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Cerebrospinal fluid and plasma vasopressin were measured in patients with cerebral disorders associated with varying levels of elevated intracranial pressure. The mean cerebrospinal fluid vasopressin concentration was significantly increased in patients with pseudotumor cerebri (2.0 +/- 0.2 [SEM] pg/ml), intracranial tumor (2.3 +/- 0.4 pg/ml), and intracranial hemorrhage (1.9 +/- 0.3 pg/ml) compared with control patients (1.2 +/- 0.1 pg/ml). A significant relationship was found between intracranial pressure and the cerebrospinal fluid vasopressin concentration within all groups of patients and in the whole sample as well (r = 0.79; p less than 0.001). In the groups of patients with intracranial tumor, hydrocephalus, and intracranial hemorrhage, some individuals showed plasma vasopressin concentrations inappropriate to the corresponding plasma osmolality, but no relationship was found between intracranial pressure and plasma vasopressin concentration. It is suggested that increased intracranial pressure is a stimulus to centrally released vasopressin. The clinical importance of increased cerebrospinal fluid vasopressin concentrations is still not known.

This report concerns three patients in whom continuous intravenous infusion of Diazemuls (diazepam dissolved in soya bean oil and emulsified) diluted in 5.5% glucose was used for the controlling of epileptic seizures (status). Diazemuls infusion was effective in one patient with complex partial status epilepticus; in another patient with convulsion secondary to a brain stem infarct, the convulsions were abolished; while only reduced jerking was achieved in the third patient suffering from myoclonic jerks caused by anoxic brain damage. Infusion time ranged from 15 to 33 h. The serum concentrations of diazepam obtained during the infusions were higher than recommended in the literature for treatment of status epilepticus, but could not be correlated to either clinical efficacy or infusion rate.

The responses of plasma and ventricular cerebrospinal fluid (CSF) vasopressin concentration to dehydration, postural changes, and induction of nausea were studied in 21 patients with hydrocephalus of various etiology. The 24-h dehydration test evoked a significant increase in plasma osmolality and vasopressin concentration, whereas the concentration of vasopressin in CSF was unchanged. Head-up tilt to 50 degrees for 45 min with a tilt bed resulted in a modest increase of plasma vasopressin in patients who did not develop presyncopal symptoms, but no changes were seen in CSF vasopressin. Induction of nausea by subcutaneously injected apomorphine provoked a marked (20- to 50-fold) rise in plasma vasopressin concentration within 15 min, and the plasma concentration was significantly increased above base-line values for 60-120 min. Despite the prolonged period of high plasma vasopressin concentration CSF vasopressin was not influenced by the apomorphine injection. The findings suggest that the concentration of vasopressin in the CSF is controlled by mechanisms other than the well-known osmotic and nonosmotic stimuli of vasopressin release into the blood.

Brain water self diffusion was investigated by magnetic resonance scanning in 7 patients fulfilling conventional diagnostic criteria for pseudotumour cerebri. Quantitative diffusion measurements were obtained using single spin echo pulse sequences with pulsed magnetic field gradients of different magnitude. In all patients the diffusion images showed an increased diffusion in various brain regions when compared with the diffusion coefficients for corresponding regions in healthy subjects. In 3 pseudotumour patients the increased self diffusion was localized to the periventricular regions, while 4 patients had increased diffusion in the whole brain. The findings indicate the presence of increased brain water content both intra- and extracellularly suggesting that patients with pseudotumour have two defects of pathogenetical significance: intracellular water accumulation and increased resistance to cerebrospinal fluid (CSF) outflow leading to an interstitial oedema.

