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Here we describe therapeutic results in a female patient who underwent bilateral slMFB DBS for OCD. During a 35-month long course of stimulation, she suffered from stimulation-induced dyskinesia of her right leg which we interpreted as co-stimulation of the adjacent anteromedial subthalamic nucleus (amSTN). After reprogramming to steer the stimulation away from the amSTN medial into the direction of the mesencephalic ventral tegmentum (MVT which contains the ventral tegmental area, VTA), the dyskinesias disappeared. Remarkably, anti-OCD efficacy in the presented patient was preserved and achieved with a bilateral stimulation which by our imaging study fully avoided the amSTN.

Although the free water content within the perilesional T2 hyperintense region should differ between glioblastomas (GBM) and brain metastases based on histological differences, the application of classical MR diffusion models has led to inconsistent results regarding the differentiation between these two entities. Whereas diffusion tensor imaging (DTI) considers the voxel as a single compartment, multicompartment approaches such as neurite orientation dispersion and density imaging (NODDI) or the recently introduced diffusion microstructure imaging (DMI) allow for the calculation of the relative proportions of intra- and extra-axonal and also free water compartments in brain tissue. We investigate the potential of water-sensitive DTI, NODDI and DMI metrics to detect differences in free water content of the perilesional T2 hyperintense area between histopathologically confirmed GBM and brain metastases. Respective diffusion metrics most susceptible to alterations in the free water content (MD, V-ISO, V-CSF) were extracted from T2 hyperintense perilesional areas, normalized and compared in 24 patients with GBM and 25 with brain metastases. DTI MD was significantly increased in metastases (p = 0.006) compared to GBM, which was corroborated by an increased DMI V-CSF (p = 0.001), while the NODDI-derived ISO-VF showed only trend level increase in metastases not reaching significance (p = 0.060). In conclusion, diffusion MRI metrics are able to detect subtle differences in the free water content of perilesional T2 hyperintense areas in GBM and metastases, whereas DMI seems to be superior to DTI and NODDI.

Aneurysmal subarachnoid hemorrhage (aSAH) is a severe cerebrovascular disease with high morbidity and case fatality [1,2]. Inpatients who survive the initial bleeding, delayed cerebral infarction(DCI) is one of the leading causes of poor outcome. The pathogenesis of DCI is hypothesized to be multifactorial and includes angiographic vasospasm, but also cortical spreading ischemia, microthrombosis and microcirculation constriction [3,4]. Seventy percent of a SAH patients develop angiographic vasospasm and20-30% progress to develop DCI [5]. Effective therapies are lacking. Since the middle of the 1970s, hypertension, hypervolemia and hemodilution (triple-H) therapy has been used with the aim of restoring impaired cerebral perfusion and, thereby, improving outcome[6]. The concept has been reshaped and hypertension (iHTN) alone has prevailed as the mainstay of therapy in neurointensive care units to treat delayed ischemia after aSAH1. Medical evidence for this therapy is lacking [1,6]. Recently, safety and efficacy of iHTN have been challenged by results from a randomized trial (HIMALAIA)[7]. Although prematurely terminated the study indicated that iHTN may be associated with adverse events (AE). In addition, the trial showed that improvement of symptomatic delayed ischemia also occurs without using iHTN [15].We introduced stereotactic catheter ventriculocisternostomy(STX-VCS) and fibrinolytic/spasmolytic lavage as a new method for DCI prevention[8,9] in 2015. Implementation of STX-VCS lead to a reduction of the DCI rate from 18% to 7.9% and the burden of delayed infarction was reduced by 64% in the unselected aSAH patient population. Further, both endovascular interventions and iHTN were largely withheld following STX-VCS introduction[8].In this monocentric retrospective study, we present new data on the effects of avoiding iHTN in our consecutive and unselected aSAH patient cohort and compare patients admitted in the 3.5 years before STX-VCS became available to patients admitted in the3.5 years after introduction of this therapy.

PURPOSE Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging. Furthermore, CNSL diagnosis often remains unconfirmed because of contraindications for invasive stereotactic biopsies. Therefore, improved biomarkers are needed to better stratify patients into risk groups, predict treatment response, and noninvasively identify CNSL. PATIENTS AND METHODS We explored the value of circulating tumor DNA (ctDNA) for early outcome prediction, measurable residual disease monitoring, and surgery-free CNSL identification by applying ultrasensitive targeted next-generation sequencing to a total of 306 tumor, plasma, and CSF specimens from 136 patients with brain cancers, including 92 patients with CNSL. RESULTS Before therapy, ctDNA was detectable in 78% of plasma and 100% of CSF samples. Patients with positive ctDNA in pretreatment plasma had significantly shorter progression-free survival (PFS, P < .0001, log-rank test) and overall survival (OS, P = .0001, log-rank test). In multivariate analyses including established clinical and radiographic risk factors, pretreatment plasma ctDNA concentrations were independently prognostic of clinical outcomes (PFS HR, 1.4; 95% CI, 1.0 to 1.9; P = .03; OS HR, 1.6; 95% CI, 1.1 to 2.2; P = .006). Moreover, measurable residual disease detection by plasma ctDNA monitoring during treatment identified patients with particularly poor prognosis following curative-intent immunochemotherapy (PFS, P = .0002; OS, P = .004, log-rank test). Finally, we developed a proof-of-principle machine learning approach for biopsy-free CNSL identification from ctDNA, showing sensitivities of 59% (CSF) and 25% (plasma) with high positive predictive value. CONCLUSION We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNSL. Our findings highlight the role of ctDNA as a noninvasive biomarker and its potential value for personalized risk stratification and treatment guidance in patients with CNSL. [Media: see text]

