Glioblastoma in the Canton of Zurich, Switzerland revisited: 2005 to 2009.

BACKGROUND: A population-based analysis of patients with glioma diagnosed between 1980 and 1994 in the Canton of Zurich in Switzerland confirmed the overall poor prognosis of glioblastoma. To explore changes in outcome, registry data were reevaluated for patients diagnosed between 2005 and 2009. METHODS: Patients with glioblastoma who were diagnosed between 2005 and 2009 were identified by the Zurich and Zug Cancer Registry. The prognostic significance of epidemiological and clinical data, isocitrate dehydrogenase 1 (IDH1)(R132H) mutation status, and O6 methylguanine DNA methyltransferase (MGMT) promoter methylation status was analyzed using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: A total of 264 patients with glioblastoma were identified, for an annual incidence of 3.9 compared with the previous incidence of 3.7. The mean age of the patients at the time of diagnosis was 59.5 years in the current cohort compared with 61.3 years previously. The overall survival (OS) rate was 46.4% at 1 year, 22.5% at 2 years, and 14.4% at 3 years in the current study compared with 17.7% at 1 year, 3.3% at 2 years, and 1.2% at 3 years as reported previously. The median OS for all patients with glioblastoma was 11.5 months compared with 4.9 months in the former patient population. The median OS was 1.9 months for best supportive care, 6.2 months for radiotherapy alone, 6.7 months for temozolomide alone, and 17.0 months for radiotherapy plus temozolomide. Multivariate analysis revealed age, Karnofsky performance score, extent of tumor resection, first-line treatment, year of diagnosis, and MGMT promoter methylation status were associated with survival in patients with IDH1(R132H) -nonmutant glioblastoma. CONCLUSIONS: The OS of patients newly diagnosed with glioblastoma in the Canton of Zurich in Switzerland markedly improved from 1980 through 1994 to 2005 through 2009. Cancer 2016;122:2206-15. © 2016 American Cancer Society.

[(12)Revascularisation and aneurysms of the posterior circulation].

This is the last article, namely, the twelfth topic, in the series "personal view and historical backgrounds of operative neurosurgery." In this article, revascularisation and aneurysms of the posterior circulation are thematized. As an example for classic posterior circulation EC-IC bypass, a case of basilar stenosis is presented. The stenosis turned out to occlusion by good patency of the STA-SCA bypass, and although it initially showed clinical improvement, it manifested as severe pontine infarction several months later. Considerations on such malignant conversion are discussed together with probable prevention methods. Other revascularisation methods involving the supracerebellar transtentorial approach(SCTTA), namely, OA-SCA or OA-PCA bypass in the sitting position, are presented and their advantages and disadvantages are discussed. As for posterior circulation aneurysms, the role of SEAC and its advantages for treating basilar bifurcation aneurysms are presented and discussed. SCTTA and SAHE approach are presented as special approaches for other PCA aneurysms, and their advantages of getting the parent artery P2 for P2-P3 junction aneurysm in the latter was emphasized. The advantage of a sitting position for revascularisation or aneurysm surgeries, cleanliness of the operative field in cases of premature rupture or clipping procedure, and through the bush of lower cranial nerves are also discussed.

[(11)Treatment of glioma. State-of-the-art: a series of 1,036 surgeries on 944 cases].

The author's own experience of 1,036 surgeries on 944 glioma cases in the period between 1993 to 2011(mostly at the University Hospital Zurich)are presented. Glioblastoma cases were the most frequent, amounting to ca. 30% of cases as is shown in Fig.4A. They were operated on 1.3 times on the average but the most frequent repetition-surgery was in cases with fibrillary astrocytomas(Fig.1), as these tended to transform into secondary glioblastomas which needed surgery again. The latter amounting to 10% of glioblastoma cases that had transformed from astrocytoma in the course of 3.8 years on the average(Fig.4B). With modern "state-of-the-art" treatment of glioma(Table), survival term for glioblastoma patients has clearly improved. This can be seen by comparison of figures between generations(Fig.4C, D):Prof. Krayenbuhl's era(macrosurgery±RT), Prof. Yasargil's era(microsurgery+RT)and the most recent part of my treatment(microsurgery+ "state-of-the-art" treatment). Representative cases of various glioma are presented in which "cured" cases of glioblastoma are also included.

Patupilone (epothilone B) for recurrent glioblastoma: clinical outcome and translational analysis of a single-institution phase I/II trial.

