Global cerebral ischemia due to circulatory arrest: insights into cellular pathophysiology and diagnostic modalities.

Circulatory arrest (CA) remains a major unresolved public health problem in the United States; the annual incidence of which is ~0.50 to 0.55 per 1000 population. Despite seminal advances in therapeutic approaches over the past several decades, brain injury continues to be the leading cause of morbidity and mortality after CA. In brief, CA typically results in global cerebral ischemia leading to delayed neuronal death in the hippocampal pyramidal cells as well as in the cortical layers. The dynamic changes occurring in neurons after CA are still unclear, and predicting these neurological changes in the brain still remains a difficult issue. It is hypothesized that the "no-flow" period produces a cytotoxic cascade of membrane depolarization, Ca2+ ion influx, glutamate release, acidosis, and resultant activation of lipases, nucleases, and proteases. Furthermore, during reperfusion injury, neuronal death occurs due to the generation of free radicals by interfering with the mitochondrial respiratory chain. The efficacy of many pharmacological agents for CA patients has often been disappointing, reflecting our incomplete understanding of this enigmatic disease. The primary obstacles to the development of a neuroprotective therapy in CA include uncertainties with regard to the precise cause(s) of neuronal dysfunction and what to target. In this review, we summarize our knowledge of the pathophysiology as well as specific cellular changes in brain after CA and revisit the most important neurofunctional, neuroimaging techniques, and serum biomarkers as potent predictors of neurologic outcome in CA patients.

Parathyroid carcinoma with intracranial metastasis at diagnosis in a patient with uncontrolled hypercalcemia.

Parathyroid carcinoma is an uncommon malignancy and a rare cause of primary hyperparathyroidism. Although this tumor is capable of metastasis, metastatic disease is very uncommon intracranially, with only seven cases reported in the literature. When intracranial metastases occur, they typically present months to years following the diagnosis of the primary tumor with hypercalcemia refractory to medical conservative treatment. Aggressive surgical resection of all metastases is necessary for control of the disease. We report a case of metastatic parathyroid carcinoma with two intracranial metastatic foci (in the left frontal lobe and left cerebellar hemisphere) identified at the time of the primary tumor diagnosis in a patient who presented with symptomatic hypercalcemia.

Atypical central neurocytoma with sarcomatous differentiation.

We report a case of an intraventricular tumor with features of atypical central neurocytoma with a sarcomatous component in a 44-year-old woman who presented with headaches and vomiting. Magnetic resonance imaging revealed a 3.4-cm lobulated enhancing mass in the occipital horn of the left lateral ventricle, and the patient subsequently underwent a left occipital-parietal craniotomy for debulking. The tumor contained 2 cell populations: round cells with perinuclear halos in a fibrillary background, and spindle cells with oval nuclei arranged in interlacing fascicles with focal necrosis. The round cells had diffuse synaptophysin immunopositivity, while the spindle cells were diffusely immunopositive for vimentin and had intercellular reticulin. The mitotic activity (8 mitotic figures per 10 high-power fields) and the high Ki-67 proliferation index (15.0%) were consistent with atypical central neurocytoma with a sarcomatous component. Although different histologic variants have been described, this is the first reported case, to our knowledge, of central neurocytoma with spindle cell sarcomatous features.

Intravascular large B-cell lymphoma presenting as acute hemorrhagic cerebral infarct with delirium.

Intravascular large B-cell lymphoma (IVLBCL) is a cumbersome diagnosis to make in vivo, particularly because of its elusive nature and ability to be a relatively nonspecific 'great mimicker'. Although it frequently has skin manifestations, it often escapes diagnosis due to its angiotrophism and predilection for vessels that are difficult to biopsy (e.g., cerebral vasculature). IVLBCL can involve the vasculature of virtually any organ but typically spares the lymph nodes themselves, and likely due to defects in adhesion molecules, remains stationary in the vessels. Histologically, the malignant lymphocytes are large and mitotically active with prominent nucleoli. Immunohistochemically, the cells stain as B-cells. The disease has an overall poor prognosis. Here we present a case of IVLBCL diagnosed at autopsy that presented as a hemorrhagic frontal lobe infarct, which progressed to delirium.

Metastatic undifferentiated pleomorphic sarcoma causing intraoperative stroke.

