Subarachnoid haemorrhage of unknown aetiology

Summary Eighty-six of 996 patients with primary subarachnoid haemorrhage (SAH) had negative panangiography studies. These 86 patients with subarachnoid haemorrhage of unknown origin (SAH-NUD) were compared with 853 patients sustaining an aneurysmal bleed (SAH-A) admitted during the same period 1980–1989. The age and sex distribution of both groups were similar. The SAH-NUD group was in better condition on admission, with less blood evident on CT scan. All 16 (repeat control) angiography studies in the SAH-NUD group were negative. During a follow-up period ranging from 1 to 10 years (mean 5.4 years), two patients experienced rebleeding with negative repeat angiographies and subsequent total recovery. Using the Glasgow Outcome Scale (GOS) the final outcome was good in 86% of the study group and 54% of the aneurysm group. However, half of the SAH-NUD patients complained of persistent symptoms at long-term follow-up. Thus, despite a generally good prognosis, for a given individual SAH-NUD may be catastrophic with many residual symptoms persisting for the rest of the person's life.     

Clinical and long-term follow-up study in patients with spontaneous subarachnoid haemorrhage of unknown aetiology

Summary Clinical characteristics and the outcomes of 50 patients with confirmed subarachnoid haemorrhage (SAH) of unknown aetiology were evaluated. Twenty-nine of these patients were interviewed with a mean follow-up of 7.7 years. Seven patients experienced early rebleeding during hospitalization, and one patient experienced late rebleeding during the follow-up period.On admission to the hospital the consciousness level was clear in 43 of the patients, drowsy in 6, and semicomatose in only 1. Of 10 patients who underwent computerized tomography (CT) within 3 days after SAH, 6 showed no abnormal CT findings and 3 had mild subarachnoid blood. Another patient showed severe SAH. Neurological deficit due to symptomatic vasospasm persisted in only 1 case.Two patients died after re-bleeding during hospitalization, and two others died during the follow-up, thereby representing an overall mortality rate of 8%. Of the latter cases, one died of an unrelated disease, and the other died suddenly from an unknown cause. The remaining forty-six patients (92%) had a good outcome. These results confirm previously reported clinical characteristics, namely that the symptoms of the majority of such cases are mild, the incidence of symptomatic vasospasm is rare, the risk of late re-bleeding is very low (less than 1% per year), and the prognosis is good. The CT findings suggest that some of these features resulted from only mild SAH. Thus, SAH of unknown aetiology seems to be a disease entity with a good prognosis.     

Cerebral vasospasm after subarachnoid haemorrhage of unknown aetiology: A clinical and transcranial Doppler study

Summary Sixteen patients (6 women, 10 men; mean age: 52.5 years) suffering from spontaneous subarachnoid haemorrhage (SAH) of unknown origin underwent a protocol of initial and then weekly computed tomography (CT), initial four-vessel digital subtraction angiography (DSA) and at least one control pancerebral DSA. Fourteen patients had magnetic resonance imaging before undergoing first control DSA. All patients had calcium-antagonists (Nimodipine) via a central venous catheter, were kept on the neurosurgical intensive care unit and followed daily with transcranial Doppler ultrasonography (TCD). One patient (6.3%) developed moderate and 5 (31.1%) developed severe cerebral vasospasm as documented with TCD and exhibited deterioration of their level of consciousness. These 6 patients were treated with induced hypertension, hypervolaemia and haemodilution. Their blood flow velocities were elevated for a mean of 8 (5–17) days with a peak after 12.5 (9–17) days following SAH. No complications due to treatment were noted. One patient of the non-vasospastic group died of pulmonary embolism, another patient had an ischaemic incident during angiography, which has led to permanent disability. On follow-up 2–24 months after SAH 14 patients had returned to their premorbid state. It is concluded that patients suffering from SAH of unknown origin should undergo repeated angiographic investigation and subsequent daily monitoring of their neurologic status including daily TCD recordings so that haemodynamic treatment can be established in the event of cerebral vasospasm, which may occur in up to one third of these patients.     

