Pharmacokinetic Modeling of Intra-arterial Nimodipine Therapy for Subarachnoid Hemorrhage-Related Cerebral Vasospasm.

PURPOSE: Intra-arterial (IA) administration of nimodipine has been shown to be an effective treatment for subarachnoid hemorrhage-related cerebral vasospasm. The concentrations achieved in cerebral arteries during this procedure, though, are unknown. Therefore, there are no clinical studies investigating dose-dependent effects of nimodipine. We aimed at providing a pharmacokinetic model for IA nimodipine therapy for this purpose. METHODS: A two-compartment pharmacokinetic model for intravenous nimodipine therapy was modified and used to assess cerebral arterial nimodipine concentration during IA nimodipine infusion into the internal carotid artery (ICA). RESULTS: According to our simulations, continuous IA nimodipine infusion at 2 mg/h and 1 mg/h resulted in steady-state cerebral arterial concentrations of about 200 ng/ml and 100 ng/ml assuming an ICA blood flow of 200 ml/min and a clearance of 70 l/h. About 85 % of the maximal concentration is achieved within the first minute of IA infusion independent on the infusion dose. Within the range of physiological and pharmacokinetic data available in the literature, ICA blood flow has more impact on cerebral arterial concentration than nimodipine clearance. CONCLUSION: The presented pharmacokinetic model is suitable for estimations of cerebral arterial nimodipine concentration during IA infusion. It may, for instance, assist in dose-dependent analyses of angiographic results.

The pre-interventional psychiatric history - an underestimated confounder in benign intracranial lesions studies.

OBJECTIVES: The current study was designed to analyze the influence of a positive pre-interventional psychiatric history on the quality of life (QOL) after successful treatment of benign intracranial extra-cerebral lesions. METHODS: Patients treated due to meningioma WHO I or unruptured intracranial aneurysms in two German neurosurgical centers between 2007 and 2013 were screened for exclusion criteria including malignant/chronic diseases, recurrence of the tumor/aneurysm and neurological deficits among others. 131 patients who met the criteria of an objectively unaffected health status were included. The pre-interventional psychiatric histories and the rates of post-interventional headaches, sleeping disorders, symptoms of chronic fatigue syndrome (CFS), post-traumatic stress disorder (PTSD) and QOL were determined by questionnaires which were mailed to the patients. RESULTS: 103 patients returned the questionnaires. Despite the objectively unaffected health status, the patients with a positive pre-interventional psychiatric history demonstrated a post-interventionally significantly lower QOL (p=0.002), a significantly higher Pittsburgh Sleep Quality Index sum score (p=0.009), as well as significantly higher rates of symptoms of a chronic fatigue syndrome (p=0.003) and PTSD (p=0.024), compared to the patient collective with a negative pre-interventional psychiatric status. CONCLUSION: The results of the current study demonstrate the importance of taking the pre-interventional psychiatric history as a significant and independent confounder into consideration when evaluating the outcome after treatment of benign intracranial extra-cerebral lesions. A pre-interventional psychiatric screening and an early psychological intervention might help to improve the overall outcome after successful treatment of such lesions.

Patient characteristics support unfavorable psychiatric outcome after treatment of unruptured intracranial aneurysms.

INTRODUCTION: Previous studies demonstrated an unfavorable psychological outcome after treatment of unruptured intracranial aneurysms despite an objectively favorable clinical and radiological outcome. The current study was therefore designed to analyze the psychiatric vulnerability of this specific patient collective. MATERIALS AND METHODS: Patients treated for a WHO grade I meningioma and incidental intracranial aneurysms in two German neurosurgical centers between 2007 and 2013 were screened for exclusion criteria including malignant/chronic diseases, recurrence of the tumor/aneurysm after more than 12 months and focal neurological deficits, among others. Seventy-five meningioma patients (M) and 56 incidental aneurysm patients (iA) met the inclusion criteria. The past medical psychiatric history, post-morbid personality characters and coping strategies were determined by questionnaires mailed to the patients in a printed version (Brief COPE, Big Five Personality Test). RESULTS: Fifty-eight M and 45 iA patients returned the questionnaires. Patients with iA demonstrated significantly higher pre-interventional rates of depressive episodes (p = 0.002) and psychological supervision (p = 0.038). These findings were especially aggravated in iA patients who received their cranial imaging for unspecific symptoms such as dizziness, headaches or tinnitus (n = 33, history of depressions: 39.4%; previous psychological supervision: 33.3%). Furthermore, the analysis of the Big Five personality traits revealed remarkably elevated neuroticism scores in the iA collective. CONCLUSION: The current study demonstrates an increased rate of positive pre-interventional psychiatric histories in the iA collective. Although those patients represent only a small subgroup, they still may play an important role concerning the overall outcome after iA treatment. Early detection and psychological support in this subgroup might help to improve the overall outcome. Further studies are needed to evaluate the influence of this new aspect on the multifactorial etiology of unfavorable psychiatric outcome after treatment of iA.

