Yuji Handa

Cerebral vasospasm and vasoconstriction caused by endothelin.

We investigated the histological changes between arteries constricted by endothelin for 7 days and vasospastic arteries induced by the double injection of autologous blood. Group 1 was a sham-operated group. Group 2 animals received a continuous cisternal injection of endothelin-1 (1.7 x 10(-9) mol/7 days) by a miniosmotic pump implanted in the neck musculature for 7 days. Group 3 received double injections of cisternal blood administered 48 hours apart. Angiography showed severe constriction of the basilar artery, 34.6% and 43% in Groups 2 and 3, respectively, on Day 7. Histological study showed marked constriction of the basilar artery in both Group 2 and Group 3. Degenerative changes in endothelial cells and smooth muscle cells were observed in both Group 2 and Group 3. Immunohistochemical study demonstrated endothelin-1 in the endothelial cells in Group 2, but not in Group 1 or in Group 3. It is suggested that endothelin-1 may play an important role in the pathogenesis of cerebral vasospasm.

The correlation between immunological reaction in the arterial wall and the time course of the development of cerebral vasospasm in a primate model.

To investigate the role of immunological reactions in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH), the authors studied the correlation between immune/inflammatory reactions in the arterial wall and the time course of vasospasm in primates. Twenty monkeys were divided into four groups of 5 animals each: 1) a control group of sham-operated animals, 2) animals subjected to angiography 3 days after the induction of SAH (3-day SAH), 3) animals subjected to angiography 7 days after SAH (1-week SAH), and 4) animals subjected to angiography 7 and 14 days after SAH (2-week SAH). To induce SAH, the main cerebral arteries on the right were dissected free of the arachnoid, and an autologous blood clot was placed around the arteries. To evaluate vasospasm, all animals underwent a baseline angiogram before SAH; angiography was repeated at different intervals in each group, as outlined above. Histopathological changes and the deposition of the immunoglobulin IgG in the arterial wall were evaluated immunohistochemically in each group. The cerebral arteries on the side of the clot showed evidence of mild vasospasm (-24.6% reduction) on the angiogram performed on Day 3, severe vasospasm (-51.7%) on Day 7, and mild vasospasm (-12.8%) on Day 14. The infiltration of inflammatory cells was most marked in the spastic arterial wall in the 1-week SAH group. In the 2-week SAH group, severe myonecrosis and intimal disruption were observed, even in the vessels that showed only mild vasospasm, and the inflammatory reactions had almost abated.(ABSTRACT TRUNCATED AT 250 WORDS)

Impairment of cerebral autoregulation during the development of chronic cerebral vasospasm after subarachnoid hemorrhage in primates.

We studied the impairment of autoregulation of cerebral blood flow (CBF) and its effect on the electrical activity of the brain during the development of chronic cerebral vasospasm after subarachnoid hemorrhage, using a vasospasm model in primates. Fourteen animals were divided into two groups: a clot group (8) and a sham-operated group (6). To induce subarachnoid hemorrhage, all the animals underwent craniectomy, and in the clot group, the autologous blood clot was located around the arteries dissected free from the arachnoid membrane. Cerebral angiography was performed before subarachnoid hemorrhage and 7 days after (Day 7). On Day 7, regional CBF in the parietal lobe--measured by the hydrogen clearance method--and central conduction time were studied during either graded hypertension or hypotension. In the clot group, the mean vessel caliber of the cerebral arteries on the right side (clot side) of the circle of Willis showed significant (P less than 0.01) reduction (more than 40%) as compared with the values on the contralateral, non-clot side. The values for the bilateral parietal CBF in the sham-operated group and the left parietal CBF in the clot group were fairly constant when the mean arterial blood pressure (MABP) was in the range of 60 to 160 mm Hg. In the clot group, right parietal CBF was significantly (P less than 0.05) smaller than that on the left side at an MABP level of 40 to 100 mm Hg, and increased at an MABP level of 180 mm Hg. The right parietal CBF increased as the arterial blood pressure increased, showing impairment of autoregulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Endothelin on the Canine Basilar Artery

Endothelin, a recently discovered peptide produced by endothelial cells, has been shown to have potent constrictor effects on major arteries in vitro. This experiment was performed to determine whether endothelin plays a physiological role in cerebral vasospasm after subarachnoid hemorrhage. A cisternal injection of endothelin (10(-8) mol or 10(-9) mol) caused severe vasoconstriction of the canine basilar artery. The degree of vasoconstriction was dose related and long lasting, persisting for more than 24 hours. This constriction was prevented completely by pretreatment with nicardipine (10(-8) mol). Endothelin produced a marked and transient elevation in blood pressure and might play an important role in cerebral vasospasm. Further investigation will be needed to determine the role of endothelin in the pathogenesis of vasospasm.

