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We herein present a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), who developed serious acute renal failure with lactic acidosis, followed by rhabdomyolysis. Despite receiving intensive care, he suffered multiple cardiopulmonary arrests and died 10 days after presentation due to a sudden deterioration of his symptoms. Renal pathology revealed diffuse tubular necrosis with interstitial edema and tubular dilatation on light microscopy, and a severe degeneration of intracellular organelles on electron microscopy. These pathological findings could have resulted from multiple cardiopulmonary arrests; however, we must be aware of the extremely rare but sudden occurrence of these fatal conditions in MELAS patients.

Respiratory insufficiency is a critical problem in amyotrophic lateral sclerosis (ALS) patients. We herein present the case of an autopsied patient with sporadic ALS who underwent diaphragm pacing (DP). The pathology showed several localized adhesions with a markedly atrophied diaphragm. A marked loss of motor neurons with Bunina bodies and phosphorylated TDP-43 positive inclusions was found in the spinal cord and primary motor cortex. Mild hyalinization and a few multinucleated giant cells were present around the electrode tracks in the diaphragm. However, no infiltration of inflammatory cells was detected. Our findings suggest that full-time DP might not cause severe damage to adjacent diaphragm tissue.

●Abstract● Purpose: A case of multiple brain infarction caused by embolism of a chondroma in the left vertebral artery is reported. Case presentation: A 38-year-old woman was admitted for cerebral infarction. On angiography, a round filling defect was observed in the V2 segment of the patent left vertebral artery, thought to be a floating embolus. The patient was successfully treated with embolectomy by means of endovascular procedures immediately after angiography. Histopathologic evaluation indicated the embolus to be a piece of chondroma. Conclusion: Cerebral embolism from tumor, especially chondroma, is extraordinarily rare. The source of the embolism in this patient is thought to most likely be the heart.

An autopsy case of diffuse axonopathic leukoencephalopathy induced by drug treatment is reported. A 70-year-old woman with multiple myeloma developed encephalopathy several days after completing a course of intravenous human immunoglobulin (IVIg) and granulocyte-colony stimulating factor (G-CSF), and died within I month. T2-weighted MRI demonstrated multifocal high-signal areas in the bilateral cerebral white matter, especially in the right frontal lobe. Neuropathologically, multifocal hydropic axonal swelling with a poor glial reaction was recognized diffusely in the bilateral deep cerebral white matter, being especially marked in the frontal lobe. The cortex, subcortical U-fibers, corpus callosum, and anterior commissure were spared. The cerebellar white matter also showed similar changes, albeit less marked, but the brainstem was spared. Microscopically, the myeloma involvement of the CNS was limited to the dura, and the cerebral arteries showed slight atherosclerosis, but neither thrombi nor angitis. This case, although ultimately fatal, neurologically and neuroradiologically resembled reversible posterior leukoencephalopathy syndrome (RPLS) induced by IVIg and/or G-CSF, and the nature and selective distribution of the neuropathological changes suggested that the pathogenesis involved vasospasm of the bilateral internal carotid artery and the main trunks of the cerebral arteries, due to unknown cause, inducing ischemia in the deep white matter, which is supplied by long nutrient arteries.

The influence of chronic hypertension (HT) on the cerebral and renal arteries was examined pathologically and morphometrically in wild cats without a specific genetic background. Chronic HT for 8-15 months was induced by uninephrectomy and salt-loading, and the blood pressure was monitored for a maximum of 5 months. The grade of systolic blood pressure elevation in each cat during the monitoring period was 21-51 mmHg. Histologically, the cerebral arachnoid and medullary arteries of all hypertensive cats showed a well-preserved medial layer, and neither loss of medial smooth muscle cells, adventitial fibrosis or fibrinoid exudation was detected. This experimental model of chronic HT in wild cats for 8-15 months induced segmental intimal elastofibrosis of the arachnoid and renal arteries, but spared the cerebral medullary artery. The parenchymal changes in the brain were negligible. Morphometrically, the arachnoid artery in control cats had a significantly thinner media than the renal artery, and the medial hypertrophy of the arachnoid artery resulting from HT occurred significantly less frequently than that of the renal artery. These findings suggest that the arachnoid and medullary arteries are relatively well protected from HT, and that this may be characteristic of cerebral arteries in general and ascribed to autoregulation.

In neural tissue injury many pathological processes are common to different neurological disorders, including cerebral ischemia. Because ischemia has a fundamentally simple impact on neural tissue, good laboratory modeling can help improve the general understanding of the neuropathological processes involved. Summarized here are some basic principles that should be followed to ensure that cerebral ischemia studies are reproducible and informative: (i) selection of an appropriate model of cerebral ischemia in an appropriate species (although rodents are widely used for genomic studies, the use of larger animals, with brain structures macroscopically similar to those of humans, is appropriate for many studies, e.g. of white matter lesions or the pathophysiology of cerebral edema); (ii) correct maintenance of physiological parameters, including body temperature, systemic blood pressure, and blood gas tensions, under appropriate general anesthesia; (iii) selection of an appropriate method of cerebral blood flow (CBF) monitoring (decisions include whether or not the experiment requires real-time monitoring, in vivo measurement, and CBF mapping); (iv) appropriate timing of drug application in therapeutic studies (many drugs that are effective when given immediately after a short period of ischemia are ineffective in clinical trials, probably because of longer periods of ischemia and delayed drug delivery in clinical settings); and (v) multiparametric evaluation of therapeutic effect (with the recent increase in diagnosis of cases of mild stroke, measurement of mortality and infarct size have proven to be insufficient for the evaluation of therapeutic effect). Use of mild ischemia models and batteries of neurological tests for individual neurological functions, such as motor, somatosensory, and visual function, are becoming important in experimental ischemia research. In histological evaluation, assessment of the extent of both selective neuronal loss and the infarct will become mandatory. Regional analysis of each brain structure and coordination of the results with the apparent neurological dysfunction is a promising approach.

