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Lennart Riemann, Daphne C. Voormolen, Katrin Rauen, Klaus Zweckberger, Andreas Unterberg, Alexander Younsi, and the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Investigators and Participants

OBJECTIVE

The aim of this paper was to evaluate the prevalence of postconcussive symptoms and their relation to health-related quality of life (HRQOL) in pediatric and adolescent patients with mild traumatic brain injury (mTBI) who received head CT imaging during initial assessment.

METHODS

Patients aged between 5 and 21 years with mTBI (Glasgow Coma Scale scores 13–15) and available Rivermead Post Concussion Questionnaire (RPQ) at 6 months of follow-up in the multicenter, prospectively collected CENTER-TBI (Collaborative European NeuroTrauma Effectiveness Research in TBI) study were included. The prevalence of postconcussive symptoms was assessed, and the occurrence of postconcussive syndrome (PSC) based on the ICD-10 criteria, was analyzed. HRQOL was compared in patients with and without PCS using the Quality of Life after Brain Injury (QOLIBRI) questionnaire.

RESULTS

A total of 196 adolescent or pediatric mTBI patients requiring head CT imaging were included. High-energy trauma was prevalent in more than half of cases (54%), abnormalities on head CT scans were detected in 41%, and admission to the regular ward or intensive care unit was necessary in 78%. Six months postinjury, 36% of included patients had experienced at least one moderate or severe symptom on the RPQ. PCS was present in 13% of adolescents and children when considering symptoms of at least moderate severity, and those patients had significantly lower QOLIBRI total scores, indicating lower HRQOL, compared with young patients without PCS (57 vs 83 points, p < 0.001).

CONCLUSIONS

Adolescent and pediatric mTBI patients requiring head CT imaging show signs of increased trauma severity. Postconcussive symptoms are present in up to one-third of those patients, and PCS can be diagnosed in 13% 6 months after injury. Moreover, PCS is significantly associated with decreased HRQOL.

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Henrik Giese, Benjamin Haenig, Anna Haenig, Andreas Unterberg, and Klaus Zweckberger

OBJECTIVE

Craniopharyngiomas are rare and benign tumors of the sellar and/or parasellar region. Primary treatment involves resection followed by adjuvant radiotherapy. While the grade of resection was frequently analyzed following surgery, the neurological outcome and especially neuropsychological deficits and quality of life have been neglected for many decades. Therefore, the authors retrospectively analyzed their patient series and prospectively assessed neuropsychological outcome and quality of life following resection of craniopharyngiomas in adults.

METHODS

In total, 71 patients (39 men and 32 women) with a mean age of 49 years were enrolled in the retrospective analysis. In addition, 36 of the 71 patients were included in the prospective arm of the study and underwent neurological and neuropsychological testing as well as quality of life (36-Item Short-Form Health Survey; SF-36) assessment. Factors influencing outcome were identified and correlations calculated.

RESULTS

Resection was performed mostly using a pterional (41.6%, 47/113 surgical procedures) or bifrontal translamina terminalis (30.1%, 34/113 surgical procedures) approach. Following surgery, visual acuity was significantly improved (> 0.2 diopters) in 32.4% (23/71) of patients, or remained stable in 45.1% (32/71) of patients. During long-term follow up, 80.3% (57/71) of patients developed pituitary insufficiency, particularly involving the corticotropic and thyrotrophic axes. In total, 75% (27/36) of patients showed neuropsychological deviations in at least 1 test item. In particular, attentiveness, cognitive speed, and short-term memory were affected. Referring to the SF-36 score, quality of life was affected in both the mental and physical score in 19.4% (7/36) and 33.3% (12/36), respectively. The risk factors that were identified were a tumor volume larger than 9 cm3, tumor extension toward/into the third ventricle or the brainstem, and resection using a bifrontal translamina terminalis or left-sided approach.

CONCLUSIONS

This study demonstrated that resection of craniopharyngiomas is frequently associated with postoperative neuropsychological deficits and hence an impaired quality of life. In addition to tumor size and extension toward/into the third ventricle or the brainstem, selection of the surgical approach may play a crucial role in the patient’s neuropsychological outcome and quality of life.

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Moritz Scherer, Christine Jungk, Michael Götz, Philipp Kickingereder, David Reuss, Martin Bendszus, Klaus Maier-Hein, and Andreas Unterberg

OBJECTIVE

In WHO grade II low-grade gliomas (LGGs), early postoperative MRI (epMRI) may overestimate residual tumor on FLAIR sequences. Consequently, MRI at 3–6 months follow-up (fuMRI) is used for delineation of residual tumor. This study sought to evaluate if integration of apparent diffusion coefficient (ADC) maps permits an accurate estimation of residual tumor early on epMRI.

