[Interdisciplinary surgery to the central skull base-current status]. / Interdisziplinäre Chirurgie der zentralen Schädelbasis ­ aktueller Stand.

BACKGROUND: The skull base is a surgically complex unit and is often only accessible via combined access routes. Newly developed surgical techniques using microsurgical visualization procedures and active instruments ("powered instruments") as well as multiport accesses enable new, less traumatic surgical corridors. This requires close interdisciplinary cooperation between ENT and neurosurgeons. Currently established access routes to the central skull base are systematized based on the authors' own clinical experience, and discussed in relation to the entity and the current study situation. MATERIALS AND METHODS: A retrospective, qualitative, and descriptive evaluation of the surgical reports of patients with pathologies of the central skull base who were jointly treated by neurosurgery and otorhinolaryngologic/head and neck surgery between 2006 and 2019 was performed. RESULTS: The surgical access routes to the central skull base can be categorized as so-called multiport access routes, partly also in combination, as follows: transnasal-transsphenoidal, subfrontal, subtemporal, transzygomatic, transpterygonal, transpetrous, translabyrinthine, and suboccipital. The choice of access route was based on the location and type of pathology, its inflammatory or space-occupying (benign or malignant tumor) nature, and the possibilities of functional preservation and complete removal. CONCLUSION: Due to the complexity of central skull base structures, the different tumor entities, and the required expertise of different medical specialties, surgery of the central skull base remains a challenge and should only be performed at special competence centers certified according to the criteria of the German Society of Skull Base Surgery.

Longitudinal stability of molecular alterations and drug response profiles in tumor spheroid cell lines enables reproducible analyses.

The utility of patient-derived tumor cell lines as experimental models for glioblastoma has been challenged by limited representation of the in vivo tumor biology and low clinical translatability. Here, we report on longitudinal epigenetic and transcriptional profiling of seven glioblastoma spheroid cell line models cultured over an extended period. Molecular profiles were associated with drug response data obtained for 231 clinically used drugs. We show that the glioblastoma spheroid models remained molecularly stable and displayed reproducible drug responses over prolonged culture times of 30 in vitro passages. Integration of gene expression and drug response data identified predictive gene signatures linked to sensitivity to specific drugs, indicating the potential of gene expression-based prediction of glioblastoma therapy response. Our data thus empowers glioblastoma spheroid disease modeling as a useful preclinical assay that may uncover novel therapeutic vulnerabilities and associated molecular alterations.

MTT Heterogeneity in Perfusion CT Imaging as a Predictor of Outcome after Aneurysmal SAH.

BACKGROUND AND PURPOSE: Impairment of tissue oxygenation caused by inhomogeneous microscopic blood flow distribution, the so-called capillary transit time heterogeneity, is thought to contribute to delayed cerebral ischemia after aneurysmal SAH but has so far not been systematically evaluated in patients. We hypothesized that heterogeneity of the MTT, derived from CTP parameters, would give insight into the clinical course of patients with aneurysmal SAH and may identify patients at risk of poor outcome. MATERIALS AND METHODS: We retrospectively analyzed the heterogeneity of the MTT using the coefficient of variation in CTP scans from 132 patients. A multivariable logistic regression model was used to model the dichotomized mRS outcome. Linear regression was used to eliminate variables with high linear dependence. T tests were used to compare the means of 2 groups. Furthermore, the time of the maximum coefficient of variation for MTT after bleeding was evaluated for correlation with the mRS after 6 months. RESULTS: On average, each patient underwent 5.3 CTP scans during his or her stay. Patients with high coefficient of variation for MTT presented more often with higher modified Fisher (P = .011) and World Federation of Neurosurgical Societies grades (P = .014). A high coefficient of variation for MTT at days 3-21 after aneurysmal SAH correlated significantly with a worse mRS score after 6 months (P = .016). We found no correlation between the time of the maximum coefficient of variation for MTT after bleeding and the patients' outcomes after 6 months (P = .203). CONCLUSIONS: Heterogeneity of MTT in CTP after aneurysmal SAH correlates with the patients' outcomes. Because the findings are in line with the pathophysiologic concept of the capillary transit time heterogeneity, future studies should seek to verify the coefficient of variation for MTT as a potential imaging biomarker for outcome.

