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金沢大学医薬保健研究域医学系, 金沢大学附属病院脳神経外科, A 16-year-old girl presented with multiple cerebral cavernous angiomas with calcifications due to repeated hemorrhages and a thrombosed cerebral arteriovenous malformation (AVM). Her 18-year-old elder sister also had multiple cerebral cavernous angiomas associated with calcifications, which suggested presence of repeated previous hemorrhages. Surgical removal via a right occipital craniotomy resulted in a good outcome. The histological diagnosis was thrombosed AVM. Evaluation of congenital vascular anomaly needs to take into consideration the combination of other congenital vascular anomalies and their familial occurrence.

金沢大学医薬保健研究域医学系, 金沢大学附属病院脳神経外科, An 81-year-old female presented with a giant aneurysm of the distal anterior cerebral artery (A3) which grew from a small saccular aneurysm to a huge aneurysm within 36 months before manifesting as a mass lesion. The thrombosed portion of the aneurysm showed growth, whereas the aneurysmal cavity did not change in size. Computed tomography and magnetic resonance imaging showed new bleeding in the thrombosed portion. Hemorrhage into the thrombus and/or aneurysmal wall might have caused the aneurysmal growth. She refused surgery and was discharged with no deficits. Distal anterior cerebral artery aneurysm which shows neuroimaging signs of growth requires regular follow up as such lesions may become giant before manifesting clinical symptoms.

金沢大学医薬保健研究域医学系, 金沢大学附属病院脳神経外科, The relationship between the grade of astrocytic tumor and the expression of deoxyribonucleic acid methyltransferase (DNA-MTase) gene was examined. The levels of DNA-MTase messenger ribonucleic acid (mRNA) were measured by semiquantitative reverse transcriptase-polymerase chain reaction in surgical specimens from 12 astrocytic tumors (4 astrocytomas, 6 anaplastic astrocytomas, and 2 glioblastomas) and two normal brain tissues, and in four glioma cell lines. Compared to normal brain tissues, the levels of DNA-MTase mRNA were increased by 16- to 55-fold in low grade astrocytomas, and significantly increased by 200- to 4500-fold in high grade astrocytomas (anaplastic astrocytomas and glioblastomas) and more than 4500-fold in glioma cell lines. In situ hybridization with paraffin-embedded surgical specimens of human astrocytic tumors showed DNA-MTase mRNA was abundantly expressed in high grade astrocytomas. The detection of increased DNA-MTase expression in astrocytic tumor indicates involvement in the tumorigenesis and suggests that blocking of this change with specific inhibitors may offer new therapeutic strategies for malignant astrocytic tumors.

Combination therapy with radiation and (1-4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)3-nitrosourea hydrochloride (ACNU) and/or N1-(2'-tetrahydrofuryl)-5-fluorouracil (5-FU) was given to 102 patients with malignant gliomas. The purpose of this study was to evaluate the efficacy of two treatment protocols after operative resection as compared with the control treatment, radiotherapy+5-FU. The three protocols were (A): adequate operation (OP)+radiation (R) (40-60 Grey/6-7 weeks)+ACNU [1-3 mg/kg, intravenously (IV) or intraarterially (IA), two times with a week interval, and repeated after 6 months]±OK-432 (2.0 “Klinische Einheit” or clinical unit/week, intramuscularly), (B): OP+R+ACNU (1-3 mg/kg, IV or IA, two times with 6-8 weeks interval, and repeated after 6 months)+5-FU (8-16 mg/kg/day orally)±OK-432, (C): OP+R+5-FU. The combination therapy with ACNU and radiation significantly improved survival time as compared with protocol (C) (p

Sequential structural changes in endothelial cells after temporary arterial clipping were studied by both scanning and transmission electron microscopy. A Heifetz clip with an occlusive pressure of 120g was applied to the carotid arteries of 33 Wistar rats for 30 minutes. The animals were sacrificed at the following intervals after clipping: 0, 1, 3, 6, and 24 hours and 3, 5, 7, 14, and 30 days. Immediately after removal of the clip, there was severe endothelial desquamation, with platelets adhering to the exposed subendothelium. Three days after clipping, repair of the endothelium was accomplished by replication of adjacent undamaged endothelial cells and was completed within 1 week. Immature regenerating cells were characterized by numerous microvillous projections at the luminal surface. These projections were approximately 100 to 150nm in width and 0.2 to 1μm in length. The immature endothelial cells contained well developed rough endoplasmic reticulum and many free ribosomes but contained few Weibel-Palade bodies and pinocytotic vesicles. However, as the endothelial cells matured, pinocytotic vesicles and Weibel-Palade bodies increased, whereas microvillous projections decreased. Within 14 days of clipping, the microvillous projections had disappeared and the endothelial cells appeared normal. These data indicate that the endothelial damage caused by temporary arterial clipping does not result in thrombus or atherosclerotic lesions and is repaired within approximately 14 days.

