Thrombin Activity in CSF after SAH is Correlated with the Degree of SAH, the Persistence of Subarachnoid Clot and the Development of Vasospasm

Summary  We previously reported that the coagulation system in cerebrospinal fluid (CSF) is strongly activated in the early stage of a subarachnoid haemorrhage (SAH). We evaluated the relationship among thrombin activity, degree of SAH, amount of clearance of SAH, and vasospasm. The CSF levels of fibrinopeptide A (FPA) were measured by radio-immunoassay in 36 SAH patients, who were diagnosed by computerized tomography (CT) within 12 hours and on whom surgery was performed within 48 hours. Clearance of SAH (%) was evaluated as the size of the clot in the basal cistern visualized between the initial and postoperative CT. The mean level of FPA in the patients of Group 3 (Fisher's CT classification) (182.2 ng/ml) was significantly higher than those in the patients of Group 2 (36.2 ng/ml). There was a significant difference in the mean level of FPA between patients with (47.6 ng/ml) and without infarction (408.3 ng/ml). In 18 of the 27 patients of Group 3 for whom the clearance of the SAH was determined, the patients showing a lower clearance rate (<50%) of SAH demonstrated a significantly higher rate of infarction and a significantly higher level of FPA (466.6 ng/ml) than did the patients with a higher clearance rate (>50%) of SAH (79.2 ng/ml). These results suggest that, the thrombin activity in CSF is correlated with the degree of SAH, the persistence of subarachnoid clot and the development of vasospasm.     

Superoxide dismutase activity in cisternal cerebrospinal fluid after aneurysmal subarachnoid haemorrhage

Summary It has been recognised that the level of superoxide dismutase (SOD) significantly increases in CSF as the result of cerebral ischaemic damage. The aim of this study was to correlate the CSF levels of SOD enzymatic activity to the patterns of subarachnoid haemorrhage with regards to ischaemic complications due to vasospasm.A series of 78 patients operated on for intracranial aneurysms was studied; all patients were monitored with serial TCD measurements every second day after SAH. CSF samples were obtained at surgery by cisternal puncture of the subarachnoid cistern nearest to the aneurysm. SOD activity was assayed spectrophotometrically.Mean cisternal CSF level of SOD in 12 control cases (12.99±2.33 U/ml) is significantly higher (p < 0.01) than in 26 patients operated on between day 1 and 3 from last SAH episode (4.44±0.7 U/ml) and in 40 patients treated by delayed surgery (7.64±0.92 U/ml). In 13 patients presenting neurological deterioration related to arterial vasospasm mean cisternal SOD level was 12.23±1.86 U/ml; in 27 cases without vasospasm mean level was 5.43±0.7 U/ml (p < 001).The present results suggest that (a) cisternal CSF levels of SOD significantly decreases after SAH, probably in relation to an impaired synthesis in the brain compartment and that (b) a substantial elevation of SOD levels is evident in patients suffering ischaemic complications vasospasm-related. Biochemical events in the brain compartment could influence the expression and release of anti-oxidant enzymes in CSF after SAH.     

The effect of very early cisternal irrigation on basilar artery spasm after SAH in the rat model

Summary The authors have investigated the effect of very early irrigation of the cerebrospinal fluid (CSF) space in the haemorrhage rat model of vasospasm. Fifteen rats had basilar cistern irrigation with physiological saline for 3 hours after subarachnoid haemorrhage (SAH), and fifteen control rats had subarachnoid haemorrhage without irrigation of clot.The changes in basilar arteries diameters were determined by angiograms obtained from the rats. The post haemorrhage angiograms showed significant basilar artery spasm in both groups (P0.0005, t-test). However in the last angiogram the basilar artery diameter was found to have the same value measured before subarachnoid haemorrhage in the irrigation group whereas no obvious change was observed in the control group. In the irrigation group the mean diameter of the basilar artery in the last angiogram was 0.412 mm. (0.30 mm to 0.50 mm). None of the animals, treated by cisternal irrigation, showed angiographic vasospasm while the latter group did (P0.0005). Animals treated with physiological saline irrigation had a median clot grade of 0.40 (range grade 0 to 2); control rats had a median grade 2.86 (range grade 1 to 4, P<0.001, Mann-Withney U test), on the brain stem, indicating significant reduction of clot by lavage.In conclusion, performance of experimental physiological saline irrigation at a very early time after subarachnoid haemorrhage prevents the arteriographic and morphological changes of both acute and late vasospasms.     

