Validation of the Berlin Grading System for moyamoya angiopathy with the use of [15O]H2O PET.

The Berlin Grading System assesses clinical severity of moyamoya angiopathy (MMA) by combining MRI, DSA, and cerebrovascular reserve capacity (CVRC). Our aim was to validate this grading system using [15O]H2O PET for CVRC. We retrospectively identified bilateral MMA patients who underwent [15O]H2O PET examination and were treated surgically at our department. Each hemisphere was classified using the Suzuki and Berlin Grading System. Preoperative symptoms and perioperative ischemias were collected, and a logistic regression analysis was performed. A total of 100 hemispheres in 50 MMA patients (36 women, 14 men) were included. Using the Berlin Grading System, 2 (2.8%) of 71 symptomatic hemispheres were categorized as grade I, 14 (19.7%) as grade II, and 55 (77.5%) as grade III. The 29 asymptomatic hemispheres were characterized as grade I in 7 (24.1%) hemispheres, grade II in 12 (41.4%), and grade III in 10 (34.5%) hemispheres. Berlin grades were independent factors for identifying hemispheres as symptomatic and higher grades correlated with increasing proportion of symptomatic hemispheres (p < 0.01). The Suzuki grading did not correlate with preoperative symptoms (p = 0.26). Perioperative ischemic complications occurred in 8 of 88 operated hemispheres. Overall, complications did not occur in any of the grade I hemispheres, but in 9.1% (n = 2 of 22) and 9.8% (n = 6 of 61) of grade II and III hemispheres, respectively. In this study, we validated the Berlin Grading System with the use of [15O]H2O PET for CVRC as it could stratify preoperative symptomatology. Furthermore, we highlighted its relevance for predicting perioperative ischemic complications.

[Operative treatment of degenerative diseases of the lumbar spine]. / Operative Versorgung degenerativer Erkrankungen der Lendenwirbelsäule.

BACKGROUND: Degenerative diseases of the lumbar spine and associated lower back pain represent a major epidemiological and health-related economic challenge. A distinction is made between specific and unspecific lower back pain. In specific lower back pain lumbar disc herniation and spinal canal stenosis with or without associated segment instability are among the most frequent pathologies. Diverse conservative and operative strategies for treatment of these diseases are available. OBJECTIVES: The aim of this article is to present an overview of current data and an evidence-based assessment of the possible forms of treatment. MATERIAL AND METHODS: An extensive literature search was carried out via Medline plus an additional evaluation of the authors' personal experiences. RESULTS: Conservative and surgical treatment represent efficient treatment options for degenerative diseases of the lumbar spine. Surgical treatment of lumbar disc herniation shows slight advantages compared to conservative treatment consisting of faster recovery of neurological deficits and a faster restitution of pain control. Surgical decompression is superior to conservative measures for the treatment of spinal canal stenosis and degenerative spondylolisthesis. In this scenario conservative treatment represents an important supporting measure for surgical treatment in order to improve the mobility of patients and the outcome of surgical treatment. CONCLUSION: The treatment of specific lower back pain due to degenerative lumbar pathologies represents an interdisciplinary challenge, requiring both conservative and surgical treatment strategies in a synergistic treatment concept in order to achieve the best results for patients.

Impact of sacropelvic fixation on the development of postoperative sacroiliac joint pain following multilevel stabilization for degenerative spine disease.

OBJECTIVE: We hypothesised, that the inclusion of the ilium for multilevel lumbosacral fusions reduces the incidence of postoperative sacroiliac joint (SIJ) pain. The primary objective of this study was to compare the frequency of postoperative SIJ pain in patients undergoing multilevel stabilization with and without sacropelvic fixation for multilevel degenerative spine disease. In addition, we aimed at identifying factors that may predict the worsening or new onset of postoperative SIJ pain. METHODS: A total of 63 patients with multisegmental fusion surgery with a minimum follow up of 12 months were evaluated. 34 patients received sacral fixation (SF group) and 29 patients received an additional sacropelvic fixation device (SPF group). Primary outcome parameters were changes in SIJ pain between the groups and the influence of pelvic parameters, the patient́s age, the patient́s body mass index (BMI) and the length of the stabilization on the SIJ pain. RESULTS: Between the two surgical groups there were no differences concerning age (p=0.3), BMI (p=0.56), length of follow up (p=0.96), length of the construct (p=0.56). In total 31.7% of the patients had a worsening/new onset of SIJ pain after surgery. An additional fixation of the SIJ with iliac screws or iliosacral plate did not have an influence on the SIJ pain (p=0.67). Likewise, pelvic parameters were not predictive for the outcome of the SIJ pain. Only an increased preoperative BMI correlated with a higher chance of a new onset of SIJ pain (p=0.037). CONCLUSION: In our retrospective study there was no influence of a sacropelvic fixation techniques on the SIJ pain in patients with multilevel degenerative spine disease after multilevel stabilization surgeries. The patients' BMI is the only preoperative factor that correlated with a higher incidence to develop postoperative SIJ pain, independently of the implantation of a sacropelvic fixation device.

