Pregnancy and delivery in moyamoya vasculopathy: experience of a single European institution.

Moyamoya vasculopathy (MMV) is a stenoocclusive cerebrovascular disease frequently affecting adolescent females. Thus, the management of pregnancy is of major interest for physicians dealing with MMV patients. However, clinical data concerning pregnant MMV patients is lacking. Our aim was to analyze the course of pregnancy in our European MMV patient cohort. We retrospectively identified MMV patients with a history of pregnancy who were treated in our institution. We analyzed demographic data, clinical symptoms, treatment, and detailed history of pregnancies. We identified 31 MMV patients (81% moyamoya disease (MMD), 6% unilateral MMD, 13% quasi MMD) with a history of pregnancy resulting in a total of 60 pregnancies and 48 deliveries. Ninety-four percent of the patients became symptomatic by ischemic events and 6% by headache. Eighty-one and nineteen percent of the patients experienced their pregnancies prior to (first group) or after the diagnosis (second group), respectively. In the first group, the mean age at first delivery and bypass treatment were 24 ± 4 and 42 ± 10, respectively. Eight percent of these patients were diagnosed as MMV due to ischemic events during perinatal period. In the second group, the mean age at first delivery and bypass treatment were 26 ± 7 and 23 ± 6, respectively. No cerebral events were reported within perinatal period in this group. All previously operated patients continued their aspirin medication at least until the 3rd trimester. The majority of the pregnancies occurred prior to diagnosis in our European patient cohort. Our data indicates a protective effect of surgical treatment for avoiding cerebral events during pregnancy and delivery for already diagnosed patients.

Hepatotoxicity by combination treatment of temozolomide, artesunate and Chinese herbs in a glioblastoma multiforme patient: case report review of the literature.

Glioblastoma multiforme (GBM) represents an aggressive tumor type with poor prognosis. The majority of GBM patients cannot be cured. There is high willingness among patients for the compassionate use of non-approved medications, which might occasionally lead to profound toxicity. A 65-year-old patient with glioblastoma multiforme (GBM) has been treated with radiochemotherapy including temozolomide (TMZ) after surgery. The treatment outcome was evaluated as stable disease with a tendency to slow tumor progression. In addition to standard medication (ondansetron, valproic acid, levetiracetam, lorazepam, clobazam), the patient took the antimalarial drug artesunate (ART) and a decoction of Chinese herbs (Coptis chinensis, Siegesbeckia orientalis, Artemisia scoparia, Dictamnus dasycarpus). In consequence, the clinical status deteriorated. Elevated liver enzymes were noted with peak values of 238 U/L (GPT/ALAT), 226 U/L (GOT/ASAT), and 347 U/L (γ-GT), respectively. After cessation of ART and Chinese herbs, the values returned back to normal and the patient felt well again. In the literature, hepatotoxicity is well documented for TMZ, but is very rare for ART. Among the Chinese herbs used, Dictamnus dasycarpus has been reported to induce liver injury. Additional medication included valproic acid and levetiracetam, which are also reported to exert hepatotoxicity. While all drugs alone may bear a minor risk for hepatotoxicity, the combination treatment might have caused increased liver enzyme activities. It can be speculated that the combination of these drugs caused liver injury. We conclude that the compassionate use of ART and Chinese herbs is not recommended during standard radiochemotherapy with TMZ for GBM.

Characterization of Clinical and Radiological Features of Quasi-Moyamoya Disease among European Caucasians Including Surgical Treatment and Outcome.

