Moise Danielpour

Neuroimaging findings in macrocephaly–capillary malformation: A longitudinal study of 17 patients

Here, we report the neuroimaging findings and neurological changes in 17 unpublished patients with Macrocephaly–Capillary Malformation (M–CM). This syndrome has been traditionally known as Macrocephaly–Cutis Marmorata Telangiectatica Congenita (M–CMTC), but we explain why M–CM is a more accurate term for this overgrowth syndrome. We analyzed the 17 patients with available brain MRI or CT scans and compared their findings with features identified by a comprehensive review of published cases. White matter irregularities with increased signal on T2‐weighted images were commonly observed findings. A distinctive feature in more than half the patients was cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy. In four such cases, we confirmed that the tonsillar herniation was an acquired event. Concurrently, with the development of these findings, ventriculomegaly (frequently obstructive) and dilated dural venous sinuses were observed in conjunction with prominent Virchow–Robin spaces in many of those in whom cerebellar tonsil herniation had developed. We postulate that this constellation of unusual features suggests a dynamic process of mechanical compromise in the posterior fossa, perhaps initiated by a rapidly growing cerebellum, which leads to congestion of the venous drainage with subsequently compromised cerebrospinal fluid reabsorption, all of which increases the posterior fossa pressure and leads to acquired tonsillar herniation. We make a distinction between congenital Chiari I malformation and acquired cerebellar tonsil herniation in this syndrome. We also observed numerous examples of abnormal cortical morphogenesis, including focal cortical dysplasia, polymicrogyria which primarily involved the perisylvian and insular regions, and cerebral and/or cerebellar asymmetric overgrowth. Other findings included a high frequency of cavum septum pellucidum or vergae, thickened corpus callosum, prominent optic nerve sheaths and a single case of venous sinus thrombosis. One patient was found to have a frontal perifalcine mass resembling a meningioma at age 5 years. This is the second apparent occurrence of this specific tumor in M–CM.

A high-definition exoscope system for neurosurgery and other microsurgical disciplines: preliminary report.

An 8-mm diameter rigid lens telescope with a focal distance of 20 cm was developed for open microsurgery. The telescope was attached to a 3-chip high-definition digital camera and then to a high-definition monitor. A pneumatic scope holder permitted repositioning. The optical quality of the device was compared with the operating microscope with a step wedge and 1-mm grid paper. Craniotomies and microsurgical dissections with the telescope system (high-definition exoscope system) were performed in a live pig model. The high-definition exoscope system provided image quality that rivaled the operating microscope even at high magnification. The system was easy to manipulate and comfortable during neurosurgical operations. The lack of stereopsis was a relative drawback of the system but was compensated for with repeated procedures. Overall, this prototype telescope-based system rivals the operating microscope optical quality and field of view. With further refinement, this system could have widespread application in many microsurgical disciplines.

Accumulation of Transforming Growth Factor-β2 and Nitrated Chondroitin Sulfate Proteoglycans in Cerebrospinal Fluid Correlates with Poor Neurologic Outcome in Preterm Hydrocephalus

Background: Progressive post-hemorrhagic hydrocephalus in preterm infants strongly predicts abnormal neurologic development, and often accompanies cystic periventricular leukomalacia (cPVL). Transforming growth factor-β1 (TGF-β1), associated with hydrocephalus, can upregulate the chondroitin sulfate proteoglycan (CSPG) synthesis. To date, CSPG and their nitrated metabolites (NT-CSPG) have not been evaluated in hydrocephalus. Objectives: We hypothesized that TGF-β1, TGF-β2, CSPG, and NT-CSPG would accumulate in cerebrospinal fluid (CSF) in preterm hydrocephalus, and their concentrations would correlate with poor long-term outcomes. Methods: TGF-β1, TGF-β2, CSPG, and NT-CSPG concentrations in CSF were measured prospectively by ELISA in 29 preterm newborns with (n = 22) or without (n = 34) progressive post-hemorrhagic hydrocephalus, and correlated with progressive neonatal hydrocephalus and neurologic outcome. Only concentrations from each patient’s initial CSF sample were used for statistical analysis. Results: Compared to neonates without hydrocephalus, CSF [TGF-β1], [TGF-β2], [CSPG] and [NT-CSPG] were significantly greater by >3-, >35-, >8-, and >3-fold, respectively. Unlike CSF [TGF-β2] and [CSPG], [TGF-β1] correlated with CSF [total protein]. Only CSF [NT-CSPG] correlated with cPVL. Unlike [TGF-β2] or [CSPG], [NT-CSPG] correlation with preterm progressive post-hemorrhagic hydrocephalus (PPHH) was explained entirely by the presence of cPVL among these patients. [TGF-β2] was >20-fold greater in preterm survivors who required a ventriculoperitoneal shunt for PPHH (n = 9), as compared to survivors who did not require a shunt (n = 2), or those without hydrocephalus (n = 12). [TGF-β2] and [NT-CSPG] correlated inversely with Bayley Index Scores (15.0 months median adjusted age). Conclusions: This is the first report that [TGF-β2], [CSPG], and [NT-CSPG], measured well before term, accumulate abnormally in preterm progressive post-hemorrhagic hydrocephalus CSF, and correlate with adverse neurologic outcome.