METHODS

From a consecutive cohort, 43 cases with an initial surgery for an LGG, and complete epMRI (< 72 hours after resection) and fuMRI including ADC maps, were retrospectively identified. Residual FLAIR hyperintense tumor was manually segmented on epMRI and corresponding ADC maps were coregistered. Using an expectation maximization algorithm, residual tumor segments were probabilistically clustered into areas of residual tumor, ischemia, or normal white matter (NWM) by fitting a mixture model of superimposed Gaussian curves to the ADC histogram. Tumor volumes from epMRI, clustering, and fuMRI were statistically compared and agreement analysis was performed.

RESULTS

Mean FLAIR hyperintensity suggesting residual tumor was significantly larger on epMRI compared to fuMRI (19.4 ± 16.5 ml vs 8.4 ± 10.2 ml, p < 0.0001). Probabilistic clustering of corresponding ADC histograms on epMRI identified subsegments that were interpreted as mean residual tumor (7.6 ± 10.2 ml), ischemia (8.1 ± 5.9 ml), and NWM (3.7 ± 4.9 ml). Therefore, mean tumor quantification error between epMRI and fuMRI was significantly reduced (11.0 ± 10.6 ml vs −0.8 ± 3.7 ml, p < 0.0001). Mean clustered tumor volumes on epMRI were no longer significantly different from the fuMRI reference (7.6 ± 10.2 ml vs 8.4 ± 10.2 ml, p = 0.16). Correlation (Pearson r = 0.96, p < 0.0001), concordance correlation coefficient (0.89, 95% confidence interval 0.83), and Bland-Altman analysis suggested strong agreement between both measures after clustering.

CONCLUSIONS

Probabilistic segmentation of ADC maps facilitates accurate assessment of residual tumor within 72 hours after LGG resection. Multiparametric image analysis detected FLAIR signal alterations attributable to surgical trauma, which led to overestimation of residual LGG on epMRI compared to fuMRI. The prognostic value and clinical impact of this method has to be evaluated in larger case series in the future.

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Moritz Scherer, Christine Jungk, Alexander Younsi, Philipp Kickingereder, Simon Müller, and Andreas Unterberg

OBJECTIVE

In this analysis, the authors sought to identify variables triggering an additional resection (AR) and determining residual intraoperative tumor volume in 1.5-T intraoperative MRI (iMRI)-guided glioma resections.

METHODS

A consecutive case series of 224 supratentorial glioma resections (WHO Grades I–IV) from a prospective iMRI registry (inclusion dates January 2011–April 2013) was examined with univariate and multiple regression models including volumetric data, tumor-related, and surgeon-related factors. The surgeon's expectation of an AR, in response to a questionnaire completed prior to iMRI, was evaluated using contingency analysis. A machine-learning prediction model was applied to consider if anticipation of intraoperative findings permits preoperative identification of ideal iMRI cases.

RESULTS

An AR was performed in 70% of cases after iMRI, but did not translate into an accumulated risk for neurological morbidity after surgery (p = 0.77 for deficits in cases with AR vs no AR). New severe persistent deficits occurred in 6.7% of patients. Initial tumor volume determined frequency of ARs and was independently correlated with larger tumor remnants delineated on iMRI (p < 0.0001). Larger iMRI volume was further associated with eloquent location (p = 0.010) and recurrent tumors (p < 0.0001), and with WHO grade (p = 0.0113). Greater surgical experience had no significant influence on the course of surgery. The surgeon's capability of ruling out an AR prior to iMRI turned out to incorporate guesswork (negative predictive value 43.6%). In a prediction model, AR could only be anticipated with 65% accuracy after integration of confounding variables.

CONCLUSIONS

Routine use of iMRI in glioma surgery is a safe and reliable method for resection guidance and is characterized by frequent ARs after scanning. Tumor-related factors were identified that influenced the course of surgery and intraoperative decision-making, and iMRI had a common value for surgeons of all experience levels. Commonly, the subjective intraoperative impression of the extent of resection had to be revised after iMRI review, which underscores the manifold potential of iMRI guidance. In combination with the failure to identify ideal iMRI cases preoperatively, this study supports a generous, tumor-oriented rather than surgeon-oriented indication for iMRI in glioma surgery.

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Miriam Ratliff, Andreas Unterberg, and Heidi Bächli

The authors present the unusual case of a 4-year-old boy who had a complex history of posthemorrhagic hydrocephalus and who underwent more than 40 surgeries related to this condition. In the course of trying to treat his condition, ventriculoperitoneal, ventriculoatrial, and ventriculopleural shunts were inserted and failed.

