Background. Pseudo-aneurysm is a rare complication of craniotomy. Blunt injury to the temporal artery region is the usual cause, but still a rare complication. Clinical presentation. A patient with subarachnoid hemorrhage was successfully treated by aneurysm clipping. The patient developed hydrocephalus, and was admitted for a shunt operation seventeen days later. The craniotomy had healed normally, but a palpable temporal lump was present in the skin incision. Intervention. The pulsating mass proved to be a postoperative aneurysm of the superficial temporal artery (S.T.A.) and was successfully occluded with 500 units Thrombostat® (thrombin glue) which was injected into the aneurysm sac using a 22-gauge needle guided by ultrasound. The permanency of the obliteration was verified by ultrasound examination.

A rare case of a leptomeningeal cyst is reported in a twin male neonate delivered using a vacuum extractor, who presented a huge, non-pulsating, oedematous mass overlying the frontal fontanelle after birth. The mass was initially diagnosed as a cephalo haematoma. Ultrasonography indicated intracranial bleeding and a subsequent CT scan revealed an intraparenchymal bleeding above the left frontal horn, combined with a thin, left-sided, subdural haematoma and subarachnoid haemorrhage in the left Sylvian fissure. Apart from a bulging soft and round formation (2 × 2 × 3 cm) next to the anterior fontanel growing since birth, the neurological development of the infant was normal. MRI examination at the age of 7 months revealed that it consisted of a cystic mass (leptomeningeal cyst) connected to the left frontal horn, stretching right through the brain and also penetrating the dura mater. No signs of the perinatal haematomas were observed at this time. Surgical treatment, with fenestration of the cyst into the frontal horn and a watertight duraplasty with a periosteal flap and thrombin glue covered by small bone chips, was performed at 9 months of age. Due to a residual skull bone defect a second cranioplasty with autologous skull bone was performed three and half years later. During a follow-up period of 12 years the neurological and psychological development of the boy has been indistinguishable to that of his twin brother, indicating the satisfactory outcome of the treatment. © 2007 Springer-Verlag.

A new scaled microgauge is described for measuring anatomical structures during microsurgery. The instrument has a tip marked in millimetres, which can be positioned in any desired angle enabling measurement in confined areas. © Springer-Verlag 2005.

OBJECTIVE : This study describes the production, under strictly standardized and controlled conditions, of radiofrequency lesions with identical neurogenerator settings: in vitro in two different albumin solutions (nongelatinous and gelatinous) and in vivo in the thalamus of the pig.

METHODS : The radiofrequency lesions were investigated in vitro by the use of a specially designed video system and in vivo by magnetic resonance imaging. Moreover, the size of the in vivo lesions was estimated with the use of histological sectioning. The statistical analysis included the calculation of a correlation coefficient for the length, width, and volume for each lesion estimation.

RESULTS : A high correlation (R = 0.96, P < 0.005; n = 14) was found between clot sizes in the two albumin solutions. Albumin clots generated in gelatinous albumin showed systematically larger volumes. In the pig, two concentric zones were seen in all magnetic resonance images and all histological preparations. The width correlation of the completely coagulated brain tissue (inner zones) was R = 0.94, P < 0.005, and n = 7. The corresponding correlation between magnetic resonance images and gelatinous albumin was R = 0.93, P < 0.005, and n = 7. As a rule, the in vitro clots were smaller than the outer zone but larger than the inner zone of the magnetic resonance imaging-recorded lesions for all of the electrode and temperature combinations tested. In vivo lesions generated with the same electrode and parameter settings showed high reproducibility.

CONCLUSION : The value of presurgical electrode tests to validate the electrode function and lesion size in vitro has become evident in this study, which shows a high correlation between the in vitro albumin clots and the in vivo lesions observed on magnetic resonance images.

Objectives – Forty percent of patients with aneurysmal subarachnoid hemorrhage have prodromal warning episodes and difficulties in identifying these events are repeatedly documented. Modifications of diagnostic and referral patterns through educational programs of local doctors may help to identify such patients before a major devastating rupture occurs.

Materials and methods– A teaching program about sudden onset headache, targeting referring doctors, was systematically applied and its impact on early misdiagnosis of ruptured aneurysms was prospectively studied.

Results– Forty percent of all studied patients experienced a warning episode, manifested as apoplectic headache, prior to hospitalization. An initial diagnostic error was evident in 12% of the patients. Diagnostic errors were reduced by 77% as a result of continuous interaction between neurosurgeons and local physicians.

Conclusion– Misdiagnosed warning episodes cause greater loss of lives and higher morbidity on a population basis than does delayed ischemic complications from vasospasm in aneurysmal SAH. Teaching programs focused on local physicians have a profound impact on outcome at low cost.

To evaluate the value of routine application ofneuroprotection and the use of temporary clips (TCL) in every day aneurysm surgery 203 patients with a total of 236 aneurysms were included in the a perioperative moderate hypothermia (MHT, <34° C) protocol. Poor grade patients (Hunt & Hess IV-V) were excluded fi·om the study. Induction of MHT averaged 0.98+/-0.37 hours and was based on a protocol for administration of cold, intravenous crystalloid fluid and barbiturates. Blood pressure was stable throughout MHT. 40% of the patients needed inotropic support during the first 12 postoperative hours. Cardiac arrhythmia was infrequent and when occurring always of benign character. In 8%, pulmonary problems with central venous congestion and/or poor systemic oxygenation occurred.

