Intramedullary spinal cord and filum tumours-long-term outcome: single institution case series.

BACKGROUND: Intramedullary spinal cord tumours are rare and account for about 2-4% of primary CNS tumours. Ependymomas and astrocytomas are most frequent. The aim of this study was to evaluate the long-term neurological outcome, quality of life (QoL), survival, need for additional treatment and frequency of neuropathic pain in a patient group treated at a tertiary university hospital. METHOD: Retrospective descriptive study of 52 long-term survivors with intramedullary or filum tumours consenting to participate in this study. Fifty-six operations were performed in 48 patients. Clinical and radiological follow-up period was 113 and 117 months, respectively. RESULTS: Good neurological outcome (ASIA score D or E, modified McCormick grade 1 or 2) was achieved in 88%. We found two negative prognostic factors in regards of severe disability which were large craniocaudal tumour size (p = 0.004) and histologic verified astrocytomas (p = 0.002). SF-36 results showed significantly lower results on all five subdomains concerning physical function, whereas scores for mental health and role emotional showed no significant differences compared to Norwegian norms. Ten patients including all astrocytoma patients, one primitive neuroectodermal tumour and three recurrent tumours of filum terminale had adjuvant therapy. None of the patients with intramedullary ependymoma had adjuvant therapy. Neuropathic pain was present in 54% of patients at the last follow-up. CONCLUSION: This series shows that good results can be obtained with surgery for intramedullary tumours, even without perioperative neurophysiological monitoring. Multicentre studies are needed for further evaluation of negative and positive prognostic factors to further improve outcome.

[Nonsurgical and surgical management of osteoporotic vertebral body fractures : Recommendations of the Spine Section of the German Society for Orthopaedics and Trauma (DGOU)]. / Nichtoperative und operative Behandlung der osteoporotischen Wirbelkörperfraktur : Empfehlungen der Sektion Wirbelsäule der Deutschen Gesellschaft für Orthopädie und Unfallchirurgie (DGOU).

STUDY DESIGN: Prospective clinical cohort study (data collection); expert opinion (recommendation development). OBJECTIVES: Treatment options for nonsurgical and surgical management of osteoporotic vertebral body fractures differ widely. Based on the current literature, the knowledge of the experts, and their classification for osteoporotic fractures (OF classification), the Spine Section of the German Society for Orthopaedics and Trauma has now introduced general treatment recommendations. METHODS: A total of 707 clinical cases from 16 hospitals were evaluated. An OF classification-based score was developed for guidance in the option of nonsurgical versus surgical management. For every classification type, differentiated treatment recommendations were deduced. Diagnostic prerequisites for reproducible treatment recommendations were defined: conventional X­rays with consecutive follow-up images (standing position whenever possible), magnetic resonance imaging, and computed tomography scans. OF classification allows for upgrading of fracture severity during the course of radiographic follow-up. The actual classification type is decisive for the score. RESULTS: A score of less than 6 points advocates nonsurgical management; in cases with more than 6 points, surgical management is recommended. The primary goal of treatment is fast and painless mobilization. Because of the expected comorbidities in this age group, minimally invasive procedures are preferred. As a general rule, stability is more important than motion preservation. It is mandatory to restore the physiological loading capacity of the spine. If the patient was in a compensated unbalanced state at the time of fracture, reconstruction of the individual prefracture sagittal profile is sufficient. The instrumentation technique has to account for compromised bone quality. We recommend the use of cement augmentation or high purchase screws. The particular situations of injuries with neurological impairment, the necessity to fuse, multiple level fractures, consecutive and adjacent fractures and fractures in ankylosing spondylitis are addressed separately. CONCLUSIONS: The therapeutic recommendations presented here provide a reliable and reproducible basis to decide for the treatment choices available. However, intermediate clinical situations with a score of 6 points remain, allowing for both nonsurgical and surgical options. As a result, individualized treatment decisions may still be necessary. In the subsequent step, the recommendations presented will be further evaluated in a multicentre controlled clinical trial.

