Bernt Due-Tønnessen

Assessment of Continuous Intracranial Pressure Recordings in Childhood Craniosynostosis

In this study, we explored two strategies of assessing continuous intracranial pressure (ICP) recordings in children with craniosynostosis, namely either by computation of the mean ICP or by computation of the accurate numbers of ICP elevations of different durations. The ICP recordings of 121 consecutive patients with a tentative diagnosis of craniosynostosis who underwent continuous ICP monitoring were examined. The relationship between mean ICP and numbers of ICP elevations was defined. The distribution of numbers of ICP elevations between patients either undergoing surgery or conservative treatment was also compared, since the choice of treatment was heavily dependent on the results of ICP monitoring. At the time of ICP monitoring, calculation of mean ICP was the main parameter for assessment of ICP curves. After a median observation period of 16 months, the ICP curves were reexamined by means of the software SensometricsTM Pressure Analyser, which presents the ICP curve as a matrix of numbers of ICP elevations of different levels (20–40 mm Hg) and durations (0.5– 20 min). Since the recording period differed between the cases, the numbers were standardized to a given recording time of 10 h, to allow for comparisons between patients. Cases with a borderline mean ICP during sleep (mean ICP 10–15 mm Hg) constituted 40.5% of the 121 patients. In this group, a rather weak relationship between mean ICP and the number of ICP elevations above 20 mm Hg was found, as well as a relatively high number of ICP elevations above 20 mm Hg of various durations. As compared to the patients undergoing surgery, a rather high number of ICP elevations above 20 mm Hg of various durations was found in patients undergoing conservative treatment. The study confirmed our hypothesis that in children with craniosynostosis, calculation of mean ICP does not describe the ICP curve in a reliable way. Decision-making should also include the computation of the distribution of numbers of ICP elevations, since this procedure represents a more sensitive strategy of detecting intracranial hypertension.

Changes in Intracranial Pressure after Calvarial Expansion Surgery in Children with Slit Ventricle Syndrome

The effect of calvarial expansion on symptom relief and intracranial pressure (ICP) in three children with slit ventricle syndrome (SVS) and intracranial hypertension despite a functioning ventricular shunt is reported. These children presented with a clinical picture of SVS, accompanied by slit-like ventricles on cranial computer tomography scan and intracranial hypertension. Calvarial expansion was performed by mans of an anterior approach in one case and a posterior approach (modified tiara plastic) in the other two cases. After calvarial expansion, symptoms of intracranial hypertension were abolished in one case and markedly reduced in two cases (observation period 25–36 months). Comparison of ICP before and after surgery was performed by means of new software (Sensometrics™ Pressure Analyser, version 1.2) that revealed a significant reduction in the number of abnormal ICP elevations after surgery. The results were not accompanied by changes in the size of the cerebral ventricles. This study demonstrates that in children with SVS and intracranial hypertension despite a functioning shunt, calvarial expansion may reduce ICP and produce long-lasting symptom relief. In these cases, we suggest that intracranial hypertension was caused by compromised intracranial volume.

Differences in quantitative characteristics of intracranial pressure in hydrocephalic children treated surgically or conservatively.

This study reports the results of quantitative analysis of continuous intracranial pressure (ICP) recordings in 33 hydrocephalic children. The aim of the study was to compare the exact numbers of increases in ICP during sleep or the awake state in hydrocephalic children who were treated either surgically or conservatively. At the time of ICP monitoring, the ICP curves were assessed by the calculation of mean ICP and visual inspection for the detection of plateau waves. Quantitative analysis was performed with the software SensometricsTM Pressure Analyser, which presented the ICP curve as a matrix of numbers of ICP elevations of different levels (20–40 mm Hg) and durations (0.5–20 min). In each case, the numbers of ICP elevations were standardized to 10 h of recording time, providing the opportunity for comparisons of ICP curves between individuals. Compared to the surgery group, there was a rather high number of ICP elevations of 20 mm Hg of various durations in the nonsurgery group, e.g. ICP elevations of 20 mm Hg lasting 10 min occurred in 13 of 19 children (68%) in the nonsurgery group. There was no apparent relationship between ICP and age or between the size of the cerebral ventricles and ICP. In children with hydrocephalus, the presentation of the ICP data as a matrix of ICP elevations of different levels and durations may enhance the informative value of continuous ICP monitoring, as compared to the calculation of mean ICP and visual detection of plateau waves.

