Alterations in the cellular immune response of patients with cerebral glioma, benign intracranial tumour, and spontaneous subarachnoid haemorrhage measured in vitro by the leucocyte migration inhibition test

Leucocyte migration inhibition in response to ubiquitous antigens was studied in 104 patients as an in vitro indicator of cell-mediated immunity. Patients with cerebral glioma, benign intracranial tumours, and subarachnoid haemorrhage demonstrated impaired inhibition of leucocyte migration compared with control subjects. The greatest impairment occurred in patients with subarachnoid haemorrhage, while the least impairment was seen in patients with glioma. Significant rises in inhibition of leucocyte migration in response to antigen preparations from glioma and normal brain were seen in the early post-operative period in patients with glioma and subarachnoid haemorrhage. Impaired cellular immunity, together with sensitivity of lymphocytes to brain-derived antigens, are features of cerebral disease in general and not specific for glioma.     

Immunological observations on patients with acute cerebral vascular disease

Cell-mediated and humoral immunity was studied in 74 patients with acute cerebral vascular disease. During the first two days after the onset of disease marked changes of cell-mediated immunity were observed, manifested as a decrease in total lymphocyte count in the peripheral blood, decrease in number of T lymphocytes, depression in lymphocyte blastogenesis and production of the migration inhibition factor, and a delayed-type skin reactivity. The changes were most evident in patients with severe lesions of brain tissue resulting from primary cerebral haemorrhage and cerebral infarction with fatal outcome. In the group of patients with cerebral infarction with improvement of neurological symptoms the immunological changes were not so pronounced as in the two above-mentioned groups, the smallest changes being found in patients with subarachnoid haemorrhage. We suppose that the depression in the immunne function was caused by severe stress during the course of disease. Impairment of the immune function may increase susceptibility to infection. The humoral immune response was not so evidently changed, and the observed increase of IgA in the sera was probably present before the stroke. In cases with good clinical course some improvement in the immunological parameters was observed, but full recovery did not occur until 3 weeks after the onset of disease.     

Leucocyte migration inhibition in myasthenia gravis

Summary Cellular hypersensitivity in myasthenia gravis (MG) to the thymus, muscles and peripheral nerves was examined by the method of the leucocyte migration inhibition test. The group of MG patients without thymoma had inhibition of leucocyte migration by thymus antigens. After thymectomy, they had a normal value of leucocyte migration. However, in the group of MG patients with thymoma, the inhibition of leucocyte migration by thymus antigens was observed after thymectomy. No significant inhibition of leucocyte migration was observed using muscle and peripheral nerve antigens. Cellular immunity in myasthenia gravis and the pathogenesis of the disease was discussed.

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Zusammenfassung Mit der Methode des Leukocytenmigrations-Hemmtestes wurde die celluläre Überempfindlichkeit der Myastheniepatienten gegenüber Thymus, Muskel und peripherem Nervengewebe untersucht. In der Gruppe von Myastheniepatienten ohne Thymom ließ sich eine Hemmung der Leukocytenmigration durch Thymusantigene nachweisen. Nach Thymektomie normalisierten sich die entsprechenden Befunde. In der Gruppe der Myastheniepatienten mit Thymon jedoch wurde die Hemmung der Leukocytenmigration durch Thymusantigene auch nach der Thymektomie festgestellt. Es wurde keine nennenswerte Hemmung der Leukocytenmigration bei Verwendung von Muskel- bzw. peripherer Nervenantigene festgestellt. Die celluläre Immunität bei der Myasthenie und die Pathogenese der Krankheit werden diskutiert.

     

DNA synthesis and intracellular calcium elevation in porcine cerebral arterial smooth muscle cells by cerebrospinal fluid from patients with subarachnoid haemorrhage.

