Diagnosis of pediatric central nervous system tumors using methylation profiling of cfDNA from cerebrospinal fluid.

Pediatric central nervous system tumors remain challenging to diagnose. Imaging approaches do not provide sufficient detail to discriminate between different tumor types, while the histopathological examination of tumor tissue shows high inter-observer variability. Recent studies have demonstrated the accurate classification of central nervous system tumors based on the DNA methylation profile of a tumor biopsy. However, a brain biopsy holds significant risk of bleeding and damaging the surrounding tissues. Liquid biopsy approaches analyzing circulating tumor DNA show high potential as an alternative and less invasive tool to study the DNA methylation pattern of tumors. Here, we explore the potential of classifying pediatric brain tumors based on methylation profiling of the circulating cell-free DNA (cfDNA) in cerebrospinal fluid (CSF). For this proof-of-concept study, we collected cerebrospinal fluid samples from 19 pediatric brain cancer patients via a ventricular drain placed for reasons of increased intracranial pressure. Analyses on the cfDNA showed high variability of cfDNA quantities across patients ranging from levels below the limit of quantification to 40 ng cfDNA per milliliter of CSF. Classification based on methylation profiling of cfDNA from CSF was correct for 7 out of 20 samples in our cohort. Accurate results were mostly observed in samples of high quality, more specifically those with limited high molecular weight DNA contamination. Interestingly, we show that centrifugation of the CSF prior to processing increases the fraction of fragmented cfDNA to high molecular weight DNA. In addition, classification was mostly correct for samples with high tumoral cfDNA fraction as estimated by computational deconvolution (> 40%). In summary, analysis of cfDNA in the CSF shows potential as a tool for diagnosing pediatric nervous system tumors especially in patients with high levels of tumoral cfDNA in the CSF. Further optimization of the collection procedure, experimental workflow and bioinformatic approach is required to also allow classification for patients with low tumoral fractions in the CSF.

Calvarial vault remodeling including pterional decompression for the treatment of nonsyndromic scaphocephaly patients: technical note and retrospective case series.

OBJECTIVE: Surgical techniques to correct scaphocephaly often rely on the implantation of foreign material and/or postoperative helmet therapy and possibly result in minimal correction of frontal bossing. Moreover, foreign material and helmet therapy are associated with extra medical care and financial costs. Frontal bossing is perceived as a prominent, disfiguring feature of scaphocephaly. Herein, authors present the results of a total cranial vault remodeling technique that corrects scaphocephaly features without relying on foreign material or postoperative helmet therapy. It includes frontal release and pterional decompression, which aim to correct frontal bossing. METHODS: All patients who had been operated on for isolated scaphocephaly at a single institution between January 2011 and December 2020 were included in this retrospective review. Operation time, transfusion volume, hospital stay, complications, cephalic index (CI), and bossing angle (BA) were analyzed. RESULTS: Sixty-five patients with nonsyndromic scaphocephaly were included in this analysis. Imaging to calculate the CI and BA preoperatively, immediately postoperatively, and 1 year postoperatively was available in 22 and 20 patients, respectively. The mean CI increased from 69.2% preoperatively to 74.6% postoperatively and 75.5% 1 year postoperatively. The mean BA decreased from 114.5° preoperatively to 111.6° postoperatively and 108.9° 1 year postoperatively. The mean operating time was 2 hours 4 minutes, and the median blood transfusion volume was 100 ml. There were no major complications or reoperations. CONCLUSIONS: The described total cranial vault remodeling technique is a safe procedure that mitigates total treatment burden, as no helmet therapy or implantation of foreign material is needed. It is effective in correcting CI and results in significant frontal bossing correction. The latter is attributed to a distinctive feature of the technique: frontal release and pterional decompression.

Intracranial myxoid mesenchymal tumor with EWSR1-CREB1 fusion.

Myxoid mesenchymal tumor with predilection for intracranial location harboring EWSR1 fusions with CREB family transcription factors is a recently described and exceedingly rare neoplasm. While some debate still exists whether this is a true separate entity or a myxoid variant of angiomatoid fibrous histiocytoma, these tumors still deserve separate attention due to localization, fairly distinct histology and higher incidence in the pediatric population. Data regarding outcome of these neoplasms are still sparse in medical literature. We report a case of an intracranial myxoid tumor with EWSR1-CREB1 fusion in a 14-year-old girl.