Associative memory is the ability to encode and retrieve relations between different stimuli. To better understand its neural basis, we investigated whether associative memory involves precisely timed spiking of neurons in the medial temporal lobes that exhibit stimulus-specific tuning. Using single-neuron recordings from epilepsy patients performing an associative object–location memory task, we identified the object- and place-specific neurons that encoded the separate elements of each memory. When patients encoded and retrieved particular memories, the relevant object- and place-specific neurons activated synchronously during hippocampal ripples. This ripple-locked coactivity of stimulus-specific neurons emerged over time as the patients’ associative learning progressed. Our results suggest a cellular account of associative memory, in which hippocampal ripples coordinate the activity of specialized cellular populations to facilitate links between stimuli.

Hippocampal sclerosis (HS) is often associated with gray-white matter blurring (GMB) of the anterior temporal lobe. In this study, twenty patients with unilateral temporal lobe epilepsy and HS were studied with 3 T MRI including T1 MP2RAGE and DTI/DMI sequences. Anterior temporal lobe white matter T1 relaxation times and diffusion measures were analyzed on the HS side, on the contralateral side, and in 10 normal controls. Resected brain tissue of three patients without GMB and four patients with GMB was evaluated ultrastructurally regarding axon density and diameter, the relation of the axon diameter to the total fiber diameter (G-ratio), and the thickness of the myelin sheath. Hippocampal sclerosis GMB of the anterior temporal lobe was related to prolonged T1 relaxation and axonal loss. A less pronounced reduction in axonal fraction was also found on imaging in GMB-negative temporal poles compared with normal controls. Contralateral values did not differ significantly between patients and normal controls. Reduced axonal density and axonal diameter were histopathologically confirmed in the temporopolar white matter with GMB compared to temporal poles without. These results confirm that GMB can be considered an imaging correlate for disturbed axonal maturation that can be quantified with advanced diffusion imaging.

Uncertainties concerning anatomy and function of cortico-subcortical projections have arisen during the recent years. A clear distinction between cortico-subthalamic (hyperdirect) and cortico-tegmental projections (superolateral medial forebrain bundle, slMFB) so far is elusive. Deep Brain Stimulation (DBS) of the slMFB (for major depression, MD and obsessive compulsive disorders, OCD) has on the one hand been interpreted as actually involving limbic (prefrontal) hyperdirect pathways. On the other hand slMFB’s stimulation region in the mesencephalic ventral tegmentum is said to impact on other structures too, going beyond the antidepressant (or anti OCD) efficacy of sole modulation of the cortico-tegmental reward-associated pathways. We have here used a normative diffusion MRT template (HCP, n = 80) for long-range tractography and augmented this dataset with ex-vivo high resolution data (n = 1) in a stochastic brain space. We compared this data with histological information and used the high resolution ex-vivo data set to scrutinize the mesencephalic tegmentum for small fiber pathways present. Our work resolves an existing ambiguity between slMFB and prefrontal hyperdirect pathways which—for the first time—are described as co-existent. DBS of the slMFB does not appear to modulate prefrontal hyperdirect cortico-subthalamic but rather cortico-tegmental projections. Smaller fiber structures in the target region—as far as they can be discerned—appear not to be involved in slMFB DBS. Our work enfeebles previous anatomical criticism and strengthens the position of the slMFB DBS target for its use in MD and OCD.

Background: Primary vitreoretinal lymphoma (PVRL), a rare malignancy of the eye, is strongly related to primary central nervous system lymphoma (PCNSL). We hypothesized that lymphoma cells disseminate to the CNS and eye tissue via distinct homing receptors. The objective of this study was to test expression of CXCR4, CXCR5, CXCR7 and CD44 homing receptors on CD20 positive B-lymphoma cells on enucleated eyes using a PCNSL xenograft mouse model. Methods: We used indirect immunofluorescence double staining for CD20/CXCR4, CD20/CXCR5, CD20/CXCR7 and CD20/CD44 on enucleated eyes of a PCNSL xenograft mouse model with PVRL phenotype (PCNSL group) in comparison to a secondary CNS lymphoma xenograft mouse model (SCNSL group). Lymphoma infiltration was evaluated with an immunoreactive score (IRS). Results: 11/13 paired eyes of the PCNSL but none of the SCNSL group were infiltrated by CD20-positive cells. Particularly the choroid and to a lesser extent the retina of the PCNSL group were infiltrated by CD20+/CXCR4+, CD20+/CXCR5+, few CD20+/CD44+ but no CD20+/CXCR7+ cells. Expression of CXCR4 (p = 0.0205), CXCR5 (p = 0.0004) and CD44 (p < 0.0001) was significantly increased in the PCNSL compared to the SCNSL group. Conclusions: CD20+ PCNSL lymphoma cells infiltrating the eye co-express distinct homing receptors such as CXCR4 and CXCR5 in a PVRL homing mouse model. These receptors may be involved in PVRL homing into the eye.