In total, temporary clipping was used in 66 cases (mean occlusion time being 10.5 ±7.3 min), 50% of which had not been expected pre-operatively. Overall, 40 aneurysms (75% 1-12 mm in size) ruptured during dissection - corresponding to 20% of the cases without preplanned use of TCL.

Excluding biasing confounding factors, TCL did not affect the outcome following aneurismal surgery. The study lends support to the idea that TCL should be considered a routine method for all aneurysm surgery.

Despite considerable advances in the management of aneurysmal subarachnoid haemorrhage (SAH) over the past decades, the overall outcome is still disappointing. Currently, not more than six patients out of every ten with a ruptured aneurysm, reaching hospital alive, will recover to a normal life. Apart from the direct effects of the initial haemorrhage, vasospasm and rebleeding clearly stand out as the leading causes of unfavourable results in this capricious disease, and both of these factors seem potentially amenable to further improvement in therapeutic intervention.

Ever since the concept of early aneurysm surgery gained wider acceptance, the focus of the neurosurgical community has shifted from re bleeding towards the problem of vasospasm and delayed ischaemic neurological deficits (DIND). During recent years, vasospasm has attracted at least five times more attention than rebleeding in terms of published articles, and huge research efforts have been offered in the pursuit of a medical solution to this problem. Although progress has been made in the treatment of vasospasm during the last decades, DIND continues to contribute significantly to unfavourable outcome in the management of aneurysmal SAH victims. Recent series report an average of 13.5% of patients suffering DIND, leading to unfavourable outcome in 7% of all cases reaching hospital for treatment. Contrary to rebleeding, there is a dominance of morbidity (4.5%) over mortality (2.5%).

Historically, the efforts aimed at reducing the risk of rebleeding have mostly been related to the controversial question of the timing of surgery. The current performance in many centers, with over 90% of all ruptured aneurysms seen being occluded within 24 hours from the haemorrhage, gives the impression that we have reached the ultimate protection against rebleeding, with little left to improve in that field. However, the term rebleeding, as we are used to defming it, apparently only represents a part of a wider spectrum of recurrent aneurysm ruptures. Index haemorrhages preceeded by warning leaks and intraoperative ruptures occurring after index haemonhages also share the features of devastating impact on clinical condition and on outcome, and from a practical point of view it may be meaningful to consider all these recurrent ruptures as a common entity - the second bleed.

In the studies presented in this thesis, the second bleed has shown to have a profound impact on management outcome in aneurysmal SAH. It accounts for morbidity and mortality in at least 12% of all patients receiving treatment, which is roughly one-third of all patients with poor management outcome. Evidently, prevention of most recurrent bleeds are within the reach of current management protocols. Modifications of strategies in use are presented, that include new guidelines for the pre-neurosurgical care to ensure detection of warning leaks and to provide protection against ultra-early rebleeds, that cannot be reached by early aneurysm occlusion. In the neurosurgical phase, modifications of the surgical protocol allowing for a routine application of intraoperative neuroprotection and liberal use of temporary clipping are advocated.

By refocusing the second bleed, identification of it's various forms and modification of treatment protocols for ruptured aneurysms aimed at reducing these recurrent bleeds, many losses can be turned into good outcome, at a cost that is much lower than the cost of pursuing the final solution of vasospasm.

Object. With increasing use of endovascular procedures, the number of aneurysms treated surgically will decline. In this study the authors review complications related to the surgical treatment of aneurysms and address the issue of maintaining quality standards on a national level.

Methods. A prospective, nonselected amalgamation of every aneurysm case treated in five of six neurosurgical centers in Sweden during 1 calendar year was undertaken (422 patients; 7.4 persons/100,000 population/year). The treatment protocols at these institutions were very similar. Outcome was assessed using clinical end points. In this series, 84.1% of the patients underwent surgery, and intraoperative complications occurred in 30% of these procedures. Poor outcome from technical complications was seen in 7.9% of the surgically treated patients. Intraoperative aneurysm rupture accounted for 60% and branch sacrifice for 12% of all technical difficulties. Although these complications were significantly related to aneurysm base geometry and the competence of the surgeon, problems still occurred apparently at random and also in the best of hands (17%). The temporary mean occlusion time in the patients who suffered intraoperative aneurysm rupture was twice as long as the temporary arrest of blood flow performed to aid dissection.

Conclusions. The results obtained in this series closely reflect the overall management results of this disease and support the conclusion that surgical complications causing a poor outcome can be estimated on a large population-based scale. Intraoperative aneurysm rupture was the most common and most devastating technical complication that occurred. Support was found for a more liberal use of temporary clips early during dissection, regardless of the experience of the surgeon. Temporary regional interruption of arterial blood flow should be a routine method for aneurysm surgery on an everyday basis. A random occurrence of difficult intraoperative problems was clearly shown, and this factor of unpredictability, which is present in any preoperative assessment of risk, strengthens the case for recommending neuroprotection as a routine adjunct to virtually every aneurysm operation, regardless of the surgeon's experience.

Object. Transportation of unstable neurosurgical patients involves risks that may lead to further deterioration and secondary brain injury from perturbations in physiological parameters. Mobile computerized tomography (CT) head scanning in the neurosurgery intensive care (NICU) is a new technique that minimizes the need to transport unstable patients. The authors have been using this device since June 1997 and have developed their own method of scanning such patients.

