Forensic aspects of post-mortem histological detection of amniotic fluid embolism.

Amniotic fluid embolism (AFE) continues to be one of the most feared and devastating complications of pregnancy. A reliable diagnosis can be made only upon histological examination. A detection of AFE every now and then has a relevant implication on medico-legal aspects of intrapartum or post-partum maternal death. However, there are only isolated reports in the literature concerning the detection interval of amniotic fluid elements after their transfer into the lungs. The objective of this study was to determine how long after the onset of clinical symptoms the elements of amniotic fluid may be detectable in the pulmonary circulation. An autopsy, as well as a histological and toxicological examination of 29 women, who died intrapartum or post-partum were performed. AFE was diagnosed in seven women (25%). The maximum survival time of the women with AFE and also the detection interval of AF in the pulmonary vasculature was 36 h. In the lungs of the women who did not die of AFE, amniotic fluid components were not found. Thus, there is no evidence for a physiologic occurrence of AFE. In women who die some days or even weeks after delivery as a consequence of a haemorrhagic shock following post-partum genital bleeding ensuing from uterine atony, AFE should be considered as a cause of a coagulopathy.

The risk of haemorrhage after image guided stereotactic biopsy of intra-axial brain tumours--a prospective study.

OBJECTIVE: To analyze prospectively the frequency and the risk of symptomatic and asymptomatic haemorrhage after image guided stereotactic biopsy of intra-axial brain tumours. METHODS: The study was conducted within a time frame of 24 months (April 1998-April 2000). 326 patients (150 males, 176 females; mean age 56.8 years) were included and 345 computerized tomography (CT)-guided stereotactic biopsies were performed/supervised by a specialized stereotactic neurosurgeon. A modified Riechert Stereotaxy System and a workstation for multiplanar trajectory planning were used in all patients. Serial biopsies (median, 5 samples) were done with small forceps (diameter 1 mm), smear preparations of the biopsy specimens were intra-operatively examined. Frequency, size, and location of any detectable bleeding were analyzed by post-biopsy CT-scan investigation. For risk estimation, logistic regression analysis was performed. The chi-square statistic was used for comparative analysis of the study results with available data from the literature. RESULTS: A conclusive tissue diagnosis could be achieved in 98%. Overall treatment morbidity was 3.1%. There was no mortality. Haemorrhage related morbidity was 0.9%. Age, Karnofsky score, mass effect of the tumour, tumour histology, tumour location and the number of specimens taken did not have any prognostic significance. The clinically silent bleeding rate was 9.6% and more often seen in patients with high grade gliomas (p = 0.03). Both the silent and non-silent bleeding rate were significantly lower as compared to available prospective data in the literature (p < 0.01). CONCLUSION: Using multiplanar image guided trajectory planning, small biopsy forceps and intra-operative smear preparations the risk of major haemorrhage related morbidity after stereotactic brain tumour biopsy is extremely low (<1%) in experienced hands.

Cerebral involvement in graft-versus-host disease after murine bone marrow transplantation.

Neurologic manifestation of graft-versus-host disease (GvHD) after allogeneic bone marrow transplantation (BMT) has until now been limited to rare neuromuscular syndromes. Investigating cerebral findings using a murine BMT model, the authors found parenchymal lymphocytic inflammation, microglia activation, and mild cerebral angiitis-like changes in allogeneic transplanted animals but not in syngeneic controls. These findings suggest that cerebral involvement during GvHD may be a new neurologic complication after BMT.

Apoptosis in the basal ganglia of the developing human nervous system.

Programmed cell death (PCD) plays a crucial role in the development of the central nervous system through controlling neuronal numbers and adequate synaptic connections. PCD has been considered to occur in the form of apoptosis. To examine how apoptosis occurs in the developing human brain, we performed a morphometric TUNEL study, using a commercially available kit (ApopTag Kit, Oncor Inc.). We examined apoptotic cells in the basal ganglia of 47 fetuses and newborns without macroscopical and microscopical evident congenital anomalies. Gestational age ranged from 12 to 40 weeks. The numerical density as well as the labeling index of TUNEL-positively labeled nuclei were evaluated. In the caudate nucleus and putamen, TUNEL-labeled cells were observed around the 12th week of gestation. The numerical density of total cells was significantly decreased, whereas the labeling index of apoptotic cells was significantly increased with advanced gestational age. In the globus pallidus, the numerical density of total cells decreased with advancing gestational age, while the labeling index of apoptotic cells increased between the 20th and 28th week, followed by a decrease until the 40th week. The analysis of TUNEL-positive cells revealed a different reaction pattern for the various basal ganglia with regard to the timing and degree of the apoptotic process in regulating cell numbers.

