D. Verbaan

The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone

BACKGROUNDnGenetic and epigenetic profiling of glioblastomas has provided a comprehensive list of altered cancer genes of which only O(6)-methylguanine-methyltransferase (MGMT) methylation is used thus far as a predictive marker in a clinical setting. We investigated the prognostic significance of genetic and epigenetic alterations in glioblastoma patients.nnnMETHODSnWe screened 98 human glioblastoma samples for genetic and epigenetic alterations in 10 genes and chromosomal loci by PCR and multiplex ligation-dependent probe amplification (MLPA). We tested the association between these genetic and epigenetic alterations and glioblastoma patient survival. Subsequently, we developed a 2-gene survival predictor.nnnRESULTSnMultivariate analyses revealed that mutations in isocitrate dehydrogenase 1 (IDH1), promoter methylation of MGMT, irradiation dosage, and Karnofsky Performance Status (KFS) were independent prognostic factors. A 2-gene predictor for glioblastoma survival was generated. Based on the genetic and epigenetic status of IDH1 and MGMT, glioblastoma patients were stratified into 3 clinically different genotypes: glioblastoma patients with IDH1mt/MGMTmet had the longest survival, followed by patients with IDH1mt/MGMTunmet or IDH1wt/MGMTmet, and patients with IDH1wt/MGMTunmet had the shortest survival. This 2-gene predictor was an independent prognostic factor and performed significantly better in predicting survival than either IDH1 mutations or MGMT methylation alone. The predictor was validated in 3 external datasets.nnnDISCUSSIONnThe combination of IDH1 mutations and MGMT methylation outperforms either IDH1 mutations or MGMT methylation alone in predicting survival of glioblastoma patients. This information will help to increase our understanding of glioblastoma biology, and it may be helpful for baseline comparisons in future clinical trials.

Is olfactory impairment in Parkinson disease related to phenotypic or genotypic characteristics

Objective: To evaluate the relation between olfactory impairment (OI) and other impairment domains in Parkinson disease (PD) and the characteristics of OI in patients with certain genotypic characteristics. Methods: In 295 nondemented patients with PD and 150 controls with a similar overall age and sex distribution, olfactory function was evaluated with the identification (ID) and discrimination (DIS) tests of the Sniffin’ Sticks. In patients, demographic and clinical characteristics were evaluated, and genetic analyses were performed. Results: Of all patients, 61% had an impaired ID and 43% had an impaired DIS. No significant correlations >0.4 were found between olfactory scores and other demographic or clinical variables. Age and sex accounted for the 22% explained variance of the ID score regression model, whereas age, sex, and disease duration accounted for the 15% explained variance of the DIS score regression model. Parkin and DJ-1 mutation carriers (homozygous or heterozygous compound, n = 6) had normal ID scores. APOE ε2 or APOE ε4 carriers had no significantly different olfactory scores than noncarriers. The allele distribution of the alpha-synuclein (SNCA)-REP1 polymorphism in groups with an impaired or normal ID or DIS was comparable. Conclusions: Olfactory impairment (OI) in Parkinson disease (PD) may be unrelated to other impairment domains of the disease, which may indicate that olfaction is an independent feature of PD. Parkin and DJ-1 mutation carriers had normal identification scores but the number of mutation carriers is too small to draw conclusions. The APOE genotype (APOE ε2 or APOE ε4 alleles) and SNCA-REP1 polymorphism do not seem to influence olfaction in PD. GLOSSARY: AAO = age at onset; BDI = Beck Depression Inventory; DIS = discrimination test of the Sniffin’ Sticks; EOPD = early-onset PD; H&Y = Hoehn & Yahr; ID = identification test of the Sniffin’ Sticks; LDE = levodopa equivalent; LUMC = Leiden University Medical Center; MMSE = Mini-Mental State Examination; OI = olfactory impairment; PD = Parkinson disease; PIGD = postural instability gait difficulty; PROPARK = PROfiling PARKinson’s disease; SCOPA = SCales for Outcomes in PArkinson’s disease; SNPs = single nucleotide polymorphisms; UPSIT = University of Pennsylvania Smell IdentificationTest; VUMC = VU University Medical Center.

Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial.

BackgroundA frequent complication in patients with subarachnoid hemorrhage (SAH) is recurrent bleeding from the aneurysm. The risk is highest within the first 6 hours after the initial hemorrhage. Securing the aneurysm within this timeframe is difficult owing to logistical delays. The rate of recurrent bleeding can also be reduced by ultra-early administration of antifibrinolytics, which probably improves functional outcome. The aim of this study is to investigate whether ultra-early and short-term administration of the antifibrinolytic agent tranexamic acid (TXA), as add-on to standard SAH management, leads to better functional outcome.Methods/DesignThis is a multicenter, prospective, randomized, open-label trial with blinded endpoint (PROBE) assessment. Adult patients with the diagnosis of non-traumatic SAH, as proven by computed tomography (CT) within 24 hours after the onset of headache, will be randomly assigned to the treatment group or the control group. Patients in the treatment group will receive standard treatment with the addition of a bolus of TXA (1 g intravenously) immediately after randomization, followed by continuous infusion of 1 g per 8 hours until the start of aneurysm treatment, or a maximum of 24 hours after the start of medication. Patients in the control group will receive standard treatment without TXA. The primary outcome measure is favorable functional outcome, defined as a score of 0 to 3 on the modified Rankin Scale (mRS), at 6 months after SAH. Primary outcome will be determined by a trial nurse blinded for treatment allocation. We aim to include 950 patients in 3 years.DiscussionThe strengths of this study are: 1. the ultra-early and short-term administration of TXA, resulting in a lower dose as compared to previous studies, which should reduce the risk for delayed cerebral ischemia (DCI), an important risk factor in the long-term treatment with antifibrinolytics; 2. the power calculation is based on functional outcome and calculated with use of recent study results of our own population, supported by data from prominent studies; and 3. the participation of several specialized SAH centers, and their referring hospitals, in the Netherlands with comparative treatment protocols.Trial registrationNederlands Trial Register (Dutch Trial Registry) number NTR3272

Patterns of motor and non-motor features in Parkinson’s disease

Objective: To evaluate the presence and nature of patterns of coherency among the motor and non-motor domains in Parkinson’s disease (PD) and to examine which clinical parameters are related to the potential patterns. Methods: A cohort of 397 patients with PD were randomly divided into two samples. Exploratory factor analysis (EFA) was performed on the motor and non-motor symptoms in PD in the first sample. Findings of the EFA were used to construct a model which was tested in the second sample by confirmatory factor analysis. Multiple regression analyses on the resulting factors were performed to evaluate the influence of clinical parameters on these factors. Results: Four factors were identified. The first and strongest factor (cognitive impairment, autonomic dysfunction, psychotic symptoms, depression, daytime sleepiness and axial symptoms) reflected advancing disease. Another factor largely reflected motor complications of therapy and was related to dopaminergic medication. The other two factors reflected sleep/depression and tremor/bradykinesia/rigidity, and were only marginally related to disease severity or medication. Conclusions: The motor and non-motor features in PD can be characterised by four distinct patterns of coherency, which provide insight into the contributions of the primary disease process and antiparkinsonian medication to the broad clinical spectrum of PD. One factor, consisting of predominantly non-motor symptoms together with axial features, clearly reflected disease severity and may provide a new basis for monitoring disease progression in PD.

Age determination of subdural hematomas with CT and MRI: A systematic review

OBJECTIVESnTo systematically review the literature on dating subdural hematomas (SDHs) on CT and MRI scans.nnnMETHODSnWe performed a systematic review in MEDLINE, EMBASE and Cochrane to search for articles that described the appearance of SDHs on CT or MRI in relation to time between trauma and scanning. Two researchers independently screened the articles, assessed methodological quality and performed data extraction. Medians with interquartile ranges were calculated. Differences were tested with a Mann-Whitney U or Kruskal-Wallis H test.nnnRESULTSnWe included 22 studies describing 973 SDHs on CT and 4 studies describing 83 SDHs on MRI. Data from 17 studies (413 SDHs) could be pooled. There were significant differences between time intervals for the different densities on CT (p<0.001). Time interval differed significantly between children and adults for iso- and hypodensity (p=0.000) and hyperdensity (p=0.046). Time interval did not differ significantly between abused and non-abused children. On MRI, time intervals for different signal intensities on T1 and T2 did not differ significantly (p=0.108 and p=0.194, respectively).nnnCONCLUSIONSnMost time intervals of the different appearances of SDHs on CT and MRI are broad and overlapping. Therefore CT or MRI findings cannot be used to accurately date SDHs.