Magnetic resonance imaging flow quantification of non-occlusive excimer laser-assisted EC-IC high-flow bypass in the treatment of complex intracranial aneurysms.

The patency of a bypass plays an important role in the postoperative recovery of patients especially when dealing with complicated intracranial aneurysms. In this study two-dimensional phase contrast magnetic resonance angiography (PC-MRA) was used to measure cerebral blood flow in 23 patients before extracranial-intracranial high-flow bypass surgery using the excimer laser-assisted non-occlusive anastomosis (ELANA) technique and in 15 patients following surgery. The results showed that PC-MRA is a suitable technique for assessing bypass patency and that with the ELANA technique the bypass has the capability of compensating the blood flow of an occluded internal carotid artery (ACI) in cases of complex aneurysms.

TrueFISP of the pediatric pineal gland: volumetric and microstructural analysis.

PURPOSE: Although high-resolution 3D-imaging has markedly improved the imaging of the pediatric pineal gland, the prevalences of typical and atypical cysts as well as in vivo volumes are unknown. The purpose of this study was to compare the frequency of typical and atypical cysts using high-resolution 3D-sequence true fast imaging with steady state precession (trueFISP) and standard sequences and to directly measure the pineal volume in a large pediatric population. METHODS: In 54 consecutively examined children (age 0-17 years, mean age 5.4 ± 5.6 years, 44% female, 56% male) the prevalence of typical and atypical cysts (thickened rim, trabeculations, asymmetry) was determined using trueFISP (isotropic, 0.8 mm) and standard sequences, 1.5-T, T1-weighted spin echo (T1-SE), T2-weighted turbo spin echo (T2-TSE) and fluid attenuated inversion recovery (FLAIR). Indistinct findings were noted separately. Volumetry was based on the trueFISP datasets. Solid and cystic compartments were approached separately. The pineal volume was correlated to gender and age. RESULTS: The detected frequency of pineal cysts was higher in trueFISP (57.4%) than in standard sequences (T1-SE 7.4%, T2-TSE 14.8%, and FLAIR 13.0%). In trueFISP 66.3% of the detected cysts were classified as atypical (standard sequences 0%). Indistinct findings were lowest in trueFISP. The mean pineal volume was 94.3 ± 159.1 mm³ and no gender related differences were found. Age and volume showed a moderate correlation (r = 0.382) which was remarkably higher in completely solid glands (r = 0.659). CONCLUSIONS: TrueFISP imaging improves the detection of pineal cysts in children. A typical cysts are frequently detected as an incidental finding. Volumetric analysis of the pediatric pineal gland is feasible and reveals enormous variation. Whereas gender effects are negligible, the pineal volume in children is dependant on age.

Dual-energy CT after peri-interventional subarachnoid haemorrhage: a feasibility study.

PURPOSE: The aim was to assess the feasibility of dual-energy computed tomography (DE-CT) for detection of peri-interventional re-bleeding in patients with aneurysmal subarachnoid hemorrhage (re-SAH). METHODS: For in vitro-analyses DE-CT of partially clotted blood intermixed with fresh blood containing contrast agent was performed. In a clinical setting, 4 patients routinely underwent DE-CT after suspected peri-interventional re-SAH. DE-CT source data images, iodine maps and virtual non-contrast images (VNC) were analyzed and regions-of-interest (ROI) measurements of density values were performed. RESULTS: In vitro experiments demonstrated the feasibility of DE-CT to discriminate between blood with and without contrast agent. In all patients peri-interventional re-SAH was confirmed by detection of extravasated iodine within the subarachnoid spaces in post-interventional DE-CT. Dual-energy CT allowed the discrimination of old blood clots of the initial SAH and blood originating from peri-interventional re-SAH. After subtraction of the iodine-related high density signal, VNC images optimized the estimation of the true amount of subarachnoid blood. CONCLUSION: Dual-energy CT allows the discrimination and subtraction of blood and iodine mixed within the subarachnoid spaces in patients with peri-interventional re-SAH. It helps to avoid overestimation of SAH after peri-interventional re-bleeding and therefore is a potentially valuable tool in the assessment of peri-interventional re-SAH.

