Riki Okeda

Chronic manganese poisoning: A neuropathological study with determination of manganese distribution in the brain

SummaryAn autopsy case of a 52-year-old man suffering from chronic manganese poisoning (CMP) is reported with determination of the manganese distribution in the brain. The patient had been working in a manganese ore crushing plant since 1965. In 1967 he began to complain of difficulties in walking and diminished libido. Later, he developed various neuro-psychiatric symptoms including euphoria, emotional incontinence, masked face, monotonous speech, “cock-walk”, increased muscle tone, weakness of upper and lower extremities, tremor of the eye lids, and exaggeration of knee jerks. The major neuro-pathological change was degeneration of the basal ganglia, in which the pallidum was severely affected. The pallidum discolsed a loss and degeneration of nerve cells, which was especially marked in the medial segment, a prominent decrease of myelinated fibers, and moderate astrocytic proliferation. The substantia nigra was intact. Distribution of manganese in the brain of the present case of CMP was determined using flameless atomic absorption spectrometry and compared with control cases and also a case of Parkinsons disease (PD). There was no significant difference between the control cases and the case of PD in average concentration of manganese and its ditribution in the brain. The present case of CMP showed no elevation in average concentration of manganese in the brain. However, there were some changes in its distribution. Thus, the continuance of neurological disorders in CMP is not linked to an elevated manganese concentration itself in the brain. CMP appears to be different from PD in neuropathology and manganese behavior in brain.

Blood-brain barrier disruption and exacerbation of ischemic brain edema after restoration of blood flow in experimental focal cerebral ischemia

SummaryThe mechanism of exacerbation of ischemic brain edema after blood flow restoration was studied in 20 cats under ketamine and alpha-chloralose anesthesia. Regional cerebral blood flow was measured by the hydrogen clearance method, and the left middle cerebral artery (MCA) was occluded for 6 h in group A, and for 3 h with subsequent 3 h recirculation in group B. Severity of brain edema was assessed by specific gravity measurement of tissue samples taken from coronal brain sections at the MCA area, while severity of blood-brain barrier (BBB) disruption was determined by measuring the amount of extravasated serum albumin by using [125I]albumin and tissue-uptake method in the same samples as those used for gravimetry. Structural and ultrastructural change was correlated with the severity of ischemic brain edema and BBB disruption. The results obtained showed that: (i) ischemic brain edema observed in group A was not associated with BBB opening to serum proteins; (ii) ischemic edema in group B was exacerbated significantly after recirculation in correlation with serum protein extravasation in most of the postischemic area; (iii) in the severely edematous area, serum protein extravasation reached a plateau and morphological examination at this type of area revealed cell membrane disruption especially of astrocytes, with leakage of intracellular substances. Our study indicated that the increase of extracellular osmotic pressure due to leakage of serum proteins via the disrupted BBB and of intracellular substances via the ischemically injured cell membrane into the extracellular space is the mechanism responsible for edema fluid accumulation in exacerbated ischemic brain edema.

Arterial Changes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Relation to Pathogenesis of Diffuse Myelin Loss of Cerebral White Matter Examination of Cerebral Medullary Arteries by Reconstruction of Serial Sections of an Autopsy Case

Background and Purpose— There is little information regarding the pathogenesis underlying diffuse myelin loss in the cerebral white matter and sparing of the U fibers in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in which the medial smooth muscle cells of systemic arteries are characteristically involved. We sought to examine the precise extent and severity of changes in the cerebral arteries in an autopsy case of CADASIL in relation to pathogenesis of the diffuse myelin loss. Methods— We reconstructed 1000 serial sections of the frontal cerebral medullary arteries of an autopsy subject, which was the first identified Japanese case of CADASIL, as confirmed by the presence of ultrastructural deposits of granular osmiophilic material in the media of some visceral arteries and by genetic analysis. Results— We reconstructed 11 medullary arteries of the frontal lobe showing diffuse myelin loss and atrophy of the white matter with sparing of the U fibers. All of these showed complete loss of medial smooth muscle cells over their entire length and severe adventitial fibrosis. Although intimal fibrosis or hyalinosis was present, luminal occlusion was scarce. These changes were also observed in the small and large arachnoidal arteries but were relatively mild in the latter and in the cortical and subcortical medullary arteries. Conclusions— These arterial changes resulted in transformation of the cerebral arteries, in particular almost all the medullary arteries, to a so-called earthen pipe state. This supports the reported findings of a reduction in vascular reactivity to fluctuations in CO2 levels and systemic blood pressure in CADASIL.

Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and α-fluoroβ-alanine

SummaryTwo metabolites of 5-fluorouracil (FU), monofluoroacetic acid (FA) and α-fluoro-β-alanine (FBAL), were continuously administered into the left ventricle of the brain in cats for up to 1 month to investigate the mechanissm of neurotoxicity of FU and its derivatives. The cumulative doses of FU and FBAL over a 1-month period were 1.5–45 mg (20 cats) and 0.2–4.8 mg (21 cats), respectively. As controls for each experimental group, acetic acid (AA) and β-alanine (BAL) were administered. In terms of survival time in relation to the cumulative dose and molecular weight, FBAL was more toxic than FA. Neuropathologically, two types of change, vacuoles and necrosis/softening-like change, were found. The vacuoles were 20–50 μm in diameter, and distributed mainly in the cerebellar nuclei, white matter and the tectum and tegmentum of the brain stem in both experimental groups. Electron microscopically, these vacuoles were due to splitting of the myelin intraperiod line or separation between the axon and the innermost layer of myelin. Necrosis/softening-like change occurred preferentially in the FBAL group and was located symmetrically in the superior and inferior colliculi, oculomotor nuclei and thalamus. Both types of neuropathological change, especially those in the FBAL group, were similar to those found in cats orally administered with FU and its derivatives. It was, therefore, concluded that the subacute and chronic neurotoxicity of FU and its derivatives in dogs and cats is due to intoxication with the monofluorinated organic metabolites, FA and FBAL, and that the direct action of FA and FBAL on myelin and the action of FBAL on energy metabolism or vessels of the mid brain were proposed as the main pathogenetic factor involved.

The pathogenesis of carbon monoxide encephalopathy in the acute phase—Physiological and morphological correlation

SummaryExperimental studies were performed to elucidate the significance of various physiological factors contributing to the pathogenesis of carbon monoxide (CO) encephalopathy, such as systemic blood pressure (BP), common carotid artery blood flow (CF), local blood flow (LBF) of the brain and blood gas including pH, and to analyse the morphological character of the cerebral white matter lesions in the acute phases with light and electron microscopes; 14 adult cats were exposed to 0.3% CO/air gas under respiratory control for 1 h and 17 min to 2 h and 50 min and killed 1.5 h to 3 weeks later.During the 1st h the CF and LBF increased along with the concentration of CO haemoglobin and the BP showed slight decrease in all the CO-exposed cats. After the 1st h, the BP dropped progressively as well as the CF and LBF. The LBF of the cortex and white matter changed in parallel, but often that of the latter approximated or exceeded that of the former in the cerebrum. During CO exposure, acidosis occurred in all the cats and haemoconcentration resulted in almost all of the cats. In all the cats except one which showed the least BP drop, lesions occurred selectively in the cerebral white matter and in six or seven cats focal coagulation necrosis or ischaemic changes occurred in the nerve cells in the bilateral pallidum, substantia nigra, and hippocampus similar to human patients. The cerebral white matter lesions were suggestive of those caused by circulatory disturbance. The severity of the white matter damage showed a good positive correlation with the intensity of the BP drop, but not with other factors, such as the duration of CO-exposure, CO-haemoglobin level, acidosis, or haemoconcentration. On the basis of such physiological and morphological findings, we have found the following to be essential for the selective damage of the cerebral white matter rather than the cerebral cortex or white matter of other regions of the CNS: (1) the coexistence of the initial phase of increase in and the succeeding decrease in the cerebral blood flow and (2) the anatomical finding that the cerebral white matter is supplied by its own long nourishing arteries with small amounts of capillary beds and a thinner media compared with that of the subarach-noidal artery.

Neoplastic angioendotheliosis. Immunohistochemical and electron microscopic findings in three cases

Three cases of neoplastic angioendotheliosis (NAE) presenting with central nervous system (CNS) disease but no skin lesions are described. The histogenesis of the neoplastic cells is discussed. Microscopic examination showed accumulation of neoplastic cells in the vascular system throughout the body and their extravascular proliferation in several organs. Electron microscopic and immunohistochemical studies revealed the presence of Weibel‐Palade bodies and factor VIII‐related antigen in intravascular and extravascular neoplastic cells in two of the three cases. In the first case the neoplastic cells did not have any T‐cell markers. However, in one case no specific markers were found in the neoplastic cells by electron microscopic, enzyme histochemical, or immunohistochemical examination. These findings, although supporting the endothelial origin of the neoplastic cells, indicate the need for further consideration of whether NAE is actually a single disease entity or several different diseases.