Methods. The scanning procedure and radiation safety measures are described. The complications that occurred in 89 patients during transportation and conventional head CT scanning at the Department of Radiology were studied prospectively. These complications were compared with the ones that occurred during mobile CT scanning in 50 patients in the NICU. The duration of the procedures was recorded, and an estimation of the staff workload was made. Two patient groups, defined as high- and medium-risk cases, were studied. Medical and/or technical complications occurred during conventional CT scanning in 25% and 20% of the patients in the high- and medium-risk groups, respectively. During mobile CT scanning complications occurred in 4.3% of the high-risk group and 0% of the medium-risk group. Mobile CT scanning also took significantly less time, and the estimated personnel cost was reduced.

Conclusions. Mobile CT scanning in the NICU is safe. It minimizes the risk of physiological deterioration and technical mishaps linked to intrahospital transport, which may aggravate secondary brain injury. The time that patients have to remain outside the controlled environment of the NICU is minimized, and the staff's workload is decreased.

Object. The author sought to describe overall management data on cerebral arteriovenous malformations (AVMs) and to focus the actuarial need for different treatment modalities on a population-based scale. Such data would seem important in the planning of regional or national multimodality strategies for the treatment of AVMs. This analysis of a nonselected, consecutive series of patients representing every diagnosed case of cerebral AVM in a population of 1,000,000 over one decade may serve to shed some light on these treatment aspects. Methods. During the 11-year period from 1989 to 1999, data from every patient harboring a cerebral AVM that was presented clinically or discovered incidentally in a strictly defined population of 986,000 people were collected prospectively. No patient was lost to follow up. There were 12.4 de novo diagnosed AVMs per 1,000,000 population per year (135 AVMs). Large high-grade AVMs (Spetzler-Martin classification) were rare, and Grade 1 to 3 lesions represented 85% of the caseload. Hemorrhage was the initial manifestation of AVM in 69.6% of the cases. Intracerebral hematoma was the most common hemorrhagic manifestation occurring in 78 patients. There were 4.4 cases per 1,000,000 population per year of hematomas needing expedient surgical evacuation. In the remaining patients who did not require hematoma surgery, small, critically located Grade 3 and Grade 4 lesions amounted to 1.6 cases per 1,000,000 population per year. There were 5.8 cases per 1,000,000 population per year of Grade 1 to 2 and larger noncritically located Grade 3 malformations. There were 0.5 cases per 1,000,000 population per year of Grade 5 AVMs. The overall outcome in 135 patients was classified as good according to the Glasgow Outcome Scale (Score 5) in 61% of the cases, and the overall mortality rate was 9%. Conclusions. In centers with population-based referral, AVM of the brain is predominantly a disease related to intracranial bleeding, and parenchymal clots have a profound impact on overall management outcome. The rupture of an AVM is as devastating as that of an aneurysm. Aneurysm ruptures are more lethal, whereas AVM rupture tends to result in more neurological disability due to the high occurrence of lobar intracerebral hematoma. In an attempt to quantify the need for different modalities of AVM treatment based on a population of 1,000,000 people, figures for surgeries performed range from six to 10 operations per year and embolization as well as gamma knife surgery procedures range from two to seven per year, depending on the strategy at hand. When using nonsurgical approaches to Grade 1 to 3 lesions, the number of patients requiring treatment with more than one method for obliteration increases drastically as does the potential risk for procedure-related complications.

OBJECTIVE: To evaluate a new intracerebral microdialysis catheter with a high-cutoff membrane and its potential for the study of macromolecules in the human brain. METHODS: Paired intracerebral microdialysis catheters were inserted in 10 patients who became comatose after subarachnoid hemorrhage or traumatic brain injury and were then treated in our neurosurgical unit. The only differences from the routine use of microdialysis in our clinic were the length (20 mm) and cutoff properties of the catheter membranes (100 kD) and the perfusion fluids used (standard perfusion fluid, 3.5% albumin, or Ringer-dextran 60). Samples were weighed (for net fluid fluxes) and analyzed at bedside (for routine metabolites) and later in the laboratory (for total protein and interleukin-6). The in vitro recovery of glucose, glutamate, and glycerol were also investigated under different conditions. RESULTS: Even brief perfusion with standard perfusion fluid resulted in a significant loss of volume from the microdialysis system. For albumin and Ringer-dextran 60 fluid, recovery was comparable to standard settings. Interleukin-6 (highest value close to 25,000 pg/ml) was sampled from all catheters, and total protein was analyzed from catheters perfused with Ringer-dextran 60 (average concentration, 234 μg protein/ml). There were detectable patterns of variations in the concentration of interleukin-6, seemingly related to concomitant variations in intracerebral conditions. In the present study, no direct comparison was made with the standard CMA 70 catheter (CMA Microdialysis, Stockholm, Sweden), but in vivo, the measured mean concentrations of glucose, glycerol, lactate, and pyruvate were comparable to those previously reported from standard catheters. In vitro, the recovery of metabolites was better when using Ringer-dextran 60 compared with albumin. CONCLUSION: Microdialysis catheters with high-cutoff membranes can be used in routine clinical practice, allowing for sampling and analysis of cytokines and other macromolecules.

Object. By pursuing a policy of very early aneurysm treatment in neurosurgical centers, in-hospital rebleeds can be virtually eliminated. Nonetheless, as many as 15% of patients with aneurysm rupture suffer ultraearly rebleeding with high mortality rates, and these individuals are beyond the reach of even the most ambitious protocol for diagnosis and referral. Only drugs given immediately after the diagnosis of subarachnoid hemorrhage (SAH) has been established at the local hospital level can, in theory, contribute to the minimization of such ultraearly rebleeding. The object of this randomized, prospective, multicenter study was to assess the efficacy of short-term antifibrinolytic treatment with tranexamic acid in preventing rebleeding.

