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Isocitrate dehydrogenase (IDH) mutation status is an important factor for surgical decision-making: patients with IDH-mutated tumors are more likely to have a good long-term prognosis, and thus favor aggressive resection with more survival benefit to gain. Patients with IDH wild-type tumors have generally poorer prognosis and, therefore, conservative resection to avoid neurological deficit is favored. Current histopathological analysis with frozen sections is unable to identify IDH mutation status intraoperatively, and more advanced methods are therefore needed. We examined a novel method suitable for intraoperative IDH mutation identification that is based on the differential mobility spectrometry (DMS) analysis of the tumor. We prospectively obtained tumor samples from 22 patients, including 11 IDH-mutated and 11 IDH wild-type tumors. The tumors were cut in 88 smaller specimens that were analyzed with DMS. With a linear discriminant analysis (LDA) algorithm, the DMS was able to classify tumor samples with 86% classification accuracy, 86% sensitivity, and 85% specificity. Our results show that DMS is able to differentiate IDH-mutated and IDH wild-type tumors with good accuracy in a setting suitable for intraoperative use, which makes it a promising novel solution for neurosurgical practice. publishedVersion

Background Spontaneous angiogram-negative subarachnoid hemorrhage (SAH) is considered a benign illness with little of the aneurysmal SAH-related complications. We describe the clinical course, SAH-related complications, and outcome of patients with angiogram-negative SAH. Methods We retrospectively reviewed all adult patients admitted to a neurosurgical intensive care unit during 2004–2018 due to spontaneous angiogram-negative SAH. Our primary outcome was a dichotomized Glasgow Outcome Scale (GOS) at 3 months. We assessed factors that associated with outcome using multivariable logistic regression analysis. Results Of the 108 patients included, 84% had a favorable outcome (GOS 4–5), and mortality was 5% within 1 year. The median age was 58 years, 51% were female, and 93% had a low-grade SAH (World Federation of Neurosurgical Societies grading I–III). The median number of angiograms performed per patient was two. Thirty percent of patients showed radiological signs of acute hydrocephalus, 28% were acutely treated with an external ventricular drain, 13% received active vasospasm treatment and 17% received a permanent shunt. In the multivariable logistic regression model, only acute hydrocephalus associated with unfavorable outcome (odds ratio = 4.05, 95% confidence interval = 1.05–15.73). Two patients had a new bleeding episode. Conclusion SAH-related complications such as hydrocephalus and vasospasm are common after angiogram-negative SAH. Still, most patients had a favorable outcome. Only acute hydrocephalus was associated with unfavorable outcome. The high rate of SAH-related complications highlights the need for neurosurgical care in these patients.

Background We wanted to understand how patients with different modified Rankin Scale (mRS) grades differ regarding their health-related quality of life (HRQoL) and how this affects the interpretation and dichotomization of the grade. Methods In 2016, all adult patients in our brain arteriovenous malformation (AVM) database (n = 432) were asked to fill in mailed letters including a questionnaire about self-sufficiency and lifestyle and the 15D HRQoL questionnaire. The follow-up mRS was defined in 2016 using the electronic patient registry and the questionnaire data. The 15D profiles of each mRS grade were compared to those of the general population and to each other, using ANCOVA with age and sex standardization. Results Patients in mRS 0 (mean 15D score = 0.954 ± 0.060) had significantly better HRQoL than the general population (mean = 0.927 ± 0.028), p p Conclusions Using 15D, we were able to find significant differences in the HRQoL between mRS 0 and mRS 1 AVM patients, against the recent findings on stroke patients using EQ-5D in their analyses. Although the dichotomization cut point is commonly set between mRS 1 and 2, patients in these grades had a similar HRQoL and a decreased ability to continue their premorbid lifestyle, in contrast to patients in mRS 0.

BACKGROUND: The use of a digital three-dimensional (3D) exoscope system in neurosurgery is increasing as an alternative to the operative microscope. The objective of this study was to compare a digital 3D exoscope system with a standard operating microscope as a neurosurgical visualization tool in a highly challenging experimental setting. METHODS: End-to-side bypass procedures, each at a depth of 9 cm, were performed in a simulation setting. The quality of the task and the depth effect, visualization, magnification, illumination, and ergonomics were evaluated. RESULTS: No major differences were noted between the microscope and the 3D exoscope in terms of the quality of the work. Working with the 3D exoscope was more time-consuming than working with the microscope. Changing the depth and focus was faster using the operative microscope. The 3D exoscope enabled higher magnification and offered better ergonomic features. CONCLUSIONS: In a highly challenging experimental setting, comparable procedural quality was found for the microscope and the 3D exoscope. Each visualization tool had advantages and disadvantages. Over time and with technologic advances, the digital 3D exoscope may become the main operative visualization system in microneurosurgery.

Cerebral Cavernous Malformation (CCM) is a brain vascular disease with various neurological symptoms. In this study, we describe the inflammatory profile in CCM and show for the first time the formation of neutrophil extracellular traps (NETs) in rodents and humans with CCM. Through RNA-seq analysis of cerebellum endothelial cells from wild-type mice and mice with an endothelial cell-specific ablation of the Ccm3 gene (Ccm3iECKO), we show that endothelial cells from Ccm3iECKO mice have an increased expression of inflammation-related genes. These genes encode proinflammatory cytokines and chemokines, as well as adhesion molecules, which promote recruitment of inflammatory and immune cells. Similarly, immunoassays showed elevated levels of these cytokines and chemokines in the cerebellum of the Ccm3iECKO mice. Consistently, both flow cytometry and immunofluorescence analysis showed infiltration of different subsets of leukocytes into the CCM lesions. Neutrophils, which are known to fight against infection through different strategies, including the formation of NETs, represented the leukocyte subset within the most pronounced increase in CCM. Here, we detected elevated levels of NETs in the blood and the deposition of NETs in the cerebral cavernomas of Ccm3iECKO mice. Degradation of NETs by DNase I treatment improved the vascular barrier. The deposition of NETs in the cavernomas of patients with CCM confirms the clinical relevance of NETs in CCM.

Background Research on the prevalence of smokers in patients with brain arteriovenous malformation (AVM) remains nonexistent, even though smoking is a well-known risk factor for intracranial aneurysms. Objective To examine the prevalence and smoking habits of AVM patients. Methods Data on smoking habits were collected with a quality-of-life questionnaire mailed in 2016 to all patients in our large AVM database. These smoking data were supplemented with registry data derived from medical records. The prevalence of smokers was compared to that of the general population, derived from statistics of National Institute for Health and Welfare. Logit transformation of proportions and Students t distribution were used to calculate the 95% CIs for prevalence estimates. Results Of the 384 patients aged over 18 yr on admission, 277 (72.1%) returned the questionnaires in 2016. When compared to age, sex, and admission year matched general population, the proportion of smokers in AVM patients was 48% (CI = 41%-55%) and 19% (CI = 16%-21%) in the general population. The difference increased in older age groups; in those aged 65 to 77 yr, the percentage of smokers reached 73% (CI = 46%-90%), while the corresponding percentage in the general population was 7% (CI = 5%-9%). Conclusion We observed considerably higher rates of smoking among AVM patients when compared to age, sex, and admission year matched general population. Our results suggest that in the development of AVMs, the role played by nicotine and other substances in tobacco smoke should be examined. Cigarette smoking could potentially be a common cerebrovascular risk factor.

Aki Laakso tutkimusryhmän jäsenenä. Currently available simulators are supposed to allow young neurosurgeons to hone their technical skills in a safe environment, without causing any unnecessary harm to their patients caused by their inexperience. For this training method to be largely accepted in neurosurgery, it is necessary to prove simulation efficacy by means of large-scale clinical validation studies. We correlated and analysed the performance at a simulator and the actual operative skills of different neurosurgeons (construct validity). We conducted a study involving 92 residents and attending neurosurgeons from different European Centres; each participant had to perform a virtual task, namely the placement of an external ventricular drain (EVD) at a neurosurgical simulator (ImmersiveTouch). The number of attempts needed to reach the ventricles and the accuracy in positioning the catheter were assessed. Data suggests a positive correlation between subjects who placed more EVDs in the previous year and those who get better scores at the simulator (p = .008) (fewer attempts and better surgical accuracy). The number of attempts to reach the ventricle was also analysed; senior residents needed fewer attempts (mean = 2.26; SD = 1.11) than junior residents (mean = 3.12; SD = 1.05) (p = .007) and staff neurosurgeons (mean = 2.89, SD = 1.23). Scoring results were compared by using the Fisher's test, for the analysis of the variances, and the Student's T test. Surprisingly, having a wider surgical experience overall does not correlate with the best performance at the simulator. The performance of an EVD placement on a simulator correlates with the density of the neurosurgical experience for that specific task performed in the OR, suggesting that simulators are able to differentiate neurosurgeons according to their surgical ability. Namely this suggests that the simulation performance reflects the surgeons' consistency in placing EVDs in the last year.