Endothelin-1 Initiates the Development of Vasospasm after Subarachnoid Haemorrhage Through Protein Kinase C Activation, but does not Contribute to Prolonged Vasospasm

Summary  Endothelium plays a role in the regulation of vascular tone. Endothelin is a family of potent vasoconstrictive peptides, and endothelin-1 (ET-1) produced in the endothelium induces a tonic contraction via specific receptor ETa. ET-1 has been postulated as an important factor in the development of vasospasm after subarachnoid haemorrhage (SAH). We have previously shown that protein kinase C (PKC) of the cerebral artery plays a pivotal role in the pathogenesis of vasospasm. The purpose of this study is to clarify the relationship between ET-1 and PKC in the development and maintenance of vasospasm.  Using a “two-haemorrhage” canine model, chronological changes of angiographic progression of vasospasm, PKC activation, and ET-1 level of the basilar artery were assessed. In an isometric tension study with a control artery, the effects of ETa- and ETa/ETb-antagonists on the tonic contraction induced by ET-1 were examined. The effects of ET-1, ET-1 and an ETa-antagonist, and ET-1 and an ETa/ETb-antagonist on PKC activation were also evaluated.  ET-1 level temporarily increased, then decreased to the control level in a later stage of vasospasm. ET-1 induced a tonic contraction and enhancement of PKC activation, but both were inhibited either by an ETa- or an ETa/ETb-antagonist.  These results indicate that ET-1 initiates the development of vasospasm through PKC activation, but does not contribute to prolonged vasospasm.     

Fibrinolytic activity in the CSF and blood following subarachnoid haemorrhage

Summary Fibrinolytic agents are administered to resolve subarachnoid clot, a major reservoir for spasmogen, to prevent delayed cerebral vasospasm (VS) in patients with subarachnoid haemorrhage (SAH). However, intracranial bleeding often occurs, which may be caused by over-activation of fibrinolysis in the cerebrospinal fluid (CSF) milieu. We measured the levels of D dimer in the CSF and blood of patients with SAH to analyse the correlation between fibrinolytic activity and VS. CSF and blood samples were obtained three times, and VS was identified by angiography. The levels of D dimer in the CSF were significantly higher than in the blood, but changes with time were inverse. Patients with VS showed significantly lower levels of D dimer in both CSF and blood in the initial stage compared to those without VS. These observations suggest that monitoring of fibrinolytic activity in the CSF to identify patients eligible for additional fibrinolytic treatment could reduce the risk of VS and iatrogenic intracranial bleeding.     

Level of consciousness and age as prognostic factors in aneurysmal SAH

Summary The prognostic value of the level of consciousness and the patient's age for the outcome of aneurysmal subarachnoid haemorrhage (SAH) is studied in 74 patients admitted on day (D)0 to D3 after aneurysm rupture.For the level of consciousness three groups of patients are compared: grade I+II (alert patients), grade III+IV (drowsy patients), and grade V (comatose patients). For the age, two groups are compared: patients aged under 50, and patients aged 50 and over. The timing of surgery was: D0–D3 51%, D4–D6 20%, D7 and later 18%, and No surgery 11%.The overall management results were: Good (satisfactory result) 43%, Fair (moderately disabled) 18%, Poor (severely disabled+vegetative survival) 19%, and Death 20%. The outcome was strongly related to the level of consciousness, the rates of Good result decreasing from 71% (grades I–II) to 14% (grades III–IV) and to zero (grade V), and the mortality rates increasing respectively from 5% to 14% and 61%.The relationship between outcome and age was less marked: 54% Good result under 50 and 30% over 50. Out of the Grade V group, 56% could be operated upon and 44% died before surgery. No patient from the other two groups died before surgery. The literature concerning the Grading Systems published so far and the various prognostic factors are discussed.     