To understand the molecular mechanism of the pathogenesis of cerebral vasospasm following subarachnoid haemorrhage, we analysed the effect of cerebrospinal fluid from patients with subarachnoid haemorrhage on DNA synthesis and cytosolic-free calcium elevation in cultured porcine cerebral smooth muscle cells. Cerebrospinal fluid from patients on day 2 after subarachnoid haemorrhage induced transient elevation in cytosolic-free calcium levels. In contrast, the maximal elevation of cytosolic-free calcium levels induced by cerebrospinal fluid from control patients (without subarachnoid haemorrhage) was significantly lower than that induced by cerebrospinal fluid from patients with subarachnoid haemorrhage. In cultured porcine cerebral arterial smooth muscle cells, cerebrospinal fluid from patients with subarachnoid haemorrhage promoted levels of [3H]-thymidine incorporation (DNA synthesis) more than 2.5-fold higher than that promoted by cerebrospinal fluid from control patients without subarachnoid haemorrhage. However, in cultured aortic smooth muscle cells, there was no significant difference in [3H]-thymidine incorporation between cerebrospinal fluid from patients with subarachnoid haemorrhage and that by control cerebrospinal fluid. From these results in cerebral arterial smooth muscle cells, cerebrospinal fluid from patients following subarachnoid haemorrhage may play not only constrictive functions, evidenced by cytosolic-free calcium elevations, but also proliferative functions, demonstrated by promotion of [3H]-thymidine incorporation. The relevance of these factors to vasospasm will be discussed.     

Intra-arterial papaverine in the management of cerebral vasospasm following subarachnoid haemorrhage

Between July 1992 and January 1993 a prospective pilot study of the efficacy of intra-arterial papaverine in the management of clinically significant angiographically confirmed cerebral vasospasm arising as a consequence of aneurysmal subarachnoid haemorrhage was conducted. During this period 40 patients were managed with aneurysmal subarachnoid haemorrhage. All patients were treated with nimodipine from day of admission and carefully monitored in the neurosurgical intensive care unit. 11 of the 40 patients subsequently developed clinically significant angiographically confirmed cerebral vasospasm and underwent angiography with selective internal carotid or vertebral artery injection of papaverine in 12 to 40 mg boluses to a maximum of 450 mg. A good angiographic response was seen in all cases. Two patients underwent repeat procedures, in one case twice. Overall clinical outcome was good in 7 cases, moderate disability in 2 cases, severe disability in 1 case and death in 1 case. In patients who underwent the procedure in less than 4 hours from the onset of their deficits (n=8) a good outcome was seen to occur in 7 patients with one patient sustaining a moderate deficit. Complications from the procedure were seizures in 3 patients and a momentary locked-in-syndrome in one case. All complications were seen with a fast bolus of the higher volume papaverine and have not occurred with a slow infusion of the lower dose boluses. None of the patients developing these complications had them recur outside the angiogram suite. Our conclusion is that this form of treatment supplements the therapeutic regimens now available in the management of cerebral vasospasm.     

Magnesium: a useful adjunct in the prevention of cerebral vasospasm following aneurysmal subarachnoid haemorrhage.

Despite recent advances in the management of aneurysmal subarachnoid haemorrhage delayed ischaemic deficits from cerebral vasospasm remains a major cause of morbidity and mortality. As magnesium is a potent cerebral vasodilator we have introduced routine supplementation in patients presented with subarachnoid haemorrhage to determine whether there has been a reduction in the incidence of cerebral vasospasm. Method: All patients presented with aneurysmal subarachnoid haemorrhage from February 1997 were included except those who presented after day 5 following bleed. Identical management protocol was used except intravenous magnesium supplementation which was introduced to all patients from May 1999. Incidence of cerebral vasospasm on angiograms among the two groups was analysed. Results: Seven out of 10 patients who did not receive magnesium supplement developed vasospasm requiring intra-arterial papaverine compared with 2 of 13 patients among the treated group (P<0.008). Conclusions: From our pilot study it appears that magnesium supplement has a beneficial role in the prevention of cerebral vasospasm following aneurysmal subarachnoid haemorrhage. Further studies would seem justified.     

