Yves Starreveld

CaV3.2 Channels and the Induction of Negative Feedback in Cerebral Arteries

Rationale: T-type (CaV3.1/CaV3.2) Ca2+ channels are expressed in rat cerebral arterial smooth muscle. Although present, their functional significance remains uncertain with findings pointing to a variety of roles. Objective: This study tested whether CaV3.2 channels mediate a negative feedback response by triggering Ca2+ sparks, discrete events that initiate arterial hyperpolarization by activating large-conductance Ca2+-activated K+ channels. Methods and Results: Micromolar Ni2+, an agent that selectively blocks CaV3.2 but not CaV1.2/CaV3.1, was first shown to depolarize/constrict pressurized rat cerebral arteries; no effect was observed in CaV3.2−/− arteries. Structural analysis using 3-dimensional tomography, immunolabeling, and a proximity ligation assay next revealed the existence of microdomains in cerebral arterial smooth muscle which comprised sarcoplasmic reticulum and caveolae. Within these discrete structures, CaV3.2 and ryanodine receptor resided in close apposition to one another. Computational modeling revealed that Ca2+ influx through CaV3.2 could repetitively activate ryanodine receptor, inducing discrete Ca2+-induced Ca2+ release events in a voltage-dependent manner. In keeping with theoretical observations, rapid Ca2+ imaging and perforated patch clamp electrophysiology demonstrated that Ni2+ suppressed Ca2+ sparks and consequently spontaneous transient outward K+ currents, large-conductance Ca2+-activated K+ channel mediated events. Additional functional work on pressurized arteries noted that paxilline, a large-conductance Ca2+-activated K+ channel inhibitor, elicited arterial constriction equivalent, and not additive, to Ni2+. Key experiments on human cerebral arteries indicate that CaV3.2 is present and drives a comparable response to moderate constriction. Conclusions: These findings indicate for the first time that CaV3.2 channels localize to discrete microdomains and drive ryanodine receptor–mediated Ca2+ sparks, enabling large-conductance Ca2+-activated K+ channel activation, hyperpolarization, and attenuation of cerebral arterial constriction.

CaV1.2/CaV3.x channels mediate divergent vasomotor responses in human cerebral arteries.

Human cerebral arteries contain three Ca2+ channel subtypes with distinct physiological roles.

Reduction of microglial activity in a model of multiple sclerosis by dipyridamole.

BackgroundDespite extensive and persistent activation of microglia in multiple sclerosis (MS), microglia inhibitors have not yet been identified for treatment of the disorder. We sought to identify medications already in clinical use that could inhibit the activation of microglia. On the basis of the reported inhibitory effects of dipyridamole on phosphodiesterase activity that result in the production of various anti-inflammatory outcomes, we selected it for study. Dipyridamole is used clinically for secondary prevention in stroke. In this study, dipyridamole was examined using microglia in culture and in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE).ResultsWe found that dipyridamole attenuated the elevation of several cytokines and chemokines in human microglia caused by Toll-like receptor stimulation. Morphological characteristics of activated microglia in culture were also normalized by dipyridamole. In mice, dipyridamole decreased the clinical severity of EAE and reduced microglial activity and other histological indices of EAE in the spinal cord.ConclusionsDipyridamole is an inhibitor of microglia activation and may have a role in MS and other neurological conditions to attenuate microglial activity.

Cost‐effectiveness of the endoscopic versus microscopic approach for pituitary adenoma resection

To evaluate the cost‐effectiveness of an endoscopic versus microscopic approach to pituitary adenoma resection.