Methods. Only patients suffering SAH verified on computerized tomography (CT) scans within 48 hours prior to the first hospital admission were included. A 1-g dose of tranexamic acid was given intravenously as soon as diagnosis of SAH had been verified in the local hospitals (before the patients were transported), followed by doses of 1 g every 6 hours until the aneurysm was occluded; this treatment did not exceed 72 hours. In this study, 254 patients received tranexamic acid and 251 patients were randomized as controls. Age, sex, Hunt and Hess and Fisher grade distributions, as well as aneurysm locations, were congruent between the groups. Outcome was assessed at 6 months post-SAH by using the Glasgow Outcome Scale (GOS). Vasospasm and delayed ischemic neurological deficits were classified according to clinical findings as well as by transcranial Doppler (TCD) studies. All events classified as rebleeding were verified on CT scans or during surgery.

Conclusions. More than 90% of patients reached the neurosurgical center within 12 hours of their first hospital admission after SAH; 70% of all aneurysms were clipped or coils were inserted within 24 hours of the first hospital admission. Given the protocol, only one rebleed occurred later than 24 hours after the first hospital admission. Despite this strong emphasis on early intervention, however, a cluster of 27 very early rebleeds still occurred in the control group within hours of randomization into the study, and 13 of these patients died. In the tranexamic acid group, six patients rebled and two died. A reduction in the rebleeding rate from 10.8 to 2.4% and an 80% reduction in the mortality rate from early rebleeding with tranexamic acid treatment can therefore be inferred. Favorable outcome according to the GOS increased from 70.5 to 74.8%. According to TCD measurements and clinical findings, there were no indications of increased risk of either ischemic clinical manifestations or vasospasm that could be linked to tranexamic acid treatment. Neurosurgical guidelines for aneurysm rupture should extend also into the preneurosurgical phase to guarantee protection from ultraearly rebleeds. Currently available antifibrinolytic drugs can provide such protection, and at low cost. The number of potentially saved lives exceeds those lost to vasospasm.

Objective. To compare the properties of a new intracerebral micro-dialysis catheter with a high cut-off membrane (molecular cut-off 100 kDalton) with a standard catheter (CMA70, molecular cut-off 20 kDalton).

Methods. Paired intracerebral microdialysis catheters were inserted in fifteen comatose patients treated in a neurosurgical intensive care unit following subarachnoid haemorrhage or traumatic brain injury. The high-cut-off catheter (D₁₀₀) differed from the CMA 70 catheter by the length (20 mm) and cut-off properties of the catheter membranes (100 kDalton) and the perfusion fluids used (Ringer-Dextran 60). Samples were collected every 4–6 hours, analyzed bedside (for glucose, glutamate, glycerol, lactate, pyruvate and urea) and later in the laboratory (for total protein).

Results. Fluid recovery was similar for the two types of catheters, but significantly more protein was recovered by the D₁₀₀ catheter. The recovery of glycerol and pyruvate did not differ, while minor differences in recovery of glutamate and glucose were observed. The recovery of lactate was considerably lower in the D₁₀₀ catheter (p < 0.01), influencing the lactate/pyruvate-ratio. The patterns of concentration changes over time were consistent for all metabolites, and independent of type of catheter.

Conclusion. Microdialysis catheters with high cut-off membranes can be used in routine clinical practice in the NSICU, adding the possibility of macro-molecule sampling from the extracellular space during monitoring.

Combining previously independently established techniques our objective was to develop and evaluate a method for bedside qualitative assessment of cerebral blood flow in neurointensive care (NICU) patients. The CT-protocol was optimized using phantoms and comparing a mobile CT-scanner (Tomoscan-M, Philips) with two stationary CT scanners. Thirty-two per cent xenon was delivered with standard equipment (Enhancer 3000). Mean cortical flow in volunteers was 48 ml/min/100 g, with the mean vascular territorial flow varying between 45 and 66 ml/min/100 g. The potential clinical usefulness was illustrated in three patients with vasospasm following subarachnoid haemorrhage. Our conclusion is that quantitative bedside measurements of CBF can be repeatedly performed in an easy and safe way in a standard NICU-setting, using xenon-inhalation and a mobile CT-scanner. The method is useful for the decision-making, and is a good example of how the quality of multi-modality monitoring in the NICU can be developed and further diversified. © The Neurosurgical Foundation.

Object. The aim of this study was to make a preliminary evaluation of whether microdialysis monitoring of cytokines and other proteins in severely diseased neurosurgical patients has the potential of adding significant information to optimize care, thus broadening the understanding of the function of these molecules in brain injury. Methods. Paired intracerebral microdialysis catheters with high-cutoff membranes were inserted in 14 comatose patients who had been treated in a neurosurgical intensive care unit following subarachnoidal hemorrhage or traumatic brain injury. Samples were collected every 6 hours (for up to 7 days) and were analyzed at bedside for routine metabolites and later in the laboratory for interleukin (IL)-1 and IL-6, in two patients, vascular endothelial growth factor and cathepsin-D were also checked. Aggregated microprobe data gave rough estimations of profound focal cytokine responses related to morphological tissue injury and to anaerobic metabolism that were not evident from the concomitantly collected cerebrospinal fluid data. Data regarding tissue with no macroscopic evidence of injury demonstrated that IL release not only is elicited in severely compromised tissue but also may be a general phenomenon in brains subjected to stress. Macroscopic tissue injury was strongly linked to IL-6 but not IL-1b activation. Furthermore, IL release seems to be stimulated by local ischemia. The basal tissue concentration level of IL-1b was estimated in the range of 10 to 150 pg/ml, for IL-6, the corresponding figure was 1000 to 20,000 pg/ml. Conclusions. Data in the present study indicate that catheters with high-cutoff membranes have the potential of expanding microdialysis to the study of protein chemistry as a routine bedside method in neurointensive care.