Additional value of intra-aneurysmal hemodynamics in discriminating ruptured versus unruptured intracranial aneurysms

BACKGROUND AND PURPOSE: Hemodynamics are thought to play an important role in the rupture of intracranial aneurysms. We tested whether hemodynamics, determined from computational fluid dynamics models, have additional value in discriminating ruptured and unruptured aneurysms. Such discriminative power could provide better prediction models for rupture. MATERIALS AND METHODS: A cross-sectional study was performed on patients eligible for endovascular treatment, including 55 ruptured and 62 unruptured aneurysms. Association with rupture status was tested for location, aneurysm type, and 4 geometric and 10 hemodynamic parameters. Patient-specific spatiotemporal velocities measured with phase-contrast MR imaging were used as inflow conditions for computational fluid dynamics. To assess the additional value of hemodynamic parameters, we performed 1 univariate and 2 multivariate analyses: 1 traditional model including only location and geometry and 1 advanced model that included patient-specific hemodynamic parameters. RESULTS: In the univariate analysis, high-risk locations (anterior cerebral arteries, posterior communicating artery, and posterior circulation), daughter sacs, unstable inflow jets, impingements at the aneurysm body, and unstable complex flow patterns were significantly present more often in ruptured aneurysms. In both multivariate analyses, only the high-risk location (OR, 3.92; 95% CI, 1.77–8.68) and the presence of daughter sacs (OR, 2.79; 95% CI, 1.25–6.25) remained as significant independent determinants. CONCLUSIONS: In this study population of patients eligible for endovascular treatment, we found no independent additional value of aneurysmal hemodynamics in discriminating rupture status, despite high univariate associations. Only traditional parameters (high-risk location and the presence of daughter sacs) were independently associated with ruptured aneurysms.

A strategy to expeditious invasive treatment improves clinical outcome in comatose patients with aneurysmal subarachnoid haemorrhage

In patients with poor clinical condition after aneurysmal subarachnoid haemorrhage (aSAH), treatment is often deferred until patients show signs of improvement. Early external ventricular drainage and aneurysm occlusion may improve prognosis also in poor grade patients. The clinical outcome of an expeditious approach was compared with that of a conservative approach.

3D Volumetric Measurement of Neurofibromatosis Type 2-Associated Meningiomas: Association Between Tumor Location and Growth Rate.

OBJECTIVEnTreatment of meningiomas in neurofibromatosis type II (NF2) patients is challenging because the natural history of these tumors is unclear. More insight in tumor growth and factors predicting growth may contribute to a better clinical management. In this study, growth characteristics of supratentorial NF-related meningiomas were examined and the association between tumor growth rate and location was evaluated.nnnMETHODSnIn all NF2 patients followed up at the VU University Medical Center, who underwent a minimum of 3 consecutive scans, tumor volumes were assessed by using 3D volumetric measurement (Brainlab, Feldkirchen, Germany). Growth patterns were visually analyzed. To assess the association between tumor growth rate and tumor location, the meningiomas were divided in 3 groups on the basis of their location: skull base, convexity, and other. Univariable and multivariable logistic regression models were built.nnnRESULTSnTwenty-one patients (13 females) with a mean (standard deviation) follow-up period of 5.55 (2.48) years and a total of 210 meningiomas were included in the analyses. Tumors followed different growth patterns and did not increase in size simultaneously within 1 patient. Skull base meningiomas had a significantly higher absolute growth rate compared with convexity (β = 0.91, 95% confidence interval [CI] 0.08-1.73) and other (β = 1.07, 95% CI 0.27-1.86) and a significantly higher relative growth rate on both linear and geometric growth rate compared with other (β = 90.73, 95% CI 5.50-175.95 and β = 18.63, 95% CI 2.94-34.31, respectively) on multivariable logistic regression.nnnCONCLUSIONnWithin a single patient, NF2-related meningiomas follow different growth patterns. Skull base meningiomas grow faster compared with other locations. Yearly magnetic resonance imaging scans and timely treatment of skull base meningiomas should be considered.

