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.     

S-100 Protein in cerebrospinal fluid after aneurysmal subarachnoid haemorrhage

Summary The concentration of S-100 protein measured in ventricular cerebrospinal fluid (CSF) from 32 patients with subarachnoid haemorrhage (SAH) during the acute phase was related to features on admission such as the Hunt and Hess neurological scale and the amount of blood at the first computed tomography (CT). The S-100 values were also related to functional outcome assessed by the Glasgow outcome scale (GOS) at 12 months. Twenty-two patients were re-examined more than 2 years after the SAH, and the initial S-100 values were related to signs of structural brain damage at CT and single photon emission computed tomography (SPECT) and to the results of neuropsychological evaluation (NPE). NPE included standardized tests for memory functions, intellectual functions, visuo-spatial abilities, sensory-motor functions, and concept formation. Life-adjustment was assessed by two separate questionnaires. Tests for agnostic dysfunction and the Western aphasia battery test (WABT) were also performed.Patients who were functionally disabled or ultimately died had significantly higher initial CSF concentrations of S-100 protein than patients showing good recovery. Patients with low-attenuated regions and/or increased ventricular size at CT and/or regionally decreased tracer uptake on SPECT had higher S-100 levels during days 2–8 than had patients showing no such changes. Logistic and multiple regression analysis of all characteristics assessed during the acute phase after SAH showed that the CSF S-100 concentration during days 2–8 was the factor best correlated to GOS and findings on CT and/or SPECT.All patients showed varying degrees of cognitive impairment at follow-up. The results of NPE and the WABT were related to outcome assessed by GOS and to increased ventricular size on CT. Women had a stronger feeling of maladjustment, but the scores for life adjustment were otherwise not related to other outcome criteria.It is concluded that the ventricular CSF S-100 concentration during the acute phase after SAH is related not only to the functional outcome as assessed by GOS but also to signs of brain damage seen on late CT and SPECT.     

Increased concentration of hypoxanthine in human central cerebrospinal fluid after subarachnoid haemorrhage

Summary The adenine nucleotide metabolites hypoxanthine, xanthine and uric acid were determined by high performance liquid chromatography in cerebrospinal fluid (CSF) from 25 patients with subarachnoid haemorrhage (SAH) and from 26 control subjects. In addition, the haemoglobin and protein levels in the CSF of the patients were determined.In 13 subjects, from which lumbar CSF was collected three, six and nine days after SAH, there was a gradual increase in 8 patients for hypoxanthine and in 3 of the 13 patients for xanthine and uric acid. The mean concentrations were not significantly higher than the controls. In 12 SAH patients, consecutive CSF fractions of 10 ml were collected peroperatively during surgical clipping of aneurysms. The hypoxanthine concentrations increased continously from lumbar to central CSF samples. Hypoxanthine levels were 6.5±1.0 M in lumbar CSF compared to 11.8±2.3 M in central CSF (p<0.001), while xanthine, uric acid, haemoglobin and protein levels were equally distributed. Furthermore, the SAH patients showed about 3 times higher concentrations of central CSF hypoxanthine (p<0.01) and xanthine (p<0.05) while that for uric acid was similar compared to all control subjects. Also, an in vitro study showed that the increased concentrations of the adenine nucleotide metabolites could not be caused by degradation of blood components in the subarachnoid space.It is presumed that the increased central CSF concentrations of hypoxanthine that were demonstrated in patients after SAH could be a sensitive marker for brain tissue ischaemia. However, since there was no correlation between the hypoxanthine levels, clinical condition or cerebral vascular diameter, other factors have to be excluded before ischaemia alone could explain the elevated central hypoxanthine levels in patients without major clinical dysfunction after SAH.This study was supported by grants from Karolinska Institutet, the Swedish National Society against Heart and Chest disease, The Swedish Society of Medical Sciences, Wibergs Foundation, Boehringer Ingelheim and the Swedish Medical Research Council (proj. no. 7485).     

Is there a difference in cognitive deficits after aneurysmal subarachnoid haemorrhage and subarachnoid haemorrhage of unknown origin?

Summary In a retrospective follow-up study 38 patients with aneurysmal subarachnoid haemorrhage (SAH) and 20 patients without an angiographically proven source of SAH were tested neuropsychologically one to five years after the acute event. All patients were operated on early within 72 hours if an aneursym was proven angiographically and all were treated with nimodipine.Both patient groups had comparable cognitive deficits in spite of the less severe SAH of non-aneurysmal origin. Only in two cognitive functions the groups differed significantly. The patients after non-aneurysmal SAH had a significantly lower mean in the IQ subtest similarities finding (p<0.05), while the patients after aneurysmal SAH had a significantly lower mean in a test of visual cognition (p<0.05).A more detailed analysis with clinically homogenous subgroups was additionally performed. The results showed in the subgroup with poor clinical grades that patients with aneurysmal SAH were significantly more disturbed in focal cognitive functions like short- and long-term memory and word-finding capacity, while patients with SAH of unknown origin scored significantly worse in a neuropsychological test related to attention, which can be regarded as a more diffuse cognitive function.     