Heavy-ion irradiation/Delayed encephalopathy/Delayed myelopathy/Brain edema/Hyperpermeability. Aim: The pathogenesis of delayed encephalopathy induced by heavy-ion irradiation was investigated experimentally in cats. The left cerebral hemispheres were irradiated with 15-40 Gy of heavy ions (carbon), and histologically and morphometrically examined 12 months later. Results: In the irradiated cerebral white matter the following occurred as the dose increased: astrocytic swelling, then the dilatation of small blood vessels with a fibrous thickening of the wall, and then loosening of the white matter with cavity formation and diffuse albumin deposition. Pathological features of these cavities suggested that they are induced by long-standing edema. Although the dilated vessels were arteries, veins, and capillaries, arteriovenous shunt and damage of the smooth muscle cells of the arterial media were absent. Changes of the cerebral cortex were scarce. Morphometrically, the irradiated cerebral white matter was swollen, and the capillary density tended to be reduced in the deep cortex and subcortical white matter, but this effect was not dose dependent. Conclusion: Heavy-ion irradiation induces delayed encephalopathy in cats, preferentially involving the white matter. The cardinal pathogenesis was long-standing edema of the white matter due to vascular hyperpermeability, and the vascular dilatation seemed to be caused by a reduction in the vascular bed and/or hemoconcentration due to hyperpermeability.

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 CO 2 levels and systemic blood pressure in CADASIL.

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 Muller cells after BCCAO. The expression of nNOS and iNOS detected in Muller cells became stronger and persisted long after BCCAO. Conclusions: In the ischemic retina, Muller cells and retinal ganglion cells expressed nNOS and iNOS. These phenomena may be involved in the ischemic damage to the retina.

The etiopathogenesis of multiple spongy necrosis (MSN) of the pontine base was analyzed by examining the spatial relationship with intra- and extrafascicular vascular structures by reconstruction of serial sections of nine lesions from three autopsy cases. All nine lesions in the fascicles were distributed without any spatial relationship to the intrafascicular vessels. Instead, these lesions were distributed in parallel with arterial and venous transverse main branches between the anteromedial and anterolateral groups of the pontine vessels. On the other hand, all lesions in the middle cerebellar peduncle were arranged obliquely along the arterial and venous main trunks of the lateral group vessels with sparing of the perivascular narrow zone of the white matter. Moreover, narrow fascicles, even though located in the dorsomedial region of the pontine base, which is consistently involved in MSN, were spared, and thick transverse and longitudinal fascicles were selectively involved. The marginal zone of fascicles was spared, and focal coagulation necrosis was sometimes found in MSN lesions. Additionally, normal fascicles did not have their own nutritional arteries, and were nourished by arterioles and capillaries from the surrounding pontine gray matter. Neither severe organic stenosis nor occlusion of pontine vessels was found. On the basis of the close topographical relationship of MSN lesions with the pontine vascular architecture in addition to preferential involvement of thick fascicles with sparing of the marginal zone and inclusion of focal coagulation necrosis, it is proposed that the etiopathogenesis of MSN is pontine ischemia on a background of the characteristic parenchymal and vascular architecture of the pontine base. As to the cause of the ischemia, it is proposed that some functional disorder such as arterial vasoconstriction in the pontine base or the vertebrobasilar artery is responsible, rather than organic changes in the vessels.

A 40-year-old woman who developed intestinal dysmobility was found, at rectal biopsy, to have marked microvacuolation of mucosal muscle layer cells, which corresponded to increased accumulation of abnormal mitochondria. Skeletal muscle biopsy specimens showed ragged-red fibers, vessels strongly reactive for succinic dehydrogenase, and focal deficiency of cytochrome c oxidase. Autopsy performed at the age of 50 revealed prominent accumulation of abnormal mitochondria in the intestinal smooth muscle cells with a mottled distribution of focal necrosis, multiple small cerebral infarcts with diffuse neuronal loss, and rarefaction of the perivascular white matter. Mitochondrial DNA analysis showed a point mutation at position 3243. This case, showing features of both mitochondrial neurogastrointestinal encephalomyopathy and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), indicates that routine intestinal biopsy can detect mitochondrial encephalomyopathy with gastrointestinal involvement. The main intestinal changes were extensive accumulation of abnormal mitochondria in the leiomyocytes and scattered focal necrosis.

Changes in the blood-brain barrier (BBB) of the rat spinal cord after irradiation with heavy ion were investigated ultrastructurally and immunohistochemically by using SMI 71, a monoclonal antibody against rat endothelial barrier antigen (EBA); anti-ZO-1, a polyclonal antibody against endothelial tight junctions, anti-rat serum to extravasated serum, and anti-vascular endothelial growth factor (VEGF). The lower thoracic and lumbar cord of male Wistar rats was singly irradiated with a carbon beam at a dose of 30 Gy. Rats were sacrificed before or after the onset of hind limb paralysis. Histologically, white-matter vacuolization was observed from 13 weeks after irradiation, and white-matter necrosis was first noted at 17 weeks. SMI 71 staining was decreased or lost 13 weeks after irradiation, just prior to the formation of white-matter necrosis, and was almost completely lost in the center and periphery of the white-matter necrosis. Although ZO-1 expression and tight junctions in the ultrastructure were preserved at that time, serum leakage occurred almostly completely in parallel with the changes in EBA. Therefore, carbon-ion irradiation at a dose of 30 Gy induces BBB breakdown 13 weeks after irradiation. The SMI 71-negative blood vessels were sparsely distributed throughout the entire white and gray matter, and there was no evidence of preferential localization. Immunostaining of smooth muscle actin showed that most of the SMI 71-negative blood vessels were veins or capillaries. These findings suggest that the hyper-permeability of the veins and/or capillaries that occurs after a certain latent period is one of the important factors in the pathogenesis of delayed radiation injury by carbon ions, the same as by X-rays. Radiation-induced functional disturbances of the endothelium and involvement of cytokines such as VEGF are suspected of being the cause of such vascular hyper-permeability.