BACKGROUND: Moyamoya disease (MMD) associated with a potentially underlying disease, such as genetic disorders or other coexisting hematological pathologies, is called quasi-MMD. This very rare disease has been characterized mainly in Asian countries, so far. As MMD reveals several significant ethnic differences, the question is raised whether characteristics of quasi-MMD would also vary among different ethnic backgrounds. Here, we report a series of 61 patients with quasi-MMD and highlight the specific clinical features of this rare disease among European Caucasians. METHODS: We retrospectively identified 61 European Caucasians with quasi-MMD who were treated in our institution between 1997 and 2014. We analyzed demographic data, clinical symptoms, associated diseases, angiographic characteristics and functional hemodynamic studies. RESULTS: Thirty-three percent of our patients were juvenile. We observed an overall female predominance of 2.8:1. Seventy-nine percent presented with a typical quasi-MMD with more pronounced unilateral and atypical quasi-MMD in pediatric population (unilateral/atypical: pediatric patients 20/15%, adults 7/7%). We identified a wide range of associated diseases. Overall, 84 and 8% of our cohort presented initially with ischemic and hemorrhagic manifestation, respectively. The hemorrhagic manifestation of quasi-MMD occurred however only in adults. Angiographic analysis revealed steno-occlusive involvement of the posterior circulation (in addition to the anterior circulation) in 31% with a higher involvement in pediatric patients (40%) compared to adults (27%). CONCLUSIONS: The characterization of our European Caucasian cohort reveals several differences when compared to reported Asian quasi-MMD cohorts and also compared to European Caucasian MMD cohort. We conclude that quasi-MMD represents a distinct disease with different ethnic clinical features.

Metronomic chemotherapy with daily low-dose temozolomide and celecoxib in elderly patients with newly diagnosed glioblastoma multiforme: a retrospective analysis.

Chemotherapy is often omitted in elderly patients with glioblastoma multiforme due to a fear of side effects. We applied metronomic chemotherapy with low-dose temozolomide and celecoxib (LD-TEM/CEL) during and after external beam radiotherapy (EBRT) and here report on how this regimen compares to standard temozolomide radiochemotherapy (SD-TEM) in elderly patients. We retrospectively analyzed records of 146 patients aged 65 years and older that underwent EBRT. Factors of interest were age, performance status, comorbidities, MGMT status, therapy (resection/biopsy, radiotherapy/dose, chemotherapy/regimen/dose), progression-free (PFS) and overall survival (OS) status. Irrespective of the regimen, addition of chemotherapy more than doubled median survival rates (EBRT only: 4.2 months; EBRT + LD-TEM/CEL: 8.5 months; EBRT + SD-TEM: 10.8 months; p ≤ 0.008). Although patients receiving metronomic LD-TEM/CEL were significantly older (62 % were ≥75 years vs. 22 %; p < 0.001), had significantly lower performance scores (50 % had a KPS <70 vs. 28 %; p = 0.049) and were significantly more comorbid (73 % had ≥4 comorbidities vs. 37 %; p = 0.002) than patients of the SD-TEM group, there were no significant differences in PFS and OS. Independent of other factors, omission of chemotherapy significantly impairs progression-free and overall survival. With all the limitations of a retrospective analysis, our data suggest that metronomic chemotherapy with LD-TEM/CEL may be equieffective and eventually better tolerated than SD-TEM. It may be offered to elderly patients that are not eligible for standard chemotherapy.

²³Na-MRI of recurrent glioblastoma multiforme after intraoperative radiotherapy: technical note.

INTRODUCTION: We report the first case of an intraoperative radiotherapy (IORT) in a patient with recurrent glioblastoma multiforme (GBM) who was followed up with a novel magnetic resonance imaging (MRI) method-(23)Na-MRI-in comparison to a standard contrast-enhanced (1)H-MRI and (18)F-FET-PET. METHODS: A 56-year-old female patient with diagnosed GBM in July 2012 underwent tumor resection, radiochemotherapy, and three cycles of chemotherapy. After a relapse, 6 months after the initial diagnosis, an IORT was recommended which was performed in March 2013 using the INTRABEAM system (Carl Zeiss Meditec AG, Germany) with a 3-cm applicator and a surface dose of 20 Gy. Early post-operative contrast-enhanced and 1-month follow-up (1)H-MRI and a (18)F-FET-PET were performed. In addition, an IRB-approved (23)Na-MRI was performed on a 3.0-T MR scanner (MAGNETOM TimTrio, Siemens Healthcare, Germany). RESULTS: After re-surgery and IORT in March 2013, only a faint contrast enhancement but considerable surrounding edema was visible at the medio-posterior resection margins. In April 2013, new and progressive contrast enhancement, edema, (23)Na content, and increased uptake in the (18)F-FET-PET were visible, indicating tumor recurrence. Increased sodium content within the area of contrast enhancement was found in the (23)Na-MRI, but also exceeding this area, very similar to the increased uptake depicted in the (18)F-FET-PET. The clearly delineable zone of edema in both examinations exhibits a lower (23)Na content compared to areas with suspected proliferating tumor tissue. CONCLUSION: (23)Na-MRI provided similar information in the suspicious area compared to (18)F-FET-PET, exceeding conventional (1)H-MRI. Still, (23)Na-MRI remains an investigational technique, which is worth to be further evaluated.