Surgery of lesions in the motor strip combining a stereotactically-guided mini-craniotomy with electrophysiological mapping of the motor cortex.

The removal of space-occupying lesions in the sensori-motor cortex carries a considerable risk of postoperative palsy. Therefore subcortical lesions located in the sensori-motor strip are often considered to be inoperable. Treatment options are stereotactic biopsy and radiosurgery beside radiological control examinations without surgery or surgery with a higher risk of postoperative deficits. The following article focusses on a combined approach involving a stereotactically guided and electrophysiologically controlled surgery. The instruments used (stereotactical system and electric stimulator) are available in almost every neurosurgical department in the Western and Eastern world and had been the first navigation systems in the human brain.

Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients.

OBJECT: It has been established that 5-aminolevulinic acid (5-ALA) induces the accumulation of fluorescent porphyrins in glioblastoma multiforme (GBM), a phenomenon potentially exploitable to guide tumor resection. In this study the authors analyze the influence of fluorescence-guided resection on postoperative magnetic resonance (MR) imaging and survival in a series of patients who underwent surgery in the authors' department. METHODS: Fifty-two consecutive patients with GBM received oral doses of 5-ALA (20 mg/kg body weight) 3 hours before induction of anesthesia. Intraoperatively, tumor fluorescence was visualized using a modified operating microscope. Fluorescing tissue was removed whenever it was considered safely possible. Residual enhancement on early postoperative MR imaging was quantified and related to each patient's characteristics to determine which factors influenced resection. Survival was analyzed using the Kaplan-Meier method and multivariate analysis was performed in which the Karnofsky Performance Scale (KPS) score, residual fluorescence, patient age, and residual enhancement on MR images were considered. Intraoperatively, two fluorescence qualities were perceived: solid fluorescence generally reflected coalescent tumor, whereas vague fluorescence mostly corresponded to infiltrative tumor. Complete resection of contrast-enhancing tumor was accomplished in 33 patients (63%). Residual intraoperative tissue fluorescence left unresected for safety reasons predicted residual enhancement on MR images in 18 of the 19 remaining patients. Age, residual solid fluorescence, and absence of contrast enhancement in MR imaging were independent explanatory factors for survival, whereas the KPS score was significant only in univariate analysis. No perioperative deaths and one case of permanent morbidity were encountered. CONCLUSIONS: The observations in this study indicate the usefulness of 5-ALA-induced tumor fluorescence for guiding tumor resection. The completeness of resection, as determined intraoperatively from residual tissue fluorescence, was related to postoperative MR imaging findings and to survival in patients suffering from GBM.

[Gliomatosis cerebri: two case reports with atypical clinical and neuroradiologic findings]. / Gliomatosis cerebri. Zwei Fallberichte mit atypischer klinischer und neuroradiologischer Befundkonstellation.

The diagnosis of the rare disease Gliomatosis cerebri requires the correlation of clinical, radiological, and pathological findings. We report on two patients with intravitally diagnosed gliomatosis cerebri. Due to the unusually high malignancy of the tumor cells, diagnosis was complicated by atypical findings such as gadolinium enhancement in MRI and raised intracranial pressure. The clinical course, differential diagnosis, and literature are summarized briefly.

Primary diffuse leptomeningeal gliomatosis: unusual MRI with non-enhancing nodular lesions on the cerebellar surface and spinal leptomeningeal enhancement.

A 28 year old man presented with a 1 month history of symptoms of intracranial hypertension. Examination showed bilateral papilloedema and meningeal signs. Magnetic resonance imaging showed nodular lesions on the cerebellar and pontine surface and thickening of the thoracic spinal leptomeninges. Throughout the course of the disease, contrast enhancement was detected in the spinal leptomeninges but not intracranially. Primary diffuse leptomeningeal gliomatosis (PDLG) was diagnosed by biopsy and later confirmed on necropsy. The present case is remarkable for the nodular superficial cerebellar lesions and the absence of intracranial contrast enhancement of the leptomeninges.