Histological changes of the cerebral arteries taken from 3 patients who died of cerebral vasospasm after subarachnoid hemorrhage were investigated and compared with those of 10 dogs with experimental vasospasm induced by a subarachnoid injection of 0.15-0.20 mgkg of epinephrine. The cerebral arteries of the human autopsy cases known to have undergone spasm exhibited a wide lumen with thin media resulting from necrosis of the smooth muscle cells. These necrotic smooth muscle cells were replaced by scattered, eosinophilic cellular debris, especially in the outer layer of the media. In the experimental study, the subarachnoid injection of epinephrine produced frank necrosis of the smooth muscle cells and marked dilatation of the arterial lumen, especially in 5 dogs, and was associated with hypothalamic infarctions and inflammatory swellings of small subarachnoid arteries. Dogs sacrificed artificially revealed myonecrotic changes that were uniformly and intensely stained with eosin, whereas those of spontaneous death revealed myonecrosis similar to human autopsy cases. It is suggested that myonecrosis might be formed as a result of prolonged, intense contraction induced by epinephrine as well as by vasoactive exudates from the hypothalamic lesions or the small subarachnoid arteries.

Local fibrinolytic activity is studied to explain the physiopathogenesis of chronic subdural hematoma. 1. Using FDP-kit (Wellcome, England), FDP levels in hematoma fluid and serum are determined in 15 cases with unilateral hematoma and a case with bilateral hematoma. The FDP values in all hematomas are higher than 20 μg/ml. Two cases show the FDP values over than 320 μg/ml. The FDP values in hematoma fluid is always higher than that in serum of the same patient. The FDP values in hematoma fluid correlate to the volume of hematoma in fluid type subdural hematomas. 2. The levels of fibrinolytic activity in hematoma fluid and plasma are determined in 12 cases with subdural hematoma by Enzo-diffusion fibrin plate (Hyland, U.S.A.). Active plasmin, available plasmin and total plasminogen in hematoma fluid are not found in all cases with subdural hematoma. The fibrinolytic activity in hematoma fluid is remarkably lower than that in plasma in all cases. Absence of plasminogen might be for consumption. 3. The amounts of tissue active plasmin in 7 cases and tissue plasminogen activator in 8 cases are measured by modified Astrup's method. Tissue active plasmin levels in dura maters, outer membranes and inner membranes are 3.7-7.2 mm (average 6.1 mm), 4.3-6.5 mm (5.5 mm) and 0-4.8 mm (1.7 mm), respectively. Tissue plasminogen activator levels in dura maters, outer membranes and inner membranes are 0-5.5 mm (average 2.7 mm), 3.3-8.1 mm (6.1 mm) and 0 mm, respectively. The tissue activator level is highest in the outer membrane. 4. Fibrinolysis autography by Todd's method demonstrates the remarkable fibrinolysis around the vessels of outer membrane. The fibrinolysis in tissue increases with time. 5. After clotting of subdural hemorrhage, capsule (grows out) from the dura mater. Then tissue plasminogen activator in outer membrane would activate fibrinolytic system in order to absorb subdural clot. If the fibrinolytic activity is adequate, the clot could be absorbed. If the fibrinolytic activity is excess, it would inhibit the coagulating system in vessels of outer membrane and so that the continual or intermittent bleeding from outer membrane would occur into subdural cavity. As the result, the FDP levels in hematoma fluid increase and the amounts of plasminogen decrease for consumption. Such fibrinolytic bleeding from outer membrane of hematoma induces gradually the enlargement of hematoma and clinical symptoms appear after a latent interval.

金沢大学医薬保健研究域医学系, 金沢大学附属病院脳神経外科, The authors describe an autopsy case of cerebellar hemorrhagic infarction in the region of the bilateral superior cerebellar arteries (SCA). A 79-year-old woman suddenly developed dysarthria, bilateral blepharoptosis, external ophthalmoplegia, left hemiparesis, dysphagia and dysuria. CT scan revealed low density in the bilateral cerebellar hemisphere. Angiography revealed narrowing of the distal portion of the basilar artery. The patient made a gradual recovery in the first two weeks, but she died of hyperglycemic non-ketotic diabetic coma on the 32nd day. Autopsy disclosed recent hemorrhagic infarctions of the bilateral SCA regions and of right Ammon's horn and numerous softenings of the brain stem, together with an old cystic infarction in the region of the middle cerebral artery. There were no occlusions in either the basilar or superior cerebellar arteries. It was suggested that an embolization due to severe atherosclerosis of the distal portion of basilar artery affected its pontine branches and bilateral SCA.