INTRAGO: intraoperative radiotherapy in glioblastoma multiforme­a phase I/II dose escalation study.

BACKGROUND: Glioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor in adults. Despite multimodal therapies, almost all GBM recur within a narrow margin around the initial resected lesion. Thus, novel therapeutic intensification strategies must target both, the population of dispersed tumor cells around the cavity and the postoperative microenvironment. Intraoperative radiotherapy (IORT) is a pragmatic and effective approach to sterilize the margins from persistent tumor cells, abrogate post-injury proliferative stimuli and to bridge the therapeutic gap between surgery and radiochemotherapy. Therefore, we have set up INTRAGO, a phase I/II dose-escalation study to evaluate the safety and tolerability of IORT added to standard therapy in newly diagnosed GBM. In contrast to previous approaches, the study involves the application of isotropic low-energy (kV) x-rays delivered by spherical applicators, providing optimal irradiation properties to the resection cavity. METHODS/DESIGN: INTRAGO includes patients aged 50 years or older with a Karnofsky performance status of at least 50% and a histologically confirmed (frozen sections) supratentorial GBM. Safety and tolerability (i.e., the maximum tolerated dose, MTD) will be assessed using a classical 3 + 3 dose-escalation design. Dose-limiting toxicities (DLT) are wound healing deficits or infections requiring surgical intervention, IORT-related cerebral bleeding or ischemia, symptomatic brain necrosis requiring surgical intervention and early termination of external beam radiotherapy (before the envisaged dose of 60 Gy) due to radiotoxicity. Secondary end points are progression-free and overall survival. TRIAL REGISTRATION: The study is registered with clinicaltrials.gov, number: NCT02104882 (Registration Date: 03/26/2014).

Approaches to temporal lobe lesions: a proposal for classification.

BACKGROUND: Tumor surgery in the temporal region is challenging due to anatomical complexity and the versatility of surgical approaches. The aim was to categorize temporal lobe tumors based on anatomical, functional, and vascular considerations and to devise a systematic field manual of surgical approaches. METHODS: Tumors were classified into four main types with assigned approaches: Type I-lateral: transcortical; type II-polar: pterional/transcortical; type III-central: transsylvian/trans-opercular; type IV-mesial: transsylvian/trans-cisternal if more anterior (=Type IV A), and supratentorial/infraoccipital if more posterior (=type IV B). 105 patients have been operated on prospectively using the advocated guidelines. Outcomes were evaluated. CONCLUSION: Systematic application of the proposed classification facilitated a tailored approach, with gross total tumor resection of 88 %. Neurological and surgical morbidity were less than 10 %. The proposed classification may prove a valuable tool for surgical planning.

Collateralization and ischemia in hemodynamic cerebrovascular insufficiency.

BACKGROUND: Moyamoya disease and atherosclerotic cerebrovascular occlusive disease lead to hemodynamic impairment of cerebral blood flow. One major differentiation between both disease entities lies in the collateralization pathways. The clinical implications of the collateralization pathways for the development of hemodynamic ischemia remain unknown. The aim was to characterize collateralization and ischemia patterns in patients with chronic hemodynamic compromise. METHODS: Hemodynamic compromise was verified using acetazolamide-stimulated xenon-CT or SPECT in 54 patients [30 moyamoya and 24 atherosclerotic cerebrovascular disease (ACVD)]. All patients received MRI to differentiate hemodynamic ischemia into anterior/posterior cortical border zone infarction (CBI), inferior border zone infarction (IBI) or territorial infarction (TI). Digital subtraction angiography was applied to evaluate collateralization. Collateralization was compared and correlated with the localization of ischemia and number of vascular territories with impaired cerebrovascular reserve capacity (CVRC). RESULTS: MM patients showed collateralization significantly more often via pericallosal anastomosis and the posterior communicating artery (flow in the anterior-posterior direction; MM: 95%/95% vs. ACVD: 23%/12%, p < 0.05). ACVD patients demonstrated collateralization via the anterior and posterior communicating arteries (flow in the posterior-anterior direction, MM: 6%/5% vs. ACVD: 62%/88%, p < 0.05). Patterns of infarction were comparable (aCBI: MM: 36% vs. ACVD: 35%; pCBI: MM: 10% vs. ACVD: 20%; IBI: MM: 35% vs. ACVD: 41%; TI: MM: 13% vs. ACVD: 18%). The number and localization of vascular territories with impaired CVRC were comparable. CONCLUSIONS: Despite significant differences in collateralization, the infarct patterns and severity of CVRC impairment do not differ between MMV and ACVD patients. Cerebral collateralization does not allow reaching conclusions about the localization of cerebral ischemia or severity of impaired CVRC in chronic hemodynamic impairment.