Changes of endothelin concentration in cerebrospinal fluid and plasma of patients with aneurysmal subarachnoid hemorrhage

To investigate the clinical significance of endothelin (ET), a potent vasoconstrictor peptide, in subarachnoid hemorrhage (SAH) and SAH-related cerebral vasospasm, we measured the ET-like immunoreactivity (ETLI) in plasma and cerebrospinal fluid (CSF) obtained serially from patients with SAH due to ruptured cerebral aneurysm who underwent aneurysmal surgery. The normal ET–LI levels in plasma and CSF (n = 24) were 12.4±2.0 (mean±s.d.) and 9.1±1.2 pg·ml^-1, respectively. Plasma ET-LI levels in patients with SAH before surgery (16.8±7.8 pg·ml^-1, n = 8) were higher than the normal values ( P <0.05), and became further elevated after surgery (22.5±9.4 pg·ml^-1). ET-LI levels in plasma and CSF one day after surgery were 18.7±5.5 and 18.4±6.8 pg·ml^-1 ( P <0.01 vs. normal values), respectively, and declined thereafter. The plasma and CSF ET-LI levels in patients who showed symptomatic vasospasm became concomitantly elevated again. These results suggest that ET is involved in SAH-related vasospasm and raise the possibility that surgical stress influences the vasospasm.     

Expression of intercellular adhesion molecule 1 (ICAM-1) on the cerebral artery following subarachnoid haemorrhage in rats

Summary In order to study how immune-inflammatory responses are involved in the pathogenesis of cerebral vasospasm after subarachnoid haemorrhage (SAH), the kinetics of expression of the intercellular adhesion molecule 1 (ICAM-1), a ligand for the leucocyte adhesion receptor, were studied on the cerebral arteries following SAH in rats.The SAH was induced by intracisternal injection of arterial blood. The rats were sacrificed at specified times: immediately after induction of SAH to seven days after SAH. Cryostat sections of the basilar artery (BA) were prepared and incubated with anti-rat ICAM-1 antibody. Morphometric analysis of the BA revealed a significant narrowing of the luminal diameter on Day 2 following SAH. While in the non-treated normal animals, no nor only weak expression of ICAM-1 was observed on the endothelial layer of the BA, there was greater expression of ICAM-1 on the endothelial layer of the BA in SAH rats, and the expression was observed also in the medial layer of the artery from Day 2 to Day 5 following SAH.The present results indicate that SAH really causes responses in the cellular immunity not only in the endothelial layer, but also in the medial layer of the artery as a target of immune damage, which is presumed to be one of the important steps in the development of cerebral vasospasm.     

Platelet derived growth factor and subarachnoid haemorrage: A study on cisternal cerebrospinal fluid

Summary Platelet derived growth factor (PDGF) was identified as a powerful mitogenic growth factor which is released from activated platelets and has a marked activity as vasoconstrictor agent. In the present study we have measured cisternal cerebrospinal fluid (CSF) levels of PDGF in 72 patients operated on for intracranial aneurysm in order to verify whether it might be related to the clinical aspects of SAH with special regard to symptomatic vasospasm.CSF samples were obtained at surgery by cisternal puncture of the subarachnoid cistern the nearest to the aneurysm before aneurysm isolation and exclusion. The specimen were frozen in liquid nitrogen and stored at-80 ° C until analysis. PDGF was measured using a commercially available reagent. Values are expressed as pg/ml of CSF.In 18 cases no radiological and clinical signs of SAH were detected and the mean cisternal CSF level of PDGF was 885.0±104.5 pg/ml; 20 patients were operated on between day 1 and 3 from the last SAH episode: mean cisternal CSF level of PDGF was 1917.5±459.4 pg/ml. In 34 patients treated with delayed surgery protocol, mean cisternal CSF level of PDGF was 995.3±73.8 pg/ml. Statistical analysis showed significant differences between groups (P: 0.011). In the subgroup of patients operated on within day 3 after SAH, 6 presented vasospasm and had mean cisternal CSF PDGF level which was significantly higher (P<0.01) than in 14 patients without vasospasm. In the delayed surgical patients there was no significant difference in cisternal CSF levels of PDGF considering the occurrence of vasospasm.The results of the present study suggest that (a) after SAH there is a significant release of PDGF early after SAH and (b) higher levels of PDGF found in cisternal CSF of patients operated on within 72 hours after SAH may be predictive of symptomatic vasospasm.     