BACKGROUND: Patients with glioblastoma (GBM) inevitably develop recurrent or progressive disease after initial multimodal treatment and have a median survival of 6-9 months from time of progression. To date, there is no accepted standard treatment for GBM relapse or progression. Patupilone (EPO906) is a novel natural microtubule-stabilizing cytotoxic agent that crosses the blood-brain barrier and has been found to have preclinical activity in glioma models. METHODS: This is a single-institution, early-phase I/II trial of GBM patients with tumor progression who qualified for second surgery with the goal of evaluating efficacy and safety of the single-agent patupilone (10 mg/m(2), every 3 weeks). Patients received patupilone 1 week prior to second surgery and every 3 weeks thereafter until tumor progression or toxicity. Primary end points were progression-free survival (PFS) and overall survival (OS) at 6 months as well as patupilone concentration in tumor tissue. Secondary end points were toxicity, patupilone concentration in plasma and translational analyses for predictive biomarkers. RESULTS: Nine patients with a mean age of 54.6 ± 8.6 years were recruited between June 2008 and April 2010. Median survival and 1-year OS after second surgery were 11 months (95% CI, 5-17 months) and 45% (95% CI, 14-76), respectively. Median PFS was 1.5 months (95% CI, 1.3-1.7 months) and PFS6 was 22% (95% CI, 0-46), with 2 patients remaining recurrence-free at 9.75 and 22 months. At the time of surgery, the concentration of patupilone in tumor tissue was 30 times higher than in the plasma. Tumor response was not predictable by the tested biomarkers. Treatment was generally well tolerated with no hematological, but cumulative, though reversible sensory neuropathy grade ≤3 was seen in 2 patients (22%) at 8 months and grade 4 diarrhea in the 2nd patient (11%). Non-patupilone-related peri-operative complications occurred in 2 patients resulting in discontinuation of patupilone therapy. There were no neurocognitive changes 3 months after surgery compared to baseline. CONCLUSIONS: In recurrent GBM, patupilone can be given safely pre- and postoperatively. The drug accumulates in the tumor tissue. The treatment results in long-term PFS in some patients. Patupilone represents a valuable novel compound which deserves further evaluation in combination with radiation therapy in patients with GBM.

ADAMTS13 gene deletion enhances plasma high-mobility group box1 elevation and neuroinflammation in brain ischemia-reperfusion injury.

Highly adhesive glycoprotein von Willebrand factor (VWF) multimer induces platelet aggregation and leukocyte tethering or extravasation on the injured vascular wall, contributing to microvascular plugging and inflammation in brain ischemia-reperfusion. A disintegrin and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) cleaves the VWF multimer strand and reduces its prothrombotic and proinflammatory functions. Although ADAMTS13 deficiency is known to amplify post-ischemic cerebral hypoperfusion, there is no report available on the effect of ADAMTS13 on inflammation after brain ischemia. We investigated if ADAMTS13 deficiency intensifies the increase of extracellular HMGB1, a hallmark of post-stroke inflammation, and exacerbates brain injury after ischemia-reperfusion. ADAMTS13 gene knockout (KO) and wild-type (WT) mice were subjected to 30-min middle cerebral artery occlusion (MCAO) and 23.5-h reperfusion under continuous monitoring of regional cerebral blood flow (rCBF). The infarct volume, plasma high-mobility group box1 (HMGB1) level, and immunoreactivity of the ischemic cerebral cortical tissue (double immunofluorescent labeling) against HMGB1/NeuN (neuron-specific nuclear protein) or HMGB1/MPO (myeloperoxidase) were estimated 24 h after MCAO. ADAMTS13KO mice had larger brain infarcts compared with WT 24 h after MCAO (p < 0.05). The rCBF during reperfusion decreased more in ADAMTS13KO mice. The plasma HMGB1 increased more in ADAMTS13KO mice than in WT after ischemia-reperfusion (p < 0.05). Brain ischemia induced more prominent activation of inflammatory cells co-expressing HMGB1 and MPO and more marked neuronal death in the cortical ischemic penumbra of ADAMTS13KO mice. ADAMTS13 deficiency may enhance systemic and brain inflammation associated with HMGB1 neurotoxicity, and aggravate brain damage in mice after brief focal ischemia. We hypothesize that ADAMTS13 protects brain from ischemia-reperfusion injury by regulating VWF-dependent inflammation as well as microvascular plugging.

[Operative neurosurgery: personal view and historical backgrounds (9) Moyamoya angiopathy (MMA): past history and status presens].