Background An increasing number of neurosurgeons use display of the dentato-rubro-thalamic tract (DRT) based on diffusion weighted imaging (dMRI) as basis for their routine planning of stimulation or lesioning approaches in stereotactic tremor surgery. An evaluation of the anatomical validity of the display of the DRT with respect to modern stereotactic planning systems and across different tracking environments has not been performed. Methods Distinct dMRI and anatomical magnetic resonance imaging (MRI) data of high and low quality from 9 subjects were used. Six subjects had repeated MRI scans and therefore entered the analysis twice. Standardized DICOM structure templates for volume of interest definition were applied in native space for all investigations. For tracking BrainLab Elements (BrainLab, Munich, Germany), two tensor deterministic tracking (FT2), MRtrix IFOD2 (https://www.mrtrix.org), and a global tracking (GT) approach were used to compare the display of the uncrossed (DRTu) and crossed (DRTx) fiber structure after transformation into MNI space. The resulting streamlines were investigated for congruence, reproducibility, anatomical validity, and penetration of anatomical way point structures. Results In general, the DRTu can be depicted with good quality (as judged by waypoints). FT2 (surgical) and GT (neuroscientific) show high congruence. While GT shows partly reproducible results for DRTx, the crossed pathway cannot be reliably reconstructed with the other (iFOD2 and FT2) algorithms. Conclusion Since a direct anatomical comparison is difficult in the individual subjects, we chose a comparison with two research tracking environments as the best possible “ground truth.” FT2 is useful especially because of its manual editing possibilities of cutting erroneous fibers on the single subject level. An uncertainty of 2 mm as mean displacement of DRTu is expectable and should be respected when using this approach for surgical planning. Tractographic renditions of the DRTx on the single subject level seem to be still illusive.

ZusammenfassungDie Kallosotomie ist eine palliative Operation, die seit fast 80 Jahren bei Patienten mit therapierefraktären, bilateralen Anfällen eingesetzt wird, wenn ein resektives Verfahren nicht möglich ist. Neuere, minimal-invasive Techniken wie die MRT-gesteuerte laserinduzierte Thermokoagulation sind vermutlich vergleichbar bezüglich Outcome und Komplikationsraten, die Datenlage ist aber insgesamt noch spärlich. In vielen Fallserien war die Kallosotomie v. a. in der Reduktion von Sturzanfällen effektiv, in geringerem Ausmaß auch für epileptische Spasmen. Eine vollständige Anfallsfreiheit wird nur sehr selten erreicht. Chirurgische Komplikationen wie Blutungen oder Infektionen treten in etwa 5 % auf. Die wichtigste, jedoch sehr seltene Nebenwirkung der Kallosotomie ist ein Diskonnektionssyndrom mit Apraxie, taktiler und visueller Anomie, Neglect oder SMA(supplementär-motorisches Areal)-Syndrom. Besonders bei Kindern ist das Diskonnektionssyndrom in aller Regel transient. Ob eine anteriore oder eine komplette Kallosotomie durchgeführt wird, variiert von Zentrum zu Zentrum. Komplette Kallosotomien sind hinsichtlich der Anfallsreduktion effizienter, gehen aber mit einem höheren Risiko für Komplikationen und Nebenwirkungen einher. Eine Option ist eine zweistufige Kallosotomie, bei der zunächst eine anteriore Diskonnektion durchgeführt wird und in den Fällen ohne hinreichenden postoperativen Nutzen in einem zweiten Schritt vervollständigt wird.

Recent developments in the postoperative evaluation of deep brain stimulation surgery on the group level warrant the detection of achieved electrode positions based on postoperative imaging. Computed tomography (CT) is a frequently used imaging modality, but because of its idiosyncrasies (high spatial accuracy at low soft tissue resolution), it has not been sufficient for the parallel determination of electrode position and details of the surrounding brain anatomy (nuclei). The common solution is rigid fusion of CT images and magnetic resonance (MR) images, which have much better soft tissue contrast and allow accurate normalization into template spaces. Here, we explored a deep-learning approach to directly relate positions (usually the lead position) in postoperative CT images to the native anatomy of the midbrain and group space.Deep learning is used to create derived tissue contrasts (white matter, gray matter, cerebrospinal fluid, brainstem nuclei) based on the CT image; that is, a convolution neural network (CNN) takes solely the raw CT image as input and outputs several tissue probability maps. The ground truth is based on coregistrations with MR contrasts. The tissue probability maps are then used to either rigidly coregister or normalize the CT image in a deformable way to group space. The CNN was trained in 220 patients and tested in a set of 80 patients.Rigorous validation of such an approach is difficult because of the lack of ground truth. We examined the agreements between the classical and proposed approaches and considered the spread of implantation locations across a group of identically implanted subjects, which serves as an indicator of the accuracy of the lead localization procedure. The proposed procedure agrees well with current magnetic resonance imaging-based techniques, and the spread is comparable or even lower.Postoperative CT imaging alone is sufficient for accurate localization of the midbrain nuclei and normalization to the group space. In the context of group analysis, it seems sufficient to have a single postoperative CT image of good quality for inclusion. The proposed approach will allow researchers and clinicians to include cases that were not previously suitable for analysis.