Angiographic vasospasm is strongly correlated with cerebral infarction after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The long-standing concept that delayed cerebral infarction after aneurysmal subarachnoid hemorrhage results exclusively from large artery vasospasm recently has been challenged. We used data from the CONSCIOUS-1 trial to determine the relationship between angiographic vasospasm and cerebral infarction after subarachnoid hemorrhage. METHODS: We performed a post hoc exploratory analysis of the CONSCIOUS-1 data. All patients underwent catheter angiography before treatment and 9±2 days after subarachnoid hemorrhage. CT was performed before and after aneurysm treatment, and 6 weeks after subarachnoid hemorrhage. Angiograms and CT scans were assessed by centralized blinded review. Angiographic vasospasm was classified as none/mild (0%-33% decrease in arterial diameter), moderate (34%-66%), or severe (≥67%). Infarctions were categorized as secondary to angiographic vasospasm, other, or unknown causes. Logistic regression was conducted to determine factors associated with infarction. RESULTS: Complete data were available for 381 of 413 patients (92%). Angiographic vasospasm was none/mild in 209 (55%) patients, moderate in 118 (31%), and severe in 54 (14%). Infarcts developed in 6 (3%) of 209 with no/mild, 12 (10%) of 118 patients with moderate, and 25 (46%) of 54 patients with severe vasospasm. Multivariate analysis found a strong association between angiographic vasospasm and cerebral infarction (OR, 9.3; 95% CI, 3.7-23.4). The significant association persisted after adjusting for admission neurological grade and aneurysm size. Method of aneurysm treatment was not associated with a significant difference in frequency of infarction. CONCLUSIONS: A strong association exists between angiographic vasospasm and cerebral infarction. Efforts directed at further reducing angiographic vasospasm are warranted.

Nicardipine pellets for the prevention of cerebral vasospasm.

Regardless of numerous efforts there is no prophylactic treatment proven to be effective in the prevention of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH). As systemic administration of vasoactive drugs has been associated with significant side effects and insufficient efficacy, intrathecal administration of nicardipine prolonged-release implants (NPRI) has been developed. At the time of surgical clipping of the ruptured aneurysm, NPRIs are positioned next to the large cerebral arteries. Several clinical protocols revealed that NPRIs dramatically reduce the incidence and severity of angiographic vasospasm, which was paralled by a reduction in cerebral infarction and delayed ischemic neurologic deficit. On average, the incidence of angiographic vasospasm decreased from approximately 70% to less than 10%. Efficacy seemed to be dose-dependent and reduced for peripheral vasospasm. Nevertheless, a significant improvement of functional outcome was demonstrated. A separate patient series demonstrated the efficacy of fewer NPRIs in the perichiasmatic cistern. Further investigations were performed in comparison to coiled patients and with intraventricular implantation of NPRIs, which had a less pronounced effect. Overall, NPRIs are a most promising option for the prevention of cerebral vasospasm after SAH and large controlled trials are needed to further confirm these results.

The use of nicardipine prolonged release implants (NPRI) in microsurgical clipping after aneurysmal subarachnoid haemorrhage: comparison with endovascular treatment.

