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Objective Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. We described in 1996 a three generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine tumors: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN). Methods All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging and therapeutic characteristics were retrospectively analyzed. Results We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, one due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22) and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in three. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed. Conclusions Multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients.

Background G lioblastoma (GBM) is associated with poor overall survival. Recently, we showed that androgen receptor (AR) protein is overexpressed in 56% of GBM specimens and AR antagonists induced dose-dependent death in several GBM cell lines and significantly reduced tumor growth and prolonged the lifespan of mice implanted with human GBM. 16β-18F-fluoro-5α-dihydrotestosterone ([18F]-FDHT) is a positron emission tomography (PET) tracer used to detect AR expression in prostate and breast cancers. This study was aimed at exploring the ability of [18F]-FDHT-PET to detect AR expression in high-grade gliomas. Methods Twelve patients with suspected high-grade glioma underwent a regular workup and additional dynamic and static [18F]-FDHT-PET/CT. Visual and quantitative analyses of [18 F]-FDHT kinetics in the tumor and normal brain were performed. Mean and maximum (max) standardized uptake values (SUVs) were determined in selected volumes of interest. The patients had surgery or biopsy after PET/CT. AR protein was analyzed in the tumor samples by western blot. Fold change in AR expression was calculated by densitometry analysis. Correlation between imaging and AR protein samples was determined. Results In six of the 12 patients, [18 F]-FDHT uptake was significantly higher in the tumor than in the normal brain. These patients also had increased AR protein expression within the tumor. Pearson correlation coefficient analysis for the tumor-to-control normal brain uptake ratio in terms of SUVmean versus AR protein expression was positive and significant (R = 0.84; P = .002). Conclusion [18 F]-FDHT-PET/CT could identify increased AR expression in high-grade glioma.

OBJECTIVE Flow-diverter stents (FDSs) are not generally used for the management of acutely ruptured aneurysms with associated subarachnoid hemorrhage (SAH). Herein, the authors present their experience with FDSs in this scenario, focusing on the antiplatelet regimen, perioperative management, and outcome. METHODS The authors retrospectively reviewed their institutional database for the treatment and outcomes of all patients with acutely ruptured aneurysms and associated SAH from July 2010 to September 2018 who had received an FDS implant as stand-alone treatment within 4 days after diagnosis. The protocol with the use of flow diversion in these patients includes a low threshold for placement of external ventricular drains before stenting, followed by the administration of aspirin and clopidogrel with platelet testing before stent implantation. With this approach, the risk of hemorrhage and stent-related thrombus formation is limited. Demographic, clinical, technical, and imaging data were analyzed. RESULTS Overall, 76 patients (61% females, mean age 42.8 ± 11.3 years) met the inclusion criteria. FDS implantation was performed a median of 2 days after diagnosis. On average, 1.05 devices were used per procedure. There was no procedural mortality directly attributed to the endovascular intervention. Procedural device-related clinical complications were recorded in a total of 6 cases (7.9%) and resulted in permanent neurological morbidity in 2 cases (2.6%). There was complete immediate aneurysm occlusion in 11 patients (14.5%), and persistent aneurysm filling was seen in 65 patients (85.5%). Despite this, no patient presented with rebleeding from the target aneurysm. There was an excellent clinical outcome in 62 patients (81.6%), who had a 90-day modified Rankin Scale score of 0–2. Among the 71 survivors, total or near-total occlusion was observed in 64/67 patients (95.5%) with a 3- to 6-month angiographic follow-up and in all cases evaluated at 12 months. Five patients (6.6%) died during follow-up for reasons unrelated to the procedure or new hemorrhage. CONCLUSIONS Flow diversion is an effective therapeutic strategy for the management of select acutely ruptured aneurysms. Despite low rates of immediate aneurysm occlusion after FDS implantation, the device exerts an important protective effect. The authors’ experience confirmed no aneurysm rerupture, high rates of delayed complete occlusion, and complication rates that compare favorably with the rates obtained using other techniques.