BACKGROUND: A supplementary grading scale (Supplemented Spetzler-Martin grade, Supp-SM) was introduced in 2010 as a refinement of the SM system to improve preoperative risk prediction of brain arteriovenous malformations (AVMs). OBJECTIVE: To determine the ability to predict surgical outcomes using the Supp-SM grading scale. METHODS: This retrospective study was conducted on 200 patients admitted to the Helsinki University Hospital between 2000 and 2014. The validity of the Supp-SM and SM grading systems was compared using the area under the receiver operating characteristic (AUROC) curves, with respect to the change between preoperative and early (3-4 mo) as well as final postoperative modified Rankin Scale (mRS) scores. RESULTS: The performance of the Supp-SM was superior to that of the SM grading scale in the early follow-up (3-4 mo): AUROC = 0.57 (95% confidence interval [CI]: 0.49-0.65) for SM and AUROC = 0.67 (95% CI: 0.60-0.75) for Supp-SM. The Supp-SM performance continued improving over SM at the late follow-up: AUROC = 0.63 (95% CI: 0.55-0.71) for SM and AUROC = 0.70 (95% CI: 0.62-0.77) for Supp-SM. The perforating artery supply, which is not part of either grading system, plays an important role in the early follow-up outcome (P = .008; odds ratio: 2.95; 95% CI: 1.32-6.55) and in the late follow-up outcome (P

INTRODUCTION Navigated transcranial magnetic stimulation (nTMS) is increasingly used for preoperative mapping of motor function, and clinical evidence for its benefit for brain tumor patients is accumulating. In respect to language mapping with repetitive nTMS, literature reports have yielded variable results, and it is currently not routinely performed for presurgical language localization. The aim of this project is to define a common protocol for nTMS motor and language mapping to standardize its neurosurgical application and increase its clinical value. METHODS The nTMS workshop group, consisting of highly experienced nTMS users with experience of more than 1500 preoperative nTMS examinations, met in Helsinki in January 2016 for thorough discussions of current evidence and personal experiences with the goal to recommend a standardized protocol for neurosurgical applications. RESULTS nTMS motor mapping is a reliable and clinically validated tool to identify functional areas belonging to both normal and lesioned primary motor cortex. In contrast, this is less clear for language-eloquent cortical areas identified by nTMS. The user group agreed on a core protocol, which enables comparison of results between centers and has an excellent safety profile. Recommendations for nTMS motor and language mapping protocols and their optimal clinical integration are presented here. CONCLUSION At present, the expert panel recommends nTMS motor mapping in routine neurosurgical practice, as it has a sufficient level of evidence supporting its reliability. The panel recommends that nTMS language mapping be used in the framework of clinical studies to continue refinement of its protocol and increase reliability.

Recently, the use of digital exoscopes has been increasingly promoted as an alternative to microscopes. The aim of this study is to compare experimental bypass quality in both visualization methods.This study used two hundred 1-mm chicken wing vessels, which were used for either exoscopic or microscopic (100 samples each) bypass procedures. All procedures were recorded between July 2018 and September 2018. The bypass quality was evaluated according to our published practical scale (time, stitch distribution, intima-intima attachment, and orifice size).Both methods are effective in doing bypass suturing (practical scale score was good, 86% vs. 85%; P = 0.84). There were no significant differences regarding intima-intima attachment (P = 0.26) and orifice size (P = 0.25). However, suturing time (P0.001) was less using the microscope, whereas stitch distribution (P = 0.001) was better using the exoscope. Different suturing techniques (interrupted vs. continuous) had overall comparable results (P = 0.55).Both methods produced equally satisfactory results in experimental bypass procedures. The exoscope has the potential for better 3-dimensional visualization and sharing the surgeon's view with others for teaching purposes.

BACKGROUND: Differences in the postgraduate training programs of neurosurgical residents are suspected throughout Europe. The influence of working hour restrictions by the European Working Time Directive (WTD) 2003/88/EC on the number of surgical procedures remains unclear. We designed a survey to collect information on the number of surgical procedures, performed by European neurosurgical trainees during residency. This article reports preliminary data. METHODS: An electronic survey was distributed among the European Association of Neurosurgical Societies (EANS) member countries by national delegates of the training committee, as well as by members of the Young Neurosurgeons' committee. The EANS mailing list of individual members was also used for distribution. All responses received between 04/2018 and 12/2018 were considered. RESULTS: From n = 180 responses received, 42 were omitted as responders were still in residency and for 58 relevant information was missing. The final sample was n = 80, with a mean responder's age of 43.0 years (SD 8.6) and 88.8% being male. Responses came from 16 European countries; board certification was received between the years of 1976-2018. The numbers of surgical procedures performed independently were 511 (mean, 95% confidence interval (CI) 413-610), supervised were 514 (95%CI 360-668) and assisted were 752 (95%CI 485-1019) throughout residency. More detailed numbers for specific procedure types are reported in the article. Independently performed cranial procedures outnumbered spinal procedures (p < 0.006), and adult procedures outnumbered pediatric procedures (p < 0.001). There was a strong decrease in caseload between 1976 and 2018, with trainees performing on average 65 cases less throughout residency for each calendar year increase in board certification (95% CI - 116 to - 15, p = 0.012). Trainees graduating residency before introduction of the European WTD 2003/88/EC participated in more procedures than those graduating afterwards (mean 2797 vs. 1418, p = 0.005). CONCLUSIONS: The preliminary analysis of the first 80 responses now provides a first reference frame for caseload that can be used by current and future European residents to critically compare their own operative numbers to. There was a strong decline in surgical cases over time, and trainees graduating after introduction of the European WTD 2003/88/EC had less surgical exposure. The survey remains open, and we invite further European neurosurgeons to provide their data in order to get even more robust estimates.

Background A major barrier to effective treatment of glioblastoma (GBM) is the large intertumoral heterogeneity at the genetic and cellular level. In early phase clinical trials, patient heterogeneity in response to therapy is commonly observed; however, how tumor heterogeneity is reflected in individual drug sensitivities in the treatment-naïve glioblastoma stem cells (GSC) is unclear. Methods We cultured 12 patient-derived primary GBMs as tumorspheres and validated tumor stem cell properties by functional assays. Using automated high-throughput screening (HTS), we evaluated sensitivity to 461 anticancer drugs in a collection covering most FDA-approved anticancer drugs and investigational compounds with a broad range of molecular targets. Statistical analyses were performed using one-way ANOVA and Spearman correlation. Results Although tumor stem cell properties were confirmed in GSC cultures, their in vitro and in vivo morphology and behavior displayed considerable tumor-to-tumor variability. Drug screening revealed significant differences in the sensitivity to anticancer drugs (p

ObjectiveTo discover the health-related quality of life (HRQOL) of patients with treated arteriovenous malformation (AVM), we used the self-applicable HRQOL instrument, the 15D, and analyzed the scores in both in the whole study population and specified cohorts.MethodsThe 15D questionnaires were mailed to adult patients with AVM alive in 2016 (n = 432) in our database. Patients with completely eradicated AVM (n = 262) were included in a subsequent analysis. The results were compared with those of the general population standardized for age and sex. Subgroup analyses were conducted for epilepsy, number of bleeding episodes, location of the lesion, modified Rankin Scale score, and Spetzler-Ponce classification (SPC) using independent-samples t test or analysis of covariance. Tobit regression was used to explain the variance in the 15D score.ResultsPatients had impaired HRQOL compared to the reference population (p < 0.0001). Deep location, multiple bleeding episodes, and refractory epilepsy were associated with impaired HRQOL. Patients in SPC A and B had similar posttreatment 15D scores, whereas those in class C had an impaired HRQOL. Significant explanatory variables in the regression model were age, sex, number of bleeding episodes, refractory epilepsy, and SPC.ConclusionsWith careful patient selection, patients in SPC B can reach as favorable HRQOL as those in SPC A provided the operation is successful. Multiple bleeding episodes should be prevented with effective treatment aiming at complete AVM obliteration. The postoperative treatment of patients with AVM should focus on preventing depressive symptoms, anxiety, and epileptic seizures. We encourage other research groups to use HRQOL instruments to fully understand the consequences of neurologic and neurosurgical diseases on patients' HRQOL.

