Acute presentation of craniopharyngioma in children and adults in a Danish national cohort.

We aimed to study the occurrence of acute-onset symptoms at initial presentation in a national Danish cohort of patients with childhood- or adult-onset craniopharyngioma, and to investigate potential risk factors for acute presentation. Medical records of 189 consecutive patients (39 children, 150 adults) presenting with craniopharyngioma during the period 1985-2004 were reviewed, and data regarding initial symptoms, neuroimaging results, vision and pituitary function were systematically collected. Acute symptoms preceding hospital admission were noted. Subgroup analyses were based on age, gender and calendar year period. Potential risk factors for acute presentation were analysed through uni- and multivariate analyses. Acute symptoms were reported in 24 (13%) patients. Acute visual symptoms, headache, nausea or vomiting were most frequently reported, and acute symptoms were more frequent among children (28%) than among adults (9%) (P < 0.01). There were no differences according to sex or calendar year period. Hydrocephalus was present in half of childhood cases and one-fifth of adult patients (P < 0.001). Intra-tumour haemorrhage was seen in two cases. Acute symptoms were more frequent among patients with tumours occupying the third ventricle (P < 0.01), radiologic signs of calcification (P < 0.05) or hydrocephalus (P < 0.01). In multivariate analysis, however, only childhood onset (P < 0.05) and calcification (P < 0.05) were independent risk factors for acute presentation. Craniopharyngioma presented with acute symptoms in 13% of patients. Childhood onset and radiologic signs of calcification were independent risk factors for acute presentation. Intra-tumour haemorrhage was rare.

Incidence of craniopharyngioma in Denmark (n = 189) and estimated world incidence of craniopharyngioma in children and adults.

We studied the incidence of craniopharyngioma in Denmark during the period 1985-2004 and estimated worldwide incidence rates (IR) of craniopharyngioma based on a literature review. Craniopharyngioma patients diagnosed during the period 1985-2004 were identified from the Danish National Patient Registry, the Danish Cancer Registry and regional registries. Medical records were reviewed. Danish population data were obtained from Statistics Denmark. European and World population data were obtained from EU and WHO homepages. Prior studies providing data on craniopharyngioma IRs were identified via PubMed and, if appropriate, were included in a weighted analysis estimating overall and children's IRs of craniopharyngioma. IRs are given as new cases per million per year. We identified 189 patients with new verified (162) or probable craniopharyngioma. The overall WHO World-standardised incidence rate was 1.86 (1.60-2.14) for all ages and 2.14 (1.53-2.92) for children (age <15 years). Peak incidence rates were observed in age groups 5-9 and 40-44 years. Fifteen prior studies (including 1,232 craniopharyngioma cases) were identified. Seven and 11 studies, respectively, were eligible for weighted all-ages and childhood population IR analyses, yielding summary IRs of 1.34 (1.24-1.46) (all ages) and 1.44 (1.33-1.56) (children). We have provided a detailed survey of the incidence of craniopharyngioma in Denmark during a recent 20-year period. Overall IR of craniopharyngioma in Denmark was 1.86 (1.60-2.14) as compared to 2.14 (1.53-2.92) among children. Weighted estimates of craniopharyngioma world IRs were 1.34 (1.24-1.46) in all ages and 1.44 (1.33-1.56) among children.

Gene transcription of receptors for growth hormone-releasing peptide and somatostatin in human pituitary adenomas.

Growth hormone (GH)-releasing peptides (GHRP) or secretagogs (GHS) constitute a family of synthetic compounds with potent and specific GH releasing activity. The receptor (GHS-R) has recently been cloned even though the endogenous ligand remains to be identified. GHRPs act both at the hypothalamic and the pituitary level through mechanisms involving amplification of GH-releasing hormone activity and functional somatostatin antagonism. In the present study we examined the co-expression of messenger RNA (mRNA) for GHS-R and all 5 somatostatin receptor subtypes (sstr 1-5) in 28 human pituitary tumors by RT-PCR. GHS-R transcription was detected in 11 out of 12 somatotroph adenomas and in 2 out of 2 prolactinomas, whereas GHS-R expression was detected in only 2 out of 14 clinically nonfunctioning adenomas (NFPA), and no expression was seen in the only ACTH secreting adenoma. Almost all tumors expressed sstr 2 mRNA (n = 24), whereas only 1 tumor expressed sstr 4 mRNA. The expression of sstr 3 mRNA was inversely associated with GHS-R expression (P < 0.001), which could be attributed to a high prevalence of sstr 3 expression in NFPA. This study suggests that GHS-R expression is predominantly observed in somatotroph adenomas and much less so in NFPA. Moreover, the presence of a distinct pattern of somatostatin receptor subtype co-expression is suggested, which may provide a molecular basis for the complex interaction between GHRPs and somatostatin.

Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy.

Active acromegaly is characterized by inappropriate tissue growth, increased mortality, and perturbations of intermediary metabolism. It is, in general, not well described to which extent these disturbances are normalized after treatment of the disease. To further assess basal and insulin stimulated fuel metabolism in acromegaly six patients with monotropic GH excess were each studied approximately 1 month prior to and 2 months after successful selective pituitary adenomectomy and compared to a control population of seven subjects. The studies consisted of a 3-h basal postabsorptive period and a 2-h hyperinsulinaemic (0.4 mU/kg/min) euglycemic clamp and the methods employed included isotopical measurement of glucose turnover, indirect calorimetry, and the forearm technique. When compared to the control subjects the patients with acromegaly were preoperatively and in the basal state characterized by: 1) increased circulating concentrations of GH, insulin, and C-peptide (P less than 0.05); 2) increased plasma glucose (5.9 +/- 0.2 vs. 5.2 +/- 0.2 mmol/L), blood lactate (710 +/- 90 vs. 580 +/- 70 mumol/L), glucose turnover (2.34 +/- 0.12 vs. 1.93 +/- 0.12 mg/kg/min), and plasma lipid intermediates and a decreased forearm glucose uptake (0.06 +/- 0.02 vs. 0.19 +/- 0.04 mmol/L) (P less than 0.05); and 3) a 20% increase in energy expenditure, a 50% elevation of lipid oxidation rates, and a 130% elevation of nonoxidative glucose turnover (P less than 0.05). During the clamp the patients with active acromegaly were substantially resistant to the actions of insulin on both glucose and lipid metabolism. Following pituitary surgery all of these metabolic abnormalities were abolished. We conclude that active acromegaly is characterized by profound disturbances of not only glucose but also lipid metabolism, which in theory may precipitate the increased mortality in this disease. By showing that these abnormalities and the concomitant overall insulin resistance can be completely reversed our results may also have important implications for other insulin-resistant states and for the potential therapeutic use of GH.

Incidence and late prognosis of cushing's syndrome: a population-based study.

The main purpose was to assess the incidence and late outcome of Cushing's syndrome, particularly in Cushing's disease. Information for all patients diagnosed with Cushing's syndrome during an 11-yr period in Denmark was retrieved. The incidence was 1.2-1.7/million.yr (Cushing's disease), 0.6/million.yr (adrenal adenoma) and 0.2/million.yr (adrenal carcinoma). Other types of Cushing's syndrome were rare. In 139 patients with nonmalignant disease, 11.1% had died during follow-up (median, 8.1 yr; range, 3.1-14.0), yielding a standard mortality ratio (SMR) of 3.68 [95% confidence interval (CI), 2.34-5.33]. The SMR was partly attributable to an increased mortality within the first year after diagnosis. Eight patients died before treatment could be undertaken. The prognosis in patients with malignant disease was very poor. Patients in whom more than 5 yr had elapsed since initial surgery were studied separately, including a questionnaire on their perceived quality of health. In 45 patients with Cushing's disease who had been cured through transsphenoidal neurosurgery, only 1 had died (SMR, 0.31; CI, 0.01-1.72) compared with 6 of 20 patients with persistent hypercortisolism after initial neurosurgery (SMR, 5.06; CI, 1.86-11.0). In patients with adrenal adenoma, SMR was 3.95 (CI, 0.81-11.5). The perceived quality of health was significantly impaired only in patients with Cushing's disease and appeared independent of disease control or presence of hypopituitarism. It is concluded that 1) Cushing's syndrome is rare and is associated with increased mortality, in patients with no concurrent malignancy also; 2) the excess mortality was mainly observed during the first year of disease; and 3) the impaired quality of health in long-term survivors of Cushing's disease is not fully explained.