Intracranial complications of midline nasal dermoid cysts.

BACKGROUND: Nasal dermoid cysts are common tumors in children. Due to anomalies in embryologic development of the nasal complex, sometimes an intracranial extension exists. When these cysts become infected they can lead to meningitis, brain abscess and death. METHODS: We report the case of a 1.5-year-old girl admitted to the paediatric intensive care unit after infection of a nasal dermoid cyst. RESULTS: The infant had a spiking fever and epileptic seizures. She was stabilized, intubated and a CT scan showed a subcutaneous mass with an adjacent zone of encephalitis and brain abscess formation. Neurosurgical interventions were necessary to lower intracranial pressure and control infectious spread. After a hospital stay of 69 days the child could be discharged. Due to her young age, irreversible brain damage is expected. CONCLUSION: Nasal midline dermoid cysts are considered benign swellings. When an intracranial extension exists, infection can lead to deleterious complications. It is important for health care practitioners to be aware of this imminent risk. Suspicion of a nasal midline dermoid cyst should prompt a careful clinical work-up with an ultrasound followed by CT or MRI imaging. The treatment is complete excision to avoid disastrous complications and recurrences.

Hydroxyapatite cranioplasty: a retrospective evaluation of osteointegration in 17 cases.

BACKGROUND: Cranial reconstruction with autologous bone is still the gold standard although several biomaterials are available to re-establish the integrity of the cranial vault. Due to their biological and morphological characteristics, hydroxyapatite implants show promising results in small clinical cohort studies, especially within the paediatric population. Its biocompatibility and osteoconductivity should allow the formation of osseous bridging at the skull-prosthesis interface. OBJECTIVE: To examine the possible occurrence of osteointegration and to quantify it. METHODS: A retrospective study of patients with a hydroxyapatite implant from 2010 to 2014 at our neurosurgical department was conducted. Demographic, surgical and radiological data were studied. A senior neuroradiologist, a staff member neurosurgeon and a resident neurosurgeon independently performed the radiological evaluation. A new software analysis technique was developed to objectively quantify the degree of osteointegration. RESULTS: Seventeen implants were evaluated with an average patient age of 39 years and a mean follow-up of 155 weeks. Through radiologic evaluation, osseous bridging was deemed higher than 50% in six prostheses and higher than 75% in three. In five patients, no osteointegration could be seen. The remaining patients exhibited sparse signs of osteointegration, estimated between 10 and 50%. Software analysis showed an average osteointegration ratio of 37.4% with a 400-HU filter and 27.3% with a 700-HU filter. CONCLUSION: In this small retrospective study of cranial hydroxyapatite implants, osteointegration did occur and to a degree of more than 50% in 1/3 of the patients.

Diplopia as presenting sign of Turcot syndrome.

PURPOSE: To describe a patient with diplopia who was diagnosed with Turcot syndrome. METHODS: A 10-year-old boy presented with a history of left-sided sixth and seventh nerve palsy. He underwent imaging of the brain and colon, a full ophthalmological and genetic work-up. RESULTS: A 10-year-old boy was referred with combined left-sided sixth and seventh nerve palsy since 1 month without symptoms of raised intracranial pressure. BCVA was 6/6 in both eyes. Fundoscopy revealed bilateral, multiple, oval pigmented ocular fundus lesions (POFLs) in the 4 quadrants. These POFLs, together with the cranial nerve palsies raised the suspicion of Turcot syndrome, a familial neoplasia syndrome characterized by familial colorectal cancer and tumours of the central nervous system. Urgent MRI scan of the brain and stereotactic biopsy showed a primitive neuroectodermal tumour (PNET) at the pons. Coloscopy revealed multiple polyps. DNA analysis of the APC gene confirmed the clinical diagnosis of Turcot syndrome. The PNET was treated with combined radio- and chemotherapy. The patient underwent a prophylactic total colectomy as virtually all patients develop a carcinoma of the colorectal region if left untreated. CONCLUSIONS: Although strabismus is not, diplopia in childhood is rare and seldom innocuous. It requires a prompt and thorough diagnostic evaluation, including thorough, dilated fundoscopy. The presence of POFLs combined with neurological symptoms suggestive of a brain tumour should alert the clinician of the possibility of Turcot syndrome. Recognition of this rare syndrome can lead to earlier diagnosis, which is vital for appropriate surveillance and early surgical intervention of the highly frequent neoplasias in Turcot Syndrome.