Reduced expression of calponin in canine basilar artery after subarachnoid haemorrhage

Summary Calponin, an actin- and tropomyosin-binding protein, has been characterized as an inhibitory factor in the smooth-muscle actomyosin activity. The level of calponin was determined in canine basilar arteries in a double-haemorrhage model. Thirty dogs were assigned to three groups: day 0 group, control; day 2 group, dogs sacrificed 2 days after cisternal injection of blood; and day 7 group, dogs given double cisternal injections of blood and sacrificed 7 days after the first injection. Constriction of the basilar artery was confirmed by arterial angiography. Portions of the affected arteries or the corresponding region in control animals were solubilized for sodium dodecylsulphate-polyacrylamide gel electrophoresis and Western blotting. A major band corresponding to calponin was seen at 34 kD in the basilar artery extracts using chicken gizzard polyclonal antibodies. The densitometer values of the band on Coomassie blue-stained gels were expressed as percentages of day 0 control values. The signals of day 2 and day 7 samples were 47%±20% and 23%±12%, respectively (mean±standard deviation). The proportions of calponin to actin/tropomyosin in the day 0, day 2, and day 7 groups were 13%±6%, 6%±2%, and 4%±2%, respectively. The reduced expression of calponin may be related to sustained contraction during cerebral vasospasm.     

Vasospasm after traumatic subarachnoid haemorrhage: Transcranial Doppler evaluation. Case report

A case of vasospasm after traumatic subarachnoid haemorrhage (SAH) is reported here. Transcranial Doppler Sonography (TCD) was used to evaluate mean flow velocity (MFV) changes of the basal cerebral arteries related to vasospasm. Accelleration of MFV of the right middle cerebral artery (MCA) indicating vasospasm was first noted on TCD evaluation, and then proved by carotid angiography (CAG). Evaluation of all TCD results revealed that the process of relaxation or normalization of the spastic artery started from the proximal side of the basal intracranial artery and gradually moving to the distal side. This interesting phenomenon could be a common process found in vasospasm cases.     

S-100 protein in cerebrospinal fluid of patients with subarachnoid haemorrhage: A potential marker of brain damage

Summary Concentrations of S-100 protein in cerebrospinal fluid (CSF) were measured by a recently developed radioimmunoassay (RIA) in 45 patients with subarachnoid haemorrhage (SAH), 44 with verified ruptured aneurysm. In each of 43 patients 2–15 serial CSF samples were analysed, and in the remainder 1 sample was examined. The concentrations of S-100 protein proved to be related to the brain damage caused by the SAH, indexed as outcome (Glasgow Outcome Scale). The S-100 concentrations were related to the severity of the haemorrhage and to the development of delayed ischaemic deterioration. Delayed ischaemic deterioration (vasospasm) was usually accompanied by an increase in CSF S-100 concentration after 4 days. Patients in whom no S-100 value exceeded 20 ng S-100 per ml during the course of the disease had a favourable outcome, whereas patients in whom one or several CSF samples contained more than 100 ng/ ml became severely disabled or vegetative or died. The present study suggests that CSF S-100 analysis may be used as an objective and early measure of the degree of brain damage sustained by the SAH patient.     

Increased levels of somatomedins in human lumbar and central cerebrospinal fluid after subarachnoid haemorrhage

Summary The somatomedins, multitargit growth-promoting peptide hormones, were measured with radio receptor assay in cerebrospinal fluid (CSF) after subarachnoid haemorrhage (SAH) in 21 patients and after head injury in 2 patients.In the first group of 10 patients, lumbar (n=8) or central (n=2) CSF was collected on days three, six and nine after SAH. 6 of the 8 patients with SAH showed an increase in somatomedin concentrations ranging between 0.52–1.26 U/ml while 2 patients fell within the normal range between 0.19–0.48 U/ml. In the 2 patients with head injury, the somatomedin concentrations were scarcely detectable.In the second group of 13 patients with SAH, CSF was collected peroperatively during surgical clipping of an aneurysm. These patients fell into two groups: 6 patients who had CSF somatomedin levels within the normal range and 7 patients with pathologically increased somatomedin concentrations ranging between 0.38–1.26 U/ml. Neither the neurological condition nor the cerebral vascular diameter correlated with the somatomedin concentrations. It is suggested that the increased somatomedin levels in CSF after SAH could be a compensatory response in order to stimulate cerebral anabolism after injury.This work was supported by grants from Karolinska Institutet, the Swedish Medical Research Council, Sävstaholmsföreningen, and Loo and Hans Osterman Research Fund.     

