CSF leukotriene C4 following subarachnoid hemorrhage

Leukotrienes derive from arachidonic acid metabolism via the lipoxygenase pathway and modulate several cellular events. In the central nervous system, leukotrienes are mainly synthesized in the gray matter and in vascular tissues. Their production is enhanced in ischemic conditions and in experimental subarachnoid hemorrhage (SAH). Previous studies have indicated the ability of the leukotrienes C4 and D4 to constrict arterial vessels in vivo and in vitro and have suggested their involvement in the pathogenesis of cerebral arterial spasm. In the present study, the authors measured lumbar and cisternal cerebrospinal fluid (CSF) levels of leukotriene C4 in 48 patients who had suffered aneurysmal SAH. In 12 of the cases, symptomatic and radiological spasm was evident. The mean lumbar CSF level of immunoreactive-like activity of leukotriene C4 (i-LTC4) was significantly higher (p less than 0.005) than in control cases, while the cisternal CSF level was higher than the lumbar mean concentration (p less than 0.005). Patients presenting with vasospasm had significantly higher levels of i-LTC4 compared to patients without symptomatic vasospasm. This is the first report concerning monitoring of i-LTC4 levels in the CSF after SAH. The results of this study suggest that: 1) metabolism of arachidonic acid via the lipoxygenase pathway is enhanced after SAH; 2) the higher cisternal CSF levels of i-LTC4 may be part of the biological response in the perianeurysmal subarachnoid cisterns after the hemorrhage; and 3) the higher CSF levels of i-LTC4 in patients presenting with vasospasm suggest that a relationship exists between this compound and arterial spasm and/or reflect the development of cerebral ischemic damage.     

Delayed traumatic vasospasm: correlation between cerebral vasospasm and contusion]

The pathogenesis of delayed traumatic vasospasm is not yet fully understood. We present six cases of delayed traumatic symptomatic vasospasm along with CT scan and angiographic findings. The cases ranging in age from 16 to 78 years all had head injury caused by traffic accidents. The Glasgow coma scale on admission was 9 - 15 except in one severe case GCS 6. Initial CT scans were obtained on the day of injury in four patients and on the 2nd and 3rd days in the other two cases respectively. There was no distinct subarachnoid hemorrhage in the suprasellar cistern. Subarachnoid hemorrhage in the Sylvian cistern was observed with particular care in all patients. However the severity of subarachnoid hemorrhage was mild (isodensity or slight high density by CT) in 4 cases. Brain contusions on CT scan were observed in the temporal and/or frontal region of 5 of 6 patients. Ischemic symptoms occurred during the period between 5 and 13 days after head injury. The cerebral angiogram taken after the occurrence of these symptoms revealed spasms in all patients, the spasm being bilateral in 2 of them. Spasms were recognized on the main arteries at the base of the brain such as C1, M1, M2 and A1. In 5 cases, the cerebral contusion and the spasm were located on the same side. Angiographically the vasospasms lasted 2 to 5 weeks. The prognosis based on the Glasgow outcome scale was good recovery in 3 patients and moderate disability in one. Two elderly patients with bilateral spasms were in a vegetative state and severe disability, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebral vasospasm in conditions other than subarachnoid hemorrhage

Intracranial arterial spasm is an arteriographically evident narrowing of the lumen of one or more of the major intracranial arteries at the base of the brain that develops in some patients 1 or more days after the rupture of an intracranial aneurysm. If it is severe enough, such cerebral vasospasm may be accompanied by cerebral ischemia or infarction. Because of its usual setting, cerebral vasospasm is thought to arise from some chemical factor or factors in the blood that accumulates within the basal subarachnoid cisterns and bathes the arteries that subsequently develop spasm. There seem to be exceptions to this basic plan, however. In patients with a ruptured aneurysm, only some of the arteries bathed in subarachnoid blood develop spasm. Of more significance, some patients develop intracranial arterial spasm without apparent subarachnoid bleeding. Until the development of CT scanning, the evidence for the lack of subarachnoid hemorrhage in such patients was weak. We now have the ability to assess cerebral vasospasm repetitively in a noninvasive manner with TCD ultrasonography and to quantitate subarachnoid hemorrhage by CT scanning. We should take advantage of this opportunity to document cases that are exceptions to the rule. Does hypothalamic damage explain such cases, or is there some other explanation? This question may be the key for unlocking the mysteries of the pathogenesis of cerebral vasospasm.     