The use of the trendelenburg position in the surgical treatment of extreme cerebellar slump.

BACKGROUND: State-of-the-art treatment for Chiari Malformation I (CM-I) consists of decompression by posterior fossa craniectomy. A rare but severe complication that develops over months to years after this procedure is cerebellar slump. Treatment options for this condition are limited. We present a new and promising approach to treat this rare condition. METHODS: The patients were placed in the Trendelenburg position to facilitate ascent of the cerebellum. After almost complete dissolution of neurologic symptoms, surgical reconstruction was performed by tonsillar resection and the creation of a new structural support using a bone graft. RESULTS: Both patients experienced good clinical and morphological outcomes immediately after surgery, and for two years thereafter. CONCLUSIONS: Neurological symptoms related to cerebellar or brainstem slump can be adequately reversed by placing the patient in the Trendelenburg position. After uneventful gravitational reversal of the slump, safe surgical reconstruction of the cerebellar support can be performed to securely preserve the anatomical reversal.

Endoscopic Treatment of Temporal Arachnoid Cysts in 34 Patients.

INTRODUCTION: Arachnoid cysts are lesions present in 1% of the population and usually found in the temporal fossa. Clinical and radiologic presentations can differ greatly. Despite intensive research, it is still debatable which patients will benefit from surgery. OBJECTIVE: This study aims to investigate the pretreatment parameters influencing the outcome after neuroendoscopic treatment of temporal arachnoid cysts. MATERIALS AND METHODS: A retrospective analysis of 34 patients who underwent an endoscopic fenestration of a temporal arachnoid cyst between July 1991 and December 2013 was performed. RESULTS: In symptomatic patients, there was a clinical improvement in 76.4% of cases. The best results were found in treating symptoms related to intracranial hypertension, acute neurologic defects, and macrocrania. Patients with temporal lobe epilepsy improved after cyst fenestration in 33.3% of cases. Behavioral problems and psychomotor retardation remained largely unchanged. Patients with a complex neurologic presentation, often from a congenital syndrome and combined with an intellectual disability, had the least benefit from endoscopic surgery. Radiologic follow-up showed a cyst volume decrease in 91.2% of cases. Complications were present in 29.4%, but were mostly minor and transient. CONCLUSION: This study demonstrates that patients with symptoms related to intracranial hypertension, acute neurologic deficits, and macrocrania have the best postoperative outcome. Also, patients with ipsilateral temporal lobe epilepsy seem to be good candidates for endoscopic arachnoid cyst fenestrations. In complex neurologic disorders without one of the previously mentioned symptoms, endoscopy remains less successful.

A novel design for steerable instruments based on laser-cut nitinol.

OBJECTIVE: Omnidirectional articulated instruments enhance dexterity. In neurosurgery, for example, the simultaneous use of 2 instruments through the same endoscopic shaft remains a difficult feat. It is, however, very challenging to manufacture steerable instruments of the requisite small diameter. We present a new technique to produce such instruments by means of laser cutting. Only 3 coaxial tubes are used. The middle tube has a cutting pattern that allows the steering forces to be transmitted from the proximal to the distal end. In this way the steering part is concealed in the wall of the tube. Large diameter articulated instruments such as for laparoscopy might benefit from the excellent tip stability provided by the same economical technology. METHOD: Coaxial nitinol tubes are laser-cut with a Rofin Stent Cutter in a specific pattern. The 3 tubes are assembled by sliding them over one another, forming a single composite tube. In a surgical simulator, the neurosurgical microinstruments and laparoscopic needle drivers were evaluated on surgical convenience. RESULTS: Simultaneous use of 2 neurosurgical instruments (1.5 mm diameter) through the same endoscopic shaft proved to be very intuitive. The tip of the steerable laparoscopic instruments (10 mm diameter) could resist a lateral force of more than 20 N. The angle of motion for either instrument was at least 70° in any direction. CONCLUSIONS: A new design for steerable endoscopic instruments is presented. It allows the construction in a range from microinstruments to 10-mm laparoscopic devices with excellent tip stability.