Dural arteriovenous malformations in the anterior cranial fossa.

Two elderly patients with dural arteriovenous malformations in the anterior cranial fossa are reported. These patients experienced rupture of the malformations at the age of 73 and 87 years. Surgical excision of the malformation was carried out on the younger patient. In the other case megavoltage x-ray therapy was applied because radical operation was not prudent. A search of the literature provided 26 other cases of this malformation involving the anterior cranial fossa. These are the first cases of rupture of arteriovenous malformation in the anterior fossa in patients over the age of 70.

Immunohistochemical and ultrastructural study of chordoid glioma of the third ventricle: its tanycytic differentiation

A chordoid glioma in the third ventricle was studied immunohistochemically and ultrastructurally. In this report, special attention is paid to the histogenesis in relation to the pathological appearance and unique anatomic location of this tumor. Light microscopic and immunohistochemical findings were similar to those reported previously. Ultrastructurally, microvilli were frequently seen, but three types of abnormal cilia were rarely observed. Basement membrane around the tumor cells and microvessels was extensive. Poorly to moderately developed intermediate (adherent) junctions were frequently seen. Resemblance of these ultrastructural features of the tumor to embryonic tanycytes suggests the tanycytic differentiation of chordoid glioma. Neuroradiologically, all of the previously reported cases of chordoid gliomas seem to arise in the anterior part of the third ventricular floor. This region includes the lamina terminalis, infundibular recess and median eminence, which corresponds to a tanycyte-rich area. These findings suggest a tanycytic origin of chordoid glioma.

Effect of cyclosporine on the development of cerebral vasospasm in a primate model.

The authors studied the effect of the immunosuppressive drug cyclosporine (CS) on the development of cerebral vasospasm after subarachnoid hemorrhage (SAH) using a primate model of vasospasm. Eighteen monkeys were randomly divided into three groups: a sham-operated control group, an SAH group, and a CS-treated group. To induce SAH, the right side of the circle of Willis was dissected free of the arachnoid and an autologous blood clot was placed around the arteries. In the CS group, CS (5 mg/kg/day) was administered intramuscularly for 7 days after the induction of SAH. The vessel caliber was evaluated on angiograms before the induction of SAH (Day 0) and 7 days after SAH (Day 7). Histological changes and the deposition of IgG in the arterial wall were studied in the three groups. The combined values of the average reduction of the right cerebral arteries at Day 7 was significant (P less than 0.05) in the SAH group (-43.3%) and in the CS group (-31.3%) as compared with the Sham group (-0.7%); however, there was no significant difference between the values in the SAH and the CS groups. In the CS group, the average reduction in vessel caliber of the right middle and anterior cerebral arteries was significantly (P less than 0.05) less than in the SAH group; this did not prove true for the internal carotid artery, however. Although the deposition of IgG in the media and an inflammatory reaction were observed in the spastic arterial wall in both the SAH and CS groups, there was no definitive difference in these immune/inflammatory reactions between the two groups. It is suggested that CS may be helpful in reducing the severity of vasospasm, but may not have a major therapeutic effect, considering its systemic toxicity.

Treatment of systemic hypertension and intracranial hypertension in cases of brain hemorrhage.

We studied the effects of nifedipine, chlorpromazine, reserpine, furosemide, and thiopental on the mean arterial blood pressure, mean intracranial pressure, and cerebral perfusion pressure in 38 patients with increased intracranial pressure resulting from either hemorrhagic cerebrovascular disease or systemic hypertension. These agents are widely used in neurosurgical practice for the treatment of systemic hypertension. Patients were assigned to two groups on the basis of their mean intracranial pressure. Group I comprised 20 patients with a mean intracranial pressure of 20-40 mm Hg (moderately increased ICP group), and Group II consisted of 18 patients with a mean intracranial pressure of greater than 40 mm Hg (severely increased ICP group). Nifedipine, chlorpromazine, and reserpine reduced mean arterial blood pressure by 18-20% in both groups (p less than 0.05 in each). In Group I these agents raised mean intracranial pressure by 10-35% and decreased cerebral perfusion pressure by 20-32% (p less than 0.05 for both), but in Group II these changes were more marked: mean intracranial pressure increased 38-64% and cerebral perfusion pressure decreased 40-54% (p less than 0.01 for both). Furosemide did not significantly reduce mean arterial blood pressure but slightly reduced mean intracranial pressure in each group. Thiopental reduced both mean arterial blood pressure and intracranial pressure in both groups. The effect on intracranial pressure was pronounced in Group II, in which mean arterial blood pressure fell by 18% (p less than 0.05) and mean intracranial pressure decreased 50% (p less than 0.01), whereas in Group I mean arterial blood pressure was reduced by 16% and mean intracranial pressure dropped 23% (p less than 0.05 in each).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of an antioxidant, ebselen, on development of chronic cerebral vasospasm after subarachnoid hemorrhage in primates