Previous studies suggest that 14–30% of glioblastoma multiforme (GBM) patients and 5–24% of patients with brain metastases demonstrate imaging treatment-effects in the first few months after treatment [1], [2], [3]. These treatment-induced imaging changes, often termed pseudoprogression/radiation-necrosis, are depicted as increasing volumes of contrast-enhancing lesions on MRI, mimicking progression. Therefore, treatment decisions, such as whether to operate on a patient with radiographic deterioration, continue current treatment or change treatment is a daily unsolved struggle. In addition, radiation-based treatments may also induce vascular malformations such as radiation-induced Cavernous malformations (RICM) and capillary telangiectasias. Cavernous malformations are low-flow vascular malformations, characterized by the lack of mural elements of mature vascular structures and intervening parenchymal neural tissue [4]. Radiation induced capillary telangiectasias (RIT), thin-walled ectatic capillaries with intervening normal brain parenchyma, usually occur 3–9 months after irradiation. Cavernomas take a longer time to develop (1–35 years) after radiation [5]. RICMs mostly develop in the pediatric population [6], but are also observed in adults. In a literature search from 2006 by Nimjee et al [7], 76 cases of RICMs were found. A retrospective study conducted at Mayo clinic found 32 RICMs [5]. RICMs latency median was 12.0 years with only 3 diagnosed in the first two years post radiation (9.3%). Kleinschmidt-DeMasters and Lillehei [8] found 13 cases between 2000 and 2016 in their surgical neuropathology databases. The latency median was 18 years. Strenger et al calculated a cumulative index of 2.24%, 3.86%, 4.95%, and 6.74% at 5, 10, 15, and 20 years following radiotherapy of children, respectively [9]. Vinchon et al [10] identified cumulative indices for their cohort in children at 10 years of 8.9%. Although RICMs are rare in adults with astrocytoma, mainly due to poor survival, three cases of long term survivals were reported in the literature to develop RICMs 10, 19 and 26 years post radiotherapy [11]. Gaensler and colleagues reported a series of 20 patients with RITs (6 proven pathologically) for whom the latency was only 2.7 years [12]. 70% of the 20 patients were 1 h (60–105 min) after a conventional injection of contrast agent. Blue/tumor regions in the TRAMs represent efficient clearance of contrast from the tissue (delayed signal early signal). The TRAMs were validated histologically in 51 resected lesions from patients with primary and metastatic brain tumors reaching 92% positive predictive value (PPV) and 100% sensitivity to morphologically active tumor. When studying the histological samples, we found that the common vessels morphology in the blue regions was undamaged vessels lumens, while vessels in the red regions presented different stages of vessel necrosis. Therefore, one explanation for the difference between the two populations may be that vessels in blue/tumor regions provide efficient contrast clearance from the tissue, while the damaged lumens in the red/treatment-effects regions are unable to clear the accumulating contrast, resulting in contrast accumulation. Over 400 adult patients have been recruited thus far to our ongoing TRAMs-based studies in Israel since 2010. As the TRAMs cannot differentiate blood vessels from active tumor (both appearing blue), we studied here whether RCIMs/RITs may mimic tumors in the TRAMs.

Purpose Children with traumatic brain injury (TBI) are at increased risk of posttraumatic epilepsy (PTE); the risk increases according to TBI severity. We examined the long-term incidence and risk factors for developing PTE in a cohort of children hospitalised at one medical centre with moderate or severe TBI. Methods Moderate brain injury was classified as Glasgow Coma Score on Arrival (GCSOA) of 9–13, and severe brain injury as GCSOA ≤8. We collected demographics and clinical data from medical records and interviewed patients and parents at 5–11 years following the TBI event. Results During a median follow-up period of 7.3 years, 9 (9%) of 95 children with moderate-to-severe TBI developed PTE; 4 developed intractable epilepsy. The odds for developing PTE was 2.9 in patients with severe compared to moderate TBI. CT findings showed fractures in 7/9 (78%) of patients with PTE, compared to 40/86 (47%) of those without PTE (p = 0.09). Of the patients with fractures, all those with PTE had additional features on CT (such as haemorrhage, contusion and mass effect), compared to 29/40 (73%) of those without PTE. One of nine (11%) PTE patients and 10 of 86 (12%) patients without PTE had immediate seizures. Two (22%) children with PTE had their first seizure more than 2 years after the TBI. Conclusion Among children with moderate or severe TBI, the presence of additional CT findings, other than skull fractures, seem to increase the risk of PTE. In our cohort, the occurrence of an early seizure did not confer an increased risk of PTE.