Directional deep brain stimulation (dDBS) electrodes allow to steer the electrical field in a specific direction. When implanted with torque, they may rotate for a certain time after implantation. The aim of this study was to evaluate whether and to which degree leads rotate in the first 24 h after implantation using a sheep brain model. dDBS electrodes were implanted in 14 sheep heads and 3D rotational fluoroscopy (3D-RF) scans were acquired to visualize the orientation of the electrode leads. Electrode leads were clockwise rotated just above the burr holes (180° n = 6, 360° n = 6, 2 controls) and 3D-RF scans were again acquired after 3, 6, 13, 17, and 24 h, respectively. One hundred eighty degree rotated electrodes showed an initial rotation of 83.5° (range: 35.4°–128.3°) and a rotation of 114.0° (range: 57°–162°) after 24 h. With 360° torsion, mean initial rotation was 201° (range: 3.3°–321.4°) and mean rotation after 24 h 215.7° (range 31.9°–334.7°), respectively. Direct postoperative imaging may not be accurate for determining the rotation of dDBS electrodes if torque is present.

Deep brain stimulation (DBS) is a complex surgical procedure that requires detailed anatomical knowledge. In many fields of neurosurgery navigation systems are used to display anatomical structures during an operation to aid performing these surgeries. In frame-based DBS, the advantage of visualization has not yet been evaluated during the procedure itself. In this study, we added live visualization to a frame-based DBS system, using a standard navigation system and investigated its accuracy and potential use in DBS surgery. As a first step, a phantom study was conducted to investigate the accuracy of the navigation system in conjunction with a frame-based approach. As a second step, 5 DBS surgeries were performed with this combined approach. Afterwards, 3 neurosurgeons and 2 neurologists with different levels of experience evaluated the potential use of the system with a questionnaire. Moreover, the additional personnel, costs and required set up time were noted and compared to 5 consecutive standard procedures. In the phantom study, the navigation system showed an inaccuracy of 2.1 mm (mean SD 0.69 mm). In the questionnaire, a mean of 9.4/10 points was awarded for the use of the combined approach as a teaching tool, a mean of 8.4/10 for its advantage in creating a 3-dimensional (3-D) map and a mean of 8/10 points for facilitating group discussions. Especially neurosurgeons and neurologists in training found it useful to better interpret clinical results and side effects (mean 9/10 points) and neurosurgeons appreciated its use to better interpret microelectrode recordings (mean 9/10 points). A mean of 6/10 points was awarded when asked if the benefits were worth the additional efforts. Initially 2 persons, then one additional person was required to set up the system with no relevant added time or costs. Using a navigation system for live visualization during frame-based DBS surgery can improve the understanding of the complex 3-D anatomy and many aspects of the procedure itself. For now, we would regard it as an excellent teaching tool rather than a necessity to perform DBS surgeries.

The two middle contacts of directional leads (d-leads) for deep brain stimulation are split into three segments, allowing current steering toward desired axial directions. To facilitate programming, their final orientation needs to be reliably determined. However, it is currently unclear whether d-leads rotate after implantation. Our objective was to assess the degree of d-lead rotation after implantation. We retrospectively analyzed d-lead orientation on intraoperative X-rays, postoperative CT scans (latencies to surgery: 108–189 min postoperatively), and rotational fluoroscopies (4–9 days postoperatively) for a consecutive series of 32 implanted d-leads. For five d-leads, a CT scan with a mean follow-up of 57 days (range 28–182) was available. All d-leads were implanted with the marker facing anterior and the intention to hit an “iron sight” (ISi) on the X-ray, indicating anterior orientation (i.e., 0° ± 6°). In nine d-leads, an ISi was visible on the final X-ray; median orientation was 1.5° (range 0.5–6.0°) at the first follow-up CT, confirming anterior orientation. In d-leads without ISi or where ISi was not evaluable, the median rotation was 15.5° (9.5–35.0°) and 26.5° (5.5-62.0°), respectively. The orientation of the initial CT was comparable with the orientation determined by the postoperative rotational fluoroscopy and second CT in all d-lead groups. D-lead orientation does not change within the first week after implantation. We provide first indications that d-lead orientation remains stable for several weeks after surgery. Determination of lead orientation using marker-based X-ray alone seems too imprecise; adding the ISi method can increase determination of intraoperative orientation.

Deep brain stimulation (DBS) is currently under research for the treatment of psychiatric disorders, e.g., obsessive-compulsive disorder (OCD) and treatment-resistant depression (TRD). Since the application of DBS in psychiatry has been in use for about 20 years, it is necessary to evaluate its long-term use now. A main issue in the long-term treatment of DBS concerns the effects of a discontinuation of stimulation due to intended as well as unintended reasons. In this contribution, the literature describing discontinuation effects following DBS in OCD and TRD is reviewed. Furthermore, a patient is reported in depth who experienced an unintended discontinuation of supero-lateral medial forebrain bundle (slMFB) DBS for TRD. In this case, the battery was fully depleted without the patient noticing. DBS had led to a sustained response for seven years before discontinuation of stimulation for just several weeks caused a progressive worsening of depression. Altogether, the rapid occurrence of symptom worsening, the absence of a notification about the stimulation status and the difficulties to recapture antidepressant response represent important safety aspects. For a further understanding of the described effects, time courses until worsening of depression as well as biological mechanisms need to be investigated in double-blind controlled trials.