[Interdisciplinary neurovascular networks: state of the art]. / Interdisziplinäre neurovaskuläre Netzwerke: eine Standortbestimmung.

BACKGROUND: In order to treat the complete spectrum of neurovascular diseases at a high level of quality, which goes beyond the purely acute treatment of stroke, the German Stroke Society (DSG) together with the German Societies for Neurosurgery and Neuroradiology developed a certification procedure for neurovascular networks (NVN). Structurally, a NVN consists of a coordinating center with at least three neurovascular network partners with a certified stroke unit. From 2018 to 2020 a total of 15 NVN have so far been audited and certified according to this new standard. OBJECTIVE: How efficient are the NVN? Are high standards maintained? MATERIAL AND METHODS: The reports of the audits were analyzed. The data were taken from the period 2017-2019. RESULTS: The 15 NVN treated a total of 86,510 stroke patients in the years examined and were networked with a total of 107 partner clinics, which were situated an average of 25 km from the coordinating center and transferred a total of 2726 patients. The coordinating centers performed 2463 thrombectomies and treated 2383 patients with nontraumatic intracerebral bleeding. In 712 patients with acute aneurysmatic subarachnoid hemorrhages endovascular treatment was carried out and clipping in 401. The audit was successful in the majority of the NVN. CONCLUSION: The certification process of NVN has been successfully established and the audits proved to be a useful instrument for quality control and improvement. The 15 NVN are highly efficient and treat more than one quarter of stroke patients in German stroke units.

Immunoluminometric assay for copeptin measurement in cerebrospinal fluid: Technical aspects and pilot study.

BACKGROUND: Copeptin acts as surrogate marker under stress stimuli, as well as an outcome predictor based on serum or plasma concentration in patients suffering intracranial hemorrhage, aneurysmal subarachnoid hemorrhage (aSAH), and stroke. The aim of this study was to establish a method for quantification of copeptin levels in cerebrospinal fluid (CSF) and to demonstrate its clinical applicability in patients following aSAH. METHODS: This assay was validated for CSF samples using a commercial immunoluminometric assay (IMLA). For the control group (10 patients), CSF copeptin levels were determined in patients without signs of acute neurological diseases and who underwent a diagnostic lumbar puncture. The pilot cohort included calculation of copeptin levels in CSF and in serum of patients following aSAH. RESULTS: The control group had CSF copeptin levels lower than 0.78 pmol/L-1. Among patients with aSAH, CSF copeptin values had a mean of 20.1 pmol/L-1 and serum copeptin concentrations had a mean of 61.39 pmol/L-1. CONCLUSIONS: This assay provides to best of our knowledge for the first time initial ranges values of CSF copeptin for patients without acute neurological disease and in patients with aSAH. Thus, it opens new doors to develop further calculations and relationships between diseases biomarker and outcome prediction.

Cranial nerve deficits in giant cavernous carotid aneurysms and their relation to aneurysm morphology and location.

BACKGROUND: Giant cavernous carotid aneurysms (GCCAs) usually exert substantial mass effect on adjacent intracavernous cranial nerves. Since predictors of cranial nerve deficits (CNDs) in patients with GCCA are unknown, we designed a study to identify associations between CND and GCCA morphology and the location of mass effect. METHODS: This study was based on data from the prospective clinical and imaging databases of the Giant Intracranial Aneurysm Registry. We used magnetic resonance imaging and digital subtraction angiography to examine GCCA volume, presence of partial thrombosis (PT), GCCA origins, and the location of mass effect. We also documented whether CND was present. RESULTS: We included 36 GCCA in 34 patients, which had been entered into the registry by eight participating centers between January 2009 and March 2016. The prevalence of CND was 69.4%, with one CND in 41.7% and more than one in 27.5%. The prevalence of PT was 33.3%. The aneurysm origin was most frequently located at the anterior genu (52.8%). The prevalence of CND did not differ between aneurysm origins (p = 0.29). Intracavernous mass effect was lateral in 58.3%, mixed medial/lateral in 27.8%, and purely medial in 13.9%. CND occurred significantly more often in GCCA with lateral (81.0%) or mixed medial/lateral (70.0%) mass effect than in GCCA with medial mass effect (20.0%; p = 0.03). After adjusting our data for the effects of the location of mass effect, we found no association between the prevalence of CND and aneurysm volume (odds ratio (OR) 1.30 (0.98-1.71); p = 0.07), the occurrence of PT (OR 0.64 (0.07-5.73); p = 0.69), or patient age (OR 1.02 (95% CI 0.95-1.09); p = 0.59). CONCLUSIONS: Distinguishing between medial versus lateral location of mass effect may be more helpful than measuring aneurysm volumes or examining aneurysm thrombosis in understanding why some patients with GCCA present with CND while others do not. CLINICAL TRIAL REGISTRATION NO: NCT02066493 ( clinicaltrials.gov ).