Platelet-Derived Growth Factor (PDGF-AB) like Immune Reactivity in Serum and in Cerebral Spinal Fluid Following Experimental Subarachnoid Haemorrhage in Dogs

Summary  The aim of this study was to evaluate the following questions: Can the platelet-derived growth factor (PDGF-AB) be identified in the serum and cerebro spinal fluid (CSF) of dogs? Is there an increase in the concentration of PDGF-AB following experimental subarachnoid haemorrhage (SAH)? Is the increase in concentration related to the angiographic cerebral vasospasm of the basilar artery. The “double haemorrhage” model was applied in seven dogs to produce experimental SAH with determination of angiographic vasospasm in the basilar artery. Blood and CSF samples were taken on the first, third and eighth days. The analyses were performed with an ELISA human PDGF-AB antibody kit (quantikine human PDGF-AB, R&D Systems, Minneapolis, USA).  The average PDGF-AB base value in the serum on the day before the SAH was 410.77±177.56 pg/ml, in the CSF it was 6.43±3.19 pg/ml. There was a significant (p=0.05) increase in the concentration of PDGF-AB (third day 717.35 pg/ml, eighth day 918.07 pg/ml) in the serum of all animals. No significant increase was found in the CSF samples of any animal. In summary, a PDGF-AB like immune reactivity was found in the serum of dogs with the human PDGF-AB ELISA kit and the concentration of PDGF-AB in the serum increased after experimental SAH but not in CSF, but there was no relationship between the increase in PDGF-AB serum concentration and angiographic vasospasm.     

The attenuation of vasospasm by using a sod mimetic after experimental subarachnoidal haemorrhage in rats

Background. Delayed cerebral vasoconstriction and brain ischemia, are critical problems in the management of a patient affected by rupture of an intracranial aneurysm. Overexpression of Cu–Zn superoxide dismutase (Cu–Zn SOD) can reduce the extent of cerebral vasospasm. We, therefore investigated if vasospasm, can be prevented by a novel, stable, and cell permeable SOD mimetic, MnTBAP [Mn(III) tetrakis (4-benzoic acid) porphyrin] which permeates the biological membranes and scavenges superoxide anions and peroxynitrite. Methods. 28 rats (225–250g) were divided equally into four groups: group 1: control; group 2: SAH only; group 3: SAH plus placebo; and group 4: SAH plus MnTBAP. We used a double haemorrhage method to produce SAH. Starting six hours after SAH, 5mg/kg MnTBAP (Calbiochem, Darmstadt-Germany; Cat. No 475870)) or an equal volume of 0.9% saline (37°C) was administered by intraperitoneal injection twice daily for 5 days to groups 4 and 3 respectively. MnTBAP or 0.9% saline injections were continued up to fifth day after SAH and rats were sacrificied on the fifth day. Brain sections at the level of the pons were examined by light microscopy. Planimetric measurements were made for the cross-sectional areas of the lumen and the vessel wall (intima plus media) of the basilar artery by a micrometer. Finding. Administration of MnTBAP significantly attenuated the vasoconstriction of the basilar artery in group 4 compared with the groups 2 and 3 (p<0.001). Interpretation. These results suggest that this SOD mimetic (MnTBAP) attenuates delayed cerebral vasoconstriction following experimental SAH and that superoxide anions have a role in the pathogenesis of vasospasm after SAH.Published online July 25, 2003     

The expression and activation of matrix metalloproteinase-1 after subarachnoid haemorrhage in rats

