True aneurysm on the posterior meningeal artery associated with a dural arteriovenous fistula: case report.

BACKGROUND: We report an unusual case of a true dural aneurysm arising from the posterior meningeal artery that fed a symptomatic dural arteriovenous fistula located at the right transverse-sigmoid sinus junction. CLINICAL PRESENTATION: A 29-year-old right-handed white woman presented with aneurysmal dilatation of hypertrophied posterior meningeal artery feeding a partially treated dural arteriovenous fistula. INTERVENTION: The aneurysm, which measured approximately 3 mm in width and 5 mm in length, was located in the intracranial space with a thin-walled dome projecting toward the cerebellum. Its afferent and efferent vessels were identified, secured, and the lesion was excised en bloc. CONCLUSION: A thorough evaluation of all diagnostic studies should be performed for patients with vascular malformations to help identify these or other unusual lesions that may aid in the risk stratification process and management plan.

Rupture of cerebral myxomatous aneurysm months after resection of the primary cardiac tumor.

BACKGROUND: The natural history of cerebral aneurysms derived from metastatic spread of cardiac myxomas is not well known, and their management presents many dilemmas. METHODS: Case report and literature review. RESULTS: An 18-year-old man presented with an intraparenchymal hemorrhage several months after resection of an atrial myxoma. Angiography showed several myxomatous aneurysms, one of which had bled. The patient had a recurrent hemorrhage before undergoing surgical resection. MRI, angiographic, and pathological data are presented for this rare condition. CONCLUSIONS: Myxomatous aneurysms are important entities for neurointensivists to recognize and can present years after diagnosis. Patients presenting with cerebral infarction or hemorrhage of unknown etiology should undergo cardiac imaging to rule out atrial myxoma, as up to 50% of patients with myxomas present initially with stroke.

Bing-Neel syndrome: an illustrative case and a comprehensive review of the published literature.

Waldenstrom's macroglobulinemia (WM) is a chronic lymphoproliferative disorder within the spectrum of lymphoplasmacytic lymphoma characterized by proliferation of plasma cells, small lymphocytes, and plasmacytoid lymphocytes. Central nervous system involvement is very rare (Bing-Neel [BN] syndrome). We present the case of a 62-year-old woman previously diagnosed with WM who presented with Bing-Neel syndrome and review the published literature which consists of only case reports. We performed a Medline search using the terms "Waldenstrom's macroglobulinemia and central nervous system" and "Bing-Neel" collecting data on presentation, evaluation, treatment, and outcome and summarizing these findings in the largest pooled series to date. Central nervous system manifestations are localization related. Serum laboratory testing reflects systemic disease. Cerebrospinal fluid analysis may show lymphocytic pleocytosis, elevated protein, and IgM kappa or lambda light chain restriction; cytology results are variable. Imaging is frequently abnormal. Biopsy confirms the diagnosis. Treatment data are limited, but responses are seen with radiation and/or chemotherapy. BN syndrome is a very rare complication of WM that should be considered in patients with neurologic symptoms and a history of WM. Treatment should be initiated as responses do occur that may improve quality of life and extend it when limited or no active systemic disease is present.

Response of an adult patient with pineoblastoma to vorinostat and retinoic acid.

We report the case of an adult patient with pineoblastoma (PBL) who had a complete radiographic response following treatment with vorinostat and retinoic acid. This regimen was used to treat bulky residual tumor that persisted despite radiation therapy (RT) and two cycles of cytotoxic chemotherapy. Vorinostat and retinoic acid were chosen as an alternative to cytotoxic chemotherapy, which our patient was unable to tolerate, based on preclinical data suggesting efficacy of this combination. MRI demonstrated a complete response to this regimen, which continues to remain stable without evidence of recurrence.

High-grade dural arteriovenous fistula simulating a bilateral thalamic neoplasm.

