Association between elevated cerebrospinal fluid D-dimer levels and delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage.

Delayed cerebral ischaemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH) is a major contributor to morbidity and mortality. It is currently not possible to reliably predict patients at risk of DCI after aSAH. The aim of this study was to quantify cerebrospinal fluid (CSF) D-Dimer and plasminogen levels and to investigate any association with development of DCI. Cerebrospinal fluid (CSF) samples collected from 30 patients within 72 h post-aSAH (n = 13 DCI and n = 17 non-DCI patients) were analysed. DCI was diagnosed when angiographic vasospasm was detected in the presence of new onset neurological deficit. Enzyme-linked immunosorbent assays were used to quantify D-dimer concentrations while western blotting was used to quantify plasminogen levels. Significant differences in CSF proteins between DCI and non-DCI cohorts were verified using Mann-Whitney test. Sensitivity and specificity of these proteins for detecting DCI was examined using a ROC curve and verified with a Fischer's exact test. CSF levels of D-dimer within 72 h post aSAH were significantly elevated in DCI patients (54.29 ng/ml, 25.35-105.88 ng/ml) compared to non-DCI patients (26.75 ng/ml, 6.9-45.08 ng/ml) [p = 0.03]. In our sample population, D-dimer levels above 41.1 ng/ml had a sensitivity of 69.2% and specificity of 75% for predicting DCI. CSF levels of plasminogen (DCI: 0.50 signal-intensity/µl, 0.20-0.73 signal-intensity/µl, non-DCI: 0.28 signal-intensity/µl, 0.22-0.54 signal-intensity/µl) did not differ between the DCI and non-DCI cohort (p > 0.05). Our study suggests that elevated D-dimer in the first 72 h after aSAH may be a potential predictive biomarker for DCI.

Dynamic evolution of D-dimer level in cerebrospinal fluid predicts poor outcome in patients with spontaneous intracerebral hemorrhage combined with intraventricular hemorrhage.

The risk of mortality in patients with intracerebral hemorrhage (ICH) significantly increases when complicated by intraventricular hemorrhage (IVH). We hypothesize that serial measurement of cerebrospinal fluid (CSF) D-dimer levels in patients with both ICH and IVH may serve as an early marker of IVH severity. We performed a prospective study of 43 consecutive ICH patients combined with IVH and external ventricular drainage placement admitted in our institution from 2005-2006. IVH severity (Graeb score) and fibrinolytic activity were evaluated continuously for 7days using CT scans and CSF D-dimer levels. The primary outcome was 30day mortality. Overall 30day mortality was 26% (n=11), with eight deaths (72.7%) after 3days (D3). Graeb score and CSF D-dimer on admission (D0) were not significantly different between survivors and non-survivors. The temporal profiles of both parameters were distinctly different, with a downward trend in survivors and an upward trend in non-survivors. A mortality rate of 54% was observed between D0-D3 when both scores increased during this interval. In contrast, the mortality was only 4% when both measures decreased during this interval. Early phase (D0-D3) CSF D-dimer or Graeb score change demonstrated high sensitivity of 88% and specificity of 81% when predicting 30day mortality. Early phase CSF D-dimer change in patients with both ICH and IVH is accurate in predicting mortality and may be utilized as a cost-effective surrogate indicator of IVH severity. Serial monitoring of CSF D-dimer dynamic changes is useful for early identification of patients with hematoma progression and poor outcome.

Intraventricular fibrinolysis with tissue plasminogen activator is associated with transient cerebrospinal fluid inflammation: a randomized controlled trial.

Locally administered tissue plasminogen activator (TPA) accelerates clearance of intraventricular hemorrhage (IVH), but its impact on neurologic outcomes remains unclear and preclinical research suggests it may have pro-inflammatory effects. We randomly allocated patients with ruptured cerebral aneurysms and IVH, treated with endovascular coiling and ventricular drainage, to receive either 2-mg intraventricular TPA or placebo every 12 hours. Cerebrospinal fluid (CSF) and serum cytokine and white blood cell (WBC) concentrations were measured before drug administration and daily for 72 hours. Cerebrospinal fluid D-dimer levels were assessed 6 and 12 hours after administration to quantify fibrinolysis. Six patients were randomized to each group. Patients treated with TPA developed higher CSF cytokine concentrations compared with placebo-treated patients (P<0.05 for tumor necrosis factor-α, interferon-γ, interleukin (IL)-1α, IL-1ß, IL-2, IL-4, and IL-6), as well as higher CSF WBC counts (P=0.03). Differences were greatest after 24 hours and decreased over 48 to 72 hours. The magnitude of the inflammatory response was significantly associated with peak CSF D-dimer concentration and extent of IVH clearance. We conclude that intraventricular TPA administration produces a transient local inflammatory response, the severity of which is strongly associated with the degree of fibrinolysis, suggesting it may be induced by release of hematoma breakdown products, rather than the drug itself.