The child presented with a dysfunction of his shunt system. A ventriculopleural shunt was inserted, but within days the patient developed dyspnea as a clinical symptom of pleural effusion that required repeated thoracentesis. A bipleural drainage system was inserted, and no relevant pleural effusions developed during the follow-up period.

Although the authors’ experience is based on a single case, they do suggest bipleural drainage in patients with clinically relevant pleural effusions when the more common alternatives are not a good choice. Bipleural drainage might particularly be an option in children, who are prone to pleural effusion because of the smaller absorbing pleural surface. The authors reviewed the English-language literature on PubMed dating back to 1952. To their knowledge, this is the only published case in which a patient was treated with a ventriculo-bipleural shunt.

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Marc-Eric Halatsch, Sarah Löw, Kay Mursch, Thomas Hielscher, Ursula Schmidt, Andreas Unterberg, Vassilios I. Vougioukas, and Friedrich Feuerhake

Object

The authors have previously reported that erlotinib, an EGFR tyrosine kinase inhibitor, exerts widely variable antiproliferative effects on 9 human glioblastoma multiforme (GBM) cell lines in vitro and in vivo. These effects were independent of EGFR baseline expression levels, raising the possibility that more complex genetic properties form the molecular basis of the erlotinib-sensitive and erlotinib-resistant GBM phenotypes. The aim of the present study was to determine candidate genes for mediating the cellular response of human GBMs to erlotinib.

Methods

Complementary RNA obtained in cell lines selected to represent the sensitive, somewhat responsive, and resistant phenotypes were hybridized to CodeLink Human Whole Genome Bioarrays.

Results

Expression analysis of 814 prospectively selected genes involved in major proliferation and apoptosis signaling pathways identified 19 genes whose expression significantly correlated with phenotype. Functional annotation analysis revealed that 2 genes (DUSP4 and STAT1) were significantly associated with sensitivity to erlotinib, and 10 genes (CACNG4, FGFR4, HSPA1B, HSPB1, NFATC1, NTRK1, RAC1, SMO, TCF7L1, and TGFB3) were associated with resistance to erlotinib. Moreover, 5 genes (BDNF, CARD6, FOSL1, HSPA9B, and MYC) involved in antiapoptotic pathways were unexpectedly found to be associated with sensitivity. Gene expressions were confirmed by quantitative polymerase chain reaction.

Conclusions

Based on an analysis of gene expressions in cell lines with sensitive, somewhat responsive, and resistant phenotypes, the authors propose candidate genes for GBM response to erlotinib. The 10 gene candidates for conferring GBM resistance to erlotinib may represent therapeutic targets for enhancing the efficacy of erlotinib against GBMs. Five additional genes warrant further investigation into their role as putative cotargets of erlotinib.

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Berk Orakcioglu, Peter Schramm, Patricia Kohlhof, Alfred Aschoff, Andreas Unterberg, and Marc-Eric Halatsch

Object

Thoracolumbar intraspinal subependymomas are very rare intramedullary low-grade tumors. The authors report on the clinical and morphological features of 2 cases of thoracolumbar intraspinal subependymomas and provide midterm follow-up data.

Methods

The clinical and radiological profiles of 2 patients with progressive spinal cord dysfunction due to thoracolumbar intraspinal subependymomas were retrospectively studied and compared with previously reported cases.

Results

Patients with intraspinal subependymomas initially presented with back pain and long-tract signs. The tumors were hyperintense on T2-weighted MR imaging, isointense on T1-weighted imaging, and noncontrast enhancing. Within 1 of the tumors, a medial septum was present on axial T2-weighted imaging. The tumors were intramedullary but grew exophytically and were amenable to gentle surgical separation from normal neural structures. Therefore, gross-total resection was feasible, and neurological outcome was good. No further adjuvant therapy was conducted. On follow-up (at 58 and 18 months, respectively), no tumor recurrence was observed.

Conclusions

Symptomatic thoracolumbar intraspinal subependymomas with a distinct appearance on MR imaging are amenable to complete excision with favorable neurological outcome. In this study no tumor recurrence was observed at midterm follow-up in either patient, neither of whom underwent adjuvant therapy.