Timing of Mean Transit Time Maximization is Associated with Neurological Outcome After Subarachnoid Hemorrhage.

PURPOSE: Computed tomography perfusion (CTP) has gained significant relevance for the radiological screening of patients at risk of developing delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). Particularly, the impact of MTTPEAK, i.e., the maximal mean transit time value in a series of CTP measurements, for the prediction of long-term outcome has recently been demonstrated by our group. Complementing this recent work, the present study investigated how the timing of MTTPEAK affected the long-term outcome after aneurysmal subarachnoid hemorrhage. METHODS: CTP examinations from 103 patients with clinical deterioration attributed to DCI after aSAH were retrospectively analyzed for time interval between SAH ictus and onset of MTTPEAK in association with modified Rankin Scale (mRS) 23.1 months after SAH. RESULTS: Patients with unfavorable outcome (mRS > = 2) suffered significant earlier MTTPEAK onsets than patients with favorable outcome (mRS = 0 and 1). MTTPEAK within the first week was associated with significantly higher mRS scores compared to later MTTPEAK. Timing of MTTPEAK together with the value of MTTPEAK and initial World Federation of Neurosurgical Societies (WFNS) grade was a significant predictor for an unfavorable outcome (mRS > = 2). CONCLUSIONS: The current findings suggest a presumably higher vulnerability of the brain to early microcirculatory impairments after aSAH and highlight that timing of MTT elevations could be considered for the identification of patients at increased risk for poor neurological outcome due to DCI.

Localization techniques in resection of deep seated cavernous angiomas - review and reevaluation of frame based stereotactic approaches.

BACKGROUND: Providing high accuracy is crucial in neurosurgery especially for resection of deep seated small cerebral pathologies such as cavernous angiomas. The goal of the present series was to reevaluate the feasibility, accuracy, efficacy and safety of frame-based, stereotactically guided resection for patients suffering from small deep-seated cavernous angiomas. Additionally a review of the literature on navigational tools in cavernoma surgery is provided comparing different navigation strategies. METHODS: Ten patients with deep-seated, small intracranial, cavernous angiomas being subject to frame-based, stereotactically aided resection are included in this survey. Based on the stereotactic-fused image, set entry and target point aimed at the rim of the cavernoma were calculated. A minicraniotomy (< 3 cm in diameter) was performed followed by positioning of the stereotactic needle. Following the needle in situ the cavernous angioma was localized and resected. Assets and drawbacks of the stereotactic-aided approach were evaluated, patients were analyzed for surgery-related neurological deficits and completeness of resection. RESULTS: Complete resection was achieved in all ten patients verified by post-surgery MRI imaging. The surgical procedure itself was only slightly aggravated by the stereotactic equipment. No adverse events such as bleedings or infections were observed in our series. CONCLUSIONS: Stereotactically guided, minimally invasive resection of deep seated and small cavernous angiomas is accurate and effective. The frame-based stereotactic guidance requires some additional time and effort which seems justified only for deep seated and small cavernous angiomas. Frameless neuronavigation is a common tool in cavernoma surgery and its spatial resolution is sufficient for the majority of cases.

Traumatic brain injuries in the ancient Egypt: insights from the Edwin Smith Papyrus.

