decreased with immunosuppressive treatment. CONCLUSIONS: For the first time it is shown that CEC are significantly elevated in patients with active PCNSV in contrast to other pathologies associated with brain infarction and correlate with disease activity. Sensitivity and specificity of the method for diagnosing PCNSV and the use of the method for treatment monitoring should be addressed in future prospective studies with a larger patient group.

Progressive osteolytic calvarial lesions in children after minor head injury.

OBJECTIVE: Osteolytic lesions of the skull in children have a broad differential diagnosis including congenital, inflammatory and neoplastic lesions. Progressive osteolysis of the skull secondary to head trauma is rare and has been poorly characterized. METHODS: The pediatric database at our hospital was screened for children with osteolytic lesions who had a previous mild head injury without fracture or dural tears. We identified 2 children with circumscribed progressive cranial osteolysis after minor head trauma detected by CT and MRI scans. Three additional cases were found in a review of the published literature. RESULTS: Ten children with an osteolytic skull lesion treated between January 1998 and February 2008 were identified in our pediatric database. In 2 children there was evidence of previous mild head injury without a skull fracture. Trauma had occurred 7 and 2 months prior to presentation, respectively. The inner table of the skull was intact in both cases. In 1 case, surgery was performed, and in the other case, a wait-and-see strategy was adopted. Pathological examination in case 1 revealed an organized hemorrhage with focal papillary endothelial hyperplasia. CONCLUSIONS: Progressive osteolytic calvarial lesions may occur in both infants and adolescents after mild head injury. They involve either only the diploe and outer table of the skull or both the inner and outer tables. These lesions might be due to intradiploic or subgaleal hematomas triggering an inflammatory process. While surgical resection can be considered to confirm a histopathological diagnosis and to exclude other diagnoses, spontaneous reossification is possible.

Bilateral sphenoorbital hyperostotic meningiomas with proptosis and visual impairment: a therapeutic challenge. Report of three patients and review of the literature.

OBJECTIVE: Bilateral hyperostotic sphenoorbital meningiomas are extremely uncommon. Due to extensive infiltration of the orbits and the frontotemporal skull base, often only a subtotal tumor resection is feasible. Thus far, no treatment algorithms have been suggested for this rare tumor entity. We report on the surgical management of 3 patients. METHODS: All 3 patients underwent a pterional approach for surgical resection. Surgery was performed in two stages, primarily treating the most affected side. Treatment consisted of microsurgical resection of the infiltrated sphenoid wing and orbital walls, intraorbital tumor removal and optic nerve decompression. Orbital wall reconstruction was performed using titanium mesh allografts. Radiation therapy was administered in 1 patient with residual tumor infiltration of the cavernous sinus. RESULTS: Our series includes 2 women (51 and 68 years old) suffering from simultaneous progressive bilateral loss of vision and proptosis and 1 woman (69 years old) who developed contralateral disease after surgical resection of a hyperostotic sphenoorbital meningioma 16 years earlier. After optic nerve decompression, vision improved in 2 cases after surgery. Initial visual deterioration was observed in 1 case but improved on longterm follow-up. The degree of proptosis was reduced in all treated eyes. CONCLUSION: In bilateral hyperostotic sphenoorbital meningiomas we propose staged surgery when clinical and radiological progression is observed. Subtotal tumor resection with the aim of optic nerve decompression and subsequent orbital reconstruction provides satisfactory results. The most affected eye should be treated first. In case of additional cavernous sinus infiltration, focal radiation therapy can be considered.

Spontaneous regression of an intracerebral lymphoma (ghost tumor) in a liver-engrafted patient.

Posttransplantation lymphoproliferative disorder involving the central nervous system is a rare and serious complication associated with solid organ transplantation. We report a liver transplant recipient who noticed unbalance, dizziness, and headache 30 months after transplantation. Magnetic resonance imaging (MRI) showed a space-occupying lesion in the corpus callosum and adjacent parenchyma of the left hemisphere. In the following month, the neurological symptoms and the MRI findings regressed without any treatment. Four months later the patient developed a left-sided hemiparesis. MRI now revealed a considerable increase of the known lesion and new lesions in other locations. Stereotactic biopsy showed a B-cell non-Hodgkin lymphoma of high malignancy. A spontaneous regression of cerebral lymphoma is possible, even in immunosuppressed patients. Hence, this diagnosis must not be dismissed if there is spontaneous regression of a lesion in the MRI or an amelioration of the clinical symptoms. Owing to the high mortality rate associated with this disease, prompt pathologic diagnosis is required to initiate appropriate therapy.

Common molecular cytogenetic pathway in papillary tumors of the pineal region (PTPR).

Primary papillary tumors of the central nervous system and particularly the pineal region are rare. Papillary tumor of the pineal region (PTPR) is a recently described neoplasm that has been formally recognized in the 2007 World Health Organization Classification of Tumors of the Nervous System. Because of their rarity, further pheno- and genotypical observations as well as therapeutic experience are necessary to differentiate PTPR from other primary or secondary papillary tumors of this region. We herein present three cases of PTPR characterized by local recurrence in two of them. Primary and recurrent tumors were analyzed by immunohistochemistry and comparative genomic hybridization (CGH). From our results clonal chromosomal aberrations can be postulated which seem to be a feasible tool to differentiate PTPRs from other primary or secondary papillary tumors of this region.

Spontaneous recovery from progressive multifocal leukoencephalopathy in a patient with non-active sarcoidosis.

