Alexander C. Flint

Calcium Waves Propagate through Radial Glial Cells and Modulate Proliferation in the Developing Neocortex

The majority of neurons in the adult neocortex are produced embryonically during a brief but intense period of neuronal proliferation. The radial glial cell, a transient embryonic cell type known for its crucial role in neuronal migration, has recently been shown to function as a neuronal progenitor cell and appears to produce most cortical pyramidal neurons. Radial glial cell modulation could thus affect neuron production, neuronal migration, and overall cortical architecture; however, signaling mechanisms among radial glia have not been studied directly. We demonstrate here that calcium waves propagate through radial glial cells in the proliferative cortical ventricular zone (VZ). Radial glial calcium waves occur spontaneously and require connexin hemichannels, P2Y1 ATP receptors, and intracellular IP3-mediated calcium release. Furthermore, we show that wave disruption decreases VZ proliferation during the peak of embryonic neurogenesis. Taken together, these results demonstrate a radial glial signaling mechanism that may regulate cortical neuronal production.

Nonsynaptic Glycine Receptor Activation during Early Neocortical Development

Glycine receptors (GlyRs) contribute to fast inhibitory synaptic transmission in the brain stem and spinal cord. GlyR subunits are expressed in the developing neocortex, but a neurotransmitter system involving cortical GlyRs has yet to be demonstrated. Here, we show that GlyRs in immature neocortex are excitatory and activated by a nonsynaptically released endogenous ligand. Of the potential ligands for cortical GlyRs, taurine is by far the most abundant in the developing neocortex. We found that taurine is stored in immature cortical neurons and that manipulations known to elevate extracellular taurine cause GlyR activation. These data indicate that nonsynaptically released taurine activates GlyRs during neocortical development. As fetal taurine deprivation can cause cortical dysgenesis, it is possible that taurine influences neocortical development by activating GlyRs.

Mechanical Thrombectomy of Intracranial Internal Carotid Occlusion. Pooled Results of the MERCI and Multi MERCI Part I Trials

Background and Purpose— Acute stroke from occlusion of the intracranial internal carotid artery (ICA) generally has a poor prognosis and appears to respond poorly to intravenous thrombolysis. Mechanical thrombectomy is a newly available modality for acute stroke therapy, but it is unknown whether this endovascular therapy may have a role in the specific setting of intracranial ICA occlusion. We therefore assessed the success rate of the Merci Retriever mechanical thrombectomy device in recanalization of intracranial ICA occlusions and sought to determine whether ICA recanalization with this therapy can result in better outcomes. Methods— All patients with acute stroke from intracranial ICA occlusion were identified in the MERCI and Multi MERCI Part I trials. We determined the success rate of ICA recanalization with endovascular thrombectomy and then assessed clinical outcomes according to whether vessel recanalization was successful. Results— Eighty patients with acute stroke from intracranial ICA occlusion were identified. Of these 80 patients, 53% had successful ICA recanalization with the Merci Retriever alone and 63% had ICA recanalization with use of the Merci Retriever plus adjunctive endovascular treatment. Baseline patient characteristics and procedural complications did not differ between the recanalized and nonrecanalized groups. Good clinical outcome, defined by a modified Rankin Scale of 0 to 2 at 90 days, occurred in 39% of patients with ICA recanalization (n=19 of 49) and in 3% of patients without ICA recanalization (n=1 of 30) (P<0.001; one patient was lost to follow up for 90-day modified Rankin Scale). Ninety-day mortality was 30% (n=15 of 50) in the recanalized group and 73% (n=22 of 30) in the nonrecanalized group (P<0.001). Symptomatic hemorrhage was not significantly different between the recanalized (6% [n=3 of 50]) and nonrecanalized (16.7% [n=5 of 30]) groups (P=0.14). Hemorrhage rates were also not found to be influenced by use of intravenous thrombolysis before mechanical thrombectomy. Multivariable logistic regression identified ICA recanalization (OR=28.4, 95% CI=2.6 to >99.9) and lack of history of hypertension (OR=0.15, 95% CI=0.04 to 0.57) as significant predictors of a good 90-day outcome. Failure to recanalize the ICA (OR=0.16, 95% CI=0.05 to 0.51) and age (per decade, OR=1.07, 95% CI=1.03 to 1.13) were significant predictors of mortality at 90 days. Conclusions— Mechanical thrombectomy of acute intracranial ICA occlusion using the Merci Retriever device, alone or in combination with adjunctive endovascular therapy, has a high rate of successful vessel recanalization. Subjects with successful ICA recanalization by this method have improved poststroke clinical outcome and survival compared with subjects in which the ICA is not successfully recanalized.