Background. Experimental data have suggested that hypothermia (32–34°C) may improve outcome after cerebral ischaemia, but its efficacy has not yet been established conclusively in humans. In this study we examined the feasibility and safety of deliberate moderate perioperative hypothermia during operations for subarachnoid aneurysms.

Methods. A total of 359 operations for intracranial cerebral aneurysms were included in this prospective study. By using cold intravenous infusions (4°C) and convective cooling our aim was to reduce the patient's core temperature to more than 34°C within 1 h before operation. The protocol assessed postoperative complications such as infections, prolonged mechanical ventilation, pulmonary complications and coagulopathies.

Results. During surgery, the body temperature was reduced to a mean of 32.5 (sd 0.4) °C. Cooling was accomplished at a rate of 4.0 (sd 0.4) °C h⁻¹. All patients were normothermic at 5 (sd 2) h postoperatively. Peri/postoperative complications included circulatory instability (n=36, 10%), arrhythmias (n=17, 5%) coagulation abnormalities and blood transfusion (n=169, 47%), infections (n=29, 8%) and pulmonary complications (infiltrate or oedema while on ventilatory support) (n=97, 27%). Eighteen patients died within 30 days (5%). There was no significant correlation between the extent of hypothermia and any of the complications. However, there was a strong correlation between the occurrence of complications and the severity of the underlying neurological disease as assessed by the Hunt and Hess score.

Conclusion. Moderate hypothermia accomplished within 1 h of induction of anaesthesia and maintained during surgery for subarachnoid aneurysms appears to be a safe method as far as the risks of peri/postoperative complications such as circulatory instability, coagulation abnormalities and infections are concerned.

We have performed a study of 137 consecutive patients with thunderclap headache (TCH), showing that a large majority of the patients do not have a subarachnoidal haemorrhage (SAH). It is concluded that 11% of all TCH is caused by SAH and that history and findings in the clinical neurological examination cannot discriminate safely between an SAH and a more benign cause. All patients should be investigated with a CT scan and an analyses of the cerebrospinal fluid to exclude a SAH if the CT scan did not show an SAH. The 10-year follow-up showed that none of the patients with TH without SAH had a cerebral haemorrhage of any kind. Pathological results on CT and CSF examinations were found in 14 of the patients with non-SAH TCH, including five with cerebral infarction, three with intracerebral haemorrhage, four with aseptic meningitis and one with venous sinus thrombosis.

Sudden onset headache is a common condition that sometimes indicates a life- threatening subarachnoid haemorrhage (SAH) but is mostly harmless. We have performed a prospective study of 137 consecutive patients with this kind of headache (thunderclap headache = TCH). The examination included a CT scan, CSF examination and follow-up of patients with no SAH during the period between 2 days and 12 months after the headache attack. The incidence was 43 per 100 000 inhabitants > 18 years of age per year; 11.3% of the patients with TCH had SAH. Findings in other patients indicated cerebral infarction (five), intracerebral haematoma (three), aseptic meningitis (four), cerebral oedema (one) and sinus thrombosis (one). Thus no specific finding indicating the underlying cause of the TCH attack was found in the majority of the patients. A slightly increased prevalence of migraine was found in the non-SAH patients (28%). The attacks occurred in 11 cases (8%) during sexual activity and two of these had an SAH. Nausea, neck stiffness, occipital location and impaired consciousness were significantly more frequent with SAH but did not occur in all cases. Location in the temporal region and pressing headache quality were the only features that were more common in non-SAH patients. Recurrent attacks of TCH occurred in 24% of the non-SAH patients. No SAH occurred later in this group, nor in any of the other patients. It was concluded that attacks caused by a SAH cannot be distinguished from non-SAH attacks on clinical grounds. It is important that patients with their first TCH attack are investigated with CT and CSF examination to exclude SAH, meningitis or cerebral infarction. The results from this and previous studies indicate that it is not necessary to perform angiography in patients with a TCH attack, provided that no symptoms or signs indicate a possible brain lesion and a CT scan and CSF examination have not indicated SAH.

Intralysosomal iron powerfully synergizes oxidant-induced cellular damage. The iron chelator, desferrioxamine (DFO), protects cultured cells against oxidant challenge but pharmacologically effective concentrations of this drug cannot readily be achieved in vivo. DFO localizes almost exclusively within the lysosomes following endocytic uptake, suggesting that truly lysosomotropic chelators might be even more effective. We hypothesized that an amine derivative of α-lipoamide (LM), 5-[1,2] dithiolan-3-yl-pentanoic acid (2-dimethylamino-ethyl)-amide (α-lipoic acid-plus [LAP]; pKa = 8.0), would concentrate via proton trapping within lysosomes, and that the vicinal thiols of the reduced form of this agent would interact with intralysosomal iron, preventing oxidant-mediated cell damage. Using a thiol-reactive fluorochrome, we find that reduced LAP does accumulate within the lysosomes of cultured J774 cells. Furthermore, LAP is approximately 1,000 and 5,000 times more effective than LM and DFO, respectively, in protecting lysosomes against oxidant-induced rupture and in preventing ensuing apoptotic cell death. Suppression of lysosomal accumulation of LAP (by ammonium-mediated lysosomal alkalinization) blocks these protective effects. Electron paramagnetic resonance reveals that the intracellular generation of hydroxyl radical following addition of hydrogen peroxide to J774 cells is totally eliminated by pretreatment with either DFO (1 mM) or LAP (0.2 μM) whereas LM (200 μM) is much less effective.