Spectrum of altered reactivity of isolated cerebral arteries following subarachnoid haemorrhage--response to potassium, pH, noradrenaline, 5-hydroxytryptamine, and sodium loading

The circular contractile responses to various stimuli have been measured in segments of cerebral arteries (both middle cerebral and basilar) taken from dogs either 3 or 7 days following the cisternal injection of autologous blood under anaesthesia. The maximum contractile response to 5-hydroxytryptamine was increased significantly 7 days following subarachnoid haemorrhage; the response to noradrenaline also increased but not significantly at 7 days. The contractile response to a raised extracellular potassium concentration (25 and 100 mM) was slightly depressed by 7 days, and the response to a fall in extracellular pH was depressed by 43% both 3 and 7 days following subarachnoid haemorrhage. The ability of these arteries to handle a sodium load was also assessed. The arteries were sodium loaded for various periods of time in mock cerebrospinal fluid with a zero potassium concentration. On transfer to 25 mM potassium solution, the duration but not the magnitude of the initial relaxation phase prior to a final contraction was greater with increasing time spent in the zero potassium solution. Both the magnitude and the duration of this relaxation phase, which reflect in part the ability of the vascular smooth muscle to extrude the sodium load, were increased in arteries following subarachnoid haemorrhage when compared with control arteries. These results demonstrate that the altered reactivity of cerebrovascular smooth muscle following subarachnoid haemorrhage persists in vitro and is more than simply an enhanced response to biogenic amines.     

DNA synthesis and intracellular calcium elevation in porcine cerebral arterial smooth muscle cells by cerebrospinal fluid from patients with subarachnoid haemorrhage

Abstract

To understand the molecular mechanism of the pathogenesis of cerebral vasospasm following subarachnoid haemorrhage, we analysed the effect of cerebrospinal fluid from patients with subarachnoid haemorrhage on DNA synthesis and cytosolic-free calcium elevation in cultured porcine cerebral smooth muscle cells. Cerebrospinal fluid from patients on day 2 after subarachnoid haemorrhage induced transient elevation in cytosolic-free calcium levels. In contrast, the maximal elevation of cytosolic-free calcium levels induced by cerebrospinal fluid from control patients (without subarachnoid haemorrhage) was significantly lower than that induced by cerebrospinal fluid from patients with subarachnoid haemorrhage. In cultured porcine cerebral arterial smooth muscle cells, cerebrospinal fluid from patients with subarachnoid haemorrhage promoted levels of [3H^-thymidine incorporation (DNA synthesis), more than 2.5-fold higher than that promoted by cerebrospinal fluid from control patients without subarachnoid haemorrhage. However*, in cultured aortic smooth muscle cells, there was no significant difference in [_3H]-thymidine incorporation between cerebrospinal fluid from patients with subarachnoid haemorrhage and that by control cerebrospinal fluid. From these results in cerebral arterial smooth muscle cells, cerebrospinal fluid from patients following subarachnoid haemorrhage may play not only constrictive functions, evidenced by cytosolic-free calcium elevations, but also proliferative functionsdemonstrated by promotion of [3H]-thymidine incorporation. The relevance of these factors to vasospasm will be discussed. [Neurol Res 1992; 14: 330-334]     

Monoamine metabolism and sympathetic nervous activation following subarachnoid haemorrhage: influence of gender and hydrocephalus

Subarachnoid haemorrhage is a serious condition, often accompanied by cerebral vasospasm and hydrocephalus, which may result in delayed cerebral ischaemia and neurological deterioration. While the mechanisms responsible remain unknown, activation of the sympathetic nervous system, leading to elevated levels of circulating catecholamines is, at least in part, implicated. In this study, we sought to examine the importance of sympathetic nervous activation and its relation to brain monoaminergic neurotransmission in 25 patients following subarachnoid haemorrhage by examining plasma and cerebrospinal fluid levels of the catecholamines noradrenaline, adrenaline and dopamine, and their metabolites. Total body sympathetic activity was concurrently assessed using isotope dilution methodology. In the early phase following subarachnoid haemorrhage patients exhibited markedly elevated rates of spillover of noradrenaline to plasma (9.11 +/- 1.12 vs. 3.39 +/- 0.26 nmol/min, p < 0.01), with rates being higher in those patients in whom hydrocephalus developed (11.15 +/- 1.40 vs. 7.90 +/- 1.41 nmol/min, p = 0.05). The degree of sympathetic nervous activation tended to be higher in females compared with males. Lower cerebral perfusion pressures were observed in those patients in whom cerebrospinal fluid concentrations of noradrenaline and dopamine metabolites were high. A marked sympathetic nervous activation, more pronounced in women and in those with hydrocephalus, occurs following subarachnoid haemorrhage. The diminished cerebral perfusion seen following subarachnoid bleeding may occur as a result of activation of central catecholaminergic neurones.     