Detection of Paroxysmal Atrial Fibrillation by 30-Day Event Monitoring in Cryptogenic Ischemic Stroke The Stroke and Monitoring for PAF in Real Time (SMART) Registry

Background and Purpose— Patients with cryptogenic ischemic stroke may have undetected paroxysmal atrial fibrillation (PAF). We established the Stroke and Monitoring for PAF in Real Time (SMART) Registry to determine the yield of 30-day outpatient PAF monitoring in cryptogenic ischemic stroke. Methods— The SMART Registry was a 3-year, prospective multicenter registry of 239 patients with cryptogenic ischemic stroke undergoing 30-day outpatient autotriggered PAF detection in Kaiser Permanente Northern California. Results— In intention-to-monitor analysis, PAF was detected in 29 of 239 patients (12.1%; 95% CI, 8.6%–16.9%). After retrospective chart review was performed, a new diagnosis of PAF was confirmed in 26 of 236 patients (11.0%; 95% CI, 7.6%–15.7%). The majority of detected PAF events were asymptomatic; only 6 of 98 recorded PAF events (6.1%) were patient-triggered or associated with symptoms. Conclusions— -Approximately 1 in every 9 patients with cryptogenic ischemic stroke was found to have new PAF within 30 days. Routine monitoring in this population should be strongly considered.

Statin Use During Ischemic Stroke Hospitalization Is Strongly Associated With Improved Poststroke Survival

Background and Purpose— Statins reduce infarct size in animal models of stroke and have been hypothesized to improve clinical outcomes after ischemic stroke. We examined the relationship between statin use before and during stroke hospitalization and poststroke survival. Methods— We analyzed records from 12 689 patients admitted with ischemic stroke to any of 17 hospitals in a large integrated healthcare delivery system between January 2000 and December 2007. We used multivariable survival analysis and grouped-treatment analysis, an instrumental variable method that uses treatment differences between facilities to avoid individual patient-level confounding. Results— Statin use before ischemic stroke hospitalization was associated with improved survival (hazard ratio, 0.85; 95% CI, 0.79–0.93; P<0.001), and use before and during hospitalization was associated with better rates of survival (hazard ratio, 0.59; 95% CI, 0.53–0.65; P<0.001). Patients taking a statin before their stroke who underwent statin withdrawal in the hospital had a substantially greater risk of death (hazard ratio, 2.5; 95% CI, 2.1–2.9; P<0.001). The benefit was greater for high-dose (>60 mg/day) statin use (hazard ratio, 0.43; 95% CI, 0.34–0.53; P<0.001) than for lower dose (<60 mg/day) statin use (hazard ratio, 0.60; 95% CI, 0.54–0.67; P<0.001; test for trend P<0.001), and earlier treatment in-hospital further improved survival. Grouped-treatment analysis showed that the association between statin use and survival cannot be explained by patient-level confounding. Conclusions— Statin use early in stroke hospitalization is strongly associated with improved poststroke survival, and statin withdrawal in the hospital, even for a brief period, is associated with worsened survival.

Post-operative expansion of hemorrhagic contusions after unilateral decompressive hemicraniectomy in severe traumatic brain injury.

Decompressive hemicraniectomy is commonly performed in patients with traumatic brain injury (TBI) with diffuse brain swelling or refractory raised intracranial pressure. Expansion of hemorrhagic contusions in TBI patients is common, but its frequency following decompressive hemicraniectomy has not been well established. The aim of this retrospective study was to determine the rate of hemorrhagic contusion expansion following unilateral hemicraniectomy in severe TBI, to identify factors associated with contusion expansion, and to examine whether contusion expansion is associated with worsened clinical outcomes. Computed tomography (CT) scans of 40 consecutive patients with non-penetrating TBI who underwent decompressive hemicraniectomy were analyzed. Hemorrhagic contusion volumes were measured on initial, last pre-operative, and first post-operative CT scans. Mortality and 6-month Glasgow Outcome Scale (GOS) score were recorded. Hemorrhagic contusions of any size were present on the initial head CT scan in 48% of patients, but hemorrhagic contusions with a total volume of >5 cc were present in only 10%. New or expanded hemorrhagic contusions of >or=5 cc were observed after hemicraniectomy in 58% of patients. The mean volume of increased hemorrhage among these patients was 37.1+/-36.3 cc. The Rotterdam CT score on the initial head CT was strongly associated with the occurrence and the total volume of expanded hemorrhagic contusions following decompressive hemicraniectomy. Expanded hemorrhagic contusion volume greater than 20 cc after hemicraniectomy was strongly associated with mortality and poor 6-month GOS even after controlling for age and initial Glasgow Coma Scale (GCS) score. Expansion of hemorrhagic contusions is common after decompressive hemicraniectomy following severe TBI. The volume of hemorrhagic contusion expansion following hemicraniectomy is strongly associated with mortality and poor outcome. Severity of initial CT findings may predict the risk of contusion expansion following hemicraniectomy, thereby identifying a subgroup of patients who might benefit from therapies aimed at augmenting the coagulation system.

A simple protocol to prevent external ventricular drain infections.