The authors report the role of local inflammatory mechanisms in outer membranes to define the physiopathogenesis of the chronic subdural hematoma enlargement. The outer membranes in 20 adult patients of chronic subdural hematoma were investigated by means of light and electron microscopy. Microscopically, perivascular small hemorrhage and hemosiderin as well as fibroblasts, hemosiderin-laden macrophages, eosinophiles and plasma cells were found around the sinusoidal channels. Perisinusoidal hemorrhage, especially red blood cells were, usually, separated from the hematoma cavity by the fibrous layer. Several sinusoids could be seen coalesced to form multiple small cavities in outer membranes, with a fibroblast like lining. Such small hemorrhagic cavities, although not often, may rupture to communicate with the hematoma cavity. Ultrastructurally, the endothelial cells of sinusoids were rich in organelles, especially rough E.R., free ribosomes, mitochondrias, pinocytotic vesicles, and endothelial specific bodies. The site of vascular leakage was identified in several sinusoids as an endothelial gap, in the range of 1-8 μ in diameter, presumably formed by separation at intercellular junctions. Perivascular exudation of plasma lead to destruct the extracellular matrix of the sinusoidal layer. Extensive accumulations of endogenous amorphous material and irregularly arranged thin collagen fibers showed interstitial edema. Fibroblasts manufacture tropocollagen molecules within the activated rough E.R., which are then secreted onto the cell surface and gradually polymerized into visible microfibrils and collagen fibers. Interstitial edema, ultimately, disappears in the fibrous layer. The fibrous layer is generally characterized by numerous collagen fibers, fibroblasts, serum proteins and only a few capillaries, some of which show direct openings into the hematoma cavity. Some perivascular edematous fluid in the sinusoidal layer may pass through the fibrous layer into the hematoma cavity. Under scanning electron microscopy, red blood cells and fibrin strands or sheets were seen especially around the outlets of the fibrous layer capillaries. The results indicate that outer membranes, once developed, enlarge chronic subdural hematoma by ruptures of small hemorrhagic cavities formed in outer membranes, direct hemorrhage from the fibrous layer capillaries, and exudation of perisinusoidal edematous fluid into the hematoma cavity.

A comparative study was made of the capsular vessels of acute subdural hematoma in its chronic healing stage and those of chronic subdural hematoma. In acute subdural hematoma in the chronic healing stage, the capsular vessels were formed secondary to hematoma. Microscopically, they were often streamlined with perivascular lymphocytic cuffings. They had scant blood components and demonstrated almost no perivascular hemorrhage. Electronmicroscopically, the endothelial cells were thick with numerous swollen mitochondria, enlarged rough endoplasmic reticula and free ribosomes. The capsular vessels seemed to be tight, as the endothelial cells were coated by fibrinoid material and had numerous tight junctions. In the chronic subdural hematoma, the capsular vessels or sinusoids were formed preceding hematoma. Microscopically, their lumina showed balloon-like enlargement and were surrounded by flattened endothelial cells. They had both perivascular hemorrhage and accumulation of various inflammatory cells. Electronmicroscopically, the endothelial cells were thinner and some had clear cytoplasms. Most characteristic was the frequency of endothelial gap junctions. The sinusoids seemed to be fragile, playing an important role in the enlargement of this hematoma.

Light and electron microscopic studies were conducted on myonecrosis following cerebral arterial spasm in meningitis. A 34-year-old female developed fever, headache and vomiting. Neurological examination revealed a drowsy state, nuchal stiffness and hemiparesis. Spinal puncture revealed a purulent fluid containing 1, 219/mm3 cells. She deteriorated steadily into semicoma 10 days after onset. Computerized tomography scan showed low density areas in bilateral basal ganglia and cerebellar hemispheres. Angiography showed vasospasm of the major cerebral arteries and vasodilatation of the left Sylvian arteries. Repeated angiography two months after onset showed a diffuse narrowing of these arteries. She died of uncal herniation 67 days after onset. Autopsy two hours after death disclosed softening in the territories of spastic arteries. Microscopically, the circle of Willis showed concentric stenosis due to an intimal proliferation. The media was remarkably atrophied and fibrotic with an infiltration of polymorphonuclear leucocytes. Electron-microscopically, the media disclosed numerous degenerating or necrotic smooth-muscle cells. The degenerating cells showed dissolution of myofilaments with resultant fine granular or filamentous material. The necrotic cells were abundant in vacuoles, lysosomes and dense bodies. The cytoplasm was eventually replaced by cellular debris and numerous collagen fibrils.

