M. Yashar S. Kalani

Wnt-mediated self-renewal of neural stem/progenitor cells

In this work we have uncovered a role for Wnt signaling as an important regulator of stem cell self-renewal in the developing brain. We identified Wnt-responsive cells in the subventricular zone of the developing E14.5 mouse brain. Responding cell populations were enriched for self-renewing stem cells in primary culture, suggesting that Wnt signaling is a hallmark of self-renewing activity in vivo. We also tested whether Wnt signals directly influence neural stem cells. Using inhibitors of the Wnt pathway, we found that Wnt signaling is required for the efficient cloning and expansion of single-cell derived populations that are able to generate new stem cells as well as neurons, astrocytes, and oligodendrocytes. The addition of exogenous Wnt3a protein enhances clonal outgrowth, demonstrating not only a critical role for the Wnt pathway for the regulation of neurogenesis but also its use for the expansion of neural stem cells in cell culture and in tissue engineering.

Genetics of the degenerated intervertebral disc.

BACKGROUND Given the genetic and proteomic advances of the past decade, understanding of the molecular etiopathogenesis of several complex diseases is increasing. Intervertebral disc disease (IVDD) is no different from other complex diseases where both environmental and genetic constituents are considered causes. This concept has challenged the traditional view that age, occupation, smoking, obesity, and primarily wear and tear are the only sources of disc degeneration. METHODS We conducted a systematic Medline review of the most current articles related to gene involvement in the development of IVDD in humans. RESULTS Candidate gene linkage and association studies involving the functional components of the intervertebral disc, including collagen I, collagen IX, collagen XI, aggrecan, extracellular matrix-degrading enzymes, inflammatory cytokines (IL-1, IL-6, and TNFα), Fas/FasL and vitamin D receptors, have had promising results. CONCLUSIONS This review emphasizes the latest advances in gene association with specific degenerated disc phenotypes, single nucleotide polymorphisms, disease heredity, and gene-environmental interactions in relation to IVDD to help improve future studies related to the genetic mechanisms underlying IVDD.

The Cancer Stem Cell–Vascular Niche Complex in Brain Tumor Formation

The cancer stem cell (CSC) theory hypothesizes that a small subpopulation of cells within a tumor mass is responsible for the initiation and maintenance of the tumor. The idea that brain tumors arise from this specific subset of self-renewing, multipotent cells that serve as the locus for tumor formation, has gained great support as evidenced by recent advancements in the biology of breast and colon cancer. It is well established that recruitment of bone marrow-derived proangiogenic progenitor cells and angiogenesis are key events in the process of brain tumor formation; however, the orchestration of these events by the CSC population has only recently been unveiled. In this review, we first introduce the CSC theory and examine the functional development of the vascular niche, its purpose, constituents, and contribution to the development of the CSC-vascular niche complex. Through this discussion, we aim to shed light on the events that may be targeted for therapeutic intervention.

Neurological morbidity and mortality associated with the endovascular treatment of cerebral arteriovenous malformations before and during the Onyx era

OBJECT The widespread implementation of the embolic agent Onyx has changed the endovascular management of cerebral arteriovenous malformations (AVMs). Recent data suggest that outcomes following embolization and resection may have worsened in the Onyx era. It has been hypothesized that there may be increased complications with Onyx embolization and increased surgical aggressiveness in patients treated with Onyx. In this study the authors analyzed their institutional experience with the endovascular treatment of cerebral AVMs prior to and after the introduction of Onyx to determine factors associated with periprocedural neurological morbidity and mortality. METHODS A retrospective review was performed of all patients with cerebral AVMs undergoing embolization at the Barrow Neurological Institute from 1995 to 2012. RESULTS Endovascular treatment of 342 cerebral AVMs was performed over 446 treatment sessions (mean age 37.8 years, range 1-83 years). Clinical presentation included hemorrhage in 47.6%, seizures in 21.9%, headaches in 11.1%, and no symptoms in 10% of cases. The endovascular pretreatment strategy was preoperative in 78.9%, preradiosurgery in 9.1%, palliative in 5.3%, targeted in 4.4%, and curative in 2.3%. The median Spetzler-Martin grade was III. The mean number of arteries embolized was 3.5 (range 0-13 arteries), and the mean number of treatment sessions was 1.3 (range 1-4 sessions). Onyx was used in 105 AVMs (30.7%), and N-butyl cyanoacrylate (NBCA) without Onyx was used in 229 AVMs (67%). AVMs treated with Onyx had a higher mean number of arterial pedicles embolized than did NBCA cases (4.3 ± 2.7 vs 3.2 ± 2.4, respectively; p < 0.001) and a greater number of sessions (1.5 ± 0.7 vs 1.2 ± 0.5, respectively; p < 0.05). Unexpected immediate postprocedural permanent neurological deficits were present in 9.6% of AVMs, while transient deficits were present in 1.8%. There was 1 death (0.3%). Spetzler-Martin grade was not associated with differences in outcome, as permanent neurological deficits were observed in 12%, 9%, 13%, 11%, and 13% of AVMs for Spetzler-Martin Grades I-V, respectively (p = 0.91). The use of Onyx compared with NBCA was not associated with differences in periprocedural morbidity (p = 0.23). This lack of a difference persisted even when controlling for number of arteries and sessions (p = 0.14). Sex was not associated with differences in outcome. CONCLUSIONS Permanent and transient postprocedural neurological deficits were noted in 9.6% and 1.8% of all cases, respectively. AVM grade was not associated with endovascular outcome. Despite the greater number of sessions required and arteries embolized for Onyx cases, there was no statistically significant difference in the risk of neurological deficits following cerebral AVM embolization with Onyx and NBCA.