Ets Factors Regulate Neural Stem Cell Depletion and Gliogenesis in Ras Pathway Glioma

As the list of putative driver mutations in glioma grows, we are just beginning to elucidate the effects of dysregulated developmental signaling pathways on the transformation of neural cells. We have employed a postnatal, mosaic, autochthonous glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional genetically engineered mouse models of cancer. We provide evidence that disruption of the Nf1-Ras pathway in the ventricular zone at multiple signaling nodes uniformly results in rapid neural stem cell depletion, progenitor hyperproliferation, and gliogenic lineage restriction. Abolishing Ets subfamily activity, which is upregulated downstream of Ras, rescues these phenotypes and blocks glioma initiation. Thus, the Nf1-Ras-Ets axis might be one of the select molecular pathways that are perturbed for initiation and maintenance in glioma.

T-cell TGF-β signaling abrogation restricts medulloblastoma progression

Significance Medulloblastoma (MB) is a tumor of the cerebellum that primarily forms in pediatric patients during brain development. The immune system ultimately fails to eradicate MB because it is “blind” to tumor cells as a result of poor brain immune surveillance caused by the existence of the blood–brain barrier and the brain’s immune privileged status. Another mechanism of tumor escape is immune suppressors that act as a “smokescreen,” blocking effective antitumor immunity. We show that blockade of the TGF-β signaling pathway promotes memory T cell development, conferring antitumor immunity to the smoothened A1 mouse model of MB. Our data lay the cellular immune mechanistic framework for blocking T cell TGF-β signaling in pediatric brain cancer. Cancer cell secretion of TGF-β is a potent mechanism for immune evasion. However, little is known about how central nervous system tumors guard against immune eradication. We sought to determine the impact of T-cell TGF-β signaling blockade on progression of medulloblastoma (MB), the most common pediatric brain tumor. Genetic abrogation of T-cell TGF-β signaling mitigated tumor progression in the smoothened A1 (SmoA1) transgenic MB mouse. T regulatory cells were nearly abolished and antitumor immunity was mediated by CD8 cytotoxic T lymphocytes. To define the CD8 T-cell subpopulation responsible, primed CD8 T cells were adoptively transferred into tumor-bearing immunocompromised SmoA1 recipients. This led to generation of CD8+/killer cell lectin-like receptor G1 high (KLRG1hi)/IL-7Rlo short-lived effector cells that expressed granzyme B at the tumor. These results identify a cellular immune mechanism whereby TGF-β signaling blockade licenses the T-cell repertoire to kill pediatric brain tumor cells.

Dynamic cervicomedullary cord compression and alterations in cerebrospinal fluid dynamics in children with achondroplasia: review of an 11-year surgical case series