The adipokine leptin mediates muscle- and liver-derived IGF-1 in aged mice.

Muscle- and liver-derived IGF-1 play important roles in muscle anabolism throughout growth and aging. Yet, prolonged food restriction is thought to increase longevity in part by lowering levels of IGF-1, which in turn reduces the risk for developing various cancers. The dietary factors that modulate IGF-1 levels are, however, poorly understood. We tested the hypothesis that the adipokine leptin, which is elevated with food intake and suppressed during fasting, is a key mediator of IGF-1 levels with aging and food restriction. First, leptin levels in peripheral tissues were measured in young mice fed ad libitum, aged mice fed ad libitum, and aged calorie-restricted (CR) mice. A group of aged CR mice were also treated with recombinant leptin for 10 days. Later, aged mice fed ad libitum were treated with saline (VEH) or with a novel leptin receptor antagonist peptide (Allo-aca) and tissue-specific levels of IGF-1 were determined. On one hand, recombinant leptin induced a three-fold increase in liver-derived IGF-1 and a two-fold increase in muscle-derived IGF-1 in aged, CR mice. Leptin also significantly increased serum growth hormone levels in the aged, CR mice. On the other, the leptin receptor antagonist Allo-aca did not alter body weight or muscle mass in treated mice compared to VEH mice. Allo-aca did, however, produce a significant (20%) decline in liver-derived IGF-1 as well as an even more pronounced (>50%) decrease in muscle-derived IGF-1 compared to VEH-treated mice. The reduced IGF-1 levels in Allo-aca treated mice were not accompanied by any significant change in growth hormone levels compared to VEH mice. These findings suggest that leptin receptor antagonists may represent novel therapeutic agents for attenuating IGF-1 signaling associated with aging, and could potentially mimic some of the positive effects of calorie restriction on longevity.

Fatal diving accidents in western Norway 1983-2007.

Despite efforts to reduce their number, fatal diving accidents still occur. The circumstances and post-mortem findings in 40 fatal diving accidents in western Norway from 1983 through 2007 were investigated. Diving experience, medical history and toxicology reports were retrieved. The material consisted of recreational divers, professional saturation divers and professional divers without experience with saturation. In 33 cases the diving equipment was examined as part of the forensic investigation. In 27 cases defects in the diving equipment were found. For six divers such defects were responsible for the fatal accidents. Eighteen divers died on the surface or less than 10 m below surface. Five divers reached below 100 msw, and two of them died at this depth. The fatalities were not season-dependent. However, wave-height and strength of currents were influential factors in some cases. Twelve divers were diving alone. Twenty divers had one buddy, 9 of these divers were alone at the time of death. The cause of death was drowning in 31 out of 40 divers; one of them had a high blood-ethanol concentration, in two other divers ethanol was found in the urine, indicating previous ethanol consumption. Nine divers died from sudden decompression, pulmonary barotraumas, underwater trauma and natural causes. The study shows that most of the fatal diving accidents could be avoided if adequate diving safety procedures had been followed.

A novel brain metastases model developed in immunodeficient rats closely mimics the growth of metastatic brain tumours in patients.

AIMS: brain metastasis is a common cause of mortality in cancer patients, and associated with poor prognosis. Our objective was to develop a clinically relevant animal model by transplanting human biopsy spheroids derived from metastatic lesions into brains of immunodeficient rats. METHODS: nine different patient brain metastases from four different primary cancers were implanted into brains of immunodeficient rats. The xenografts were compared with patient tumours by magnetic resonance imaging, histochemistry, immunohistochemistry and DNA copy number analysis. RESULTS: after transplantation, tumour growth was achieved in seven out of nine human brain metastases. Spheroids derived from four of the metastases initiated in the rat brains were further serially transplanted into new animals and a 100% tumour take was observed during second passage. Three of the biopsies were implanted subcutaneously, where no tumour take was observed. The animal brain metastases exhibited similar radiological features as observed clinically. Histological comparisons between the primary tumours from the patients, the patient brain metastases and the derived xenografts showed striking similarities in histology and growth patterns. Also, immunohistochemistry showed a strong marker expression similarity between the patient tumours and the corresponding xenografts. DNA copy number analysis between the brain metastases, and the corresponding xenografts revealed strong similarities in gains and losses of chromosomal content. CONCLUSION: we have developed a representative in vivo model for studying the growth of human metastatic brain cancers. The model described represents an important tool to assess responses to new treatment modalities and for studying mechanisms behind metastatic growth in the central nervous system.