We review our experience with four patients who presented to our Medical Center from 2005-2015 with adult idiopathic occlusion of the foramen of Monro (FM). All patients underwent CT scanning and MRI. Standard MRI was performed in each patient to rule out a secondary cause of obstruction (T1-weighted without- and with gadolinium, T2-weighted, fluid-attenuated inversion recovery [FLAIR] and diffusion-weighted imaging [DWI] protocols). When occlusion of the FM appeared to be idiopathic, further high-resolution MRI with multiplanar reconstructions for evaluation of stenosis or an occluding membrane at the level of the FM was performed (T1-weighted without- and with gadolinium, T2-weighted 3D turbo spin-echo). Occlusion of the FM was due to unilateral stenosis and septum pellucidum deviation in two patients, to an occluding membrane in one, and to bilateral stenosis in one patient. Urgent surgical intervention is mandatory when there are signs of increased intracranial pressure while asymptomatic patients may be managed conservatively. In this patient series, truly bilateral stenotic obstruction of the FM was best managed with ventriculoperitoneal shunt and patients with membranous obstruction or unilateral stenosis with septum deviation were treated endoscopically.

Meningiomas are one of the most common brain tumors. World Health Organisation (WHO) Grade II and Grade III meningiomas are grouped together as non-benign meningioma (NBM). There are several controversies surrounding NBM management, including the significance of extent of resection and the efficacy of post-operative radiation and drug treatment. We reviewed the literature to develop recommendations for management of NBM. The questions we sought to answer were: Does gross total resection (GTR) improve patient outcome? Is radiation therapy (RT) warranted after complete or after incomplete resection of NBM? What drug therapies have been proven to improve outcome in patients with NBM? We found that GTR improves outcome in WHO Grade II meningioma, and should be attempted whenever considered safe. GTR correlates less closely to outcome in Grade III meningioma compared to subtotal resection (STR). Extreme measures to completely resect Grade III meningioma are not warranted. RT following GTR of Grade II meningioma does not improve patient outcome, and may be reserved for recurrence. RT improves outcome following STR of Grade II meningioma. RT improves outcome after resection of Grade III meningioma. No drug therapy has been shown to improve outcome in NBM. This review elucidates recommendations for some of the controversies involving NBM.

Ventriculoperitoneal (VP) shunt placement is the mainstay of treatment for hydrocephalus, yet shunts remain vulnerable to a variety of complications. Although fat droplet migration into the subarachnoid space and cerebrospinal fluid pathways following craniotomy has been observed, a VP shunt obstruction with fat droplets has never been reported to our knowledge. We present the first reported case of VP shunt catheter obstruction by migratory fat droplets in a 55-year-old woman who underwent suboccipital craniotomy for removal of a metastatic tumor of the left medullocerebellar region, without fat harvesting. A VP shunt was inserted 1month later due to communicating hydrocephalus. The patient presented with gait disturbance, intermittent confusion, and pseudomeningocele 21days after shunt insertion. MRI revealed retrograde fat deposition in the ventricular system and VP shunt catheter, apparently following migration of fat droplets from the fatty soft tissue of the craniotomy site. Spinal tap revealed signs of aseptic meningitis. Steroid treatment for aseptic "lipoid" meningitis provided symptom relief. MRI 2months later revealed partial fat resorption and resolution of the pseudomeningocele. VP shunt malfunction caused by fat obstruction of the ventricular catheter should be acknowledged as a possible complication in VP shunts after craniotomy, even in the absence of fat harvesting.

