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Nimodipine Treatment in Poor-Grade Aneurysm Patients

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Cerebral perivascular nerves in subarachnoid hemorrhage

A histochemical and immunohistochemical study

Hideaki Hara, Michael Nosko, and Bryce Weir

✓ The authors have studied the changes induced by subarachnoid hemorrhage (SAH) in the density and distribution of cerebral perivascular nerves in monkeys and rats. The SAH was induced in monkeys by placement of an autologous blood clot after opening the basal cisterns over the arteries of the circle of Willis on one side. In the rat study, SAH was induced by injection of autologous arterial blood into the cisterna magna. The nerves examined were adrenergic nerves, acetylcholinesterase (AChE)-containing nerves, vasoactive intestinal polypeptide (VIP)-like immunoreactive nerves, and substance P-like immunoreactive nerves. In the monkey study, all animals underwent baseline cerebral angiography, then had repeat angiography just before sacrifice on Day 2, 7, 28, or 70 after SAH. Two sham-operated monkeys underwent the surgical procedure without clot placement and were sacrificed on postoperative Day 7, after repeat angiography. Clot placement in monkeys reduced staining of all middle cerebral artery (MCA) perivascular nerves for between 2 and 28 days post-SAH. The number of stained nerve fibers of MCA's on the non-operated side was slightly reduced on Days 2 and 7 after SAH. Sham-operated monkeys showed a mild reduction of staining in all nerves, but only on the operated side. Cerebral vasospasm was observed on all angiograms taken on Days 2 and 7 following SAH. No vasospasm was found in normal or sham-operated monkeys. The disappearance of nerve staining without associated vasospasm was found on the operated side of the sham-operated monkeys and on the clot side of the animal sacrificed on Day 28 after SAH. Rats sacrificed on Days 2 and 7 post-SAH showed reduction in adrenergic and VIP-like immunoreactive staining around basilar arteries, while nerves containing AChE were not affected. Saline-injected rats exhibited no change in the appearance of perivascular innervation. These results suggest that SAH as well as surgical manipulation of the vessel wall caused a reduction of the studied substances in cerebral perivascular nerves. This reduction in immunoreactive staining of perivascular nerves did not correlate with the development of angiographic vasospasm after SAH.

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A randomized placebo-controlled double-blind trial of nimodipine after SAH in monkeys

Part 1: Clinical and radiological findings

Francisco Espinosa, Bryce Weir, Thomas Overton, William Castor, Michael Grace, and Donald Boisvert

✓ The authors have developed a method to induce chronic cerebral vasospasm after subarachnoid hemorrhage (SAH) in monkeys. With microsurgical techniques, 33 monkeys had a frontotemporal craniectomy and unilateral opening of the subarachnoid cisterns. Cerebrospinal fluid was drained and a fresh hematoma, obtained from an average of 7 ml of autologous blood, was carefully placed against the major arteries of the anterior circulation on one side. The 30 monkeys studied for 7 to 14 days after the SAH were allocated randomly to two treatment groups of 15: one group received placebo and the other nimodipine, 1 mg/kg every 8 hours. Indices monitored before and after SAH included neurological status, cerebral blood flow, computerized tomography, and angiographic vessel caliber.

In the placebo group, delayed ischemic neurological deficit developed in one monkey 4 days after clot placement and was present at sacrifice on Day 14. No such deficit occurred in the nimodipine group. The effect of nimodipine on vessel caliber at this dosage was equivocal. Significant vasospasm (31% to 100% reduction in vessel caliber) developed in 87% (26 of 30) of the animals. Overall, vasospasm was slightly more common in the placebo group: in this group, on Days 7 and 14, the incidence of vasospasm was significantly higher (p < 0.05) than in the nimodipine group. However, the average percentage reduction in vessel caliber of the maximally constricted vessel in each monkey was not significantly different between the two groups.