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.     

S-100 protein plasma levels after aneurysmal subarachnoid haemorrhage

Summary We investigated the level of S-100 protein in blood as an indicator of brain damage in 71 patients suffering from subarachnoid haemorrhage (SAH) due to ruptured aneurysms.Concentrations of S-100 protein were determined by micro-titre based immunofluorometic assay detecting predominantly S-100_b on blood samples obtained 24 hours, 3 days and 7 days after onset of symptoms in patients with SAH and from 120 healthy control subjects. Neurological status was assessed using the Hunt and Hess (HH) scale on admission and by the Glasgow Outcome Scale (GOS) 6 months later.Mean concentrations of S-100 protein in blood were significantly (p<0.0001) higher in patients 24 hours (0.263±0.387 g/l), 3 days (0.192±0.288 g/l) and 7 days (0.256±0.442 g/l) after onset of SAH symptoms compared to controls (0.050±0.081 g/l). More severe neurological symptoms (higher HH scale scores) on admission correlated with higher S-100 levels on admission (R=0.70) and Day 3 (R=0.66) (p<0.0001). Worse outcome (lower GOS score) 6 months after SAH was also associated with higher plasma concentration of S-100 in the first week after SAH.In summary, this study showed that in patients with SAH due to ruptured aneurysm, S-100 protein levels correlate with early neurological deficit and are as sensitive as HH scores in predicting neurological outcome (GOS scores). Measurement of S-100 protein in blood is a reliable non-invasive method and may be clinically useful to screen for and monitor progression of central nervous system diseases of various origins.     

Sequential changes of cerebral blood flow after aneurysmal subarachnoid haemorrhage

Summary A total of 226 measurements of cerebral blood flow (CBF) were performed in 96 postoperative patients with aneurysmal subarachnoid haemorrhage (SAH). The global CBF was significantly reduced in the first week after SAH, and the extent of the CBF reduction was less in the patients with good outcome than in those with fair/ poor outcome. The good outcome patients showed a progressive increase in CBF in the following 3 weeks. Although the CBF decreased further in the second week in some of those patients, it turned to a steady increase thereafter. On the other hand, in the fair/poor outcome patients CBF remained far below the normal control value for at least 3 months after SAH. When looking into the effect of age on CBF in the patients with good outcome, those in their thirties and forties had a significantly reduced CBF during the first 2 weeks, whereas in those in their fifties and sixties a significant reduction persisted for 3 months to 1 year after SAH. Management of the older patients needs special attention even if they are apparently in good clinical condition, since the CBF threshold to ischaemia is diminished.     

Seasonal variation of aneurysmal subarachnoid haemorrhage

Summary In a prospective consecutive series of 1,076 patients with aneurysmal subarachnoid haemorrhage (SAH) admitted to the 6 Danish neurosurgical departments in the 5-year period April 1, 1978 to March 31, 1983 a significantly higher seasonal incidence of SAH was seen during spring and autumn compared to summer and winter. No significant seasonal differences in monthly mortality or between females and males were registered. Contrary to several other studies concerning cerebral apoplexy excluding SAH no explanation to the seasonal variation was obtained from differences in weather conditions. A correlation between seasonal variation of aneurysm rupture and physical activity is possible.     

Endothelin-1 in plasma, cisternal CSF and microdialysate following aneurysmal SAH

Summary Objective. Endothelin-1 (ET-1) is postulated to play an important role in the development of cerebral vasospasm (CVS) following SAH. This study was conducted to investigate the time course of ET-release in three different sources: CSF, plasma and microdialysate. Methods. In a prospective study ET-1-concentrations were measured in plasma, cisternal CSF and microdialysate in 20 patients with aneurysmal SAH for at least 8 days after hemorrhage. Results. ET-1 concentration in microdialysate was almost four times higher compared to CSF and plasma. (p<0.001) Only in CSF ET-1-release showed a significant increase over time with highest values on day 5 post ictus (p = 0.03). This was parallel to the increase of transcranial Doppler velocities. ET-1 in plasma and microdialysate did not change over time. Conclusion. ET-1 may have a different biological function in different biological tissues. Only ET-1 in CSF seemed to be associated with CVS. An erratum to this article is available at .     