The second international meeting on the Moyamoya angiopathy (MMA) was held in mid. July 2011 at the children's hospital Zurich by Frau PD Dr.Khan and Prof.Meuli. On this occasion I was asked to give a survey of this disease, so the following points were presented and discussed: 1. Who was the person who discovered this disease. 2. How has the Research Committee of the Ministry of Health and Welfare, Japan (RCMHWJ) contributed to clarify the epidemiology, etiology, pathophysiology and treatments. 3. What is the current situation in foreign countries especially Euroamerican to date on these topics. 4. How the treatment technique developed and who did the initial revascularization procedures for the first. 5. Update of the disease. 1. Established view; discovery of the disease by Tekeuchi and Shimizu in 1955 could have been called somewhat into question as they described neither abnormal vasculature nor transdural anastomosis. Kudo who described "spontaneous occlusion of the circle of Willis" more precisely, but seemed to have thought that the occlusion site of the internal carotid artery (ICA) is around the origin of the ophthalmic artery. Suzuki and Takaku who coined the name Moyamoya disease (MMD) in 1969 and described 6 stages of progression on the basis of observation on 20 cases. 2. The RCMHWJ founded in 1977 has contributed to clarifying the epidemiology, pathophysiology, treatment and etiology by interdisciplinary cooperative study having some epoch making events especially; (1)by setting the guide lines -diagnostic criteria of the disease at the end of 1970, (2)applying MRI and MRA at the beginning of 1990 for the diagnosis instead of angiography used until then. (3)By finding and focusing, therefore, on the cases of asymptomatic or oligosymptomatic presentation around the middle of 2000, which have almost doubled or tripled in incidence and/or prevalence and also changed the age distribution with the higher peak for adult cases. Achievements of research for the etiology and pathophysiology by genetics and molecular biology have enabled the discovery of basic FGF and other cytokines-angiogenetic factors and recently the genetic linkage site 17q25.3 in relation to the familiar incidence. Pathological studies verified by molecular biological methods have indicated that the vascular occluding process with intimal proliferation with thrombus formation does not occur only at the carotid fork originally researched intensively, but also at more distal parts of the cerebral arteries which could be verified with the help of molecular biology. 3. Occurrence but less incidence of the disease in the Euroamerican countries had already been noticed at the beginning of 1970 and its reason has been researched and discussed intensively in relation also to the etiology of the disease. 4. The first extracranial-intracranial (EC-IC) bypass surgery for a case of cerebral ischemia of the disease might have been carried out by Prof.Yasargil and Prof.Reichman independently around the end of 1972. The indirect revascularization methods such as EMS, EDAS are now combined with or without EC-IC bypass to augment cerebral blood flow (CBF) of the hemodynamically compromised territory not only of the MCA, but also of the ACA and PCA. The big disadvantage of indirect revascularization might be the large size of the craniotomy necessitated for the purpose, which would decrease CBF of the brain surface. The author is doing multiple bypass procedures (bilateral EC-IC bypass plus STA-ACA bypass) in one session in accordance with the findings of CBF examination with small craniotomies. Prevention of rebleeding by revascularization is still under study but its results should be scrutinized on the basis of various etiologies and sites of the bleeding. 5. Besides some increase of epidemiological knowledge of asymptomatic or oligosymptomatic cases and of etiological molecular biological and genetic linkage studies, clinically, the mechanism of contralateral ischemia in patients in whom one side is operated upon or/and hyperperfusion after revascularization and its prevention seems to be one of main topics in recent journals.

[Operative neurosurgery: Personal view and historical backgrounds. (10) Microneurosurgery and PET scan: clinical experience of a neurosurgeon].

During the author's clinical activity at three institutes : Kyoto University Hospital (Kyoto 1965-1969, 1977-1985), National Cardiovascular Center NCVC (Osaka 1986-1992) and Zurich University Hospital (Zurich 1970-1976, 1993-2007), He has experienced (underlined periods) working with PET scan and SPECT in relation to microsurgical treatment. The following describes how and for what the author has been engaged in this regard. 1. As preparation for the work with PET, SPECT with a rotating gamma camera was used to know blood distribution with the use of Kr-81m infusion from a selectively located catheter in the ICA, ECA or VA, e.g. to know the flow distribution of a newly constructed EC-IC bypass, which was quite separated from and not mixed up with that of already functioning inherent collaterals (Fig. 1). 2. With the use of inhalation PET scan (15O labelled CO2 and O2 inhalation and 15O CO inhalation) basic knowledge of hemodynamics of MMD was acquired (Fig. 2) 3. With the use of H215 O-PET scan with DiamoxR loading, indication for and effectiveness of EC-IC bypass surgery for occlusive cerebrovascular disease (atherosclerosis (anterior circulation (Fig. 5), posterior circulation (Fig. 6, 7)), MMD (Fig. 9), congenital disease (Fig. 8) have been settled or demonstrated. 4. In epileptic seizures, interictally or intraictally, the active locus has been identified by the use of FDG-PET, flumazenil-PET, H 2 15 O or 13 NH 3-PET respectively (Fig. 12). In this relation, selective Wada test with the use of Tc-99 m-ECD selective infusion together with Amytal R through a catheter inserted selectively into the anterior choroidal artery is an important preoperative test for the SAHE (Fig. 13). 5. FDG-PET and/or tyrosine PET supply important clues concerning appropriate surgical treatment strategy, and also for intractable glioblastoma or high grade glioma, so that in combination with radiotherapy and chemotherapy one may expect more excellent long term outcome with good quality of life (Fig. 16, 17). Furthermore, there must be cases with dementia in which some revascularization procedure might be of help, for which FDG-and H 2 15O-PET could be helpful for differential diagnosis and indication of surgery (Fig. 18).