Fibrinolytic activity in cerebrospinal fluid of dogs with different neurological disorders.

BACKGROUND: Fibrinolytic activity in cerebrospinal fluid (CSF) is activated in humans by different pathologic processes. OBJECTIVES: To investigate fibrinolytic activity in the CSF of dogs with neurological disorders by measuring CSF D-dimer concentrations. ANIMALS: One hundred and sixty-nine dogs with neurological disorders, 7 dogs with systemic inflammatory diseases without central nervous system involvement (SID), and 7 healthy Beagles were included in the study. Dogs with neurological disorders included 11 with steroid-responsive meningitis-arteritis (SRMA), 37 with other inflammatory neurological diseases (INF), 38 with neoplasia affecting the central nervous system (NEO), 28 with spinal compressive disorders (SCC), 15 with idiopathic epilepsy (IE), and 40 with noninflammatory neurological disorders (NON-INF). METHODS: Prospective observational study. D-dimers and C-reactive protein (CRP) were simultaneously measured in paired CSF and blood samples. RESULTS: D-dimers and CRP were detected in 79/183 (43%) and in 182/183 (99.5%) CSF samples, respectively. All dogs with IE, SID, and controls had undetectable concentrations of D-dimers in the CSF. CSF D-dimer concentrations were significantly (P < .001) higher in dogs with SRMA than in dogs with other diseases and controls. CSF CRP concentration in dogs with SRMA was significantly (P < .001) higher than in dogs of other groups and controls, except for the SID group. No correlation was found between blood and CSF D-dimer concentrations. CONCLUSIONS AND CLINICAL IMPORTANCE: Intrathecal fibrinolytic activity seems to be activated in some canine neurological disorders, and it is high in severe meningeal inflammatory diseases. CSF D-dimer concentrations may be considered a diagnostic marker for SRMA.

Uso de fibrinógeno humano en la generación de soportes para la obtención de equivalentes tisulares / Use of human fibrinogen in the generation of scaffold for obtaining Tissue equivalents

Desde sus orígenes, la Ingeniería de Tejidos ha buscado diversos materiales que puedan ser utilizados para la generación de soportes que sirvan para el anclaje, proliferación y diferenciación celular que conduzcan a la obtención de tejidos humanos. Muchos materiales de tipo cerámico, polimérico y metálico se han evaluado, pero hasta la fecha muchos de ellos han sido rechazados por diversas razones, entre otras su escasa biocompatibilidad y biodegradabilidad, la respuesta inmune generada, la baja resistencia mecánica o el riesgo de transmisión de virus o priones. El fibrinógeno es una proteína presente en el plasma sanguíneo que puede ser utilizada para la generación de soportes tridimensionales que favorezcan el crecimiento de células; se obtiene a partir del propio paciente, bancos de sangre o como proteína purificada (Tisseel® o Tissucol®, Laboratorios Baxter). El fibrinógeno evita el desencadenamiento de una respuesta inmunológica y el uso de productos xenogénicos. Debido a la estructura proteica, la adhesión y proliferación celular se ven favorecidas dando excelentes resultados en la generación de equivalentes de piel, cartílago, córnea y reemplazos cardiacos en aplicaciones in vitro e in vivo. Como desventajas presenta su rápida degradación y su baja resistencia mecánica; sin embargo, en los últimos años se han venido evaluando mezclas con algunos biopolímeros como ácido poliláctico (PLLA), ácido poli-glicólico (PGA) y alginato de sodio. Esta revisión presenta algunas de las principales aplicaciones del fibrinógeno en Ingeniería de Tejidos.