Subarachnoid haemorrhage of unknown origin: Clinical and tomographical aspects

Summary 65 patients with negative but technically satisfactory 4 vessel angiography —all admitted to our Department in the years 1976–1983 — were evaluated in the present study. CT scan was undertaken in all cases (in 47 cases within 4 days of haemorrhage). Arterial hypertension was present on admission in 9% of cases. The period of follow-up ranged from 4 to 11 years, with a mean of 5,3 years.The study group was compared to a control group, comprising 760 patients with subarachnoid haemorrhage from ruptured aneurysms, admitted during the same period. Clinical grade on admission (Hunt's classification) was better in patients belonging to the study group. The amount of cisternal deposition on CT scan was less significant than in patients with ruptured aneurysms, and the deposition was often atypical (circumpeduncular, ambiental, and/or tentorial). Clinical deterioration associated with vasospasm was observed in 5% of patients in this study and in 27% of patients in the control group. In patients with a consistent or thick cisternal layer (CT scan at risk) the incidence of clinical vasospasm was 21%, against 47% in controls. One or more rebleedings occurred in 12% of patients in the study group, against 25% of patients in the control group. A significant ventricular dilatation was observed in 15% of patients in the first group (requiring a shunt in 8%), against 25% of patients in the second group (requiring a shunt in 11%). Final outcome was favourable in 95% of patients in this study group and in 63% of patients in the control group, with a mortality rate of 5% in the first group and 32% in the second group.     

The course of vasospasm following subarachnoid haemorrhage in rats

Summary The course of vasospasm following subarachnoid haemorrhage in rats was studied using vertebrobasilar angiography. Wistar and Sprague Dawley rats were compared with respect to vasospastic response after bleeding. A more pronounced vasospasm was found in Sprague Dawley rats. In order to avoid a possible toxic effect on the contrast medium, only one angiogram per animal was initially performed. However, a comparison with the results obtained in a separate series of non-challenged animals demonstrated a difficulty due to high variability in basilar artery size in the latter group. Therefore, vasospasm can be more readily shown if multiple angiograms are used in the same animal so that the vasospasm can be expressed as a percentage of the initial diameter of the basilar artery. It was found that multiple angiograms are well tolerated when nonionic contrast media are used.     

Symmetrical bilateral low-density lesions in the areas of supply by Heubner's arteries after aneurysm surgery

Summary Forty three patients of subarachnoid haemorrhage of unknown aetiology have been studied for their clinical presentation, rebleed rate, morbidity and mortality. The results have been compared with other similar studies. The present study and those of others indicate a very good prognosis in acute stage. The rebleed rate ranged between 0 and 7% over a period of two to three years. The mortality rate ranged between 0 and 5% during the same period of follow-up. Majority of the patients returned to their full working capacity. The benign nature of this subgroup as compared to the poor outcome of subarachnoid haemorrhage as a whole prompted us to call it Benign subarachnoid haemorrhage.     

Management of sub-arachnoid haemorrhage

Spontaneous subarachnoid haemorrhage (SAH) is a neurovascular emergency with sudden onset, which requires rapid recognition and early treatment to minimize the occurrence of serious complications. The most common cause is a cerebral aneurysm, which develops at areas of turbulent flow, especially within the circle of Willis. Initial aims are to provide appropriate resuscitation to the patient and to maintain cerebral oxygenation and perfusion. Anaesthesia involves prompt airway control and precise management of physiological parameters to reduce further neurological injury, such as from re-bleeding or delayed cerebral ischaemia. Once stabilized SAH patients should be admitted to a neurointensive care unit and managed by a skilled multidisciplinary team. Definitive treatment then involves either endovascular coiling or surgical clipping, preferably in hospitals managing high volumes of SAH cases per year. Care should be also taken throughout to avoid non-neurological complications such as infections or venous thromboembolism.     

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.     