Malignant Fibrous Histiocytoma was historically the most commonly diagnosed soft tissue sarcoma of adults. In 2002, the World Health Organization declassified malignant fibrous histiocytoma as a formal diagnostic entity. They recommended renaming the disease "Pleomorphic Undifferentiated Sarcoma". Current thoughts about the origin of this tumor are being debated. We report a case of a dedifferentiated liposarcoma that metastasized to the lung within one year. The histologic morphology of the metastasis was more aggressive than the primary lesion, and was consistent with a pleomorphic undifferentiated sarcoma. Following surgical resection of the metastatic pulmonary lesion, the patient never fully regained consciousness. He expired the day following his surgery. At autopsy, the patient was found to have died from a massive hemorrhagic stroke involving almost the entire left cerebrum. Tumor emboli from the pulmonary metastasis were seen in the left middle cerebral artery, causing the cerebral infarct. The embolic lesion was consistent with a pleomorphic undifferentiated sarcoma. This case illustrates the evolution that soft tissue sarcomas can undergo as they metastasize and become increasingly undifferentiated, and confirms the surgical risk of resecting such lesions.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids following influenza vaccination.

Inflammatory processes within the central nervous system are challenging for the clinician, radiologist, and pathologist alike. They often can mimic other more well-known and defined disease processes. We present the case of a patient with a newly described inflammatory process that primarily involves the pons and adjacent structures, which is called chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). An 80-year-old man presented with numbness of his right hand that ultimately progressed to involve both lower extremities and face and was associated with mild dysarthria and ataxia. He had received the influenza vaccination 2 weeks prior. The biopsy revealed primarily reactive T-cell lymphocytic infiltrates with macrophages and gliosis. Treatment required long-term immunosuppressive therapy. CLIPPERS is a recently described central nervous system inflammatory condition that should be considered in the differential diagnosis when a prominent lymphocytic inflammatory infiltrate is encountered in brainstem, spinal cord, midbrain, or cerebellar biopsies.

Angiocentric glioma with high proliferative index: case report and review of the literature.

With less than 50 cases previously reported in literature, angiocentric glioma (AG) is an uncommon, slow-growing tumor of the CNS that typically exhibits a low proliferative rate and is generally surgically curable. We report the case of a 3-year-old child who presented with seizures and was found to have a non-enhancing parietal lobe lesion with overlying calvarial remodeling. Following complete resection of the tumor, histopathological examination revealed bipolar spindle cells centered on cortical blood vessels, forming pseudorosettes with an ependymomatous appearance. Tumor cells were glial fibrillary acidic protein (GFAP) positive, yet failed to label with synaptophysin. Scattered tumor cells had a "dot-like" cytoplasmic staining with the antibody against epithelial membrane antigen (EMA). Collectively, these features favored a diagnosis of AG. Interestingly, the monoclonal antibody against Ki-67 (MIB-1) labeling rate averaged approximately 10.0%. The child continues to be tumor- and seizure-free ten months postoperatively. Long-term follow up is required to determine if the high proliferative rate observed in this AG translates into altered clinical behavior and/or a worse prognosis.

Papillary tumor of the pineal region: two case studies and a review of the literature.

Papillary tumor of the pineal region (PTPR) is a newly recognized distinct entity in the 2007 World Health Organization nomenclature. This tumor is characterized by epithelial-appearing areas with papillary features and more densely cellular areas that often display ependymal-like differentiation. Ultrastructurally, this rare neuroepithelial tumor possesses neuroendocrine, secretory, and ependymal organelles that likely originate from the subcommissural organ (SCO) near the aqueduct of Sylvius. To date, approximately fifty-seven described cases worldwide have been recognized, with ages ranging from 5 years to 66 years (mean age=32 years). Clinical presentation most often includes headache and obstructive hydrocephalus. The tumor, which is well circumscribed, may be cystic and radiographically is often considered to be consistent with the findings of a pineocytoma. Microscopic evaluation often demonstrates a lesion with papillary areas lined by epithelioid tumor cells with eosinophilic cytoplasm and more cellular areas with cells exhibiting clear or vacuolated cytoplasm. Perivascular and true rosettes may be identified. Distinctive immunohistochemical features including reactivity for keratins (AE1/AE3, CAM 5.2, CK18) and only focal GFAP staining help distinguish this neoplasm from an ependymoma. The relative paucity of data compiled for this tumor makes giving an accurate diagnosis and prognosis a daunting task. We discuss two additional cases of PTPR that presented to us within a three-month span in order to more fully elucidate the possible presentations of this rare entity. Furthermore, we examine now 59 reported cases of PTPR in order to review the current diagnostic and treatment modalities in addition to exploring emerging research encompassing this unusual neoplasm.

Plasma cell neoplasm in conjunction with glioblastoma of the conus medullaris.

We report a plasma cell neoplasm in conjunction with a glioblastoma multiforme (GBM) of the conus medullaris in a 42-year-old man. Glioblastoma is a World Health Organization (WHO) grade IV neoplasm that requires surgical intervention, radiation, and possibly chemotherapy. Astrocytomas of the spinal cord are rare neoplasms, with intramedullary glioblastomas comprising only 1% to 3%. Plasma cell neoplasms result from monoclonal proliferation of mature B cells; they have been reported as a primary malignancy with gliomas arising after treatment. Secondary plasma cell neoplasms arising within glioblastomas have not previously been described. However, there have been reports of glioblastomas related to other plasma cell and hematopoietic diseases such as Waldenstrom's macroglobulinemia and myeloid sarcomas.