Background and Purpose— Delayed cerebral infarction (DCI) is an important cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Stereotactic catheter ventriculocisternostomy (STX-VCS) and fibrinolytic/spasmolytic lavage is a new method for DCI prevention. Here, we assess the effects of implementing STX-VCS in an unselected aSAH patient population of a tertiary referral center. Methods— Retrospective cohort study of all consecutive aSAH patients admitted to a neurosurgical referral center during a 7-year period (April 2012 to April 2019). Midterm STX-VCS was introduced and offered to patients at high risk for DCI. We compared the incidence and burden of DCI, neurological outcome, and the use of induced hypertension and endovascular rescue therapy in this consecutive aSAH population 3.5 years before versus 3.5 years after STX-VCS became available. Results— Four hundred thirty-six consecutive patients were included: 222 BEFORE and 214 AFTER. Fifty-seven of 214 (27%) patients received STX-VCS. Stereotactic procedures resulted in one (2%) subdural hematoma. Favorable neurological outcome at 6 months occurred in 118 (53%) patients BEFORE and 139 (65%) patients AFTER (relative risk, 0.79 [95% CI, 0.66–0.95]). DCI occurred in 40 (18.0%) patients BEFORE and 17 (7.9%) patients AFTER (relative risk, 0.68 [95% CI, 0.57–0.86]), and total DCI volumes were 8933 (100%) and 3329 mL (36%), respectively. Induced hypertension was used in 97 (44%) and 30 (15%) patients, respectively (relative risk, 0.55 [95% CI, 0.46–0.65]). Thirty (13.5%) patients BEFORE versus 5 (2.3%) patients AFTER underwent endovascular rescue therapies (relative risk, 0.17 [95% CI, 0.07–0.42]). Conclusions— Selecting high-risk patients for STX-VCS reduced the DCI incidence, burden, and related mortality in a consecutive aSAH patient population. This was associated with an improved neurological outcome.

Intraoperative CT imaging is becoming increasingly used, but often little attention is paid to the underlying radiation exposure to the patient. This work showed that the dosimetrically assessed radiation exposure for cervical and lumbar 3D scans with an intraoperative CT is considerably higher than with a 3D C-arm. Therefore, proper selection of the intraoperative 3D imaging system is essential, and further technological developments and dose-saving protocols are warranted to further reduce patient radiation exposure.

Background Intracranial recordings with stereoelectroencephalography (SEEG) aims at defining the epileptogenic zone in patients with pharmacoresistant epilepsy. Currently used techniques for depth electrode implantation include stereotactic frame-based and navigated frameless applications, both either conventional or robot-assisted. Safety and diagnostic effectiveness depend on accuracy of implantation. Objective To evaluate the planning experience, accuracy of stereotactic electrode placement as well as accuracy predictors with the use of latest generation planning software. Methods Retrospective study of 15 consecutive patients who received depth electrodes using the Leksell stereotactic frame, after planning with Elements (Brainlab, Munich, Germany). For each electrode, we calculated the entry point error (EPE) as lateral deviation and target point error (TPE) both as lateral deviation and distance to tip. Multivariate regression analysis and computation of 95% confidence intervals using the bootstrap method were applied for statistical analysis and evaluation of accuracy predictors. Results The mean EPE, lateral deviation at TP and distance to tip at TP were 0.6 0.5 mm, 1.1 0.7 mm and 1.5 0.8 mm respectively. Order of implantation (1-6 vs. >6) is predictor for distance to tip at TP and length of electrode predictor for the lateral deviation at TP. Localization of electrode generally did not correlate to error, but insular electrodes were significantly less accurate than lobar ones. Conclusion Combination of frame-based stereotaxy with latest generation planning software may offer a better planning and implantation experience. Accuracy predictors should be analyzed and be considered for the improvement of accuracy and safety of SEEG implantation methods.

Object: The initial amount of subarachnoid and ventricular blood is an important prognostic factor for outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). In this comparative study of an unselected aSAH-population, we assess the modifiability of these factors by implementation of blood clearance by cisternal lavage. Methods: All patients with aSAH treated in our department between October 2011 and October 2019 (8 years, n = 458) were included in our study. In the first 4-year period (BEFORE, n = 237), patients were treated according to international guidelines. In the second 4-year period (AFTER, n = 221), cisternal lavage methods were available and applied in 72 high-risk patients (32.5%). The cisternal and ventricular blood load was recorded by the Hijdra score. Multivariable regression models were used to assess the prognostic significance of risk factors, including blood load, in relation to common aSAH characteristics in both study groups. Results: Worse neurological outcomes (mRS > 3) occurred in the BEFORE population with 41.45% versus 30.77% in the AFTER cohort, 6 months after aSAH (HR: 1.59, 95% CI 1.08–2.34, p = 0.01). Admission WFNS grade, comorbidities (Charlson Comorbidity Index), herniation signs, concomitant intracerebral hemorrhage, and the development of delayed cerebral infarction were strongly associated with poor outcome in both study groups. Intraventricular and cisternal blood load and, particularly, a cast fourth ventricle (Cast 4) represented strong prognosticators of poor neurological outcome in the BEFORE cohort. This effect was lost after implementation of cisternal lavage (AFTER cohort). Conclusion: Cisternal and ventricular blood load – in particular: a Cast 4 – represent important prognosticators in patients with aSAH. They are, however, amenable to modification by blood clearing therapies.