BACKGROUND: Arteriovenous malformations (AVMs) of the posterior fossa are demanding lesions that often present with rupture. Studies including outcome analyses in surgically operated patients with ruptured infratentorial AVMs are scarce. Certain anatomic and demographic features have shown associations with postoperative outcomes. METHODS: Eighty-six patients with infratentorial AVM were collected from our AVM database. Fifty-four patients were admitted from 1990 onward, and their demographic, lesion, and treatment characteristics were analyzed. The cohort was further refined to 38 consecutive patients with surgically treated ruptured infratentorial AVM admitted to our center between 1990 and 2014, and statistical analyses of factors influencing outcomes were conducted. RESULTS: Twenty-seven patients (69%) had a favorable outcome at early follow-up and 24 (67%) had a favorable outcome at final follow-up. Factors associated with poor outcome in early recovery on univariate analyses were deep venous drainage of the lesion (odds ratio (OR 5.3; P = 0.037) and high Hunt & Hess score (P = 0.003). In the multivariate model, independent predictors for poor outcome were deep venous drainage (OR, 14.5; P = 0.010) and older age at admission (OR, 1.06; P = 0.028). The sole independent predictor for poor outcome at last follow-up was deep venous drainage (OR, 5.00; P = 0.046). The total follow-up time was 370 person-years. CONCLUSIONS: AVMs of the posterior fossa usually present with rupture and thus require prompt clinical treatment. The majority of surgically treated patients recover favorably. Our data show that venous drainage patterns have the greatest influence on the patient's postoperative condition. Other influencing factors include the severity of hemorrhage and patient age at admission.

Objective To assess prospectively neuro-ophthalmic findings associated with unruptured intracranial aneurysms and treatment morbidity and to identify factors predicting these findings. Methods Patients admitted to Helsinki University Central Hospital and treated surgically or endovascularly during 2011 underwent a neuro-ophthalmic examination, including formal visual field testing, before operation, at discharge, and 2–4 months and ≥6 months postoperatively. Univariate and multivariate analysis was used to identify factors predicting eye movement disorders. Results Study participants included 142 patients with 184 treated aneurysms: 7 (5%) had a third, fourth, or sixth nerve palsy or skew deviation preoperatively, and 16 (11%) had a third, fourth, or sixth nerve palsy or skew deviation postoperatively; the frequency was 8 (6%) at the last follow-up evaluation. Other findings included compressive optic neuropathy (n = 4), ischemic optic neuropathy (n = 1), Weber syndrome (n = 3), Benedikt syndrome (n = 1), and Wallenberg syndrome (n = 1). Of the 140 survivors at 6 months, 7 (5%) presented with visual field defects resulting from the aneurysm or its treatment. In the best bivariate model, factors independently predicting postoperative eye movement disorders were aneurysm location in the posterior circulation with an odds ratio of 142.02 (95% confidence interval = 20.13–1002.22) and aneurysm size (odds ratio = 1.28 for each 1-mm increase in diameter, 95% confidence interval = 1.12–1.47). Conclusions Management of unruptured intracranial aneurysms is fairly safe from a neuro-ophthalmic perspective, with some treatment-related morbidity being transient and minor. Although rare, an irreversible deficit is possible and should be taken into account when considering preventive treatment.

There are conflicting opinions regarding the optimal waiting time to perform surgery after rupture of supratentorial arteriovenous malformations (AVMs) to achieve the best possible outcome. To analyze factors influencing outcomes for ruptured supratentorial AVMs after surgery, paying particular attention to the timing of the surgery. We retrospectively investigated 59 patients admitted to our center between 2000 and 2014 for surgical treatment of ruptured supratentorial AVMs. We evaluated the effect of timing of surgery and other variables on the outcome at 2-4 months (early outcome), at 12 months (intermediate outcome) after surgery, and at final follow-up at the end of 2016 (late outcome). Age over 40 years (OR 18.4; 95% CI 1.9-172.1; p = 0.011), high Hunt and Hess grade (4 or 5) before surgery (OR 13.5; 95% CI 2.1-89.2; p = 0.007), hydrocephalus on admission (OR 12.9; 95% CI 1.8-94.4; p = 0.011), and over 400 cm(3) bleeding during surgery (OR 11.5; 95% CI 1.5-86.6; p = 0.017) were associated with an unfavorable early outcome. Age over 40 years (OR 62.8; 95% CI 2.6-1524.9; p = 0.011), associated aneurysms (OR 34.7; 95% CI 1.4-829.9; p = 0.029), high Hunt and Hess grade before surgery (OR 29.2; 95% CI 2.6-332.6; p = 0.007), and over 400 cm(3) bleeding during surgery (OR 35.3; 95% CI 1.7-748.7; p = 0.022) were associated with an unfavorable intermediate outcome. Associated aneurysms (OR 8.2; 95% CI 1.2-55.7; p = 0.031), high Hunt and Hess grade before surgery (OR 5.7; 95% CI 1.3-24.3; p = 0.019), and over 400 cm(3) bleeding during surgery (OR 5.8; 95% CI 1.2-27.3; p = 0.027) were associated with an unfavorable outcome at last follow-up. Elapsed time between rupture and surgery did not affect early or final outcome. Early surgery in patients with ruptured supratentorial arteriovenous malformation is feasible strategy, with late results comparable to those achieved with delayed surgery. Many other factors than timing of surgery play significant roles in long-term outcomes for surgically treated ruptured supratentorial AVMs.

Objectives: To evaluate the efficacy and adverse effects of subthalamic deep brain stimulation (STN-DBS) in patients with advanced Parkinson's disease (PD) and the possible correlation between electrode location and clinical outcome. Methods: We retrospectively reviewed 87 PD-related STN-DBS operations at Helsinki University Hospital (HUH) from 2007 to 2014. The changes of Unified Parkinson's Disease Rating Scale (UPDRS) part III score, Hoehn & Yahr stage, antiparkinson medication, and adverse effects were studied. We estimated the active electrode location in three different coordinate systems: direct visual analysis of MRI correlated to brain atlas, location in relation to the nucleus borders and location in relation to the midcommisural point. Results: At 6 months after operation, both levodopa equivalent doses (LEDs; 35%, Wilcoxon signed-rank test = 0.000) and UPDRS part III scores significantly decreased (38%, Wilcoxon signed-rank test = 0.000). Four patients (5%) suffered from moderate DBS-related dysarthria. The generator and electrodes had to be removed in one patient due to infection (1%). Electrode coordinates in the three coordinate systems correlated well with each other. On the left side, more ventral location of the active contact was associated with greater LED decrease. Conclusions: STN-DBS improves motor function and enables the reduction in anti-parkinson medication with an acceptable adverse effect profile. More ventral location of the active contact may allow stronger LED reduction. Further research on the correlation between contact location, clinical outcome, and LED reduction is warranted.