Comparison of perioperative morbidity after LeFort III and monobloc distraction osteogenesis

We have compared distraction by monobloc and LeFort III osteotomy in the treatment of midfacial retrusion. We treated 14 patients with midface distraction (Crouzon syndrome (n = 9), Apert disease (n = 3), and other (n = 2)), 7 of whom had monobloc distraction and 7 who had LeFort III osteotomy. We compared duration of operation, peroperative blood loss, and complications. The two groups were comparable with respect to diagnosis, type of distraction (internal or external device), and duration of distraction. The operating time was longer in the monobloc than in the LeFort III group, but not significantly so (p = 0.09). The weight-adjusted blood losses were significantly different (66 ml/kg and 34 ml/kg, respectively (p = 0.05). The two groups had similar numbers of complications (p = 0.3), and similar duration of hospital stay. Both techniques seem safe. The choice of operation, therefore, should be tailored to the individual patient and the monobloc procedure should be used if indicated.

The Gravity-Assisted Paedi-Gav Valve in the Treatment of Pediatric Hydrocephalus

Objective: A single-center, prospective, nonrandomized pilot study was performed to assess the Paedi-Gav gravity-assisted valve for the treatment of pediatric patients with hydrocephalus. Methods: Participants were pediatric patients (age <16 years) who were candidates for a hydrocephalus shunt system that required a valve insertion at the time of enrollment. The primary outcome event was shunt malfunction; subclassified into shunt obstruction, shunt overdrainage, loculated ventricles, or infection. The shunt obstructions were further subclassified according to site. A total of 32 patients were enrolled onto the study, with 2 undergoing first shunt insertion after failed ventriculostomy and 30 undergoing shunt revisions. On average, the patients had had 3.3 shunt procedures prior to insertion of a Paedi-Gav valve. Results: During a follow-up interval of minimum 52 weeks and a median of 24 months after the first implantation on-study, shunt revisions were required in 17 (53.1%) of the 32 patients. The 12-month shunt-survival rate without revision of any component was 53%, with a median shunt-survival time of 388 days. The most common reasons for shunt revision were shunt obstructions (12/17) and overdrainage (3/17). Shunt obstructions were caused by valve-related failures (9/12) and distal obstructions (3/12). Conclusion: Although the small number of patients enrolled in this study warrants cautious conclusions, the overall results are comparable to those reported for primary shunt insertions with conventional valves in pediatric patients with hydrocephalus. Although this study provides a rationale for examining the Paedi-Gav gravity-assisted shunt valve in a larger prospective randomized controlled trial, the shunt failure pattern, with a rather high frequency of valve-related failures, may indicate potential for further improvements in the valve design and/or manufacturing.

Midface distraction osteogenesis: Internal vs. external devices

This study compares internal and external distraction devices in the treatment of midface retrusion. 20 patients were treated with midface distraction (12 Crouzon, 4 Apert, 4 others); 12 with internal distraction (MID device), 8 with external distraction (Red or Blue device). The two groups were compared regarding operation time, peroperative blood loss and complications. The groups were comparable regarding patient age, sex, weight and diagnosis. In the MID-group, 7 of 12 patients (58%) underwent Le Fort III, 5 underwent 12 monobloc (32%). In the Blue device group, three of eight patients underwent Le Fort II (38%), three of eight underwent Le Fort III (38%), and two of eight underwent monobloc (25%). Operation time was shorter in the Blue device (mean 298 min) than in the MID group (mean 354 min). Peroperative blood loss and complication rates were similar. The internal distraction device is the gold standard for treating midface retrusion. The use of an external distraction device in midface distraction osteogenesis is associated with a shorter operation time; peroperative blood loss and complications were similar. An external device affords better 3-dimensional control during the distraction process, so external distraction is preferable in patients who will tolerate this treatment.

Assessment of intracranial pressure volume relationships in childhood: the lumbar infusion test versus intracranial pressure monitoring

Abstract. Object: This study was undertaken to compare the results of two tests that are widely used to assess intracranial pressure–volume relationships in children: the lumbar steady state infusion test providing information about the resistance to cerebrospinal fluid (CSF) outflow (Rout), and continuous intracranial pressure (ICP) monitoring. Methods: The study included 28 children aged 5–91xa0months, on whom both tests were performed. The median duration between the tests was 1xa0month. With the child in general narcosis, the lumbar CSF pressure was recorded before and during infusion of artificial CSF, and the Rout was calculated on the basis of the opening (Po) and plateau (Pp) pressures (Rout=Pp-Po/infusion rate). ICP was recorded every 5xa0s using a computer-based system. Conclusions: We found no significant correlation between Rout and mean ICP asleep. There were no significant relationships between abnormal mean ICPs during sleep (defined as either 10 or 15xa0mmHg) and abnormally high Rout values (defined as either 10 or 12xa0mmHg/ml/min), and no significant relationships between abnormally high Rout values (10 or 12xa0mmHg ml–1 min–1) and the presence of abnormal ICP elevations (defined as either 20 or 25xa0mmHg and lasting 5xa0min). Therefore the calculation of Rout by the infusion test performed on children under general anesthesia gave no reliable prediction of abnormal ICP.