Dural arteriovenous fistulae (dAVF) provide a diagnostic challenge and must be part of a broad differential in pursuit of a difficult diagnosis or unusual presentation. This case report demonstrates an initially misguided diagnosis of bilateral thalamic neoplasm and demonstrates the importance of continued pursuit until the correct diagnosis is obtained. Moreover, to our knowledge, this is the first reported case of a dAVF simulating a bilateral thalamic neoplasm. We present a patient with a provisional diagnosis of bilateral thalamic neoplasm based on clinical history and an advanced imaging workup including MR spectroscopy. Subsequent biopsy suggested venous congestion, hypoxia, and edema without neoplasia. Routine post-operative CT the following day revealed suggestion of dAVF due to the presence of residual contrast from prior unrelated abdominal CT. Cerebral angiography eventually revealed a Cognard grade IIb dAVF. Trans-arterial Onyx embolization resulted in a dramatic clinical and radiographic improvement. This case highlights an unusual presentation and challenging diagnosis of a dAVF and the importance of pursuing the correct diagnosis.

Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.

Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons.

Multiple brain abscesses due to Actinomyces species.

We report a case of multiple brain abscesses due to Actinomyces species in a 35-year-old immunocompetent man who presented with a 2-month history of headache, diplopia, fever, and weight loss. Despite receipt of broad-spectrum antibiotics for over a month, he continued to have headaches and diplopia. He subsequently underwent right anterior temporal lobectomy and evacuation of abscesses. The diagnosis was aided by identification of sulfur granule on histopathological examination of cerebral cavitary lesion and Gram-positive filamentous rods seen on tissue-Gram stain.

Phosphorylation of beta-amyloid precursor protein (APP) cytoplasmic tail facilitates amyloidogenic processing during apoptosis.

Secretion and progressive cerebral accumulation of beta-amyloid peptides (Abeta) derived by endoproteolytic ("amyloidogenic") processing of beta-amyloid precursor protein (APP) represent collectively an early and necessary event in the pathogenesis of Alzheimer's disease. We previously demonstrated that secretion of the neurotoxic species Abeta42 increases during staurosporine-induced apoptosis in undifferentiated PC12 cells, in an endocytosis-dependent manner. In the present study, we tested whether phosphorylation of the APP cytoplasmic-tail is contributory to this apoptosis-related increased Abeta-secretory response. We demonstrate that cytoplasmic-tail phosphorylation specifically at amino-acid residue T668 (APP-695 numbering) increases during staurosporine-induced apoptosis, in parallel with activation of the mitogen-activated, proline-directed serine/threonine protein kinase ERK1. We demonstrate additionally that specific ERK inhibition during staurosporine induction, with serum-free conditions, results in down-regulation of APP phosphorylation at T668, together with attenuation of the increased Abeta-secretory response. These results are consistent with APP cytoplasmic-tail phosphorylation at T668 during apoptosis as contributory to increased Abeta42 secretion originating from the endocytotic pathway, likely with cell-line restriction.

The endocytotic pathway is required for increased A beta 42 secretion during apoptosis.

Secretion and progressive cerebral accumulation of beta-amyloid peptides (A beta), which derive by endoproteolytic ('amyloidogenic') processing of beta-amyloid precursor protein (APP), are felt to represent collectively an early and necessary event in the pathogenesis of Alzheimer's disease. APP amyloidogenic processing can occur via secretory or endocytotic pathways, but the relative contribution of these pathways to A beta secretion remains to be established. The effect of apoptosis on amyloidogenic processing and A beta secretion similarly is incompletely understood. We tested the hypothesis that APP processing by the endocytotic pathway represents a stress-related neural cell response, by comparing A beta secretion after induction of apoptosis in PC12 cells transfected either for endocytosis-competent or -deficient APP. Newly prepared adenoviral vectors encompassing targeted mutagenesis of the cytoplasmic tail YENP tetrapeptide sequence, which serves as the principal APP internalization signal, were used to express endocytosis-deficient holoprotein. We report that the endocytotic pathway is required for the generation and secretion of A beta 42, and that secretion of this neurotoxic peptide increases significantly during apoptosis. We demonstrate additionally that more A beta 40 apparently is generated in secretory compartments during apoptosis when APP processing by the endocytotic pathway is impaired.

Differential expression of cholesterol hydroxylases in Alzheimer's disease.