The Effect of Contouring Variability on Dosimetric Parameters for Brain Metastases Treated With Stereotactic Radiosurgery

PURPOSE To quantify the effect of contouring variation on stereotactic radiosurgery plan quality metrics for brain metastases. METHODS AND MATERIALS Fourteen metastases, each contoured by 8 physicians, formed the basis of this study. A template-based dynamic conformal 5-arc dose distribution was developed for each of the 112 contours, and each dose distribution was applied to the 7 other contours in each patient set. Radiation Therapy Oncology Group (RTOG) plan quality metrics and the Paddick conformity index were calculated for each of the 896 combinations of dose distributions and contours. RESULTS The ratio of largest to smallest contour volume for each metastasis varied from 1.25 to 4.47, with a median value of 1.68 (n=8). The median absolute difference in RTOG conformity index between the value for the reference contour and the values for the alternative contours was 0.35. The variation of the range of conformity index for all contours for a given tumor varied with the tumor size. CONCLUSIONS The high degree of interobserver contouring variation strongly suggests that peer review or consultation should be adopted to standardize tumor volume prescription. Observer confidence was not reflected in contouring consistency. The impact of contouring variability on plan quality metrics, used as criteria for clinical trial protocol compliance, was such that the category of compliance was robust to interobserver effects only 70% of the time.

Anaplastic meningioma arising from a radiologically diagnosed arachnoid cyst: case report.

OBJECTIVE AND IMPORTANCEWe report the first example of an anaplastic meningioma arising from an intracranial arachnoid cyst and discuss the diagnostic challenges of this case, including the useful role of genetic markers. CLINICAL PRESENTATIONA 72-year-old man presented with transient episodes of expressive dysphasia and focal motor seizures, superimposed on a 6-month history of worsening headaches and dizziness. His past history was significant for a previously drained left-sided chronic subdural hematoma and a radiologically diagnosed left middle fossa arachnoid cyst. Magnetic resonance imaging on admission showed variable wall thickening of the arachnoid cyst with mild mass effect on the left frontotemporal lobes. INTERVENTIONThe patient underwent decompression of the arachnoid cyst and biopsy of the cyst wall. Histologic and immunohistochemical studies of the thickened portion initially suggested a metastatic carcinosarcoma, but fluorescence in situ hybridization (FISH) studies confirmed the diagnosis of anaplastic meningioma based on characteristic chromosomal deletions. The patient returned 2 months later with progressive disease, leading to his death 6 weeks later despite repeat surgery for tumor debulking. CONCLUSIONMalignant transformation of meningothelial elements in arachnoid cysts is an exceptionally rare complication that poses considerable diagnostic challenges. Genetic markers may be particularly helpful in such cases.

Population based analysis ependymoma patients in Alberta from 1975 to 2007.

BACKGROUND Ependymomas are rare tumors of the central nervous system whose management is controversial. This population-based study of adults and children with ependymoma aims to (1) identify clinical and treatment-related factors that impact survival and (2) determine if postoperative radiotherapy (RT) can improve survival of patients with subtotal resection (STR) to levels similar to patients who had gross total resection (GTR). METHODS This retrospective population-based study evaluated 158 patients with ependymoma diagnosed between 1975-2007 in Alberta, Canada. RESULTS Younger patients (<7 years of age) were more likely to be diagnosed with grade III tumors compared with adults in whom grade I tumors were more common (p=0.003). Adults were more likely to have spinally located tumors compared to young children whose tumors were typically found in the brain. Overall, young children with ependymoma were more likely to die than older children or adults (p=0.001). An equivalent number of patients underwent GTR as compared with STR (48% vs 45%, respectively). Overall, older age, spinal tumor location, lower grade, and GTR were associated with improved progression free survival but only GTR was associated with significant improvement in overall survival. Median survival after STR and RT was 82 months compared with 122 months in patients who had GTR (p=0.0022). CONCLUSIONS This is the first Canadian population-based analysis of patients with ependymoma including adults and children. Extent of resection appears to be the most important factor determining overall survival. Importantly, the addition of RT to patients initially treated with STR does not improve survival to levels similar to patients receiving GTR.

