Physiological effects of auditory nerve myelinopathy in chinchillas

The goals were to study the physiological effects of auditory nerve myelinopathy in chinchillas and to test the hypothesis that myelin abnormalities could account for auditory neuropathy, a hearing disorder characterized by absent auditory brainstem responses (ABRs) with preserved outer hair cell function. Doxorubicin, a cytotoxic drug used as an experimental demyelinating agent, was injected into the auditory nerve bundle of 18 chinchillas; six other chinchillas were injected with vehicle alone. Cochlear microphonics, compound action potentials (CAPs), inferior colliculus evoked potentials (IC-EVPs), cubic distortion product otoacoustic emissions and ABRs were recorded before and up to 2 months after injection. Cochleograms showed no hair cell loss in any of the animals and measures of outer hair cell function were normal (cubic distortion product otoacoustic emissions) or enhanced (cochlear microphonics) after injection. ABR was present in animals with mild myelin damage (n = 10) and absent in animals with severe myelin damage that included the myelin surrounding spiral ganglion cell bodies and fibers in Rosenthal's canal (n = 8). Animals with mild damage had reduced response amplitudes at 1 day, followed by recovery of CAP and enhancement of the IC-EVP. In animals with severe damage, CAP and IC-EVP thresholds were elevated, amplitudes were reduced, and latencies were prolonged at 1 day and thereafter. CAPs deteriorated over time, whereas IC-EVPs partially recovered; latencies remained consistently prolonged despite changes in amplitudes. The results support auditory nerve myelinopathy as a possible pathomechanism of auditory neuropathy but indicate that myelinopathy must be severe before physiological measures are affected.     

Intracerebral (parenchymal) infusion of methotrexate: report of a case

Summary This report describes the neuropathological findings in a 32 year old woman with acute myelogenous leukemia (AML) and central nervous system (CNS) involvement, who received a total of 48 mg of methotrexate (MTX) intended to be delivered to the ventricle. At autopsy, the tip of the infusion catheter was found to have been inadvertently placed in the left basal ganglia. The delivery of the MTX at that site caused white matter lesions characteristic of those previously reported in MTX encephalopathy following diverse modes of administration. This case is unusual in that there was the direct infusion of MTX into cerebral parenchyma, circumventing both the blood:brain and cerebrospinal fluid:brain barriers. Axonal abnormalities were widespread in the MTX-infused tissue, frequently but not always accompanied by myelin loss. Since radiation therapy had not been employed, this case permitted the assessment of pathologic changes largely attributable to MTX.     

Multifocal vacuolar leucoencephalopathy: a distinct HIV-associated lesion of the brain

A 20-year-old male AIDS patient developed rapidly progressive dementia for more than 3 months prior to death. Autopsy showed, in addition to adrenal cytomegalovirus (CMV) infection and focal cerebral necrosis due to toxoplasmosis, multifocal subcortical white matter lesions of the brain which were strikingly similar to the histopathology of vacuolar myelopathy in AIDS. These distinct lesions contained macrophages which were rarely multinucleated and expressed HIV antigens by immunocytochemistry. The distribution of lesions mimics extrapontine myelinolysis and progressive multifocal leucoencephalopathy (PML); PML was excluded by the absence of papovaviruses by immunocytochemistry and by in situ DNA hybridization. Tissue damage in multifocal vacuolar leucoencephalopathy is different from hitherto characterized HIV-specific neuropathology such as HIV encephalitis and HIV leucoencephalopathy, and should be included in the list of conditions with damage of the brain white matter in AIDS.     

Neonatal non-ketotic hyperglycinemia

The typical imaging findings of neonatal non-ketotic hyperglycinemia have rarely been described in the radiologic literature with only few individual cases or small series reported. In this article, we present a case of neonatal onset non-ketotic hyperglycinemia, imaged at 6 days of age, and discuss characteristic MRI and MR spectroscopic findings.     

An extract of Hydrilla verticillata and associated epiphytes induces avian vacuolar myelinopathy in laboratory mallards

Avian vacuolar myelinopathy (AVM) is a neurological disease affecting bald eagles (Haliaeetus leucocephalus), American coots (Fulica americana), waterfowl, and other birds in the southeastern United States. The cause of the disease is unknown, but is thought to be a naturally produced toxin. AVM is associated with aquatic macrophytes, most frequently hydrilla (Hydrilla verticillata), and researchers have linked the disease to an epiphytic cyanobacterial species associated with the macrophytes. The goal of this study was to develop an extraction protocol for separating the putative toxin from a hydrilla-cyanobacterial matrix. Hydrilla samples were collected from an AVM-affected reservoir (J. Strom Thurmond Lake, SC) and confirmed to contain the etiologic agent by mallard (Anas platyrhynchos) bioassay. These samples were then extracted using a solvent series of increasing polarity: hexanes, acetone, and methanol. Control hydrilla samples from a reference reservoir with no history of AVM (Lake Marion, SC) were extracted in parallel. Resulting extracts were administered to mallards by oral gavage. Our findings indicate that the methanol extracts of hydrilla collected from the AVM-affected site induced the disease in laboratory mallards. This study provides the first data documenting for an "extractable" AVM-inducing agent.     

Calpain Immunoreactivity and Morphological Damage in Chinchilla Inner Ears after Carboplatin

Carboplatin produces an unusual pattern of damage in the chinchilla inner ear, characterized by early destruction of type I afferent fibers and preferential loss of type I hair cells in the vestibular end organs and inner hair cells (IHCs) in the cochlea. In the present study, we investigated a potential role of calpains, a family of calcium-activated proteases, in carboplatin ototoxicity. Chinchillas received carboplatin (100 mg/kg IP) and were sacrificed 12, 24, 48, or 72 h later for morphological evaluation or immunocytochemistry. Nerve fibers and myelin were the initial sites of increased calpain immunoreactivity (IR) and morphological damage. At 12 h, granular immunoreactive puncta were present within nerve fibers and their myelin sheaths in the spiral ganglion. In the habenula perforata, dense reaction product was present in large vacuoles in the myelin surrounding the nerve fibers. At 24 h, nerve fibers and myelin were destroyed in the habenula, and those in the spiral ganglion showed increased calpain IR and morphological damage. At 72 h, nerve fibers and myelin were completely destroyed. Calpain IR was not a prominent feature of IHCs, type I vestibular hair cells, or ganglion cells at any time after carboplatin. The results show a correlation between calpain IR and carboplatin-induced axon and myelin degeneration. We propose that calpain-induced axonopathy and myelinopathy are primary features of carboplatin ototoxicity in chinchilla.