Grading of moyamoya disease allows stratification for postoperative ischemia in bilateral revascularization surgery.

BACKGROUND: Moyamoya disease (MMD) may be graded based on DSA, the presence of ischemia in MRI and cerebrovascular reserve capacity allowing the prediction of ischemic symptoms in patients. Cerebral ischemia represents a severe complication in revascularization surgery. Focusing on different clinical features of hemodynamic impairment, MMD grading may allow prediction of ischemic complications. It was the aim to analyze whether MMD grading stratifies for ischemic complications in revascularization surgery for MMD. METHOD: In 37 MMD patients a bilateral, standardized, one-staged revascularization approach consisting of STA-MCA bypass/encephalomyosynangiosis (EMS) and single EMS on the contralateral hemisphere was performed. Clinical data including DSA, MRI and rCBF (Xenon-CT) studies were assessed and used for grading MMD. All patients were observed on the ICU for at least 24 h and received CT imaging on the first postoperative day and in case of neurological deterioration. Ischemic complications were analyzed until the day of discharge and at 6-month follow-up. RESULTS: Grading of MMD revealed 11 hemispheres (15 %) as grade I, 33 hemispheres (44 %) as grade II and 30 hemispheres (41 %) as grade III. Eight ischemic complications were observed (11 %). MMD grading demonstrated a significant correlation with ischemic complications: 0 complications in grade I, 3 in grade II (9 %) and 5 in grade III hemispheres (16 %; p < 0.05, Fisher's exact test). CONCLUSIONS: The proposed grading system allows to stratify for ischemic complications in MMD patients that receive bilateral, one-staged revascularization surgery. Future studies will have to investigate its use for predicting ischemic complications in other revascularization strategies for MMD.

F8-SIP mediated targeted photodynamic therapy leads to microvascular dysfunction and reduced glioma growth.

The extra domain A (ED A) of fibronectin has been identified as a tumor vessel specific neovascular marker in glioma. Antibody based vascular targeting against ED A of fibronectin allows precise accumulation of photosensitizer in glioma microvasculature and thereby promises to overcome drawbacks of current photodynamic therapy (PDT) for glioma treatment. Our aim was to characterize microcirculatory consequences of F8-small immunoprotein (SIP) mediated PDT by intravital microscopy (IVM) and to analyze the effects on glioma growth. For IVM SF126 glioma cells were implanted into dorsal skinfold-chamber of nude mice. PDT was performed after intravenous injection of photosensitizer (PS)-coupled F8-SIP or PBS (n = 4). IVM was performed before and after PDT for 4 days. Analysis included total and functional (TVD, FVD) vessel densities, perfusion index (PI), microvascular permeability and blood flow rate (Q). To assess tumor growth SF126 glioma cells were implanted subcutaneously. PDT was performed as a single and repetitive treatment after PS-F8-SIP injection (n = 5). Subcutaneous tumors were treated after uncoupled F8-SIP injection as control group (n = 5). PDT induced microvascular stasis and thrombosis with reduced FVD (24 h: 115.98 ± 0.7 vs. 200.8 ± 61.9 cm/cm(2)) and PI (39 ± 11 vs. 70 ± 10 %), whereas TVD was not altered (298 ± 39.2 vs. 278.2 ± 51 cm/cm(2)). Microvascular dysfunction recovered 4 days after treatment. Microvascular dysfunction led to a temporary reduction of glioma growth in the first 48 h after treatment with complete recovery 5 days after treatment. Repetitive PDT resulted in sustained reduction of tumor growth. F8-SIP mediated PDT leads to microvascular dysfunction and reduced glioma growth in a preclinical glioma model with recovery of microcirculation 4 days after treatment. Repetitive application of PDT overcomes microvascular recovery and leads to prolonged antiglioma effects.

Research Progresses in Understanding the Pathophysiology of Moyamoya Disease.