Extracranial-intracranial arterial bypass in the management of symptomatic vasospasm

Delayed neurologic deterioration from vasospasm remains the greatest cause of morbidity and mortality following subarachnoid hemorrhage. The authors performed superficial temporal artery-middle cerebral artery bypass in three patients with symptomatic vasospasm and studied its effects on cerebral hemodynamics. All three patients responded neurologically to the bypass procedure within 24 hours. The average cerebral blood flow in the region supplied by the spastic middle cerebral artery increased from 40 ml/100 g/min to 49 ml/100 g/min after bypass. Angiography disclosed dilatation of donor vessels during the peak of spasm, followed by their decrease in caliber coincident with alleviation of vasospasm. The authors conclude that superficial temporal artery-middle cerebral artery anastomosis for the management of symptomatic vasospasm can increase blood flow in the ischemic region supplied by the spastic artery. This management strategy may lower the incidence of death and disability from vasospasm after subarachnoid hemorrhage.     

Use of extracranial-intracranial bypass in the management of symptomatic vasospasm

Delayed ischemic deficits from vasospasm after subarachnoid hemorrhage remain a major source of death and disability to patients surviving subarachnoid hemorrhage. Ideal treatment for this condition would prevent or reverse spasm in major subarachnoid vessels. This goal remains elusive. Considerable success has been obtained with augmentation of flow in ischemic regions by induced hypertension and hypervolemia. Some patients are not good candidates for this therapy because of underlying cardiovascular disease or the presence of unsecured aneurysms. A total of 11 patients have recently undergone extracranial-intracranial bypass for the treatment of symptomatic vasospasm. Bypass was performed in 4 patients due to failure of medical management and in 7 patients due to our reluctance to induce hypertension in the setting of unsecured aneurysms. Eight of the 11 patients responded neurologically to the bypass procedure within 24 hours. In 6 cases, neurological deficits either improved or resolved. After operation, all 8 patients maintained their preoperative neurological status with lower mean arterial blood pressures than before bypass. Noncomatose patients with focal middle cerebral ischemic deficits and secured aneurysms in whom medical management has failed or in whom these measures are contraindicated may indeed benefit from extracranial-intracranial bypass. Patients with unsecured aneurysms remote from an ischemic middle cerebral territory should probably be revascularized if cautious hypertension fails to improve their conditions.     

Transcranial Doppler in cerebral vasospasm

Transcranial Doppler provides a noninvasive method for recording blood flow velocity (and indirectly, diameter) in the basal cerebral arteries and therefore is especially useful in detecting vasospasm following subarachnoid hemorrhage. Vasospasm most commonly involves the basal arteries, where the changes in vessel diameter will be inversely proportional to the mean velocity measurements. Examination of patients requires that the examiner be experienced and familiar with the vascular anatomy and the various TCD indicators of vasospasm. Normal mean velocity for the MCA is 62 +/- 12 cm/sec. Significant spasm on angiogram of the MCA corresponds to a mean velocity of 120 cm/sec. Mean velocities of the MCA of 200 cm/sec or greater indicate severe spasm and correlate with 50% or greater narrowing on angiogram. Cerebral blood flow changes that can occur after subarachnoid hemorrhage and as a result of vasospasm may affect velocity values. A simultaneous index of CBF with either direct flow measurement techniques or by recording extracranial carotid artery velocity measurements may be helpful in reflecting these changes. Knowledge of the time course of the development and resolution of vasospasm using TCD can help the clinician predict which patients are at higher and lower risk of developing ischemic deficits, thereby guiding treatment. Several features of TCD assessment of vasospasm are similar to angiography. High TCD velocities, like severe angiographic vasospasm, are associated with delayed ischemic deficits and infarction, although some patients can remain asymptomatic despite these changes. Delayed ischemic deficits or infarctions in patients following subarachnoid hemorrhage usually will be preceded by markedly elevated velocity or other indicators of severe vasospasm.     