Aneurysms of the posterior cerebral artery and approach selection in their microsurgical treatment: emphasis on the approaches: SAHEA and SCTTA.

Aneurysms of the posterior cerebral artery (PCA) are infrequent and located in the central depth of the brain. Hence their optimal microsurgical management has not been discussed systematically, as institutions and/or neurosurgeons have only limited experience. The purpose of this communication is to report our considerations on this topic with emphasis on the selection of approaches by reviewing our 20 consecutive cases of PCA aneurysms out of more than 1,000 aneurysm patients seen over the past 15 years. Although the subtemporal approach appears to be prevalent in the literature, in our series we applied the pterional approach with or without selective extradural anterior clinoidectomy (SEAC) for P1, P1-P2 aneurysms, and either a selective amygdalohippocampectomy approach (SAHEA) or supracerebellar transtentorial approach (SCTTA) for P2 and P2-P3 aneurysms. Construction of an extracranial-intracranial EC-IC bypass, when necessary, in conjunction with parent artery occlusion or with trapping of aneurysms was adapted to selected approaches.

Extracranial-intracranial bypass in atherosclerotic cerebrovascular disease: report of a single centre experience.

Despite the failure of the international extracranial-intracranial (EC-IC) bypass study in showing the benefit of bypass procedure for prevention of stroke recurrence, it has been regarded to be beneficial in a subgroup of well-selected patients with haemodynamic impairment. This report includes the EC-IC bypass experience of a single centre over a period of 14 years. All consecutive 72 patients with atherosclerotic occlusive cerebrovascular lesions associated with haemodynamic compromise treated by EC-IC bypass surgery were retrospectively reviewed. Pre-operatively, 61% of patients presented with minor stroke and the remaining 39% with recurrent transient ischemic attacks (TIAs) despite maximal medical therapy. Angiography revealed a unilateral internal carotid artery (ICA) stenosis/occlusion in 79%, bilateral ICA stenosis/occlusion in 15%, MCA stenosis/occlusion in 3% and other multiple vessel stenosis/occlusion in 3% of the cases. H(2)(15)O positron emission tomography (PET) or 99mTc-HMPAO SPECT with acetazolamide challenge was performed for haemodynamic evaluation of the cerebral blood flow (CBF). All the patients had impaired haemodynamics pre-operatively in terms of reduced regional cerebrovascular reserve capacity and rCBF. Standard STA-MCA bypass procedure was performed in all patients. A total of 68 patients with 82 bypasses were reviewed with a mean follow-up period of 34 months. Stroke recurrence took place in 10 patients (15%) resulting in an annual stroke risk of 5%. Improved cerebral haemodynamics was documented in 81% of revascularised hemispheres. Patients with unchanged or worse haemodynamic parameters had significantly more post-operative TIAs or strokes when compared to those with improved perfusion reserves (30% vs.5% of patients, p<0.05). In conclusion, EC-IC bypass procedure in selected patients with occlusive cerebrovascular lesions associated with haemodynamic impairment has revealed to be effective for prevention of further cerebral ischemia, when compared with a stroke risk rate of 15% reported to date in patients only under antiplatelet agents or anticoagulant therapy.

[Operative neurosurgery: personal view and historical backgrounds (8) suboccipital craniotomy-sitting position-linear incision].

Suboccipital craniotomy (SOC) can be classified into three types: midline, paramedian and lateral according to the site of linear incision. They are subdivided horizontally into cranial, intermediate and caudal, while the latter of the lateral SOC should be included into the paramedian caudal one (Fig. 1, 19). Sitting position for the craniotomy has several advantages over other positionings in spite of several known drawbacks especially air embolism: cleanliness of the operative field, good anatomical orientation, wider operative spaces obtained by gravitational downward displacement of the cerebellar hemisphere above all. Linear incision is considered to have no definite drawbacks as compared with other incisions such as the horse shoe or the hockey-stick incision and rather have advantages such as enabling effective access to the surgical target by the use of navigation, simpleness of craniotomy in the opening and the closure, and less pseudomeningocele complication. Although cranial and intermediate lateral SOCs are mainly for lesions in the upper and middle CP angle such as acoustic neurinomas or meningioma besides MVD for trigeminal neuralgia, these are applied also for cavernomas of the tectal and cerebellar peduncle, and meningiomas or chordomas of the upper and middle 1/3 of the petroclival region (Fig. 2-5). Importance of the SCTTA by cranial paramedian SOC for the management of lesions in the temporoposteromedial region including the tentorium and its incisura was emphasized and peduncular lesions at the lamina tecti and pons as well. Caudal paramedian SOC is appropriate for lesions in the lower CP angle along with MVD for hemifacial spasm and is furthermore applicable for foramen magnum meningiomas or lower clivus meningiomas by TVDRA (Fig. 6-13). Cranial midline SOC (paraculminar approach) is applicable for tumors of pineal regions and for lesions at the midbrain, thalamus, posterior part of the IIIrd ventricle. The TFUTA by lower midline SOC enables simple access to the IV ventricle and its floor for management of lesions at the tegmentum pontis such as cavernomas (Fig. 14-17). Statistics of a series of consecutive 1,573 surgical cases in the sitting position (1994-2003) are presented including detection rate of air embolism on the anesthetic charts (Fig. 18, Table). Air embolism was most frequent (21%) in the lateral SOC as compared with other SOCs (8.8% on the average). This happened during the extradural procedures in 80% and in 20% in the intradural procedures. Some important technical managements of bridging veins, venous plexus and cerebellar retraction are discussed in carrying out the SOCs.