Activation of the coagulation system in the subarachnoid space after subarachnoid haemorrhage: Serial measurement of fibrinopeptide A and bradykinin of cerebrospinal fluid and plasma in patients with subarachnoid haemorrhage

Summary Fibrinopeptide A (FPA) levels as an indicator of thrombin activity in the cerebrospinal fluid (CSF) and plasma of 25 patients with subarachnoid haemorrhage (SAH) were measured serially by radioimmunoassay (RIA). FPA levels in CSF were extremely high on days 0–1 (1253±269 ng/ml, mean ± standard error) but decreased rapidly (11.3±3.9 ng/ml on days 2–4, 10.7±5.9 ng/ml on days 5–7, and 6.3±1.5 ng/ml on days 8–14). In the controls the FPA concentration in CSF was 1.2±0.9 ng/ml (mean ± standard deviation). Plasma FPA levels in patients with SAH showed no statistically significant changes with time.The bradykinin (BK) concentration in CSF and plasma in 27 patients with SAH was measured serially by RIA. The cocentrations in CSF were 122.7±22.7 pg/ml (mean ± standard error) on day 0, 38.6±6.1 pg/ml on day 1,22.7±6.3 pg/ml on day 2, and 17.1±3.0 pg/ml or less thereafter. Plasma BK levels in patients with SAH were higher than those in the control group, but there was no statistically significant change over time.From the measurement of FPA it was apparent that the coagulation system in the subarachnoid space is strongly activated in the early stage of SAH. The formation of BK in CSF after SAH is thought to be due to the contact activation of Hageman factor (intrinsic factor) in the subarachnoid space. Trabeculae as collagen bundles in the subarachnoid space were considered to have a possible role in activating the Hageman factor of the coagulation system in SAH.     

Does nimodipine influence sex difference in outcome after aneurysmal subarachnoid haemorrhage?

Summary Before nimodipine was introduced as a standard treatment in patients with aneurysmal subarachnoid haemorrhage (SAH) females had a significantly poorer outcome which might be due to a higher frequency of delayed cerebral ischaemia (DCI). We evaluated the overall outcome with regard to gender in 188 consecutive patients with a verified ruptured intracranial aneurysm treated with nimodipine. The only significant differences concerning prognostic factors between the sexes were a higher frequency of SAH at the primary CT in females (p<0.05) and a higher frequency of middle cerebral artery aneurysms in females (p<0.01). These factors affect the outcome in females unfavourably. However, contrary to previous studies, we found no difference in overall outcome after three months between the sexes in this clinical material. Our observation can be explained by a positive effect of nimodipine on DCI.     

Time course of the blood-arterial wall barrier disruption following experimental subarachnoid haemorrhage

Summary The time course of the blood-arterial wall barrier disruption following experimental subarachnoid haemorrhage (SAH) was studied in 24 rabbits. Animals with SAH received two successive blood injections through the cisterna magna. Horseradish peroxidase (HRP) was given intravenously 30 minutes before sacrifice to assess the integrity of the barrier. In the basilar arteries taken from animals that were sacrificed 4 days after the first SAH, HRP-reaction products were diffusely observed in the subendothelial space. Three weeks following the first SAH, permeation of HRP was still observed in half of the animals. However, in animals sacrificed 7 weeks after the first SAH, no permeation of HRP into the subendothelial space was noted. Opening of the interendothelial space seemed to be the major mechanism for HRP permeation into the subendothelial space rather than transendothelial vesicular transport. Disruption of the bloodarterial wall barrier in the major cerebral arteries following SAH may play a role in the pathogenesis of vasospasm.     

Management of subarachnoid haemorrhage

Subarachnoid haemorrhage is an acute life-threatening neurosurgical emergency affecting all ages and causing high mortality and morbidity. The rupture of an aneurysm of an intracranial artery at a point of turbulent blood flow within the circle of Willis usually causes it. Diagnosis begins with a non-contrast CT of the head, followed by more definitive angiography. The focus after diagnosis is to minimize further neurological injury called secondary injury. Initial stabilization with an ABCDEF approach should focus on maintaining adequate cerebral oxygenation and cerebral perfusion pressure (CPP). In emergent cases, this may require intubation and mechanical ventilation. Transfer to a specialist neuroscience centre for ongoing management is the next priority. Culprit aneurysms should be secured promptly by endovascular coiling or surgical clipping. Anaesthesia for either clipping or coiling must be neuroprotective. Recognition and management of complications are best undertaken in a centre managing high volumes of these patients. Vasospasm and delayed cerebral ischaemia are common and feared complications of subarachnoid haemorrhage. All patients should be given nimodipine for prophylaxis and management of these complications. Future research into the pathophysiology of the injured brain in SAH can guide us to novel therapies.     

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.