Infarct rim: effect of hyperglycemia on direct current potential and [14C]2-deoxyglucose phosphorylation.

Focal ischemia was produced by occlusion of the right middle cerebral artery (MCA) in normo- and hyperglycemic rats. In the cortical infarct rim, regional [14C]2-deoxyglucose [( 14C]2-DG) phosphorylation was correlated to spontaneous transient changes in extracellular potassium recorded as direct current (DC) potential deflections. In normoglycemic rats the DC potential showed transient but recurrent deflections in the first hours following MCA occlusion. The 2-DG phosphorylation was elevated by 200% in the same area. In contrast, hyperglycemic rats had no, or a single, deflection of the DC potential in the rim, and the 2-DG phosphorylation remained normal. The same pattern was obtained by application of 3 M KCl to the exposed cortex. In normoglycemia potassium application resulted in recurrent deflections of the DC potential, and 2-DG phosphorylation increased in most parts of the hemisphere. Hyperglycemic animals had a nearly stable DC potential, and 2-DG phosphorylation increased only in the tissue area situated directly below the site of potassium application. The results indicate that metabolism in the cortical infarct rim is stimulated by spontaneous and recurrent changes in extracellular potassium--a phenomenon that may be related to spreading depression--and that the metabolism remained normal in the same area in hyperglycemic animals owing to an inhibition of transient increases of extracellular potassium.

The influence of the input function on quantitative rCBF by the Xe/CT method.

Measurements of rCBF by the Xe/CT method are based on the assumption of identity between the end-tidal xenon curve which is applied as input function, and the arterial xenon curve being the true input function to the brain. In this study corresponding end-tidal and arterial xenon curves were measured in an experimental animal model (part 1) and in 5 patients with traumatic brain injury (part 2) and used for rCBF calculation. In both studies rCBF was underestimated by using the end-tidal xenon concentration curve as brain input function. In part 1 rCBF underestimation was depended on pulmonary gas exchange; high or low levels of rCBF; tissue type; and xenon inhalation protocols. In part 2 the mean rCBF underestimation was 18.8 +/- 8.3%. In conclusion, non-invasive estimate of the input function should be considered as a source of error when defining quantitative blood flow values e.g. the flow thresholds of ischaemic infarction.

Cerebral blood flow in volunteers measured by PET and Xe CT/CBF. A comparison.

Aim of this study was to compare two quantitative CBF methods. Seven young, healthy volunteers were studied with PET (15-0 labelled water) and afterwards with Xe CT/CBF (30% xenon in oxygen, 3 minutes wash-in, 5 minutes washout protocol). Xe CT/CBF showed greater differences between high and low flow areas than PET CBF. Correlation was found within subjects between ROI's, but no agreement or correlation between the methods could be demonstrated. The disagreement in this study could be due to changes in PCO2.

Pulmonary function affects the quantification of rCBF by non-invasive xenon methods.

Estimates of regional cerebral blood flow (rCBF) by non-invasive xenon methods (133-xenon inhalation, xenon-enhanced computed tomography (Xe/CT) and 133-xenon iv injection) are frequently applied in the diagnosis and evaluation of patients suffering from diseases which cause disturbances in the cerebrovascular circulation. These methods all depend on an estimate of the arterial xenon concentration curve derived non-invasively from measurements of the end-tidal xenon concentration curve and used as brain input function in the Kety equation. We have studied the influence of impaired pulmonary gas exchange on the end-tidal and arterial xenon concentration curves in nine anaesthetized pigs by simultaneously measurements of both the end-tidal xenon and arterial xenon concentration curves. Computer simulations were performed to determine the deviations in the calculated rCBF values when using the end-tidal as compared to the arterial xenon concentration curve as brain input function. The results indicated that impairment of the pulmonary gas exchange caused a significant further 'delay' in the arterial xenon concentration curve in comparison to the end-tidal xenon concentration curve. The time constants of arterial curve delay were 11.9 s in the normal pulmonary group, 21 s in the right lung atelectasis group, and 19.7 s in the left pulmonary artery occlusion group. Accordingly, computer simulations indicated a statistically significant 'underestimation' of rCBF due to: (1) pulmonary gas exchange; (2) high or low levels of rCBF; (3) partition coefficient (lambda) of gray and white matter; and (4) xenon inhalation protocols. Our results indicate that quantitative measurements of rCBF by non-invasive xenon methods are markedly affected by deviations between the end-tidal and arterial xenon concentration curve, so that estimates of flow thresholds for infarction are problematic under conditions of impaired pulmonary gas exchange.