Successful granulocyte-colony stimulating factor treatment of Crohn's disease is associated with the appearance of circulating interleukin-10-producing T cells and increased lamina propria plasmacytoid dendritic cells.

Granulocyte-colony stimulating factor (G-CSF) has proved to be a successful therapy for some patients with Crohn's disease. Given the known ability of G-CSF to exert anti-T helper 1 effects and to induce interleukin (IL)-10-secreting regulatory T cells, we studied whether clinical benefit from G-CSF therapy in active Crohn's disease was associated with decreased inflammatory cytokine production and/or increased regulatory responses. Crohn's patients were treated with G-CSF (5 microg/kg/day subcutaneously) for 4 weeks and changes in cell phenotype, cytokine production and dendritic cell subsets were measured in the peripheral blood and colonic mucosal biopsies using flow cytometry, enzyme-linked immunosorbent assay and immunocytochemistry. Crohn's patients who achieved a clinical response or remission based on the decrease in the Crohn's disease activity index differed from non-responding patients in several important ways: at the end of treatment, responding patients had significantly more CD4(+) memory T cells producing IL-10 in the peripheral blood; they also had a greatly enhanced CD123(+) plasmacytoid dendritic cell infiltration of the lamina propria. Interferon-gamma production capacity was not changed significantly except in non-responders, where it increased. These data show that clinical benefit from G-CSF treatment in Crohn's disease is accompanied by significant induction of IL-10 secreting T cells as well as increases in plasmacytoid dendritic cells in the lamina propria of the inflamed gut mucosa.

Analysis of mouse brain using a clinical 1.5 T scanner and a standard small loop surface coil.

With increasing numbers of in vivo experiments in the field of neuroscience, the interest in methods for in vivo imaging of animal brains as small as those of mice has increased. Because highly specialized small bore scanners with high field strengths are not commonly available, clinical magnetic resonance imaging (cMRI) scanners have been used in the past to image rat and more recently also mouse brains in combination with specifically developed RF coils. These studies have demonstrated that imaging of small animal brains is feasible, and that tumor volumes measured by cMRI correlate well with histological tumor volume analysis. This protocol describes the cMRI settings at 1.5 T for imaging of mouse brain with resolutions up to 120 x 120 microm using an inexpensive, commercially available small loop surface coil. This allows easy establishment of a small animal MRI facility without the need for cost intensive dedicated small animal scanners or special custom made coils. In this study, we demonstrate high-resolution imaging of intracranial xenografts in a mouse glioma model and monitor the treatment effect of external field irradiation by cMRI.

Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL.

A cerebral arteriopathy with subcortical infarcts and leukoencephalopathy is described with a pedigree suggestive for an autosomal dominant condition. In contrast to the vasculopathy designated with the acronym CADASIL, no deposits of granular osmiophilic material were detected in the vasculature and no point mutations in the NOTCH 3 gene were found. The disease occurred in a family living near Hamburg, Germany, and affected 11 women and 11 men over the last six generations. Onset of the disease was between the age of 12 and 50. Clinical symptoms included gait disturbances, dysarthria, sensomotoric deficits and a progressive dementia. Migraine-like complaints and epileptic seizures were observed in one case each. Cranial computer tomography and magnetic resonance imaging scans showed large confluent areas with decreased density in the white matter and small necroses in the brain stem, the basal ganglia and the white matter. A correlation with factors predisposing for vascular diseases could not be demonstrated. In five cases an autopsy was performed which disclosed an angiopathy affecting predominantly the penetrating arteries with consecutive lacunar infarcts, diffuse demyelination and rarefication of the subcortical white matter and degeneration of the pyramidal tracts. Histologically, the vessels showed concentric and excentric intimal proliferation, an elastosis and hyalinosis, splitting of the lamina elastica interna and a degeneration of the tunica muscularis. Electron microscopy revealed fragmentation and thickening of the basal lamina but electron-dense granules characteristic for CADASIL were not detected.