BACKGROUND Oxidation and/or free radical reactions after subarachnoid hemorrhage (SAH) may be involved in the development of chronic cerebral vasospasm. The inhibition of these reactions is thought to be one of the therapeutic strategies for prevention of cerebral vasospasm. We investigated the effect of Ebselen, a synthetic seleno-organic compound, which exhibits anti-oxidation by glutathione peroxidaselike activity to inhibit free radical reactions by lipid peroxidation on the development of chronic cerebral vasospasm in a primate model. METHODS Seventeen monkeys were used. SAH was produced by introduction of a blood clot around the right middle cerebral artery and the right side of the circle of Willis in all animals. The monkeys were randomly divided into three groups according to Ebselen dosage: 1) no dosage or non-treated group; 2) high-dose Ebselen group; and 3) low-dose Ebselen group. The drug was administered at 10 mg/Kg in the high-dose group and 5 mg/Kg in the low-dose group twice a day in each group for 7 days after SAH. The vessel diameter was evaluated on angiograms before the induction of SAH and at Day 7 following SAH. RESULTS In the untreated group, the angiograms showed significant (p < 0.05) reductions of the mean vessel caliber of the right internal carotid (ICA) (38 +/- 10% reduction) and the middle cerebral artery (MCA) (56 +/- 9.7%) compared with the baseline value before SAH. In the high-dose Ebselen-treated group, the mean percent reduction in vessel caliber of the right ICA (16 +/- 11%) and MCA (28 +/- 9.5%) on Day 7 angiograms were significantly (p < 0.05) lower than those in the nontreated group, whereas the mean percent reduction of these vessels in the low-dose Ebselen-treated group showed no significant difference compared with the untreated group. CONCLUSIONS Chronic cerebral vasospasm was inhibited in the animals in which a relatively large amount of Ebselen was administered for 7 days after SAH. The results suggest that the oxidation or free radical reaction by lipid peroxidation after SAH might be involved in the pathogenesis of vasospasm, and that inhibition of these reactions by drugs, such as Ebselen, may have a promising effect for prevention of vasospasm.

In Vivo Proton Magnetic Resonance Spectroscopy for Metabolic Changes in Brain during Chronic Cerebral Vasospasm in Primates

OBJECTIVE To study how neuronal cells are affected by development of chronic cerebral vasospasm after subarachnoid hemorrhage (SAH), the changes in neuronal metabolites during development of vasospasm were evaluated by in vivo localized proton magnetic resonance spectroscopy (MRS) in primates. METHODS SAH was produced by introduction of a blood clot around the right middle cerebral artery and the right side of the circle of Willis. MRS experiments were performed before SAH and on Days 7 and 14 after SAH. Multislice magnetic resonance images were obtained to locate the volume of interest (1.0 cm3) in the bilateral parietal regions. The peak areas for choline compounds, the sum of creatine and phosphocreatine, and N-acetyl-aspartate were calculated. RESULTS Angiograms revealed approximately 50% reduction of vessel caliber for the right main cerebral arteries on Day 7. Magnetic resonance imaging revealed no apparent cerebral infarction, even in the spasm-side hemisphere. MRS revealed a significant (P < 0.05) reduction of the N-acetyl-aspartate/creatine and phosphocreatine ratio on Days 7 and 14 and a significant increase in the choline/creatine and phosphocreatine ratio on Day 7, in the spasm-side parietal region. In the sham-operated animals, there were no significant changes in these ratios in the bilateral parietal region on Days 7 and 14 after the operation. CONCLUSION The results suggested that the development of cerebral vasospasm after SAH caused ischemic injury in a subpopulation of neuronal cells, even when no apparent cerebral infarction was shown. Proton MRS may be useful to evaluate how neuronal cells are affected by the ischemic insult during development of vasospasm in clinical situations.