BackgroundTo establish a practical risk chart for prediction of delayed cerebral infarction (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) by using information that is available until day 5 after ictus.MethodsWe assessed all consecutive patients with aSAH admitted to our service between September 2008 and September 2015 (n = 417). The data set was randomly split into thirds. Two-thirds were used for model development and one-third was used for validation. Characteristics that were present between the bleeding event and day 5 (i.e., prior to >95% of DCI diagnoses) were assessed to predict DCI by using logistic regression models. A simple risk chart was established and validated.ResultsThe amount of cisternal and ventricular blood on admission CT (Hijdra sum score), early sonographic vasospasm (i.e., mean flow velocity of either intracranial artery >160 cm/s until day 5), and a simplified binary level of consciousness score until day 5 were the strongest predictors of DCI. A model combining these predictors delivered a high predictive accuracy [the area under the receiver operating characteristic (AUC) curve of 0.82, Nagelkerke's R2 0.34 in the development cohort]. Validation of the model demonstrated a high discriminative capacity with the AUC of 0.82, Nagelkerke's R2 0.30 in the validation cohort.ConclusionAdding level of consciousness and sonographic vasospasm between admission and postbleed day 5 to the initial blood amount allows for simple and precise prediction of DCI. The suggested risk chart may prove useful for selection of appropriate candidates for interventions to prevent DCI.

Hypothalamische Hamartome (HH) sind seltene, nichtneoplastische Anlagestorungen, die sich typischerweise durch gelastische Anfalle manifestieren und eine kausale Rolle bei den mit ihnen assoziierten Anfallen spielen. Da eine medikamentose Therapie meist erfolglos ist, ist eine fruhe chirurgische bzw. interventionelle Therapie sinnvoll. Offene Operationen haben hohe Komplikationsraten und werden mehr und mehr verlassen. Bei endoskopischen Operationen konnte gezeigt werden, dass die Diskonnektion des HH ein wichtiger Teil der Operation ist und oft ausreicht, um eine Anfallsfreiheit zu erreichen. Weniger invasive Verfahren wir die Radiochirurgie und Brachytherapie sind komplikationsarme Behandlungsoptionen. Die besten Raten an Anfallsfreiheit wurden bei lasionierenden Verfahren durch stereotaktisch gefuhrte Laser- oder Radiofrequenzablation beschrieben. Um die Komplikationsrate dieser Verfahren zu minimieren, ist es sinnvoll, das Ziel der Diskonnektion und nicht zwingend der Destruktion der Lasion zu verfolgen.

Delayed cerebral infarction (DCI) contributes to the burden of morbidity and mortality acquired by patients with aneurysmal subarachnoid hemorrhage (SAH). Cisternal lavage may prevent DCI. Delivery of lavage therapy to the basal cisterns, however, is challenging. Here, we report a novel method for the delivery of cisternal lavage using a cisterno-ventricular catheter (CVC) inserted via the fenestrated lamina terminalis during aneurysm clipping. In two high-risk aSAH patients a CVC was inserted into the third ventricle through the fenestrated lamina terminalis during aneurysm clipping. Post-operatively, continuous cisternal lavage using Urokinase or Nimodipine was applied using an external ventricular drain (EVD) as inflow tract and the CVC as outflow tract. Neurological outcome at 6 months was assessed by modified Rankin scale. Catheter placement into the third ventricle through the fenestrated lamina terminalis was performed without complications. Application of a free-running electrolyte solution containing Urokinase or Nimodipine via the EVD and drainage via the CVC was feasible. Cisternal Nimodipine application normalized sonographic vasospasm in both cases. DCI did not occur. CVC placement for ventriculo-cisternal lavage may represent a useful method for DCI prevention. It can be considered in aSAH patients at risk for DCI if the chiasmatic region is accessed during aneurysm clipping.

Delayed Cerebral Infarction (DCI) due to Cerebral Vasospasm (CVS) is an important contributor to poor outcome after aneurysmal subarachnoid haemorrhage (aSAH). Despite established risk factors CVS and DCI are unpredictable at the individual patient level. Efficient treatments are lacking. We report a novel rescue therapy for DCI: Access to the basal cisterns by stereotactic catheter ventriculocisternostomy (STX-VCS) and direct cisternal application of the spasmolytic agent Nimodipine. On the basis of individual treatment decisions three aSAH patients who developed CVS underwent STX-VCS. Continuous lavage with Nimodipine was performed. CVS was assessed by daily transcranial doppler ultrasonography. Neurological outcome at 3 months was assessed by modified Rankin scale. STX-VCS was performed without complications in all patients. CVS rapidly resolved upon cisternal application of Nimodipine. CVS recurred in two patients upon interruption of Nimodpine application and resolved upon restart of Nimodipine. DCI did not occur in all three cases. STX-VCS and cisternal Nimodipine application is a novel rescue therapy for CVS treatment and DCI-prevention in patients with aSAH.