Angiitis of the central nervous system after allogeneic bone marrow transplantation?

BACKGROUND AND PURPOSE: There is only limited information about late neurological complications after bone marrow transplantation (BMT). The purpose of this study is to describe a cerebral angiitis-like syndrome after allogeneic BMT. METHODS: Clinical and diagnostic findings of 5 BMT patients with chronic graft versus host disease and neuropathological data of 1 patient were reported. RESULTS: In the described patients, focal neurological signs and neuropsychological abnormalities occurred years after BMT. MRI revealed periventricular white matter lesions, lacunar or territorial infarctions, leukoencephalopathy, and hemorrhages. Angiitis of the central nervous system was confirmed in 1 patient at autopsy, and an angiitis-like syndrome was suspected in the other patients because of the clinical course and response to treatment. Three patients received cyclophosphamide and steroids (2 improved, 1 died), 1 patient improved after steroids alone, and 1 patient without immunosuppressive therapy deteriorated further. CONCLUSIONS: We propose that an angiitis-like syndrome of the central nervous system can be a neurological manifestation of graft versus host disease, which should be considered a possible cause of cerebral ischemic episodes and pathological MRI scans in BMT patients with graft versus host disease.

Inducible nitric oxide synthase: a possible key factor in the pathogenesis of chronic vasospasm after experimental subarachnoid hemorrhage.

OBJECT: The role of nitric oxide (NO) in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH) is not well understood. Nitric oxide is a well-established vasodilatory substance; however, in SAH, NO may become a major source for the production of injurious free-radical species, leading to chronic cerebral vasospasm. Reactive overproduction of NO to counteract vascular narrowing might potentiate the detrimental effects of NO. The focus of the present study is to determine the extent of reactive induction of inducible nitric oxide synthase (iNOS) after experimental SAH. METHODS: Chronic vasospasm was induced in male Wistar rats by an injection of autologous blood (100 microl) into the cisterna magna followed by a second injection 24 hours later. A control group of 10 animals was treated with injections of 0.9% sodium chloride solution. Vasospasm was verified by pressure-controlled angiography after retrograde cannulation of the external carotid artery 7 days later. In 11 of 15 animals radiographic evidence of cerebral vasospasm was seen. The animals were perfusion fixed and their brains were removed for immunohistochemical assessment. With the aid of a microscope, staining for iNOS was quantified in 40-microm floating coronal sections. Immunohistochemical staining for iNOS was markedly more intense in animals with significant angiographic evidence of vasospasm. Virtually no staining was observed in control animals. Seven days after the second experimental SAH, labeling of iNOS was found in endothelial cells, in vascular smooth-muscle cells, and, above all, in adventitial cells. Some immunohistochemical staining of iNOS was observed in rod cells (activated microglia), in glial networks, and in neurons. CONCLUSIONS: The present study demonstrates induction of iNOS after experimental SAH.

Differential expression of MHC class II molecules by microglia and neoplastic astroglia: relevance for the escape of astrocytoma cells from immune surveillance.

There is increasing evidence that microglia serve as antigen presenters in the human CNS. Although the occurrence of MHC class II immunoreactive cells has been reported in astrocytic gliomas, the relative contribution of microglia to this cell population has not been studied in detail. Using computer-assisted image analysis, we have investigated the expression of MHC class II molecules and of the microglia/macrophage markers Ki-MIP, RCA-1, KP1 and iba1, in 97 astrocytic gliomas comprising all WHO grades to answer the question whether there is a correlation between tumour grade and the number of MHC class II positive microglia/macrophage profiles. Microglia expressing MHC class II were common in astrocytomas and anaplastic astrocytomas but rare in pilocytic tumours although there was significant variation within each group. MHC class II immunoreactivity was reduced in highly cellular areas of glioblastomas where large numbers of cells expressing macrophage markers were still present. Thus, there was no simple relationship between tumour grade and microglial/macrophage MHC class II expression. In addition, up to 55% of astrocytic gliomas contained MHC class II immunoreactive tumour cells. Microglia but not tumour cells were found to express the BB1/B7 costimulator. We conclude that microglia in astrocytic gliomas are well equipped to function as antigen presenting cells. Yet, neoplastic astroglia appear to acquire the capacity to downregulate microglial MHC class II expression and, at the same time, may induce T-cell clonal anergy through aberrant expression of MHC class II molecules.