Selective changes in GABAA receptor subtypes in white matter neurons of patients with focal epilepsy.

Mapping the distribution of GABAA receptor subtypes represents a promising approach to characterize alterations in cortical circuitry associated with neurological disorders. We previously reported subtype-selective changes in GABAA receptor expression in the grey matter of patients with focal epilepsy. In the present follow-up study, we focused on the subcortical white matter in the same tissue specimens obtained at surgery from 9 patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis, 12 patients with TLE associated with neocortical lesions and 5 patients with frontal lobe epilepsy; post-mortem tissue from 4 subjects served as controls. The subunit composition and distribution of three major GABAA receptor subtypes were determined immunohistochemically with subunit-specific antibodies. In all cases, a majority of neurons in the white matter was distinctly labelled, allowing detailed visualization of their dendritic arborization and revealing a differential, cell type-specific expression pattern of alpha-subunit variants. In controls, alpha1-subunit staining was most prominent, displaying a gradient that decreased with depth, in parallel with the density of NeuN-positive cells. Subsets of pyramidal cells were alpha3-subunit-positive, and alpha2-subunit-labelled neurons were rare. In 19 of the 26 patients with focal epilepsy, no changes were detected as compared with controls. In five patients with TLE, striking changes in the dendritic arborization of a subset of white matter neurons were seen with the alpha1-subunit antibody. In two further patients with TLE, we observed a disorganized dendritic network immuno-positive for the alpha1-subunit, cell clusters selectively expressing the alpha2-subunit and small neuronal aggregates that expressed all subunits and appeared to connect to neighbouring white matter neurons. All seven patients with anomalies in the white matter had a selective reduction in alpha3-containing GABAA receptors in the superficial layers of the grey matter. These results demonstrate a distinct organization of GABAA receptors in human white matter neurons, consistent with an inhibitory network that is likely to be integrated functionally with the overlying grey matter. The altered dendritic morphology and changes in GABAA receptor expression in the white matter of a subset of patients with focal epilepsy are suggestive for a rewiring of neuronal circuits.

Posterior circulation EC-IC bypass via supracerebellar transtentorial SCTT approach applied in a young patient with congenital multiple occlusive cerebrovascular anomalies - case report and technical note.

A case of remarkable vertebrobasilar insufficiency due to congenital multiple occlusive cerebro-vascular anomalies is presented. Anomalies are of the anterior and posterior circulation, presumably induced by "segmental vulnerability" and modified by infection of recurrent tonsillitis. Symptoms of repeated faintness and black-out attacks and deterioration of cognitive function compromised the quality of life considerably. Successful treatment was achieved by combination of a new type of posterior circulation revascularization procedure, namely occipital artery - superior cerebellar artery bypass via the supracerebellar transtentorial SCTT approach in the sitting position in combination with a standard superficial temporal artery STA-MCA bypass.

[Operative neurosurgery: personal view and historical backgrounds. 6. Positioning, instruments].

