Die in-vivo-Effekte von "Pigment Epithelium-derived Factor" (PEDF) auf die Neurogenese im Rattengehirn nach experimentellem Hirntrauma

Fragestellung: Das Schädelhirntrauma (SHT) ist weltweit eine Hauptursache für Morbidität und Mortalität. In Deutschland wird bei 34,5 % aller Patienten mit schwerem SHT eine ungünstige Prognose, d.h. Tod oder ein Status vegetativus, beobachtet. Das Gehirn ist in der Lage, sich durch die Proliferation und Differenzierung endogener Progenitoren selbst zu regenerieren, sofern das molekulare Mikromilieu geeignete Vorraussetzungen bietet. Der Pigment Epithelium-derived Factor (PEDF) ist ein potenter antiangiogener und Tumor-differenzierender Faktor, der zugleich neuroprotektive und neuronal differenzierende Eigenschaften aufweist. Bisher wurden die neurotrophen Effekte von PEDF vornehmlich an in vitro-Experimenten nachgewiesen. Die vorliegende Studie hat zum Ziel, die Bioeffekte von PEDF auf die neuronalen Stammzellen der subventrikulären Zone (SVZ) und der subgranulären Zone (SGZ) des Gyrus dentatus (DG) des Hippocampus (HC) an Tieren zu untersuchen, die einem experimentellen SHT unterzogen worden sind. Weiter ist von Interesse, ob PEDF Einfluss auf die Größe und Zellproliferation des Läsionsareals nimmt. Material und Methodik: Als Versuchstiere dienten 35 männliche Fischer-Ratten mit einem Körpergewicht (KG) von 240-270 g. 30 Ratten wurden einer kontrollierten kortikalen Kontusion (CCII) unterzogen, weitere 5 Tiere (iCON) wurden ohne Trauma oder spezielle Behandlung als Kontrollgruppe eingesetzt. Die Behandlungs-Kontrollgruppe (Lx; n = 9) wurde kontusioniert, erfuhr jedoch keine zusätzliche Behandlung. Den übrigen Tieren wurde während einer Versuchsphase von 8 Tagen über eine miniosmotische Pumpe intraventrikulär PEDF infundiert, entweder in der Konzentration (Konz.) von 5 µg/ml (PEDF 5; n = 7) oder von 10 µg/ml (PEDF 10; n = 8). Den Kontrolltieren (aCSF; n = 6) wurde artifizieller zerebrospinaler Liquor als Vehikel infundiert. Zur Analyse der DNA-Synthese wurde allen Versuchstieren vom Versuchsbeginn am Tag 1 an (CCII; Pumpenimplantation) täglich 5’-Bromo-2’-Deoxyuridin (BrdU) (50 mg/kg KG) injiziert. Nach 8 Tagen wurde die Versuchsreihe durch transkardiale Perfusion beendet, und die Gehirne wurden zur histologischen Untersuchung aufbereitet. Die Ausdehnung des Läsionsareals wurde mit einer Kresylviolett (CV)-Färbung dargestellt und anschließend durch die immunhistochemischen Anfärbung mit den Markern BrdU und ED1 untersucht. Die Analyse der Stammzell-Proliferation erfolgte immunhistochemisch mit BrdU und Doublecortin (DCX); ED1 diente der Darstellung inflammatorischer Reaktionen, BrdU detektierte stattgehabte DNA-Synthese und DCX frühe neuronale Vorläuferzellen. Ergebnisse: Die Ausdehnung des Kontusionsareals war in allen Behandlungsgruppen nahezu identisch. PEDF-behandelte Tiere wiesen keine Zeichen der Toxizität auf. Auch das Ausmaß der inflammatorischen Reaktion zeigte keine signifikanten Unterschiede zwischen den Behandlungsgruppen. Allerdings wurden nach Behandlung mit PEDF dosisabhängig vermehrt BrdU-gelabelte Zellen in der SVZ nachgewiesen. Der Nachweis der Signifikanz und der Beweis, ob es sich bei den BrdU-positiven proliferierenden Zellen möglicherweise um sich aktiv teilende Glial Fibrillary Acidic Protein (GFAP)-positive Typ B-Stammzellen handeln könnte, bleibt weiterführend durch eine Doppelfärbung GFAP/BrdU zu erbringen. Schlussfolgerung: Es fanden sich keinerlei Anzeichen für eine toxische Schädigung der PEDF-behandelten Tiere, was für eine gute Verträglichkeit der Methodik per se und somit für die potentielle Option einer klinischen Anwendbarkeit spricht. Wenngleich die Ausdehnung des Läsionsareals nach CCII nicht positiv beeinflusst wurde, lassen die vorliegenden Daten vermuten, dass die Infusion von PEDF eine proliferationsfördernde Wirkung auf die neuronalen Stammzellen der SVZ hat. Dies könnte letztlich eine gesteigerte Neurogenese nach SHT induzieren