Background Population-based long-term data on pediatric patients with cerebral arteriovenous malformations (AVMs) are limited. Objective To clarify the characteristics and long-term outcome of pediatric patients with AVM. Methods A retrospective analysis was performed on 805 consecutive brain AVM patients admitted to a single center between 1942 and 2014. The patients were defined as children if they were under 18 yr at admission. Children were compared to an adult cohort. Changing patterns of presentation were also analyzed by decades of admission. Results The patients comprised 127 children with a mean age of 12 yr. The mean follow-up time was 21 yr (range 0-62). Children presented more often with intracerebral hemorrhage (ICH) but less often with epilepsy than adults. Basal ganglia, cerebellar, and posterior paracallosal AVMs were more common in pediatric than in adult patients. Frontal and temporal AVMs, in contrast, were more common in adult than in pediatric patients. As the number of incidentally and epilepsy-diagnosed AVMs increased, ICH rates dropped in both cohorts. In total, 22 (82%) pediatric and 108 (39%) adult deaths were assessed as AVM related. After multivariate analysis, small AVM size and surgical treatment correlated with a favorable long-term outcome. Conclusion Hemorrhagic presentation was more common in children than in adults. This was also reflected as lower prevalence of epileptic presentation in the pediatric cohort. Lobar and cortical AVM locations were less frequent, whereas deep and cerebellar AVMs were more common in children. Hemorrhagic presentation correlated negatively with incidentally and epilepsy-diagnosed AVMs. In children, AVM was a major cause of death, but in adults, other factors contributed more commonly to mortality.

Aneurysms at the junction of the vertebral artery (VA) and posterior inferior cerebellar artery (PICA) are relatively rare. Their treatment is challenged by the diverse anatomy of the VA and PICA, close involvement of the PICA in the aneurysm neck, and scant space deep in the posterior fossa next to the cranial nerves, brain stem, and obstructing structures of the skull base. Computed tomography angiography (CTA) visualizes bony structures in addition to the vasculature, and being noninvasive and easily available, it can serve for planning microsurgical treatment. We analyzed the anatomy of PICA aneurysms imaged by CTA to promote planning the treatment.We examined the CTA images of 70 consecutive patients with a saccular PICA aneurysm who were all treated in the Department of Neurosurgery, Helsinki, Finland, 2001 to 2011.Each of the 70 patients had 1 aneurysm at the VA-PICA junction. The proportion of small aneurysms (7 mm) was high, 67%. The dome-to-neck ratio was1.2 in 24 (34%) of the aneurysms. In the coronal view, 58 (83%) aneurysms projected cranially, and only 2 (3%) caudally. The aneurysms were located from 1 mm below the foramen magnum to 31 mm above it, most arising at the level of the jugular tubercle. The median distance to the aneurysm from the midline was 6 mm, ranging from 7.5 mm contralateral to the origin of the parent artery to 14 mm ipsilateral. Compared with the right VA, the left VA was larger, it harbored the most aneurysms, and its aneurysms were more often ruptured.Relation of PICA aneurysms to skull base structures is highly variable; the aneurysms can also be extracranial, or lie on the site of the skull contralateral to the origin of the parent artery. These anatomical variations demand meticulous study of the angiography in each individual case, especially before surgical treatment of the aneurysm.

Backgound/Objective: To determine the level of association between uptake of the amyloid positron emission tomography (PET) imaging agent [18F]flutemetamol and the level of amyloid-ß measured by immunohistochemical and histochemical staining in a frontal cortical region biopsy site. Methods: Seventeen patients with probable normal pressure hydrocephalus (NPH) underwent prospective [18F]flutemetamol PET and subsequent frontal cortical brain biopsy during ventriculoperitoneal shunting. Tissue amyloid-ß was evaluated using the monoclonal antibody 4G8, thioflavin S and Bielschowsky silver stain. Results: Four of the 17 patients (23.5%) had amyloid-ß pathology based on the overall pathology read and also showed increased [18F]flutemetamol uptake. [18F]Flutemetamol standardized uptake values from the biopsy site were significantly associated with biopsy specimen amyloid-ß levels (Pearson's r = 0.67; p = 0.006). There was also good correlation between the biopsy specimen amyloid-ß level and uptake of [18F]flutemetamol in the region contralateral to the biopsy site (r = 0.67; p = 0.006), as well as with composite cortical [18F]flutemetamol uptake (r = 0.65; p = 0.008). The blinded visual read showed a high level of agreement between all readers (κ = 0.88). Two of 3 readers were in full agreement on all images; 1 reader disagreed on 1 of the 17 NPH cases. Blinded visual assessments of PET images by 1 reader were associated with 100% sensitivity to the overall pathology read, and assessments by the 2 others were associated with 75% sensitivity (overall sensitivity by majority read was 75%); specificity of all readers was 100%. Conclusions: [18F]Flutemetamol detects brain amyloid-ß in vivo and shows promise as a valuable tool to study and possibly facilitate diagnosis of Alzheimer's disease both in patients with suspected NPH and among the wider population.

Background and Purpose— Long-term angiographic follow-up studies on pediatric aneurysm patients are scarce. Methods— We gathered long-term clinical and angiographic follow-up data on all pediatric aneurysm patients (≤18 years at diagnosis) treated at the Department of Neurosurgery, Helsinki University Central Hospital, between 1937 and 2009. Results— Fifty-nine patients with cerebral aneurysms in childhood had long-term clinical and radiological follow-up (median, 34 years; range, 4–56 years). Twenty-four patients (41%) were diagnosed with altogether 25 de novo and 11 recurrent aneurysms, with 9 (25%) of the aneurysms being symptomatic. New subarachnoid hemorrhage occurred in 7 patients; 4 of these patients died. Eight patients (33%) had multiple new aneurysms. The annual rate of hemorrhage was 0.4%, and the annual rate for the development of de novo or recurrent aneurysm was 1.9%. There were no de novo aneurysms in 7 patients with previously unruptured aneurysms. However, 1 recurrent aneurysm was diagnosed. Current and previous smoking (risk ratio, 2.44; 95% confidence interval, 1.07–5.55) was the only statistically significant risk factor for de novo and recurrent aneurysm formation in patients with previous subarachnoid hemorrhage, whereas hypertension, sex, or age at onset had no statistically significant effect. Smoking was also a statistically significant risk factor for new subarachnoid hemorrhage. Conclusions— Patients with ruptured intracranial aneurysms in childhood have a high risk for new aneurysms and new subarachnoid hemorrhage, especially if they start to smoke as adults. Life-long angiographic follow-up is mandatory.

When delivered over a specific cortical site, TMS can temporarily disrupt the ongoing process in that area. This allows mapping of speech-related areas for preoperative evaluation purposes. We numerically explore the observed variability of TMS responses during a speech mapping experiment performed with a neuronavigation system. We selected four cases with very small perturbations in coil position and orientation. In one case (E) a naming error occurred, while in the other cases (NEA, B, C) the subject appointed the images as smoothly as without TMS. A realistic anisotropic head model was constructed of the subject from T1-weighted and diffusion-weighted MRI. The induced electric field distributions were computed, associated to the coil parameters retrieved from the neuronavigation system. Finally, the membrane potentials along relevant white matter fibre tracts, extracted from DTI-based tractography, were computed using a compartmental cable equation. While only minor differences could be noticed between the induced electric field distributions of the four cases, computing the corresponding membrane potentials revealed different subsets of tracts were activated. A single tract was activated for all coil positions. Another tract was only triggered for case E. NEA induced action potentials in 13 tracts, while NEB stimulated 11 tracts and NEC one. The calculated results are certainly sensitive to the coil specifications, demonstrating the observed variability in this study. However, even though a tract connecting Broca's with Wernicke's area is only triggered for the error case, further research is needed on other study cases and on refining the neural model with synapses and network connections. Case-and subject-specific modelling that includes both electromagnetic fields and neuronal activity enables demonstration of the variability in TMS experiments and can capture the interaction with complex neural networks.

Background Various surgical approaches for the removal of tuberculum sellae meningiomas (TSMs) have previously been described. Objective To assess the reliability and safety of the lateral supraorbital (LSO) approach to remove TSMs. Methods We identified all TSM patients operated on at the Department of Neurosurgery at Helsinki University Central Hospital, Finland, by the senior author (J.H.) using the LSO approach between September 1997 and August 2010. We retrospectively analyzed the clinical data, radiological findings, surgical treatment, histology, and outcome of patients and discuss the operative technique. Results Apparent complete tumor removal was achieved in 45 patients (87%). Of 42 patients, preexisting visual deficit improved in 22, remained the same in 13, and worsened in 7, and de novo visual deficit occurred in 1 patient. At 3 months post-discharge, 47 patients (90%) had a good recovery, 4 (8%) were moderately disabled, and 1 (2%) died 40 days after surgery of unexplained cardiac arrest. Seven patients (13%) had minimal residual tumors, 2 of which required reoperation. During the median follow-up of 59 months (range, 1-133 months), tumor recurred in 1 of the patients who had undergone a second operation. Conclusion TSMs of all sizes can be removed via the LSO approach with minimal morbidity and mortality. Low-power or no coagulation is recommended near the optic nerves and the optic chiasm to preserve their vascular support from the internal carotid artery perforators. Our results are comparable to those obtained using more extensive and time-consuming approaches. We recommend the LSO approach to remove TSMs.