Important points of positioning and instruments at the time of performing microneurosurgery according to the traditional Zuerich school style were presented based on the experience of ca. 1,000 surgeries/year for around 13.5 years. Most of the instruments and equipment had been taken over from the time of Prof. Yasargil. Positioning: Three positions, supine, knee-elbow and siting position were almost all the positions, which we have used and special mention was directed to the sitting position. Around 1/3 of our surgeries were done in the sitting position. Its indication includes lesions not only in the posterior fossa, but in the parieto-occipital region and in the cervico-thoracal region down to the Th5. Good fixation of the head with Mayfield 3-pin-fixation apparatus with the use of one pin mostly around the medial root of the mastoid process (thickness of the bone and small amount of soft tissue) is of cardinal importance and prevention of excessive flexion (with the one-finger breadth between the chin and its underlying neck), so that strangulation of the tracheal tube and the jugular venous system can be avoided and also the below mentioned jugular compression maneuver can be done effectively. Basic knowledge of prevention of air embolism was pointed out: knowledge of usual anatomical entrance sites of the air (emissary veins, diploic veins, veins entering into the venous sinuses, venous plexus around the craniocervical junction etc.), detection of the air entrance sites by jugular compression and their sealing with tissue adhesives Tissucol. Endotidal CO2 value should be above 4.0 kPk. Importance of reclination of the position in case of further falling down of the CO2 value was emphasized. Special mention was made about the patent foramen ovale as a risk of air embolism. Advantages of the sitting position in the performance of supracerebellar infratentorial/transtentorial SCIT/SCTT approach and transvertebralis dural ring approach TVDRA were emphasized and the use of linear incision was stressed at the time of performance of all these surgeries including the posterior circulation revascularization, occipital artery-posterior cerebral artery/superior cerebellar artery OA-PCA/SCA bypass and occipital artery-posterior inferior cerebellar artery OA-PICA bypass. As for the operating microscope, importance of the eyepiece-lens assembly with mouthpiece was emphasized. Appropriate selection of this system enables surgery of long duration in a comfortable and non-tiring condition in terms of the arm length of the surgeon and his immediate reaction especially at the time of intraoperative premature rupture of an aneurysm or of minute delicate focusing at the time of microvascular suturing without withdrawal of one or both hands from the operative field for handling the operating microscope. An arm rest enables secure, effective, precise and tireless performance of microsurgery in every operating position, so that the use of height an adjustable oil pressure driven arm rest was presented along with a simply height adjustable and easily movable chair. As for the bipolar coagulator pincette, the followings were discussed: more than three different lengths of byonett forceps, each of three different tip-sizes, with isolated tips, dosis and method of coagulation. Practically no need of monopolar coagulation was pointed out. Suction tube also should have different length and size according to the depth and situations. Its vacuum power should be regulated also in accordance with changing situation in every stage of surgery. The vacuum power is regulated at surgeon's request by scrub nurses or circulating nurses, so that the surgeon can concentrate only on the precise maneuver of the tip of the suction tube. For the same reason, foot pedals for the bipolar coagulator, drilling and trepanation should be stepped by other than the surgeon, so that he can concentrate on the tip the of instrument for precise maneuvering. As tissue destruction apparatus, we prefer to use CUSA to laser, as the former enables preservation of blood vessels at the time of tissue destruction and suction by appropriate power application. Besides these, the followings items were discussed: scissors (blunt tips), Lyla retractor (variously tapered tips and fixation or holding at the other peripheral end), drilling (turning direction adjustable, cutting and diamond burr) etc.

[Operative neurosurgery: personal view and historical backgrounds (7) reappraisal of approaches].

Selection of an appropriate approach is one of the most important factors for the success in neurosurgery, so the following approaches were reappraised in this session by giving examples from recent cases. Their standard use has already been mentioned elsewhere in the series: 1. Selective extradural anterior clinoidectomy SEAC was once more discussed: 1. the origin of en bloc removal has originated, 2. meaning of an en bloc replacement, if any, and 3. further development of this procedure for low lying upper basilar aneurysms. 2. Trans-sulcus circularis insulae approach TSCIA, which is a part of the selective amygdalohippocampectomy approach SAHEA was applied for removal of a ganglioglioma originating from the head of the hippocampus (cause of intractable temporal lobe epilepsy) of the dominant hemisphere without performing SAHE due to a positive selective Wada test and the full SAHEA for P2 or P2-3 junction aneurysms (Fig. 1, 2, 3). 3. Trans-rostrum corporis callosi-lamina terminalis approach TRCLA revealed to be less invasive and helpful for removal of a small recurrent craniopharyngioma located between the chiasma opticum and the AcomA complex with the use of a small craniotomy, avoiding previous craniotomy routes, both pterional and subfrontal, for fear of structural adhesion (Fig. 4, 5, 6). 4. Within the scope of the trans-lobulus quadrangularis approach TLQA, the paramedian supracerebellar transtentorial approach SCTTA revealed to be useful for removal of a cavernous angioma located at the parahippocampal gyrus corresponding to the head of the hippocampus of the dominant hemisphere, so that the possible impairment of cognitive function could be avoided, because the incision to the temporal stem and to the hippocampus involved in the above mentioned SAHEA could be avoided. Furthermore the approach seems to be more rational in the treatment of P2, P2-P3 junction aneurysms than other approaches especially in the dominant hemisphere (Fig. 7, 8, 9). 5. Trans-vertebralis dural ring approach TVDRA revealed to be useful in the treatment of microvascular decompression for glossopharyngeal neuralgia, because mobilization and displacement of the vertebral artery by circumferential incision from its dural ring plays an important role for the purpose (Fig. 10, 11). Although the sitting position is necessary for the performance of SCTTA and TVDRA, one should know their usefulness and be ready for their performance.

[Operative neurosurgery: personal view and historical backgrounds. (5) Meningioma].