Subarachnoid haemorrhage of unknown aetiology

Summary One hundred and forty consecutive subarachnoid haemorrhages (SAH) which presented either an intracranial vascular malformation (102 cases: aneurysm 80 cases, AVH 22 cases) or remained of unknown aetiology (38 cases) were studied. SAH caused by other factors (neoplasms, thrombo-embolisms, systemic diseases etc.) were excluded. The 38 cases with bleeding of unknown aetiology have been studied by complete cerebral angiography, pneumoencephalogram or CT scan, and have been followed for two years.The most important clinical factors in the three groups have been compared by a statistical method to verify the hypothesis that SAH of unknown aetiology is caused by vascular micromalformations which are angiographically not evident either because of their small size or because of their spontaneous recovery after bleeding due to thrombosis and disappearance of the malformation.From the data collected it may be concluded that SAH of unknown aetiology is a benign lesion, typically occurring in middle age, but with no clear characteristics that enable identification of the anatomical substratum from it originates.     

No Apparent Role for Neutrophils and Neutrophil-Derived Myeloperoxidase in Experimental Subarachnoid Haemorrhage and Vasospasm: A Preliminary Study

Summary ?Objective. The literature contains investigations and discussion of the role of neutrophils and neutrophil-derived myeloperoxidase (MPO) in inflammatory processes, local ischaemia, and ischaemia-reperfusion injury models. Our aim was to determine whether the same roles existed for neutrophils and the system involving neutrophil-derived MPO in experimental subarachnoid haemorrhage (SAH) and associated ischaemia. Material and Method. Forty-eight adult New Zealand white rabbits were divided into six groups of eight. The first SAH model was applied to 16 animals. Eight of these rabbits were sacrificed after 48 hours (Group 1) and the remaining eight were killed after 96 hours (Group 2). The second SAH model applied to another 16 rabbits, which were sacrificed in two groups at the above time periods, forming Groups 3 and 4, respectively. There were two groups of 8 control animals, one group per SAH model, and these rabbits were sacrificed after 48 hours. We carried out histopathological studies using haematoxylin and eosin (H&E) stain, elastin stain, MPO immunohistochemistry, and determination of basilar artery cross-sectional diameter. We also did biochemical analysis of cerebral hemisphere and brainstem specimens, measuring tissue lipid peroxidase and MPO activity. Results were compared between the groups and with their related controls. Results. In contrast to previous experimental findings in local ischaemia and ischaemia-reperfusion models, we found no histopathological or biochemical evidence to suggest a role for neutrophils and neutrophil-derived MPO in relation to subarachnoid haemorrhage and resultant vasospasm. Although we confirmed the successful induction of significant vasospasm and observed the clinical evidences of subsequent ischaemia, there was no notable accumulation of neutrophils or activity of neutrophil-derived MPO in the tissues studied. This suggests that the biological process induced by SAH follows a different pattern from that seen in local ischaemia and ischaemia-reperfusion injury.     

Prevention of vasospasm in subarachnoid haemorrhage. A controlled study with nimodipine

Summary A prospective randomized double blind study was conducted in 70 patients suffering from subarachnoid haemorrhage, due to aneurysm rupture, to determine if the use of nimodipine reduces the severity of ischaemic deficits secondary to vasospasm.At the end of the study, two patients had severe deficit or died in the treated group, while 10 had a bad outcome in the placebo group. Angiographic vasospasm was not significantly different in its frequency or its severity between the two groups. However, the association of extensive and diffuse vasospasm was less frequent in the nimodipine group.This study confims the effectiveness of Nimodipine in reducing the occurrence of neurological deficit due to vasospasm, even if this action is not observed in all cases.     