The variation in vasopressin concentrations of ventricular cerebrospinal fluid and plasma throughout a 24-h period was studied in 10 patients with hydrocephalus. In 6 control patients, the diurnal variation in plasma vasopressin concentrations was studied. Vasopressin concentrations were determined by radioimmunoassay in plasma and in extracted and unextracted cerebrospinal fluid. Cortisol and osmolality in plasma were also measured. Vasopressin concentrations measured in extracted cerebrospinal fluid showed only small intra- and interindividual variation, while the corresponding values for unextracted cerebrospinal fluid were 2-5-fold higher and showed more variation. Plasma vasopressin concentrations varied considerably throughout the 24-h period in the individual hydrocephalic patient and between the patients. The pattern of variation was inconstant with no circadian rhythm, and the variation was not related to any changes in plasma osmolality, blood pressure or intracranial pressure. In some of the patients, the normal diurnal pattern of variation in plasma cortisol was broken, however, without a relation to the observed fluctuations in vasopressin concentrations. The abnormal variation of plasma vasopressin and cortisol was considered to reflect stress in connection with the intracranial pressure monitoring procedure. In the control patients, plasma vasopressin showed only small variations and plasma cortisol showed a normal diurnal rhythm. It is concluded that cerebrospinal fluid vasopressin concentration in patients with hydrocephalus is very constant throughout the day, even when plasma vasopressin concentrations show marked episodic increases. Thus, a circadian rhythm in the cerebrospinal fluid vasopressin concentration, as reported in several animal species, could not be confirmed in these patients.

CSF concentrations of vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), noradrenaline (NA) and dopamine (DA) were measured in the lateral ventricles and at the lumbar level in patients with normal pressure hydrocephalus (NPH). The concentrations of VIP (n = 15), NA (n = 10) and DA (n = 10) were significantly higher at the lumbar level than at the ventricular level, whereas the concentrations of CCK (n = 9) were similar at the two sites. A significant positive correlation between the concentrations measured at the two levels was found for VIP (rs = 0.65; p less than or equal to 0.01) and DA (rs = 0.94; p less than or equal to 0.001). The results indicate that the concentrations of transmitter substances measured in CSF at the lumbar level not necessarily are indicative for concentrations measured more centrally. The negative correlations between Evans ratio and L-CSF VIP (rs = -0.76; p less than or equal to 0.001), and between resistance to outflow and V-CSF as well as L-CSF CCK (rs = -0.75); p less than or equal to 0.05) might be explained by a reduction in number of cortical neurons or by disturbances in CSF dynamics in patients with NPH.

The development of sensitive radioimmunoassays has permitted measurement of the low concentration of vasopressin in the human cerebrospinal fluid. There is accumulating evidence to suggest that vasopressin is involved in a variety of brain functions. As an effective blood-cerebrospinal fluid barrier to vasopressin has been demonstrated, the concentration of vasopressin in the cerebrospinal fluid probably reflects the release of vasopressin within the brain. In human subjects without intracranial disease, the concentration of vasopressin in the cerebrospinal fluid is in the range 0.5-2.0 pg/ml with only little diurnal variation. Intracranial disorders associated with increased intracranial pressure may cause increased cerebrospinal fluid vasopressin concentrations, whereas degenerative brain diseases are associated with low concentrations. Only little is known about the physiologic stimuli which alter the concentration of vasopressin in cerebrospinal fluid. The concentration in cerebrospinal fluid is not influenced by a number of stimuli that cause release of vasopressin into the blood, i.e. changes in plasma osmolality, postural changes, and nausea. Elevation of the intracranial pressure, changes in the composition of the cerebrospinal fluid, electrical stimulation of the hypothalamus, and severe hemorrhage provoke an increase in cerebrospinal fluid vasopressin level.

Resistance to CSF-outflow (Rout) and intracranial pressure (ICP) were measured in 33 patients with hydrocephalus after subarachnoid haemorrhage (SAH). Eleven patients examined between 10 to 30 days after SAH had high pressure hydrocephalus (HPH). Twenty-two patients had normal pressure hydrocephalus (NPH). All HPH-patients had ICP above 15 mmHg, plateau waves and B-waves, a median Rout of 59 mmHg x ml-1 x min-1 (range 29-100). All NPH-patients had a normal ICP level, no plateau waves, but long periods of B-waves and a median Rout of 22 mmHg x ml-1 x min-1 (range 6-47). Of the 11 patients with HPH six were shunted and five had temporary ventricular drainage. Five patients improved and six died. Of the five survivors only one went back to work. Of the 22 NPH-patients 18 were treated with a shunt, one refused shunt operation and three had normal Rout. Seventeen improved after shunting. At follow-up 12 had a normal social life, 5 lived in a nursing home and 1 was dead. Thus, early development of hydrocephalus after subarachnoid haemorrhage is associated with a high Rout and a high ICP, whereas late (more than one month) hydrocephalus may be associated with normal ICP and high Rout. Patients with NPH and a high Rout have frequent B-waves and should be shunted. Patients with a long interval from subarachnoid haemorrhage to the diagnosis of hydrocephalus often have a normal ICP, low frequency of B-waves, normal CSF-dynamics and need no shunting.