Summary Background. Collagen lattice contraction has been reported as another aspect of the pathogenesis of cerebral vasospasm after subarachnoid haemorrhage (SAH). Recently, some authors have suggested that matrix metalloproteinase-1 (MMP-1) plays an important role in collagen lattice contraction. Therefore, this study aimed to clarify a role of MMP-1 during cerebral vasospasm in a rat SAH model.Method. We used a single-SAH model in rats and assessed the basilar arteries (BAs) at 30 minutes and on 2 days after SAH by cross-sectional area measurement and other histological parameters. Immunohistochemistry and Western blot analysis were used to quantify MMP-1 expression and activation.Results. BAs in rats significantly exhibited severe cerebral vasospasm at 30 minutes after SAH and moderate vasospasm on Day 2. The immunohistochemistry and Western blotting performed in BAs of rats demonstrated that both expression and activation in MMP-1 peaked at 30 minutes after SAH and then declined to the control level.Conclusions. MMP-1 is expressed and activated in a parallel time course to the development of cerebral vasospasm in an experimental model of SAH.     

Efficacy of steroid hormone in solution for intracranial irrigation during aneurysmal surgery for prevention of the vasospasm syndrome

Summary A series of 55 patients with ruptured cerebral aneurysms were treated with moderate removal of subarachnoid clot followed by intracranial irrigation with pH 8.0 Hartmann solution containing 1 mg/ml of methylpredonizolone sodium succinate after the aneurysmal clipping during early (before day 3) operation. Six (11%) of the 55 patients suffered vasospasm syndrome postoperatively. The clinical results are significantly better than a series of 68 patients operated on and treated before day 3 by intracranial irrigation with Hartmann solution (pH 8.0) only. The possible preventive effect of direct intracranial administration of steroid hormone is discussed.     

Admission blood glucose levels and early change of neurological grade in poor-grade patients with aneurysmal subarachnoid haemorrhage

Summary Background. The neurological grade of poor-grade subarachnoid haemorrhage (SAH) often changes soon after the patient is admitted to the hospital. It is important to closely monitor for such changes within a short period of time after admission; however, there are other problems that can occur during this time such as rebleeding. The aim of this study was to evaluate the relationship between admission blood glucose levels (ABGL) and early change of neurological grade after admission in patients with poor-grade SAH. Methods. Forty-six patients with poor-grade SAH (Hunt & Kosnik Grade IV or V), who were admitted within 3 hrs after SAH onset, and who did not have haematomas causing mass effect, or a history of diabetes mellitus, were included in the study. Patients were pretreated to control blood pressure and intracranial pressure, and they were monitored for early change of grade after admission. Blood glucose level was measured at the time of admission. Findings. Spontaneous grade improvement was observed in 9 of 17 Grade IV patients and 9 of 29 Grade V patients. The ABGL of the patients with grade improvement were significantly lower than the ABGL of the patients who did not improve or who got worse. ABGL were lower than 180 mg/dl in 15 of 18 patients who showed grade improvement. Conclusions. Our results showed that there was a relationship between ABGL and neurological grade changes which were observed after admission in patients with poor-grade SAH. These results suggest that ABGL might be a useful parameter for making therapeutic decisions.     

Basilar Vasospasm Following Spontaneous and Traumatic Subarachnoid Haemorrhage: Clinical Implications