The prevalence of skull fractures after mild head trauma is 2 % in children of all ages and 11 % in children younger than 2 years. The current standard management for a child diagnosed with an isolated skull fracture (ISF), in our institute, is hospitalization for a 24-h observation period. Based on data from the literature, less than 1 % of all minor head injuries require neurosurgical intervention. The main objective of this study was to evaluate the risk of neurological deterioration of ISF cases, in order to assess the need for hospitalization. We reviewed the medical charts of 222 children who were hospitalized from 2006 to 2012 with ISF and Glascow Coma Scale—15 at the time of arrival. We collected data regarding demographic characteristics, mechanism of injury, fracture location, clinical symptoms and signs, need for hospitalization, and need for repeated imaging. Data was collected at three time points: at presentation to the emergency room, during hospitalization, and 1 month after admission, when the patients’ parents were asked about the course of the month following discharge. None of the 222 children included in the study needed neurosurgical intervention. All were asymptomatic 1 month after the injury. Two children underwent repeated head CT due to persistence or worsening of symptoms; these CT scans did not reveal any new findings and did not lead to any intervention whatsoever. Children arriving at the emergency room with a minor head injury and isolated skull fracture on imaging studies may be considered for discharge after a short period of observation. Discharge should be considered in these cases provided the child has a reliable social environment and responsible caregivers who are able to return to the hospital if necessary. Hospital admission should be reserved for children with neurologic deficits, persistent symptoms, suspected child abuse, or when the parent is unreliable or is unable to return to the hospital if necessary. Reducing unnecessary hospitalizations can prevent emotional stress, in addition to saving costs for the child’s family and the health care system.

BACKGROUND GBM is associated with poor overall survival partly due to lack of effective treatment. Recently we showed that androgen receptor (AR) protein is overexpressed in 56% of GBM specimens and that AR antagonists induced dose-dependent death in several glioblastoma cell lines. Treatment of mice implanted with human GBM with AR antagonists significantly reduced the growth of the tumor and prolonged the lifespan of the mice. 18f-fluorine-radiolabeled Dihidrotestosteron (DHT), a natural ligand of AR, [16β-18F-fluoro-5α-dihydrotestosterone ([18F]-FDHT)] is one of the PET tracers used to detect AR expression in metastatic prostate cancer. The aim of this study was to identify AR-expressing GBM tumors in real time using PET-CT scan with [18F]-FDHT. MATERIALS AND METHODS Twelve patients with GBM underwent a dynamic (first 30 min) and whole body static (later 60-80 min) [18F]-FDHT PET/CT (296-370 MBq) scans 2-4 days prior to the surgery or biopsy. Protein was extracted from the tumor and subjected to western blot analysis. AR Protein fold change of each tumor sample was calculated by densitometry analysis compared with that of normal brain, following normalization to GAPDH. RESULTS At ~60 min after injection, 6 of the 12 patients showed significantly higher tumor accumulation of [18F]-FDHT, compared to reference tissue (SUV/Control)mean: 1.33-2.63 fold, (SUV/control)max: 1.4-3.43 fold. The patient who had higher tumor accumulation of [18F]-FDHT, demonstrated also high (1.6-2.27 fold/normal brain) AR protein expression within the tumor. Pearson-correlation-coefficient analysis for the (SUV/Control)mean at ~60 min after the injection versus AR protein expression, was positive and significant (R=0.841;p=0.0024). CONCLUSION This study demonstrated for the first time that [18F]-FDHT PET can identify AR-positive-GBM-tumors (with sensitivity and specificity at 100%) and may therefore be a powerful tool to select patients eligible for treatment with AR antagonists. It could possibly be employed also to monitor treatment response and/or progression during the course of therapy.