Vasopressin (ADH) was measured in CSF and plasma in 75 evaluable patients with known or suspected CNS metastases from small-cell bronchogenic carcinoma (SCBC), and in 66 control patients having neither malignant disease nor organic CNS disease. The presence of CNS metastases was confirmed or excluded on the basis of computed tomographic scans, neurologic examination, and autopsy. Twenty-four of the 75 patients had no CNS metastases. Ten of the 51 patients with CNS metastases had leptomeningeal carcinomatosis (MC). CSF-ADH was significantly increased in patients with MC (P less than .05), but not in patients having exclusively parenchymatous CNS metastases. Taking 2 pg/mL (95th percentile of control patients) as the upper limit of normal, 15 SCBC patients had elevated CSF-ADH, including 12 patients with CNS metastases and six patients with MC. The CSF-ADH to plasma ADH ratio was significantly increased in patients with CNS metastases (P less than .05). Patients without CNS metastases had a ratio less than or equal to 0.8 whereas the ratio was greater than 0.8, in 21 of the 51 patients with CNS metastases. The positive and negative predictive values with 95% confidence limits were 84% to 100% and 31% to 59%, respectively. Patients with inappropriate secretion of ADH (SIADH) constituted a significantly greater proportion of patients with elevated CSF-ADH than of patients with normal CSF-ADH levels (P less than .05). In addition, patients with SIADH constituted a significantly greater proportion of patients with MC than of patients with parenchymatous metastases (P less than .05). The diagnostic application of these findings is limited because of the large number of false-negative results, but it may prove to be of value in conjunction with the measurement of other tumor markers.

Lumbar CSF concentration of 5-HIAA, MHPG, and HVA were measured in patients with depression, dementia due to normal pressure hydrocephalus (NPH) and in controls. Moreover, ventricular concentrations of the metabolites were measured in patients with NPH. It was aimed to match patients and controls for age, sex, and body height. Non-parametric statistics were used throughout the study. No differences in lumbar concentrations of CSF 5-HIAA, MHPG and HVA were found between the different diagnostic groups. A ventriculo-lumbar gradient of 5-HIAA and HVA being 4:1 and 5:1, respectively, was found in patients with NPH. No correlation between the difference in ventricular and lumbar concentrations and body height was found, suggesting that body height may be an inaccurate measure for the rostro-caudal gradient. Moreover, no correlation between ventricular and lumbar levels of 5-HIAA and HVA was seen.

Stroke incidence in Copenhagen, Denmark was recorded in a random population sample of 19,327 persons invited for two health examinations with 5 years' interval from 1976 to 1983. Stroke incidence increased exponentially with age. After adjustment to the age and sex distribution of the Danish population in 1980, the estimated incidence of first stroke was 1.41/1000 women and 2.48/1000 men; the total incidence was 1.94/1000 population. Risk factor analysis was based on the initial examination of 13,088 persons greater than 35 years old without previous stroke who responded to the first invitation, in whom 295 first strokes were subsequently observed. We used the regression model of Cox. However, our use of this model differs from the somewhat automatic procedures normally used to develop prognostic models. Evaluation of the causative effect of a particular risk factor requires that the direction of mutual influences between the factor in question and other risk factors is established/postulated. Among the 16 potential risk factors for stroke we examined, significant effects were found for age, sex, household income, smoking habits, systolic blood pressure, diabetes, plasma cholesterol concentration, ischemic heart disease, and atrial fibrillation. No significant effect could be demonstrated for a positive family history of stroke, years of school education, marital status, alcohol consumption, daily use of tranquilizers, body mass index, or postmenopausal hormone treatment.

We report a case of early syphilis with multiple bone lesions which all resolved after treatment with penicillin. We discuss why bone lesions may be more prevalent than generally believed and why 99m-Tc-MDP-bone scintigraphy is more sensitive than radiography in detecting syphilitic periostitis.