Very late-onset symptomatic cerebral vasospasm caused by a large residual aneurysmal subarachnoid hematoma--case report

A 70-year-old female developed delayed ischemic neurological deficits at 35 days after subarachnoid hemorrhage (Hunt and Kosnik grade III, Fisher group 4) caused by a ruptured aneurysm of the left middle cerebral artery. Angiography indicated late-onset cerebral vasospasm probably due to the mass effect of a large hematoma remaining in the sylvian fissure and an intracerebral hematoma after surgery. Patients with a large subarachnoid hematoma after subarachnoid hemorrhage should receive therapy to prevent cerebral vasospasm until the mass effect of the hematoma has diminished.     

Chronic cerebral vasospasm: effect of volume and timing of hemorrhage in a canine model

The effect of altering the volume and timing of hemorrhage on the severity of spasm was studied in a canine model. All animals received three cisterna magna injections of fresh unheparinized autologous arterial blood. Selective left vertebral arteriograms were obtained during the week before and exactly 7 days after the initial subarachnoid injection. Increasing volumes of hemorrhage (from 9 to 15 ml of blood) delivered over 24 hours produced increasingly more severe arterial spasm, with reductions in basilar artery diameter of 37% +/- 14 (SD) and 58% +/- 15, respectively. Delay of the final injection of blood to 96 hours in the 15-ml hemorrhage group resulted in even more intense spasm, with an average 71% +/- 12 reduction in basilar artery diameter. Serial angiographic evaluation demonstrated the resolution of spasm in this group over approximately 3 weeks. Finally, small, late rebleeding episodes resulted in the rapid onset of intense spasm. Our results support the clinical impression of previous studies that the severity of spasm is related to the volume of hemorrhage and, in addition, suggest that the time course of hemorrhage may play a significant role in determining the overall severity of chronic cerebral vasospasm.     

Cerebral artery spasm. A histological study at necropsy of the blood vessels in cases of subarachnoid hemorrhage

From a larger series of autopsies with subarachnoid hemorrhage (SAH), 20 cases were selected for the known complication of cerebral vasospasm. Evidence for vasospasm was radiological and pathological in 17 cases and pathological alone in three. A systematic histological examination of the large arteries in places known formerly to have been in spasm showed that, in the 12 early cases (death before 3 weeks), there were relevant changes in all the layers of the arterial wall, the most significant being evidence of necrosis in the tunica media. In the eight late cases (death after 3 weeks), in addition to the sequelae of the earlier acute changes, there was marked concentric intimal thickening by subendothelial fibrosis, again located in the segments of arteries formerly in spasm. Changes were also found in the small arteries, capillaries, and veins, both in the early and late cases but these changes, although striking, were thought to be caused by the ischemia due to the vasospasm; similar changes were also seen in the control cases with ischemia from arterial occlusion.     

Distribution of angiographic vasospasm after subarachnoid hemorrhage: implications for diagnosis by transcranial Doppler ultrasonography

A study was undertaken to determine how frequently angiographic vasospasm occurs outside the normal access range of transcranial Doppler ultrasound in patients who have suffered a subarachnoid hemorrhage. Vasospasm located in the basal vessels is readily identifiable using transcranial Doppler ultrasound whereas spasm affecting the more distal, vertically oriented arteries is outside the standard detection range. It is therefore speculated that the sensitivity of the technique would be adversely affected by a high incidence of distal vasospasm. A total of 136 angiograms performed on 68 patients after a subarachnoid hemorrhage from anterior circulation aneurysms were reviewed to determine the typical distribution of vasospasm. Of the 40 cases that showed greater than or equal to 25% vessel narrowing, 50.0% had spasm restricted to the basal vessels, 42.5% had spasm involving both basal and distal segments, and 7.5% had spasm of the distal segments only. None of the patients with distal vasospasm alone developed delayed ischemic deficits. It is concluded that most patients with anterior circulation aneurysms who develop vasospasm will have involvement of the basal vessels, but a small number of patients may develop vasospasm only in distal vessels.     