We describe the presentation, management, and outcome of spontaneous spinal epidural hematoma (SSEH) in two tertiary academic centers. We retrospectively reviewed clinical and imaging files in patients diagnosed with SSEH from 2002-2011. Neurologic status was assessed using the American Spinal Injury Association (ASIA) Impairment Scale (AIS). A total of 17 patients (10 females; mean age 54 years, range 10-89) were included. Among patients presenting with AIS A, 5/8 showed no improvement and 3/8 reached AIS C. Among those presenting with AIS C, 5/6 reached AIS E and 1/6 reached AIS D. Of those presenting with AIS D, 3/3 reached AIS E. Mean time-to-surgery (TTS) was 28 hours (range 3-96). TTS surgery in two patients remaining at AIS A was ⩽ 12 hours; in 4/8 patients recovering to AIS E it was > 12 hours, including three patients operated on after > 24 hours. In patients remaining at AIS A, a mean of 4.4 levels were treated compared with means of 3.7 and 3.5 in those with AIS C and E, respectively, at late follow-up. In this series, preoperative neurological status had greater impact on late outcome than time from symptom onset to surgery in patients with SSEH.

OBJECTIVEPosttraumatic epilepsy (PTE) is a known complication of traumatic brain injury (TBI). The true incidence of PTE in children is still uncertain, because most research has been based primarily on adults. This study aimed to determine the true incidence of PTE in a pediatric population with mild TBI (MTBI) and to identify risk factors for the development of epileptic events.METHODSData were collected from electronic medical records of children 0–17 years of age, who were admitted to a single medical center between 2007 and 2009 with a diagnosis of MTBI. This prospective research consisted of a telephone survey between 2015 and 2016 of children or their caregivers, querying for information about epileptic episodes and current seizure and neurological status. The primary outcome measure was the incidence of epilepsy following TBI, which was defined as ≥ 2 unprovoked seizure episodes. Posttraumatic seizure (PTS) was defined as a single, nonrecurrent convulsive episode that occurred > 24 hours following injury. Seizures within 24 hours of the injury were defined as immediate PTS.RESULTSOf 290 children eligible for this study, 191 of them or their caregivers were reached by telephone survey and were included in the analysis. Most injuries (80.6%) were due to falls. Six children had immediate PTS. All children underwent CT imaging; of them, 72.8% demonstrated fractures and 10.5% did not demonstrate acute findings. The mean follow-up was 7.4 years. Seven children (3.7%) experienced PTS; of them, 6 (85.7%) developed epilepsy and 3 (42.9%) developed intractable epilepsy. The overall incidence of epilepsy and intractable epilepsy in this cohort was 3.1% and 1.6%, respectively. None of the children who had immediate PTS developed epilepsy. Children who developed epilepsy spent an average of 2 extra days in the hospital at the time of the injury. The mean time between trauma and onset of seizures was 3.1 years. Immediate PTS was not correlated with PTE.CONCLUSIONSIn this analysis of data from medical records and long-term follow-up, MTBI was found to confer increased risk for the development of PTE and intractable PTE, of 4.5 and 8 times higher, respectively. As has been established in adults, these findings confirm that MTBI increases the risk for PTE in the pediatric population.

We investigated the prevalence, onset, characteristics, and long-term course of epilepsy disease in children who underwent surgical intervention for diagnosed brain tumors.We reviewed the medical records of children with diagnosed brain tumors who underwent surgery during 2004-2014 at the Hadassah Medical Center. All patients with epilepsy were invited to a clinical visit that included a neurologic examination. The primary outcome measures were neurologic status according to the Glasgow outcome score (GOS) and postoperative seizure outcome according to the Engel system. We compared clinical characteristics according to the timing of epilepsy onset.The mean follow-up was 49 months. Of 128 patients included in the study, 44 (34%) had seizures; 23 (18%) developed epilepsy after surgery. Of the 30 patients with epilepsy who survived, 21 (70%) are in Engel class I and 13% Engel are in class II. Forty-five percent of the children are classified as GOS 5. Children who developed epilepsy after surgery were more likely to be in GOS 1-2 than were those who had seizures before surgery (P = 0.0173). Children with seizures were more likely to have cortical tumors and less likely to have tumors of the posterior fossa (P0.001). Children who underwent gross total resection were less likely to have epilepsy (P0.001).We show a high incidence of epilepsy in the late course of pediatric brain tumor disease. In the long term, seizure outcome was excellent. However, postsurgical onset of epilepsy was associated with a less favorable neurologic outcome.