We analyzed the mechanism of the selective vulnerability in the midbrain which results in the inferior colliculus being affected, but the adjacent superior colliculus usually being spared, in thiamine-defkient encephalopathy. After first confirming in an in vivo experiment that the same selective vulnerability occurs in weanling rats, fragments of the superior and inferior colliculi of embryonic day 18 of fetal rats were cultured in nutrient medium for three weeks and then cultured in a thiamine-free medium with or without the addition of pyrithiamine in concentrations of 10-7 mol/L, 10-5 mol/L, and 10-4 mol/L, for a maximum of two additional weeks. In vitro, as early as the third day of thiamine deficiency, ultrastructural examination showed hydropic swelling of the neuronal processes and then of the perikarya that later resulted in cell death in the superior and inferior colliculi. In contrast to the in vivo findings, the astrocytes and oligodendrocytes were relatively preserved. These changes occurred equally in both cultured tissue of the inferior colliculus and of the superior colliculus. It was confirmed in an in vitro recovery experiment that these changes were attributable to thiamine deficiency, not pyrithiamine-toxicity, and that their severity paralleled the concentration of pyrithiamine. On the basis of these findings, two possible mechanisms are proposed to explain the selective vulnerability of the inferior colliculus in thiamine-deficient encephalopathy: (i) functional and/or structural specificity of the blood vessels in the inferior colliculus; or (ii) peculiarities of the neuronal inputs into it.

A 5-year-old boy with Werdnig-Hoffmann disease (WHD), who had been mechanically ventilated for the majority of his life, was examined pathologically. In addition to the classic features of WHD, extensive sensory involvement, including pronounced glial bundle formation in the posterior nerve root, severe demyelination of the posterior column in the whole spinal cord and thalamic neuronal loss were observed. Mechanical ventilation for 5 years prolonged the patient's survival beyond its natural course and produced the unusual pathological findings such as the phrenic motoneuronal loss and severe diaphragmatic and intercostal muscle atrophy. This also appeared to be responsible for the extensive sensory involvement. Data from this case and from previous reports show that WHD is a potential multisystem disorder affecting primarily, but not exclusively, the motor system. We observed marked neuronal accumulation of eosinophilic intracytoplasmic granules in the oculomotor nucleus, substantia nigra, locus ceruleus and nucleus raphe pontis, which appeared as intramitochondrial electron-dense granules on electron-microscopy and myoglobin-positive granules by immunostaining.

Recently cases of ganglioneurocytoma and cerebral neurocytoma, very rare variants of central neurocytoma, have been reported. The former is characterized by differentiation toward ganglion cells and the latter by extraventricular origin in the cerebrum, but their existence as distinct clinicopathological entities, is controversial. We report an unusual case of neurocytoma, which arose extraventricularly from the frontal lobe, formed a large cystic lesion and showed ganglioid differentiation, in a 11-year-old girl. Following subtotal tumor resection, she showed a satisfactory clinical course and no evidence of recurrence. This is a very rare case of central neurocytoma-like tumor outside the ventricular system and also of ganglioneurocytoma. This case may provide some insight into the tumorigenesis and widen the clinicopathological concept of neurocytoma.

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, alpha-fluoro-beta-alanine (FBAL) and fluoroacetic acid (FA), were added to the medium of cultured murine cerebellar myelinated fibers. On day 1 of exposure to 7 microM 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 microM) 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 microM, on day 4. However, groups treated with 0.7 microM FBAL and FA, 5-FU (7 microM) and controls exposed to beta-alanine and acetic acid concentrations of 0.7, 7 and 70 microM showed no marked injury. We concluded that these anticancer drug metabolites injure myelin fibers directly, resulting in vacuolation due to myelin splitting and destruction.

The pathogenesis of delayed radiation injury was examined experimentally. Exposure fields in the thoracic and lumbar spinal cords of 54 adult female specific pathogen-free Wistar rats were X-ray irradiated. The rats were observed clinically and pathologically for up to 6 months after irradiation and the relationships between the chronological progress of paralysis and pathological findings and between vascular and parenchymal changes were analyzed by reconstructing serial spinal cord sections.

We examined regional differences in the activity of a mitochondrial respiratory enzyme, succinic dehydrogenase (SDH), in the hippocampi of normal and postischemic gerbils, using a quantitative imaging method. Gerbils ( n = 21) without ischemia, and gerbils which had experienced 5 rnin of bilateral common carotid artery occlusion 12 h or 2 days previously, were sacrificed. Coronal sections of the brains were prepared for quantitative imaging of SDH activity and histological examination. In the control gerbils, SDH activity in the pyramidal cell layer of the CA 1 sector (Sommer's sector) was 106.3 ± 10.3% (mean ± SD; SDH activity as a percentage of the cerebellar SDH activity), which was lower than in the other subfields of the hippocampus. SDH activity in the oriens layer, stratum radiatum and lacunosum molecular layer of the CA 1 sector was lower than in the corresponding layers of the CA 2 and CA 3 sectors. After transient ischemia, SDH activity remained unchanged in the CA 1 sector. Histologically, selective neuronal necrosis was observed in the pyramidal cell layer of the CA 1 sector 2 days after ischemia. The observed low level of this mitochondrial respiratory enzyme in the pyramidal cell layer of the CA 1 sector should be taken into account as a possible trigger of the selective vulnerability of the region to ischemia.