Saccular intracranial aneurysms (sIA) are pouch-like pathological dilatations of intracranial arteries that develop when the cerebral artery wall becomes too weak to resist hemodynamic pressure and distends. Some sIAs remain stable over time, but in others mural cells die, the matrix degenerates, and eventually the wall ruptures, causing life-threatening hemorrhage. The wall of unruptured sIAs is characterized by myointimal hyperplasia and organizing thrombus, whereas that of ruptured sIAs is characterized by a decellularized, degenerated matrix and a poorly organized luminal thrombus. Cell-mediated and humoral inflammatory reaction is seen in both, but inflammation is clearly associated with degenerated and ruptured walls. Inflammation, however, seems to be a reaction to the ongoing degenerative processes, rather than the cause. Current data suggest that the loss of mural cells and wall degeneration are related to impaired endothelial function and high oxidative stress, caused in part by luminal thrombosis. The aberrant flow conditions caused by sIA geometry are the likely cause of the endothelial dysfunction, which results in accumulation of cytotoxic and pro-inflammatory substances into the sIA wall, as well as thrombus formation. This may start the processes that eventually can lead to the decellularized and degenerated sIA wall that is prone to rupture.

Arteriovenous malformations (AVMs) of the brain are relatively rare congenital developmental vascular lesions. They may cause hemorrhagic stroke, epilepsy, chronic headache, or focal neurologic deficits, and the incidence of asymptomatic AVMs is increasing due to widespread availability of noninvasive imaging methods. Since the most severe complication of an AVM is hemorrhagic stroke, most epidemiologic studies have concentrated on the hemorrhage risk and its risk factors. In this article, the authors discuss the epidemiology, presenting symptoms, and hemorrhage risk associated with brain AVMs.

BACKGROUND Most cavernomas in the central nervous system are characterized by a benign natural course. Progressive symptoms warrant surgical removal. In the literature, the factors affecting long-term postoperative outcome are not statistically well confirmed. OBJECTIVE To perform a multifactorial analysis of risk factors on a large patient series and to use the results to propose a simple grading scale to predict outcome. METHODS We studied 303 consecutive patients with cavernomas treated surgically at our department from 1980 to 2009. Follow-up assessment was performed on average 5.7 years postoperatively (range, 0.2-36 years). The main outcome measure was the patients' condition at the last follow-up on Glasgow Outcome Scale. For statistical analysis, the outcome measure was dichotomized to favorable (Glasgow Outcome Scale 5) and unfavorable (Glasgow Outcome Scale 1-4). Binary logistic regression analysis was used to estimate the effect of age, sex, seizures, preexisting neurological deficits, hemorrhage, and size and location of cavernoma on long-term outcome. RESULTS Infratentorial, basal ganglia, or spinal location and preexisting neurological deficit were the only independent risk factors for unfavorable outcome, with relative risks of 2.7 (P = .008) and 3.2 (P = .002), respectively. We formulated a grading system based on a score of 1 to 3. When applied to our series, the proposed grading system strongly correlated with outcome (P < .001, Pearson χ test). The risk for long-term unfavorable outcome was 13%, 22%, and 55% for grades 1 through 3, respectively. CONCLUSION The proposed grading system showed a convincing correlation with postoperative outcome in surgically treated cavernoma patients.

Background Anterior clinoidal meningiomas (ACMs) are a subgroup of meningiomas accounting for less than 10% of supratentorial meningiomas. Objective To assess the reliability and safeness of the lateral supraorbital approach (LSO) to remove ACMs. Methods Between September 1997 and October 2009, a total of 73 ACM patients were operated on at the Department of Neurosurgery, Helsinki University Central Hospital, by the senior author (J.H.). We retrospectively analyzed the clinical data, radiological findings, surgical treatment, histology, and outcome of patients, and discuss the operative technique. Results Seventy-three patients were operated on by applying the LSO approach. Apparently complete removal was achieved in 57 patients (78%). Anterior clinoidectomy was performed in 21 cases. Preexisting visual deficit improved in 11 of 39 patients and worsened in 4; 3 had de novo visual deficit. At 3 months after discharge, 60 (82%) patients had a good recovery, 9 (12%) patients were moderately disabled, 1 presented with severe disability, and 3 (4%) patients died of surgery-related causes. Sixteen (22%) patients had residual tumors, 6 of which required reoperation. During the median follow-up of 36 months (range, 3-146), tumor recurred in 3 patients: 2 were followed-up and 1 was reoperated on. Conclusion ACMs can be removed via the LSO approach with relatively low morbidity and mortality. Anterior clinoidectomy is required only in selected cases, and we prefer the intradural approach during the LSO approach. High-power coagulation should be avoided in proximity of the optic nerve.

Background Treatment of Spetzler-Martin Grade IV and V brain arteriovenous malformations (ie, high-grade AVMs) carries a high risk of morbidity and even mortality. However, little is known about the behavior of these lesions if left untreated. Objective To investigate the natural history of patients with high-grade AVMs. Methods Patients with untreated high-grade AVMs admitted to our center between 1952 and 2005 were followed from admission until death, AVM rupture, or initiation of treatment. Rates of rupture and various risk factors were analyzed using Kaplan-Meier life table analyses and Cox proportional hazards models. Functional outcome was assessed 1 year after possible AVM rupture using the Glasgow Outcome Scale. Results Sixty-three patients with a mean follow-up time of 11.0 years (range, 1 month to 39.6 years) were identified. Twenty-three patients (37%) experienced a subsequent rupture. The average annual rate of rupture was 3.3%. In patients with hemorrhagic presentation, the annual rate was 6.0%, compared to 1.1% in patients with unruptured AVMs (P = .001, log-rank test; hazard ratio, 5.09 [1.40-18.5, 95% CI]; P = .013, multivariate Cox regression model). One year after the first subsequent rupture, 6 patients (26%) had died, and 9 (39%) had moderate or severe disability. Conclusion Untreated high grade AVMs presenting with hemorrhage have a significant risk of subsequent rupture, and their rupture carries a higher risk of case fatality and permanent morbidity than AVMs in general. The risks associated with their treatment should be appraised in light of perilous natural history.

BACKGROUND: Residual and recurrent intracranial aneurysms after endovascular treatment with Guglielmi detachable coils may necessitate a microsurgical occlusion. OBJECTIVE: To analyze the microsurgical technique and describe how the location, morphology, and appearance of the coiled aneurysm affect the technique. METHODS: We retrospectively analyzed 81 patients with 82 previously coiled aneurysms treated microsurgically at 2 Finnish neurosurgical university hospitals in Helsinki and Kuopio between July 1995 and August 2009. Seven videos were selected to demonstrate the microsurgical strategy in various locations. RESULTS: Fifty-eight aneurysms (71%) were located at anterior circulation and 24 (29%) at posterior circulation. Fifteen patients were operated on within the first month (early surgery) after coiling, whereas 66 were treated later (late surgery). Complete or partial removal of coils during surgery may facilitate clipping, but is significantly (P < .001) more difficult to accomplish in late surgery. Removal of coils may also increase the chance of poor outcome. Chance of poor outcome also increased with intraoperative aneurysm rupture, size of the aneurysm, and posterior circulation location. Good clinical outcome (same or better clinical condition 3 months after surgery) was achieved in 71 patients (88%). After microsurgery, 4 patients were severely disabled and 6 patients died, 3 of them because of poor clinical condition. CONCLUSION: Complete microsurgical occlusion of the residual aneurysm is possible. However, in large or giant aneurysms direct microsurgery is a challenging high-risk procedure, and we recommend that these patients be referred to a dedicated neurovascular center to minimize surgical complications. Even in experienced hands, use of different bypass procedures may be the best option for demanding growing lesions, especially those in the posterior circulation.