BACKGROUND: Nicardipine prolonged release implants (NPRI) have been shown to decrease the incidence of cerebral vasospasm and infarcts significantly in patients after aneurysmal subarachnoid haemorrhage (SAH) following microsurgical clipping. Yet, the comparison with results after endovascular coiling is lacking. This study was conducted to determine the differences in the incidence of cerebral vasospasm and infarctions between those two treatment modalities METHODS: The design of this investigation reflects a case-control study; 27 patients suffering from acute SAH were treated by microsurgical clipping and received an intracisternal implantation of NPRI. Twenty-seven matching consecutive patients after microsurgical treatment without implantation of NPRI or endovascular treatment, respectively, served as controls. The incidence of angiographic vasospasm and cerebral infarctions were documented. RESULTS: All groups were comparable concerning demographics and severity of SAH. Twenty-four of 81 patients developed angiographic vasospasm (>33% constriction). The incidence of vasospasm was 48%, 44% and 11% for patients after endovascular treatment, microsurgical clipping without NPRI and microsurgical clipping with NPRI, respectively. New cerebral infarctions occurred in 28%, 22% and 7% of the treated patients, respectively. A good clinical recovery 1 year after the initial bleeding (modified Rankin scale 0-2) was seen in 48%, 50% and 77% of the treated patients, respectively. CONCLUSION: The use of NPRI during microsurgical clipping was confirmed to be safe and effective. Patients who received intracisternally implanted NPRI during clipping after aneurysmal SAH yielded significantly lower vasospasm and infarction rates, and showed a better clinical outcome when compared with clipping without NPRI and also when compared with endovascular coiling.

Feasibility of intraventricular nicardipine prolonged release implants in patients following aneurysmal subarachnoid haemorrhage.

OBJECTIVE: Intracisternal nicardipine prolonged release implants (NPRI) have been shown to be effective in the prophylaxis of cerebral vasospasm (VS). However, they cannot be used in patients following coil occlusion of the aneurysm. As a certain dissemination of nicardipine within the cerebrospinal fluid (CSF) has been described, we examined the feasibility of intraventricular use of NPRI in patients that underwent clip and coil occlusion of their aneurysms following aneurysmal subarachnoid haemorrhage (aSAH). By comparison with an historical control group, an estimation of their effectivity in regard to angiographic vasospasm and the development of cerebral infarction has been performed. METHODS: Thirty-one patients suffering from aSAH were prospectively included in this trial. Study participants received prior to clipping (n = 17) or coiling (n = 14) 6 (n = 15) or 10 NPRI (n = 16) into the lateral ventricles. Physiological data were collected, proximal and global VS were determined using pre-operative and day 8 ± 1 angiography, and incidence of hydrocephalus and VS related infarcts were evaluated and compared to a historical control group consisting of 16 operated patients without NPRI implantation. RESULTS: Intraventricular NPRI were tolerated well. There were no adverse side effects detectable, physiological variables such as heart rate (HR), mean arterial blood pressure (MAP), intracranial pressure (ICP) and electrolytes showed no difference compared to control. There was no difference in the proportion of patients that required CSF shunting. A significant positive angiographic effect could only be observed in clipped patients (proximal vessel diameters: control, 80 ± 30%; NPRI 90 ± 24%; incidence of moderate/severe global VS: control, 73%; NPRI, 41%). CONCLUSIONS: The use of intraventricular NPRI seems to be safe and tolerated well. There is preliminary evidence for effectivity on angiographic VS for clipped patients only. A further increase of the effective dose might also exert efficacy in the subset of patients following coil occlusion.

Correlation of clinical outcome with pressure-, oxygen-, and flow-related indices of cerebrovascular reactivity in patients following aneurysmal SAH.