The neuroprotective properties of glutamate receptor antagonists arise from their ability to antagonize the excitotoxic actions of endogenous excitatory amino acids. However, J. W. Olney et al. (1989, Science 224: 1360-1362) have reported that MK-801, an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, induced morphological damage in neurons in the cerebral cortex of rats. YM90K is a potent alpha-amino-3-hydroxy-5-methylisoxazole propionic acid receptor antagonist which has high neuroprotective efficacy against delayed neuronal injury. The purpose of this study was to investigate whether YM90K induces a vacuolar reaction in the cytoplasm of neurons similar to that seen after the administration of MK-801. All experiments were performed on female F344 rats. YM90K was administered by iv infusion for 3 h at the dose of 40 mg/kg/h. MK-801 was given by single sc injection at the dose of 1 mg/kg. All rats receiving MK-801 showed neuronal vacuolation. The affected neurons were recognized as medium-sized pyramidal-shaped neurons which were distributed between layers II and IV in the posterior cingulate and retrosplenial neocortices. Most of these vacuoles contained multiple small and round structures that appeared to be remnants of mitochondria. Other vacuoles were recognized as enlarged sER or those present within the bilaminar nuclear membrane. MK-801 also induced heat shock protein immunoreactivity in the same neurons. In contrast, no such pathomorphological changes could be detected in the YM90K-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The nature and distribution of vascular changes in acute Wernicke's encephalopathy (WE) were analyzed in three autopsy cases. Lesions of the lateral vestibular nucleus of the medulla oblongata (three cases) and lateral ventricular wall (one case) were examined by reconstruction of 200 serial sections, and the capillary diameter in the tegmentum of the medulla oblongata was measured morphometrically in all cases. The vascular changes commonly found in and around the parenchymal lesions in all cases were: (1) dilatation and endothelial swelling of almost all vessels ranging from small arteries to veins, being especially severe with undulation in small arteries and arterioles, and (2) fibrinoid degeneration and hemorrhage involving selectively the arterioles and capillaries on the arterial side. These vascular changes in the medulla oblongata were essentially the same as those in the third ventricular wall, but differed in their severity. Capillary diameter in these cases was significantly larger than that in seven control cases. Such vascular changes, especially a dysoric change on the arterial side, could not be ascribed to secondary change following changes in the parenchyma, and were, therefore, considered to be a lesion essential to WE, as in the case of the parenchymal lesion.

We have reported an autopsy case of primary granulomatous angiitis of the CNS preferentially involving the small veins with a granulomatous leukoencepalitis-like lesion in the cerebral white matter of a 48-year-old man. The latter lesion was ischemic necrosis due to circumferential multiple perivenous granulomas in the adjacent Virchow-Robin space. Multifocal progressive involvement of venular adventitia by granulomas, leaving behind mural fibrosis and luminal stenosis, was related clinically to the prolonged stepwise deterioration observed in the patient, and pathologically to diffuse loosening with dilated veins in the deep cerebral white matter and subcortical hemorrhagic infarction in the left parietal lobe through chronic venous stagnation. PCR demonstrated negativity for Mycobacterium tuberculosis and Propionibacterium acnes, and in situ hybridization with EBV-encoded small nuclear RNA probe was also negative. The possibility of subarachnoidal latent infection with an unknown avirulent agent causing exclusively perivascular granulomas is proposed. It will be necessary to examine by autopsy whether the type (artery or vein) and size of the involved vessels and the pathological subtype of angiitis is related to the etiopathogenesis and prognosis. It is also pointed out that the entity of lymphocytic angiitis is problematic.

We have reported an autopsy case of primary granulomatous angiitis of the CNS preferentially involving the small veins with a granulomatous leukoencepalitis-like lesion in the cerebral white matter of a 48-year-old man. The latter lesion was ischemic necrosis due to circumferential multiple perivenous granulomas in the adjacent Virchow-Robin space. Multifocal progressive involvement of venular adventitia by granulomas, leaving behind mural fibrosis and luminal stenosis, was related clinically to the prolonged stepwise deterioration observed in the patient, and pathologically to diffuse loosening with dilated veins in the deep cerebral white matter and subcortical hemorrhagic infarction in the left parietal lobe through chronic venous stagnation. PCR demonstrated negativity for Mycobacterium tuberculosis and Propionibacterium acnes, and in situ hybridization with EBV-encoded small nuclear RNA probe was also negative. The possibility of subarachnoidal latent infection with an unknown avirulent agent causing exclusively perivascular granulomas is proposed. It will be necessary to examine by autopsy whether the type (artery or vein) and size of the involved vessels and the pathological subtype of angiitis is related to the etiopathogenesis and prognosis. It is also pointed out that the entity of lymphocytic angiitis is problematic.