Summary. Summary.   Background: Cerebral vasospasm has been commonly described following subarachnoid haemorrhage (SAH) though its impact on neurological outcome, especially in head trauma, has not been yet elucidated. The purpose of this study was to monitor and correlate neurological condition and flow velocities (FVs) in the arteries of the brain after SAH and more particularly to investigate the influence of basilar artery (BA) vasospasm on neurological outcome.   Methods: Daily transcranial Doppler (TCD) evaluations were conducted in 116 consecutive patients with subarachnoid haemorrhage. SAH was of traumatic origin (tSAH) in 59 patients and spontaneous (sSAH) in 57 patients. Vasospasm in the MCA and ACA was defined by a mean FV exceeding 120 cm/s and three times the mean FV of the ipsilateral ICA. Basilar artery (BA) vasospasm was defined as moderate whenever the FV was higher than 60 cm/s and severe above 85 cm/s.   Findings: Sixty-two patients (53.4%) had elevated FVs in the BA, among these 34 (29.3%) had FVs above 85 cm/s. Basilar vasospasm was significantly more common in tSAH (59.7%) than in sSAH (40.3%, P=0.041). In patients with moderate and severe BA vasospasm, FVs in the BA increased on the third day after admission and remained elevated for a week before returning to normal value by the end of the second week. This elevation in BA FVs in patients with BA vasospasm was followed by a significant and progressive worsening in the neurological condition at the end of the first week. Permanent neurological deficit was associated with elevated BA FVs consistent with moderate BA vasospasm whereas patients who remained in persistent vegetative state, had FVs consistent with severe BA vasospasm (P=0.00019).   Interpretation: The present results further support that BA vasospasm may act as an independent factor of ischaemic brain damage following SAH, especially in head trauma.     

Reversal of Cerebral Vasospasm by the Nitric Oxide Donor SNAP in an Experimental Model of Subarachnoid Haemorrhage

The constant release of nitric oxide (NO) is essential to maintain basal cerebrovascular tone. Oxyhaemoglobin, liberated by lysis of red blood cells after subarachnoid haemorrhage binds NO and prevents its entry into vascular smooth muscle cells. While endothelium-dependent vasoconstriction is preserved, decreased levels of NO inhibit endothelium-dependent relaxation and may cause vasospasm. S-nitrosothiols are potent vasodilators and precursors of NO. The authors' aim was to determine whether S-nitroso-N-acetylpenicillamine (SNAP), a stable S-nitrosothiol compound, could reverse vasospasm in an experimental vasospasm model in rabbit. Experimental subarachnoid haemorrhage (SAH) was induced in 37 New Zealand white rabbits. The animals were divided into four groups. Control (no SAH), SAH only, SAH plus saline and SAH plus SNAP. SNAP (15 micrograms/kg/min) or 0.09% saline (equal volume) was infused 46 hours after induction of SAH. All animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed, sectioned and their cross sectional areas were evaluated in a blind manner, by light microscopy and by using computer assisted morphometry. Experimental SAH elicited vasospasm in all animals of SAH only and SAH plus saline group. In animals treated with SNAP, arterial narrowing was markedly attenuated without producing systemic hypotension. This widening achieved statistical significance when compared to the arteries of the SAH only and SAH plus saline group (p < 0.01). This study indicates that the NO donor SNAP is a potentially useful drug to reverse cerebral vasospasm due to SAH.     

Transcranial Doppler diagnosis of cerebral vasospasm following subarachnoid haemorrhage: Correlation and analysis of results in relation to the age of patients

Summary A retrospective analysis was undertaken to determine whether cerebral vasospasm following subarachnoid haemorrhage (SAH) correlates with the age of patients. For at least 3 weeks after bleeding 80 subjects underwent very close follow-up with clinical examination and transcranial Doppler records of the blood velocities within the basal cerebral arteries.Firstly a correlation between measured maximal mean blood flow velocities and age was made. Secondly, according to their age and the maximum of recorded mean velocitites (v), the patients were divided into groups as follows: age 55 years or less, age more than 55 years; and maximum velocity v1<90cm/s, 90cm/s160cm/s.There was a significant correlation of the measured maximum mean velocities and the age of the patients (r =–0.525, p<0.01). With regard to the velocity groups there was a significant (chisquared statistic for contingency tables, p<0.01) difference between both age-groups: 32% (n=18) of the younger fell into group v4 with maximum mean velocities of more than 160cm/s, but none of the older had such. Vice versa, 63% (n=15) of the older compared with only 14% (n=8) of the younger fell into group v1 with maximum mean velocities of less than 90 cm/s. Clinical follow-up also depicted differences between both age groups. 13 of 18 younger patients with maximum mean velocities >160 cm/s exhibited symptomatic vasospasm with a delayed neurological deficit. This typical course did not occur in the older age group.We conclude from this analysis that the increase of blood velocity in the basal cerebral arteries following subarachnoid haemorrhage depends on the age of the patient. Furthermore, young patients will be more prone to a delayed ischaemic deficit. On the other hand, older patients may also suffer ischaemic deficits following subarachnoid haemorrhage but often without measurable vasospasm according to transcranial Doppler criteria and without the typical delayed appearance.     