Factors influencing the reliability of intraoperative testing in deep brain stimulation for Parkinson’s disease

Background Several meta-analyses comparing the outcome of awake versus asleep deep brain stimulation procedures could not reveal significant differences concerning the postoperative improvement of motor symptoms. Only rarely information on the procedural details is provided for awake operations and how often somnolence and disorientation occurred, which might hamper the reliability of intraoperative clinical testing. The aim of our study was to investigate possible influencing factors on the occurrence of somnolence and disorientation in awake DBS procedures. Methods We retrospectively analyzed 122 patients with Parkinson's disease having received implantation of a DBS system at our centre. Correlation analyses were performed for the duration of disease prior to surgery, number of microelectrode trajectories, AC-PC-coordinates of the planned target, UPDRS-scores, intraoperative application of sedative drugs, duration of the surgical procedure, perioperative application of apomorphine, and the preoperative L-DOPA equivalence dosage with the occurrence of intraoperative somnolence and disorientation. Results Patients with intraoperative somnolence were significantly older (p=0.039). Increased duration of the DBS procedure (p=0.020), delayed start of the surgery (p=0.049), higher number of MER trajectories (p=0.041), and the patients’ % UPDRS improvement (p=0.046) also correlated with the incidence of intraoperative somnolence. We identified the main contributing factor to intraoperative somnolence as the use of sedative drugs applied during skin incision and burr hole trepanation (p=0.019). Perioperatively applied apomorphine could reduce the occurrence of somnolent phases during the operation (p=0.026). Conclusion Several influencing factors were found to seemingly increase the risk of intraoperative somnolence and disorientation, while the use of sedative drugs seems to be the main contributing factor. We argue that awake DBS procedures should omit the use of sedatives for best clinical outcome. When reporting on awake DBS surgery these factors should be considered and adjusted for, to permit reliable interpretation and comparison of DBS study results

Impact of bedside percutaneous dilational and open surgical tracheostomy on intracranial pressure, pulmonary gas exchange, and hemodynamics in neurocritical care patients

Aim was to compare the impact of bedside percutaneous dilational tracheostomy (PDT) and open surgical technique (ST) on intracranial pressure (ICP), pulmonary gas exchange and hemodynamics. We retrospectively analyzed data of 92 neurocritical care patients with invasive ICP monitoring during either PDT (43 patients) or ST (49 patients). Peak ICP levels were higher during PDT (22 [17-38] mm Hg vs 19 [13-27] mm Hg, P=.029). Mean oxygen saturation (SpO(2)) and end-tidal carbon dioxide partial pressure (etCO(2)) did not differ. Episodes with relevant desaturation (SpO(2)50mm Hg) occurred rarely (5/49 during ST vs 3/43 during PDT for SpO(2)<90%; 2/49 during ST vs 5/43 during PDT for hypercapnia). Drops in mean arterial pressure (MAP) below 60mm Hg were seen more often during PDT (8/43 vs 2/49, P=. 026). Mean infusion rate of norepinephrine did not differ (0.52mg/h during ST vs 0.45mg/h during PDT). No fatal complications were observed. Tracheostomy can be performed as ST and PDT safely in neurocritical care patients. The impact on ICP, pulmonary gas exchange and hemodynamics remains within an unproblematic range

The endogenous neuropeptide calcitonin gene-related peptide after spontaneous subarachnoid hemorrhage–A potential psychoactive prognostic serum biomarker of pain-associated neuropsychological symptoms