Angiographic follow-up of vertebrobasilar artery aneurysms treated with detachable coils.

Endovascular treatment of ruptured vertebrobasilar artery aneurysms with Gugliemi detachable coils (GDC) has become an alternative to surgery. Mid-term angiographic follow-up can now be reported. Of 111 vertebrobasilar aneurysms in 110 patients we treated with GDC since 1992, 53 underwent angiography within 1 year and 59 after more than 18 months. We did not achieve complete occlusion on initial treatment of 23 aneurysms (21%). Complications were observed in 19 patients (17%), leading to permanent clinical disability in eight. Enlargement of the neck or reopening was seen in 12 (23%) of 53 aneurysms followed by angiography within 12 months. Documented recanalisation was treated in four (8%). Angiography was performed after 18-78 months in 59 patients, of whom nine, including three with initially incomplete occlusions, were retreated with GDC. Within the entire second observation period, three (5%) of the 59 patients had a further haemorrhage and were retreated with GDC. Rebleeding proved to be the only factor influencing the clinical outcome of retreated patients.

[Diagnostic and therapeutical considerations in the treatment of giant aneurysms]. / Diagnostik und Therapie der intrakraniellen Riesenaneurysmen.

The treatment of giant aneurysms requires a thorough surgical and endovascular planning as this entity is accompanied by complex vascular and blood flow particularities. Even in experienced neurovascular centers the clinical outcome varies considerably. Within a series of 1386 aneurysm patients 72 (5%) giant (>25 mm) aneurysms were treated in our institution. Their age ranged between 26 and 81 years (medium age 52 years). 22 patients were suffering of a subarachnoid hemorrhage (SAH). Additionally there were 50 patients with nerve palsies or unspecific symptoms due to unruptured giant aneurysms (UGA). Treatment modalities included surgical clipping (n = 35), balloon occlusion of the ICA (n = 12), endovascular coiling (n = 7) or a combined regimen of balloon occlusion, surgical clipping and EC-IC bypass (n = 8). 10 patients could not be treated on due to their high age or minor clinical status (H&H IV and V). 6 of 15 (40%) SAH-patients were discharged without any complaints compared to 26% (12 of 47 patients) in the group of unruptured aneurysms. 1 SAH-patients (7%) versus 13 UGA (28%) patients suffered persisting nerve palsies or minor neurological disorders. 32% (n = 15) of the UGA-patients were suffering of major neurological deficits and required further professional help. 5 patients remained in a vegetative state, 3 of these had been admitted with an incidental finding of an UGA. 6 of 15 (40%) SAH-patients died, 5 of them admitted with H&H grade IV or V. However only 3 of 47 (6%) UGA patients died. 2 of these had a fatal SAH before treatment, 1 underwent EC-IC bypass surgery with insufficient hemispheric vascularization followed by gross infarction. The clinical status and age of the patient are significant factors influencing treatment associated morbidity and mortality. The individual vascular situation may lead to a complex therapeutical regimen thereby predisposes higher complication rates. We believe that surgical clipping is the first choice of treatment allowing temporarily clipping and reconstruction of the normal anatomy by shrinking or/and reconstructive clipping while reducing the mass effect. Whereas endovascular coiling alone is less favorable due to the packing of the coils a combined endovascular and surgical approach have to be considered in selected cases.

Operative or endovascular treatment of ruptured intracranial vertebral artery aneurysms?

Our purpose was to evaluate the surgical and endovascular treatment outcomes of ruptured intracranial vertebral artery aneurysms (RIVAA). The outcomes of 44 patients with RIVAA treated between 1983 and 1998 surgically (26), endovascularly (20) or both (2) were evaluated. The aneurysms were clipped in 24 patients, and clipped and wrapped in two. We treated 20 by the endovascular approach, 12 with Guglielmi detachable coils (GDC), and eight by parent-vessel occlusion using detachable balloons. Three patients had endovascular treatment after a failed or inadequate surgical attempt. Posttreatment follow-up was 17-183 months (mean 101 months) for surgically treated patients. For the GDC-treated group angiographic follow-up was carried at 8-49 months (mean 19 months). The condition of seven (27 %) of the surgically treated patients worsened due to procedure-related complications, compared with 10% in the endovascular treatment group. Of the patients initially presenting with Hunt and Hess grade IV or V, three of five (60%) died who were treated surgically and two of eight (25%) who were treated endovascularly. A good outcome was achieved in 17 surgically treated patients (85% of the survivors) and in 16 of the endovascular group (89% of the survivors). This present "same-site" report on treatment of a specific abnormality, RIVAA, treated surgically or by an endovascular approach indicates that especially in poorer Hunt and Hess grade patients, the latter may offer a clinical outcome as good as that of surgery, although long-term efficacy of GDC treatment is still to be determined.

