Hydrogel versus Bare Platinum Coils in Patients with Large or Recurrent Aneurysms Prone to Recurrence after Endovascular Treatment: A Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Some patients are at high risk of aneurysm recurrence after endovascular treatment: patients with large aneurysms (Patients Prone to Recurrence After Endovascular Treatment PRET-1) or with aneurysms that have previously recurred after coiling (PRET-2). We aimed to establish whether the use of hydrogel coils improved efficacy outcomes compared with bare platinum coils. MATERIALS AND METHODS: PRET was an investigator-led, pragmatic, multicenter, parallel, randomized (1:1) trial. Randomized allocation was performed separately for patients in PRET-1 and PRET-2, by using a Web-based platform ensuring concealed allocation. The primary outcome was a composite of a residual/recurrent aneurysm, adjudicated by a blinded core laboratory, or retreatment, intracranial bleeding, or mass effect during the 18-month follow-up. Secondary outcomes included adverse events, mortality, and morbidity (mRS > 2). The hypothesis was that hydrogel would decrease the primary outcome from 50% to 30% at 18 months, necessitating 125 patients per group (500 for PRET-1 and PRET-2). RESULTS: The trial was stopped once 250 patients in PRET-1 and 197 in PRET-2 had been recruited because of slow accrual. A poor primary outcome occurred in 44.4% (95% CI, 35.5%-53.2%) of those in PRET-1 allocated to platinum compared with 52.5% (95% CI, 43.4%-61.6%) of patients allocated to hydrogel (OR, 1.387; 95% CI, 0.838-2.295; P = .20) and in 49.0% (95% CI, 38.8%-59.1%) in PRET-2 allocated to platinum compared with 42.1% (95% CI, 32.0%-52.2%) allocated to hydrogel (OR, 0.959; 95% CI, 0.428-1.342; P = .34). Adverse events and morbidity were similar. There were 3.6% deaths (1.4% platinum, 5.9% hydrogel; P = .011). CONCLUSIONS: Coiling of large and recurrent aneurysms is safe but often poorly effective according to angiographic results. Hydrogel coiling was not shown to be better than platinum.

Insular ischemic stroke: clinical presentation and outcome.

BACKGROUND: The insula is a small but complex structure located in the depth of the sylvian fissure, covered by the frontal, parietal and temporal operculum. Ischemic strokes limited to the insula are rare and have not been well studied. Our objective is to better define the clinical presentation and outcome of insular ischemic strokes (IIS). METHODS: We reviewed the institutional prospective, consecutive stroke database from two centers to identify patients with IIS seen between 2008 and 2010. We also searched the Medline database using the keywords insula(r), infarction and stroke to identify previously published IIS cases confirmed by MRI. Minimal extension to an adjacent operculum or subinsular area was accepted. Clinicoradiological correlation was performed by distinguishing IIS involving the anterior (AIC) or posterior insular cortex (PIC). We collected clinical, demographic and radiological data. The outcome was determined using the modified Rankin Scale (mRS). RESULTS: We identified 7 patients from our institutions and 16 previously published cases of IIS. Infarcts were limited to the AIC (n = 4) or the PIC (n = 12) or affected both (n = 7). The five most frequent symptoms were somatosensory deficits (n = 10), aphasia (n = 10), dysarthria (n = 10), a vestibular-like syndrome (n = 8) and motor deficits (n = 6). A significant correlation was found between involvement of the PIC and somatosensory manifestations (p = 0.04). No other statistically significant associations were found. IIS presentation resembled a partial anterior circulation infarct (n = 9), a lacunar infarct (n = 2) or a posterior circulation infarct (n = 2). However, most cases presented findings that did not fit with these classical patterns (n = 10). At the 6 month follow up, mRS was 0 in 8/23 (35%) patients, 1-2 in 7/23 (30%) and unknown in 8/23 (35%). CONCLUSIONS: IIS presentation is variable. Due to the confluence of functions in a restricted region, it results in multimodal deficits. It should be suspected when vestibular-like or motor but especially somatosensory, speech or language disturbances are combined in the same patient. The outcome of IIS is often favorable. Larger prospective studies are needed to better define the clinical presentation and outcome of IIS.

Iatrogenic arterial perforation during acute stroke interventions.

Arterial perforation is a feared complication of acute stroke intervention. A high index of suspicion is important to recognize this complication and tailor patient management to prevent further deterioration in clinical outcome. This report describes the endovascular management of microcatheter arterial perforation in a 66-year-old woman with an acute left middle cerebral artery stroke. The microcatheter was retained in the patient to seal the perforated site, resulting in good outcome at 3-month follow-up.

Increased anticardiolipin antibody IgG titers do not predict recurrent stroke or TIA in children.

