Objectives Acute liver failure produces cerebral dysfunction and edema, mediated in part by elevated ammonia concentrations, often leading to coma and death. The pathophysiology of cerebral edema in acute liver failure is incompletely understood. In vitro models of the cerebral effects of acute liver failure have predominately consisted of dissociated astrocyte cultures or acute brain slices. We describe a stable long-term culture model incorporating both neural and glial elements in a three-dimensional tissue structure offering significant advantages to the study of astrocytic-neuronal interactions in the pathophysiology of cerebral edema and dysfunction in acute liver failure. Methods We utilized chronic organotypic slice cultures from mouse forebrain, applying ammonium acetate in iso-osmolar fashion for 72 hours. Imaging of slice thickness to assess for tissue swelling was accomplished in living slices with optical coherence tomography, and confocal microscopy of fluorescence immunochemical and histochemical staining served to assess astrocyte and neuronal numbers, morphology, and volume in the fixed brain slices. Results Ammonia exposure at 1–10 mM produced swelling of immunochemically-identified astrocytes, and at 10 mM resulted in macroscopic tissue swelling, with slice thickness increasing by about 30%. Astrocytes were unchanged in number. In contrast, 10 mM ammonia treatment severely disrupted neuronal morphology and reduced neuronal survival at 72 hours by one-half. Discussion Elevated ammonia produces astrocytic swelling, tissue swelling, and neuronal toxicity in cerebral tissues. Ammonia-treated organotypic brain slice cultures provide an in vitro model of cerebral effects of conditions relevant to acute liver failure, applicable to pathophysiological investigations.
Summary:We present a case of death likely to be directly due to cyclosporine (CsA) neurotoxicity. To date, there have been no reports of deaths directly due to CsA neurotoxicity, nor has an associated histological lesion been described independent of confounding processes. A 54-year-old male received an HLA-matched-unrelated BMT for CML. He developed progressive encephalopathy and on day ؉79 had a generalized seizure. All CSF studies were negative for infectious causes. MRI revealed diffuse, symmetrical white matter abnormalities located in the occipital sub-cortex, thalamus, mid brain, pons, and cerebellum which were typical of CsA toxicity. The patient died of central respiratory failure within 72 h of discontinuing CsA. Autopsy revealed diffuse patchy white matter edema and astrocytic injury without evidence of axonopathy, demyelination, microvascular injury, or infectious/inflammatory process. This case demonstrates previously undescribed lethal CsA neurotoxicity and may reveal an associated primary pathological lesion. Keywords: cyclosporine; neurotoxicity; MRI; CML; allogeneic bone marrow transplant Neurological complications cause morbidity and mortality in up to 37% of patients following allogeneic bone marrow transplantation. 1 Case reports and retrospective case series implicate CsA neurotoxicity as a significant contributor to these complications. 1,2 This toxicity can range from the most common finding of tremors to the most severe syndrome of seizures, visual disturbances, and radiographically characteristic white matter abnormalities often involving the occipital lobes. 2,3 This distinguishable clinical and radiographic syndrome, however, has not been reported to be directly fatal. [2][3][4] Here, we present a patient with typical CsA CNS neurotoxicty, a fatal outcome, and no other overt cause of death. We also describe the previously unreported Case reportPhiladelphia chromosome-negative CML was diagnosed in June 1996 in a 54-year-old male with adult onset diabetes. In July 1997, while still in chronic phase, he received an HLA-identical unrelated allogeneic BMT following CY/TBI conditioning. He was treated with routine GVHD prophylaxis consisting of CsA/MTX according to the Seattle regimen. 5 Engraftment (Ͼ500 neutrophils) occurred on day ϩ20, and platelet requirements ceased after day ϩ22. His post-transplant course was notable for the development of acute skin GVHD on day ϩ26 not requiring increased immunosuppression and symptomatic biopsyproven upper gastrointestinal GVHD on day ϩ65 requiring treatment with methylprednisolone (1 mg/kg i.v. twice daily).After complaining of intermittent 'blurred vision' for several days, he was noted by his wife to be confused on day ϩ78. Neurological examination and routine laboratory studies were normal. The following day he was increasingly somnolent. Deep tendon reflexes were symmetrical but plantar reflexes were absent. Otherwise, sensory/motor and cranial nerve examinations were normal. On day ϩ79 he had a single generalized tonic-clonic seizure that was...
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