The author reports his experience of 410 surgeries of meningiomas on 365 cases during the last 13.5 years, including 51 surgeries on recurrent meningiomas and 8 surgeries with the change of initial approach on the same meningiomas. In the surgical management of meningiomas, following comments are to be emphasized: Appropriate approach and interruption of blood supply are of cardinal importance in surgical management of meningiomas. For the latter purpose, preoperative embolization of feeding arteries is recommended especially in deep seated and large meningiomas more than 3 cm in diameter for carrying out their surgical extirpation fast and radically. Olfactory groove meningiomas, planum sphenoidal meningiomas, tuberculum sellae meningiomas and sphenoid ridge meningiomas are managed with pterional approach. The latter two meningiomas may necessitate selective extradural anterior clinoidectomy SEAC. For the management of large midline meningiomas, combination with interhemispheric approach is necessary to manage pial supply appropriately for the preservation of circulation of the anterior cerebral artery ACA. Extension of the former two meningiomas to the other side can be managed with falcal incision and/or drilling out of the crista galli without performing a bifrontal approach. Reduction of exophthalmos due to sphenoid ridge meningiomas infiltrating Periorbita and extraocular muscles is hardly to be expected even after subtotal removal and extensive decompression of the orbita at the superior and lateral walls in combination with SEAC. Accidental compromise of the lenticulostriate arteries arising from M1 portion embraced by tumor nodules should be managed with oxycellulose and fibrin glue at first without their bipolar coagulation, as resulting infarction in the territory causes persistent hemiparesis. Meningiomas in the cavernous sinus should be observed as long as possible in case of no growth, as they remain the same in their size and extension mostly for a long time. In case of growth, stereotactic radiosurgery is the first choice and at last would come surgical intervention at the cost of quality of life QOL. Appropriate approaches for meningiomas arising from the incisura tentorii would be either the amygdalohippocampectomy AHE approach namely transSylvian transsulcus circularis approach for their anterior localization or the supracerebellar transtentorial SCTT approach for the posterior localization in the sitting position. In the latter following structures are to be preserved with great care: A. parietooccipitalis, trochlear nerve, Vena Rosenthal and the superior cerebellar artery which could have considerable supply to the tumor. Meningiomas of the falcotentorial junction are managed also with this approach but may necessitate combination of the suboccipital transtentorial approach large upper clivus meningiomas can be removed more effectively by paramedian or lateral suboccipital craniotomy via SCTT approach in the sitting position rather than the subtemporal transpetrosal approach. Clean and wider operative fields in the former approach are emphasized. Special mention is made to transvertebralis (dural) ring approach TVRA for the foramen magnum or lower clivus meningiomas, in which the vertebral artery can be mobilized without performing more extensive far lateral approach. Difficulties of management of recurrent parasagittal meningiomas with the location corresponding to the gyrus paracentralis plus supplementary motor area are to be emphasized. Role of the venous sinus reconstruction is discussed. Difficulties of management of recurrent meningiomas represented by atypical or anaplastic meningiomas WHO grade II or III which can not be managed only by surgical removal is discussed by presenting some example cases. Biological activity of meningiomas in different location can be quite different in multiple recurrent meningiomas. Meningiomas intractable to irradiation and/or chemotherapy are another challenging topic, being beyond the scope of this paper.

Fetal blood-brain barrier P-glycoprotein contributes to brain protection during human development.

During brain development and blood-brain barrier (BBB) differentiation the expression of P-glycoprotein (P-gp) may complement the protective function of the placental barrier against xenobiotic substances. To establish an immunohistochemical procedure for P-gp detection, different anti-P-gp monoclonal antibodies were first tested on a fibrosarcoma cell line and colonic carcinoma tissue. The protocol was then tested on adult human brains as a BBB-P-gp tissue-specific control and for double labeling with anti-P-gp and the astroglia marker glial fibrillary acidic protein (GFAP). The protocol was then used to analyze the expression and localization of P-gp in human fetuses during cerebral cortex formation. At the earliest examined stage, 12 weeks of gestation (wg), P-gp was detectable as diffuse cytoplasmic labeling of the endothelial cells lining the primary cortex microvessels. At 18 wg, a punctate P-gp staining pattern was detected on cortex and subcortical vessels and on their side branches. At 22 wg, P-gp staining was linear and concentrated on endothelial cell membranes. In all examined ages, GFAP-positive radial glial cells and astrocytes did not stain for P-gp, even at their perivascular processes, whereas faint P-gp labeling was seen on vimentin-reactive radial glia at the earliest examined fetal age. At midgestation, P-gp colocalized with caveolin-pY14 on the abluminal endothelial cell membrane. These results demonstrate that P-gp is expressed early during human cerebral cortical microvessel development, and suggest that at midgestation there may be efflux activity that is regulated by interactions with the caveolar endothelial cell compartment.

Endothelial cell barrier impairment induced by glioblastomas and transforming growth factor beta2 involves matrix metalloproteinases and tight junction proteins.