Since its origin, Tissue Engineering has sought various materials that can be used for generation of scaffolds that serve to anchor, proliferation and cell differentiation leading to the production of human tissues. Many materials such as ceramic, polymeric and metal type have been evaluated to date but many have been rejected for various reasons, including its limited biocompatibility and biodegradability, immune response generated, low mechanical strength or the risk of transmission of virus or prions. Fibrinogen is a protein present in blood plasma that can be used to generate three-dimensional scaffolds that favors growth of cells, it is obtained from the patient itself, bank of blood or purified protein (Tisseel® or Tissucol®, Laboratorios Baxter). Fibrinogen acts slowing or reversing the immune response and avoiding the use of xenogeneic materials. Because the protein structure, adhesion and cell proliferation is favored with excellent results in the generation of skin equivalents, cartilage, cornea and even heart replacements in vitro and in vivo. The disadvantages presented are the rapid degradation and low mechanical strength, but in recent years it has been evaluating some biopolymer mixtures as polylactic acid (PLLA), poly-glycolic acid (PGA) and sodium alginate. This review presents some of the main applications of fibrinogen in Tissue Engineering.

Relationship between elevated cerebrospinal fluid levels of plasminogen activator inhibitor 1 and neuronal destruction in patients with neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: A homeostatic imbalance between coagulation and fibrinolysis might occur intrathecally in neuropsychiatric systemic lupus erythematosus (NPSLE). However, there are no published data on levels of fibrinolytic factors in the cerebrospinal fluid (CSF) of patients with NPSLE. The present study was undertaken to assess CSF levels of fibrinolytic molecules, including urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), D-dimer, and plasminogen activator inhibitor 1 (PAI-1), in SLE patients with clinically verified neuropsychiatric involvement and to compare these levels with those in SLE patients without neuropsychiatric involvement and in healthy subjects. METHODS: Levels of uPA, tPA, and PAI-1 were assessed in CSF from 94 patients with SLE (33 who had NPSLE, 56 who did not have NPSLE, and 5 who were positive for antiphospholipid antibody [not included in the NPSLE or non-NPSLE group]) and from 53 age-matched controls. Patients were evaluated clinically, with magnetic resonance imaging of the brain, analyses of neuronal/glial degradation products in CSF, and neuropsychiatric testing. RESULTS: In the group of patients with NPSLE, intrathecal PAI-1 levels were significantly elevated compared with levels in SLE patients without overt neuropsychiatric involvement (P < 0.05) and in healthy controls (P < 0.001). In contrast, intrathecal levels of uPA did not differ significantly. Intrathecal levels of PAI-1 correlated significantly with CSF levels of interleukin-6 (IL-6) (r = 0.34, P < 0.001) and IL-8 (r = 0.33, P < 0.001). Importantly, increased PAI-1 and D-dimer levels were observed in SLE patients who had pathologically elevated levels of glial fibrillary acidic protein, neurofilament triplet protein, and tau protein in CSF. CONCLUSION: Intrathecal release of PAI-1 is increased in patients with NPSLE. This results in impaired fibrinolysis, which might contribute to neuronal and astrocytic damage in NPSLE.

Coagulation and fibrinolytic activity in patients with acute cerebral infarction.

OBJECTIVE: To measure the concentration of D-dimer (DD), tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and plasminogen (PLG) activity in plasma and cerebrospinal fluid in patients with acute cerebral infarction and to investigate their clinical significance. METHODS: The concentrations of D-dimer, t-PA, and PAI-1 in plasma and cerebrospinal fluid in patients were measured by enzyme-linked immunosorbent assay (ELISA). The PLG biological activity was detected using the chromophore method. The results were compared with those of the controls. RESULTS: The concentrations of D-dimer, t-PA and PAI-1 in cerebrospinal fluid and plasma in patients with acute cerebral infarction were much higher than those of normal subjects (P < 0.01). Conversely, the level of PLG activity was significantly lower in the patients than in the controls (P < 0.01). CONCLUSION: Hypercoagulability and secondary hyperfibrinolysis exist in patients with acute cerebral infarction.

Effects of thrombin inhibitor on thrombin-related signal transduction and cerebral vasospasm in the rabbit subarachnoid hemorrhage model.