Cranial meninges of humans were studied by electron microscopy after fixation in situ and histochemical demonstration of nicotinamide-adenine dinucleotide diaphorase within mitochondria. There was an intimate fusion between the innermost portion of the dura mater (dural border cells) and the outermost portion of the arachnoid (arachnoid barrier layer). Cranial meninges did not contain a true subdural space, when specimens were well prepared with spatial relationships preserved. If cleavage had occurred during preparation, the subdural space was artificially formed by the separation of dural border cells, because the latter showed a paucity of intercellular contacts and weak collagenous reinforcements. The arachnoid barrier layer was a squamous layer of elongated cells with numerous tonofilaments, desmosomes and tight junctions. There was a lining of junctional devices between the innermost two cell layers. There was a number of extracellular lacunae, being separated by interdigitations and containing collagen fibrils, elastins, granular material and matrix vesicles with or without psammoma bodies. The mitochondrial enzymes of this layer showed negative activity in intact specimens, but a positive one in cleaved dural border cells and arachnoid trabecular cells. An incomplete basement membrane covered the innermost aspect of this layer. The arachnoid trabecular cells generally had electron-lucent cytoplasm with a few tonofilaments. The cells beneath the arachnoid barrier layer had oval nuclei and wide cytoplasm containing numerous mitochondria. This layer was anchored by flattened or button-shaped pedicles, otherwise these cells formed an epithelial cluster. The cells lying within the subarachnoid space had elongated nuclei and cytoplasmic projections. The arachnoid trabeculae consisted of both a network of arachnoid trabecular cells and interwoven collagen fibrils. Alternating with these cells were numerous resting macrophages.

金沢大学医薬保健研究域医学系, 金沢大学附属病院脳神経外科, The capsule of a retrocerebellar glio-ependymal cyst, which was incidentally found in a 54-year-old asymptomatic female, was studied by both light and electron microscopy. Microscopically, the capsule measured 25-400 ﾎｼm in thickness and consisted of four layers. The external covering was an arachnoid cell layer abutting on the thick connective tissue with scattered vessels, whereas the luminal lining was a layer of ependymal cells abutting on the glial tissue. The ependymal cells were cuboidal in shape and some, but not all, were ciliated. The glial tissue underneath the ependymal lining contained numerous corpora amylacea, especially in its abluminal side. Electronmicroscopically, the arachnoid cell layer consisted of both arachnoid epithelium and the underlying arachnoid cells. The former showed a relatively higher electron density than the latter. There was a distinct basement membrane between them. In the former, a moderate number of desmosomes and intermediate junctions assured contacts between the arachnoid cells. In the latter, there were many extracellular clefts containing numerous collagen fibrils and microfibrils. Neighboring cytoplasmic processes often formed interdigitations. The luminal surface of ependymal cells displayed variable numbers of microvilli with or without cilia, whereas the abluminal surface abutted directly on the astrocytic processes of the glial layer. There were some interdigitations of the plasmalemma of adjacent cells, with surface specializations consisting of fasciae adherentes joined by gap junctions. Two or more adjacent cells contributed to the development of microrosettes, packed with both numerous surface microvilli and several profiles of cilia. The corpora amylacea varied 5-15 ﾎｼm in diameter and consisted of randomly oriented filaments with the fine osmiophilic granules. The fibrillar elements within the processes of the fibrillary astrocytes swept around the corpora amylacea or impinged upon the latter. Although their outline was usually smooth and clearly demarcated, no membrane or space intervened between the corpora amylacea and the surrounding structures. It is most probable that the present glio-ependymal cyst arose from the displaced segment of the wall of the neural tube, which corresponds to the sites from which the tela chorioidea forms.