Fusion genes with ALK as recurrent partner in ependymoma-like gliomas: a new brain tumor entity?

BACKGROUNDnWe have previously characterized 19 ependymal tumors using Giemsa banding and high-resolution comparative genomic hybridization. The aim of this study was to analyze these tumors searching for fusion genes.nnnMETHODSnRNA sequencing was performed in 12 samples. Potential fusion transcripts were assessed by seed count and structural chromosomal aberrations. Transcripts of interest were validated using fluorescence in situ hybridization and PCR followed by direct sequencing.nnnRESULTSnRNA sequencing identified rearrangements of the anaplastic lymphoma kinase gene (ALK) in 2 samples. Both tumors harbored structural aberrations involving the ALK locus 2p23. Tumor 1 had an unbalanced t(2;14)(p23;q22) translocation which led to the fusion gene KTN1-ALK. Tumor 2 had an interstitial del(2)(p16p23) deletion causing the fusion of CCDC88A and ALK. In both samples, the breakpoint of ALK was located between exons 19 and 20. Both patients were infants and both tumors were supratentorial. The tumors were well demarcated from surrounding tissue and had both ependymal and astrocytic features but were diagnosed and treated as ependymomas.nnnCONCLUSIONSnBy combining karyotyping and RNA sequencing, we identified the 2 first ever reported ALK rearrangements in CNS tumors. Such rearrangements may represent the hallmark of a new entity of pediatric glioma characterized by both ependymal and astrocytic features. Our findings are of particular importance because crizotinib, a selective ALK inhibitor, has demonstrated effect in patients with lung cancer harboring ALK rearrangements. Thus, ALK emerges as an interesting therapeutic target in patients with ependymal tumors carrying ALK fusions.

Genomic characterization of ependymomas reveals 6q loss as the most common aberration

Ependymomas are rare tumors of the central nervous system (CNS). They are classified based on tumor histology and grade, but the prognostic value of the WHO grading system remains controversial. Treatment is mainly surgical and by radiation. An improved knowledge of ependymoma biology is important to elucidate the pathogenesis, to improve classification schemes, and to identify novel potential treatment targets. Only 113 ependymoma karyotypes with chromosome aberrations are registered in the Mitelman database. We present the first study of ependymoma genomes combining karyotyping and high resolution comparative genomic hybridization (HR-CGH). Nineteen tumor samples were collected from three pediatric and 15 adult patients treated at Oslo University Hospital between 2005 and 2012. Histological diagnoses included subependymoma and myxopapillary ependymoma (WHO grade I), ependymoma (WHO grade II) and anaplastic ependymoma (WHO grade III). Four tumors were intraspinal and 15 were intracranial. Seventeen samples were successfully karyotyped, HR-CGH analysis was undertaken on 17 samples, and 15 of 19 tumors were analyzed using both methods. Twelve tumors had karyotypic abnormalities, mostly gains or losses of whole chromosomes. Structural rearrangements were found in four tumors, in two of which 2p23 was identified as a breakpoint region. Twelve tumors displayed genomic imbalances by HR-CGH analysis with loss of material at 6q as the most common. 6q loss, which was detected by one or both methods in seven of 12 (58%) abnormal tumors, and 5p gain (observed in five tumors; 42%) were the most common genomic aberrations in this series.

Novel fusion genes and chimeric transcripts in ependymal tumors

We have previously identified two ALK rearrangements in a subset of ependymal tumors using a combination of cytogenetic data and RNA sequencing. The aim of this study was to perform an unbiased search for fusion transcripts in our entire series of ependymal tumors. Fusion analysis was performed using the FusionCatcher algorithm on 12 RNA‐sequenced ependymal tumors. Candidate transcripts were prioritized based on the softwares filtering and manual visualization using the BLAST (Basic Local Alignment Search Tool) and BLAT (BLAST‐like alignment tool) tools. Genomic and reverse transcriptase PCR with subsequent Sanger sequencing was used to validate the potential fusions. Fluorescent in situ hybridization (FISH) using locus‐specific probes was also performed. A total of 841 candidate chimeric transcripts were identified in the 12 tumors, with an average of 49 unique candidate fusions per tumor. After algorithmic and manual filtering, the final list consisted of 24 potential fusion events. Raw RNA‐seq read sequences and PCR validation supports two novel fusion genes: a reciprocal fusion gene involving UQCR10 and C1orf194 in an adult spinal ependymoma and a TSPAN4‐CD151 fusion gene in a pediatric infratentorial anaplastic ependymoma. Our previously reported ALK rearrangements and the RELA and YAP1 fusions found in supratentorial ependymomas were until now the only known fusion genes present in ependymal tumors. The chimeric transcripts presented here are the first to be reported in infratentorial or spinal ependymomas. Further studies are required to characterize the genomic rearrangements causing these fusion genes, as well as the frequency and functional importance of the fusions.