Insights into the development of molecular therapies for craniosynostosis.

For the past 2 decades, clinical and basic science researchers have gained significant insights into the molecular and genetic pathways associated with common forms of craniosynostosis. This has led to invaluable information for families and physicians in their attempts to understand the heterogeneity of craniosynostosis. Genetic mutations have been identified in the fibroblast growth factor receptors (FGFRs) as well as in other targets, including TWIST1, BMP, and RUNX2. Greater understanding of these and other pathways has led to the development of innovative approaches for applying medical therapies to the treatment of craniosynostosis, in particular by maintaining suture patency. In this article, the authors discuss the molecular pathophysiological mechanisms underlying various forms of craniosynostosis. They also highlight recent developments in the field of molecular craniosynostosis research with the hope of identifying targets for medical therapies that might augment the results of surgical intervention.

Enzyme replacement therapy for congenital hypophosphatasia allows for surgical treatment of related complex craniosynostosis: a case series.

Hypophosphatasia (HPP) is a rare inherited disorder of bone metabolism that results in the loss of function of the gene coding for tissue-nonspecific alkaline phosphatase (TNSALP). Patients with HPP have defective bone mineralization as well as craniosynostosis that can be seen in the infantile and childhood forms of this disease. Traditionally, HPP has had a poor prognosis, with few children surviving to exhibit the phenotype of clinical craniosynostosis that requires surgical intervention. Here, the authors report on new advancements in enzyme replacement therapy (ERT) for children affected by HPP, allowing these patients to survive and undergo surgery to address complex craniosynostosis. The authors discuss their case series of 4 HPP patients treated at their institution with ERT who have undergone successful surgical intervention for craniosynostosis. These children had no complications related to their surgeries and exhibited decreased neurological symptoms following cranial vault remodeling. This study reveals that ERT administered either pre- or post- operatively paired with cranial vault remodeling strategies can yield improved neurological outcomes in children affected by HPP.

Natural history and management of cervical spine disease in chondrodysplasia punctata and coumarin embryopathy.

PURPOSE: Chondrodysplasia punctata (CDP) is a group of skeletal dysplasias manifesting with progressive cervical instability that leads to neurological deficits and eventual death. The major clinical features of CDP also present in a phenocopy known as coumarin embryopathy (CE) which results from coumarin exposure during pregnancy. The objective of this study was to assess treatment strategies employed for children affected by CDP or CE with cervical instability and to determine a strategy on how best to diagnose and treat affected neonates. METHODS: We performed a systematic review of the English literature for cases reporting cervical spine involvement in CDP and CE and identified 44 such patients. We extracted clinical information on these disorders and identified two patients from our craniovertebral junction database of over 6,000 patients evaluated at our institution. RESULTS: Patients most frequently present with hyperreflexia (21%) and weakness (21%), and there were various conservative treatment strategies. Twenty-one percent of patients who were treated conservatively had neurological complications in their clinical course. There were two deaths reported, one resulting from conservative treatment and one from surgical treatment. We also report long-term follow-up analysis for a patient treated at our institution for the last 30 years and agree with all other reports that suggest that monitoring patients for neurological changes is essential to prevent further neurological injury. CONCLUSIONS: This study emphasizes the need for careful neurological and surgical evaluation of pediatric patients with cervical spine abnormalities affected by CDP or CE in order to prevent progressive instability.

The role of primary cilia in the pathophysiology of neural tube defects.

Neural tube defects (NTDs) are a set of disorders that occur from perturbation of normal neural development. They occur in open or closed forms anywhere along the craniospinal axis and often result from a complex interaction between environmental and genetic factors. One burgeoning area of genetics research is the effect of cilia signaling on the developing neural tube and how the disruption of primary cilia leads to the development of NTDs. Recent progress has implicated the hedgehog (Hh), wingless-type integration site family (Wnt), and planar cell polarity (PCP) pathways in primary cilia as involved in normal neural tube patterning. A set of disorders involving cilia function, known as ciliopathies, offers insight into abnormal neural development. In this article, the authors discuss the common ciliopathies, such as Meckel-Gruber and Joubert syndromes, that are associated with NTDs, and review cilia-related signaling cascades responsible for mammalian neural tube development. Understanding the contribution of cilia in the formation of NTDs may provide greater insight into this common set of pediatric neurological disorders.