The response of plasma and ventricular cerebrospinal fluid vasopressin concentration to short-time induced intracranial hypertension was studied in 8 patients with hydrocephalus, defined as ventricular enlargement on computerized tomography. In connection with measurement of conductance to cerebrospinal fluid outflow, the concentration of vasopressin in plasma and cerebrospinal fluid was measured during perfusion at a low (less than 10 mmHg) and at a high (greater than 20 mmHg) intraventricular pressure level. Mean plasma vasopressin concentration was increased from 2.4 +/- 0.4 pg/ml (SEM) during perfusion at the low pressure level to 4.2 +/- 0.8 pg/ml (p less than 0.01) at the high pressure level. The cerebrospinal fluid concentrations of vasopressin at the low and high intraventricular pressure were 1.2 +/- 0.1 pg/ml and 1.7 +/- 0.2 pg/ml (p less than 0.05), respectively. However, only half of the patients responded to the increase in intraventricular pressure with an increase in cerebrospinal fluid vasopressin concentration exceeding 50%. The results of the present study suggest that an increase in the intracranial pressure might be a stimulus for vasopressin release in both the blood and the cerebrospinal fluid.

The passage of the vasopressin analogue, 1-deamino-8-D-arginine-vasopressin (DDAVP) into the cerebrospinal fluid (CSF) following intravenous (i.v.) administration was studied in human subjects. After i.v. injection of DDAVP, resulting in plasma levels exceeding normal plasma concentrations of vasopressin (AVP) by 100-fold, serial blood and ventricular CSF specimens were sampled during 2 h. Plasma and CSF were analysed by radioimmunoassay using two different AVP antisera: one specific against natural AVP and another cross-reacting 100% with DDAVP. No changes in the joint concentrations of DDAVP + AVP in CSF were found following i.v. infusion of DDAVP when compared with the concentration before the infusion. Neither was any difference between CSF concentrations of AVP and DDAVP + AVP observed at any sampling time following the i.v. DDAVP administration. Hence, it is concluded that no measurable amounts of DDAVP can be found in the CSF for up to 2 h after i.v. administration of the peptide, and that for all practical purposes a blood-CSF barrier to DDAVP exists.

The concentration of glial fibrillary acidic protein (GFAP) in lumbar cerebrospinal fluid (CSF) was measured in 12 patients with normal pressure hydrocephalus (NPH) 11 patients with primary degenerative dementia (PDD), 8 patients with various other neurological diseases, and 18 patients without signs of organic nervous disease (controls). Mean CSF GFAP concentration was significantly higher in NPH patients: 96 +/- 23 ng/ml (SEM) when compared with PDD patients: 8.2 +/- 1.9 ng/ml (P less than 0.01), or with controls: 4.3 +/- 0.7 ng/ml (P less than 0.01). Only 2 NPH patients had a GFAP concentration within the range of the control group (2-14 ng GFAP/ml CSF). No significant differences were found between the PDD patients and the control group, or between the group of patients with other neurological diseases and the control group. In addition, a rostro-caudal gradient of GFAP in CSF could be demonstrated. In 6 NPH and 2 PDD patients both ventricular and lumbar CSF samples were investigated. In all cases the ventricular GFAP concentration was higher than the lumbar concentration. The difference was statistically significant (P less than 0.01). Our results suggest that determination of CSF GFAP concentration might be of diagnostic value in discrimination between NPH patients and patients with enlarged ventricles associated with degenerative brain disease.

We measured the fluctuations in plasma pyridostigmine concentration from day to day on 3 consecutive days and hour to hour during 1 day in 11 myasthenic patients, by studying their usual dosage regime. Plasma pyridostigmine was measured by gas chromatography/mass spectrometry. The intraindividual day-to-day variation in plasma pyridostigmine levels was small. A highly significant relationship was found between the oral pyridostigmine dose and the area under the plasma concentration/time curve. The bioavailability of oral pyridostigmine was 3.6%, estimated by replacing one dose with an intravenous dose amounting to 1/30 of the oral dose. The relatively stable kinetic behavior of pyridostigmine is in contrast to the interpatient variability in dose requirement, indicating that monitoring of plasma pyridostigmine levels should be reserved for special cases.