Blood-arterial wall barrier disruption to various sized tracers following subarachnoid haemorrhage

Summary Disruption of the blood-arterial wall barrier in the major cerebral arteries occurs following subarachnoid haemorrhage (SAH) and may be related to the pathogenesis of cerebral vasospasm. Using FITC dextrans of various sizes, the present study was undertaken to determine if the barrier disruption shortly after SAH occurs equally to various sized tracers. Forty-two Sprague-Dawley rats were divided into 5 groups. Four groups were injected with FITC-dextrans of differing molecular weights (MW): FD4 (MW=4,080), FD40 (MW=40,500), FD 70 (MW=71,400), and FD 150 (MW=156,900). One group was injected with horseradish peroxidase (HRP: MW=40,000). Each group was further divided into two subgroups: with or without SAH. SAH was induced by injecting arterial blood into the cisterna magna. To assess the integrity of the blood-arterial wall barrier by transmission electron microscope, the tracers were intravenously injected prior to sacrificing the animals. The groups without SAH showed no permeability of tracers into the subendothelial spaces of the basilar arteries. In contrast, with the exception of FD 150, FITC-dextrans (FD 4, FD 40, FD 70) were noticed in the subendothelial spaces. The distribution of FITC-dextrans in the elastic lamina was similar to that of HRP. These results suggest that barrier disruption occurs with a wide range of molecular sizes of FITC-dextrans, although there seems to be some limitation to the permeation of the larger molecules. The present study suggests that the mechanism of barrier disruption of the major cerebral arteries in the acute stage following SAH may be vesicular rather than by separation of tight junctions.     

Changes of glycogen and ATP contents of the major cerebral arteries after experimentally produced subarachnoid haemorrhage in the dog

Summary The contents of glycogen and ATP in the major cerebral arteries were examined in dogs undergoing subarachnoid haemorrhage (SAH). SAH was produced by a single injection of autologous arterial blood (1 ml/kg body weight) into the cisterna magna. Vertebral angiograms showed biphasic basilar arterial narrowings after the injection of blood: Early arterial narrowing occurred immediately after the injection and continued for a few hours. Late arterial narrowing occurred from Day 1 to Day 14 of post-SAH period, and recovered to the normal level on Day 21 of post-SAH period. The content of glycogen in the large pial arteries significantly decreased from Day 1 to Day 14 and returned to the control level on Day 21. The content of ATP in the large pial arteries also decreased from Day 1 to Day 7 and returned to the control level on Day 14. These results show that energy stores in the major cerebral arteries might be diminished during late arterial narrowing.     

Magnetic resonance imaging in experimental subarachnoid haemorrhage

Summary Background. We developed an MRI protocol to measure cerebrovascular diameter and blood flow velocity, and if we could detect cerebrovascular alterations after SAH and their impact on cerebral ischaemia.Method. SAH was induced in 15 Wistar rats by means of the endovascular filament method; 6 other rats served as control. MRI measurements were performed on a 4.7T NMR spectrometer 1 and 48 hours after SAH and 9 days thereafter. Diffusion-weighted and T₂-weighted images were acquired to detect cerebral ischaemia. The arterial spin labelling method was used to measure CBF. MR angiography was used to measure vessel diameter and blood flow velocity, from which the arterial blood flow was calculated.Findings. The ischemic lesion volume increased between 1 and 48 hours after SAH from 0.039 to 0.26 ml (P = 0.003). CBF decreased from 53.6 to 39.1 ml/100 g/min. The vessel diameter had narrowed, the blood flow velocity diminished as did the arterial blood flow in most vessels, but only the vasoconstriction in the right proximal ICA reached significance (0.49 mm to 0.43 mm, P = 0.016). Baseline values were restored at day 9.Conclusions. We showed that it is feasible to detect alterations of in-vivo vessel diameter and blood flow velocities and their consequences for brain damage after experimental SAH in the rat. The growth of the infarct volume between day 0 and 2 after SAH and the parallel vasoconstriction suggest that delayed cerebral ischaemia after SAH occurs in rats and that this may be caused by vasoconstriction.     