OBJECT Achondroplasia may be associated with compression at the cervicomedullary junction. Determining which patients are at greatest risk for neurological complications of cervicomedullary compression can be difficult. In the current study the authors reviewed their records to determine the incidence and clinical significance of dynamic cervicomedullary stenosis and obstruction of CSF flow along with surgical outcomes following posterior fossa decompression. METHODS The authors reviewed 34 consecutive cases involving symptomatic children with achondroplasia undergoing cervicomedullary decompression performed by a single surgeon over 11 years. Of these patients, 29 had undergone preoperative dynamic MRI of the cervicomedullary junction with cine (cinema) CSF flow studies; 13 of these patients underwent postoperative dynamic MRI studies. Clinical outcomes included changes in polysomnography, head circumference percentile, and fontanel characteristics. Radiographic outcomes included changes in dynamic spinal cord diameter, improvement in CSF flow at the foramen magnum, and change in the Evans ratio. RESULTS Patients were predominantly female, with a mean age at presentation of 6.6 years and mean follow-up of 3.7 years (range 1-10 years). All patients had moderate to excellent improvement in postoperative polysomnography, slight decrease in average head circumference percentile (from 46.9th percentile to 45.7th percentile), and no subjective worsening of fontanel characteristics. The Evans ratio decreased by 2%, spinal cord diameter increased an average of 3.1 mm, 5.2 mm, and 0.2 mm in the neutral, flexed, and extended positions, respectively, and CSF flow improved qualitatively in all 3 positions. There were no postoperative infections, CSF leaks, or other major complications. None of the patients undergoing initial foramen magnum decompression performed at our medical center required reoperation. CONCLUSIONS Patients with achondroplasia and symptomatic cervicomedullary compression have increased risk of dynamic stenosis at the foramen magnum evident upon dynamic cine MRI. Operative decompression may be offered with low risk of complications or need for reoperation.

Rapid genetic targeting of pial surface neural progenitors and immature neurons by neonatal electroporation

BackgroundRecent findings have indicated the presence of a progenitor domain at the marginal zone/layer 1 of the cerebral cortex, and it has been suggested that these progenitors have neurogenic and gliogenic potential. However, their contribution to the histogenesis of the cortex remains poorly understood due to difficulties associated with genetically manipulating these unique cells in a population-specific manner.ResultsWe have adapted the electroporation technique to target pial surface cells for rapid genetic manipulation at postnatal day 2. In vivo data show that most of these cells proliferate and progressively differentiate into both neuronal and glial subtypes. Furthermore, these cells localize to the superficial layers of the optic tectum and cerebral cortex prior to migration away from the surface.ConclusionsWe provide a foundation upon which future studies can begin to elucidate the molecular controls governing neural progenitor fate, migration, differentiation, and contribution to cortical and tectal histogenesis. Furthermore, specific genetic targeting of such neural progenitor populations will likely be of future clinical interest.

Long-term survival in a child with a central nervous system medulloepithelioma

Central nervous system medulloepitheliomas are extremely rare and malignant (World Health Organization Grade IV) primitive neuroectodermal tumors (PNETs) that arise in childhood. Unlike other PNETs, medulloepitheliomas have a dismal prognosis, with only 2 reported cases in the literature in which the patient survived beyond 5 years after treatment. The authors report on the third known case of a child who survived longer than 5 years. A review of all the published cases of medulloepithelioma is also presented, and alternative treatment strategies for PNET tumors, including high-dose chemotherapy with stem-cell rescue, are discussed.

Basic Biology and Mechanisms of Neural Ciliogenesis and the B9 Family

Although the discovery of cilia is one of the earliest in cell biology, the past two decades have witnessed an explosion of new insight into these enigmatic organelles. While long believed to be vestigial, cilia have recently moved into the spotlight as key players in multiple cellular processes, including brain development and homeostasis. This review focuses on the rapidly expanding basic biology of neural cilia, with special emphasis on the newly emerging B9 family of proteins. In particular, recent findings have identified a critical role for the B9 complex in a network of protein interactions that take place at the ciliary transition zone (TZ). We describe the essential role of these protein complexes in signaling cascades that require primary (nonmotile) cilia, including the sonic hedgehog pathway. Loss or dysfunction of ciliary trafficking and TZ function are linked to a number of neurologic diseases, which we propose to classify as neural ciliopathies. When taken together, the studies reviewed herein point to critical roles played by neural cilia, both in normal physiology and in disease.

Giant cell tumor of the odontoid in an adolescent male: radiation, chemotherapy, and resection for recurrence with 10-year follow-up

Giant cell tumors (GCTs) are rare lesions of the cervical spine, with only 14 previously reported pediatric cases in the literature, all occurring in females. The authors present the case of a 15-year-old boy with neck pain who was found to have a lytic GCT of the odontoid process. Following resection, recurrent disease was treated with radiotherapy and chemotherapy and then a final resection. He has remained tumor free for more than 10 years. The rarity of GCTs can make their diagnosis difficult in the cervical spine. Because of their aggressive behavior and relative resistance to adjuvant therapy, GCTs must be monitored diligently and treated aggressively.