Analysis of demographics, risk factors, clinical presentation, and surgical treatment modalities for the ossified posterior longitudinal ligament

OBJECT Ossification of the posterior longitudinal ligament (OPLL) is a rare disease that results in progressive myeloradiculopathy related to pathological ossification of the ligament from unknown causes. Although it has long been considered a disease of Asian origin, this disorder is increasingly being recognized in European and North American populations. Herein the authors present demographic, radiographic, and comorbidity data from white patients with diagnosed OPLL as well as the outcomes of surgically treated patients. METHODS Between 1999 and 2010, OPLL was diagnosed in 36 white patients at Barrow Neurological Institute. Patients were divided into 2 groups: a group of 33 patients with cervical OPLL and a group of 3 patients with thoracic or lumbar OPLL. Fifteen of these patients who had received operative treatment were analyzed separately. Imaging analysis focused on signal changes in the spinal cord, mass occupying ratio, signs of dural penetration, spinal levels involved, and subtype of OPLL. Surgical techniques included anterior cervical decompression and fusion with corpectomy, posterior laminectomy with fusion, posterior open-door laminoplasty, and anterior corpectomy combined with posterior laminectomy and fusion. Comorbidities, cigarette smoking, and previous spine surgeries were considered. Neurological function was assessed using a modified Japanese Orthopaedic Association Scale (mJOAS). RESULTS A high-intensity signal on T2-weighted MR imaging and a history of cervical spine surgery correlated with worse mJOAS scores. Furthermore, mJOAS scores decreased as the occupying rate of the OPLL mass in the spinal canal increased. On radiographic analysis, the proportion of signs of dural penetration correlated with the OPLL subtype. A high mass occupying ratio of the OPLL was directly associated with the presence of dural penetration and high-intensity signal. In the surgical group, the rate of neurological improvement associated with an anterior approach was 58% compared with 31% for a posterior laminectomy. No complications were associated with any of the 4 types of surgical procedures. In 3 cases, symptoms had worsened at the last follow-up, with only a single case of disease progression. Laminoplasty was the only technique associated with a worse clinical outcome. There were no statistical differences (p > 0.05) between the type of surgical procedure or radiographic presentation and postoperative outcome. There was also no difference between the choice of surgical procedure performed and the number of spinal levels involved with OPLL. CONCLUSIONS Ossification of the posterior longitudinal ligament can no longer be viewed as a disease of the Asian population exclusively. Since OPLL among white populations is being diagnosed more frequently, surgeons must be aware of the most appropriate surgical option. The outcomes of the various surgical treatments among the different populations with OPLL appear similar. Compared with other procedures, however, anterior decompression led to the best neurological outcomes.

Embryological development of the human insula and its implications for the spread and resection of insular gliomas

The human insular cortex, or the lobus insularis, is considered the developmentally most primitive lobe of the telencephalon. Covered by an overlying cortical lid, the insula has functions that are distinct from yet related to those of the adjacent temporal lobe and deep limbic structures. In the first part of this paper the authors outline the development of the human insula, including the cellular heterogeneity comprising the various parts of the insular lobe. Using the understanding gained from the development of the insula they then address implications of insular development for cortical development and connection as well as for tumorigenesis and tumor spread from the insula to other cortical structures, most notably the temporal lobe. An understanding of cortico-insular development and interconnection allows for both a better understanding of insular pathology and also facilitates planning of resection of cortico-insular gliomas to avoid damage to eloquent structures.