46-year-old man with a spinal cord mass.

Medulloblastoma accounts for only 1% of all adult CNS tumors. Likewise, recurrence of adult medulloblastoma greater than 20 years after initial diagnosis is extremely rare.We describe a case of adult medulloblastoma with late relapse of disease. The patient was 24 years old when first diagnosed and was treated with total tumor resection and craniospinal radiation. At the age of 45, an enhancing 1.3 cm intradural extramedullary spinal cord lesion at T5 was discovered on MRI. This was presumed to be recurrent medulloblastoma in the form of drop metastasis and the patient was treated with spinal radiation. Several months following treatment, at the age of 46, a follow-up MRI demonstrated an enhancing 1.4 cm intradural extramedullary spinal cord lesion at T7. The lesion was resected and histopathologic examination was most consistent with medulloblastoma, late drop metastasis. Although rare, adult medulloblastoma recurring 20 years after initial diagnosis should always be considered in the main differential diagnosis when working up CNS lesions at or outside the primary tumor site.

Papillary glioneuronal tumor: a case report and review of the literature.

We report a papillary glioneuronal tumor occurring in the right frontal lobe of a 26-yr-old woman and we review the pertinent literature. Papillary glioneuronal tumor (PGNT) is a rare cerebral neoplasm, identified in approximately 37 cases to date. In 2007, the World Health Organization (WHO) classified the PGNT as a grade I neuronal-glial tumor because of its biphasic neurocytic and glial components and indolent clinical course. Patients commonly present with headaches or seizures, but may be asymptomatic with the mass discovered incidentally upon neuroimaging. Histology demonstrates a pseudopapillary architecture with a single or a pseudostratified layer of glial cells overlying hyalinized vasculature with interpapillary regions of neurocytic or ganglion cells. Peripheral eosinophilic granular bodies, Rosenthal fibers, hemosiderin, and areas of calcification are often noted. The PGNT displays moderate cellularity and is typically devoid of necrosis, microvascular proliferation, and mitoses. Its immunohistochemical profile includes glial fibrillary acidic protein (GFAP)-positive glial cells, synaptophysin-positive interpapillary neurocytes, and MIB-1 labeling in the range of 1-2%.

Choroid plexus carcinoma.

Choroid plexus carcinoma is an uncommon neoplasm of the central nervous system most commonly found in the pediatric population. It is associated with a dismal prognosis, especially if incompletely resected. Accurate histopathologic diagnosis is imperative, and this neoplasm should always be included in the differential diagnosis of a papillary intraventricular tumor. Histopathologic features include blurring of papillary architecture, layers of neoplastic choroid plexus epithelial cells with pleomorphic nuclei, increased nuclear-to-cytoplasmic ratio, increased mitotic activity, areas of necrosis, and brain invasion. Current accepted treatment is gross total surgical resection of the tumor as the goal. Use of adjuvant chemotherapy is controversial at this time; however, it is considered in some cases.

Novel presentation of central core disease with nemaline bodies (rods) in the setting of diploid/triploid mosaicism.

Diploid/triploid mosaicism is an uncommon malformation syndrome thought to result from incorporation of the second polar body into a blastomere nucleus of the developing embryo. Clinical manifestations include mental and growth retardation, truncal obesity, body asymmetry, hypotonia, syndactyly, clino-/camptodactyly, malformed low-set ears, and small phallus. Although muscular atrophy has been documented in 35% of cases of diploid/triploid mosaicism, to our knowledge histologic evidence of myopathy has not been reported. We present a novel case of diploid/triploid mosaicism with evidence of central core disease and nemaline bodies (rods). The histologic and ultrastructural features are described. A review of the literature is provided, including discussion of the various theories regarding the co-expression of central cores and nemaline rods.

Increased ALZ-50 immunoreactivity in CSF of pseudotumor cerebri patients.

