Jennifer L. Quon

Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell Tsc1 deletion

Neurological symptoms in tuberous sclerosis complex (TSC) and associated brain lesions are thought to arise from abnormal embryonic neurogenesis due to inherited mutations in Tsc1 or Tsc2. Neurogenesis persists postnatally in the human subventricular zone (SVZ) where slow-growing tumors containing Tsc-mutant cells are generated in TSC patients. However, whether Tsc-mutant neurons from the postnatal SVZ contribute to brain lesions and abnormal circuit remodeling in forebrain structures remain unexplored. Here, we report the formation of olfactory lesions following conditional genetic Tsc1 deletion in the postnatal SVZ using transgenic mice or targeted single-cell electroporation. These lesions include migratory heterotopias and olfactory micronodules containing neurons with a hypertrophic dendritic tree. Most significantly, our data identify migrating glial and neuronal precursors that are re-routed and infiltrate forebrain structures (e.g. cortex) and become glia and neurons. These data show that Tsc1-mutant cells from the neonatal and juvenile SVZ generate brain lesions and structural abnormalities, which would not be visible using conventional non-invasive imaging. These findings also raise the hypothesis that micronodules and the persistent infiltration of cells to forebrain structures may contribute to network malfunction leading to progressive neuropsychiatric symptoms in TSC.

Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly

Recessive mutations in WD repeat domain 62 (WDR62) cause microcephaly and a wide spectrum of severe brain malformations. Disruption of the mouse ortholog results in microcephaly underlain by reduced proliferation of neocortical progenitors during late neurogenesis, abnormalities in asymmetric centrosome inheritance leading to neuronal migration delays, and altered neuronal differentiation. Spindle pole localization of WDR62 and mitotic progression are defective in patient-derived fibroblasts, which, similar to mouse neocortical progenitors, transiently arrest at prometaphase. Expression of WDR62 is closely correlated with components of the chromosome passenger complex (CPC), a key regulator of mitosis. Wild type WDR62, but not disease-associated mutant forms, interacts with the CPC core enzyme Aurora kinase B and staining of CPC components at centromeres is altered in patient-derived fibroblasts. Our findings demonstrate critical and diverse functions of WDR62 in neocortical development and provide insight into the mechanisms by which its disruption leads to a plethora of structural abnormalities.

Oversized self-expanding stents as an alternative to flow-diverters for blister-like aneurysms

Abstract Objective: Blister-like aneurysms (BLAs) are challenging to treat. Their friable nature makes them high risk for both traditional microsurgical and endovascular treatments. We discuss employing a single oversized self-expanding stent in the treatment of these treacherous lesions. Methods: A retrospective review from our institution was conducted. Five patients with BLAs were identified, who went on to be treated with a single oversized self-expanding stent, defined as 1 mm larger than the parent vessel, by the senior author (KRB), who is dual fellowship trained in both cerebrovascular/skull base microsurgery and endovascular neurosurgery. Additionally, a literature review was performed on BLAs treated with sole stenting and outcomes discussed. Results: Our five patients had complete aneurysm occlusion at long-term follow-up and all had good neurological outcomes. The literature review demonstrated that most aneurysms at long-term follow-up were either completed occluded or progressively becoming occluded, with patients overall having a good functional outcome based on the modified Rankin scale (mRS). Conclusion: In our experience, oversized self-expanding stents are a treatment option that should be considered for BLAs. This strategy avoids the need for dual antiplatelet therapy and therefore increases its utility in the case of subarachnoid hemorrhage (SAH).

Hypoxia-inducible factor 1a is a Tsc1-regulated survival factor in newborn neurons in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in TSC1 or TSC2 resulting in hyperactivity of the mammalian target of rapamycin and disabling brain lesions. These lesions contain misplaced neurons enriched in hypoxia-inducible factor 1a (HIF1a). However, the relationship between TSC1/2 and HIF1a and the function of HIF1a in TSC neurons remain unexplored. Here, we examine the degree of HIF1a activity and its function in newborn Tsc1(null) neurons in a mouse model of TSC. Using single cell electroporation in the neurogenic subventricular zone (SVZ) of neonatal mice, we deleted Tsc1 and generated olfactory lesions containing misplaced Tsc1(null) neurons as previously reported. These newborn neurons displayed elevated HIF1a-mediated transcriptional activity when compared with Tsc1 heterozygote neurons and a marked resistance to cell death induced by a HIF1a antagonist. Electroporation of Hif1a targeting short hairpin RNA (shRNA) or dominant negative HIF1a constructs resulted in 80-90% loss of Tsc1(null) newborn neurons although sparing SVZ stem cells. Consistent with this later finding, induction of Hif1a shRNA expression during synaptic integration thus bypassing neuron production also resulted in newborn neuron death. Collectively, these results suggest that HIF1a acts as a molecular determinant of newborn neuron survival and that its TSC1-dependent up-regulation gave Tsc1(null) neurons a survival advantage, despite their misplacement in a novel microenvironment.