Objective To assess the incidence of cerebrospinal fluid (CSF) leak and meningitis, and the need for prophylactic antibiotics, antipneumococcal vaccination, and surgical interventions, in children with a skull base fracture. Methods We reviewed the records of children with a skull base fracture who were admitted to our tertiary care center between 2009 and 2014. Results A total of 196 children (153 males), age 1 month to 18 years (mean age, 6 ± 4 years), were hospitalized with skull base fracture. Causes of injury were falls (n = 143), motor vehicle accidents (n = 34), and other (n = 19). Fracture locations were the middle skull base in 112 patients, frontal base in 62, and occipital base in 13. Fifty-four children (28%) had a CSF leak. In 34 of these children (63%), spontaneous resolution occurred within 3 days. Three children underwent surgery on admission owing to a CSF leak from an open wound, 3 underwent CSF diversion by spinal drainage, and 4 (2%) required surgery to repair a dural tear after failure of continuous spinal drainage and acetazolamide treatment. Twenty-eight children (14%) received prophylactic antibiotic therapy, usually due to other injuries, and 11 received pneumococcal vaccination. Two children developed meningitis, and 3 children died. Long-term follow up in 124 children revealed 12 children with delayed hearing loss and 3 with delayed facial paralysis. Conclusions This is the largest pediatric series of skull base fractures reporting rates of morbidity and long-term outcomes published to date. The rate of meningitis following skull base fracture in children is low, supporting a policy of not administering prophylactic antibiotics or pneumococcal vaccine. Long-term follow up is important to identify delayed complications.

Ventriculo-peritoneal (VP) shunt malfunction due to proximal and distal catheter migration has been rarely reported in the literature. Shunt migration has been proposed to occur as a result of a combination of various mechanisms, including the windlass effect, retained memory of the shunt tubing, inadequate shunt fixation, and increased intra-abdominal pressures. We describe a rare case of a 6-week-old child who presented in our department with VP shunt malfunction due to complete proximal migration and coiling of the peritoneal and ventricular VP shunt catheters within a subgaleal pocket at the left occipital area.

INTRODUCTION: TRAMs calculated from delayed-contrast MRI enable reliable (sensitivity/specificity>70%) differentiation between tumor (blue in the TRAMs) and non-tumoral tissues (red). The TRAMs are calculated by subtracting 3D T1-MRIs acquired 5min (early time point) post-contrast injection from those acquired 60-105min (late point) later. Here we studied the sensitivity to tumor/treatment-effects as a function of the early T1-MRI acquisition time. METHODS: 7 patients with high grade glioma and 6 with brain metastases were scanned by the standard TRAMs protocol with the addition of a rapid 3D T1-MRI sequence (20 sec) acquired 2, 5, 12, 17, 20, 24 and 70 min post-contrast. Rapid-TRAMs were calculated using the rapid T1-MRIs, where the late time point was fixed at 70 min and the early time point changed from 2 to 24 min post-contrast. Enhancing volumes were determined on the T1-MRIs and copied to the TRAMs. Blue/tumor and red/treatment-effects volumes were calculated within the enhancing regions. RESULTS: The blue/tumor volumes, calculated from the rapid-TRAMs, increased by a factor of 4.4 ± 2.6 when moving the early time point from 2min to 15.7 ± 2.2min, where they plateaued. The increase between 5min (standard) and 15.7min was by 1.5 ± 0.3. In contrast, when moving from 2 min to 15.7min the red/treatment-effects volumes decreased by 0.7 ± 0.2, and by 0.8 ± 0.1 when moving from 5min. CONCLUSIONS: The TRAMs were shown to provide reliable differentiation between tumor/treatment-effects. The early time point is fixed at 5min post-contrast. Using shorter delays may significantly decrease the sensitivity to tumor. Still, increasing the delay to 15min may increase the sensitivity to tumor. This over-estimation of the tumor volume may be explained by the tumor vasculature clearing contrast diffusing into further brain regions surrounding the tumor. An additional 3D-T1 acquired at 15min may be applied for calculating additional TRAMs with higher sensitivity to tumor, for depicting small tumor regions.