Vagus nerve stimulation after lead revision.

OBJECT: Vagus nerve stimulation (VNS) has demonstrated benefit in patients with medically intractable partial epilepsy. As in other therapies with mechanical devices, hardware failure occurs, most notably within the VNS lead, requiring replacement. However, the spiral-designed lead electrodes wrapped around the vagus nerve are often encased in dense scar tissue hampering dissection and removal. The objective in this study was to characterize VNS lead failure and lead revision surgery and to examine VNS efficacy after placement of a new electrode on the previously used segment of vagus nerve. METHODS: The authors reviewed all VNS lead revisions performed between October 2001 and August 2011 at the University of Iowa Hospitals and Clinics. Twenty-four patients underwent 25 lead revisions. In all cases, the helical electrodes were removed, and a new lead was placed on the previously used segment of vagus nerve. All inpatient and outpatient records of the 25 lead revisions were retrospectively reviewed. RESULTS: Four cases were second lead revisions, and 21 cases were first lead revisions. The average time to any revision was 5 years (range 1.8-11.1 years), with essentially no difference between a first and second lead revision. The most common reason for a revision was intrinsic lead failure resulting in high impedance (64%), and the most common symptom was increased seizure frequency (72%). The average duration of surgery for the initial implantation in the 15 patients whose VNS system was initially implanted at the authors' institution was much shorter (94 minutes) than the average duration of lead revision surgery (173 minutes). However, there was a significant trend toward shorter surgical times as more revision surgeries were performed. Sixteen of the 25 cases of lead revision were followed up for more than 3 months. In 15 of these 16 cases, the revision was as effective as the previous VNS lead. In most of these cases, both the severity and frequency of seizures were decreased to levels similar to those following the previous implantation procedure. Only 1 complication occurred, and there were no postoperative infections. CONCLUSIONS: Lead revision surgery involving the placement of a new electrode at the previously used segment of vagus nerve is effective at decreasing the seizure burden to an extent similar to that obtained following the initial VNS implantation. Even with multiple lead revisions, patients can obtain VNS efficacy similar to that following the initial lead implantation. There is a learning curve with revision surgery, and overall the duration of surgery is longer than for the initial implantation. Note, however, that complications and infection are rare.

Endoscopic total corpus callosotomy: cadaveric demonstration of a new approach.

BACKGROUND: Callosotomy is a surgical option for treatment of a small number of patients with intractable seizures who are not candidates for surgical resection. The procedure is done conventionally with the aid of a microscope. In this article, we describe a new technique of endoscopic callosotomy through a parasagittal burr hole in a cadaveric model. METHODS: We utilized this technique with a single frontal burr hole. Callosotomies were performed on 4 silicon-injected cadaver heads in our minimally invasive neurosurgical laboratory. RESULTS: We were able to successfully perform total callosotomies in all cadaveric specimens without injury to the adjacent neurovascular structures. The advantages of our technique over microsurgery are the minimally invasive nature of the exposure and the improved visualization of the vascular structures near the rostrum and genu of the corpus callosum. A potential disadvantage we anticipate is the difficulty controlling bleeding in the event of vascular injury. CONCLUSION: We believe that this minimally invasive approach could have potential clinical applications.

Proteins and protein pattern differences between glioma cell lines and glioblastoma multiforme.