Gliomas, particularly glioblastoma multiforme, perturb the blood-brain barrier and cause brain edema that contributes to morbidity and mortality. The mechanisms underlying this vasogenic edema are poorly understood. We examined the effects of cocultured primary cultured human glioblastoma cells and glioma-derived growth factors on the endothelial cell tight junction proteins claudin 1, claudin 5, occludin, and zonula occludens 1 of brain-derived microvascular endothelial cells and a human umbilical vein endothelial cell line. Cocultured glioblastoma cells and glioma-derived factors (e.g. transforming growth factor beta2) enhanced the paracellular flux of endothelial cell monolayers in conjunction with downregulation of the tight junction proteins. Neutralizing anti-transforming growth factor beta2 antibodies partially restored the barrier properties in this in vitro blood-brain barrier model. The involvement of endothelial cell-derived matrix metalloproteinases (MMPs) was demonstrated by quantitative reverse-transcriptase-polymerase chain reaction analysis and by the determination of MMP activities via zymography and fluorometry in the presence or absence of the MMP inhibitor GM6001. Occludin, claudin 1, and claudin 5 were expressed in microvascular endothelial cells in nonneoplastic brain samples but were significantly reduced in anaplastic astrocytoma and glioblastoma samples. Taken together, these in vitro and in vivo results indicate that glioma-derived factors may induce MMPs and downregulate endothelial tight junction protein and, thus, play a key role in glioma-induced impairment of the blood-brain barrier.

Magnesium sulfate in the management of patients with aneurysmal subarachnoid hemorrhage: a randomized, placebo-controlled, dose-adapted trial.

BACKGROUND: Recent studies suggest that high-dose MgSO4 therapy is safe and reduces the incidence of DIND and subsequent poor outcome after SAH. We intended to assess the safety and efficacy of high-dose MgSO4 therapy after SAH as means to prevent DIND and to evaluate the impact on clinical outcome. METHODS: This was a prospective, randomized, single-blind, placebo-controlled study. The MgSO4 infusion was adjusted every 12 hours until day 12 according to the target serum Mg2+ level. The occurrence of DIND, secondary infarction, side effects, and the outcome after 3 and 12 months were assessed. RESULTS: Fifty-eight patients were randomized; 27 received placebo and 31 MgSO4. The difference in occurrence of DIND and secondary infarction was not significant. The intention-to-treat analysis revealed a trend toward better outcome (P = .083) after 3 months. On-treatment analysis showed a significantly better outcome after 3 months (P = .017) and a trend toward better outcome after 1 year (P = .083). Significantly more often hypotension (P = .040) and hypocalcemia (P = .005) occurred as side effects in the treatment group. In 16 patients (52%), the MgSO4 therapy had to be stopped before day 12 because of side effects. No predictive factor leading to termination was found in a postrandomization analysis. CONCLUSIONS: High-dose MgSO4 therapy might be efficient as a prophylactic adjacent therapy after SAH to reduce the risk for poor outcome. Nevertheless, because of the high frequency of the side effects, patients should be observed in an intensive or intermediate care setting.

Altered expression of alpha3-containing GABAA receptors in the neocortex of patients with focal epilepsy.

Impaired transmission in GABAergic circuits is thought to contribute to the pathogenesis of epilepsy. Although it is well established that major reorganization of GABA(A) receptor subtypes occurs in the hippocampus of patients with medically refractory temporal lobe epilepsy (TLE), it is unclear whether this disorder is also associated with alterations in GABA(A) receptor subtypes in the neocortex. Here we have investigated immunohistochemically the subunit composition and neocortical distribution of three major GABA(A) receptor subtypes using antibodies specifically recognizing the subunits alpha1, alpha2, alpha3, beta2/3 and gamma2. Cortical tissue was obtained at surgery from patients with TLE and hippocampal sclerosis (HS; n = 9), TLE associated with neocortical lesions (non-HS; n = 12) and frontal lobe epilepsy (FLE; n = 5), with post-mortem samples serving as controls (n = 4). A distinct laminar and neuronal expression pattern of the alpha-subunit variants was found across the neocortical regions examined in the temporal and frontal lobes in both control and patient tissue samples. In the five patients with FLE, GABA(A) receptor subunit staining was unchanged as compared to controls. In patients with TLE we observed a marked decrease in alpha3-subunit staining in the superficial neocortical layers (I-III), but no change in the deep layers (V and VI) or in the expression pattern of the alpha1 and alpha2-subunits. Reduced expression in alpha3-containing GABA(A) receptors was detected in six out of nine patients of the HS group and four out of twelve patients of the non-HS group. Histopathological changes were present in eight out of the ten patients with decreased alpha3-subunit staining. The selective reduction in alpha3-containing GABA(A) receptors was confirmed using semiquantitative measurements of optical density (OD). The specific changes unique to alpha3-subunit expression in the superficial neocortical layers of patients with TLE suggest that this subtype is of particular significance in the reorganization of cortical GABAergic systems in focal epilepsy.