Background: The pronociceptive neuromediator calcitonin gene-related peptide (CGRP) is associated with pain transmission and modulation. After spontaneous subarachnoid hemorrhage (sSAH), the vasodilatory CGRP is excessively released into cerebrospinal fluid (CSF) and serum and modulates psycho-behavioral function. In CSF, the hypersecretion of CGRP subacutely after good-grade sSAH was significantly correlated with an impaired health-related quality of life (hrQoL). Now, we prospectively analyzed the treatment-specific differences in the secretion of endogenous CGRP into serum after good-grade sSAH and its impact on hrQoL. Methods: Twenty-six consecutive patients (f:m = 13:8; mean age 50.6 years) with good-grade sSAH were enrolled (drop out n = 5): n = 9 underwent endovascular aneurysm occlusion, n = 6 microsurgery, and n = 6 patients with perimesencephalic SAH received standardized intensive medical care. Plasma was drawn daily from day 1 to 10, at 3 weeks, and at the 6-month follow-up (FU). CGRP levels were determined with competitive enzyme immunoassay in duplicate serum samples. All patients underwent neuropsychological self-report assessment after the onset of sSAH (t1: day 11–35) and at the FU (t2). Results: During the first 10 days, the mean CGRP levels in serum (0.470 ± 0.10 ng/ml) were significantly lower than the previously analyzed mean CGRP values in CSF (0.662 ± 0.173; p = 0.0001). The mean serum CGRP levels within the first 10 days did not differ significantly from the values at 3 weeks (p = 0.304). At 6 months, the mean serum CGRP value (0.429 ± 0.121 ng/ml) was significantly lower compared to 3 weeks (p = 0.010) and compared to the first 10 days (p = 0.026). Higher mean serum CGRP levels at 3 weeks (p = 0.001) and at 6 months (p = 0.005) correlated with a significantly poorer performance in the item pain, and, at 3 weeks, with a higher symptom burden regarding somatoform syndrome (p = 0.001) at t2. Conclusion: Our study reveals the first insight into the serum levels of endogenous CGRP in good-grade sSAH patients with regard to hrQoL. In serum, upregulated CGRP levels at 3 weeks and 6 months seem to be associated with a poorer mid-term hrQoL in terms of pain. In migraineurs, CGRP receptor antagonists have proven clinical efficacy. Our findings corroborate the potential capacity of CGRP in pain processing

Surgical resection of sporadic and hereditary hemangioblastoma: Our 10-year experience and a literature review

Background: Hemangioblastomas (HBLs) are benign neoplasms that contribute to 1-2.5% of intracranial tumors and 7-12% of posterior fossa lesions in adult patients. HBLs either evolve hereditarily in association with von Hippel-Lindau disease (vHL) or, more prevalently, as solitary sporadic tumors. Only few authors have reported on the clinical presentation and the neurological outcome of HBL. Methods: We retrospectively analyzed the clinical, radiological, surgical, and histopathologic records of 24 consecutive patients (11 men, 13 women; mean age 51.3 years) with HBL of the posterior cranial fossa, who had been treated at our center between 2001 and 2012. We reviewed the current literature, and discussed our findings in the context of previous publications on HBL. The study protocol was approved by the local ethics committee (14-101-0070). Results: Mean time to diagnosis was 14 weeks. The extent of resection (EOR) was total in 20 and near total in 4 patients. Four patients required revision within 24 h because of relevant postoperative bleeding. One patient died within 14 days. One patient required permanent shunting. At discharge, 75% of patients [n = 18, modified Rankin scale (mRS) 0-1] showed no or at least resolved symptoms. Mean follow-up was 21 months. Two recurrences were detected during follow-up. Conclusions: In comparison to other benign entities of the posterior fossa, time to diagnosis was significantly shorter for HBL. This finding indicates the rather aggressive biological behavior of these excessively vascularized tumors. In our series, however, the rate of complete resection was high, and morbidity and mortality rates were within the reported range

Vasoplegic Syndrome after Oral Nimodipine Application in Patients with Subarachnoid Hemorrhage

the underlying aneurysm leading to decrease of immediate complications such as rebleeding, cerebral vasospasm remains the major cause for mortality and morbidity after subarachnoid hemorrhage. The only FDA approved drug for treatment of cerebral vasospasm is the calcium antagonist Nimodipine that has shown beneficial effects on outcome. It is safe, cost efficient and the most widely studied drug for treatment of cerebral vasospasm. But it has reported side effects such as systemic hypotension, especially when used intravenously. The present paper reports about the occurence of severe systemic catecholamine refractory hypotension after oral application of the standard dosage of 60 mg nimodipine. In those patients we were only able to establish a sufficient arterial blood pressure after application of methylene blue suggesting that at least part of the underlying mechanism was NO related vasoplegia. Keeping in mind that vasoplegia can occur even after oral nimodipine application we suggest that there should be a test dosage of 15-30 mg nimodipine applied to evaluate the impact on each patient and avoid potential lethal hypotension