In a series of 20 consecutive patients with pseudotumor cerebri, five patients had a protracted course of the disease with complaints of persistent disturbances in learning and memory functions. Neuropsychological examination disclosed a light general intellectual impairment with most marked disturbances in verbal tests. After intensive medical treatment or ventriculo-atrial shunt operation, psychological re-examination showed improvement in the test results in accordance with the improvement of the patients' occupational and social situation. Cognitive dysfunction can be the result of a prolonged course of benign intracranial hypertension, and the term "benign" may be misleading in these cases. However, the intellectual impairment, even when long-standing, seems to be reversible in most patients after medical or surgical measures to lower the intracranial pressure.

Sleep apnea has been overlooked for many years. However new studies show, that sleep apnea is very prevalent. Approximately 2-5 per cent of the adult population suffer from obstructive sleep apnea. Sleep apnea is related to several symptoms including hypersomnia, headache and cognitive dysfunctions. Sleep apnea is probably a risk factor for cardio- and cerebrovascular complications. Treatment reduce symptoms and the cardio- and cerebrovascular risk. The most effective treatment is Nasal Continuous Positive Airway Pressure (NCPAP), but surgical treatment is effective in selected cases, and includes UvuloPalatoPharyngoPlasty (UPPP), mandibular advancement, nasal surgery and partial tongue resections. No medical treatment is actually know to reduce obstructive sleep apnea.

Cerebral blood flow (CBF) was measured by xenon-133 inhalation and single photon emission tomography in 17 demented patients with normal-pressure hydrocephalus before and after shunt treatment. All patients had a decreased conductance to outflow (C out) of cerebrospinal fluid as measured by lumboventricular perfusion (C out less than 0.12 ml X mm Hg-1 X min-1). Computerized tomography (CT) scanning, clinical assessment, and neuropsychological grading were performed pre- and postoperatively. The preoperative CBF studies revealed abnormal flow patterns in all patients. Fourteen patients showed moderate-sized, large, or very large central low-flow areas, and four patients had reduced flow bilaterally in the occipital and contiguous temporoparietal regions. After shunting, six patients had a significant reduction in the size of the central low-flow area on the CBF map, agreeing well with the changes of ventricular size on the CT scan. All six patients showed an improvement in either clinical or neuropsychological grading. In 10 of the remaining 11 patients flow patterns were essentially unchanged; one patient deteriorated further. Four of these 11 patients improved on postoperative clinical or neuropsychological testing. Thus, a positive correlation was found between the changes in CBF and the reduction of the ventricular size on the CT scan, but changes in CBF as measured by the present technique did not accompany improvement in the functional state in all patients.

After four weeks of medication-free baseline observation, 29 patients with common migraine randomly received flunarizine (10 mg daily) or placebo for a 16-week period. After four weeks wash-out they crossed treatments for another 16 weeks; 27 patients completed the trial. Compared with placebo, flunarizine significantly reduced the frequency of migraine attacks and the derived headache indices, but the duration and severity of single attacks remained unchanged (Mann-Whitney U-test). The effect of flunarizine increased during the 16-week treatment period and during the last four weeks the number of migraine attacks reduced to 50% compared to the wash-out period. The only side-effect of flunarizine was mild daytime sedation in three patients. It is concluded that flunarizine is a valuable new prophylactic agent for common migraine.

A retrospective follow-up study of 243 patients with transient ischemic attacks (TIA) is reported. The long-term mortality of the patients was higher than that of the corresponding general population. It is demonstrated that the excess mortality over the whole period of observation, irrespective of the age and sex of the patients, can be characterized by a single figure expressing the slope of the curve obtained by semilogarithmic plotting of the ratios of observed to expected survival against time. The use of this numerical expression--in the present series -0.04--will thus facilitate comparisons of the survival of TIA patients drawn from different populations. Unfavourable prognostic factors were: carotid TIA, associated extracerebral disease, and a history of hypertension. Fatal strokes, being four times as frequent as expected according to published incidence figures, accounted for 20% of the deaths, heart disease 38%. Stroke deaths tended to occur earlier than cardiac deaths. The results support the concept that most TIAs, like strokes, are incidents in the progressive course of a generalized vascular disease. The finding of a constant excess mortality over the years following a TIA makes it difficult to recommend a discontinuation of prophylactic therapy at any particular time.