Cisternal and lumbar CSF concentration of arachidonate metabolites in vasospasm following subarachnoid hemorrhage from ruptured aneurysm: biochemical and clinical considerations

Two representative cases of subarachnoid hemorrhage in which prostaglandin D2 (PGD2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), stable metabolite of prostacyclin (PGI2), were monitored with serial lumbar punctures and detected in cisternal CSF during operations for aneurysm, are reported. In the case with demonstrated arterial vasospasm, prostaglandin D2 has a concentration trend with characteristic peak related to vasospasm; the synthesis of prostacyclin appears inhibited after the hemorrhage. In the patient without radiologic evidence of vasospasm, arachidonate metabolite concentration trend appears in a steady-state. Cisternal prostaglandin D2 concentration in the patient with demonstrated vasospasm is two times the highest lumbar CSF concentration, while 6-keto-prostaglandin F1 alpha concentration is very low. This suggests the role of the clotting phenomenon and likely confirms the importance of arachidonate metabolites in the genesis of cerebral arterial spasm following subarachnoid hemorrhage.     

Value of transcranial Doppler examination in the diagnosis of cerebral vasospasm after subarachnoid hemorrhage

In 21 patients with subarachnoid hemorrhage secondary to ruptured intracranial aneurysms, we performed serial neurological evaluations, transcranial Doppler examinations, and cerebral blood flow (CBF) determinations. We classified 8 patients as having vasospasm (delayed neurological deterioration, appropriate reduction of CBF) and 13 patients as having no spasm on the basis of this information. Transcranial Doppler flow velocities in the middle cerebral artery and the anterior cerebral artery were significantly elevated for the group with vasospasm on posthemorrhage Days 4 through 12. Elevation of transcranial Doppler velocities preceded clinical signs of cerebral ischemia. The maximal transcranial Doppler flow velocities achieved were compared on the basis of the extent of clot on early computed tomographic (CT) scans. The mean anterior cerebral artery flow velocities were significantly different between CT Grades II and III. The initial transcranial Doppler flow velocities were compared on the basis of the patient's Hunt and Hess grade upon admission. The flow velocities for Grade V patients were significantly lower than those for Grade IV patients. Transcranial Doppler flow velocities were compared with arteriographically observed anterior cerebral artery and middle cerebral artery radii in 12 instances. The correlation was poor, but the data should be interpreted cautiously in view of the small number of arteriograms. We conclude that transcranial Doppler examination has considerable potential in the early diagnosis of delayed ischemic neurological deficit (clinical vasospasm) in patients with subarachnoid hemorrhage.     

Aneurysm in the horizontal segment of the anterior cerebral artery confirmed by cerebral vasospasm--case report.

A rare aneurysm in the horizontal segment (A1) of the right anterior cerebral artery was found in a 58-year-old male presenting with subarachnoid hemorrhage. No obvious bleeding source was observed on the day of onset, but 7 days later, a definite diagnosis was made based on the discovery of cerebral vasospasm by a repeat angiogram. The aneurysm was clipped via the right frontotemporal approach 15 days after onset. He suddenly developed neurological symptoms such as consciousness disturbance, right hemiplegia, and aphasia on the 4th postoperative day, when remission of the cerebral vasospasm was confirmed by transcranial Doppler ultrasound examinations and cerebral angiography. The ischemic symptoms were probably due to cerebral embolus caused by intraluminal thrombi, which had formed during the maximum phase of vasospasm and became detached during the remission phase.     

Clinical effect of nitroglycerin (GTN) on prevention of cerebral vasospasm

Nitroglycerin (GTN) is widely used as a safe and effective dilator in patients with ischemic heart disease, and it is said that it dilates the cerebral vessels. So the authors are now using GTN for the prevention of cerebral vasospasm. 125 patients classified as Fisher's Group 2, 3 or 4 were operated on within 72 hours after subarachnoid hemorrhage due to ruptured cerebral aneurysm. 58 patients (GTN group) were treated with continuous intravenous infusions of GTN (0.5-1.0 micrograms/kg/min) for about 2 weeks after their operation, and another 67 patients (control group) were not administered GTN. The frequency of occurrence of symptomatic vasospasm decreased in each GTN group of Fisher's classification, and the severity of angiographic vasospasm also tended to decrease. Especially in patients with severe subarachnoid hemorrhage classified as CT group 3 or 4, symptomatic vasospasm occurred in 11 patients (30.6%) in the GTN group, but in 26 patients (63.4%) in the control group. Regarding the outcome, 10 patients (17.2%) in the GTN group showed poor results or died, as opposed to 22 patients (32.9%) in the control group. This difference was significant. Moreover the GTN group had no cases of mortality due to cerebral vasospasm. These results indicate that GTN can be effective for prevention of cerebral vasospasm and improve the prognosis in patients with serious subarachnoid hemorrhage due to a ruptured aneurysm.     