Objective Anterior choroid artery aneurysms (AChAAs) constitute 2%-5% of all intracranial aneurysms. They are usually small, thin walled with one or several arteries originating at their base, and often associated with multiple aneurysms. In this article, we review the practical microsurgical anatomy, the preoperative imaging, surgical planning, and the microneurosurgical steps in the dissection and the clipping of AChAAs. Methods This review, and the whole series on intracranial aneurysms (IAs), are mainly based on the personal microneurosurgical experience of the senior author (J.H.) in two Finnish centers (Helsinki and Kuopio) that serve, without patient selection, the catchment area in Southern and Eastern Finland. Results These two centers have treated more than 10,000 patients with IAs since 1951. In the Kuopio Cerebral Aneurysm Database of 3005 patients with 4253 IAs, 831 patients (28%) had altogether 980 internal carotid artery (ICA) aneurysms, of whom 95 patients had 99 (2%) AChAAs. Ruptured AChAAs, found in 39 patients (41%), with median size of 6 mm (range = 2-19 mm), were associated with intracerebral hematoma (ICH) in only 1 (3%) patient. Multiple aneurysms were seen in 58 (61%) patients. Conclusions The main difficulty in microneurosurgical management of AChAAs is to preserve flow in the anterior choroid artery originating at the base and often attached to the aneurysm dome. This necessitates perfect surgical strategy based on preoperative knowledge of 3 dimensional angioarchitecture and proper orientation during the microsurgical dissection.

Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects similar to 2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment(1). The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24-1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm(2-5). Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells(6-8), suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role(9). These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.

Objective Long-term follow-up studies in patients with brain arteriovenous malformations (AVM) have yielded contradictory results regarding both risk factors for rupture and annual rupture rate. We performed a long-term follow-up study in an unselected, consecutive patient population with AVMs admitted to the Department of Neurosurgery at Helsinki University Central Hospital between 1942 and 2005. Methods Patients with untreated AVMs were followed from admission until death, occurrence of AVM rupture, initiation of treatment, or until the end of 2005. Patients with at least 1 month of follow-up were included in further analysis. Annual and cumulative incidence rates of AVM rupture as well as several potential risk factors for rupture were analyzed using Kaplan-Meier life table analyses and Cox proportional hazards regression models. Results We identified 238 patients with a mean follow-up period of 13.5 years (range, 1 month-53.1 years). The average annual risk of hemorrhage from AVMs was 2.4%. The risk was highest during the first 5 years after diagnosis, decreasing thereafter. Risk factors predicting subsequent AVM hemorrhage in univariate analysis were young age, previous rupture, deep and infratentorial locations, and exclusively deep venous drainage. Previous rupture, large AVM size, and infratentorial and deep locations were independent risk factors according to multivariate models. Conclusion According to this long-term follow-up study, AVMs with previous rupture and large size, as well as with infratentorial and deep locations have the highest risk of subsequent hemorrhage. This risk is highest during the first few years after diagnosis but remains significant for decades.

BACKGROUND: Vertebral artery (VA) aneurysms comprise approximately one-third of posterior circulation aneurysms. They are morphologically variable, and located critically close to the cranial nerves and the brainstem. We aim to represent the characteristics of these aneurysms and their treatment, and to analyze the outcome. METHODS: We reviewed retrospectively 9709 patients with intracranial aneurysms. Of these, we included 190 with aneurysms at the VA or VA posterior inferior cerebellar artery junction. The patients were treated in the Department of Neurosurgery, Helsinki, Finland, between 1934 and 2011. RESULTS: The 190 patients had 193 VA aneurysms, among which 131 (68%) were ruptured, The VA aneurysm caused a mass effect in 7 and ischemia in 2 patients. Compared to 4387 patients with a ruptured aneurysm in other locations, those with a VA aneurysm were older, their aneurysms were more often fusiform, and more often caused intraventricular hemorrhages. Among surgically treated aneurysms, clipping was the treatment in 91 (88%) saccular and 11 (50%) fusiform aneurysms. Treatment was endovascular in 13 (9%), and multimodal in 6 (4%) aneurysms, Within a year after aneurysm diagnosis, 53 (28%) patients died. Among the survivors, 104 (93%) returned to an independent or to their previous state of life; only 2 (2%) were unable to return home. CONCLUSIONS: Microsurgery is a feasible treatment for VA aneurysms, although cranial nerve deficits are more common than in endovascular surgery. Despite the challenge of an often severe hemorrhage, of challenging morphology, and risk for laryngeal palsy, most patients surviving the initial stage return to normalcy.

Navigated transcranial magnetic stimulation (nTMS) is employed in eloquent brain area localization prior to intraoperative direct cortical electrical stimulations and neurosurgery. No commercial archiving or file transfer protocol existed for these studies. The aim of our project was to establish a standardized protocol for the transfer of nTMS results and medical assessments to the end users in pursuance of improving data security and facilitating presurgical planning. The existing infrastructure of the hospital’s Radiology Department was used. Hospital information systems and networks were configured to allow communications and archiving of the study results, and in-house software was written for file manipulations and transfers. Graphical user interface with description suggestions and user-defined text legends enabled an easy and straightforward workflow for annotations and archiving of the results. The software and configurations were implemented and have been applied in studies of ten patients. The creation of the study protocol required the involvement of various professionals and interdepartmental cooperation. The introduction of the protocol has ended previously recurrent involvement of staff in the file transfer phase and improved cost-effectiveness.

The A1 allele of the Taql restriction fragment length polymorphism (RFLP) of the human dopamine D2 receptor gene (DRD2) is associated with a low density of D2 dopamine receptors in the striatum. Because of the important role of D2 autoreceptors in regulating dopamine synthesis, we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain. We also studied the effects of two other DRD2 polymorphisms, C957T and - 141C Ins/Del, which have been suggested to affect D2 receptor levels in brain. The relationships between the TaqlA RFLP, C957T and -141C Ins/Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [ 18 F]fluorodopa ([ 18 F]FDOPA), a radiolabelled analog of the dopamine precursor L-DOPA. Heterozygous carriers of the A1 allele (A1/A2; 10 subjects) had significantly higher (18%) [ 18 FIFDOPA uptake in the putamen than subjects without the A1 allele (A2/A2; 23 subjects). C957T and -141C Ins/Del polymorphisms did not significantly affect [ 1B F]FDOPA Ki values. These results demonstrate that the A1 allele of DRD2 gene is associated with increased striatal activity of aromatic L-amino acid decarboxylase, the final enzyme in the biosynthesis of dopamine and the rate-limiting enzyme for trace amine (e.g. β-phenylethylamine) synthesis. The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function, and suggests that dopamine and/or trace amine synthesis rate is increased in the brains of A1 allele carriers.

Background There are sex differences in the clinical features of several neuropsychiatric illnesses associated with dopamine dysfunction. The effects of sex on brain dopaminergic function have been sparsely studied in human subjects using modern imaging techniques. We have previously reported that the apparent affinity of [11C]raclopride for striatal D2 dopamine receptors in vivo is lower in women than in men, whereas D2 receptor density is not different. This finding indirectly suggests that women have a higher synaptic concentration of dopamine in the striatum. We explored further the basis of this phenomenon in an independent study and hypothesized that striatal presynaptic dopamine synthesis capacity would also be elevated in women. Methods A total of 23 healthy men and 12 healthy women (age range 20–60 years) were studied using positron emission tomography and [18F]fluorodopa. Results Women had significantly higher striatal [18F]fluorodopa uptake (Ki values) than men. The difference was more marked in the caudate (+26%) than in the putamen (+12%). In addition, there was a negative correlation between striatal [18F]fluorodopa Ki values and age in men but not in women. Conclusions The results further substantiate sex differences in striatal dopaminergic function in humans. This finding may be associated with sex differences in vulnerability and clinical course of neuropsychiatric disorders with dopaminergic dysregulation, e.g., schizophrenia, alcohol dependence, and Parkinson’s disease.