BACKGROUND AND PURPOSE: Thrombin is activated in the cerebrospinal fluid (CSF) after a subarachnoid hemorrhage (SAH). However, the relationship between thrombin and cerebral vasospasm has not yet been fully established. The aim of this study was to investigate the possibility of thrombin as a causative factor for cerebral vasospasm and to delineate the signal transduction mechanism that results in thrombin-inducing sustained vasoconstriction in cerebral vasospasm. METHODS: In the SAH group, SAH was simulated by the 2-hemorrhage rabbit model. In the treatment group, antithrombin III (AT-III) was injected into the cisterna magna just before production of the SAH. CSF samples were obtained serially to measure d-dimer with latex photometric immunoassay. On day 4, the basilar artery was excised after perfusion-fixation. The degree of cerebral vasospasm was evaluated by measuring the cross-sectional area of each basilar arterial lumen, and the expression of mitogen-activated protein kinase (MAPK) in the vascular wall was examined with an immunohistochemical technique. RESULTS: In the treatment group, the value of d-dimer on day 4 was 0.83+/-0.07 microg/mL, which was statistically significantly lower than that in the nontreated SAH group (2.49+/-0.09 microg/mL, P<0.01). The cross-sectional area of the arterial lumen in the treatment group was 3.67x10(5)+/-1.58x10(4) square pixels, which was statistically significantly larger than that in the nontreated SAH group (2.60x10(5)+/-2.29x10(4) square pixels; P<0.01). MAPK was detected diffusely in the vascular smooth muscle cell layer in the nontreated SAH group, but it was absent in the treatment group. CONCLUSIONS: Inhibition of thrombin activity leads to amelioration of cerebral vasospasm and suppression of MAPK diphosphorylation. This suggests that thrombin and its related signal transduction, including the MAPK cascade, appear to play an important role in the pathogenesis of cerebral vasospasm after SAH.

Worst headache and subarachnoid hemorrhage: prospective, modern computed tomography and spinal fluid analysis.

STUDY OBJECTIVE: This study investigated the hypothesis that modern computed tomographic (CT) imaging is sufficient to exclude subarachnoid hemorrhage (SAH) in patients with severe headache. METHODS: All 38,730 adult patients who presented to Hermann Hospital in Houston, Texas, during a 16-month period were prospectively screened to detect those with "the worst headache of my life." Two neuroradiologists blinded to the study hypothesis interpreted the CT scans. Patients with negative scans underwent comprehensive cerebrospinal fluid (CSF) analysis including cell count in first and last tubes, visual and spectrophotometric detection of xanthochromia, and CSF D-dimer assay. RESULTS: A chief complaint of headache was elicited in 455 patients, and 107 of these had "worst headache" and were enrolled in the study. CT-confirmed SAH was found in 18 of the 107 (17%). Only 2 patients (2.5%, 95% confidence interval, .3% to 8.8%) had SAH detected by CSF analysis among those with negative CT imaging result. CSF spectrophotometric detection was the most sensitive test for blood. Three patients with less than 6 red blood cells in tube 1 had positive spectrophotometric results, but in all 3, tube 4 was negative on spectrophotometric analysis, suggesting a high false-positive rate. CONCLUSION: Modern CT imaging is sufficient to exclude 97.5% of SAH in patients presenting to the ED with "worst headache" symptoms.

Bilirubin, ferritin, D-dimers and erythrophages in the cerebrospinal fluid of patients with suspected subarachnoid haemorrhage but negative computed tomography scans.

AIM: To assess the diagnostic value of cerebrospinal fluid (CSF) spectrophotometry, cytology, ferritin, and D-dimer measurements in the investigation of suspected subarachnoid haemorrhage in patients with negative or equivocal computed tomography (CT) scans. METHODS: CSF specimens submitted for assessment of xanthochromia were examined for erythrophages using a cytospin preparation stained with Wright's stain, for ferritin using the Ciba-Corning Magic IRMA assay, D-dimers using the Dimertest 2 latex agglutination slide test, and for bilirubin by scanning spectrophotometry. The patients were divided into three groups for data analysis and the results compared with the existing methods, CT, and angiogram results. Final diagnoses were reviewed by a consultant neurologist. RESULTS: Thirty six patients were recruited. In those patients with confirmed subarachnoid haemorrhage CSF cytology had a low sensitivity and there were false negative results with both the D-dimer and ferritin assays. Eleven patients with a negative or equivocal CT scan underwent angiography, but only one aneurysm and no arterio-venous malformations or bleeding points were identified. In the patient with the aneurysm there was no laboratory evidence of subarachnoid haemorrhage. Six patients had CSF abnormalities detected by the special tests only and in none of these cases was subarachnoid haemorrhage confirmed. All results were normal in four out of five cases of traumatic tap. CONCLUSIONS: This is a small study, but it shows that, depending on the timing of the lumbar puncture, false negative results can occur with both ferritin and D-dimer measurements. It suggests that neither of these tests adds significantly to the information provided by CT, visualisation of CSF, and spectrophotometry and confirms that, despite the use of spectrophotometry, D-dimer and ferritin assays in selecting patients for angiography, the proportion of patients with negative CT scans and colourless CSF with demonstrable vascular lesions remains low.