Direct effects, especially the distribution of medial thickening due to chronic hypertension on the renal arterial tree, were examined pathologically and morphometrically in cats with one-kidney DOCA-salt hypertension. Twenty-one adult male cats were divided into three groups: (i) an experimental group of one-kidney DOCA-salt hypertension (12 cats): (ii) a uninephrectomized group without administration of DOCA and salt (four cats); and (iii) a group without uninephrectomy and administration of DOCA and salt (five cats). The duration of hypertension varied from 3 weeks to 4 months and the aortic blood pressure was monitored every 5 min. The increase of mean blood pressure (MBP) of the experimental group was 15-44 mmHg. A significant medial thickening of the right renal arterial tree was evaluated by a comparison of the right and left regression lines of each case between the midwall radius (R) and medial thickness (D) of arteries in a distended state. The evaluation was made separately for arteries with R values above or below 40 microns, because a regression line between R and D showed a maximum bend at a level of R from 30 to 40 microns. The arteries of the right kidney with a diameter less than 40 microns, corresponding to the interlobular arteries and afferent arterioles, showed significant medial thickening in six cases. Medial thickening was absent in other cats of the experimental group and cats of a control group given uninephrectomy alone. Increase of MBP during the hypertensive phase of these six cases was above 34.6 mmHG and all values of other cats without medial thickening were below this level.(ABSTRACT TRUNCATED AT 250 WORDS)

The cellular binding sites of an antineuronal antibody were characterized in an autopsy case of the paraneoplastic encephalo-myelo-ganglionitis. A 61 year-old woman developed a subacute sensorimotor polyneuropathy and, later, multiple involvement of cranial nerves, disturbance of consciousness, and generalized seizure. An autopsy revealed a small cell lung carcinoma and neuropathological changes that included disseminated encephalitis, spinal anterior horn lesions, severe loss of dorsal root ganglion neurons, and secondary degeneration and loss of the nerve fibers in the spinal posterior column and peripheral nerves. The serum IgG from the patient contained antineuronal antibody(s) including an antibody to 35- to 37-kDa neuronal antigens called anti-Hu as demonstrated in Western blot. In immunohistochemical studies, the serum IgG immunostained neurons of the brains, spinal cords, and dorsal root ganglia of humans or rats. Confocal laser-scanning microscopy revealed binding of the patient's IgG in the neuronal nuclei and cytoplasm, but not in the nucleoli. In immunoelectron microscopic studies, immunolabelling with the IgG was found diffusely in the karyoplasm, excluding nucleoli, and in the cytoplasmic matrix between the cisternae of the reticulums, Golgi apparatus, and mitochondria. Encephalo-myeloganglionitis is a clinicopathological entity frequently associated with the presence of neoplasm and antineuronal antibody, however, the role of the antibody in the pathogenesis remains to be elucidated.

Cerebral hypoxia and ischemia are two of the most common disorders of the central nervous system. The pathomechan-ism has been a focus of interest in neuroscience for many years not only because of the clinical significance but also because of the peculiar distribution of the lesion (selective vulnerability) depending on the type of injury. This article reviews recent advances in the study of hypoxia-induced tissue injury of the central nervous system.

An experimental model for induction of gliomas corresponding to human anaplastic astrocytomas and glioblastomas is reported. Eleven week old F344 and ACI rats were given 100 or 200 p.p.m. N-methyl-N-nitrosourea (MNU) solution as their drinking water for 42 weeks. Gliomas were induced at very high incidences (82.5-92.5%) in each group. Induced gliomas showed apparent evidence of morphologic malignancy by an analysis based on diagnostic criteria of human astrocytomas. All of the gliomas from the killed animals were classified histologically into subtypes according to the classification scheme used in the diagnosis of human gliomas. The majority of macrotumors more than 1 mm in diameter in both strains were diagnosed as anaplastic astrocytomas and glioblastomas. Immunohistochemically, tumor cells in these tumors were almost negative for glial fibrillary acidic protein, while ultrastructurally neoplastic astrocytes contained glial filaments. A strain difference was observed in the ratio of histological subtypes of macrotumors. In F344 rats, astrocytic tumors diagnosed as anaplastic astrocytomas and glioblastomas of an astrocytic type formed the majority, whereas glioblastomas of mixed oligo-astrocytic type predominated in ACI rats. The results indicate that MNU-administration to adult F344 rats may provide a suitable experimental model for gliomas which occur in adult humans.

We re-examined the measurement of the mass flow ratio at model bifurcations as a function of the inlet Reynolds number, which has been used to study the role of arterial bifurcation in distal blood supply. However, this relationship was found not to be applicable to investigations of blood circulation, because the measured mass flow ratio is strongly dependent on the resistance downstream of the bifurcation, and therefore is specific to the experimental set-up. An alternative approach for studying the role of arterial bifurcation is presented, in which the flow division ratio is used as a parameter.

The neuropathological features of the central nervous system in 15 autopsy cases of Japanese male with AIDS were reported. Nine patients had various histological changes including a variety of opportunistic infections in six patients (40%), primary malignant lymphoma of the brain in two (13%), AIDS encephalopathy in four (27%) and vacuolar myelopathy in one (7%). Usually, these pathological changes were present concomitantly. AIDS encephalopathy was characterized by infiltration of mono- and multinucleated cells and myelin pallor with astrogliosis located predominantly in the cerebral white matter and subcortical gray matter. Furthermore, unevenly distributed neuronal loss of the cerebral cortex was apparent in one case. Diffuse astrocytosis of the gray matter out of proportion to neuronal loss was also an outstanding finding in another case. The present study suggested that not only the white matter changes but also gray matter alterations might be the morphological substrates of AIDS encephalopathy.