BACKGROUND: Traumatic brain injury (TBI) is probably as old as human beings. The Edwin Smith Papyrus is the first treatise describing the treatment of patients with TBI and allows insights into the medical examination and treatment of head-injured patients in ancient Egypt. METHOD: Clinical, diagnostic, and therapeutic principles in the treatment of TBI in ancient Egypt were analyzed. RESULTS: Methodically, cases and the presentation of each case are neatly classified within the papyrus. The papyrus contains the first description of the brain, pulsations, contusions as the result of TBI, the dura, and cerebrospinal fluid, revealing a more or less sophisticated knowledge of cerebral anatomy. Furthermore, ancient physicians examined wounds, fractures, signs of basal skull fractures, and associated neurological or infectious symptoms, and classified the injury pattern according to their prognosis. Therapeutic options at this time seemed to have been limited. CONCLUSIONS: The Edwin Smith Papyrus reveals astonishing observation skill when considering the methods and limits of ancient times. These physicians were able to recognize many symptoms of TBI and assign them a prognostic value.

A comparative study of perfusion CT and 99m Tc-HMPAO SPECT measurement to assess cerebrovascular reserve capacity in patients with internal carotid artery occlusion.

BACKGROUND AND PURPOSE: Patients with internal carotid artery (ICA) occlusion can demonstrate impaired cerebral vascular reserve (CVR). The detection of CVR using single photon emission CT (SPECT) is nowadays widely accepted as a predictor in the diagnostic pathway in patients considered for cerebral revascularization. Recently perfusion CT (PCT) gained widely acceptance in stroke imaging. The present study was aimed at comparing the results of perfusion CT (PCT) and 99m Tc-HMPAO SPECT with acetazolamide challenge in patients with ICA occlusion. METHODS: 13 patients were included in the prospective evaluation. Both PCT and 99m Tc-HMPAO SPECT were performed before and after the administration of acetazolamide. In detail, regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), adapted time to peak (Tmax) and mean transit times (MTT) were compared with SPECT data. - RESULTS: 99m Tc-HMPAO SPECT demonstrated an impairment of CVR in six patients. A preserved CVR was present in seven patients. All patients with impaired CVR proven by SPECT had a delayed MTT (mean +2.98 s) and a delayed Tmax (mean + 5.9 s), (both p <0.005 compared with the non occluded side). 66% of patients with impaired CVR in SPECT showed a complete correlation of Tmax measurements in PCT with a high positive predictive value (PPV: 88.8%). - CONCLUSION: The prospective study demonstrated a highly significant correlation of perfusion parameters as detected by 99m Tc-HMPAO SPECT and the Tmax as detected by PCT in patients with ICA occlusion. Therefore this easy-to-perform technique seems to be an adequate method for the evaluation of cerebral perfusion in patients with ICA occlusion.

Heat-shock protein 70-dependent dendritic cell activation by 5-aminolevulinic acid-mediated photodynamic treatment of human glioblastoma spheroids in vitro.

BACKGROUND: T-cell responses contribute to the anti-tumoural effect of photodynamic therapy (PDT). For such responses to occur, dendritic cells (DCs) have to migrate to the tumour, take up tumour antigens and respond to danger signals with maturation, before they engage in T-cell activation. Here, we have studied the effect of 5-aminolevulinic acid (ALA)-mediated PDT on DCs in vitro in a human spheroid model of glioblastoma (GB). METHODS: Spheroids of the GB cell lines U87 and U251 were treated with ALA/PDT, and effects on attraction, uptake of tumour antigens and maturation of DCs were studied. To block heat-shock protein-70 (HSP-70) on the spheroids, neutralising antibodies were used. RESULTS: 5-Aminolevulinic acid /PDT-treated GB spheroids attracted DCs that acquired tumour antigens from the spheroids effectively. Moreover, co-culture with ALA/PDT-treated spheroids induced DC maturation as indicated by the upregulation of CD83 and co-stimulatory molecules as well as increased T-cell stimulatory activity of the DCs. Heat-shock protein-70 was upregulated on the spheroids after ALA/PDT treatment. Uptake of tumour antigens and DC maturation induced by the ALA/PDT-treated spheroids were inhibited when HSP-70 was blocked. CONCLUSION: ALA/PDT treatment of glioma spheroids promotes the three initial steps of the afferent phase of adaptive immunity, which is at least partially mediated by HSP-70.