The relationship of clinical manifestations to hematoma volume and regional cerebral blood flow (r-CBF) was analyzed in 65 adult patients with chronic subdural hematoma (CSH). Hematoma volume was measured in computed tomographic scan images with a semi-automatic analyzer (Leitz ASM), and r-CBF by 133Xe inhalation method. Headache, hemiparesis, and later consciousness impairment occurred with increase of hematoma volume. Headaches due to increased intracranial pressure were common in younger patients, while a third of the aged cases with neurological deficits complained of no headaches. Older patients who retained CSH over 3 months showed mental symptoms. Neurological deficits occurred in cases with over 95 ml of hematoma in the 40 to 60-year age group, and over 120 ml with those aged over 60 years. The degree of the midline shift in unilateral CSH was not always correlated with hematoma volume. Such differences in the critical hematoma volume and the degree of midline shift were probably due to age-dependent changes in the brain weight and intracranial free space. Twenty cases with unilateral CSH showed bilateral decrease in r-CBF. The r-CBF in the hemiparesis group decreased especially at the frontal and parietal lobes, ipsilateral to the hematoma.

564 patients with subarachnoid hemorrhage caused by ruptured cerebral aneurysm were studied statistically with a correlation between retinal hemorrhage (RH) and outcome. Of these, 142 patients (or 25%) exhibited RH. No correlation was demonstrated between the frequency of RH and age or sex. Unilateral RH was seen in 34 patients with middle cerebral artery or internal carotid artery aneurysm and out of them, 25 patients (or 74%) had RH in the aneurysm side. The mortality rate of the patients with RH was 35% which is higher than that of patients without RH (13%). Of the 93 survivors with RH, 68 patients (or 73%) required daily-care. In contrast, out of 367 survivors without RH, 124 patients (or 34%) required daily-care. There was a significant correlation between the severity of RH and survival rate or activities of daily living, although there was no difference in the outcome between the patients with unilateral and bilateral RH. There were 15 cases (or 2.7%) with Terson's syndrome (TS). The mortality rate of patients with TS was 20% and all of the 12 survivors required daily-care. It is concluded that ruptured cerebral aneurysms with RH show a poorer prognosis than those without RH.

Among 126 cases of chronic subdural hematoma, 6 cases (4.8%) were diagnosed as acute subdural hematoma in chronic stage. They were 3 males and 3 femals whose age ranged from 46 to 79 years (average 62.8 years). All of them received major trauma to the head, but surgical treatment was not necessary until a mean period of 22.7 days, ranging from 17 to 30 days. Acute subdural hematoma in its chronic stage has subdural granulation tissue similar to that of the outer membrane of chronic subdural hematoma. This membrane was formed in the dural surface of the hematoma and was partially liquefied near the arachnoidal surface, but none of them had a macroscopically well-formed inner membrane. The subdural granulation tissue was of irregular thickness ranging from 1-2 mm, and was tightly adhered to the hematoma. Histologically, the granulation tissue consisted mainly of old fibrous connective tissue, having less capillaries than the outer membrane, and with scant blood components and few inflammatory cells. Pigments such as hemosiderin or hematoidin, and macrophages laden with these pigments accumulated in the granulation tissue, while new hemorrhagic foci were rare around the capillaries. The border layer between the subdural granulation tissue and the hematoma was generally irregular and not clearly discriminated, where many fibroblasts with mitotic figures and the macrophages irregularly accumulated. Thus, acute subdural hematoma in chronic stage differed from chronic subdural hematoma, both in its clinical and pathological aspects. The results suggest that the existence of an inner membrane plays an important role in defining the chronicity of subdural hematomas. It is advisable to investigate not only the clinical course, but also the existence of an inner membrane and the histology of the subdural granulation tissue in order to differentiate acute subdural hematoma in chronic stage from chronic subdural hematoma.

Relationship of clinical manifestations to regional cerebral blood flow (r-CBF) was analyzed in 21 adult patients with unilateral chronic subdural hematoma (CSH) before and after operation. The r-CBF was measured by the 133Xe inhalation method and was represented by the initial slope index from Fourier analysis. All the cases showed bilateral decrease in mean hemispheric CBF (mCBF) values, and in 90% of cases the m-CBF values of compressed side by the hematoma were less than or approximately equal to those of contralateral side. The m-CBF values of all the patients with headaches and 56% of cases with neurological deficits stayed within age-matched normal values. The preoperative r-CBF values in the headache group were normal in all detector sites of bilateral hemispheres, while those in the hemiparesis group decreased, especially at the Rolandic motor and sensory area of the hematoma side, which normalized with neurological recovery after hematoma evacuation. In the groups of consciousness disturbance and mental symptom, preoperative r-CBF patterns, which normalized after operation, could be divided as follows: 1) bilateral and total decrease below normal value; 2) no local decrease from the normal value. Some cases showed the relative decrease in r-CBF at a part of frontal lobe. It is suggested that neurological deficits of CSH result from the local circulatory disturbance of blood flow at the brain cortex compressed by hematoma.