Can morphology predict 1p/19q loss in oligodendroglial tumours?

AIMS: To investigate the relationship between phenotype and genotype in oligodendroglial tumours and evaluate whether 1p/19q status can be reliably predicted from histological findings. METHODS AND RESULTS: Three neuropathologists reviewed the association between 10 histological variables, location and genetic losses at 1p, 19q and 17p13 in 63 oligodendroglial tumours (cohort 1). Based on these findings, a multiple logistic regression model for prediction of 1p/19q status was constructed. The ability of this model to predict 1p/19q status was tested on cohort 2, comprising 20 oligodendroglial tumours. Loss of heterozygosity at 1p, 19q and 17p13 was analysed using polymerase chain reaction. Combined 1p/19q loss and losses at 17p13 were mutually exclusive (P < 0.001). The variable H1a (more or <50% of cells with round, uniform nuclei and perinuclear halos) demonstrated the strongest association with 1p/19q status (odds ratio 11.9, 95% confidence interval 3.6, 39.6, P < 0.001). Calcifications, absence of gemistocytic cells and a non-temporal/non-insular location were also associated. The correct 1p/19q status was predicted in 80% of cases in cohort 2. CONCLUSIONS: There is a strong association between phenotype and genotype in oligodendroglial tumours. However, even when all significant variables are accounted for, perfect prediction (100%) of 1p/19q status cannot be obtained.

Posterior uveal melanoma treated with I-125 brachytherapy or primary enucleation.

PURPOSE: To study the incidence, clinical findings, and tumour characteristics of posterior uveal melanoma in Western Norway, and to report the results of a consistent treatment strategy (I-125 brachytherapy or primary enucleation) over a 13-year period. METHODS: The clinical records of all patients with posterior uveal melanoma referred between January 1993 and December 2005 were reviewed. Clinical data, radiation parameters, visual outcome, and mortality were analysed in a dedicated database. RESULTS: The study included 111 consecutive patients. The annual age-adjusted incidence (per million population) of posterior uveal melanoma was 8.5 for women and 8.9 for men. Fifty-six patients underwent I-125 brachytherapy, 52 were enucleated, and three received no treatment. The median follow-up time was 36 months (mean, 52 months; range, 2 months to 13 years). In the brachytherapy group, two eyes were enucleated owing to tumour recurrence and two because of neovascular glaucoma. A visual acuity of 0.1 or better, present in 87% of the patients before brachytherapy, was retained in 40% after a median follow-up of 61 months. After brachytherapy, the 5- and 10-year melanoma-specific mortality rates were 13.4 and 23.8%, respectively. The corresponding mortality rates for patients treated with primary enucleation were 49.5 and 49.5%. CONCLUSION: After brachytherapy, many patients lost useful vision due to radiation-induced complications. The probability of retaining the eye was high and only two patients experienced recurrent tumour growth. The mortality rates compare well with published series, and the differences in tumour size explain the difference in mortality between the two treatment groups.

A girl with spina bifida, an extra leg, and ectopic intestinal loops--a "foetus in foetu" or a whim of the neural crest?