Background: Some degree of recanalization is reported in up to one-third of intracranial aneurysms treated with endovascular coiling. A technical development potentially effective in avoiding recanalization is the Matrix Detachable Coil (MDC), which is covered with a biodegradable polymeric material that enhances intra-aneurysmal clot organization and fibrosis. Purpose: To report the initial clinical experience of MDC for endovascular aneurysm coiling in a single-center, single-operator, and well-defined population setting. Material and Methods: 118 aneurysms in 104 patients (73 with subarachnoid hemorrhage, SAH) were embolized with MDC alone (n=52) or combined with bare platinum coils (n=66). Results: Initial aneurysm obliteration was class 1 (complete obliteration) in 45 aneurysms (38.1%), class 2 (residual neck) in 44 (37.3%), and class 3 (residual aneurysm) in 29 (24.6%). Procedure-related morbidity was 4.8%, and mortality 0.96%. Clinical follow-up of 61 patients with SAH (mean 5.9 months, range 1-17 months) showed good outcome (Glasgow Outcome Scale, GOS 4-5) in 39 (63.9%), and poor outcome or death (GOS 1-3) in 22 (36.1%). Imaging follow-up of 73 aneurysms (average 6.5 months, range 1-17 months) showed class 1 in 47 (64.4%), class 2 in 18 (24.7%), and class 3 in eight (10.9%). Recanalization occurred in 11 aneurysms (15%), of which four (5.5%) required re-treatment. Conclusion: This study confirms that aneurysm coiling with MDC is feasible, effective, and safe. © 2007 Taylor and Francis.

[No abstract available]

Purpose: To report the feasibility of using ethylene vinyl alcohol copolymer (EVAC) for embolization of lower-falx meningiomas. Material and Methods: Three patients were treated. The procedures were done under general anesthesia. A terminal branch of the middle cerebral artery in the proximity of the tumor was catheterized as near as possible or into the pre-falcine arterial anastomotic network around the superior sagittal sinus, and embolization with EVAC was performed with a standard injection technique. Results: This technique resulted in filling of the tumor-supplying dural arteries including all collaterals from both sides, filling of the dural territory of the tumor circulation, and some obliteration of the tumor's pial supply. On later operation, the tumors could be removed from the inside out with minimal brain retraction. Conclusion: Effective preoperative embolization of lower-falx meningiomas using EVAC is feasible. This technique has a sound anatomical basis, and it can be used with benefit even in falx meningiomas with predominantly pial vascular supply. © 2007 Taylor & Francis.

We have investigated possible sex differences in the regional concentrations of neuropeptides in the rat brain. Immunoreactive neurotensin (NT), neurokinin A (NKA), galanin (GAL), calcitonin gene-related peptide (CGRP), substance P (SP) and neuropeptide Y (NPY) were measured by radioimmunoassay in frontal cortex, occipital cortex, hippocampus, striatum, hypothalamus and pituitary in male and female pre- and postpubertal rats. Sex differences were found for NPY (p < 0.001), NT (p < 0.01) and GAL (p < 0.05), in particular in hippocampus, striatum, hypothalamus and pituitary, but not for CGRP, SP and NKA. Results from analysis of neuropeptides in one sex may not be entirely applicable to the other.

Concentrations of immunoreactive galanin were compared in eight gross brain regions of ovariectomized female rats treated with either estradiol, estradiol + progesterone, estradiol + norethisterone, or placebo. Higher concentrations with estradiol treatment compared with placebo were found in the pituitary (357%), frontal cortex (162%), occipital cortex (174%), hippocampus (170%), and median eminence (202%). A more profound difference with addition of progesterone or norethisterone was seen in the pituitary (529% and 467%, respectively). Sex steroids, particularly estradiol, modulate galanin concentrations not only in reproductive, but also in nonreproductive, brain regions.

[No abstract available]

During a 3-year period, mobile xenon-computerized tomography (Xe-CT) for bedside quantitative assessment of cerebral blood flow was used as an integrated tool for decision making during the care of complicated patients in our neurosurgical intensive care units (NSICU), in an attempt to make a preliminary evaluation regarding the usefulness of this method in routine work in the neurosurgical intensive care. With approximately 200 studies involving 75 patients, we identified six different categories where the use of bedside Xe-CT significantly influenced (or, with more experience, could have influenced) the decision making, or facilitated the handling of patients. These categories included identification of problems not apparent from other types of monitoring, avoidance of adverse effects from treatment, titration of standard treatments, evaluation of the vascular resistance reserve, assessment of adequate perfusion pressure and better utilization of resources from access to the bedside cerebral blood flow (CBF) technology. We conclude that quantitative bedside measurements of CBF could be an important addition to the diagnostic and monitoring arsenal of NSICU-tools. © The Neurosurgical Foundation.