Multimodal evaluation of CSF dynamics following extradural decompression for Chiari malformation Type I

OBJECT Extradural decompression is a minimally invasive technique for treating Chiari malformation Type I (CM-I) that avoids the complications of dural opening. While there is no agreement on which surgical method is optimal, mounting evidence demonstrates that extradural decompression effectively treats clinical symptoms, with a minimal reoperation rate. Neurological symptoms such as headache may be related to obstructed flow of CSF, and one aspect of successful extradural decompression is improved CSF dynamics. In this series, the authors report on their use of phase-contrast cine flow MRI to assess CSF flow as well as satisfactory decompression. METHODS The authors describe their first surgical series of 18 patients with CM-I undergoing extradural decompression and correlate clinical improvement with radiological changes. Patients were categorized as having complete, partial, or no resolution of their symptoms. Posterior fossa area, cisterna magna area, and tonsillar herniation were assessed on T2-weighted MRI, whereas improvement of CSF flow was evaluated with phase-contrast cine flow MRI. All patients received standard pre- and postoperative MRI studies; 8 (44.4%) patients had pre- and postoperative phase-contrast cine, while the rest underwent cine studies only postoperatively. RESULTS All 18 patients presented with symptomatic CM-I, with imaging studies demonstrating tonsillar herniation ≥ 5 mm, and 2 patients had associated syringomelia. All patients underwent suboccipital decompression and C-1 laminectomy with splitting of the dura. Patients with complete resolution of their symptoms had a greater relative increase in cisterna magna area compared with those with only partial improvement (p = 0.022). In addition, in those with complete improvement the preoperative cisterna magna area was smaller than in those who had either partial (0.020) or no (0.025) improvement. Ten (91%) of the 11 patients with improved flow also had improvement in their symptoms. There was 1 postoperative complication of dysphagia and dysphonia. None of the patients have required a second operation. CONCLUSIONS Extradural decompression has the potential to be the first-line treatment for CM-I but has been lacking an objective measure by which to assess surgical success as well as the need for reoperation. An increase in the CSF spaces and improved CSF dynamics may be associated with resolution of clinical symptoms. Including cine imaging as part of routine pre- and postoperative evaluation can help identify which patients are most likely to benefit from surgery.

A patient with a novel homozygous missense mutation in FTO and concomitant nonsense mutation in CETP

The fat mass and obesity associated (FTO) gene has previously been associated with a variety of diseases and conditions, notably obesity, acute coronary syndrome and metabolic syndrome. Reports describing mutations in FTO as well as in FTO animal models have further demonstrated a role for FTO in the development of the brain and other organs. Here, we describe a patient born of consanguineous union who presented with microcephaly, developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia and other various phenotypic abnormalities. Whole-exome sequencing revealed a novel homozygous missense mutation in FTO and a nonsense mutation in the cholesteryl ester transfer protein (CETP). Exome copy number variation analysis revealed no disease-causing large duplications or deletions within coding regions. Patient’s, her parents’ and non-related control’ fibroblasts were analyzed for morphologic defects, abnormal proliferation, apoptosis and transcriptome profile. We have shown that FTO is located in the nucleus of cells from each tested sample. Western blot analysis demonstrated no changes in patient FTO. Quantitative (qPCR) analysis revealed slightly decreased levels of FTO expression in patient cells compared with controls. No morphological or proliferation differences between the patient and control fibroblasts were observed. There is still much to be learned about the molecular mechanisms by which mutations in FTO contribute to such severe phenotypes.

Thoracic Epidural Teratoma: Case Report and Review of the Literature

Purpose Spinal teratomas comprise a rare subset of spinal cord tumors, and here, we describe an even rarer childhood thoracic extradural-intracanalicular teratoma. The clinical presentation, management, and pathophysiology of these tumors are reviewed to promote recognition and guide treatment of these lesions. Methods We report the case of a 21-month-old boy who presented with marked spasticity, as well as failure to ambulate and meet motor milestones. Additionally, we provide a literature review of spinal teratomas, including their clinical presentation, work-up, pathophysiology, and underlying genetics. Results An MRI of the spine revealed a large dorsal epidural tumor extending from T3 to T10 with heterogeneous contrast enhancement and severe spinal cord compression. The tumor was resected revealing a cystic mass with tissue resembling hair, muscle, as well as cartilage; pathology confirmed the diagnosis of teratoma. Gross total resection was achieved, and the child eventually gained ambulatory function. Conclusions Given that spinal teratomas are rare entities that can present with significant neurologic compromise, they must remain on clinicians’ differentials. Unfortunately, the exact origin of these tumors remains inconclusive and requires further investigation.