Cholesterol is eliminated from neurons by oxidization, which generates oxysterols. Cholesterol oxidation is mediated by the enzymes cholesterol 24-hydroxylase (CYP46A1) and cholesterol 27-hydroxylase (CYP27A1). Immunocytochemical studies show that CYP46A1 and CYP27A1 are expressed in neurons and some astrocytes in the normal brain, and CYP27A1 is present in oligodendrocytes. In Alzheimer's disease (AD), CYP46A1 shows prominent expression in astrocytes and around amyloid plaques, whereas CYP27A1 expression decreases in neurons and is not apparent around amyloid plaques but increases in oligodendrocytes. Although previous studies have examined the effects of synthetic oxysterols on the processing of amyloid precursor protein (APP), the actions of the naturally occurring oxysterols have yet to be examined. To understand the role of cholesterol oxidation in AD, we compared the effects of 24(S)- and 27-hydroxycholesterol on the processing of APP and analyzed the cell-specific expression patterns of the two cholesterol hydroxylases in the human brain. Both oxysterols inhibited production of Abeta in neurons, but 24(S)-hydroxycholesterol was approximately 1000-fold more potent than 27-hydroxycholesterol. The IC(50) of 24(S)-hydroxycholesterol for inhibiting Abeta secretion was approximately 1 nm. Both oxysterols induced ABCA1 expression with IC(50) values similar to that for inhibition of A beta secretion, suggesting the involvement of liver X receptor. Oxysterols also inhibited protein kinase C activity and APP secretion following stimulation of protein kinase C. The selective expression of CYP46A1 around neuritic plaques and the potent inhibition of APP processing in neurons by 24(S)-hydroxycholesterol suggests that CYP46A1 affects the pathophysiology of AD and provides insight into how polymorphisms in the CYP46A1 gene might influence the pathophysiology of this prevalent disease.

Surgical management of a ruptured posterior choroidal intraventricular aneurysm associated with moyamoya disease using frameless stereotaxy: case report and review of the literature.

OBJECTIVE AND IMPORTANCE: Prevention of rebleeding is the most important aspect of the management of hemorrhagic moyamoya disease, because rebleeding causes significant morbidity and mortality. CLINICAL PRESENTATION: A 26-year-old male patient with a history of moyamoya disease since the age of 3 years and multiple strokes was in a semicomatose state at presentation. He was found to have intraventricular and periventricular hemorrhages abutting the atrium of the right ventricle. His hospital course was complicated by a second hemorrhage. Both bleeding events were believed to be secondary to a ruptured right lateral posterior choroidal aneurysm. INTERVENTION: The aneurysm was excised and revealed histopathology consistent with a true saccular aneurysm. Frameless stereotactic guidance was used during surgery to minimize damage to collateral vessels and to shorten the surgical corridor. CONCLUSION: The management of hemorrhagic moyamoya disease should be modified based on the source of hemorrhage and its relation to a specifically located aneurysm. In the case of aneurysms arising from the choroidal artery, the general belief is that most of these represent pseudoaneurysms and have a tendency to regress spontaneously. Because of the rebleeding risk, we recommend early intervention in treating ruptured intracranial aneurysms using the least invasive surgical techniques.

Presenilins mutated at Asp-257 or Asp-385 restore Pen-2 expression and Nicastrin glycosylation but remain catalytically inactive in the absence of wild type Presenilin.

The Presenilins are part of the gamma-secretase complex that is involved in the regulated intramembrane proteolysis of amyloid precursor protein and other type I integral membrane proteins. Nicastrin, Pen-2, and Aph1 are the other proteins of this complex. The Presenilins probably contribute the catalytic activity to the protease complex. However, several investigators reported normal Abeta-peptide generation in cells expressing Presenilins mutated at the putative catalytic site residue Asp-257, contradicting this hypothesis. Because endogenously expressed wild type Presenilin could contribute to residual gamma-secretase activity in these experiments, we have reinvestigated the problem by expressing mutated Presenilins in a Presenilin-negative cell line. We confirm that Presenilins with mutated Asp residues are catalytically inactive. Unexpectedly, these mutated Presenilins are still partially processed into amino- and carboxyl-terminal fragments by a "Presenilinase"-like activity. They are also able to rescue Pen-2 expression and Nicastrin glycosylation in Presenilin-negative cells and become incorporated into large approximately 440-kDa complexes as assessed by blue native gel electrophoresis. Our study demonstrates that the catalytic activity of Presenilin and its other functions in the generation, stabilization, and transport of the gamma-secretase complex can be separated and extends the concept that Presenilins are multifunctional proteins.