D-dimer levels in the cerebrospinal fluid: a marker of central nervous system involvement in neoplastic disease.

D-dimer assay was performed on 145 cerebrospinal fluid (CSF) samples from patients with or without neoplastic diseases. Levels of D-dimers were significantly higher in carcinoma and lymphoid malignancies with clinical or biological evidence of central nervous system (CNS) involvement than in diseases without such complications. In one patient, serial determinations of D-dimers were well correlated with the appearance and disappearance of CNS involvement. Although this test is not specific for neoplastic affections, our data suggest that the measurement of D-dimers in CSF may be useful in the diagnosis of CNS involvement of neoplastic cells and in monitoring intrathecal therapy in patients with lymphoma, acute lymphoblastic leukaemia or carcinoma. In this study, the D-dimer assay was also positive in some non neoplastic diseases, but failed to differentiate subarachnoid haemorrhage from traumatic lumbar puncture.

Monitoring of fibrin and fibrinogen degradation products (FDP) in the cerebrospinal fluid of patients with subarachnoid haemorrhage due to ruptured aneurysm. Report of 55 cases.

Fibrin and fibrinogen degradation products in the cerebrospinal fluid (CSF-FDP) were first studied in a group of 29 patients observed during the first and the second week after subarachnoid hemorrhage (SAH), then in a second group of 26 patients for a total of 55 patients. In the latter group only the first FDP value obtained as soon as possible after SAH was taken in consideration. In the whole series of 55 patients several noteworthy factors were found: 1) FDP determination should be performed as soon as possible after SAH; 2) CSF-FDP at or above 40, 80 micrograms/ml was found both in the patients with severe neurological deficits and in those with cerebral ischemia (statistically significant); 3) the significance of CSF-FDP in patients who rebled was also evaluated. In conclusion CSF-FDP could be considered useful in predicting cerebral ischemia.

Intraventricular streptokinase increases cerebrospinal fluid D dimer in preterm infants with posthaemorrhagic ventricular dilatation.

Failure to lyse multiple small blood clots in the cerebrospinal fluid (CSF) reabsorption pathways may be one of the mechanisms leading to posthaemorrhagic ventricular dilatation (PHVD). It has been suggested that intraventricular administration of streptokinase may resolve PHVD but it is not known whether such treatment produces an increase in fibrin degradation products in the CSF. Ventricular CSF was collected from six infants with PHVD before and during intraventricular treatment with streptokinase 1000 units/h. In all six infants, CSF D dimer increased during streptokinase treatment. Median D dimer before treatment was 1642 micrograms/l and during treatment 5440 micrograms/l (p < 0.05). Undetectable D dimer levels in plasma during streptokinase treatment ruled out the possibility that D dimer had merely diffused into the CSF. This augmentation of local fibrinolysis may have therapeutic potential. There was no evidence of systemic fibrinolysis.

Analysis of cerebrospinal fluid from patients with psychiatric and neurological disorders by two-dimensional electrophoresis: identification of disease-associated polypeptides as fibrin fragments.

Two-dimensional electrophoresis (2-DE) of cerebrospinal fluid (CSF) samples--from 347 patients with various psychiatric and neurological disorders--and subsequent silver staining revealed two additional polypeptides (Mr 40,000) in 49% of 111 schizophrenics, 46% of 43 schizoaffective patients, 36% of 41 patients with affective disorders, 43% of 28 patients with multiple sclerosis, but not in 25 patients without neurological symptomatology, nor in 9 patients with Lues, and in only 2 of 25 patients with AIDS. The two polypeptides, as detected by 2-DE, eluted after size exclusion chromatography in fractions containing proteins with Mr greater than 200,000. After 2-DE of CSF samples, enriched by gel chromatography, the polypeptides were immobilized by blotting onto glass-fiber membranes and subjected to N-terminal sequencing. Polypeptide A was identified as beta-chain remnant (beta 2), derived from plasmin cleavage of fibrin(ogen). After size exclusion chromatography, 2-DE, and Western blotting, polypeptide A and B, as well as several other spots, reacted with fibrinogen antibodies, suggesting that the polypeptides are subunits of a fibrin degradation complex.