Craniopharyngioma is a rare benign intracranial epithelial tumor that, however, often recurs and sometimes kills the affected patients, one-third of which are children. In many cases, the patients acquire growth hormone deficiency and postoperatively need substitution. Generally, growth hormone promotes local release of insulin-like growth factor I (IGF-I), which in turn activates the IGF-I receptor (IGF-IR) if present. Together, these circumstances raise the question whether IGF-IR may be involved in craniopharyngioma growth. To address this issue, we analyzed phenotypically well-characterized primary low-passage craniopharyngioma cell lines from nine different patients for IGF-IR expression and IGF-I dependency. Two of the cell lines showed no/very low expression of the receptor and was independent on IGF-I, whereas five cell lines exhibited a strong expression and was clearly contingent on IGF-I. The two remaining cell lines had low receptor expression and IGF-I dependency. Upon treatment with an IGF-IR inhibitor, cells with high IGF-IR expression responded promptly with decreased Akt phosphorylation followed by growth arrest. These responses were not seen in cells with no/very low receptor expression. Growth of cell lines with tow IGF-IR expression was only slightly affected by IGF-IR inhibition. Taken together, our data suggest that IGF-IR may be involved in the growth of a subset of craniopharyngiomas and points to the possibility of the involvement of IGF-IR inhibitors as a treatment modality to obtain complete tumor-free conditions before growth hormone substitution. © 2005 American Association for Cancer Research.

Under ischemic conditions, a number of cytotoxic metabolic products are formed. Reactive oxygen species are known to be important mediators of progressive ischemic cell injury, and the synergistic damage to cells caused by the combination of such oxygen species and redox-active iron is well appreciated. The acidic interior of lysosome leads to the trapping of substances with high pK₄ values. A large variety of molecules, being weak bases, may thus concentrate within this acidic vacuolar compartment, potentially leading to both beneficial and detrimental effects. A major part of the intracellular pool of redoxactive iron is likely to be located in the lysosomal compartment, and iron chelators that are lysosomotropic due to high pK₄ values may prove to be important pharmacological tools to protect the brain from oxidative stress. Among a variety of substances formed in the ischemic penumbra zone is the polyamine metabolite, 3-aminopropanal (3-AP), a substance of extreme neurotoxicity. 3-AP is a weak base and may theoretically exert its toxic action through induction of cell death after intralysosomal accumulation.

On the 1774 mouse histiocytic lymphoma cell line, we used the common lysosomotropic agent NH₃ to increase lysosomal pH, the lysosomotropic iron chelator, 5-[1,2] dithiolan-3-yl-pentanoic acid (2-dimethylamino-ethyl)-amide (LAP) and the lysosomotropic iron binder, WR-1065, a metabolite of amifostine, as tools to determine that proton trapping within the lysosomal acidic vacuolar compartment plays an important role in oxidative stress-induced apoptosis. We also used another lysosomotropic agent, 3-AP, on the J774 cell line and on the SH-SY5Y human neuroblastoma cell line. The results indicate that proton trapping of this toxin within the lysosome might explain its toxicity to cells.

Sulfide-silver cytochemical detection of iron revealed a pronounced decrease in the lysosomal content of redox-active iron following reduced acidity of the lysosome, and electron spin-resonance studies showed that no hydroxyl radicals [OH^•] were formed from hydrogen peroxide under these conditions. This suggests that lysosomes contain most of the free, redox-active iron. In further support of this idea, the lysosomotropic agents LAP and WR-1065 were found to be 5000 and 2500 times more effective, respectively, in protecting cells from oxidative stress, compared with the well-known iron chelator desferrioxamine [DFO]. Evidence was obtained that LAP and WR-1065 exerted their effect on intralysosomal redox-active iron, and that the effect was linked to the acidity of the lysosome. Being weak bases (LAP, pK_a = 8.0; WR-1065, pK_a = 9.2), these compounds accumulate intralysosomally by proton trapping. The neurotoxic effect of 3-AP (pK_a = 9.3) could be linked to a dose-dependent induction of cell death, most likely based on intralysosomal proton trapping of this molecule followed by lysosomal rupture. The lysosomal rupture seems to induce a chain of intracellular events (including generation of oxidative stress), leading to mitochondrial damage directly or indirectly caused by the release of lysosomal proteases.

We conclude that the low pH of the lysosome may both serve to attract basic toxins, such as 3-AP, and promote the accumulation of protective agents, such as LAP and WR-1065. Prevention of lysosomal damage from both oxidants and neurotoxins by lysosomotropic agents has great potential therapeutic utility.

Amifostine (2-[(3-aminopropyl)amino]ethane-thiol dihydrogen phosphate ester; WR-2721) is a radioprotective agent used clinically to minimize damage from radiation therapy to adjacent normal tissues. This inorganic thiophosphate requires dephosphorylation to produce the active, cell-permeant thiol metabolite, WR-1065. The activation step is presumably catalyzed by membrane-bound alkaline phosphatase, activity of which is substantially higher in the endothelium of normal tissues. This site-specific delivery may explain the preferential protection of normal versus neoplastic tissues. Although it was developed several decades ago, the mechanisms through which this agent exerts its protective effects remain unknown. Because WR-1065 is a weak base (pKa = 9.2), we hypothesized that the drug should preferentially accumulate (via proton trapping) within the acidic environment of intracellular lysosomes. These organelles contain abundant 'loose' iron and represent a likely initial target for oxidant- and radiation-mediated damage. We further hypothesized that, within the lysosomal compartment, the thiol groups of WR-1065 would interact with this iron, thereby minimizing iron-catalyzed lysosomal damage and ensuing cell death. A similar mechanism of protection via intralysosomal iron chelation has been invoked for the hexadentate iron chelator, desferrioxamine (DFO; although DFO enters the lysosomal compartment by endocytosis, not proton trapping). Using cultured J774 cells as a model system, we found substantial accumulation of WR-1065 within intracellular granules as revealed by reaction with the thiol-binding fluorochrome, BODIPY FL L-cystine. These granules are lysosomes as indicated by co-localization of BODIPY staining with LysoTracker Red. Compared to 1 mM DFO, cells pre-treated with 0.4 ?M WR-1065 are protected from hydrogen peroxide-mediated lysosomal rupture and ensuing cell death. On a molar basis in this experimental system, WR-1065 is approximately 2500 times more effective than DFO in preventing oxidant-induced lysosomal rupture and cell death. This increased effectiveness is most likely due to the preferential concentration of this weak base within the acidic lysosomal apparatus. By electron spin resonance, we found that the generation of hydroxyl radical, which normally occurs following addition of hydrogen peroxide to J774 cells, is totally blocked by pretreatment with either WR-1065 or DFO. These findings suggest a single and plausible explanation for the radioprotective effects of amifostine and may provide a basis for the design of even more effective radio- and chemoprotective drugs.