Treatment of spontaneous subarachnoid hemorrhage and self-reported neuropsychological performance at 6 months &#8211; results of a prospective clinical pilot study on good-grade patients

AIM: Limited focus has been placed on neuropsychological patient profiles after spontaneous subarachnoid hemorrhage (sSAH). We conducted a prospective controlled study in good-grade sSAH patients to evaluate the time course of treatment-specific differences in cognitive processing after sSAH. MATERIAL and METHODS: Twenty-six consecutive sSAH patients were enrolled (drop out n=5). Nine patients received endovascular aneurysm occlusion (EV), 6 patients were treated microsurgically (MS), and 6 patients with perimesencephalic SAH (pSAH) underwent standardized intensive medical care. No patient experienced serious vasospasm-related ischemic or hemorrhagic complications. All patients were subjected to neuropsychological self-report assessment (36-Item Short Form Health Survey and ICD-10-Symptom-Rating questionnaire) subacutely (day 11 - 35) after the onset of bleeding (t 1) and at the 6-month follow-up (FU; t 2). RESULTS: From t 1 to t 2, MS and EV patients significantly improved in physical functioning (Pfi; p=.001 each) and the physical component summary (p=.010 vs. p=.015). Bodily pain (Pain; MS p=.034) and general health perceptions (EV p=.014) significantly improved, and nutrition disorder (EV p=.008) worsened. At FU, MS patients reported significantly better Pfi (vs. EV p=.046), less Pain (vs. EV p=.040), and more depression (vs. pSAH p=.035). Group-rate analyses of test differences showed a significant alleviation in nutrition disorder in MS (vs. EV p=.009). CONCLUSION: All sSAH groups reported a significant deterioration in health. Though both MS and EV patients, improved in several physical items over time, our data suggest a better short-term Pfi, less Pain and improved nutrition disorder in surgically treated patients. pSAH patients performed significantly better in various aspects of physical and psychological functioning than patients with aneurysmal SAH

Endogenous calcitonin gene-related peptide in cerebrospinal fluid and early quality of life and mental health after good-grade spontaneous subarachnoid hemorrhage – A feasibility series

The vasodilatory calcitonin gene-related peptide (CGRP) is excessively released after spontaneous subarachnoid hemorrhage (sSAH) and modulates psycho-behavioral function. In this pilot study, we prospectively analyzed the treatment-specific differences in the secretion of endogenous CGRP into cerebrospinal fluid (CSF) during the acute stage after good-grade sSAH and its impact on self-reported health-related quality of life (hrQoL). Twenty-six consecutive patients (f:m = 13:8; mean age 50.6 years) with good-grade sSAH were enrolled (drop out 19% (n = 5)): 35% (n = 9) underwent endovascular aneurysm occlusion, 23% (n = 6) microsurgery, and 23% (n = 6) of the patients with perimesencephalic SAH received standardized intensive medical care. An external ventricular drain was inserted within 72 h after the onset of bleeding. CSF was drawn daily from day 1-10. CGRP levels were determined via competitive enzyme immunoassay and calculated as "area under the curve" (AUC). All patients underwent a hrQoL self-report assessment (36-Item Short Form Health Survey (SF-36), ICD-10-Symptom-Rating questionnaire (ISR)) after the onset of sSAH (t(1): day 11-35) and at the 6-month follow-up (t(2)). AUC CGRP (total mean +/- SD, 5.7 +/- 1.8 ng/ml/24 h) was excessively released into CSF after sSAH. AUC CGRP levels did not differ significantly when dichotomizing the aSAH (5.63 +/- 1.77) and pSAH group (5.68 +/- 2.08). aSAH patients revealed a higher symptom burden in the ISR supplementary item score (p = 0.021). Multiple logistic regression analyses corroborated increased mean levels of AUC CGRP in CSF at t(1)as an independent prognostic factor for a significantly higher symptom burden in most ISR scores (compulsive-obsessive syndrome (OR 5.741,p = 0.018), anxiety (OR 7.748,p = 0.021), depression (OR 2.740,p = 0.005), the supplementary items (OR 2.392,p = 0.004)) and for a poorer performance in the SF-36 physical component summary score (OR 0.177,p = 0.001). In contrast, at t(2), CSF AUC CGRP concentrations no longer correlated with hrQoL. To the best of our knowledge, this study is the first to correlate the levels of endogenous CSF CGRP with hrQoL outcome in good-grade sSAH patients. Excessive CGRP release into CSF may have a negative short-term impact on hrQoL and emotional health like anxiety and depression. While subacutely after sSAH, higher CSF levels of the vasodilator CGRP are supposed to be protective against vasospasm-associated cerebral ischemia, from a psychopathological point of view, our results suggest an involvement of CSF CGRP in the dysregulation of higher integrated behavior