Microglia and the development of spongiform change in Creutzfeldt-Jakob disease.

Recent in vitro experiments suggest that neurotoxicity of the prion protein is dependent on the presence of microglia. We have studied 11 cases of Creutzfeldt-Jakob disease (CJD) using immunocytochemistry in combination with computerized image analysis to clarify the relationship between spongiform change and microglial activation. MHC class II-positive microglia were almost exclusively confined to cortical gray matter where the neuropil area occupied by these cells exceeded that of controls more than 350-fold. In cortical regions with a bimodal distribution of spongiform degeneration, the presence of class II-positive microglia correlated well with the presence of vacuolation in layer V, but significantly less with spongiform change in layers II and III. In areas where spongiform degeneration affected the entire depth of the cortex, activated microglia were predominantly located in the inner one-half of the cortex or were evenly distributed throughout all cortical laminae. Here, microglia exhibited atypical, tortuous cell processes and occasionally intracytoplasmic vacuoles, suggesting that microglia themselves may become a disease target. Taken together, our results provide indirect evidence against an early causative involvement of microglia in the development of spongiform change. At later stages, however, diseased microglia could produce harmful factors which mediate both astrogliosis and neuronal injury.

Clinical outcome of supratentorial astrocytoma WHO grade II.

OBJECTIVE: There are divergent opinions about the prognostic value of the extent of surgery and of different histological subtypes in supratentorial astrocytomas WHO grade II. METHODS: We reviewed 75 consecutive patients (36 females, 39 males) with supratentorial astrocytomas WHO grade II (59 primary and 16 recurrent tumours) operated on between 1991 and 1995. RESULTS: Gross total resection could be achieved in 40 astrocytomas, subtotal resection (including biopsy) was performed in 35 cases. Histological assessment confirmed 60 fibrillary, 6 gemistocytic, 9 oligo-astrocytic and no protoplasmic astrocytomas. There were no postoperative deaths. Early outcome 6 to 12 weeks after surgery according to the Glasgow Outcome Scale was good in 46 patients, 24 patients had moderate, and 5 had severe neurological deficits. Survival rates 1, 2, 3, and 4 years following surgery were 100%, 96%, 96%, 96% for patients who underwent gross total tumour resection and 86%, 77%, 77%, 64% for patients with subtotal tumour resection. The cumulative recurrence or progression rates after 4 years were 26% after gross total resection and 80% after subtotal resection, and this result is statistically significant. Recurrences after gross total resection or progressions after subtotal resection occurred more often in gemistocytic astrocytomas (40% and 100%, respectively) than in other subtypes. Dedifferentiation to a more malignant tumour seems to be more prominent in the gemistocytic subtype. CONCLUSION: Gross total resection should be the leading therapeutic option for patients with astrocytomas WHO grade II. For the gemistocytic subtype further studies will have to prove whether additional radiotherapy is of any benefit.

Primary intracranial metatypical basal cell carcinoma: case report.

OBJECTIVE AND IMPORTANCE: A case of primary intracranial metatypic basal cell carcinoma in a 20-year-old man is described. CLINICAL PRESENTATION: A 20-year-old man presented with palsies of the left cranial nerves VI through XII, including complete facial and vestibulocochlear nerve palsy and signs of cerebellar dysfunction, which included left-sided brachydiadochokinesis and nystagmus when looking to the left. There was no evidence of extracranial tumor manifestation. Imaging showed a tumor located in the left pyramidal bone, filling the left cerebellopontine cistern and compressing the brain stem with an extension into the middle cranial fossa as far as the internal carotid artery. INTERVENTION: Subtotal tumor removal was accomplished by a combined neurosurgical-otolaryngological procedure through a transpetrosal approach. A histopathological examination revealed a metatypical basal cell carcinoma. Postoperatively, a total dose of 60 Gy of radiation therapy was administered over a period of 6 weeks. CONCLUSION: Although it is rare, primary intracranial basal cell carcinoma should be considered in the differential diagnosis of tumors of the temporal bone.