Meningeal hemorrhage at a neurological intensive care unit. Study of a series of 234 unselected cases

In a 6-year-period, 234 cases of subarachnoid haemorrhage were observed in a neurological intensive care unit: 74 were male and 69 were female, aged from 15 to 94 years. In 15 cases no other investigation than C.T. scan or lumbar puncture was performed. In 143 patients, cerebral angiography demonstrated a ruptured aneurysm of cerebral vessels and 99 were operated. The prognosis was poor in old age, with aneurysms located on the anterior part of the circle of Willis, severe neurological involvement and extensive subarachnoid or ventricular haemorrhage. A recurrence of the haemorrhage occurred in 18 cases and cerebral ischaemia was present in 69 patients. The mortality rate of patients with ruptured aneurysms was 47.5 p. 100 (30.4 p. 100 when operated). Seventeen patients probably had a ruptured cerebral aneurysm but cerebral angiography was not conclusive; 12 of them died. In 15 other cases, the haemorrhage was related to cerebral angiomas (3 cases), endocarditis (2), coagulation disorders (6), cranial trauma (3) and Moya-Moya disease (1). In 44 patients, the aetiology of subarachnoid haemorrhage was unknown and the mortality rate was 14 p. 100. The poor prognosis of subarachnoid haemorrhage, worse than in neurosurgical series, is emphasized. It may be explained by the lack of selection of the patients in a non-surgical department.     

A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project--1981-86. 2. Incidence, case fatality rates and overall outcome at one year of cerebral infarction, primary intracerebral and subarachnoid haemorrhage.

The age and sex specific incidence rates for cerebral infarction, primary intracerebral haemorrhage and subarachnoid haemorrhage in a population of approximately 105,000 are presented. Over four years 675 patients with a first-ever stroke were registered with the Oxfordshire Community Stroke Project. The pathological diagnosis was confirmed by computerised tomography (CT) scan, necropsy or lumbar puncture (cases of subarachnoid haemorrhage only) in 78% of cases and a further 17% were diagnosed according to the Guy's Hospital Stroke Diagnostic Score. The proportion of all first-ever strokes by pathological type was: cerebral infarction 81% (95% confidence interval 78-84), primary intracerebral haemorrhage 10% (8-12), subarachnoid haemorrhage 5% (3-7) and uncertain type 5% (3-7). These proportions are similar to other community-based studies. The overall 30 day case fatality rate was 19% (16-22), that for cerebral infarction being 10% (7-13), primary intracerebral haemorrhage 50% (38-62) and subarachnoid haemorrhage 46% (29-63). One year post stroke 23% (19-27) with cerebral infarction were dead and 65% (60-70) of survivors were functionally independent. The figures for primary intracerebral haemorrhage were 62% (43-81) dead and 68% (50-86) of survivors functionally independent and for subarachnoid haemorrhage were 48% (24-72) dead and 76% (56-96) of survivors functionally independent. There are important differences between these rates and those from other sources possibly due to more complete case ascertainment in our study. Nevertheless, the generally more optimistic early prognosis in our study, particularly for cases of cerebral infarction, has important implications for the planning of clinical trials and for the expected impact that any treatment might have on the general population.     

Impaired thymus-derived lymphocyte function in patients with malignant brain tumour

Cell-mediated immunity was evaluated in 28 patients with malignant glioma, using in vivo and in vitro tests of lymphocyte function. The results were compared to those found in patients with carcinomatosis (11 subjects), benign brain tumours (9), other neurological disorders (20) and normal, healthy controls (21). Significant impairments of delayed hypersensitivity responses to common antigens was found in patients with malignant glioma and in those with generalised malignancy. A less significant depression of lymphocyte responses was also detected in patients with meningioma. The impairment in cell-mediated immunity was shown not be due to a serum blocking factor. Our data indicate that there is defective T cell function in patients with glioma, similar to that reported in cases with malignancies outside the central nervous system. This impaired immunity may have clinical significance.     

Subarachnoid haemorrhage in children caused by cerebral tumour.

Subarachnoid haemorrhage in children is uncommon. In a review of 110 children with an intracranial tumour over a 20 year period there were four patients (3.6%) who presented with the typical features of a subarachnoid haemorrhage. During the same period of time there were 15 children who presented with subarachnoid haemorrhage of which 26% were secondary to a cerebral tumour. This study suggests that cerebral tumour is a common cause of subarachnoid haemorrhage in children.     