The pathogenesis of dementia associated with Fabry disease was examined neuropathologically in an autopsy case. The patient was a 47-year-old computer programmer who developed renal failure at the age of 36, necessitating peritoneal dialysis, and thereafter suffered in succession episodic pulmonary congestion, bradyacusia, heart failure, and dementia, before dying of acute myocardial infarction. MRI of the brain demonstrated leuko-araiosis. The CNS parenchyma showed widespread segmental hydropic swelling of axons in the bilateral cerebral and cerebellar deep white matter in addition to neuronal ballooning due to glycolipid storage in a few restricted nuclei and multiple tiny lacunae. Hydropic axonal swelling was also sparsely distributed in the pyramidal tract, pedunculus cerebellaris superior and brachium colliculi inferioris, but wallerian degeneration of these tracts was absent. Additional features included angiopathy of the subarachnoidal arteries due to Fabry disease, such as medial thickening resulting from glycolipid deposition in smooth muscle cells (SMCs) and adventitial fibrosis with lymphocytic infiltration, together with widespread subtotal or total replacement of medial SMCs by fibrosis, associated with prominent intimal fibrous thickening and undulation of the internal elastic membrane of medium-sized (1000-100 microm diameter) arteries. The findings in this case suggest that axonopathic leukoencephalopathy due to multisegmental hydropic swelling of axons in the bilateral cerebral deep white matter is responsible for the dementia associated with Fabry disease, and may be caused by ischemia resulting from widespread narrowing and stiffening of medium-sized subarachnoidal arteries and progressive heart failure.

Two 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.

脳腫瘍45例における細胞塗抹標本を免疫細胞化学的に検討してみた.GFAPではependymomaを含めたglia系腫瘍に陽性であり, それ以外の腫瘍との鑑別に有用と思われた.またgliomaにおいては悪性度が高くなるにしたがい不均一性となり減少傾向を示した.NFPはglioblastomaの一部の症例とpituitary adenomaに陽性であり, glioblastomaにおいては異分化への発現が示唆された.VimentinはgliomaにおいてGFAPと逆相関する形で陽性となり, glioma細胞の脱分化が示唆された.Cytokeratinはmetastatic carcinomaとpituitary adenomaのみに認められ, 他の脳腫瘍との鑑別に有用と思われた.NSEは特異性を示さず多くの脳腫瘍に陽性であった.S-100はmetastatic carcinomaのみに陰性を示した.また染色性の違いにより細胞像がよく類似するmeningiomaとneurinomaとの鑑別にも有用と思われた.

Binswanger's disease (BD) is not rare in the aged. The aim of the present study was to compare the etiopathogenesis of BD of the aged (aged-BD) with that of classic-BD, with the aid of morphometry of the arterial medial thickness and reconstruction of the cerebral medullary arteries using serial sections from five autopsy cases. The age range of the aged-BD cases was 73-89 years. The mean heart weight of these cases was 296 g, in contrast to 391 g of the five age-matched cases of hypertension without diffuse myelin loss and atrophy of the cerebral white matter (HT). Although significant medial hypertrophy of the subarachnoid and medullary arteries was not found in all aged-BD cases, differently from classic-BD, all five cases of aged-BD commonly presented significantly widespread loss of the medial smooth muscle cells (SMC) of the medullary arteries as compared with HT, similar to the case in classic-BD. The etiopathogenesis of aged-BD is common to that of classic-BD; stiffening caused by hypertensive changes of the medullary artery, especially SMC loss, is responsible for the diffuse myelin loss and atrophy of the cerebral white matter of BD, rather than grade of hypertension itself or hypertensive medial hypertrophy. As the mechanism of such an especially severe involvement of the cerebral medullary artery in BD, some genetic abnormality in the functional response or vulnerability to hypertension of the artery should be considered.

Hypertension (HT) is a serious risk factor of not only cerebral infarction and bleeding, but also Binswanger's encephalopathy (BE). In BE especially, severe stiffening of the cerebral medullary arteries because of hypertensive changes with loss of medial smooth muscle cells (SMC) occurs, which induces diffuse atrophy of the cerebral white matter. But, it is not yet ascertained whether HT is particularly severe in BE. Therefore, a spectrum of the pathological changes of the cerebral arteries were investigated by reconstruction of serial sections and morphometry of the medial thickness in five autopsied patients with malignant nephrosclerosis (MN) of exacerbated form. Each presented clinically acute progression of long-standing HT at the terminal stage and pathologically typical renal changes. The heartweight was 380-900 g. Morphometry of the medial thickness of the arachnoid arteries presented significant medial hypertrophy in four cases of MN, but in the medullary arteries it presented in only two cases with marked cardiomegaly of 700 g and 900 g. In four cases of MN, only a few medullary arteries showed slight pathological changes. However, in another case with cardiomegaly of 900 g, all 10 medullary arteries showed multiple segments of atheroma, medial SMC loss, and prominent dilatation; edematous concentric intimal fibrosis with luminal obstruction and atrophy of the white matter were absent. In conclusion, only one case of MN showing marked cardiomegaly of 900 g presented severe pathological changes of the cerebral medullary arteries comparable with those of BE, although other MN-cases showing severe cardiac hypertrophy presented only trivial arterial changes. Therefore, the cerebral medullary artery seems to be protected from HT, yet it is involved in a case of severe and long-standing HT inducing an extreme cardiomegaly.

¶A 17-year-old boy with epileptic seizures due to meningio-angiomatosis without neurofibromatosis type 2 is presented. Low grade astrocytoma in the left temporal lobe was resected when he was 11 years old. A recurrence was suspected on following-up MRI and a positive PET scan with 11C-methionine PET 6 years later around the resected area. The language area was mapped using H2 15O PET activation technique. The lesion was completely resected while preserving the verbal area assisted by three-dimensional imaging protocol of MR-registered PET. The patient was well and seizure-free for 8 years thereafter without antiepileptic drugs. Histologically, there was an increase of dilated arterioles and meningothelial cell-like spindle cells around them, which are characteristic pathological features of meningio-angiomatosis. It is most likely that angiomatous tissue developed perivascular meningiomatous components and formed the meningio-angiomatosis in our presented case. In addition, we presented our protocol of functional neuro-imaging which was useful in terms of the functional neurosurgery.