Fibrinolysis in cerebrospinal fluid after intraventricular haemorrhage.

Concentrations of cross linked fibrin degradation products were measured in the cerebrospinal fluid from five 'normal' preterm infants (median 102 ng/ml), four preterm infants with intraventricular haemorrhage (median 315 ng/ml), and five infants with progressive post-haemorrhagic ventricular dilatation (median 1000 ng/ml). Serial samples of cerebrospinal fluid from one infant showed a peak concentration two weeks after the haemorrhage.

[FDP levels in the cerebrospinal fluid are elevated in patients with meningitis].

Since the level of fibrinogen degradation products (FDP) are elevated with severity of inflammation, we assumed that FDP in the cerebrospinal fluid (CSF) could be a marker of meningitis. We, therefore, measured FDP in the CSF of 6 patients with bacterial meningitis and 6 aseptic meningitis. The range of FDP levels in the CSF in patients without meningitis was 0.21 +/- 0.01 microgram/ml. While, the level of FDP in patients with aseptic meningitis (0.43 +/- 0.10 microgram/ml) and in bacterial meningitis (1.78 +/- 0.42 micrograms/ml) was significantly elevated (p less than 0.05). The value was significantly (p less than 0.01) higher in the group of septic meningitis than in aseptic meningitis. In one patient with septic meningitis, we could measure FDP in the CSF several times during the course of the disease, in which the level of FDP got into the high range earlier than the changes in levels of protein, glucose and cell counts in the CSF. FDP in the CSF well correlated to the clinical course of the meningitis. Eventually, we found that FDP in the CSF was definitely elevated in patients with bacterial meningitis, whereas it was slightly elevated in patients with aseptic meningitis. The measurement of FDP in the CSF, therefore, is concluded to be useful for the differential diagnosis of meningitis, and to assess the clinical course of meningitis.

Rapid differentiation of subarachnoid hemorrhage from traumatic lumbar puncture using the D-dimer assay.

The D-dimer assay of 40 cerebral spinal fluid (CSF) samples accurately differentiated subarachnoid hemorrhage (SAH) from traumatic lumbar puncture. The D-dimer assay was positive in all six patients with subarachnoid hemorrhage. Negative D-dimer values were obtained in control groups of 14 patients with hemorrhagic CSF secondary to traumatic lumbar puncture (LP) and in 20 patients with normal CSF. The D-dimer assay proved to be a better test than xanthochromia or the decline in erythrocyte count in sequentially collected tubes in differentiating subarachnoid hemorrhage from traumatic LP.

[Vascular spasm and cerebral ischemia after meningeal hemorrhage caused by rupture of an aneurysm]. / Spasme vasculaire et ischémie cérébrale après hémorragie méningée par rupture anévrysmale.

The author discusses the epidemiology, the diagnosis, the clinical and morphological aspects of cerebral vasospasm from his personal experience and a study of the literature. Prediction and diagnosis of vasospasm is possible by evaluation of the amount of blood on CT scan, measuring fibrin breakdown products in the CSF and the findings of early EEG and Transcranial Doppler Sonography. CBF measurement is helpful in following the process of ischemia and deciding the right moment for operation. Early surgery on cerebral aneurysms is advocated in order to prevent rebleeding and for early removal of blood clot from the basal cisterns. If vasospasm and ischemia do develop, energetic treatment with hypervolemia and induced hypertension can be started without fear of rebleeding. Prophylactic intravenous administration of Nimodipine is thought to be of real value. Since the introduction of early surgery by the author 80 patients have been operated within 3 days after S.A.H. The mortality was 11% and the morbidity 7.5%. Management mortality and morbidity for the total group of 209 patients with S.A.H. treated either medically or surgically were 23.5% and 6% respectively. If one excludes the 18 patients that died within 24 hours the mortality was 15.6%.