BACKGROUND: Impaired cerebrovascular reactivity (CR) has been reported to be associated with adverse outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, CR may be determined using different paradigms and it is unclear, which measurement method most suitable reflects the clinical course or is able to predict clinical deterioration. METHODS: Twenty-one aSAH patients were included in this study. Following occlusion of the aneurysms with or without implantation of nicardipine prolonged release implants (NPRIs), mean arterial and mean intracranial pressure, regional tissue oxygenation, and regional cerebral blood flow was determined. Based on these data, pressure-, oxygen-, and flow-related autoregulatory indices (PRx, ORx, FRx) were simultaneously calculated and correlated with outcome parameters including the Glasgow outcome score (GOS) and the modified Rankin (mRankin) scale. RESULTS: Eight patients showed newly developed cerebral infarcts. Low values of GOS and mRankin scale highly correlated with the incidence of cerebral infarcts (GOS, P = 0.001; mRankin, P = 0.003). However, indices of CR did not differ significantly between the infarction (I) and the noninfarction group (NI) (PRx, I, 0.058 +/- 0.096, NI, 0.097 +/- 0.203, P = 0.538; ORx, I, 0.162 +/- 0.316, NI, 0.094 +/- 0.176, P = 0.690; FRx, I, 0.395 +/- 0.200, NI, 0.265 +/- 0.177, P = 0.119). No correlation was found between indices and clinical outcome parameters (all not significant). However, ORx and FRx correlated well (P = 0.016). CONCLUSIONS: Due to the low number of included subjects, the obtained results are preliminary. However, they indicate that either the present technique of index-determination is not sensitive enough or that there is no strong relation between the measured indices and clinical outcome. Future verification is required of continuous against already established non-continuous monitoring techniques of CR in order to relate both to clinical outcome.

Impact of systemic inflammatory response syndrome on vasospasm, cerebral infarction, and outcome after subarachnoid hemorrhage: exploratory analysis of CONSCIOUS-1 database.

BACKGROUND: Systemic inflammatory response syndrome (SIRS) may develop after aneurysmal subarachnoid hemorrhage (SAH). We investigated factors associated with SIRS after SAH, whether SIRS was associated with complications of SAH such as vasospasm, cerebral infarction, and clinical outcome, and whether SIRS could contribute to a difference in outcome between patients treated by endovascular coiling or neurosurgical clipping of the ruptured aneurysm. METHODS: This was exploratory analysis of 413 patients in the CONSCIOUS-1 study. SIRS was diagnosed if the patient had at least 2 of 4 variables (hypothermia/fever, tachycardia, tachypnea, and leukocytosis/leukopenia) within 4 days of admission. Clinical outcome was measured on the Glasgow outcome scale 3 months after SAH. The relationship between clinical and radiologic variables and SIRS, angiographic vasospasm, delayed ischemic neurologic deficit (DIND), cerebral infarction, vasospasm-related infarction, and clinical outcome were modeled with uni- and multivariable analyses. RESULTS: 63% of patients developed SIRS. Many factors were associated with SIRS in univariate analysis, but only poor WFNS grade and pneumonia were independently associated with SIRS in multivariable analysis. SIRS burden (number of SIRS variables per day over the first 4 days) was associated with poor outcome, but not with angiographic vasospasm, DIND, or cerebral infarction. The method of aneurysm treatment was not associated with SIRS. CONCLUSION: SIRS was associated with poor outcome but not angiographic vasospasm, DIND, or cerebral infarction after SAH in the CONSCIOUS-1 data. There was no support for the notion that neurosurgical clipping is associated with a greater risk of SIRS than endovascular coiling.

Increased levels of circulating endothelial progenitor cells in patients with Moyamoya disease.

BACKGROUND AND PURPOSE: Chronic cerebral ischemia leads to higher risk for strokes attributable to insufficient collateralization, resulting from inadequate capacity for arteriogenesis and angiogenesis. Patients with Moyamoya disease (MMD) have similar transient ischemic attack frequencies compared to patients with chronic cerebral ischemia with other etiologies, but a strong capacity for arteriogenesis and angiogenesis. The mechanisms involved in the upregulation of the arteriogenesis and angiogenesis in MMD still remain unknown. In the present study we investigated if circulating endothelial progenitor cells are increasingly mobilized during MMD. METHODS: Twenty MMD patients, 8 patients with atherosclerotic cerebrovascular disease, and 15 healthy individuals were included in this study. Peripheral blood mononuclear cells were isolated by Ficoll density gradient centrifugation and circulating endothelial progenitor cells were characterized by triple staining using antibodies against CD133, CD34, and vascular endothelial growth factor receptor-2. Serum concentrations of vascular endothelial growth factor and granulocyte-macrophage colony-stimulating factor were determined by enzyme-linked immunosorbent assay. RESULTS: In MMD patients the number of circulating endothelial progenitor cells was significantly higher than in atherosclerotic cerebrovascular disease patients (P<0.002) and healthy controls (P<0.0001). Serum vascular endothelial growth factor concentrations in MMD patients and in atherosclerotic cerebrovascular disease patients were significantly higher compared to those in healthy controls (P<0.0001). Similar findings were observed for granulocyte-macrophage colony-stimulating factor. An inverse correlation between circulating endothelial progenitor cell numbers and serum levels of vascular endothelial growth factor (r=-0.53; P<0,02) was found in the MMD group. CONCLUSIONS: Our results show increased circulating endothelial progenitor cell numbers in MMD, which may play a role in the increased arteriogenesis and angiogenesis in MMD. Moreover, our results suggest that increased circulating endothelial progenitor cell mobilization in MMD may not be entirely mediated by vascular endothelial growth factor or granulocyte-macrophage colony-stimulating factor.