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A randomized placebo-controlled double-blind trial of nimodipine after SAH in monkeys

Part 2: Pathological findings

Francisco Espinosa, Bryce Weir, Theodor Shnitka, Thomas Overton, and Donald Boisvert

✓ Chronic cerebral vasospasm was induced in monkeys by placement of an autologous blood clot after the basal cisterns had been opened over the arteries of the circle of Willis on one side. The experimental protocol was detailed in Part 1 of this paper. Twenty of the 30 monkeys studied from both groups (one receiving placebo and the other nimodipine) underwent cerebral fixation (Day 14) at controlled pressure by intra-arterial perfusion. The arteries at the base of the brain were studied by light microscopy and scanning (SEM) and transmission electron microscopy (TEM). Cerebral angiography on Day 7 showed that vasospasm was significantly more common (p < 0.0001) and more severe (p < 0.01) on the clot side compared to the control or non-clot side. Vasospasm was less severe on Day 14, just before sacrifice. On SEM, 80% of the 20 middle cerebral artery (MCA) specimens that had been in spasm (Day 7) showed marked corrugation, and in some the endothelium had a fish-scale appearance. All of the 10 MCA's on the clot side examined by TEM that had been in spasm (Day 7) showed marked changes such as endothelial swelling, subendothelial proliferation, corrugation of the elastic lamina, and myonecrosis. With few exceptions, none of the basilar arteries or MCA's on the non-clot (control) side showed any abnormalities. The pathological findings of vessels in spasm were considered to be slightly less severe in the nimodipine group; however, the trial drug (1 mg/kg/8 hrs) did not prevent such abnormalities from occurring. The ultrastructural changes in the arterial walls of specimens from both placebo and nimodipine groups in vasospasm are described. Since dramatic changes are present in the vessel walls even after radiologically visible vasospasm has almost completely abated, we believe that vasospasm is due to long-lasting smooth-muscle constriction and not to vessel wall thickening caused by a cellular or subcellular infiltrate.

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Intraventricular hemorrhage from ruptured aneurysm

Retrospective analysis of 91 cases

Gerard Mohr, Gary Ferguson, Moe Khan, David Malloy, Reginald Watts, Brien Benoit, and Bryce Weir

✓ Intraventricular hemorrhage (IVH) from aneurysm rupture is generally considered to be of grave prognostic significance. Ninety-one cases have been studied retrospectively from seven medical centers. The overall mortality rate was 64%. The dramatically poor condition of these patients leads to their rapid admission to the hospital. Eighty-seven percent were admitted on Day 0 or 1, and more than half were classified neurologically as Grade 4 or 5. A multiple regression analysis explained 56% of the variance in survival, using the variables of ventriculocranial ratio (VCR), day of admission, diastolic blood pressure, location of aneurysm, associated intracerebral hematoma, age, grade on admission, sex, and systolic blood pressure. No patient with a VCR of more than 0.25, as calculated from the initial computerized tomography (CT) scan, survived. No patient whose smallest VCR was 0.23 or more survived. This ratio can be simply measured with a millimeter ruler from the CT scan. Patients with IVH usually had enlarged ventricles, even initially. The overall results suggest that early management of intracranial hypertension should be more generally considered, although even when this was done the prognosis was still guarded. The timing of surgery was not an important determinant of outcome, although a significant number of patients died awaiting surgery.

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Timing of surgery for intracerebral hematomas due to aneurysm rupture

Brian Wheelock, Bryce Weir, Reginald Watts, Gerard Mohr, Moe Khan, Michael Hunter, Derek Fewer, Gary Ferguson, Felix Durity, Douglas Cochrane, and Brien Benoit