Nimodipine is an L-type calcium channel blocker and is used to treat vasospasm in patients with subarachnoid hemorrhage. Its putative mechanism of action is relaxation of smooth muscle cells in cerebral arteries. In addition, nimodipine may have pleiotropic effects against vasospasm. Systemic hypotension is an adverse effect when patients are treated with oral or intravenous nimodipine. Intracranial administration of nimodipine formulations may produce higher concentration of nimodipine in the cerebrospinal fluid (CSF) than is possible to achieve orally or intravenously, while resulting in lower incidence of systemic hypotension. The aim of this study was to provide information on plasma and CSF levels of nimodipine in beagle dogs as a comparative data for development of experimental intracranial treatment modalities. Plasma levels of nimodipine were measured after current 30 and 60 mg single oral dose of nimodipine (Nimotop(A (R)) 30 mg tablets), a single intravenous bolus 0.72 mg/dog of nimodipine (Nimotop(A (R)) 0.2 mg/ml infusion solution) and CSF levels after 60 mg single oral dose of nimodipine. CSF/Plasma concentration ratio of nimodipine after oral administration of 60 mg at 1 h was 0.013 +/- A 0.0005. The mean terminal elimination half-life of nimodipine after i.v. bolus dose 0.72 mg was 1.8 h and mean plasma clearance was 40.3 and 3.4 l/h/kg. Absolute bioavailability was 22 %. Maximum plasma concentration and area under the plasma concentration-time curve from time of administration until the last measurable plasma concentration increased in a dose-proportional manner comparing the exposure parameters at oral doses of 30 and 60 mg. Individual variation in the kinetic profile of nimodipine was measured.

Objective: We investigated whether risk alleles of single nucleotide polymorphisms associated with intracranial aneurysm (IA) are enriched in patients with familial IA, IA located at the middle cerebral artery (MCA), or IA rupture at a younger age. Methods: In this case-only study, we calculated genetic risk scores (GRS) for 973 Dutch and 718 Finnish patients with IA by summing effect size–weighted risk allele counts of 7 single nucleotide polymorphisms associated with IAs previously identified through genome-wide association studies. We tested the GRS for association with presence of familial IA or IA at the MCA using logistic regression, and with age at time of IA rupture using linear regression. We also calculated odds ratios with 95% confidence intervals for the proportion of patients with each characteristic in the highest compared with the lowest GRS tertile. Results: GRS were higher in IA at the MCA in the Dutch ( p = 2.5 × 10 −4 ), Finnish ( p = 0.039), and combined cohort ( p = 4.9 × 10 −5 ). GRS were not associated with familial IA in the Dutch ( p = 0.34), Finnish ( p = 0.45), and combined cohort ( p = 0.98), or with age at time of IA rupture in the Dutch ( p = 0.28), Finnish ( p = 0.86), and combined cohort ( p = 0.45). In the combined cohort, odds ratios were 0.89 (0.67–1.20) for familial IA, 1.03 (0.79–1.34) for lower age, and 1.54 (1.20–1.98) for MCA aneurysms. Conclusions: Our findings suggest that genetic risk factors have a larger role in the development of IA at the MCA than at other sites, and that genetic heterogeneity should be considered in future genetic studies.

Terson's syndrome (TS) is a vitreous hemorrhage in association with subarachnoid hemorrhage (SAH). Its diagnosis is often delayed, which may result in vision loss secondary to treatable conditions. Methods to hasten early diagnosis and consequent ophthalmic referral are desirable. The aims of this study were 1) to assess the specificity and sensitivity of conventional head CT for diagnosing TS in patients with aneurysmal SAH (aSAH); and 2) to determine the incidence of TS and its association with age, sex, aSAH severity, and overall mortality.Patients admitted to Helsinki University Central Hospital who underwent surgery or endovascular treatment for a ruptured intracranial aneurysm during 2011 were participants in this prospective study. They underwent serial dilated fundoscopic examinations during a 6-month period. Two radiologists independently reviewed ocular findings suggestive of TS on conventional CT head scans obtained in all patients as a routine diagnostic procedure. Associations between TS and relevant clinical, radiological, and demographic data were analyzed with uni- and multivariate logistic regression.Of 121 participants, 13 (11%) presented with TS, and another 22 (18%) with intraretinal hemorrhages. For reviewing CT head scans, the overall observed agreement between the 2 raters was 96% (116 of 121 cases), with a substantial κ of 0.69 (95% CI 0.56-0.82). The sensitivity of the CT findings for TS was 42%, and the specificity was 97%. Associations of the World Federation of Neurosurgical Societies (WFNS) and Hunt and Hess grades on admission, the presence of intracerebral hemorrhage, female sex, and aneurysm length with TS were all statistically significant. Logistic regression demonstrated that sex and WFNS grade were independently associated with TS and provided the best fit to the data.Routinely looking for TS findings in CT head scans may prove valuable in clinical practice. Terson's syndrome is associated with female sex and poor clinical condition on admission.

Visual field defects (VFDs) negatively affect activities of daily living and rehabilitation following aneurysmal subarachnoid haemorrhage (aSAH). The aim here was to assess VFDs in patients with aSAH and their associations with age, gender, aSAH severity, and clinical outcome.Patients admitted to Helsinki University Central Hospital and treated during 2011 were participants in this prospective study. Findings obtained with the Octopus 900 perimeter (Haag-Streit Inc, Koenic, Switzerland), the Goldmann perimeter (Haag-Streit Inc, Bern, Switzerland), or the confrontation visual field test on admission and 3 days, 14 days, 2 to 4 months, and 6 months postoperatively were assigned to 16 classes. Associations between post-chiasmal VFDs and relevant clinical, radiological, and demographic data were analysed with uni- and multivariate logistic regression.Of 105 survivors at 6 months, 20 (19 %) had VFDs occurring for aneurysm- or operation-related reasons; homonymous hemianopias or quadrantanopias were the most common finding, occurring in 16 patients (15 %). Posterior ischaemic optic neuropathy presented in two patients (2 %). Ten survivors (10 %) no longer fulfilled visual field requirements for driving licences. Significant associations emerged between VFDs at 6 months and the Hunt and Hess (HH), World Federation of Neurosurgical Societies (WFNS), and Fisher grades on admission, presence of intracerebral haemorrhage (ICH), hydrocephalus, or postoperative infarction, and higher modified Rankin Scale scores at 6 months. Multivariate logistic regression showed the HH grade and presence of ICH to independently predict VFDs.Assessing VFDs is advisable, especially among patients with poor-grade aSAH (HH grade IV or V) and ICH.

Background and Purpose— Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. Methods— Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. Results— Genome-wide evidence of association was detected in the discovery sample on chromosome 9 ( CDKN2BAS ; rs10733376: P −11 ), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9 , was associated with IA (rs10230207; P =4.14×10 −8 ). This association replicated in the Dutch sample ( P =0.01) but failed to show association in the Finnish sample ( P =0.25). Meta-analysis results of the 3 cohorts reached statistical significant ( P =9.91×10 −10 ). Conclusions— We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9 ), suggesting a possible genetic link between this stroke subtype and IA.

3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is >2× increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p, Author Summary Genome-wide association studies (GWAS) have been extensively used to identify common genetic variants associated with complex diseases. As common genetic variants have explained only a small fraction of the heritability of most complex diseases, there is a growing interest in the role of how low frequency and rare variants contribute to the susceptibility. Low frequency variants are more often specific to populations of distinct ancestries. Saccular intracranial aneurysms (sIA) are balloon-like dilatations in the arteries on the surface of the brain. The rupture of sIA causes life-threatening intracranial bleeding. sIA is a complex disease, which is known to sometimes run in families. Here, we utilize the recent advancements in knowledge of genetic variation in different populations to examine the role of low-frequency variants in sIA disease in the isolated population of Finland where sIA related strokes are more common than in most other populations. By studying >8000 Finns we identify four low-frequency variants associated with the sIA disease. We also show that the association of two of the variants are seen in other European populations as well. Our findings demonstrate that multiple study designs are needed to uncover more comprehensively their genetic background, including population isolates.