Characterization of functional outcome and quality of life following subarachnoid hemorrhage in patients treated with and without nicardipine prolonged-release implants.

OBJECT: The use of nicardipine prolonged-release implants (NPRIs) is associated with a significant improvement in the therapy of patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) regarding the occurrence and severity of cerebral vasospasm, new infarcts, and functional outcome (FO). Because quality of life (QOL) measurements more reliably seem to describe the patient's true condition, the present study was conducted to assess FO and QOL 1 year after aneurysm rupture in patients with and without NPRIs. METHODS: From the initial series of 32 patients, 18 were assessed 1 year after aSAH (7 of the control and 11 of the NPRI group). The patients underwent neurological investigation, a structured interview followed by a measurement of QOL (Mini-Mental State Examination [MMSE]; 36-Item Short Form Health Survey [SF-36]; and the Hamilton Depression Rating Scale). There were no intergroup differences in the patient characteristics (that is, localization of aneurysm, initial Hunt and Hess grade, or age). RESULTS: In addition to the previously reported improvement of the National Institutes of Health Stroke Scale and modified Rankin Scale scores, the NPRI group's Karnofsky Performance Scale and the MMSE scores were markedly to significantly improved (p < 0.05 [Karnofsky Performance Scale] and p = 0.053 [MMSE]). In contrast, anxiety, oblivion, and mild symptoms of depression were equally present in both study groups (p = 0.607 [anxiety]; p = 0.732 [oblivion]; and p = 0.509 [Hamilton Depression Rating Scale]). Furthermore, no intergroup differences were observed in any of the SF-36 domains. The scores in the SF-36 domains of Role-Physical, Vitality, and Role-Emotional were significantly reduced in the NRPI group compared with those observed in an age-matched control population (p < 0.001 [Role-Physical]; p = 0.001 [vitality]; and p = 0.01 [Role-Emotional]). Considering consequent costs, no difference was detectable regarding the duration of in- and outpatient rehabilitation (p = 0.135 and 0.171, respectively) or the Prolo score (p = 0.094). CONCLUSIONS: Despite FO improvement in terms of a lower incidence of cerebral vasospasm, new infarcts, morbidity in the treatment of aSAH in patients with NPRIs, a patient's QOL seems to be related to the severity of the aSAH itself.

Clinical evaluation of the safety and efficacy of lumbar cerebrospinal fluid drainage for the treatment of refractory increased intracranial pressure.

OBJECT: Several approaches have been established for the treatment of intracranial hypertension; however, a considerable number of patients remain unresponsive to even aggressive therapeutic strategies. Lumbar CSF drainage has been contraindicated in the setting of increased intracranial pressure (ICP) because of possible cerebral herniation. The authors of this study investigated the efficacy and safety of controlled lumbar CSF drainage in patients suffering from intracranial hypertension following severe traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH). METHODS: The authors prospectively evaluated 100 patients-45 with TBI and 55 with SAH-having a mean age of 43.7 +/- 15.7 years (mean +/- SD) and suffering from refractory intracranial hypertension (ICP > 20 mm Hg). Intracranial pressure and cerebral perfusion pressure (CPP) before and after the initiation of lumbar CSF drainage as well as related complications were documented. Patient outcomes were assessed 6 months after injury. RESULTS: The application of lumbar CSF drainage led to a significant reduction in ICP from 32.7 +/- 10.9 to 13.4 +/- 5.9 mm Hg (p < 0.05) and an increase in CPP from 70.6 +/- 18.2 to 86.2 +/- 15.4 mm Hg (p < 0.05). Cerebral herniation with a lethal outcome occurred in 6% of patients. Thirty-six patients had a favorable outcome, 12 were severely disabled, 7 remained in a persistent vegetative state, and 45 died. CONCLUSIONS: Lumbar drainage of CSF led to a significant and clinically relevant reduction in ICP. The risk of cerebral herniation can be minimized by performing lumbar drainage only in cases with discernible basal cisterns.