This article describes a girl with an extra leg attached to her lower back, combined with a spina bifida and a myelomeningocele. Despite lacking sensory or motor functions, the leg grew proportionately with the rest of the body. The bony structures were almost normal. A cross section showed fat tissue with some centrally situated blood vessels, nerve bundles, and muscular fragments. Proximally, an isolated colon loop was found. The extra leg and intestine respected the dorsal fascia, without connection with the peritoneal or retroperitoneal compartments. The finding is discussed with reference to existing hypotheses for limb formation.

Grey matter pathology in multiple sclerosis.

Although multiple sclerosis (MS) has been considered a white matter disease, MS lesions are known to occur in grey matter. Recent immunohistochemical studies have demonstrated extensive grey matter demyelination in chronic MS. The most common lesion type consists of purely cortical lesions extending inward from the surface of the brain, this lesion subgroup is grossly underestimated by standard histochemical myelin staining methods. Some MS patients have subpial demyelination in all cortical areas of the brain; this pattern has been termed ''general cortical subpial demyelination''. Extensive cortical demyelination is associated with the progressive phases of disease, as less cortical demyelination has been detected in relapsing-remitting MS. The pathology of grey matter lesions differs from that of white matter lesions; grey matter lesions are less inflammatory, with less macrophage and lymphocyte infiltration. In purely cortical lesions there is no significant increase in lymphocytes compared with non-demyelinated adjacent cortical areas in MS patients or cerebral cortex in control patients. Significant axonal transection and neuronal loss have been demonstrated in grey matter MS lesions. Current magnetic resonance imaging (MRI) methods are not sensitive for purely cortical MS lesions. The clinical significance of cortical MS lesions may not be characterised until more sensitive MRI methods are developed.

Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration.

The present study examined the extent and distribution of lymphocyte infiltration in demyelinated lesions in the cerebral cortex of multiple sclerosis (MS) patients. Tissue sections from the brain of 10 MS patients and five patients without neurological disease were double labeled for myelin basic protein and the lymphocyte markers CD3, CD4, CD8, CD45RO, and CD20. The highest density of CD3-positive T cells was found in MS white matter lesions (40.4/10 high power fields (hpf)). Fewer T cells were detected in cortical lesions that extended through both white and gray matter (12.1/10 hpf; P < 0.001). The lowest number of T cells was detected in intracortical demyelinated lesions (1.1/10 hpf). This was equal to the lymphocyte density in nondemyelinated cerebral cortex within the same tissue block (1.1/10 hpf) or cerebral cortex in control brains (1.8/10 hpf). A similar distribution was found using the CD4, CD8, and CD45RO markers. CD20-positive B cells were scarce in all specimens examined. These data indicate that areas of intracortical demyelination in chronic MS are not associated with an increased number of lymphocytes, or an altered distribution of lymphocyte subsets, when compared with control areas in MS and control patients. This finding indicates that the extent of lymphocyte infiltration in MS lesions is dependent on lesion location.

Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions.

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that causes motor, sensory, and cognitive deficits. The present study characterized demyelinated lesions in the cerebral cortex of MS patients. One hundred twelve cortical lesions were identified in 110 tissue blocks from 50 MS patients. Three patterns of cortical demyelination were identified: Type I lesions were contiguous with subcortical white matter lesions; Type II lesions were small, confined to the cortex, and often perivascular; Type III lesions extended from the pial surface to cortical layer 3 or 4. Inflammation and neuronal pathology were studied in tissue from 8 and 7 patients, respectively. Compared to white matter lesions, cortical lesions contained 13 times fewer CD3-positive lymphocytes (195 vs 2,596/mm3 of tissue) and 6 times fewer CD68-positive microglia/macrophages (11,948 vs 67,956/mm3 of tissue). Transected neurites (both axons and dendrites) occurred at a density of 4,119/mm3 in active cortical lesions, 1,107/mm3 in chronic active cortical lesions, 25/mm3 in chronic inactive cortical lesions, 8/mm3 in myelinated MS cortex, and 1/mm3 in control cortex. In active and chronic active cortical lesions, activated microglia closely apposed and ensheathed apical dendrites, neurites, and neuronal perikarya. In addition, apoptotic neurons were increased significantly in demyelinated cortex compared to myelinated cortex. These data support the hypothesis that demyelination, axonal transection, dendritic transection, and apoptotic loss of neurons in the cerebral cortex contribute to neurological dysfunction in MS patients.