BACKGROUND External ventricular drains (EVDs) are associated with high rates of infection, and EVD infections cause substantial morbidity and mortality. OBJECTIVE To determine whether the introduction of an evidence-based EVD infection control protocol could reduce the rate of EVD infections. METHODS This was a retrospective analysis of an EVD infection control protocol introduced in a tertiary care neurointensive care unit. We compared rates of cerebrospinal fluid culture positivity and ventriculitis for the 3 years before and 3 years after the introduction of an evidence-based EVD infection control protocol. A total of 262 EVD placements were analyzed, with a total of 2499 catheter-days. RESULTS The rate of cerebrospinal fluid culture positivity decreased from 9.8% (14 of 143; 11.43 per 1000 catheter-days) at baseline to 0.8% (1 of 119; 0.79 per 1000 catheter-days) in the EVD infection control protocol period (P = .001). The rate of ventriculitis decreased from 6.3% (9 of 143; 7.35 per 1000 catheter-days) to 0.8% (1 of 119; 0.79 per 1000 catheter-days; P = .02). CONCLUSION The introduction of a simple, evidence-based infection control protocol was associated with a dramatic reduction in the risk of EVD infection.

Calcium Dynamics of Neocortical Ventricular Zone Cells

Cell-cell signaling within the neocortical ventricular zone (VZ) has been shown to influence the proliferation of VZ precursor cells and the subsequent differentiation and fate of postmitotic neurons. Calcium (Ca²⁺), a ubiquitous second messenger implicated in the regulation of many aspects of development, may play a role in these signaling events. Accordingly, we have examined the spatiotemporal patterns of spontaneous intracellular free Ca²⁺ ([Ca²⁺]_i) fluctuations of cells within the intact neocortical VZ. Previous observations have demonstrated that similar patterns of spontaneous [Ca²⁺]_i increase occur in both proliferative and postmitotic cortical cells, suggesting that they may be mechanistically similar. Our results suggest that the changes in [Ca²⁺]_i in VZ cells and cortical plate neurons are likely triggered by different mechansims, and imply that similar changes in [Ca²⁺]_i may underlie different signaling events during distinct phases of neocortical development.

MECHANISMS UNDERLYING NEURONAL MIGRATION DISORDERS AND EPILEPSY

Neuronal migration disorders are often associated with intractable epilepsy. These cortical malformations are quite heterogeneous, suggesting that they may result from interference with a diverse set of processes during corticogenesis. Progress toward understanding the pathophysiologic basis of these disorders is coming from research into the basic mechanisms of corticogenesis, animal models of cortical malformations, and molecular genetic approaches to migration disorders.

Effect of Statin Use During Hospitalization for Intracerebral Hemorrhage on Mortality and Discharge Disposition

IMPORTANCE Statin use during hospitalization is associated with improved survival and a better discharge disposition among patients with ischemic stroke. It is unclear whether inpatient statin use has a similar effect among patients with intracerebral hemorrhage (ICH). OBJECTIVE To determine whether inpatient statin use in ICH is associated with improved outcomes and whether the cessation of statin use is associated with worsened outcomes. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of 3481 patients with ICH admitted to any of 20 hospitals in a large integrated health care delivery system over a 10-year period. Detailed electronic medical and pharmacy records were analyzed to explore the association between inpatient statin use and outcomes. MAIN OUTCOMES AND MEASURES The primary outcome measures were survival to 30 days after ICH and discharge to home or inpatient rehabilitation facility. We used multivariable logistic regression, controlling for demographics, comorbidities, initial severity, and code status. In addition, we used instrumental variable modeling to control for confounding by unmeasured covariates at the individual patient level. RESULTS Among patients hospitalized for ICH, inpatient statin users were more likely than nonusers to be alive 30 days after ICH (odds ratio [OR], 4.25 [95% CI, 3.46-5.23]; P < .001) and were more likely than nonusers to be discharged to their home or an acute rehabilitation facility (OR, 2.57 [95% CI, 2.16-3.06]; P < .001). Patients whose statin therapy was discontinued were less likely than statin users to survive to 30 days (OR, 0.16 [95% CI, 0.12-0.21]; P < .001) and were less likely than statin users to be discharged to their home or an acute rehabilitation facility (OR, 0.26 [95% CI, 0.20-0.35]; P < .001). Instrumental variable models of local treatment environment (to control for confounding by unmeasured covariates) confirmed that a higher probability of statin therapy was associated with a higher probability of 30-day survival (with an increase in probability of 0.15 [95% CI, 0.04-0.25]; P = .01) and a better chance of being discharged to home or an acute rehabilitation facility (with an increase in probability of 0.13 [95% CI, 0.02-0.24]; P = .02). CONCLUSIONS AND RELEVANCE Inpatient statin use is associated with improved outcomes after ICH, and the cessation of statin use is associated with worsened outcomes after ICH. Given the association between statin cessation and substantially worsened outcomes, the risk-benefit balance of discontinuing statin therapy in the acute setting of ICH should be carefully considered.