BACKGROUND: The pathogenesis of moyamoya disease (MMD) is still unknown. The detection of inflammatory molecules such as cytokines, chemokines and growth factors in MMD patients' biological fluids supports the hypothesis that an abnormal angiogenesis is implicated in MMD pathogenesis. However, it is unclear whether these anomalies are the consequences of the disease or rather causal factors as well as these mechanisms remain insufficient to explain the pathophysiology of MMD. The presence of a family history in about 9-15% of Asian patients, the highly variable incidence rate between different ethnic and sex groups and the age of onset support the role of genetic factors in MMD pathogenesis. However, although some genetic loci have been associated with MMD, few of them have been replicated in independent series. Recently, RNF213 gene was shown to be strongly associated with MMD occurrence with a founder effect in East Asian patients. However, the mechanisms leading from RNF213 mutations to MMD clinical features are still unknown. SUMMARY: The research on pathogenic mechanism of MMD is in its infancy. MMD is probably a complex and heterogeneous disorder, including different phenotypes and genotypes, in which more than a single factor is implicated. KEY MESSAGE: Since the diagnosis of MMD is rapidly increasing worldwide, the development of more efficient stratifying risk systems, including both clinical but also biological drivers became imperative to improve our ability of predict prognosis and to develop mechanism-tailored interventions.

Distinct clinical and radiographic characteristics of moyamoya disease amongst European Caucasians.

BACKGROUND AND PURPOSE: Occlusive cerebrovascular moyamoya disease (MMD) is rare and has been characterized mainly in Asian countries, so far. In recent years, MMD has been increasingly reported worldwide, raising the question whether its clinical presentation would vary amongst different ethnic backgrounds. Here, a homogeneous series of 153 patients with MMD are reported and the specific clinical features of this rare disease amongst European Caucasians are highlighted. METHODS: A total of 153 European Caucasians with MMD who were treated in our institution between 1997 and 2014 were retrospectively identified. Demographic data, clinical symptoms, angiographic characteristics and functional hemodynamic studies were analyzed. RESULTS: Moyamoya disease presented with a female predominance of 2,9:1.,78% presented with a typical MMD, 17% with a unilateral MMD and 5% with an atypical MMD. 16% of our patients belonged to the pediatric population. Overall, 81% and 8.5% of our cohort presented initially with ischaemic and hemorrhagic manifestation, respectively. The rate of hemorrhagic manifestation of MMD amongst the pediatric group was slightly higher (12%). Angiographic analysis revealed steno-occlusive involvement of the posterior circulation in 34% with a higher involvement in pediatric patients (64%) compared to adults (28%). CONCLUSIONS: The characterization of our homogeneous European Caucasian cohort reveals several significant differences compared to Asian cohorts. In contrast, MMD presents similarly amongst European and North American cohorts, suggesting that non-Asian MMD is characterized by distinct clinical features.

Antiangiogenic therapy inhibits the recruitment of vascular accessory cells to the perivascular niche in glioma angiogenesis.

OBJECTIVE: Antiangiogenic therapies could be limited by various escape mechanisms including bone marrow-derived myeloid cell-induced vasculogenesis. The recruitment of vascular accessory cells (VACs) to the tumor neovasculature is as a multistep process. However, the recruitment process of these cells during antiangiogenic treatment remains unknown. The aim of our study was to characterize the recruitment of VACs during antiangiogenic therapy using sunitinib. METHODS: C6 glioma cells were implanted into dorsal skinfold chambers. Animals received antiangiogenic therapy intraperitoneally for 5 days prior to VAC application intra-arterially. Intravital microscopy was performed during VAC injection and 1 and 48 h after injection. Analyses included total (TVD) and functional vessel densities (FVD), the perfusion index (PI), microvascular permeability, blood flow rate (Q), microvascular diameter (D), red blood cell velocity (RBCV), wall shear rate (γ), wall shear stress (τ), first and firm adhesions of VACs, and accumulation in the perivascular niche. RESULTS: Antiangiogenic therapy resulted in a significant reduction in TVD (365 ± 47 cm/cm(2) vs. 183 ± 37 cm/cm(2)) and FVD (227 ± 65 cm/cm(2) vs. 147 ± 25 cm/cm(2)) and an increase in PI, Q, D, and RBCV. γ and τ remained unaltered. Initial adhesion and firm adhesion were unaffected by antiangiogenic therapy; however, the accumulation in the perivascular niche was significantly diminished in treated tumors (53.7 ± 8% vs. 24.0 ± 17%). CONCLUSIONS: Antiangiogenic treatment inhibits the accumulation of VACs in the perivascular niche and therefore interferes with consecutive neovascularization.

Sacropelvic fixation versus fusion to the sacrum for spondylodesis in multilevel degenerative spine disease.