Excessive release of endogenous neuropeptide Y into cerebrospinal fluid after treatment of spontaneous subarachnoid haemorrhage and its possible impact on self-reported neuropsychological performance – results of a prospective clinical pilot study on good-grade patients

Objectives: Neuropsychological dysfunction after treatment of spontaneous subarachnoid haemorrhage (sSAH) is common but underreported. The vasoconstrictor neuropeptide Y (NPY) is excessively released after sSAH and in psychiatric disorders. We prospectively analysed the treatment-specific differences in the secretion of endogenous cerebrospinal fluid (CSF) NPY during the acute stage after sSAH and its impact on cognitive processing. Methods: A total of 26 consecutive patients (f:m = 13:8; mean age 50.6 years) with good-grade sSAH were enrolled (drop out n = 5): n = 9 underwent endovascular aneurysm occlusion, n = 6 microsurgery, and n = 6 patients with perimesencephalic SAH received standardized intensive medical care. Ventricular CSF was drawn daily from day 1-10. CSF NPY levels were determined with competitive enzyme immunoassay. All patients underwent neuropsychological self-report assessment [36-Item Short Form Health Survey (SF-36) and ICD-10-Symptom-Rating questionnaire (ISR)] after the onset of sSAH (day 11-35; t(1)) and at the 6-month follow-up (t(2)). Results: At t(1), increased mean levels of NPY in CSF significantly correlated with impaired performance in most ISR scores (ISR total p = .018, depression p = .035, anxiety p = .008, nutrition disorder p = .047, supplementary items p = .038) and in several psychological SF-36 items (vitality p = .019, general mental health p = .001, mental component summary p = .025). Discussion: To the best of our knowledge, this study is the first to correlate the levels of endogenous NPY in supratentorial CSF with cognitive outcome in good-grade sSAH patients. Excessive NPY release into CSF may have a short-term influence on the pathogenesis of neuropsychological deficits. The impact of cerebrovascular manipulation on NPY release has to be further elucidated

Treatment of Unruptured Intracranial Aneurysms and Cognitive Performance: Preliminary Results of a Prospective Clinical Trial

BACKGROUND: Few studies have addressed the effect of treatment of unruptured intracranial aneurysm (UIA) on cognitive function. OBJECTIVE: Neuropsychological assessment after UIA treatment is underreported, and prospective trials have repeatedly been demanded. In 2014, we conducted a prospective controlled study to evaluate the differences in cognitive processing caused by the treatment of anterior circulation UIAs. PATIENTS AND METHODS: Thirty patients were enrolled until September 2015. Ten patients received endovascular aneurysm occlusion (EV), 10 patients were treated microsurgically (MS), and 10 patients with surgically treated degenerative lumbar spine disease (LD) served as control. All patients underwent extended standardized neuropsychological assessment before (t(1)) and 6 weeks after treatment (t(2)). Tests included verbal, visual, and visuospatial memory, psychomotor functioning, executive functioning, and its subdomains verbal fluency and cognitive flexibility. We statistically evaluated intragroup and intergroup changes. RESULTS: Intragroup comparisons and group-rate analysis showed no significant impairment in overall neuropsychological performance, either postinterventionally or postoperatively. However, the postoperative performance in cognitive processing speed, cognitive flexibility, and executive functioning was significantly worse in the MS group than in the EV (P=0.038) and LD group (P=0.02). Compared with the EV group, patients with MS showed significant postoperative impairment in a subtest for auditory-verbal memory (Wechsler Memory Scale, Fourth Edition, Logical Memory II; MS vs. EV P=0.011). The MS group trended toward posttreatment impairment in subtests for verbal fluency and semantic memory (Regensburg Word Fluency Test; MS vs. EV P=0.083) and in auditory-verbal memory (Wechsler Memory Scale, Fourth Edition, Logical Memory II; MS vs. LD P=0.06). CONCLUSIONS: Our preliminary data showed no effect of anterior circulation UIA treatment on overall neuropsychological function but impaired short-term executive processing in surgically treated patients