Pseudotumor cerebri (PTC) is characterized by increased intracranial pressure and papilledema without a mass lesion. PTC predominantly affects obese women. Currently, the pathogenesis of PTC is obscure. Since cytoskeletal abnormalities are found in many neurodegenerative diseases, we hypothesized that some cytoskeletal protein might be involved in the pathophysiology of PTC. Western blotting with specific antibody probes was employed to evaluate ALZ-50 immunoreactive protein, cytoskeletal microtubule-associated protein (MAP), and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) samples from 8 PTC patients and 6 controls. Immunoblotting of ALZ-50 in CSF revealed intense staining of 50 kDa protein bands in 7 of 8 PTC patients, while weak staining was found in 4 of 6 controls. Moderate staining of ALZ-50 was seen in 1 of 8 PTC patients and in 2 of 6 controls. CSF blots with anti-ALZ-50 antibody also showed intense staining of a 65 kDa protein band in 3 of the 8 patients but in none of the controls. In anti-MAP CSF blots of the PTC patients and controls, weak staining of the MAP 60 kDa and 50 kDa protein bands was observed. Weak staining of 60 kDa bands was also observed in anti-GFAP CSF blots of all PTC patients and controls. In CSF blots reacted with anti-GFAP antibody, 65 kDa and 32 kDa bands were evident in some PTC patients, but in none of the controls. This study indicates that ALZ-50 immunoreactivity is elevated in CSF of PTC patients. The ALZ-50 immunoreactive protein, either normal tau protein or its phosphorylated variant, may be useful as a biomarker for the diagnosis of PTC. Since the ALZ-50 monoclonal antibody was generated against brain homogenate from Alzheimer's disease (AD) patients, this study suggests a possible link between PTC and AD.

Glial cell number and neuron/glial cell ratios in postmortem brains of bipolar individuals.

BACKGROUND: There are several lines of evidence implicating a glial abnormality in the pathophysiology of bipolar disorder. Previous studies have reported a wide range of abnormalities but with little consistency between their findings. METHODS: Sixty frozen postmortem temporal cortical brain samples from normal, schizophrenic, bipolar, and depressed subjects were obtained from the Stanley Neuropathology Consortium. Nissl stain was utilized to visualize cellular structures. The sections were analyzed for neuron and glial content using the computer programs SPOT Advanced and Metamorph. Three representative fields from each subject were counted and the average numbers obtained. RESULTS: There was no critical difference in glia number across the four diagnostic groups. Compared with normal controls, area occupied by glia was reduced in bipolar subjects (P = 0.018), and the ratio of glial area to neuronal area was reduced (P = 0.028). DISCUSSION: The percent glial space was substantially lower in bipolar disorder subjects compared to normal controls, suggesting that the glia may be smaller in bipolar subjects. The size reduction may be reflective of glial dysfunction. LIMITATIONS: Postmortem interval of 29.4 +/- S.D. 13.4 h may have affected cellular structure and reduced the quality of the staining.

Dementia with Lewy bodies: a commonly unrecognized cause of dementia.

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative cause of dementia of the elderly following Alzheimer's disease. The significant clinical features include: fluctuating cognition with pronounced variations in attention and alertness, recurrent visual hallucinations, and spontaneous motor features of parkinsonism. As an alpha-synucleinopathy, DLB is characterized by Lewy bodies of both classical and cortical types with neuritic degeneration. This report describes an autopsy of an elderly woman with DLB and reviews the clinical and pathologic features of dementia with Lewy bodies.

Apoptosis and necrosis in developing cerebellum and brainstem induced after focal cerebral hypoxic-ischemic injury.

Focal cerebral hypoxia-ischemia due to isolated vascular insufficiency is well known to cause ipsilateral, but not contralateral, cerebral apoptosis. Hypoxic-ischemic damage to the cerebellum and brainstem in such a model has not been established. This experimental rodent study demonstrates, through deoxyribonucleic acid fragmentation and terminal deoxynucleotidyl transferase-mediated deoxyuridine 5'-triphosphate-digoxigenin nick end labeling analysis, that neuronal cells in these infratentorial regions also suffer mild apoptosis and necrosis after focal cerebral hypoxic-ischemic injury in the newborn rat. These data provide additional insight into the mechanisms of neurological injury in the cerebellum and brainstem areas resulting from a focal cerebral hypoxic-ischemic insult and demonstrate that future therapeutic interventions for hypoxic-ischemic encephalopathy system should deal with the entire central nervous system.

Extensive aortic thromboembolism due to acquired hypercoagulable state: an autopsy case report.

Aortic thrombosis rarely occurs without severe atherosclerosis, aneurysm, or cardiosurgical or traumatic state. Arterial thrombosis is commonly related to an inherited and/or acquired hypercoagulable state. A 50-year-old woman presented with diffuse abdominal pain. One day after her admission, she experienced bloody stools. Computed tomography showed multiple extensive thromboses in the aorta and superior mesentery arteries. She underwent a partial jejunoileostomy and colectomy for extensive bowel infarction. Following surgery, her condition deteriorated and she died on the fourth hospital day. At autopsy, gross examination showed 2 large thrombi (7 and 8 cm in length) in the proximal and descending (thoracic) aorta, with mild atherosclerosis. A mesenteric artery thromboembolus with extensive bowel infarction was present. Postmortem laboratory studies revealed an elevated anticardiolipin immunoglobulin G antibody level. The thrombotic state in this patient was considered multifactorial secondary to acquired risk factors, including obesity, mild aortic atherosclerosis with coronary artery disease, and presence of a high titer anticardiolipin antibody.