In vivo estimation of cerebral blood flow, oxygen consumption and glucose metabolism in the pig by [15O]water injection, [15O]oxygen inhalation and dual injections of [18F]fluorodeoxyglucose.

There is a need for suitable non-primate laboratory animals for studies of brain function by positron emission tomography (PET). To provide a comparative index of the circulatory physiology of the pig, we have applied novel PET tracer methodology to seven anaesthetized pigs, and measured cerebral regional oxygen consumption (CMR[O2]), cerebral blood flow (CBF), and cerebral glucose metabolism (CMR[glc]). Blood flow and flow-metabolism couple were estimated for selected cerebral regions of interest. We found an average hemispheric CMR(O2) of 171 +/- 18 micromol/100 cm3/min. Individual hemispheric CBF measurements varied between 33 and 41 ml/100 cm3/min, with an average of 37 +/- 3 ml/100 cm3/min at an average PaCO2 of 4.3 +/- 0.9 kPa. The blood flow dependency on arterial PCO2 was calculated from the results of the carbon dioxide response in two pigs in which the CBF measurements obeyed the equation CBF (ml/100 cm3/min) = 8.9 PaCO2 (kPa). In each pig, CMR(glc) was studied twice with a double-injection FDG method. In the first session, the values of CMR(glc) averaged 27 +/- 3 and 23 +/- 4 micromol/100 cm3/min, estimated by multilinear and linear regression analysis, respectively. In the second session, the corresponding averages were 27 +/- 3 and 24 +/- 3 micromol/100 cm3/min, respectively. The average oxygen extraction fraction was 0.46 +/- 0.09 and the oxygen-glucose ratio was 6.1 +/- 0.8. The findings indicate that the pig is suitable for PET studies of cerebral blood flow, cerebral oxygen consumption and glucose metabolism.

Effects of reduced cerebral blood flow upon EEG pattern, cerebral extracellular potassium, and energy metabolism in the rat cortex during bicuculline-induced seizures.

Progressive cerebral ischemia was induced by blood pressure (BP) reduction in rats during status epilepticus, and the sequence of cerebral functional (EEG, extracellular K+ activity) and metabolic (levels of high energy phosphates, glucose, glucose-6-phosphate, lactate, pyruvate, alpha-ketoglutarate) changes were determined. Very moderate reductions of BP were accompanied by tissue lactate accumulation and a decrease of the rate of re-uptake of K+ extruded during discharges. These changes were pronounced at BP about 50 mm Hg, when also the energy state showed some deterioration, and the EEG activity changed from one of bursts and suppressions into single spikes. At BP about 30 mm Hg EEG activity was abolished, but not until a slightly lower BP level was there a severe energy depletion and a massive K+ release, indicating generalized membrane depolarization. The results show an increased susceptibility to ischemia during seizures with changes of membrane pump function, and energy metabolism appearing at moderate reductions of BP. Concomitant decrease of seizure activity delayed to some extent the development of massive energy failure and membrane depolarization.

The increase in extracellular potassium concentration in the ischemic brain in relation to the preischemic functional activity and cerebral metabolic rate.