Oligodendrogliomas: reproducibility and prognostic value of histologic diagnosis and grading.

Prognostic value of histological grading of oligodendroglial tumors is controversial and interobserver reproducibility in grading of these tumors is unknown. Seven neuropathologists and 6 surgical pathologists experienced in brain tumor-diagnosis assessed 124 oligodendroglial tumors operated at the Mayo Clinic (1960-1990). Among histologic parameters upon which current oligodendroglioma grading systems are based, only high cellularity, presence of mitoses, microcalcifications, endothelial hypertrophy, endothelial proliferation, and necrosis appeared to be reproducible. Reproducible histologic features, based on consensus ratings among neuropathologists (defined as > 60%), were evaluated for the association with cause-specific survival by fitting Cox regression models. By univariate analysis, a significant association with survival was found for age, high cellularity, presence of mitoses, endothelial hypertrophy and proliferation and necrosis. On multivariable analysis with a stepwise variable selection method, only age and presence of endothelial proliferation were found to be independently associated with survival with a discriminatory index of the model of 0.68. Mitotic index was significantly associated with survival based on the grading from each separate neuropathologist, but it was not based on consensus, most likely because this was classified as indeterminate in 54% of cases. Alternatively, "models fit" considering the assessment of single neuropathologists, identified a model based on age and on mitotic index with similar discriminatory indices of 0.69-0.7. Our study found few factors independently associated with cause specific-survival among morphological parameters. These findings are consistent with the present WHO stratification of oligodendrogliomas into low- and high-grade variants.

Invasiveness in vitro and biological markers in human primary glioblastomas.

Invasion of spheroids from 20 human primary glioblastomas into precultured fetal rat brain tissue in culture has been studied and quantified. Between 30 and 98 percent of the normal brain tissue was destroyed by invading glioma cells within 4 days. The degree of invasion did not correlate with patient survival. A slightly higher invasiveness and shorter survival was seen in tumors with EGF receptor overexpression, and the opposite pattern was found for tumors with a TP53 mutation. The degree of invasiveness in vitro was far higher than would be expected from the dynamics of clinically observed tumor spread. This suggests that mechanisms suppressing invasion may be operative in the normal brain; alternatively the differences may be due to a higher permissiveness of the fetal brain tissue for invasion in vitro.

Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients.

Axonal degeneration has been proposed as a cause of irreversible neurological disability in multiple sclerosis (MS) patients. The purpose of this study was to quantify axonal loss in spinal cord lesions from 5 paralyzed (Expanded Disability Status Scale score > or =7.5) MS patients and to determine if axonal number or volume correlated with levels of the neuronal marker N-acetyl aspartate (NAA). Axonal loss in MS lesions ranged from 45 to 84% and averaged 68%. NAA levels were significantly reduced (>50%) in cross sections of spinal cords containing MS lesions. Reduced NAA correlated with reduced axonal numbers within lesion areas. In addition, NAA levels per axonal volume were significantly reduced in demyelinated axons (42%) and in myelinated axons in normal-appearing white matter (30%). The data support axonal loss as a major cause of irreversible neurological disability in paralyzed MS patients and indicate that reduced NAA as measured by magnetic resonance spectroscopy can reflect axonal loss and reduced NAA levels in demyelinated and myelinated axons.

[Polyneuropathy is an early finding in primary systemic amyloidosis]. / Polynevropati er et tidlig funn ved primaer systemisk amyloidose.