Prevention of cerebral vasospasm in the rat by depletion or inhibition of substance P in conducting vessels.

Cisternal blood injection in the rat induces a biphasic angiographic vasospasm, with a maximal acute spasm at 10 minutes and a maximal late spasm at 2 days after the subarachnoid hemorrhage (SAH). Depletion of substance P-containing sensory nerves to the cerebral arteries with capsaicin prior to SAH prevents the development of both acute and late spasm. Intrathecal administration of the substance P antagonist spantide 2 hours prior to SAH also prevents the development of vasospasm, while spantide administration 1 hour before SAH only hinders the occurrence of late vasospasm. Intracisternal administration of spantide 2 hours post-SAH prevents the development of late vasospasm. This antagonist per se can induce a short-lasting dose-dependent angiographic vasoconstriction. Substance P-containing nerve fibers on the cerebral arteries could constitute the sensory link in a reflex arc system involved in the development of vasospasm in which the presence of blood in the subarachnoid space stimulates sensory substance P-containing nerve fibers on the cerebral arteries inducing a centripetal impulse to the A2-nucleus tractus solitarius setting into motion the events in the brain stem leading to acute and late vasospasm.     

Effect of lesioning of medullary catecholamine neurons or the median eminence on the development of cerebral vasospasm in the squirrel monkey

Summary Injections of blood into the interpeduncular fossa and cisterna magna in the squirrel monkey produce an angiographically demonstrable, biphasic cerebral vasospasm with a maximal acute spasm at ten minutes and a maximal late spasm at six days after the subarachnoid haemorrhage (SAH). Selective lesioning of the A 2 nucleus in the medulla oblongata or the median eminence in the hypothalamus prior to the SAH prevents the development of both the acute and late cerebral vasospasm. The present data indicate that the A 2 nucleus and the median eminence participate in the development of vasospasm in the squirrel monkey.     

Levels of catecholamine in plasma and cerebrospinal fluid in aneurysmal subarachnoid hemorrhage.

Despite intensive investigation into the cause of cerebral vasospasm (focal ischemic deficit) after subarachnoid hemorrhage, the morbidity and mortality associated with this condition remain high. Various studies have shown levels of catecholamine in plasma and cerebrospinal fluid (CSF) to be increased in subarachnoid hemorrhage, and it is possible that these vasoactive substances play an important role in the subsequent vasospasm. In an attempt to elucidate this possibility, the study presented here was undertaken to investigate the relationship between catecholamine levels in plasma and CSF and focal ischemic deficit (FID); the rupture of aneurysms on blood vessels supplying the hypothalamus as compared with the rupture of aneurysms on blood vessels supplying other areas of the brain; and the clinical outcome of the patients. Concentrations of adrenaline and noradrenaline in plasma and CSF samples obtained from 21 patients who had suffered aneurysmal subarachnoid hemorrhage were determined by a radioenzymatic technique. Significantly higher levels of adrenaline were found at the time of surgery in the CSF of patients with FID. A similar trend, though not statistically significant, was also observed for plasma. Patients with a rupture of aneurysms on blood vessels supplying the hypothalamus showed a tendency towards higher catecholamine levels in plasma and CSF. Subjects with a bad clinical outcome (i.e., those who were severely disabled or had died) had significantly higher levels of catecholamine in plasma than did those with a good clinical outcome (i.e., those with moderate or no disability). Further detailed analysis of the interrelationships showed that, within the group of patients with FID, those with rupture of aneurysms on blood vessels supplying the hypothalamus had significantly higher catecholamine levels in plasma than did those with rupture of aneurysms on other cerebral vessels. Furthermore, in the group of patients with rupture of aneurysms on blood vessels supplying the hypothalamus, those with a bad clinical outcome had significantly higher catecholamine levels in plasma than did those with a good clinical outcome. These findings lend support to the possibility that damage to the hypothalamus and subsequent elevations in catecholamine levels may be associated with FID and poor clinical outcome.     