Background and Purpose— With advances in the therapy of stroke at the postacute phase, the use of animal models for chronological and region-specific evaluation of neurological function has become increasingly important. Our aim was to test long-term behavioral dysfunction in gerbils after focal ischemia and to correlate the results with the regional distribution of infarction in the coordinating cortical regions. Methods— Repetitive unilateral hemispheric ischemia (two 10-minute occlusions, 5-hour interval) was induced in Mongolian gerbils. The elevated body swing test (EBST), bilateral asymmetry test (BAT), and T-maze test were performed to assess asymmetrical motor behavior, somatosensory deficit, and spatial cognitive dysfunction during 4 weeks after ischemia. The results were correlated against the regional infarction volume of the primary motor, somatosensory, and primary visual cortices at 4 weeks after ischemia. Results— In all postischemic gerbils, persistent sensorimotor and cognitive dysfunctions were detectable throughout the postischemic period. Histological examination revealed that a cortical zone of infarction surrounded the selective neuronal death in the ipsilateral cerebral hemisphere. The regional infarction volumes of the primary motor, somatosensory, and visual cortices were significantly correlated with the scores of the EBST, BAT, and T-maze test, respectively. These combinations had the highest regression coefficient of all pairs. Conclusions— Postischemic motor and somatosensory functions were significantly correlated with regional infarction volumes in the corresponding cortical regions. In gerbils, visual abnormality could be independently detected by the T-maze test. Such regional analyses of ischemic lesions would be useful for investigating the functional outcomes of stroke therapy.

The purpose of the present study was to examine the role of histamine in the pathogenesis of experimental thiamine-deficient encephalopathy. By studying sagittal serial sections the authors were able to examine the topographical relationship between histamine-positive neurons and fibers, the number of mast cells, and localized lesions in the thalamus (TH) and inferior colliculus (IC). Adult rats were given a thiamine-deficient diet and pyrithiamine was given intraperitoneally (30 microg/100 g bodyweight per day), and the distribution of vulnerable regions and petechial bleeding was histologically examined by reconstruction of the sagittal serial sections. The distribution of mast cells and histamine-positive neurons and fibers was examined immunohistochemically in control rats, and compared between the vulnerable and non-vulnerable regions of the TH and tectum. Changes in the aforementioned measures during the thiamine-deficient state were also examined. The blood-brain barrier was examined using antibodies against rat endothelial barrier antigen (EBA) and albumin. The density of histamine-positive fibers in the vulnerable regions of the TH and IC was very low and not different from the non-vulnerable regions, and the number of mast cells was significantly higher in the lateral portion of the TH than the medial portion of the TH. The numbers of mast cells increased on days 7-10 after the start of the experiment, and significantly decreased on days 14-21. Histamine-positive neurons and fibers in the TH and IC also had the same changes. Bleeding of the IC occurred exclusively around arteries, and perivenous bleeding was absent. Albumin exudation and suppression of EBA expression of capillaries were found in the spongy lesions of the TH and IC. The role of histamine in selective vulnerability of the TH and IC in experimental thiamine-deficient encephalopathy was not supported. Findings in the present study suggest that the spongy change is a primary event, and vascular changes are secondary.

Endovascular treatment with Guglielmi detachable coil has been developed as a less invasive treatment for cerebral aneurysm. The aim of this study is to clarify the mechanism of the preventive effect of coil embolization.Two aneurysm models were employed. One was a T-shaped bifurcation tube with a spherical dome made of glass, which was used for the measurement of pressure and visualization of flow pattern. The other model was a T-shaped glass tube with a spherical elastic silicone dome, which was used for the measurement of aneurismal wall displacement due to pulsation of flow.1, Guglielmi detachable coil caused no change in intra-aneurismal fluid pressure. 2, Coil insertion obstructed and slowed intra-aneurismal flow. This flow stagnation in the aneurysm might promote thrombus formation. 3, With increase in numbers of coils anchored at the intra-aneurismal wall, the displacement of the wall was considerably depressed. This suggests that coil insertion decreases the stress on the aneurismal wall.1, Coil insertion depresses the pulsatile aneurysm wall movement, and diminishes the stress of the aneurysm wall. 2, Coil insertion obstructs intra-aneurismal flow and facilitates thrombus formation in the aneurysm. These two factors may operate synergistically to prevent aneurysm rupture.

The aim of the present study was to elucidate the relationship between specific tasks and the responsible ischemic lesions after experimentally induced cerebral hemispheric ischemia in Mongolian gerbils. We used the elevated body swing test (EBST) to evaluate asymmetry motor behavior, the bilateral asymmetry test (BAT) to evaluate sensory dysfunction, and the T-maze test to assess cognitive deficit during 4 weeks after either 10-min single unilateral carotid artery occlusion (sCCAO) or 10-min repeated unilateral occlusion (rCCAO). rCCAO produced persistent sensorimotor and severe cognitive deficits. Infarction was confined to the ipsilateral cerebral cortex, hippocampus, dorsolateral nucleus of thalamus and caudate nucleus. sCCAO did not induce sensorimotor abnormalities, but did produce mild cognitive deficits; these animals also showed increased locomotor activity during the early post-ischemic period. In sCCAO, neuronal death was confined to the ipsilateral CA1 sector of the hippocampus. Thus, unilateral CA1 neuronal death was sufficient for evolution of cognitive deficits in this model of experimental focal ischemia. Ischemic lesions extending to the ipsilateral cerebral cortex, basal ganglia, and hippocampus produced persistent and severe sensorimotor impairment accompanying severe cognitive deficits. These findings regarding region-specific behavioral tasks in cerebral ischemia will facilitate improved assessment of stroke therapy.