Effects of Intracisternal Methylprednisolone on Lipid Peroxidation in Experimental Subarachnoid Haemorrhage

Summary  The efficacy of intracisternal methylprednisolone was examined on lipid peroxidation in a canine subarachnoid haemorrhage (SAH) model. The concentration of lipid peroxides increased significantly in the cerebrospinal fluid (CSF) supernatant on Day 4, and also in the arterial wall on Day 7. Intracisternal administration of methylprednisolone reduced markedly the products of lipid peroxidation both in CSF and in the arterial wall. The findings suggest that lipid peroxidation might play a significant role in the genesis of vasospasm after SAH, and that direct administration of methylprednisolone into the subarachnoid space might reduce lipid peroxides in the arterial wall and so influence the prevention of vasospasm.     

Subarachnoid haemorrhage of unknown origin

Summary This study concerns 64 patients with angiographically negative subarachnoid haemorrhage (SAH) hospitalized in the period 1970–1982. Requisites for inclusion in the study were adequate angiographic demonstration of the carotid and vertebrobasilar systems and no clinical signs of spinal SAH or spontaneous intracerebral haematoma. The clinical data on the 64 cases confirm the close similarity, except for the prognostic factors, between angiographically negative SAH and SAH secondary to rupture of an intracranial saccular aneurysm. The study underlines the benign character of the clinical course and of the medium and long-term prognosis of the condition under study. In view of this, the hypothesis advanced sometime ago relating angiographically negative SAH to the rupture of microaneurysms (Ø<2 mm) of the large cerebral arteries with subsequent complete repair of the artery wall, or to the spontaneous thrombosis of intracranial saccular aneurysms, with the possibility of subsequent recanalization and risk of fresh rupture, would appear to be a reasonable one.     

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.     

Rapid bedside technique for percutaneous ventricular drainage in patients with severe subarachnoid haemorrhage. Technical note

Summary Using immediate ventricular drainage and aggressive postoperative therapy, poor-grade patients suffering ruptured cerebral aneurysms could have a greater opportunity for meaningful recovery. This treatment protocol is facilitated by percutaneous ventricular drainage at the bedside. A simple and less invasive technique reported here is particularly useful for neurosurgeons responsible for the treatment of severe subarachnoid haemorrhage on an emergency basis.     

Preventive therapy against delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage: Trials of thromboxane A2 synthetase inhibitor and hyperdynamic therapy

Summary The effects of thromboxane A₂ synthetase inhibitor and hyperdynamic therapy on delayed cerebral ischaemia following aneurysmal subarachnoid haemorrhage were evaluated in a series of twenty eight patients, who underwent aneurysmal clipping with 72 hours after subarachnoid haemorrhage. Postoperatively, 13 patients were treated with thromboxane A₂ synthetase inhibitor, Xanbon^® {sodium (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoate}. Hyperdynamic therapy with dobutamine was given to the remaining 15 patients. Of the 13 patients treated with Xanbon^®, nine patients (69%) developed delayed cerebral ischaemia and cerebral infarcts occurred in eight patients (62%). On the other hand, of the 15 patients treated with hyperdynamic therapy, only three patients (20%) manifested delayed cerebral ischaemia and two patients (13%) developed cerebral infarcts.In the present study, the patients treated with hyperdynamic therapy met an expected incidence of ischaemic events after subarachnoid haemorrhage by today's standards, while those treated with thromboxane A₂ synthetase inhibitor did not.     

Subarachnoid haemorrhage of unknown aetiology: what next?

Subarachnoid haemorrhage (SAH) is often associated with negative cerebral angiography. Following the exclusion of other causes, a patient may be suspected of harbouring an occult intracranial aneurysm, with risk of recurrent bleeding and death. These patients are often identified on the basis of clinical presentation and computed tomography (CT) findings, and require expeditious further investigation if morbidity and mortality are to be minimized. Currently available options include repeated cerebral angiography, surgical exploration, and the newer technologies of computed tomography angiography (CTA) and magnetic resonance angiography (MRA). We review these options, based on current literature, with particular emphasis on the expanding roles of CTA and MRA. A multimodality management protocol is proposed, with decisions based on clinical urgency, patient progress and the natural history of aneurysmal SAH, particularly vasospasm and aneurysm thrombosis.