Sex chromosome determination in extragonadal teratomas by interphase cytogenetics: clues to histogenesis.

Teratomas are neoplasms that are composed of tissues from all three germinal layers. The exact histogenetic origin of teratomas, however, is still controversial. In order to gain more insight into histogenesis of extragonadal teratomas (EGTs), the gonosomal status in 13 congenital EGTs was studied by means of interphase cytogenetics using nonradioactive in situ hybridization (NISH) with centromere-specific DNA probes. By use of this technique a direct correlation of cytogenetic results with morphology was possible. In all EGTs analyzed the gonosomal status in tissues derived from the different germinal layers was identical to that of the nontumorous fetal and placental tissue. This was true irrespective of localization, age, histological type, and classification of the EGT. Our results strongly suggest that EGTs arise from pluripotent diploid precursor cells, for example, either premeiotic germ cells that have not yet undergone the first meiotic division or pluripotent ectopic embryonal or extraembryonal cells. Our data do not support the theory of parthenogenetic EGT development, at least in males.

Rediscovery of the case described by Alois Alzheimer in 1911: historical, histological and molecular genetic analysis.

In 1911, Alois Alzheimer published a detailed report (Zbl. ges. Neurol. Psych. 4: 356-385) on a peculiar case of the disease that had been named after him by Emil Kraepelin in 1910. Alzheimer describes a 56-year-old male patient (Johann F.) who suffered from presenile dementia and who was hospitalized in Kraepelin's clinic for more than 3 years. Post-mortem examination of the patient's brain revealed numerous amyloid plaques but no neurofibrillary tangles in the cerebral cortex, corresponding to a less common form of Alzheimer disease which may be referred to as 'plaque only'. We have identified well-preserved histological sections of this case and performed mutational screening of exon 17 of the amyloid precursor protein gene and genotyping for apolipoprotein E alleles. The patient was shown to be homozygous for apolipoprotein allele epsilon3 and lacked APP mutations at codons 692, 693, 713 and 717. This case is of historical importance as it may have convinced Kraepelin to name the disease after his co-worker, Alois Alzheimer.

MRI of primary meningeal sarcomas in two children: differential diagnostic considerations.

Meningeal sarcomas are very rare, highly aggressive tumours affecting children more frequently than adults. The clinical course and MRI of meningeal sarcomas in two cases are discussed with special regard to possible misinterpretation. In one case MRI demonstrated a circumscribed mass in contact with the meninges, with central areas of haemorrhage. In the other, a case of primary leptomeningeal sarcomatosis, several MRI examinations over the course of almost a year were unhelpful, despite severe neurological complaints. Then MRI revealed meningeal contrast enhancement all over the brain and spinal canal, together with cerebral infarcts. MRI of meningeal sarcomas has not been discussed in the literature. MRI did not permit specific diagnosis, but enabled visualisation of the extent of the tumour and/or meningeal involvement. Early histological diagnosis is indispensable for adequate treatment.

Long-lasting perivascular accumulation of major histocompatibility complex class II-positive lipophages in the spinal cord of stroke patients: possible relevance for the immune privilege of the brain.

Six cases of middle cerebral artery occlusion are presented in which the cellular changes accompanying descending degeneration of the lateral corticospinal tract were studied at different time points (5 days-10 years) following the insult. Microglia and perivascular cells were found to ingest large amounts of myelin degradation products, while expressing high levels of major histocompatibility complex (MHC) class II molecules. Activation of perivascular macrophages, as indicated by increased class II expression, lasted for many years and appeared to follow down-regulation of both phagocytic activity and class II expression on parenchymal microglia. TUNEL labeling was absent from both microglia and perivascular cells at all time points investigated. Indirect evidence is presented that microglia may transfer myelin degradation products to the perivascular space. Perivascular cells which express MHC class II molecules constitutively do not appear to leave the perivascular compartment in large numbers and could release myelin degradation products into the cerebrospinal fluid. The possible immunological consequences of these findings are discussed with respect to their possible relevance for antigen presentation and autoimmune central nervous system disease.