Age-dependent revascularization patterns in the treatment of moyamoya disease in a European patient population.

OBJECT: Different revascularization procedures are used in the treatment of patients with moyamoya disease (MMD). The aim of this study was to investigate the relative contribution of direct and indirect revascularization procedures to the restoration of collateral blood supply in adult and pediatric patients with MMD. METHODS: The authors performed 39 combined cerebral revascularization procedures (standard extraintracranial bypass [STA-MCA bypass] plus encephalomyosynangiosis [EMS]) in 10 pediatric and 10 adult patients. All patients underwent physical examination and digital subtraction angiography before and 6 months after surgery. The STA-MCA bypass and EMS function were graded as Grade I (poor), II (moderate), or III (good) on the basis of the angiograms. RESULTS: In pediatric patients, bypass function was Grade I in 12, Grade II in 8, and Grade III in 0 hemispheres; EMS function was Grade I in 0, Grade II in 12, and Grade III in 8 hemispheres. In the adult patients, bypass function was Grade I in 8, Grade II in 8, and Grade III in 3 hemispheres; EMS function was Grade I in 10 hemispheres, Grade II in 5, and Grade III in 1 hemisphere. In the pediatric patients disease was classified as improved in 14 hemispheres on the basis of clinical results and stable in 6. In the adults it was classified as improved in 12 hemispheres stable in 7 hemispheres. CONCLUSIONS: Combined revascularization led to good angiographic and clinical results in both patient populations. Especially in pediatric patients, EMS represents a suitable alternative to bypass surgery.

Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma (INTRAGO): An Open-Label, Dose-Escalation Phase I/II Trial.

BACKGROUND: The median time to recurrence of glioblastoma (GB) following multimodal treatment is ∼7 mo. Nearly all cancers recur locally, suggesting that augmenting local treatments may improve outcomes. OBJECTIVE: To investigate whether intraoperative radiotherapy (IORT) to the resection cavity is safe and effective. METHODS: INTRAGO was a phase I/II trial to evaluate the safety and tolerability of IORT with 20 to 40 Gy of low-energy photons in addition to standard radiochemotherapy (ClinicalTrials.gov ID, NCT02685605). The primary endpoint was safety as per occurrence of dose-limiting toxicities. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). We also performed an exploratory analysis of the local PFS (L-PFS), defined as recurrence within 1 cm of the treated margin. RESULTS: Fifteen patients were treated at 3 dose levels. Of these, 13 underwent incomplete resection, 6 had unresected satellites, and 3 did not receive per-protocol treatment (PPT). The MGMT promoter was unmethylated in 10 patients. The median follow-up was 13.8 mo. The majority of grade 3 to 5 adverse events were deemed unrelated to IORT. Five cases of radionecrosis were observed, 2 were classified as grade 3 events. Other grade 3 events judged related to radiotherapy (external-beam radiotherapy and/or IORT) were wound dehiscence (n = 1), CSF leakage (n = 1), cyst formation (n = 1). No IORT-related deaths occurred. The median PFS was 11.2 mo (95% confidence interval [CI]: 5.4-17.0) for all patients and 11.3 mo (95% CI: 10.9-11.6) for those receiving PPT. The median L-PFS was 14.3 mo (95% CI: 8.4-20.2) for all patients and 17.8 mo (95% CI: 9.7-25.9) for those receiving PPT. The median OS was 16.2 mo (95% CI: 11.1-21.4) for all patients and 17.8 mo (95% CI: 13.9-21.7) for those receiving PPT. CONCLUSION: These data suggest that IORT is associated with manageable toxicity. Considering the limitations of a 15-patient phase I/II trial, further studies aimed at assessing an outcome benefit are warranted.