The course of ischemic increase of extracellular potassium concentration ([K+]e) was studied in rat cerebral cortex with potassium selective microelectrodes and correlated to the preischemic functional and metabolic state. Complete cerebral ischemia was induced in artificially ventilated rats by cardiac arrest. Seven different functional states including conditions with cerebral hypermetabolism (seizures, amphetamine intoxication, hyperthermia) and hypometabolism (barbiturate anesthesia, hypothermia) were chosen in order to cover a wide range of cerebral metabolic rates (CMRO2 : 28.7--2.4 ml O2/(100 g)/min). The ischemic increase of [K+]e was delayed in conditions with low CMRO2 and accelerated in conditions with high CMRO2; the time interval to the terminal steep rise in extracellular potassium concentration varied within the extremes of 35 +/- 5 and 365 +/- 12 sec (means +/- S.E.M.), the control state (N2O-analgesia) being 116 +/- 5 sec. In groups with high CMRO2 electrocortical activity ceased within 15 sec and in groups with low CMRO2 within 22 sec. The rates of the ischemic [K+]e increase, measured as rate of change in the potassium electrode potential (mV/sec), remained high in conditions with high preischemic CMRO2 and low in conditions with low CMRO2, indicating a remaining influence of the preischemic metabolism on membrane ion permeability. These results support previous metabolic data indicating that the rate of consumption of high energy phosphates during ischemia mirrors the preischemic cerebral metabolic rate. Phenobarbital anesthesia did not change the initial rate of [K+]e increase but reduced the rate of [K+]e increase later during ischemia, suggesting a special effect of barbiturates on partly depolarized membranes.

Effect of stable xenon inhalation on intracranial pressure during measurement of cerebral blood flow in head injury.

Xenon-enhanced computerized tomography (CT) is well suited for measurements of cerebral blood flow (CBF) in head-injured patients. Previous studies indicated divergent results on whether inhalation of xenon may cause a clinically relevant increase in intracranial pressure (ICP). The authors employed Xe-enhanced CT/CBF measurements to study the effect of 20 minutes of inhalation of 33% xenon in oxygen on ICP, cerebral perfusion pressure (CPP), and arteriovenous oxygen difference (AVDO2) in 13 patients 3 days (mean 1 to 5 days) after severe head injury (Glasgow Coma Scale score < or = 7). The patients were moderately hyperventilated (mean PaCO2 4.3 kPa or 32.3 mm Hg). Six patients were studied before and during additional hyperventilation. All 13 patients reacted with an increase in ICP and 11 with a decrease in CPP. The mean ICP increment was 6.9 +/- 7.7 (range 2 to 17 mm Hg). The mean CPP decrement was -9.7 +/- -14.6 (range 17 to 47 mm Hg). The time course of the ICP changes indicated that ICP increased rapidly during the first 5 to 6 minutes, then declined to a plateau (peak-plateau type in four of 13 patients), remained at a plateau (plateau type in six of 13), or continued to increase in three of 13, indicating individual variance in xenon reactivity. Additional hyperventilation had no effect on the xenon-induced increments in ICP but these occurred at lower ICP and higher CPP baseline levels. The AVDO2 values, an index of flow in relation to metabolism, indicated a complex effect of xenon on CBF as well as on metabolism. This study indicates that xenon inhalation for Xe-CT CBF measurements in head-injured patients according to our protocol causes clinically significant increments in ICP and decrements in CPP. It is suggested that the effect of xenon is analogous to anesthesia induction. Individual variations were observed indicating possible individual tolerance, possible influence of type and extent of the cerebral injury, disturbances in cerebrovascular reactivity, and possible influence of medication. These effects of xenon suggest that hyperventilation should be ensured in patients with evidence of reduced compliance or high ICP. On the other hand, inhalation of stable xenon is not believed to pose a risk because no signs of cerebral oligemia or ischemia were indicated in the AVDO2 values.

[Intraoperative use of ultrasound in neurosurgery]. / Peroperativ anvendelse af ultralyd i neurokirurgi.

Modern ultrasound technique, as in other specialities, has provided the neurosurgeon with an adjuvant which may be employed intraoperatively and which supplements the neuroradiological methods of investigation. The technique provides the surgeon with the possibility of direct visualization, localization and characterization of the pathological and normal structures intracranially and intraspinally by scanning directly on the surfaces of the dura or brain or medulla. The technique provides a good possibility for planning and controlling the extent of tumour resection. By means of a stand with guiding of the cannula, tissue biopsies may be obtained with great certainty and cysts and abscesses may be punctured and evacuated. Placing of a drain in the ventricular system or cysts may be carried out precisely and can be documented by ultrasonic guidance. The technique is employed in approximately one third of the total number of operations in a department of neurosurgery. The technique is simple to use, reasonable inexpensive, does not require addition running costs and may, in addition, be employed as an alternative to CT in neonatal diagnosis and control of hydrocephalus, in particular, by scanning via the fontanelles.