Treatment of cystic craniopharyngioma by endocavitary instillation of yttrium9° radioisotope--still a valuable treatment option.

Craniopharyngiomas are a challenging pathology in neurosurgery because of their anatomic localization in the (supra)sellar region and their contact with diencephalic structures around the third ventricle. Among the different treatment modalities, stereotactic intracavitary treatment by instillation of yttrium9° radioisotope is a minimally invasive technique of particular use in the treatment of cystic or partially cystic craniopharyngiomas. It can be performed under local anesthesia during a short hospitalization and has a long-lasting effect. This treatment can be repeated or used in combination with other treatment modalities such as microsurgery, endoscopy, conformal external radiation therapy, or stereotactic radiosurgery. Thus, this old and perhaps almost forgotten treatment option is still valuable in the treatment of cystic craniopharyngiomas.

Endoscopic coagulation of choroid plexus hyperplasia.

Hydrocephalus is a clinical disorder resulting from an imbalance between the production of CSF and its resorption, of which the latter is mostly a disadvantage. In rare cases of choroid plexus papilloma or carcinoma, hydrocephalus is due to an overproduction of CSF. Choroid plexus hyperplasia (CPH) is a distinct clinicopathological entity in which the enlarged choroid plexus produces large amounts of CSF. Historically, patients with CPH were treated by shunt procedures or by microsurgical removal of the choroid plexus, which is associated with a high complication rate. In this paper the authors show that endoscopic plexus coagulation can result in restoring the equilibrium of the intracranial fluid volumes, resulting in shunt independency. In this way, both the shunt-related complications and the bleeding risks of microsurgical plexectomy are avoided. In instances of hydrocephalus, thorough efforts should be made to demonstrate the underlying pathophysiology to choose the optimal treatment, of which shunt procedures should receive the least priority.

Migration of pump for intrathecal drug delivery into the peritoneal cavity. Case report.

BACKGROUND: We report on a patient in whom a subfascially implanted pump for the intrathecal delivery of baclofen spontaneously migrated into the peritoneal cavity. CASE DESCRIPTION: A 54-year-old male patient presented with a refilling problem of a drug pump that had been implanted 16 months earlier subfascially through a right-sided incision 10 cm below the costal margin. Because we were unable to refill the pump even under fluoroscopy, we presumed a backward turning of the pump. At exploration, we found that the deeper part of the pocket had spontaneously eroded and had caused the migration of the pump into the peritoneal cavity. The peritoneum and the abdominal wall were closed and the pump was placed in a subcutaneous pouch. We suppose that the migration of the pump was due to its particular implantation site with the lower extent of the device at or below the level of the linea semilunaris. Below this line, the aponeuroses of all 3 lateral abdominal muscles pass in front of the rectus muscle, leaving only the transversal fascia underneath the rectus, which is not a solid layer. Not considering this anatomical detail may facilitate the inward migration of implanted material. CONCLUSION: When creating a pocket for subfascial implantation, a high subcostal incision should be used so that the lower extent of the pocket will still be above the level of the linea semilunaris, hence ensuring a strong fascial layer between the pump and the peritoneum.

Are psychotic symptoms related to vagus nerve stimulation in epilepsy patients?

Four patients with refractory epilepsy presented with psychotic symptoms following treatment with vagus nerve stimulation (VNS) to control seizures. Besides its anti-epileptic effect VNS has been shown to have an effect on various cognitive and behavioural functions. VNS is known to increase alertness and reduce sedation, which is independent from seizure control. VNS has also been shown to positively affect cognition and to exert strong antidepressant effects. Co-morbidity in epilepsy often comprises psychiatric illnesses. Increased psychiatric symptoms have mainly been described in association with successful outcome following epilepsy surgery as a result of 'forced normalisation'. Different hypotheses on the underlying aetiology of VNS-induced psychotic symptoms other than the previously described 'forced normalisation' are discussed.