Background Automatic segmentation is gaining relevancy in image-based targeting of neural structures. Objective To evaluate its feasibility, we retrospectively analyzed the concordance of magnetic resonance imaging (MRI)-based automatic segmentation of the subthalamic nucleus (STN) and intraoperative microelectrode recordings (MERs). Methods Electrodes (n = 60) for deep brain stimulation were implanted in the STN of patients (n = 30; median age 57 yr) with Parkinson disease (n = 29) or rapid-onset dystonia parkinsonism (n = 1). Elements (Brainlab, Munich, Germany) were used to segment the STN, using 2 volumetric T1 (±contrast) and volumetric T2 images as input. The stereotactic computed tomography was coregistered with the imaging, and the original stereotactic coordinates were imported. MERs (0.5-1 mm steps) along the anterior, central, and lateral trajectories were used to determine differences between the image-segmented STN boundary and MER-based STN entry and exit. Results Of 175 trajectories, 105 penetrated or touched (≤0.7 mm) the STN. The overall median deviation between the segmented STN boundary and electrophysiological recordings was 1.1 mm for MER-based STN entry and 2.0 mm for STN exit. Regarding the entry point of the STN, there was no statistically significant difference between MRI-based automatic segmentation and the electrophysiological trajectories analyzed with intraoperative MER. The exit point was significantly different between both methods in the central and lateral trajectories. Conclusion MRI-based automatic segmentation of the STN is a viable, patient-specific targeting approach that can be used alongside traditional targeting methods in deep brain stimulation to support preoperative planning and visualization of target structures and aid postoperative optimization of programming.

Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative and neuroinflammatory diseases of the central nervous system1-4. These highly diverse and specialized functions may be executed by subsets of microglia that already exist in situ, or by specific subsets of microglia that develop from a homogeneous pool of cells on demand. However, little is known about the presence of spatially and temporally restricted subclasses of microglia in the central nervous system during development or disease. Here we combine massively parallel single-cell analysis, single-molecule fluorescence in situ hybridization, advanced immunohistochemistry and computational modelling to comprehensively characterize subclasses of microglia in multiple regions of the central nervous system during development and disease. Single-cell analysis of tissues of the central nervous system during homeostasis in mice revealed specific time- and region-dependent subtypes of microglia. Demyelinating and neurodegenerative diseases evoked context-dependent subtypes of microglia with distinct molecular hallmarks and diverse cellular kinetics. Corresponding clusters of microglia were also identified in healthy human brains, and the brains of patients with multiple sclerosis. Our data provide insights into the endogenous immune system of the central nervous system during development, homeostasis and disease, and may also provide new targets for the treatment of neurodegenerative and neuroinflammatory pathologies.

For specific indications in neurosurgery, such as the removal of brain tumors in eloquent locations and the deep brain stimulation, awake craniotomy offers multiple advantages. However, due to the severe discomfort experienced during burr-hole drilling, patients are hesitant to opt for awake craniotomy. Laser systems provide an alternative to surgical drills as a silent and vibration-free bone cutting method. Until now no laser system achieved adequate ablation rates (> 2:5mm3/s) at sufficiently high aspect ratio (>5) to fulfill the requirements for craniotomy. The aim of this study is to investigate the ablation of bone tissue under the needs for neurosurgery using three different Q-switched infrared laser sources assisted by a water spray system. One of the laser sources is a commercial Q-switched CO2 laser system operating at 10:6 μm with a pulse energy of 4 mJ. In addition, two in-house developed, short-pulsed IR-laser sources operating at 2:91 μm (Cr:ZnSe) with a pulse energy of 0:76mJ and at 1:9 μm (Tm:YLF) with a pulse energy of 2:2mJ are investigated. The results show that highly efficient bone ablation with the CO2 laser at rates of 6mm3/s is possible without carbonization. With an ablation strategy using the effect of multiple reflections inside the kerf an aspect ratio of 17 was achieved for narrow incisions at widths smaller than 100 μm. Another ablation strategy shows a twofold higher ablation depth shifting the laser focus stepwise into propagation direction. Even though a high ablation efficiency can be achieved with the Cr:ZnSe laser source and the CO2 laser source, the Cr:ZnSe laser cannot fulfill the required ablation rates. The CO2 laser shows a fast ablation in significant depth with a maximum depth of 7 mm. Further investigations will concentrate on increasing the ablation depth to 10 mm.

Interictal epileptiform discharges (IEDs) are a widely used biomarker in patients with epilepsy but lack specificity. It has been proposed that there are truly epileptogenic and less pathological or even protective IEDs. Recent studies suggest that highly pathological IEDs are characterized by high-frequency oscillations (HFOs). Here, we aimed to dissect these ‘HFO-IEDs’ at the single-neuron level, hypothesizing that the underlying mechanisms are distinct from ‘non-HFO-IEDs’. Analysing hybrid depth electrode recordings from patients with temporal lobe epilepsy, we found that single-unit firing rates were higher in HFO- than in non-HFO-IEDs. HFO-IEDs were characterized by a pronounced pre-peak increase in firing, which coincided with the preferential occurrence of HFOs, whereas in non-HFO-IEDs, there was only a mild pre-peak increase followed by a post-peak suppression. Comparing each unit’s firing during HFO-IEDs to its baseline activity, we found many neurons with a significant increase during the HFO component or ascending part, but almost none with a decrease. No such imbalance was observed during non-HFO-IEDs. Finally, comparing each unit’s firing directly between HFO- and non-HFO-IEDs, we found that most cells had higher rates during HFO-IEDs and, moreover, identified a distinct subset of neurons with a significant preference for this IED subtype. In summary, our study reveals that HFO- and non-HFO-IEDs have different single-unit correlates. In HFO-IEDs, many neurons are moderately activated, and some participate selectively, suggesting that both types of increased firing contribute to highly pathological IEDs.