Comparative study on pathogenesis of selective cerebral lesions in carbon monoxide poisoning and nitrogen hypoxia in cats

SummarySince in a previous study hypoxia and subsequent hypotension were considered to be essential for the pathogenesis of carbon monoxide encephalopathy (CO-encephalopathy), experiments were conducted to see whether a combination of nitrogen hypoxia and subsequent systemic hypotension of similar degree and duration as in the previous experimental CO poisoning could induce the same lesion in the CNS of cats. The partial pressure of blood oxygen was reduced to less than 26 mm Hg by increasing the concentration of nitrogen in N2/O2 gas to be inhaled in 1.5 h and then the aortic blood pressure (BP) was reduced to 60–80 mm Hg by blood depletion and ganglion-blockage for 1 h. In 11 of the 15 cats, lesions were produced in the CNS which were similar by light and electron microscopy to those in CO-encephalopathy. In control groups which were treated by hypoxemia only, hypotension only or a combination of CO2-gas inhalation and hypotension without hypoxemia, such lesions were not found in the cerebral white matter.Considering the pathogenesis of lesions in the cerebral white matter in both nitrogen hypoxia and CO-poisoning, two factors, i.e., hypoxemia and subsequent systemic hypotension, are common and essential. Further, the enormous vasodilation in the cerebral white matter induced by hypoxemia and subsequent drop in BP seem to cause a more severe circulatory disturbance in the cerebral white matter than in the cortex.

Nitric Oxide Synthase Expression in Ischemic Rat Retinas

PURPOSE To investigate the expression of nitric oxide synthase (NOS) in the ischemic retina. METHODS Retinal ischemia was induced in rats by bilateral common carotid artery occlusion (BCCAO) for various lengths of time. Using the retina after BCCAO, expression of neuronal NOS (nNOS) and inducible NOS (iNOS) and identification of their positive cells were studied by histological and immunohistochemical examinations. RESULTS Histological examinations revealed significant reduction in the thickness of the inner plexiform layer and the outer plexiform layer of the retina. Expression of nNOS was detected in retinal ganglion cells, amacrine cells, and Müller cells after BCCAO. The expression of nNOS and iNOS detected in Müller cells became stronger and persisted long after BCCAO. CONCLUSIONS In the ischemic retina, Müller cells and retinal ganglion cells expressed nNOS and iNOS. These phenomena may be involved in the ischemic damage to the retina.

Pathology of radiation myelopathy.

Radiation myelopathy is principally a white matter injury of the spinal cord induced by ionizing radiation after a certain latent period. It involves myelinated fibers and blood vessels, and the lateral funiculi is most preferentially affected. Several factors, such as radiation dose, fractionation or linear energy transfer, modify its occurrence and severity. Although glial cells and vascular endothelium are proposed to be the main targets, and to play a role in the pathogenesis of radiation myelopathy, experimental researches support that radiation‐induced vascular damage resulting in vascular hyperpermeability and venous exudation is a basic process. Effect of ionizing radiation on each cellular component of the central nervous system, their contribution to radiation myelopathy, mechanisms of selective permeability and remaining problems are discussed.

Metabolites of 5-fluorouracil, ·-fluoro-‚-alanine and fluoroacetic acid, directly injure myelinated fibers in tissue culture

Abstract The neurotoxicity of two 5-fluorouracil (5-FU) derivatives, tegafur (FT) and carmofur (HCFU), which selectively induce leukoencephalopathy involving the cerebral white matter in humans and vacuolation of myelinated fibers in dogs and cats, was examined in vitro. The common metabolites of these drugs, α-fluoro-β-alanine (FBAL) and fluoroacetic acid (FA), were added to the medium of cultured murine cerebellar myelinated fibers. On day 1 of exposure to 7 μM FBAL and FA, which corresponds to their blood concentrations 2 h after oral administration of 10 mg · kg–1 HCFU to dogs that induced central nervous system vacuolation after 30 days, partial splits of the myelinic intraperiod line were observed by electron microscopy. On days 4–7, phase contrast microscopy revealed spindle-shaped swelling and granulation of myelin and electron microscopy demonstrated prominent dissociation of the myelinic intraperiod line with monolocular and multilocular vacuolation. More severe changes, such as myelin loss, were found in cultures exposed to a higher concentration (70 μM) of FBAL and FA, but no remarkable neuronal, astrocytic or oligodendrocytic changes occurred. Quantitative evaluation of myelin injury by electron microscopy revealed significant toxicity of FBAL and FA, at concentrations of 7 and 70 μM, on day 4. However, groups treated with 0.7 μM FBAL and FA, 5-FU (7 μM) and controls exposed to β-alanine and acetic acid concentrations of 0.7, 7 and 70 μM showed no marked injury. We concluded that these anticancer drug metabolites injure myelin fibers directly, resulting in vacuolation due to myelin splitting and destruction.