A NEUROSURGEON'S GUIDE TO STEM CELLS, CANCER STEM CELLS, AND BRAIN TUMOR STEM CELLS

Stem cells and their potential applications have become the forefront of scientific, political, and ethical discourse. Whereas stem cells were long accepted as units of development and evolution, it is now becoming increasingly clear that they are also units of oncogenesis. Although the field of stem cell biology is expanding at an astounding rate, the data attained are not readily translatable for the physicians who may eventually deliver these tools to patients. Herein, we provide a brief review of stem cell and cancer stem cell biology and highlight the scientific and clinical implications of recent findings regarding the presence of cancer-forming stem cells in brain tumors.

Hydrocephalus and aquaporins: lessons learned from the bench

PurposeHydrocephalus is a common disorder of defective cerebrospinal fluid (CSF) turnover. The identification of the aquaporin water channels (AQPs) led to the study of their role in the composition of biological fluids including CSF. The purpose of this study is to review the potential role of aquaporins in the pathogenesis, compensation, and possibly treatment of hydrocephalus.MethodsWe performed a MEDLINE search using the terms “aquaporin AND hydrocephalus.” The search returned a total of 20 titles. Eleven studies fulfilled the criteria for this review.ResultsMost studies were performed in animal models. The expression of AQPs in hydrocephalus is significantly altered. Aquaporin-1 levels at the choroid plexus are decreased in most models of hydrocephalus while CSF production and intracranial pressure are reduced in AQP1 knockout mice. In contrast, the expression of AQP4 in hydrocephalus is increased at its sites of expression. Aquaporin-4 knockout mice show a decreased clearance of brain edema via blood–CSF and blood–brain barrier (BBB) pathways and decreased survival in hydrocephalus models.ConclusionsAquaporin-1 is highly expressed at the choroid plexus and is related to CSF production. Aquaporin-4 is expressed at the ependyma, glia limitans, and at the perivascular end feet processes of astrocytes of the BBB, facilitating the water movement across these tissue interfaces. The observations obtained from animal studies and few cases in humans indicate an adaptive and protective role of AQPs in hydrocephalus by decreasing CSF production and increasing edema clearance. Aquaporins are attractive targets for the pharmaceutical treatment of hydrocephalus.

Wnt-Signaling in Retinal Development and Disease

The Wnt-signaling pathway is a known regulator of stem cell maintenance, cellular proliferation and differentiation, and cancer development in various tissues. Wnt proteins play a central role during various stages of retinal development; retinal field establishment, retinal and hyaloid vasculogenesis, cornea and lens development, eye field formation, and maintenance of retinal stem cell and neuronal specification in many species are Wnt-regulated processes. Uncontrolled Wnt signaling may cause retinal diseases such as familial exudative vitroretinopathy, retinitis pigmentosa, and Norries disease, further underscoring the importance of the Wnt-signaling pathway in the retina. This review summarizes major developments and discoveries regarding the role of the Wnt-signaling pathway as it pertains to retinal development and disease.

Long-term follow-up of blister aneurysms of the internal carotid artery.

BACKGROUND Blister aneurysms of the internal carotid artery (ICA) are uncommon. There is a paucity of data on the long-term outcomes of patients. OBJECTIVE To review our experience with the treatment of these lesions. METHODS We retrospectively reviewed all aneurysms treated at our institution between 1994 and 2005. Relevant operative notes, radiology reports, and inpatient/outpatient records were reviewed. RESULTS Seventeen patients (3 male, 14 female) with 18 blister aneurysms of the ICA were identified. The mean age was 44.6 years (range, 17-72; median, 42 years). Twelve patients (70.6%) presented with aneurysmal subarachnoid hemorrhage. The mean admission Glasgow Outcome Scale score was 4.3 (range, 2-5; median, 5). All patients were initially treated using microsurgical technique with direct clipping (n = 15; 83.3%) or clip-wrapping with Gore-Tex (n = 3, 16.7%). There were 4 cases of intraoperative rupture, all associated with attempted direct clipping; all 4 cases were successfully clipped. Two cases rebled post-treatment. Both rebleeding episodes were managed with endovascular stenting. Follow-up angiography was available for 14 patients and revealed a new aneurysm adjacent to the site of clipping in 1 patient and in-stent stenosis in 2. At the mean follow-up of 74.5 months (median, 73; range, 7-165), the mean Glasgow Outcome Scale score was 4.6 (range, 2-5; median, 5). CONCLUSION Microsurgical treatment of blister aneurysms of the ICA results in excellent outcome. In the evolution of treating these friable aneurysms, we have modified our clip-wrapping technique and use this technique when direct clipping is not feasible.