Influence of blood pressure variability on short-term outcome in patients with subarachnoid hemorrhage.

OBJECTIVE: Several recent investigations have demonstrated a significant influence of blood pressure variation during the immediate period after stroke. The present study was conducted to evaluate the effect of blood pressure, intracranial pressure and cerebral perfusion pressure variation on short-term outcome in patients after severe subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: 105 patients suffering from severe SAH were included in the study. The Glasgow Coma Scale (GCS) Score and World Federation of Neurological Surgeons (WFNS) grading were used to describe the patients on admission, and the short-term outcome was assessed using the GCS and the Glasgow Outcome Scale (GOS) Score. In all patients, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were continuously recorded. For each recorded parameter (SBP, DBP, MAP, ICP and CPP) the first recorded value was defined as the baseline value (bas). The minimum (min), maximum (max) and average (mean) value was identified from all recorded values for each parameter and the range between minimum and maximum value was calculated (range). Based on the individual parameter range (absolute values) the variability of successive values was determined as the successive variation (sv). Finally, the values obtained were correlated to clinical outcome and analyzed statistically. RESULTS: In 105 patients the database offered an average of 330.4 single readings (median 318). SBPmax, and SBPrange were significantly lower in the group with an improving short-term GCS than in the group with constant or deteriorating GCS ( P=0.0079 and P=0.0006, respectively). SBPmin was significantly higher in the improved GCS group (P=0.0235). With regard to successive variation (SBPsv) we could not demonstrate a significant difference between both groups (mean SBPsv 15.7 vs. 14.7; P=0.1223), and no correlation with either GCS at discharge (P=0.91) or GOS at discharge (P=0.841) was detectable. There was no statistically significant difference in CPP and ICP between both outcome groups. CONCLUSION: Systolic blood pressure levels and range appear to be of importance for the management of patients suffering from SAH and may influence patient outcome.

[Diagnostic work-up and therapy of spinal vascular malformations: an update]. / Diagnostik und Therapie der spinalen vaskulären Malformationen: Ein Update.

INTRODUCTION: Spinal vascular malformations are rare disease patterns with a clinical incidence of about 5-10/year/1 million comprising spinal arteriovenous malformations (sAVM), spinal arteriovenous fistulas (sAVF) and spinal cavernomas. Long courses of disease before diagnosis deteriorate the prognosis despite successful treatment. METHODS: Selective review of the literature in consideration of present guidelines. RESULTS: Spinal vascular pathological conditions can be classified into different subtypes especially by use of magnetic resonance imaging (MRI) and selective digital subtraction angiography (DSA). Diagnosis and treatment of spinal dural arteriovenous fistula (type I) as well as spinal arteriovenous malformations (type II-V) ideally require a close co-operation between neurosurgeons and neuroradiologists. Surgery can in general be considered as curative. Endovascular therapy of arteriovenous malformations results in reduction of size and concomitant haemodynamic effects. A curative approach is generally not possible. Particularly in cases of lumbosacral and craniosacral arteriovenous fistulas the interventional procedure provides advantages. Treatment of spinal cavernomas nowadays consists of neurosurgical approaches exclusively. The significance of radiosurgical therapy, especially with the CyberKnife, remains indistinct. Today, interdisciplinary neurosurgical and neuroradiological co-operation in specialized centres allows most spinal vascular malformations to be diagnosed at an early stage and to be treated with satisfying results.

A multimodal concept in patients after severe aneurysmal subarachnoid hemorrhage: results of a controlled single centre prospective randomized multimodal phase I/II trial on cerebral vasospasm.