By experiments of acute carbon-monoxide intoxication, acute nitrogen hypoxia and histotoxic hypoxia using sodium cyanide in cats, and by hemodynamic studies using plastic branch models, the following was elucidated; (1) severe tissue bypoxia, regardless of the underlying cause, and subsequent slight ischemia of the brain due to mild hypotension induce selective involvement of the cerebral white matter and pallidum, these two conditions being necessary and sufficient and this encephalopathy should be separately categorized as “hypoxic-ischemic encephalopathy” in hypoxic brain injuries, (2) the background of the selective involvement of these structures is an enormous development of the cerebrum in the brain, which induces thick white matter resulting in proper and long medullary artery, and especially small diameter ratio of the pallidal perforators to the middle cerebral artery, (3) the long course of the medullary artery produces the blood pressure drop in the deep white matter according to Hagen-Poiseuille’s low, and according to that the smaller the diamter ratio, the larger the branching-loss coefficient (energy-loss coefficient), smaller diameter ratio of the pallidal perforator, as compared with that of the putaminal perforator, induces more severe loss of the local blood flow selectively to the pallidum. This state seems to be a failure of compromise between the cardiovascular system and the brain parenchyma.

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.

Surgical specimens of four adult cases of cerebral pial arteriovenous malformation (AVM) were examined by reconstruction of serial sections to disclose the actual anatomical structure and to analyze the mechanism of gradual growth and rupture. More than seven arteriovenous shunts (AV-shunts) per case were found in all four cases, and these were divided into two types; one or a few shunts larger than 700 microm, and those with several shunts smaller than 700 microm in diameter. The former were located exclusively in the subarachnoid space and showed severe mural fibrosis. The vessels just ahead of and just behind these segments were also markedly involved by so-called arterialization of the vein and segmental loss of the internal elastic membrane (IEM), and/or smooth muscle cells (SMCs) and aneurysm formation of the artery. However, the smaller shunts were mainly localized in the cerebral parenchyma, where dilated small arteries showed abrupt loss of IEM and gradual loss of SMCs and transformed into dilated and tortuous veins, and the mural fibrosis was mostly absent at the shunts and segments ahead of and behind these shunts. It is suggested, on the basis of these findings, that AV-shunt of pial AVM occurs first in the subarachnoid space, probably prenatally, and gradually dilates along with developement of the brain and body, and that the subsequent abnormal burden of the blood inflow to the peripheral or related territory secondarily induces formation of new small AV-shunts mainly in the parenchyma. This secondary shunt formation may also be a component of growth of pial AVM in adults. Moreover, our reconstruction study suggested that hemorrhage of AVM is caused by rupture of not only dilated veins, but also intranidal microaneurysms and that thrombosis is not always necessary.

A new syndrome of ataxia and retinitis pigmentosa with vitamin E deficiency caused by the missense mutation of alpha-tocopherol transfer protein (alpha-TTP) gene was recently proposed. After studying the first postmortem case with this mutation pathologically and biochemically, whether the symptoms can be treated by supplementation of vitamin E or not is discussed. The major pathological findings were retinal atrophy; severe dying back-type degeneration of the posterior column; and massive accumulation of lipofuscin in neurons including dorsal root ganglion (DRG) cells, which were almost identical to those in vitamin E deficient animals and patients with fat malabsorption. Also, mild loss of Purkinje cells was noted. Because robust expression of alpha-TTP was detected in the cerebellum as well as in the liver and the tissue concentration of vitamin E in the cerebellum was still low even after oral supplementation, the mild Purkinje cell loss might be related to the mutant alpha-TTP in the cerebellum. By contrast, in the DRG, thought to be mainly responsible for ataxia, no expression of alpha-TTP was detected, and the tissue concentration of vitamin E increased to normal after supplementation. It is therefore considered that oral supplementation of vitamin E should effectively counteract the progression of ataxia.

Object. The authors examined the correlation between changes in the apparent diffusion coefficient, regional water content, and tissue ultrastructure after vasogenic brain edema.Methods. Vasogenic edema was induced in the white matter of six cats by cortical cold lesioning. The trace of diffusion tensor (Trace[D]) obtained from magnetic resonance imaging to measure the orientationally averaged water diffusibility was compared with the corresponding tissue water content determined by gravimetric studies and with ultrastructural water localization. Edema fluid had spread to the subcortical and deep white matter by 4.5 hours postlesioning. The increase in Trace(D) showed a significant linear correlation with the increase in tissue water content, both in the subcortical and deep white matter as follows: y = 45.5x − 2367 (r = 0.94) and y = 37.0x − 1769 (r = 0.93), respectively, where x is the water content (gram water/gram tissue) and y the Trace(D) (× 10−6 mm2/second). On histological examination, nerve fibers were found to be dissociated in the white matter and the extracellular space was markedly enlarged with protein-rich fluid. No noticeable hydropic swelling of the cellular components was observed.Conclusions. A linear correlation was observed between increases in Trace(D) and increases in extracellular water volume in in vivo vasogenic brain edema. A similar correlation between the subcortical and deep white matter showing different arrangements of nerve fibers (parallel compared with intermingled, respectively) indicated that measurement of Trace(D) is a suitable parameter for the evaluation of vasogenic brain edema.

Early detection of irreversible neuronal change after transient cerebral ischemia is important so that adequate treatment can be initiated within the therapeutic window. We have examined the correlation between changes in middle-latency auditory evoked potentials (MAEPs) and histological changes in the auditory cortex of awake Mongolian gerbils subjected to 4 min or 12 min of transient cerebral ischemia. Post-ischemic MAEPs were characterized by the appearance of a markedly large negative and positive component at approximately 17-22 ms latency in both groups. Delay in the appearance of the high amplitude (maximal amplitude at 45 min after recirculation in the 12-min ischemia group) precedes the slowly developing death of neurons in the auditory cortex that results from transient cerebral ischemia.