[Warning bleedings prior to subarachnoid hemorrhage from intracranial, sacculate aneurysms. A consecutive, prospective study]. / Advarselsblødninger ved subaraknoidalblødninger fra intrakraniale, sakkulate aneurismer. En konsekutiv, prospektiv undersøgelse.

The incidence of warning leaks prior to subarachnoid hemorrhage was found to be 36.4% in 99 consecutive patients admitted consecutively to a neurosurgical department suffering from subarachnoid hemorrhage from ruptured intracranial, sacculate, arterial aneurysms. The durations of delays before admission to a neurosurgical department and the reasons for these, were analyzed. The patients who experienced a warning leak were in significantly poorer clinical condition than would have been the fact if they had been admitted at the time of the warning leak. It is important to bear the possibility of subarachnoid hemorrhage in mind, when a patient who has not previously complained of headache experiences violent sudden onset of headache. A program for investigation of suspected subarachnoid hemorrhage is suggested.

[Neurosurgical treatment of acromegaly]. / Neurokirurgisk behandling af akromegali.

The results of transsphenoidal surgery in 45 consecutive patients with pituitary adenoma and acromegaly are reviewed. The cure rate defined in clinical terms is specifically related to the size of the adenoma. 20 out of 21 patients with intrasellar adenomas were cured by surgery. Of 24 patients with extrasellar adenomas eight were cured and ten had improved, while six had no clinical effect of the operation. Overall 62.2% were cured, 24.4% had improved and 13.3% were unchanged. The complications were 3 patients with pituitary insufficiency, rhinoliquorrhoea successfully treated with surgery in one patient, and an internal carotid artery lesion treated with trapping without sequelae in one patient. No recurrences were observed over two years. It is concluded that treatment of acromegaly is teamwork for internists and surgeons, and that transsphenoidal pituitary surgery is at present the primary treatment of choice.

[CO2 and indomethacin vasoreactivity in patients with cranial trauma]. / CO2-og indometacinvasoreaktivitet hos patienter med kranietraume.

The purpose of this study was to compare the effect of hyperventilation and indomethacin on cerebral circulation, metabolism and systemic and intracerebral pressures in patients with severe head injury. Fourteen moderately (PaCO2 = 4.05 kPa) hyperventilated patients with median [CP = 14.8 mmHg entered the study. Cerebral blood flow (CBF), intracranial pressure (ICP), arteriovenous difference of oxygen (AVDO2) and lactate (AVdL) and oxygen saturation in the jugular bulb (SvjO2) were measured before and after hyperventilation and after a bolus dose of indomethacin (30 mg). During hyperventilation CBF decreased by 11.8%/kPa and ICP decreased by 3.8 mmHg. AVDO2 increased by 34.0%/kPa. After indomethacin CBF decreased by 14.7% and ICP decreased by 4.3 mmHg. AVDO2 increased with 27.8%. No changes in median SvjO2 and AVdL were observed after the two treatments. The risk of cerebral ischaemia seems identical after the two treatments. No correlations between the effects of the two treatments on CBF, ICP and AVDO2 were found. These results suggest that indomethacin and hyperventilation might act independently or in a complementary fashion in the treatment of patients with severe head injury.

[Indomethacin in severe cerebral contusions with intracranial hypertension]. / L'indométacine dans les contusions cérébrales sévères avec hypertension intracrânienne.

In five head-injured patients with cerebral contusion and oedema in whom it was not possible to control ICP by hyperventilation and barbiturate sedation, indomethacin Confortid was used as a cerebral vasoconstrictor drug. In all patients indomethacin reduced ICP below 20 mmHg for several hours. Studies of cerebral circulation and metabolism during indomethacin treatment showed a decrease in cerebral blood flow (CBF) at 2 hours. After 7 hours. ICP remained below 20 mmHg in three patients, and these still had reduced CBF. In two patients a return of ICP and CBF to pretreatment levels was observed. In all patients indomethacin treatment was followed by a fall in rectal temperature. Outcome scaling has not yet been performed, but all patients left hospital without neurological deficits. These results suggest that indomethacin is an alternative in the treatment of intracranial hypertension in head-injured patients.