OBJECTIVE: Recent publications suggest that a combination of head-shaking and cisternal irrigation might reduce symptomatic cerebral vasospasm after subarachnoid hemorrhage (SAH). The present clinical prospective randomized phase I/II study was initiated in order to analyze the prophylactic effect of intracisternal lysis in combination with kinetic treatment followed by intrathecal nimodipine lavage. METHODS: Twenty patients with aneurysmal SAH, WFNS grade 2 to 5 (GCS 13-3) and Fisher grade 3 or 4 were included in this prospective randomized study which had been approved by the local Ethics Research Committee. Following insertion of a ventricular drain, securing of the aneurysm by a microsurgical or endovascular route and the insertion of two lumbar catheters, intracisternal lysis with urokinase 120 000 IU/d was performed for 48 h in the patients of the study group. Intrathecal pressure was monitored by the second lumbar catheter. After intracisternal lysis, intrathecal nimodipine lavage was applied for 7 d. For comatose patients kinetic head-rotation was also performed. Vasospasm was clinically identified with a focus on delayed neurological deficits (DINDs) by daily transcranial Doppler (TCD), computerized tomography (CT), perfusion CT (pCT) and cerebral angiography (DSA). RESULTS: There was no DIND in the study group among the patients who were awake, while two DINDs occurred in the control group. The pooled TCD flow velocities over an average period of 14 d revealed no statistically significant difference between the groups. Vasospasm-related infarction on CT was seen in two patients of the control group. Evident vasospasm on DSA appeared in three patients of the study group compared with 7 patients in the control group. Moreover there was a neurological improvement in the study population as measured by mRS at 3-month follow-up (P=0.266). In two consecutive patients randomized to the study group a paresis of the lower extremities of unknown origin occurred. As a result of these complications the study was stopped in accordance with the local Ethics Research Committee guidelines. CONCLUSION: A multimodal approach with translumbar lysis in combination with kinetic therapy followed by intrathecal nimodipine lavage proved to be effective against cerebral vasospasm and for clinical outcome. However, due to the observed complications with the occurrence of paraparesis in two patients of the study group the trial was stopped. Nevertheless, the promising preliminary results suggest a further development of the clinical protocol using a modified multimodal concept to prevent and treat cerebral vasospasm after severe SAH.

Results of direct and indirect revascularisation for adult European patients with Moyamoya angiopathy.

There is little information concerning clinical data and revascularization procedures in adult European patients with Moyamoya disease. More data are available on juvenile European Moyamoya angiopathy and its microsurgical therapies. This analysis summarizes our clinical experience in European adult patients with Moyamoya angiopathy. Nine adult European patients underwent surgical revascularization for Moyamoya angiopathy between 1997 and 2005. Direct intracranial-extracranial (EC-IC) bypass was considered the primary surgical modality. In case of unsuitable donor or recipient arteries, encephalo-myo-synangiosis (EMS) was chosen as an indirect modality. The current analysis confirms that direct EC-IC-bypass is a feasible option for most cases of adult European Moyamoya disease. Exact definition of long-term benefits would require a multicentric study. EMS appears to be of questionable value in the adult European population.

Intra-arterial nimodipine for severe cerebral vasospasm after aneurysmal subarachnoid hemorrhage: influence on clinical course and cerebral perfusion.

BACKGROUND AND PURPOSE: The efficacy of intra-arterial administration of nimodipine (IAN) in patients with severe vasospasm after aneurysmal subarachnoid hemorrhage (SAH) remains unproved. The goal of the present study was to investigate the clinical effect and cerebral perfusion after IAN in patients with severe vasospasm refractory to hemodynamic treatment. MATERIALS AND METHODS: Twenty-six of 214 patients with aneurysmal SAH were included in the prospective study, approved by the local ethics committee. All patients met the criteria of medically refractory cerebral vasospasm. Effectiveness was monitored angiographically by digital subtraction angiography and by transcranial Doppler (TCD), perfusion CT (PCT), and neurologic examination during treatment course and follow-up. RESULTS: No angiographic effect was observed in 8 patients. The pooled PCT values revealed a reduction of time to peak (P = .03) and mean transit time (P = .17) 1 day after intervention. This effect did not persist during the following days. The pooled TCD analysis demonstrated a transient increase in flow 1 day after intervention (P = .03). No trend was evident during the next 7 days after intervention. Additional infarction was experienced by 61.1% of patients. CONCLUSIONS: IAN in a selective patient group resulted in a positive response with reduction of angiographic vasospasm and increase in cerebral perfusion as detected by PCT after 24 hours. Therefore, IAN appears more effective than intra-arterial papaverine. Nevertheless the efficacy of IAN is temporary. Therefore, the search for more effective treatment strategies to reduce critical vasospasm and to improve cerebral perfusion must be continued.