INTRODUCTION: Research into the pathogenesis, molecular signaling, and treatment of glioblastoma multiforme (GBM) has traditionally been conducted using cell lines derived from malignant gliomas. We compared protein expression patterns between solid primary GBMs and GBM cell lines to identify proteins whose expression may be altered in cell culture. METHODS: We cultured cell lines U87, U118, U251, and A172 and used tissue-selective microdissection of eight primary GBMs to obtain pure populations of tumor cells, which we studied using two-dimensional gel electrophoresis (2DGE) and examined using differential expression software. Select protein targets expressed differentially between GBM tumors and GBM cell lines were sequenced using tandem mass spectrometry. RESULTS: Analysis of the primary GBM tumor samples (n = 8) and the GBM cell lines revealed reproducibly similar proteomic patterns for each group, which distinguished tumors from the cell lines. Gels contained up to 500 proteins that were consistently identified in the pH 4 to 7 range. Comparison of proteins identified in the GBM tumors and in the cell lines showed approximately 160 proteins that were gained and 60 proteins that were lost on culture. Using normalized intensity patterns from the 2DGE images, ANOVA tests were done and statistically significant spots were identified. Seven proteins found in the cell lines were significantly increased when compared with the GBM tumors (P < 0.05), whereas 10 proteins were significantly decreased from cell lines compared with the GBM tumors. Proteins identified included transcription factors, tumor suppressor genes, cytoskeletal proteins, and cellular metabolic proteins. CONCLUSION: Global protein and proteomic differences were identified between primary GBM tumor samples and GBM cell lines. The proteins identified by 2DGE analysis elucidate some of the selection pressures of in vitro culture, help accentuate the advantages and limitations of cell culture, and may aid comprehension of gliomagenesis and enhance development of new therapeutics.

Coexpression of erythropoietin and erythropoietin receptor in von Hippel-Lindau disease-associated renal cysts and renal cell carcinoma.

Von Hippel-Lindau (VHL) disease is characterized by multiple tumors in specific target organs. The tumors at different sites share distinct morphologic and genetic characteristics but their cell of origin is unknown. We show that VHL disease-associated renal clear cell carcinomas (RCC) consistently coexpress erythropoietin (Epo) and Epo receptor (EpoR). In addition, coexpression of Epo and EpoR is detected in many renal cysts, providing further evidence that renal cysts are potential precursors for RCC. In conjunction with VHL gene deficiency, coexpression of Epo and EpoR in renal cysts and tumors may reflect a developmental arrest in immature mesenchymal cells. Such arrest may lead to autocrine stimulation, cell proliferation, and renal tumor development, similar to tumorigenesis of VHL disease-associated hemangioblastomas.

Differential expression of erythropoietin and its receptor in von hippel-lindau-associated and multiple endocrine neoplasia type 2-associated pheochromocytomas.

Pheochromocytoma is a neuroendocrine tumor associated with a variety of genetic disorders, which include von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1, hereditary paraganglioma, and succinate dehydrogenase gene-related tumors. Previous studies of VHL-associated and MEN 2-associated pheochromocytomas suggest morphological, biochemical, and clinical differences exist among the tumors, but the process by which they develop remains unclear. Studies in other VHL-associated tumors suggest that VHL gene deficiency causes coexpression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth. The objective of this study was to understand the different process of tumorigenesis for VHL and MEN 2-associated pheochromocytomas. Ten pheochromocytomas (VHL patients n = 5, MEN 2 patients n = 5) were examined for the presence or absence of Epo and Epo-R using Western blot, immunohistochemistry, and RT-PCR analyses. Coexpression of Epo and Epo-R was found in all five VHL-associated pheochromocytomas; in contrast, expression of Epo-R, but not Epo, was documented in all five MEN 2-associated pheochromocytomas. Expression of Epo appears to be a result of VHL gene deficiency, possibly through activation of the hypoxia inducible factor-1 pathway, whereas Epo-R is an embryonal marker whose sustained expression in both VHL- and MEN 2-associated pheochromocytomas reflects an arrest or defect in development. These findings suggest an alternative process of tumorigenesis in VHL- and MEN 2-associated pheochromocytomas and implicate Epo as a clinical biomarker to differentiate these tumors.

Coexpression of erythropoietin and its receptor in endolymphatic sac tumors.