STUDY DESIGN: Retrospective study. OBJECTIVE: For successful multilevel correction and stabilization of degenerative spinal deformities, a rigid basal construct to the sacrum is indispensable. The primary objective of this study was to compare the results of two different sacropelvic fixation techniques to conventional stabilization to the sacrum in patients with multilevel degenerative spine disease. METHODS: A total of 69 patients with multisegmental fusion surgery (mean number of stabilized functional spinal units: 7.0 ± 3.3) with a minimum of 1-year follow-up were included. 32 patients received fixation to the sacrum (S1), 23 patients received S1 and iliac screw fixation (iliac) and 14 patients were treated with iliosacral plate fixation (plate). Primary outcome parameters were radiographic outcome concerning fusion in the segment L5-S1, rate of screw loosening, back and buttock pain reduction [numeric rating scale for pain evaluation: 0 indicating no pain, 10 indicating the worst pain], overall extent of disability after surgery (Oswestry Disability Index) and the number of complications. RESULTS: The three groups did not differ in body mass index, ASA score, the number of stabilized functional spinal units, duration of surgery, the number of previous spine surgeries, or postoperative complication rate. The incidence of L5-S1 pseudarthrosis after 1 year in the S1, iliac, and plate groups was 19, 0, and 29 %, respectively (p < 0.05 iliac vs. plate). The incidence of screw loosening after 1 year in the S1, iliac, and plate groups was 22, 4, and 43 %, respectively (p < 0.05 iliac vs. plate). Average Oswestry scores after 1 year in the S1, iliac, and plate groups were 40 ± 18, 42 ± 20, and 58 ± 18, respectively (p < 0.05 both S1 and iliac vs. plate). CONCLUSION: The surgical treatment of multilevel degenerative spine disease carries a significant risk for pseudarthrosis and screw loosening, mandating a rigid sacropelvic fixation. The use of an iliosacral plate resulted in an inferior surgical and clinical outcome when compared to iliac screws.

NDRG1 prognosticates the natural course of disease in WHO grade II glioma.

There is a lack of relevant prognostic and predictive factors in neurooncology besides mutation of isocitrate dehydrogenase 1, codeletion of 1p/19q and promoter hypermethylation of O (6) -methylguanine-DNA-methyltransferase. More importantly, there is limited translation of these factors into clinical practice. The cancer genome atlas data and also clinical correlative analyses suggest a pivotal role for the epidermal growth factor receptor /protein kinase B/mammalian target of rapamycin (mTOR) pathway in both biology and the clinical course of gliomas. However, attempts to stratify gliomas by activating alterations in this pathway have failed thus far. The tumors of 40 patients with WHO grade II gliomas without immediate postoperative genotoxic treatment and known progression and survival status at a median follow-up of 12.2 years were analyzed for expression of the mTOR complex 2 downstream target N-myc downstream regulated gene (NDRG)1 using immunohistochemistry. Baseline characteristics for NDRG1 absent/low versus moderate/high patients were similar. Time to reintervention was significantly longer in the NDRG1 group (P = 0.026). NDRG1 may become a novel biomarker to guide the decision which WHO°II glioma patients may be followed without postsurgical intervention and which patients should receive genotoxic treatment early on. Validation of this hypothesis will be possible with the observational arm of the RTOG 9802 and the pretreatment step of the EORTC 22033/26032 trials.

Combined temozolomide and sunitinib treatment leads to better tumour control but increased vascular resistance in O6-methylguanine methyltransferase-methylated gliomas.

INTRODUCTION: Combined antiangiogenic and cytotoxic treatment represents an appealing treatment approach for malignant glioma. In this study we characterised the antitumoural and microvascular consequences of sunitinib (Su) and temozolomide (TMZ) therapy and verified the ideal treatment protocol, with special focus on a potential therapeutic window for combined scheduling. MATERIALS AND METHODS: O(6)-Methylguanine methyltransferase (MGMT) status was analysed by pyrosequencing. Tumour growth of subcutaneous xenografts was assessed under different treatment protocols (TMZ, SU, SU followed by TMZ, TMZ followed by SU, combined TMZ/SU). Intravital microscopy (dorsal skinfold chamber model) assessed microvascular consequences. Immunohistochemistry included tumour and endothelial cell proliferation, apoptosis and vascular pericyte coverage. Real-time polymerase chain reaction (RT-PCR) analysed the expression of angiogenesis-related pathways in response to therapy. RESULTS: Combined TMZ/SU resulted in significantly reduced tumour growth compared to either monotreatment (TMZ: 106 ± 13 mm(3); SU: 114 ± 53 mm(3); TMZ/SU: 34 ± 7 mm(3)) by additional antiangiogenic effects and synergistic induction of apoptosis versus TMZ monotreatment. Sequential treatment protocols did not show additive antitumour responses. TMZ/SU aggravated vascular resistance mechanisms characterised by significantly higher blood flow rate (TMZ: 74 ± 34 µl/s; SU: 164 ± 36 µl/s; TMZ/SU: 254 ± 95 µl/s), reduced permeability (TMZ: 1.05 ± 0.02; SU: 0.99 ± 0.07; TMZ/SU: 0.89 ± 0.05) and recovery of pericyte-endothelial interactions (TMZ: 89 ± 7%; SU: 67 ± 9%, TMZ/SU:80 ± 10%) versus either monotreatment. Vascular resistance was paralleled by an increase in Ang-1 and Tie-2 and by the downregulation of Dll4. CONCLUSION: Sequential application of TMZ and SU in the angiogenic window does not add antitumour efficacy to monotherapy. Simultaneous application yields beneficial tumour control due to additive antiangiogenic and proapoptotic effects. Combined treatment may aggravate pericyte-mediated vascular resistance mechanisms by altering Ang-1-Tie-2 and Dll4/Notch pathways.