Clival Chordoma With Brainstem Invasion

Chordoma is a rare neoplasm derived from remnants of the fetal notochord, with incidence of approximately 1/1,000,000. Classic locations for chordoma include the lumbosacral spine (30-50%) and clivus (30-35%). Clival chordoma has a high rate of recurrence due to its aggressive biology as well as technical difficulty with gross total resection. These tumors frequently present with neuro-ophthalmologic findings. Intradural and extradural extension of clival chordoma are known phenomena, but brainstem involvement is exceedingly rare. A 62-year-old man presenting with right-sided cranial nerve VI palsy was found on MRI to have a large sellar mass with invasion of the retroclival space, thought to be an aggressive pituitary macroadenoma. The patient was booked for endoscopic transsphenoidal resection of this tumor. Intraoperatively, the tumor was noted to erode through the floor of the sella turcica and involved bony destruction of the clivus, consistent with chordoma. The tumor was noted to extend through a small dural defect into the prepontine cistern. Near gross total resection of the tumor was achieved, except a small portion anterior to the brainstem. Final pathology revealed chordoma. The patient had two repeat transsphenoidal resections 10 months and 18 months after his initial debulking, with intraoperative note made of brainstem invasion. He also received radiation therapy following his third surgery. He was then followed with MRI to monitor recurrence at 6-month intervals. The patient remained free of recurrence until 1 year after his third operation. At that time radiologic recurrence was noted with only minor symptoms. After 6 months, the patient developed lower cranial nerve deficits including swallowing issues and drop attacks. An attempt at surgical decompression was undertaken via a retrosigmoidal approach, but the tumor had become too adherent to the brainstem, extending from the prepontine cistern into the belly of the pons with cystic component (Figure 1), with adjacent signal changes on FLAIR and T2 images. Diffusion weighted imaging showed some areas of restriction suggestive of infarction. The patient passed away during admission, likely from brainstem perforator infarct (Figures 2-4). Brainstem invasion of clival chordoma is exceedingly rare, with only four cases reported in the literature. Aggressive extradural and intradural involvement is well known. Occasionally, chordoma can occur as a primary intradural lesion, which can be quite benign with good outcomes, though can rarely exhibit aggressive character. Other differential diagnosis for chordoma includes fetal notochord, ecchordosis physaliphora, atypical meningioma and chondrosarcoma. Treatment of chordoma is by surgical debulking. Conventional radiotherapy adds no benefit to treatment of these tumors, though postoperative proton therapy has been shown to improve survival. Surgical approaches include transsphenoidal, transcranial, transoropharygeal and maxillary osteotomy. The endoscopic transsphenoidal approach represents a useful, minimally invasive option with good visualization of the sella, clivus and retroclivus. Patients with chordoma require extensive follow-up due to high risk for recurrence. Clival chordoma is a rare intracranial neoplasm with many presentations. Extensive follow-up is required for patients with these tumors. Posterior fossa involvement and especially brainstem extension are associated with several catastrophic complications, including basilar artery compression and lower cranial nerve deficits. Figure 1: Coronal and sagittal post-gadolinium T1 magnetic resonance images showing clival chordoma at the time of diagnosis. The tumor demonstrates destruction of the clivus and involvement of the prepontine cistern but no intrapontine extension.

Sequestered intradural lumbar disc.

A 42-year-old farmer was lifting a hay bale and experienced a sudden onset of sharp pain radiating down his left leg. Over the ensuing week, the pain became less pronounced, but was replaced with a progressive left greater than right leg numbness, foot weakness, and urinary hesitancy. He presented to his local hospital, where he was initially managed conservatively, and then transferred to our institution for consultation after an MR lumbar spine was completed. On physical exam, he had grade 1/5 weakness of left and right dorsi- and plantar flexion. Sensory testing showed a moderate decrease in pinprick sensation in his left leg from L1 to S1 dermatomes. He was symmetrically hyporeflexic with grade 1 knee reflexes and absent ankle jerks. Peri-anal sensation was intact, but there was moderately reduced rectal tone. The remainder of his neurological exam was normal.