OBJECT: Von Hippel-Lindau (VHL) disease is characterized by multiple tumors in specific organs. The cell of origin and the reason for the particular organ distribution of the tumors remains unknown. Endolymphatic sac tumor (ELST) is one of the lesions associated with VHL disease. Data from previous studies of VHL disease-associated hemangioblastomas (HBs) and renal cell carcinomas (RCCs) have indicated that VHL gene deficiency causes coexpression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth. METHODS: The authors studied ELSTs from five patients with VHL germline mutations. Analysis of the five ELST samples revealed loss of the wild-type allele, consistent with Knudson's two-hit hypothesis for tumorigenesis. All five ELST specimens were characterized microscopically and by immunohistochemical analysis. Coexpression of Epo and Epo-R was found in all five tumors on immunohistochemical studies and confirmed through reverse transcription-polymerase chain reaction and Western blot analysis. CONCLUSIONS: Expression of Epo appears to be a result of VHL gene deficiency, whereas the simultaneous coexpression of Epo-R may reflect a developmental mechanism of tumorigenesis. Coexpression of Epo and Epo-R in ELSTs together with the morphological and genetic similarities of these lesions with other VHL disease-associated tumors indicates that VHL disease-associated tumors in different organs share common pathogenetic pathways.

Hypothalamic hamartoma simulating a suprasellar arachnoid cyst: resolution of precocious puberty following microsurgical lesion resection.

Hypothalamic hamartomas (HHs) are rare developmental lesions arising from the inferior hypothalamus that may cause gelastic seizures and central precocious puberty. Cystic changes in HHs are rare, usually occurring in giant lesions. The authors describe an unusual case of cystic HH masquerading as a suprasellar arachnoid cyst in an 18-month-old girl presenting with precocious puberty. Microsurgical removal of the lesion led to complete resolution of the precocious puberty on long-term follow-up. This case is the first reported HH with pathological demonstration of corticotropin-releasing hormone immunostaining in the solid tumor and glial cells in the cyst wall of the lesion. The clinical and radiological characteristics of HHs are reviewed, along with the unique surgical strategies used to manage cystic lesions in the suprasellar region.

Acalvaria.

Acalvaria is a rare congenital malformation characterized by an absence of skin and skull. The authors describe a newborn at an estimated 38 weeks gestational age who was delivered via cesarean section from a 32-year-old mother. Upon delivery, the child was noted to have a frontal encephalocele and an absence of calvaria including skull and skin overlying the brain. A thin membrane representing dura mater was overlying the cortical tissue. After multiple craniofacial operations, including repair of the encephalocele and application of cultured keratinocytes over the rostral defect, the patient demonstrated significant closure of the calvarial defect and was alive at an age of more than 17 months with near-average development.

A comparison of costs associated with endoscope-assisted craniectomy versus open cranial vault repair for infants with sagittal synostosis.

OBJECT: The surgical management of infants with sagittal synostosis has traditionally relied on open cranial vault remodeling (CVR) techniques; however, minimally invasive technologies, including endoscope-assisted craniectomy (EAC) repair followed by helmet therapy (HT, EAC+HT), is increasingly used to treat various forms of craniosynostosis during the 1st year of life. In this study the authors determined the costs associated with EAC+HT in comparison with those for CVR. METHODS: The authors performed a retrospective case-control analysis of 21 children who had undergone CVR and 21 who had undergone EAC+HT. Eligibility criteria included an age less than 1 year and at least 1 year of clinical follow-up data. Financial and clinical records were reviewed for data related to length of hospital stay and transfusion rates as well as costs associated with physician, hospital, and outpatient clinic visits. RESULTS: The average age of patients who underwent CVR was 6.8 months compared with 3.1 months for those who underwent EAC+HT. Patients who underwent EAC+HT most often required the use of 2 helmets (76.5%), infrequently required a third helmet (13.3%), and averaged 1.8 clinic visits in the first 90 days after surgery. Endoscope-assisted craniectomy plus HT was associated with shorter hospital stays (mean 1.10 vs 4.67 days for CVR, p < 0.0001), a decreased rate of blood transfusions (9.5% vs 100% for CVR, p < 0.0001), and a decreased operative time (81.1 vs 165.8 minutes for CVR, p < 0.0001). The overall cost of EAC+HT, accounting for hospital charges, professional and helmet fees, and clinic visits, was also lower than that of CVR ($37,255.99 vs $56,990.46, respectively, p < 0.0001). CONCLUSIONS: Endoscope-assisted craniectomy plus HT is a less costly surgical option for patients than CVR. In addition, EAC+HT was associated with a lower utilization of perioperative resources. Theses findings suggest that EAC+HT for infants with sagittal synostosis may be a cost-effective first-line surgical option.