Enlargement of the third ventricle and hyponatraemia in aneurysmal subarachnoid haemorrhage.

Hyponatraemia following aneurysmal subarachnoid haemorrhage is associated with an increased risk of cerebral infarction. Whether the development of hyponatraemia was related to enlargement of the third ventricle on the admission CT scan was investigated in a consecutive series of 133 patients who were seen within 72 hours of aneurysmal haemorrhage. Hyponatraemia occurred significantly more often in patients with enlargement of the third ventricle (with or without dilatation of the lateral ventricles) than in patients with a normal ventricular system (20/41 versus 24/92, p = 0.016). After ventricular drainage, the sodium levels returned to normal in two patients in whom the size of the third ventricle decreased and not in four patients with persistent enlargement of the third ventricle. The significant relationship between enlargement of the third ventricle and hyponatraemia remained after adjustment for the amount of cisternal blood, but not after adjustment for the amount of intraventricular blood. These results suggest that the size of the third ventricle is an important but not the only factor in the relationship between acute hydrocephalus and hyponatraemia in patients with aneurysmal subarachnoid haemorrhage.     

Spasm index in subarachnoid haemorrhage: consequences of vasospasm upon cerebral blood flow and oxygen extraction

A spasm index, defined as transcranial Doppler detected flow velocity in the middle cerebral artery divided by regional cortical cerebral blood flow (CBF), was used on 24 patients with subarachnoid haemorrhage (SAH). The aim was to estimate degree and time course of vasospasm, even in cases with great day-to-day variation in CBF, and correlate to CBF and oxygen extraction. All patients showed increase in spasm indices with peak index in the second or third week. The index seemed stable in spite of day-to-day fluctuations in CBF. Severe vasospasm were associated with poor clinical condition, reduced CBF (less than 30) and high AVDO2. The same picture could be seen with minor degree of vasospasm, probably, in some cases, due to high intracranial pressure. The results suggest that the spasm index is useful in monitoring patients with subarachnoid haemorrhage, and that severe vasospasm has a negative influence on clinical condition, CBF and oxygen extraction.     

Characteristics of intracranial aneurysms and subarachnoid haemorrhage in patients with polycystic kidney disease

Background and Purpose: Subarachnoid haemorrhage is a common cause of death in patients with autosomal dominant polycystic kidney disease (ADPKD), but little is known about specific characteristics of subarachnoid haemorrhage and intracranial aneurysms in this group of patients. We performed a systematic review on site, size and number of aneurysms, age at time of rupture, gender, and family history in patients with ADPKD and intracranial aneurysms. We also studied the frequency of ADPKD in patients with subarachnoid haemorrhage treated in our hospital. Methods: We performed a MEDLINE search and checked the reference lists of all relevant publications to identify all articles published from 1980 to 2000 on intracranial aneurysms or subarachnoid haemorrhage in ADPKD. We studied our database of patients with subarachnoid haemorrhage treated between 1978 and 1999 for the presence of ADPKD. Results: We included 53 articles on 369 ADPKD patients (139 [54 %] women) with 462 intracranial aneurysms. Of the 273 aneurysms with specified locations 105 (38 %) were located on the middle cerebral artery in and on the anterior communicating artery in 83 patients (30 %). In 253 patients with data about relatives, the family history was positive for intracranial aneurysms or subarachnoid haemorrhage in 102 (40 %). The average age at which subarachnoid haemorrhage had occurred in 258 was 41 years; of 158 in whom the gender was given; 96 (52 %) were women. Of the 160 patients with data on outcome, 69 (43 %) had died as the result of the subarachnoid haemorrhage. Of the 1147 patients treated for aneurysmal subarachnoid haemorrhage in our institution (mean age 53 years; 65.5 % women), 5 (0.44 %) had ADPKD. Conclusions: Compared with data on patients without ADPKD, subarachnoid haemorrhage in patients with ADPKD occurs not only often in a familial setting of subarachnoid haemorrhage, but also at an earlier age and more often in men. In patients with ADPKD, the most frequent site of aneurysms is the middle cerebral artery. The proportion of patients with ADPKD among all patients with subarachnoid haemorrhage is very small. Received: 17 April 2002, Received in revised form: 11 October 2002, Accepted: 16 October 2002 Correspondence to Professor Gabriel J. E. Rinkel     