We have previously reported that average striatal dopamine transporter (DAT) binding in vivo is unaltered in neuroleptic-naive first-episode schizophrenic patients [Laakso et al., Am. J. Psychiatry 157 (2000) 269]. However, as it has been suggested that some of the brain changes in schizophrenia may vary depending on the illness phase, we studied DAT density in eight stable, medicated chronic schizophrenic patients and eight matched controls using positron emission tomography and [18F]CFT, a marker of dopamine nerve terminals. [18F]CFT binding potentials were significantly lower in chronic schizophrenic patients than in controls, both in the caudate and the putamen (-9 to -16%). Together with the finding of unchanged average striatal DAT levels in first-episode patients and relative insensitivity of striatal [18F]CFT binding to endogenous dopamine and neuroleptic drugs, the result is in line with a relative loss of striatal dopaminergic nerve terminals and/or decreased expression of DAT in a subset of chronic schizophrenic patients.

We have characterized the usage of [18F]CFT (also known as [18F]WIN 35,428) as a radioligand for in vivo studies of human dopamine transporter by PET. CFT was labeled with 18F to a high specific activity, and dynamic PET scans were conducted in healthy volunteers at various time points up to 5 h from [18F]CFT injection. The regional distribution of [18F]CFT uptake correlated well with the known distribution of dopaminergic nerve terminals in the human brain and also with that of other dopamine transporter radioligands. Striatal binding peaked at 225 min after injection and declined thereafter, demonstrating the reversible nature of the binding to the dopamine transporter. Therefore, due to the relatively long half-life of 18F (109.8 min), PET scans with [18F]CFT could easily be conducted during the binding equilibrium, allowing estimation of Bmax/Kd values (i.e., binding potential). Binding potentials for putamen and caudate measured at equilibrium were 4.79 ± 0.11 and 4.50 ± 0.23, respectively. We were able to also visualize midbrain dopaminergic neurons (substantia nigra) with [18F]CFT in some subjects. In conclusion, the labeling of CFT with 18F allows PET scans to be conducted at binding equilibrium, and therefore a high signal-to-noise ratio and reliable quantification of binding potential can be achieved. With a high resolution 3D PET scanner, the quantification of extrastriatal dopamine transporters should become possible. Synapse 28:244–250, 1998. © 1998 Wiley-Liss, Inc.

Recent in vivo studies have shown low dopamine D2 receptor and dopamine transporter densities among late onset (type 1) alcoholics. We have now studied 6-[18F]-FDOPA (FDOPA) uptake in 10 type 1 alcoholics and eight matched controls to test the hypothesis that striatal presynaptic dopamine function is lower among alcoholics. Markedly low FDOPA uptake (Ki) was observed in the left caudate of two alcoholic patients, but the mean striatal uptake values of the patient group were higher than those of the control group. The greatest difference was observed in the mean FDOPA intake in the left putamen, which was 28% higher in the patient group (t = 3.00, P = 0.008, d.f. = 16, independent samples t-test), and in the right caudate (difference 36%, t = 2.87, P = 0.01). The elevated FDOPA uptake in putamen and caudate correlated with poor Wisconsin Card Sorting Test (WCST) performance (error %) among alcoholics (correlation coefficients from 0.49 to 0.56), which suggests that the magnitude of presynaptic dopamine function alteration correlates with the degree of disability to modify one's behavior. The results do not give support to the hypothesis of generally decreased striatal dopamine turnover in type 1 alcoholism, but on the contrary indicate an increased presynaptic dopamine function. This may represent a compensatory mechanism to low postsynaptic DA function. The low presynaptic DA function observed in the left caudate of two patients suggests that type 1 alcoholism may be a heterogeneous disorder.

Objective Overlooking eye movement abnormalities associated with aneurysmal subarachnoid hemorrhage (aSAH) is common, although these abnormalities may greatly affect quality of life. Their prevalence remains undetermined. The aim of the study was to assess preoperative and postoperative eye movement abnormalities and their recovery in follow-up of patients with aSAH and their association with age, gender, and aSAH severity. Methods Patients admitted to Helsinki University Central Hospital who underwent surgery or endovascular treatment for a ruptured intracranial aneurysm during 2011 were participants in this prospective study. A neuro-ophthalmic examination was performed on admission, and 3 days, 14 days, 2–4 months, and 6 months postoperatively. For those patients with third, fourth, or sixth nerve palsies or brainstem vascular syndromes, follow-up was 12 months. Associations between neuro-ophthalmic findings and relevant clinical, radiologic, and demographic data were studied. Two intraoperative videos were selected to show rare cases of aneurysms causing cranial nerve palsies. Results Of 121 participants, 11 (9%) presented on admission and 16 (13%) postoperatively showed signs of third, fourth, or sixth nerve palsy. Most of these palsies resolved; leaving 2.5% of all patients presenting with a partial palsy at 1 year. We also evaluated the frequencies of horizontal gaze pareses ( n = 9) and Parinaud's syndromes ( n = 3). No statistically significant associations emerged between neuro-ophthalmic findings and other clinical variables. Conclusions Eye movement abnormalities are a quite common finding in the acute stage of aSAH. Within 1 year, however, marked improvement occurs. Identifying these neuro-ophthalmic findings can assist in localization of the underlying pathology.

Epilepsy work-up is based on history and scalp EEG. Drug resistant epilepsy should be evaluated in a dedicated epilepsy surgery unit. Sometimes non-invasive studies fail to localize the epileptogenic area in focal epilepsy and then the work up can be complemented with intracranial EEG. Intracranial electrodes are implanted either in the subdural space or intraparenchymally. This is followed by one to two weeks of EEG monitoring in a specialized videotelemetry unit. Intracranial EEG helps to define the borders of the epileptogenic area for resection. The ultimate objective is to render the patient seizure free. The outcome of resective epilepsy surgery depends on the etiology of epilepsy, localization of the epileptogenic area and MR image yield.

The aim of this study was to assess the early and long-term excess mortality in patients with intracranial dural arteriovenous fistula (DAVF) compared with a matched general Finnish population in an unselected, population-based series.The authors identified 227 patients with DAVFs admitted to 2 of the 5 Departments of Neurosurgery in Finland--Helsinki and Kuopio University Hospitals--between 1944 and 2006. All patients were followed until death or the end of 2009. Long-term excess mortality was estimated using the relative survival ratio compared with the general Finnish population matched by age, sex, and calendar year.The median follow-up period was 10 years (range 0-44 years). Two-thirds (67%) of the DAVFs were located in the region of transverse and sigmoid sinuses. Cortical venous drainage (CVD) was present in 28% of the DAVFs (18% transverse and sigmoid sinus, 42% others). Of the 61 deaths counted, 11 (18%) were during the first 12 months and were mainly caused by treatment complications (5 of 11, 45%). The 1-year survivors presenting with hemorrhage experienced excess mortality until 7 years from admission. However, DAVFs with CVD were associated with significant, continuous excess mortality. There were more cerebrovascular and cardiovascular deaths in this group of patients than expected in the general Finnish population. Location other than transverse and sigmoid sinuses was also associated with excess mortality.In the patients with DAVF there was excess mortality during the first 12 months, mainly due to treatment complications. Thereafter, their overall long-term survival became similar to that of the matched general population. However, DAVFs with CVD and those located in regions other than transverse and sigmoid sinuses were associated with marked long-term excess mortality after the first 12 months.

An UPLC-MS/MS method was developed for the determination of serotonin (5-HT), dopamine (DA), their phase I metabolites 5-HIAA, DOPAC and HVA, and their sulfate and glucuronide conjugates in human brain microdialysis samples obtained from two patients with acute brain injuries, ventricular cerebrospinal fluid (CSF) samples obtained from four patients with obstructive hydrocephalus, and a lumbar CSF sample pooled mainly from patients undergoing spinal anesthesia in preparation for orthopedic surgery. The method was validated by determining the limits of detection and quantification, linearity, repeatability and specificity. The direct method enabled the analysis of the intact phase II metabolites of 5-HT and DA, without hydrolysis of the conjugates. The method also enabled the analysis of the regioisomers of the conjugates, and several intact glucuronide and sulfate conjugates were identified and quantified for the first time in the human brain microdialysis and CSF samples. We were able to show the presence of 5-HIAA sulfate, and that dopamine-3-O-sulfate predominates over dopamine-4-O-sulfate in the human brain. The quantitative results suggest that sulfonation is a more important phase II metabolism pathway than glucuronidation in the human brain.