Outcomes After Endoscopic Endonasal Resection of Craniopharyngiomas in the Pediatric Population

BACKGROUND Craniopharyngiomas have traditionally been treated via open transcranial approaches. More recently, endoscopic transsphenoidal approaches have been increasingly used; however, few case series exist in the pediatric population. METHODS A retrospective review of patients (aged <18 years) undergoing endoscopic transsphenoidal resection of craniopharyngiomas between 1995 and 2016 was performed. Preoperative data included presenting symptoms, tumor size, location, and components. Postoperative outcomes included symptom resolution, visual outcomes, endocrine outcomes, disease recurrence, and major complications. RESULTS Sixteen pediatric patients with mean age of 11.0 years (range, 5-15 years) were included. The median follow-up time was 56.2 months. Mean maximal tumor diameter was 3.98 cm. Most of the tumors had suprasellar (93.8%) and intrasellar (68.8%) components. The gross total resection rate was 93.8%. The most common presenting symptoms were vision changes (81.3%) and increased intracranial pressure (56.3%). Most patients (66.7%) had their presenting symptoms resolved by their first postoperative visit. Vision improved or remained normal in 69.2% of patients. Postoperatively, new incidence of panhypopituitarism or diabetes insipidus developed in 63.6% and 46.7% of patients, respectively. New hypothalamic obesity developed in 28.6% of patients. The postoperative cerebrospinal fluid leak rate was 18.8%. One patient died of intraventricular hemorrhage postoperatively. The major complication rate was 12.5%. Disease recurrence occurred in 1 patient with gross total resection (6.3%). CONCLUSIONS Endoscopic transsphenoidal resection for craniopharyngiomas can achieve high rates of total resection with low rates of disease recurrence in larger tumors than previously described. However, hypothalamic-pituitary dysfunction and cerebrospinal fluid leak remain significant postoperative morbidities.

201 Transnasal Endoscopic Approach for Pediatric Skull Base Tumors: A Case Series.

INTRODUCTION Transnasal endoscopic transphenoidal approaches are an essential technique for the resection of skull base tumors in adults. Originally devised and most commonly used to treat pituitary adenomas, they have also been used for a variety of other pathologies. However, in the pediatric population, sellar and suprasellar lesions have historically involved a craniotomy. Transnasal endoscopic transphenoidal techniques in children have only been reported as single case reports and only in regard to purely sellar lesions. METHODS We present the first reported series of transnasal endoscopic transphenoidal approaches for pediatric skull base tumors. We performed a retrospective review of pediatric patients at our institution who had undergone endoscopic transphenoidal approaches for either a biopsy or resection of their sellar or suprasellar lesions between 2000 and 2015. RESULTS Our series included 29 patients with ages ranging between 4 and 17 years. Headache (59%), visual changes (55%), and diabetes insipidus (34%) were the predominant presenting symptoms. Twenty-six patients (90%) noted some improvement in their symptoms postoperatively. The majority of patients had secreting pituitary adenomas (38%) followed by Rathke cleft cysts/craniopharyngiomas (31%) and germinomas (13%). Other pathologies included lymphocytic hypophysitis, mature teratoma, and clival chordoma. Patients primarily underwent gross total resections (56%) with a low rate (27.5%) of reresection. Only 2 cases (7%) necessitated a subsequent craniotomy for tumor regrowth into anatomically challenging areas. Eleven (30%) patients had septal flaps, 17 (46%) had fat grafts, and 13 (45%) had intraoperative placement of a lumbar drain. Two patients (7%) had postoperative cerebrospinal fluid leak. The majority of patients (79%) required hormonal supplementation following resection, with fewer requiring subsequent chemotherapy (24%) and radiation (24%). CONCLUSION Transnasal endoscopic transphenoidal approaches are preferable to craniotomy and are safe and effective for accessing sellar, suprasellar and parasellar lesions in children. Further refinement in technology will allow for more widespread use in the pediatric population.

A rare case of congenital fibrosis of extraocular muscle type 1A due to KIF21A mutation with Marcus Gunn jaw-winking phenomenon.

BACKGROUND Congenital fibrosis of the extraocular muscles (CFEOM1) is classically a congenital, non-progressive, restrictive strabismus syndrome characterized by bilateral ptosis and ophthalmoplegia with an infraducted position of the globes. This autosomal dominant syndrome is caused by mutations in the KIF21A gene. METHODS AND RESULTS In this report we describe a 5-year-old boy, and his mother, both of whom have a mutation in the KIF21A gene, who possesses typical features of CFEOM1 syndrome. Besides displaying typical features of CFEOM1, he demonstrated Marcus Gunn jaw-winking phenomenon. The patient additionally had a positive family history of such features. CONCLUSION This is first report of the coexistence of CFEOM and Marcus Gunn jaw-winking phenomenon in a patient with a KIF21A mutation from Turkey. We explain the phenotypic findings associated with mutations in KIF21A including CFEOM1A and Marcus Gunn jaw-winking phenomenon.