Association of Automatically Quantified Total Blood Volume after Aneurysmal Subarachnoid Hemorrhage with Delayed Cerebral Ischemia

The authors retrospectively studied clinical and radiologic data of 333 consecutive patients with aneurysmal SAH between January 2009 and December 2011. Adjusted odds ratios werecalculated for the association between automatically quantified total blood volume on NCCT and delayed cerebral ischemia (clinical, radiologic, and both). The adjusted OR of total blood volume for delayed cerebral ischemia was 1.02 per milliliter of blood. They conclude that a higher total blood volume measured with the automated quantification method is significantly associated with delayed cerebral ischemia. BACKGROUND AND PURPOSE: The total amount of extravasated blood after aneurysmal subarachnoid hemorrhage, assessed with semiquantitative methods such as the modified Fisher and Hijdra scales, is known to be a predictor of delayed cerebral ischemia. However, prediction rates of delayed cerebral ischemia are moderate, which may be caused by the rough and observer-dependent blood volume estimation used in the prediction models. We therefore assessed the association between automatically quantified total blood volume on NCCT and delayed cerebral ischemia. MATERIALS AND METHODS: We retrospectively studied clinical and radiologic data of consecutive patients with aneurysmal SAH admitted to 2 academic hospitals between January 2009 and December 2011. Adjusted ORs with associated 95% confidence intervals were calculated for the association between automatically quantified total blood volume on NCCT and delayed cerebral ischemia (clinical, radiologic, and both). The calculations were also performed for the presence of an intraparenchymal hematoma and/or an intraventricular hematoma and clinical delayed cerebral ischemia. RESULTS: We included 333 patients. The adjusted OR of total blood volume for delayed cerebral ischemia (clinical, radiologic, and both) was 1.02 (95% CI, 1.01–1.03) per milliliter of blood. The adjusted OR for the presence of an intraparenchymal hematoma for clinical delayed cerebral ischemia was 0.47 (95% CI, 0.24–0.95) and of the presence of an intraventricular hematoma, 2.66 (95% CI, 1.37–5.17). CONCLUSIONS: A higher total blood volume measured with our automated quantification method is significantly associated with delayed cerebral ischemia. The results of this study encourage the use of rater-independent quantification methods in future multicenter studies on delayed cerebral ischemia prevention and prediction.

Spinal axis imaging in non-aneurysmal subarachnoid hemorrhage: a prospective cohort study

In 15xa0% of all spontaneous subarachnoid hemorrhages (SAH), no intracranial vascular pathology is found. Those non-aneurysmal hemorrhages are categorized into perimesencephalic SAH (PMSAH) and non-perimesencephalic SAH (NPSAH). Searching for spinal pathology might reveal a cause for the hemorrhage in some patients. Our goal was to assess the yield of magnetic resonance (MR) imaging of the complete spinal axis in search for a spinal origin in non-aneurysmal SAH. In a prospective, observational study at a tertiary SAH referral center, we assessed clinical and radiological characteristics of patients who consecutively presented with spontaneous non-aneurysmal SAH, diagnosed by computed tomography (CT) or lumbar puncture, and negative CT angiography and digital subtraction angiography (DSA). Eligible patients were enrolled for investigation of the complete spinal axis by standard T1- and T2-weighted MR-imaging. Ninety-seven non-aneurysmal SAH patients were included in the study. Baseline characteristics were comparable between PMSAH and NPSAH patients. DSA and spinal MR-imaging were performed in 95 and 91xa0% of patients, respectively. This revealed one lumbar ependymoma in a 43-year-old male who was diagnosed by LP (yield 1xa0%). No spinal origin for the SAH was found in 51 PMSAH patients. The yield of MR-imaging of the complete spinal axis in spontaneous non-aneurysmal SAH patients is low. Routine radiological investigation of the spinal axis in non-aneurysmal SAH patients is therefore not recommended.