During cerebral ischemia and following trauma, potent cytotoxic polyamine-derived aminoaldehydes form, diffuse, and damage adjacent tissues not directly subjected to the initial insult. One such aldehyde is 3-aminopropanal (3-AP). The mechanisms by which such a small aldehydic compound is excessively cytotoxic have been unclear until recently when we showed that 3-AP, having the structure of a weak lysosomotropic base, concentrates within the acidic vacuolar compartment and causes lysosomal rupture that, in turn, induces caspase activation and apoptotic cell death. Here, using cultured J774 cells and 3-AP as a way to selectively burst lysosomes, we show that moderate lysosomal rupture induces a transient wave of oxidative stress. The start of this oxidative stress period is concomitant with a short period of enhanced mitochondrial membrane potential that later fades and is replaced by a decreased potential before the oxidative stress diminishes. The result of the study suggests that oxidative stress, which has often been described during apoptosis induced by agonists other than oxidative stress per se, may be a consequence of lysosomal rupture with direct and/or indirect effects on mitochondrial respiration and electron transport causing a period of passing enhanced formation of reactive oxygen species.

As a result of continuous digestion of iron-containing metalloproteins, the lysosomes within normal cells contain a pool of labile, redox-active, low-molecular-weight iron, which may make these organelles particularly susceptible to oxidative damage. Oxidant-mediated destabilization of lysosomal membranes with release of hydrolytic enzymes into the cell cytoplasm can lead to a cascade of events eventuating in cell death (either apoptotic or necrotic depending on the magnitude of the insult). To assess the importance of the intralysosomal pool of redox-active iron, we have temporarily blocked lysosomal digestion by exposing cells to the lysosomotropic alkalinizing agent, ammonium chloride (NH₄Cl). The consequent increase in lysosomal pH (from ca. 4.5 to > 6) inhibits intralysosomal proteolysis and, hence, the continuous flow of reactive iron into this pool. Preincubation of J774 cells with 10 mM NH₄Cl for 4 h dramatically decreased apoptotic death caused by subsequent exposure to H₂O₂, and the protection was as great as that afforded by the powerful iron chelator, desferrioxamine (which probably localizes predominantly in the lysosomal compartment). Sulfide-silver cytochemical detection of iron revealed a pronounced decrease in lysosomal content of redox-active iron after NH₄Cl exposure, probably due to diminished intralysosomal digestion of iron-containing material coupled with continuing iron export from this organelle. Electron paramagnetic resonance experiments revealed that hydroxyl radical formation, readily detectable in control cells following H₂O₂ addition, was absent in cells preexposed to 10 mM NH₄Cl. Thus, the major pool of redox-active, low-molecular-weight iron may be located within the lysosomes. In a number of clinical situations, pharmacologic strategies that minimize the amount or reactivity of intralysosomal iron should be effective in preventing oxidant-induced cell death.

3-Aminopropanal (3-AP), a degradation product of polyamines such as spermine, spermidine and putrescine, is a lysosomotropic small aldehyde that causes apoptosis or necrosis of most cells in culture, apparently by inducing moderate or extensive lysosomal rupture, respectively, and secondary mitochondrial changes. Here, using the human neuroblastoma SH-SY5Y cell line, we found simultaneous occurrence of apoptotic and necrotic cell death when cultures were exposed to 3-AP in concentrations that usually are either nontoxic, or only cause apoptosis. At 30 mM, but not at 10 mM, the lysosomotropic base and proton acceptor NH₃ completely blocked the toxic effect of 3-AP, proving that 3-AP is lysosomotropic and suggesting that the lysosomal membrane proton pump of neuroblastoma cells is highly effective, creating a lower than normal lysosomal pH and, thus, extensive intralysosomal accumulation of lysosomotropic drugs. A wave of internal oxidative stress, secondary to changes in mitochondrial membrane potential, followed and gave rise to further lysosomal rupture. The preincubation of cells for 24 h with a chain-breaking free radical-scavenger, α-tocopherol, before exposure to 3-AP, significantly delayed both the wave of oxidative stress and the secondary lysosomal rupture, while it did not interfere with the early 3-AP-mediated phase of lysosomal break. Obviously, the reported oxidative stress and apoptosis/necrosis are consequences of lysosomal rupture with ensuing release of lysosomal enzymes resulting in direct/indirect effects on mitochondrial permeability, membrane potential, and electron transport. The induced oxidative stress seems to act as an amplifying loop causing further lysosomal break that can be partially prevented by α-tocopherol. Perhaps secondary brain damage during a critical post injury period can be prevented by the use of drugs that temporarily raise lysosomal pH, inactivate intralysosomal 3-AP, or stabilize lysosomal membranes against oxidative stress.