We report the case of a 50-year-old female patient with non-active sarcoidosis and no kind of immunosuppression, admitted to our hospital because of increasing confusion and focal neurological deficits. Initially a tumor, herpes encephalitis, or neurosarcoidosis were suspected, but surprisingly biopsy revealed progressive multifocal leukoencephalopathy, additionally confirmed by JC-positive PCR in cerebrospinal fluid. Cases of sarcoidosis and progressive multifocal leukoencephalopathy have been reported before. This is the first case of a patient with no sign of active sarcoidosis and without immunosuppressive therapy who recovered spontaneously with a follow-up time of nearly 3 years.

Treatment of recurrent trigeminal neuralgia due to Teflon granuloma.

Recurrent trigeminal neuralgia after microvascular decompression (MVD) may be due to insufficient decompression, dislocation of the implant to pad the neurovascular contact, or the development of granuloma. Here, we report on our experience with Teflon granuloma including its treatment and histopathological examination. In a series of 200 patients with trigeminal neuralgia MVD was performed with Teflon felt according to Jannetta's technique. In three patients with recurrent facial pain Teflon granuloma was found to be the cause for recurrence. In each instance, the granuloma was removed for histopathological examination. Mean age at the first procedure was 62.3 years and at the second procedure 66.3 years. Recurrence of pain occurred between 1 and 8.5 years after the first procedure. MRI scans demonstrated local gadolineum enhancement in the cerebellopontine angle, and CT scans showed local calcification. Intraoperatively dense fibrous tissue was found at the site of the Teflon granuloma. Histopathological examination revealed foreign body granuloma with multinuclear giant cells, collagen-rich hyalinized scar tissue, focal hemosiderin depositions, and microcalcifications. The Teflon granuloma was completely removed, and a new Teflon felt was used for re-decompression. Patients were free of pain after the second procedure at a mean of 40.3 months of follow-up. Teflon granuloma is a rare cause for recurrent facial pain after MVD. Small bleeding into the Teflon felt at surgery might trigger its development. A feasible treatment option is surgical re-exploration, nerve preserving removal of the granuloma, and repeat MVD.

Microtransplantation of dopaminergic cell suspensions: further characterization and optimization of grafting parameters.

Intracerebral transplantation of dopaminergic (DA) cells is currently further explored as a potential restorative therapy for Parkinson's disease (PD). However, before they can be considered for a more widespread clinical use a number of critical issues have to be resolved, including an optimized transplantation protocol. This study has been performed in a rat 6-hydroxydopamine model of PD and is based on the microtransplantation approach. The results demonstrate a reduced survival (threefold) for a single cell suspension of E14 rat ventral mesencephalon compared to a fragment suspension when a metal cannula is used for implantation. However, fragment suspensions result in a more variable graft survival and ectopically placed cells along the implantation tract. When a glass capillary is used for implantation, the survival of the single cell suspension (so-called "micrograft") improved by fourfold (vs. single cells/metal cannula) and is superior to the combination of the metal cannula and fragment suspension (+40%). The micrografts show a reduced variability in DA neuron survival as well as fewer ectopically placed cells. Moreover, the implantation time can significantly be reduced from 19 to 7 min in micrografted animals without a compromise in DA graft survival and functional behavioral outcome. Using the microtransplantation approach graft size can be tailored effectively by varying the density of the final cell suspension at least between 11,000 and 320,000 cells/microl, resulting in comparable survival of tyrosine hydroxylase (TH)-positive neurons in the range of 2-4%. With this approach no more than 100 surviving TH-positive neurons are necessary to produce functional effects in the amphetamine-induced rotation test. Interestingly, we found that DA micrografts into lesion striatum present 20% higher survival rates of TH neurons in comparison to the intact striatum. In summary, these results provide further evidence for the usefulness of the microtransplantation approach and allow for a more precise and tailored adaptation of the implantation parameters for further studies on DA, and possibly also other neural-, glial-, and stem cell-derived grafts.

Exophytic giant cell glioblastoma of the medulla oblongata.

Giant cell glioblastoma is a rare variant within the spectrum of glioblastoma multiforme (GBM) tumors. A giant cell glioblastoma may be associated with a better prognosis than the common type of GBM after combined treatment involving tumor resection and radiochemotherapy. A giant cell glioblastoma may occur at various sites in the brain and spinal cord. To the authors' knowledge, this type of tumor has not been previously reported as arising as an exophytic tumor from the medulla oblongata. The authors report on a 40-year-old man who presented with a large tumor located in the caudal fourth ventricle. The tumor was removed completely and the patient underwent percutaneous radiotherapy with 60 Gy and concomitant chemotherapy with temozolomide. Histopathological examination of the tumor revealed the typical features of a giant cell glioblastoma. At the 2-year follow-up the patient was doing well and showed no signs of tumor recurrence. It is important to identify variants of GBM because they may predict favorable long-term outcome, even when they arise from the caudal brainstem.

Cavernous angioma of the geniculate ganglion.

Intracranial extraaxial cavernous angiomas are rare vascular malformations. Their occurrence at the geniculate ganglion of the facial nerve within the temporal bone is exceptional. The authors describe a 35-year-old man who developed a slowly progressing facial palsy. Initial cranial MR imaging showed no pathological findings, but 2 years later another MR examination detected a small tumor located at the geniculate ganglion of the facial nerve. The tumor was removed via a subtemporal approach. Histological examination revealed a cavernous angioma. Even small cavernomas located at the geniculate ganglion of the facial nerve may result in facial palsy. Isolated facial palsy in a young person should be monitored closely using imaging studies even if the initial imaging study is negative. Early decompression of the facial nerve may help to preserve its function.