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Andreas Unterberg, Walter Schmidt, Michael Wahl, Earl F. Ellis, Anthony Marmarou, and Alexander Baethmann

✓ Leukotrienes are powerful metabolites of arachidonic acid which are known to increase the permeability of peripheral blood vessels. These substances are found in brain tissue in association with cerebral ischemia, and in brain tumors. Therefore, it has been proposed that leukotrienes have a mediator function in brain edema. This hypothesis was subjected to further experimental analysis in this study, in which the authors investigated whether: 1) superfusion of the exposed brain surface with leukotrienes increases the permeability of extraparenchymal blood vessels in vivo; 2) intraparenchymal infusion of leukotrienes induces brain edema; and 3) pharmacological inhibition of leukotriene formation by BW755C, an inhibitor of leukotriene synthesis, reduces formation of brain edema from a standardized traumatic insult.

The pial vessels of the parietal cortex of cats were examined by fluorescence microscopy during cerebral superfusion with the leukotrienes C4 (LTC4), D4 (LTD4), or E4 (LTE4) by using an open cranial window preparation. Intravenous Na+-fluorescein served as an in vivo blood-brain barrier (BBB) indicator. Superfusion of the pia with leukotrienes (up to 2 µM) did not open the barrier to fluorescein, but was associated with a significant constriction (up to 25%) of arterial and venous vessels. In experiments with slow infusion of leukotriene B4 (LTB4) or LTC4 into the white matter of feline brain, the tissue water content was subsequently determined in serial brain slices using the specific gravity method. Tissue water profiles obtained after a 15- µM infusion of either LTB4 or LTC4 were virtually identical with those of control animals infused with mock cerebrospinal fluid. Thus, neither LTB4 nor LTC4 led to an augmentation of infusion-induced brain edema. In a final series, a cold lesion of the left parietal cortex was induced in rabbits. Twenty-four hours later, swelling of the exposed hemisphere was quantified by gravimetrical comparison of its weight with that of the contralateral nontraumatized hemisphere. Eight animals received BW755C intravenously prior to and after trauma to inhibit formation of leukotrienes. Seven rabbits were infused with an equivalent volume of saline as a control study. The resulting hemispheric swelling was 7.7% ± 0.6% (mean ± standard error of the mean) 24 hours later in animals receiving BW755C and 7.8% ± 1.2% in the control group, indicating that inhibition of leukotrienes was ineffective in preventing formation of vasogenic brain edema.

The findings demonstrate that leukotrienes administered to the brain in concentrations occurring under pathological conditions do not open the BBB nor do they induce brain edema. Moreover, formation of brain edema from a standard insult was not therapeutically influenced by inhibition of leukotriene synthesis. Thus, the current findings taken together do not support a role of leukotrienes as mediators in brain edema.

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The kallikrein-kinin system as mediator in vasogenic brain edema

Part 3: Inhibition of the kallikrein-kinin system in traumatic brain swelling

Andreas Unterberg, Claudia Dautermann, Alexander Baethmann, and Werner Müller-Esterl

✓ Evidence has previously been provided that administration of kinins to the cerebrum causes edema and opening of the blood-brain barrier. It has further been shown that these highly active compounds are formed in the brain under pathophysiological conditions. Their formation was enhanced when cerebral blood flow became compromised by an increase in intracranial pressure. Final evidence, however, was not available as to whether specific inhibition of the kallikrein-kinin (KK) system has a therapeutic function in acute head injury. The authors have demonstrated in rabbits that inhibition of the activating enzyme kallikrein by aprotinin or by aprotinin plus soybean trypsin inhibitor (SBTI), which interfere with plasma and tissue kallikrein, is associated with a decrease in formation of posttraumatic swelling after a standardized cold lesion to the brain. Saline-treated control animals with cerebral cold-induced injury had an increase in hemispheric weight 24 hours later of 13.0% ± 0.8% (standard error of the mean) in the damaged hemisphere compared to the contralateral nondamaged hemisphere. Administration of aprotinin or aprotinin plus SBTI led to a significant reduction of hemispheric swelling of 10.1% ± 0.7% or 10.4% ± 0.7%, respectively. In animals receiving SBTI only, hemispheric swelling evolving from cold injury was not significantly reduced. Therapeutic reduction of brain edema by aprotinin cannot be attributed to a nonspecific effect on the blood pressure, which in the experimental groups remained almost normal as compared to the control animals. Failure of SBTI to influence posttraumatic brain swelling may have resulted from disturbances in intravascular coagulation. Measurements of aprotinin in plasma and tissue demonstrate that the inhibitor doses employed are within an effective therapeutic range. Attenuation of brain edema by specific inhibition of the KK system provides evidence for a mediator role of kinins in vasogenic edema. Clinical trials with inhibitors of the KK system in acute forms of traumatic lesions associated with vasogenic edema appear worthwhile.