Two-step presurgical endovascular treatment of five arteriovenous malformations partially fed by single vessels en passage.

PURPOSE: To describe a method for the preoperative embolization of arteriovenous malformations (AVM) containing vessels en passage (VeP). First, before embolization of the primary AVM, the distal portion of the VeP beyond the AVM, which supplies the parenchymal compartment, is blocked through placement of an endovascular ligature (fibered coils). This protects the post lesional parenchymal tissue and isolates malformational compartments before embolization. Thus the proximal AVM-supplying segment of the VeP can be safely embolized. PATIENTS AND METHODS: Five of 204 AVM patients admitted for preoperative embolization between 1989 and 1997 fulfilled the following treatment criteria for the placement of an endovascular ligature in a VeP before embolization: 1. The diameter of the distal portion of the VeP behind the AVM was large whereas the parenchymal blush was poor; 2. The VeP fed a large portion of the AVM; 3. The VeP was judged to be accessible only late in the surgical procedure; 4. The VeP and its off branches were an integral part of the AVM periphery and thus not suitable for microdissection. RESULTS: In all five cases the leptomeningeal collateral perfusion (the arterial supply to parenchymal brain areas) served to supply brain areas distal to the AVM after primary blockage of a VeP by endovascular ligature with fibered coils. Embolization and complete surgical dissection of the AVM was then achieved in all cases. No neurological deficits occurred. CONCLUSION: Experience with our five cases indicates that a preparatory endovascular ligature of a VeP between parenchyma and the malformational compartment followed by embolization of the AVM can serve as an alternative to open surgical dissection of a vessel en passage and that it safely allows effective preoperative embolization.

Predicting hemodynamic ischemia by transcranial Doppler monitoring during therapeutic balloon occlusion of the internal carotid artery.

PURPOSE: Our objective was to evaluate the sensitivity of transcranial Doppler (TCD) sonographic monitoring during permanent balloon occlusion of the internal carotid artery (ICA) in predicting hemodynamic ischemia. METHODS: Thirty-two consecutive patients underwent controlled therapeutic balloon occlusion of the ICA. Selection criteria included assessment of the circle of Willis by compression angiography, clinical tolerance during a 20-minute test occlusion, and TCD monitoring of the ipsilateral middle cerebral artery. The mean blood flow velocity (MBFV) (n = 32) and pulsatility index (PI) (n = 28) were recorded. In 25 patients, MBFV changes upon motor stimulation were recorded before and after ICA occlusion. RESULTS: Twenty-eight (88%) of the patients had no complications. Three patients suffered delayed symptoms 30 minutes to 20 hours after balloon detachment. Two of these patients recovered spontaneously within 1 day, the other improved after extracranial/intracranial (EC/IC) bypass surgery. One patient, who did not tolerate the test occlusion, suffered a hemodynamic stroke despite EC/IC bypass before permanent balloon occlusion. No embolic complications occurred. The mean MBFV reduction was 20% (range, 0% to 55%); the mean PI reduction was 20% (range, 0% to 56%). No complications occurred in patients who had mild MBFV and PI reduction (30% or less, n = 21). All three patients with severe MBFV or PI reduction (> 50%) had neurologic symptoms. Among those with moderate MBFV or PI reduction (30% to 50%, n = 8), symptoms developed in only one patient who had moderate reduction of both MBFV (33%) and PI (38%). Motor vasoreactivity showed wide variation and was markedly reduced in two symptomatic patients. CONCLUSION: TCD monitoring reflects changes in cerebral hemodynamics after therapeutic balloon occlusion of the ICA. MBFV and PI reductions under 30% are highly predictive of clinical tolerance. A reduction of more than 50% may be a critical threshold for the occurrence of symptoms; in such cases, EC/IC bypass should be considered before proceeding with permanent balloon occlusion.