Spatial navigation and memory rely on neural systems that encode places, distances, and directions in relation to the external world or relative to the navigating organism. Place, grid, and head-direction cells form key units of world-referenced, allocentric cognitive maps, but the neural basis of self-centered, egocentric representations remains poorly understood. Here, we used human single-neuron recordings during virtual spatial navigation tasks to identify neurons providing a neural code for egocentric spatial maps in the human brain. Consistent with previous observations in rodents, these neurons represented egocentric bearings towards reference points positioned throughout the environment. Egocentric bearing cells were abundant in the parahippocampal cortex and supported vectorial representations of egocentric space by also encoding distances towards reference points. Beyond navigation, the observed neurons showed activity increases during spatial and episodic memory recall, suggesting that egocentric bearing cells are not only relevant for navigation but also play a role in human memory.

Objective(s). Intracerebral hemorrhage (ICH) contributes considerably to the high morbidity and mortality of aneurysmal subarachnoid hemorrhage (aSAH). Specific patterns of aSAH-associated ICH that are not compatible with favorable outcome remain unknown. The main objective of this study is to report patterns of aSAH-associated ICH that result in unfavorable outcomes. Methods. This is a retrospective analysis of 1036 consecutive aSAH patients admitted to an academic neurosurgical center in a 15-year period (01/2005-12/2019). Admission imaging was investigated for presence, location and size of intracerebral hemorrhage. The rates of favorable outcome at 6 months (modified Rankin Scale) relative to ICH location and volume were analyzed to identify patterns of ICH which were incompatible with favorable outcome. Results. 284 of 1036 patients (27.4%) suffered from aSAH-related ICH. The median ICH volume was 14.0 ml. Outcome of patients with ICH < 10 ml was comparable to patients without ICH. ICH volumes > 10 ml were associated with worse outcomes. We identified the fronto-basal brain to tolerate even larger ICH without compromise of neurological outcomes. ICH located in the frontal, fronto-insular, temporo-insular and temporal regions were associated with intermediate prognoses as outcome declined with larger ICH volumes. ICH located in the basal ganglia, cerebellum, corpus callosum and bifrontal ICH were associated with particularly poor outcomes irrespective of ICH volumes. Conclusion. aSAH-associated ICH of the basal ganglia, cerebellum, corpus callosum and bifrontal brain are associated with exceptionally poor outcomes. ICH volume alone is insufficient for prognostic considerations.

Background Percutaneous rhizotomy of the Gasserian ganglion for trigeminal neuralgia is an effective therapeutic procedure. Yet, landmark-guided cannulation of the foramen ovale is manually challenging and difficult to learn. Objective To overcome these limitations, we assessed the feasibility and accuracy of an augmented reality (AR)-guided puncture of the foramen ovale. Methods A head phantom with soft tissue structures of the facial area was built. A three-dimensional (3D)-dataset of the phantom was generated using a stereotactic planning workstation. An optimal trajectory to the foramen ovale was created and then transferred to an AR headset. A total of 2 neurosurgeons and 2 neuroradiologists independently performed 8 AR-guided and 8 landmark-guided cannulations of the foramen ovale, respectively. For each AR-guided cannulation, the hologram was manually aligned with the phantom. Accuracy of the cannulation was evaluated using the Euclidean distance to the target point as well as the lateral deviation of the achieved trajectory from the planned trajectory at target point level. Results With the help of AR guidance, a successful cannulation of the foramen ovale was achieved in 90.6% compared to the purely landmark-based method with 18.8%. Euclidean distance and lateral deviation were significantly lower with AR guidance than landmark guidance (P Conclusion AR greatly improved accuracy of simulated percutaneous rhizotomy of the Gasserian ganglion.

Craniopharyngiomas are typically located in the sellar region and frequently contain space-occupying cysts. They usually cause visual impairment and endocrine disorders. Due to the high potential morbidity associated with radical resection, several less invasive surgical approaches have been developed. This study investigated stereotactic-guided implantation of cysto-ventricular catheters (CVC) as a new method to reduce and control cystic components. Twelve patients with cystic craniopharyngiomas were treated with CVC in our hospital between 04/2013 and 05/2017. The clinical and radiological data were retrospectively analysed to evaluate safety aspects as well as ophthalmological and endocrine symptoms. The long-term development of tumour and cyst volumes was assessed by volumetry. The median age of our patients was 69.0 years and the median follow-up period was 41.0 months. Volumetric analyses demonstrated a mean reduction of cyst volume of 64.2% after CVC implantation. At last follow-up assessment, there was a mean reduction of cyst volume of 92.0% and total tumour volume of 85.8% after completion of radiotherapy. Visual acuity improved in 90% of affected patients, and visual field defects improved in 70% of affected patients. No patient showed ophthalmological deterioration after surgery, and endocrine disorders remained stable. Stereotactic implantation of CVC proved to be a safe minimally invasive method for the long-term reduction of cystic components with improved ophthalmological symptoms. The consequential decrease of total tumour volumes optimised conditions for adjuvant radiotherapy. Given the low surgical morbidity and the effective drainage of tumour cysts, this technique should be considered for the treatment of selected cystic craniopharyngiomas.

Knowing the orientation of directional deep brain stimulation electrodes enables imaging-based adjustment of the stimulation settings. A rotational X-ray based examination was developed to determine the electrodes orientation. By identifying the patient´s 0° axis and the electrode´s rotation using the “iron sights”-sign, the exact orientation of the electrode in relation to the ACPC-line is given. The presented imaging approach offers a reliable diagnostic tool for visualization of the implanted DBS electrode orientation in clinical routine.