Characterization of direct and indirect cerebral revascularization for the treatment of European patients with moyamoya disease.

BACKGROUND: The best revascularization strategy for moyamoya disease (MMD) remains unknown. Our aim was to characterize angiographic revascularization effects of a bilateral standardized revascularization approach, consisting of superficial temporal artery (STA)-middle cerebral artery (MCA) bypass and encephalomyosynangiosis (EMS) on one hemisphere and single EMS on the contralateral hemisphere of each patient, and to compare the effects of both revascularization strategies on cerebral hemodynamics. METHODS: In 30 patients (18 females/12 males, age 8-63 years), standardized revascularization was performed. Digital subtraction angiography was performed preoperatively and at 7 days, 6 months and 12 months postoperatively. STA-MCA and EMS functions were graded I (poor), II (medium) or III (extensive) according to angiographic aspects. In 20 patients, cerebrovascular reserve capacity (CVRC) was assessed pre- and postoperatively (at 12 months) using xenon CT. RESULTS: After 12 months, STA-MCA/EMS function was grade 1 in 40/40%, grade 2 in 27/26%, and grade 3 in 27/10% of hemispheres, respectively. Twelve months after surgery, single EMS showed grade I in 37%, grade II in 27%, and grade III in 20% of hemispheres. Combined revascularization improved CVRC significantly compared to preoperative measurement (preoperative: 16.5 ± 34.6% vs. postoperative: 60.8 ± 64.22%; p < 0.05). Single EMS did not improve CVRC significantly (preoperative: 21.8 ± 35.9% vs. postoperative: 34.8 ± 63.0%; p < 0.05). CONCLUSIONS: Combined and indirect revascularization may be successfully applied in a bilateral standardized approach. STA-MCA/EMS is superior to single EMS in restoring CVRC in adult MMD patients.

Proposal for a new grading of Moyamoya disease in adult patients.

BACKGROUND: Moyamoya disease (MMD) is graded based on digital subtraction angiography (DSA) with limited clinical applications. The aim was to identify clinically relevant parameters that may be used to develop a novel MMD grading system. METHODS: In 40 MMD patients bilateral revascularization surgery was performed. Clinical data including DSA, MRI and regional cerebral blood flow studies were assessed. χ(2) test corrected for dependency of measurements at the same subject and analysis of receiver operating characteristics were used to identify key parameters. Grading system included: DSA (stenosis/occlusion = 1 point; stenosis/occlusion + intracranial compensation = 2 points; stenosis/occlusion + intracranial compensation + extra-intracranial compensation = 3 points), MRI (no sign of ischemia = 0 points; signs of ischemia = 1 point) and cerebrovascular reserve capacity (CVRC > -5% = 0 points; CVRC < -5% = 2 points). MMD grade I referred to 1-2 points, grade II to 3-4 and grade III to 5-6 points. RESULTS: DSA, MRI and CVRC were dependent factors associated with the occurrence of clinical symptoms. Receiver operating characteristics analysis indentified the grading system as superior to each single parameter in predicting clinical symptoms. Fourteen hemispheres were graded as mild (grade I), 35 as moderate (grade II) and 31 as severe (grade III); 21% of grade I, 63% of grade II and 93% of grade III hemispheres were clinically symptomatic. CONCLUSIONS: The proposed grading system allows to stratify for clinical symptomatology in MMD patients. Future studies will have to investigate its value for assessing clinical symptoms and treatment risks.