Leflunomide prevents vasospasm secondary to subarachnoid haemorrhage

Summary Background. Though cerebral vasospasm is one of the most serious complications of subarachnoid haemorrhage (SAH), its complex pathogenesis is poorly understood and available clinical treatment options are unsatisfactory. This study was designed to examine the efficacy of leflunomide, an immunomodulatory agent with inhibitory properties, on vascular smooth muscle cell proliferation and inflammation in a rabbit cerebral vasospasm model. Methods. Twenty-two adult New-Zealand rabbits were assigned to 4 groups: control, SAH, SAH plus vehicle, SAH plus leflunomide. Subarachnoid haemorrhage was induced by administration of 1 ml of fresh unheparinised autologous arterial blood into the cisterna magna. Oral leflunomide (2 mg/kg) or vehicle treatment was started 12 h after the induction of subarachnoid haemorrhage and administered once a day. Three days later, the animals were sacrificed and the basilar artery was examined histologically for the lumen area and the thickness of the vessel wall. Inflammatory reaction was also examined by counting white blood cells within the vessel wall by means of light microscopic examination using haematoxylin and eosin staining. Findings. Severe and moderate vasospasms were detected in the basilar artery of the SAH and SAH plus vehicle treated groups, respectively. Leflunomide effectively reduced the vasospasm of the basilar artery. Compared to the vehicle treated group, leflunomide significantly reduced the lumen area (p < 0.01) and hyperplasia of the vessel wall (p < 0.01). Although inflammatory response within the vessel wall was reduced in the leflunomide treated group, no statistical significance was found between groups (p = 0.07). Conclusion. This study demonstrates for the first time that leflunomide treatment attenuates cerebral vasospasm in a rabbit SAH model while inflammatory reaction in the vessel wall is not affected. Although further studies are needed to reveal its molecular mechanisms in relieving vasospasm, leflunomide may provide a therapeutic potential for human cerebral vasospasm induced by SAH.     

Blood Flow Velocities in the Basal Vein after Subarachnoid Haemorrhage A Prospective Study Using Transcranial Duplex Sonography

Summary. Summary. Background: Early recognition of emerging delayed neurological deficits (DND) in patients after subarachnoid haemorrhage (SAH) is not always possible by transcranial Doppler sonography. Aim of this study was to investigate a) whether determination of blood flow velocities in deep cerebral basal veins can predict DND in these patients b) the correlation of venous flow velocity to cerebral blood flow (CBF). Methods: a) We prospectively investigated the mean flow velocity in the basal vein (V_BVR), in the middle cerebral artery (V_MCA) and in the extracranial internal carotid artery (V_ICA) in 66 patients after spontaneous SAH. Examinations were performed daily during the first 10 days, using transcranial duplex sonography. Thirty-seven patients had V_MCA exceeding 120 cm/s. They were categorised in three groups: I: no delayed neurological deficit; II: transient DND; III: permanent DND or death associated with vasospasm. b) In another group of 14 patients, interdiane variations in global cerebral blood flow (CBF) measured by the Kety-Schmidt-method were correlated with variations in V_BVR, V_MCA, and V_ICA. Findings: a) In patients without deficit, V_BVR was significantly elevated above normal values the first day (p<0.05), and days 5 and 6 (p<0.1) after V_MCA exceeding 120 cm/s. In group III (permanent deficit), flow velocities in the BVR were significantly below normal on day 5 (p<0.05) and 9 (p<0.1). b) The correlation between changes in V_BVR to changes in CBF (r=0.78, p<0.001) was closer than between changes in V_MCA to the changes in CBF (r=0.54, p<0.05). Interpretation: In case of elevated V_MCA, patients with higher V_BVR seem to have a better outcome. Changes in CBF correlate better with V_BVR than with arterial flow velocities.