The effect of very-low-dose aspirin as an antithrombotic agent was evaluated blindly in 301 patients who had recently undergone carotid endarterectomy. After randomization, 150 patients received aspirin and 151 received placebo. The two groups were comparable with regard to age, sex, blood pressure, previous cerebrovascular events, and smoking habits. The effect of the study medication on platelet aggregation was measured twice in each patient during the first 2 months and at each follow-up visit; the dose was individually adjusted. In 76% of the patients receiving aspirin, 50 mg/day gave satisfactory platelet inhibition, 13% needed 60 mg/day, 8% needed 70 mg/day, and 3% needed 100 mg/day. Platelet aggregation was found to be inhibited in only 1.2% of the measurements in the patients receiving placebo. Observation during treatment averaged 21 months; total intention-to-treat follow-up averaged 25 months. For the combined outcome events of transient ischemic attack, stroke, acute myocardial infarction, and vascular death, aspirin reduced risk by 11% (95% confidence limits: -38% to 48%, p greater than 0.1). Thus, there was no significant effect of very-low-dose aspirin in our trial.

Four patients are described presenting papilloedema, increased pressure and reduced CSF absorption--caused by either spinal tumours, leptomeningeal carcinomatosis or encephalitis. Remarkably they all had a normal CT without signs of hydrocephalus. A 24-hour intracranial pressure monitoring showed a mean pressure of 30-35 mm Hg, recurrent plateau waves and high occurrence of B waves. Conductance to CSF outflow studied by a constant perfusion test was severely reduced 0.010-0.026 ml min-1 mm Hg-1 (normal greater than 0.12 ml mm Hg-1 min-1). Despite these findings no ventricular enlargement was seen on serial CT scans. The reason therefore remains unknown. Disappearance of papilloedema and a variable clinical improvement followed shunt-insertion.

In a prospective study, 24 consecutive patients with pseudotumor cerebri were followed for an average of 49 months with regular neurologic and ophthalmologic examinations. At the first examination the intracranial pressure was between 18 and 45 mm Hg; several patients had pressure waves up to 70 mm Hg and decreased conductance to cerebrospinal fluid outflow. In the majority, medical treatment, usually with diuretics and acetazolamide, induced a rapid relief of symptoms, but about 25% had a more protracted disease course with persistent headache, asthenia and memory disturbances interfering with daily life. Five patients required a shunt operation. Chronic changes of the optic disc developed in nearly half the patients, and one had optic atrophy and severe visual impairment. Repeated measurements of the intracranial pressure and conductance to cerebrospinal fluid outflow showed that abnormalities can persist for a long time, even in cases without symptoms of intracranial hypertension.

Vasopressin was determined in CSF and plasma of 243 patients with different neurological and psychiatric disorders, including control patients. CSF vasopressin was significantly higher in patients with high pressure hydrocephalus, intracranial tumour, benign intracranial hypertension, intracranial haemorrhage, ischaemic stroke, and craniocerebral trauma. In patients with primary degenerative dementia, CSF vasopressin was lower than in control patients. Among patients with psychiatric disorders, CSF vasopressin was increased in manic patients, while in patients with depression CSF concentration of this hormone did not differ from that found in controls. However, an increase in CSF vasopressin level was found in patients recovering from a depression. The clinical significance of changes in CSF vasopressin concentrations in groups of patients with neurological and psychiatric disorders is still unknown.

The long-term prognosis and quality of life of 201 patients admitted to hospital with reversible ischemic attacks (RIA) were estimated in a prospective study. The median follow-up time was 58 months. Further RIAs were reported by 91 patients (45%) and 48 (24%) suffered a stroke. The risk of stroke was markedly higher in the first 6 months after RIA, after which the annual stroke rate was rather constant with an average of 4.8%, about 8 times higher than expected. The average annual mortality rate for the RIA patients was 5.9%, which is significantly higher than expected. Cardiovascular deaths accounted for more than half of all deaths, stroke for one fourth. Life-table analysis of subgroups disclosed a much more favorable prognosis for women under 60 years. High systolic blood pressure, diabetes, and previous myocardial infarction were identified as risk factors. The occurrence of RIA had significantly influenced the quality of life and occupational status for the majority of the patients, even for those who did not suffer a subsequent stroke. Decreased working capacity, general asthenia and fatigue and impaired memory were the most common complaints. We conclude that RIA may be a more serious vascular event than generally believed. Apart from carrying a substantial risk of stroke and death, even a single RIA can cause permanent psychological dysfunction influencing the quality of life.