The role of endoscopic third ventriculostomy in the treatment of hydrocephalus.

OBJECT: Hydrocephalus remains a major public health problem. Conventional treatment has relied on extracranial shunting of CSF to another systemic site, but this approach is associated with a high rate of complications. Endoscopic third ventriculostomy (ETV) is a novel treatment for select forms of hydrocephalus that can eliminate the need for implantation of a lifelong ventricular shunt system. However, the indications for ETV are contested and its long-term effectiveness is not well established. METHODS: The authors selected 100 consecutive patients who underwent ETV for hydrocephalus beginning in 1994. Patients were enrolled and treated at a single institution by a single surgeon. The primary outcome was success of ETV, with success defined as no need for subsequent surgery for hydrocephalus. RESULTS: Ninety-five patients satisfied the inclusion criteria. The mean follow-up period was 5.1 years (median 4.7 years) with follow-up data available for as long as 17 years. Patients commonly presented with headache (85%), ataxia (34%), emesis (29%), and changes in vision (27%). The success rate for ETV was 75%. Twenty-one patients (22%) in the series had malfunctioning shunts preoperatively and 13 (62%) were successfully treated with ETV. Preoperative inferior bowing of the third ventricle floor on MRI was significantly associated with ETV success (p < 0.05). CONCLUSIONS: Endoscopic third ventriculostomy is an effective and durable treatment for select patients with hydrocephalus. When successful, the procedure eliminates the lifelong complications associated with implanted ventricular shunts.

The lost art of localization: Franc Ingraham's legacy in pediatric neurosurgery.

The authors describe an 8-year-old girl who underwent emergency posterior fossa surgery for resection of a large cerebellar astrocytoma in November 1939. The surgery was carried out by Franc D. Ingraham at Boston Children's Hospital a decade after he established the first pediatric neurosurgical service in the world at the same institution. Four years later the tumor recurred and the patient underwent repeat resection followed by external-beam radiation therapy. The pathological diagnosis by Sidney Farber was fibrillary astrocytoma. The young girl is currently a healthy, functional 82-year-old woman. The authors believe that this 74-year follow-up represents one of the longest in history, if not the longest, of a patient undergoing resection of a brain tumor. A recent MRI study shows postoperative changes with no evidence of residual or recurrent tumor. The original block tissue specimen had been preserved. It was restained and examined, revealing the pathological diagnosis to be juvenile pilocytic astrocytoma. The case is analyzed in the context of Ingraham's powerful and lasting impact on the field of pediatric neurosurgery.

Novel neurodevelopmental disorder in the case of a giant occipitoparietal meningoencephalocele.

Giant occipitoparietal encephaloceles are rare forms of neurodevelopmental defects whose etiologies remain uncertain. Their occurrence can lead to variable neurological outcomes depending on the extent of cerebral cortex involved and the ability to repair the defect. In addition, encephaloceles may be associated with various genetic syndromes and familial inheritance. Here, the authors describe a unique constellation of malformations associated with the case of a giant occipitoparietal meningoencephalocele with herniation of cortical tissue and continuity with the ventricular system. The patient had a cleft lip and palate, hemivertebrae of the thoracic spine, a patent ductus arteriosus, a ventricular septal defect, and coarctation of the aorta. To identify the genetic underpinnings of these malformations, fluorescence in situ hybridization and microarray analysis were performed and revealed an 80.65-kb gain within chromosome band 2p11.2. Duplications of this region involving RMND5A, whose product contains a C-terminal to lis homology (LisH) domain, have not previously been associated with a defined phenotype but may present insight into encephalocele formation. Surgical repair and follow-up for the neurological malformations are also discussed.

Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model.

Hydrocephalus is a common neurological disorder that leads to expansion of the cerebral ventricles and is associated with a high rate of morbidity and mortality. Most neonatal cases are of unknown etiology and are likely to have complex inheritance involving multiple genes and environmental factors. Identifying molecular mechanisms for neonatal hydrocephalus and developing noninvasive treatment modalities are high priorities. Here we use a hydrocephalic mouse model of the human ciliopathy Bardet-Biedl Syndrome (BBS) and identify a role for neural progenitors in the pathogenesis of neonatal hydrocephalus. We found that hydrocephalus in this mouse model is caused by aberrant platelet-derived growth factor receptor α (PDGFR-α) signaling, resulting in increased apoptosis and impaired proliferation of chondroitin sulfate proteoglycan 4 (also known as neuron-glial antigen 2 or NG2)(+)PDGFR-α(+) neural progenitors. Targeting this pathway with lithium treatment rescued NG2(+)PDGFR-α(+) progenitor cell proliferation in BBS mutant mice, reducing their ventricular volume. Our findings demonstrate that neural progenitors are crucial in the pathogenesis of neonatal hydrocephalus, and we identify new therapeutic targets for this common neurological disorder.

Don't take the plunge: avoiding adverse events with cranial perforators.

OBJECT: The object of this study was to evaluate the causes of plunging events associated with automatic-releasing cranial perforators at the authors' institution. METHODS: The authors analyzed a consecutive series of 1652 cranial procedures involving one type of automatic-releasing cranial perforator over a 2-year period. Plunging occurrences were recorded for 2 drill speeds: 1000 rpm in the 1st year and 800 rpm during the 2nd year. Intraoperative observations, neuroimaging studies, and clinical data were evaluated for each plunging event. RESULTS: The authors identified 9 plunging events for an overall incidence of 0.54%. In the 1st year, they identified 2 plunging events at a speed of 1000 rpm for an incidence of 0.19%. In an effort to reduce this occurrence, the speed of the drill was lowered to 800 rpm. There were 7 additional events, for a significantly increased incidence of 1.16% (p = 0.014, Fisher exact test) after the change was implemented. These cases spanned a number of procedures in adults and pediatric patients, including ventriculostomy placement, craniotomies for tumor resection, tumor biopsy, and endoscopic third ventriculostomy. Despite plunging, no immediate postoperative complications were noted on clinical examination. CONCLUSIONS: While technology continues to improve cranial perforator performance, the use of such a device is still associated with a risk of complications causing dural lacerations and injury to the underlying cortex. Decreasing the drill speed may not decrease the incidence of plunging.

Use of confirmatory imaging studies to illustrate adequate treatment of cerebrospinal fluid leak in spontaneous intracranial hypotension.

Spontaneous intracranial hypotension (SIH) is a syndrome with serious neurological sequelae. As demonstrated by the following report, recurrent episodes of SIH can be difficult to diagnose when associated with other neurosurgical procedures, such as craniectomies. In this paper, the authors demonstrate SIH presenting as a subdural hematoma with recurrence of CSF leaks. Spontaneous intracranial hypotension was further complicated by paradoxical herniation following a craniectomy. Treatment of SIH necessitated multiple epidural blood patches for CSF leaks at different spinal levels and at different times. The efficacy of each epidural blood patch was confirmed with radionuclide imaging. Confirmation of effective blood patch placement may be useful for identifying patients at risk for a failed epidural blood patch or for patients whose neurological examination results have not fully improved.