BACKGROUND: Polyneuropathy is associated with several pathological conditions. Amyloidosis is a less common cause of polyneuropathy. Amyloidosis is caused by the accumulation of insoluble protein fibrils (amyloid) in the extracellular matrix. Primary systemic amyloidosis is caused by B-lymphocyte dyscrasia. Polyneuropathy is the first sign of primary systemic amyloidosis in about 20% of the cases, and is characterised by relentless progression, painfulness, and prominent symptoms of autonomic neuropathy. MATERIAL AND METHODS: We describe three cases of primary systemic amyloidosis that started with polyneuropathy. RESULTS: The diagnosis of primary systemic amyloidosis is often delayed more than two years after the onset of polyneuropathy. Biopsy of rectum, fat tissue, bone marrow, or peripheral nerve are diagnostic tools. INTERPRETATION: The survival of non-treated patients is about 18 months after the diagnosis. With chemotherapy the survival is prolonged to approximately 38 months.

[Diffusion-weighted magnetic resonance tomography--a new instrument in the diagnosis of Creutzfeldt-Jakob disease]. / Diffusjonsvektet magnetisk resonanstomografi--nytt i diagnostikken av Creutzfeldt-Jakobs sykdom.

Creutzfeldt-Jakob's disease (CJD) is characterised by rapidly progressive dementia, ataxia, myoclonus, and several other neurological deficits. It generally affects older adults and occurs in sporadic, genetic and iatrogenic forms. Death occurs usually within one year after onset of the disease. The diagnosis is based on clinical criteria, neurophysiological and radiological findings, and confirmed by postmortal histopathology. During the last two years several cases of CJD have been reported with diffusion-weighted magnetic resonance imaging (MR) abnormalities, represented by increased signal intensity indicating reduced diffusion in basal ganglia and/or cortex cerebri. These abnormalities seem to be characteristic of CJD. We report a case of CJD in a 54-year-old woman who developed vertigo, nystagmus, ataxia, myoclonus, and dementia over a period of eight months. Diffusion-weighted magnetic resonance imaging showed increased signal intensity in corpus striatum and gyrus cinguli. The diagnosis was postmortally confirmed with histopathology.

[Orbital tumors]. / Svulster i orbita.

BACKGROUND: Orbital tumours are relatively uncommon, and few series of patients with such tumours have been reported from Scandinavia. Here we present the experience of a Norwegian referral centre. MATERIAL AND METHODS: We have retrospectively evaluated the records of 278 patients with orbital tumours hospitalized at the Department of Ophthalmology, Haukeland University Hospital from 1961 to 1999. RESULTS: In 177 patients, a benign tumour was present, while 96 patients suffered from malignant disease. In five cases, the malignant potential of the tumour could not be assessed. A total of 71 different histological entities were observed. Surgical treatment performed at our department was in 22 patients exenteration, in 87 lateral orbitotomy, in 47 anterior orbitotomy and in 41 biopsy through an anterior approach. INTERPRETATION: This series illustrates the wide panorama of space-occupying lesions that may be present in the orbit. Since the lesions are rare and management in many cases complex, the treatment should be centralized to an eye department with a defined interest in orbital disease.

Expression of oligodendrocyte progenitor cell antigens by gliomas: implications for the histogenesis of brain tumors.

The early events in neoplastic transformation can be understood only by comparison of the neoplastic cell with its nontransformed counterpart. The most common central nervous system gliomas traditionally are thought to arise from mature astrocytes and oligodendrocytes. We examined the possibility that gliomas arise from a population of glia that has properties of oligodendrocyte progenitors. These glial cells express the NG2 chondroitin sulfate proteoglycan and the alpha receptor of platelet-derived growth factor in vivo. We identified NG2 and the alpha receptor of platelet-derived growth factor expression in tissue from seven of seven oligodendrogliomas, three of three pilocytic astrocytomas, and one of five glioblastoma multiforme. These data provide evidence that glial tumors arise from glial progenitor cells. Molecules expressed by these progenitor cells should be considered as targets for novel therapeutics.