Beneficial effect of renin-angiotensin system for maintaining blood pressure control following subarachnoid haemorrhage

Subarachnoid haemorrhage is a serious condition often accompanied by delayed cerebral ischaemia. Earlier reports have provided evidence suggesting a role for angiotensin II in the development of cerebral vasospasm following subarachnoid bleeding. We sought to examine the influence of angiotensin II blockade with losartan on blood pressure and survival in animals following experimental subarachnoid haemorrhage, induced in conscious rats by injecting homologous blood via a catheter placed along the surface of the brain. We combined measurements of plasma renin activity with blood pressure recording in order to examine renin-angiotensin system activation following experimental subarachnoid haemorrhage. Following subarachnoid injury an approximately three-fold increase in plasma renin activity occurred (3.4 +/- 1.0 vs. 10.1 +/- 1.8 ng angiotensin I produced/ml/h, p < 0.01). In animals treated with losartan (20 mg/kg) prior to the induction of subarachnoid haemorrhage blood pressure fell dramatically following the cerebral injury (124 +/- 5 vs. 94 +/- 7 mmHg, p < 0.001), whereas blood pressure remained unchanged in control animals. Survival was markedly reduced in those animals treated with losartan. Given the pronounced decrease in blood pressure and impaired survival following subarachnoid haemorrhage in animals treated with losartan, it would appear that the acute activation of the renin-angiotensin system following this insult is in fact a desirable, compensatory response.     

The urinary catecholamine and plasma cortisol levels in patients with subarachnoid haemorrhage

In a study of 37 cases of subarachnoid haemorrhage high urinary catecholamine (normetanephrine and metanephrine) and plasma cortisol excretion were observed. These high levels persisted over a 14-day period in patients who appeared otherwise well and could not be attributed to a normal stress response. Nevertheless higher levels reflected an impaired conscious state and suggested a correlation with cerebral vasospasm. On the basis of cerebral angiographic findings, cases were divided into non-spasm and spasm groups, and a third group of patients who showed no spasm in their initial angiogram but did so on a subsequent angiogram, was termed the prespasm group. This revealed significantly raised urinary catecholamine and plasma cortisol values in the pre-spasm group compared with the non-spasm group, and, on developing spasm, a further significant increase in urinary normetanephrine levels was noted. The possible role of the sympathetic nervous system, under the sensitizing action of corticosteroids, in the production and maintenance of cerebral artery spasm in subarachnoid haemorrhage is discussed.     

False positive diagnosis of subarachnoid haemorrhage on computed tomography scan

Five cases are presented in which subarachnoid haemorrhage (SAH) was diagnosed by clinicians and/or radiologists on computed tomography (CT) scan. No macroscopic SAH was present on neuropathologic examination. In retrospect it was considered that the neurologic signs and the neuropathologic features close to the time of CT scan were in keeping with the patients being brain dead, i.e. had no cerebral blood flow at the time of the scans. On review of the CT scans it was considered the hyperdense material seen in the subarachnoid space must have been blood in congested subarachnoid blood vessels. The cases demonstrate that if a patient presents comatose and CT scan shows cerebral oedema then the presence of high attenuation material in the subarachnoid space should not necessarily be considered to represent SAH. The value of seeking radiological opinion is highlighted but even then diagnosis may be difficult.     

Does alcohol intoxication precipitate aneurysmal subarachnoid haemorrhage?

Seventy-five consecutive patients aged 15 to 55 years with aneurysmal subarachnoid haemorrhage verified by CSF examination and cerebral angiography or at necropsy were studied. In 19 cases (25%; four women and 15 men) the bleeding was preceded within 24 hours by a bout of alcohol drinking. Alcohol-related cases composed 33% and 14% of the patients in the age groups 15-40 and 41-55 years, respectively. Alcohol intoxication preceding the subarachnoid haemorrhage was two to four times as common in male and three to five times as common in female patients as alcohol intoxication in the general Finnish population of the same age and sex. Occasional alcohol intoxication seems to carry an increased risk of aneurysmal subarachnoid haemorrhage.