Acute operation and preventive nimodipine improve outcome in patients with ruptured cerebral aneurysms

Sixty-five patients with ruptured aneurysms were operated upon within 48 to 72 hours after subarachnoid hemorrhage (SAH) and were treated with a regimen of intra- and postoperative nimodipine for the prevention of symptomatic vasospasm. The clinical grading (Hunt and Hess) was I to III in 49 patients and IV or V in 16. The SAH was mild in 15 patients, moderate in 27, and severe in 23; 12 patients harbored an intracerebral hematoma, and 6 had intraventricular bleeding. Acute hydrocephalus was observed on preoperative computed tomography (CT) in 19 patients. On CT 3 days postoperatively (i.e., Day 3-4 after SAH), 30 of 65 patients still had subarachnoid blood; however, severe symptomatic vasospasm as the deciding threatening event during the delayed postoperative period was not encountered in this series. Transient symptoms of ischemia were noted in 2 patients (3%) and were accompanied by angiographic spasm in 1. Irreversible neurological deficit occurred in 2 patients (3%); in 1 of these, it was a complication of postoperative control angiography. Of the patients preoperatively graded I or II, 96% had an excellent to fair outcome 6 months postoperatively, and 1 patient (4%) had died because of a surgical complication. Among patients preoperatively graded III or IV, 86% had an excellent to fair outcome, and the remaining 14% had a poor outcome. Shunt-dependent hydrocephalus developed in 7% of the patients. Acute surgical repair of ruptured cerebral aneurysms and preventive topical and intravenous administration of nimodipine reduce management complications and improve outcome; above all, ischemic lesions from symptomatic vasospasm are reduced to a minimum.     

Symptomatic arterial luminal narrowing presenting months after subarachnoid hemorrhage and aneurysm clipping

The authors describe three cases of clinical cerebral ischemia associated with angiographic evidence of cerebral arterial luminal narrowing presenting 7, 14, and 52 weeks after subarachnoid hemorrhage (SAH) and aneurysm clipping. Delayed vasospasm, in its usual time setting 1 or 2 weeks after hemorrhage, did not occur symptomatically in these patients. No evidence for aneurysm clip migration or rebleed was present. All patients responded favorably to volume expansion and elevation of blood pressure. This unusual occurrence of a very delayed vasospasm may further the understanding of the vasospastic process. The symptomatic onset of arterial luminal narrowing months after SAH may suggest that a proliferative vasculopathy more accurately explains the observed vessel narrowing, rather than conventional active constriction of vascular smooth muscle.     

Experimental Subarachnoid hemmorrhage in dogs--effect of various drugs and sympathectomy on cerebral arterial spasm (author's transl)]

Adult mongrel dogs were used. The posterior communicating artery was punctured with a fine needle and subarachnoid hemorrhage was produced, which simulated aneurysmal rupture in human. The cerebral basal arteries were constricted remarkably after the puncture. However this vasospasm disappeared in about 60-120 minutes. After this restoration, the vessels began to be constricted again and reduced their diameter in greater degree with lapse of time. Effect of various drugs and sympathectomy on the experimental spasm induced by this method were studied utilizing the magnified vertebral angiography. The drugs used were papverine, isoxuprine, methysergide, phentolamine and propranolol. One of these drugs was given to each dog into the vertebral artery 15 minutes after the puncture of the artery for study of the early spasm, and the same procedure was carried out 24 hours after the late spasm. Vertebral arteriograms were taken immediately after and at 5, 10 and 30 minutes after injection of the drug. Diameter changes of the cerebral basal arteries were measured on the film. Smooth muscle relaxtants, papaverine and isoxsuprine, were effective on relieving the early and the late spasm. An antiserotonin agent, methysergide, relieved slightly the early spasm, but it had no effect on the late spasm. Phentolamine, that is an adrenergic blocking agent, relieved the early spam remarkably, but it was less effective on the late spam. A beta adrenergic blocking agent, propranolol, was effective on relieving neither the early nor the late spasm. Two weeks after the removal of the bilateral upper cervical ganglia, subarachnoid hemorrhage was produced by the smae method as mentioned above in four dogs. Arteriograms taken 24 hours after puncture of the posterior communicating artery in these dogs showed vasoconstriction as same as in the non-sympathectomized dogs. From these experimental results, it was suggested that an etiological difference in the early and the late spasm may exist, and that the occurence of the late spasm may not be influenced by the sympathetic system.