✓ Intracerebral hematomas (ICH) from aneurysm rupture are not rare and can now be diagnosed easily and accurately by computerized tomography. The authors have collected 132 such cases from 11 medical centers. Of these patients, 38% died prior to discharge from the hospital. Seventy-eight percent of cases were admitted to the neurosurgical services on Day 0 or 1 after rupture of the aneurysm; of these patients, 15% died without surgery, 28% had surgery and died postoperatively, and 57% were operated on and survived. Mortality rates were increased in patients who were hypertensive, had poor neurological grades, showed evidence of brain herniation, or had larger clots. If the patient lived beyond the first few days and did not have brain herniation, the timing of surgery was not of great consequence, although there was a tendency toward lower morbidity in earlier surgery. This was true despite the fact that earlier operations were carried out on an initially sicker group of patients. Ischemic deterioration attributed to vasospasm occurred in 26% of cases; even when deaths at the acute stage were excluded, it was no more common in patients with early than in those with late surgery. Morbidity and mortality rates were prohibitively high in operations consisting solely of evacuation of ICH without clipping of the aneurysm. Parietal hematomas were particularly dangerous, while those in the temporal lobe were associated with the best outcome. Since it is impossible to predict survival with a high degree of reliability, even when the prognostic indicators are known, the authors recommend that patients with a significant ICH have it removed as soon as possible and that their ruptured aneurysm be clipped at the same time.

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Factors affecting coagulation: fibrinolysis in chronic subdural fluid collections

Bryce Weir and Philip Gordon

✓ Plasminogen, alpha2-antiplasmin, fibrinogen, fibrin degradation products (FDP's), and hemoglobin were measured in the supernatant fluid of 25 chronic subdural hematomas and five chronic subdural hygromas. The 30 patients underwent pre- and postoperative computerized tomography. The hematomas were characterized by low fibrinogen and high fibrin degradation product concentrations. The hemoglobin content varied directly with the alpha2-antiplasmin, and inversely with the plasminogen. Four patients underwent reoperation for recurrences. The initial fluid from these cases was characterized by relatively high plasminogen and low alpha2-antiplasmin. The hygromas had no hemoglobin, and low fibrinogen, high FDP's, low alpha2-antiplasmin, and variable plasminogen levels. It is possible that those cases having the greatest capacity to produce plasmin (high plasminogen and low alpha2-antiplasmin) can produce more FDP's which in turn causes more rebleeding and an increased risk of reaccumulation of chronic subdural hematomas.

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Chronic cerebral vasospasm after large subarachnoid hemorrhage in monkeys

Francisco Espinosa, Bryce Weir, Donald Boisvert, Thomas Overton, and William Castor

✓ The authors have developed a model of chronic cerebral vasospasm analogous to the clinical situation, by inducing a large subarachnoid hemorrhage (SAH) in monkeys. With this model, the size of the SAH apparent on the first computerized tomography (CT) scan was correlated with the incidence and severity of cerebral vasospasm that developed. Indices monitored for up to 21 days after SAH included cranial CT scan, cerebral blood flow, vessel caliber, and neurological status. The 18 monkeys studied for 48 hours or more were divided into two groups according to the size of the SAH on CT scan. Vasospasm was more common in the group with large SAH. In this group, on Days 0, 7, and 14, the incidence of vasospasm was significantly higher than at other times (p < 0.001, p < 0.01, and p < 0.05, respectively), and the percentage reduction in vessel caliber was significantly greater than in the group with small/medium SAH (Day 7, p < 0.02; Days 0 and 14, p < 0.05). Delayed neurological deficit developed in two monkeys with large SAH. Apathy was noted from Day 17 to Day 21 in one, and unsteadiness and drowsiness were noted on Days 4 and 5 in the other. Overall, the incidence, degree, and time course of vasospasm reflected the size of the hemorrhage.

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Dermatofibrosarcoma protruberans of the scalp treated by radical excision, immediate cranioplasty, and free groin flap

Case report

Gary W. Lobay, Bryce Weir, and Robert Carter

✓ The authors describe a case of dermatofibrosarcoma protruberans of the frontal region in a young girl. The condition was treated by radical excision of the scalp, frontal bone, and sinuses, and immediate reconstruction with an acrylic cranioplasty and microsurgical transfer of a free groin flap. Pathological examination revealed the margins of the excised specimen were clear of tumor. The initial flap failed, but a second graft was immediately transferred successfully, with a good cosmetic result.

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Postoperative Angiography