BACKGROUND: Increased anticardiolipin antibody (ACLA) immunoglobulin (Ig) G titers are commonly found in children with arterial ischemic stroke (AIS) or TIA (AIS/TIA). The associated risk of recurrent thromboembolism is unknown. OBJECTIVE: To determine the risk of recurrent thromboembolism associated with persistently increased ACLA titers of the IgG isotype in children with AIS/TIA. METHODS: The authors studied a cohort of children surviving first AIS/TIA tested by standardized ELISA for beta2-glycoprotein I-dependent ACLA of the IgG isotype. Children with ACLA titers >15 IgG phospholipid (GPL) units (per manufacturer's cutoff point) on more than two occasions > or =6 weeks apart were classified as ACLA-positive (ACLA+) and compared with ACLA-negative (ACLA-) children with respect to recurrent thromboembolic events (AIS/TIA, sinovenous thrombosis, and extracerebral thromboembolism). RESULTS: The authors recruited 34 ACLA+ children and 151 ACLA- children. Most ACLA+ children (30/34; 88%) had ACLA titers < or =40 GPL units. During the follow-up period (median duration, 2.8 years for ACLA+ children and 3.0 years for ACLA- children), AIS/TIA recurred in 26% of ACLA+ children and in 38% of ACLA- children; none developed sinovenous thrombosis or extracerebral thromboembolism. Based on survival analysis, this difference was nonsignificant (p = 0.54). Using binary partition evaluation, no titer criteria for ACLA positivity (range, 0 to 60 GPL units) predicted recurrent AIS/TIA. CONCLUSION: In children surviving arterial ischemic stroke/TIA, increased anticardiolipin antibody immunoglobulin G titers do not predict recurrent thromboembolism.

Isolated angiitis of the CNS in children.

OBJECTIVE: To clarify the clinical features and pathologic manifestations of isolated angiitis of the CNS (IACNS) in children. METHODS: The authors report two new cases and summarize the literature of childhood IACNS confirmed by pathology. RESULTS: IACNS affecting small vessels (n = 5). Neurologic manifestations included headaches, focal seizures, and progressive, behavioral, or multifocal neurologic impairment. MRI showed multifocal, T2-hyperintense, cerebral lesions without mass effect or tumor-like lesions. CSF, erythrocyte sedimentation rate, and cerebral angiograms were often normal.CNS biopsy disclosed a nongranulomatous vasculitis. Children were treated with prednisone alone or combined with cyclophosphamide. One child died. Four children had a favorable outcome. IACNS affecting large and medium arteries (n =5). Three children presented with acute ischemic stroke or TIA. Brain CT showed ischemic infarcts. Two children presented with subarachnoid hemorrhage. In this group, CSF, erythrocyte sedimentation rate, and angiograms were often abnormal. No patient received immunosuppressive therapy. Five children died. Autopsy showed granulomatous IACNS (n =5). CONCLUSIONS: Clinical and radiologic features correlate with the size of affected vessels. Prognosis differs between groups. Potential markers of poor outcome are acute stroke presentation secondary to large and medium-sized artery involvement, granulomatous angiitis, and delayed institution of immunosuppressive therapy.

Stroke in children: the coexistence of multiple risk factors predicts poor outcome.

OBJECTIVE: To characterize the risk factors for stroke in children and their relationship to outcomes. METHODS: We reviewed charts of children with ischemic and hemorrhagic stroke seen at Hopital Sainte-Justine, Montreal between 1991 and 1997. RESULTS: We found 51 ischemic strokes: 46 arterial and 5 sinovenous thromboses. Risk factors were variable and multiple in 12 (24%) of the 51 ischemic strokes. Ischemic stroke recurred in 3 (8%) patients with a single or no identified risk factor and in 5 (42%) of 12 patients with multiple risk factors (p = 0.01). We also found 21 hemorrhagic strokes, 14 (67%) of which were caused by vascular abnormalities. No patient with hemorrhagic stroke had multiple risk factors. Hemorrhagic stroke recurred in two patients (10%). Outcome in all 72 stroke patients was as follows: asymptomatic, 36%; symptomatic epilepsy or persistent neurologic deficit, 45%; and death, 20%. Death occurred more frequently in patients with recurrent stroke (40%) than in those with nonrecurrent stroke (16%). CONCLUSIONS: Multiple risk factors are found in many ischemic strokes and may predict stroke recurrence. Recurrent stroke tends to increase rate of mortality. Because of the high prevalence and importance of multiple risk factors, a complete investigation, including hematologic and metabolic studies and angiography, should be considered in every child with ischemic stroke, even when a cause is known.

Understanding factors that limit the productivity of suspension-based perfusion cultures operated at high medium renewal rates.

One of the key parameters in perfusion culture is the rate of medium replacement (D). Intensifying D results in enhanced provision of nutrients, which can lead to an increase in the viable cell density (X(v)). The daily MAb production of hybridoma cells can thus be increased proportionally without modifying the bioreactor scale, provided that both viable cell yield per perfusion rate (Y(Xv/D)) and specific MAb productivity (q(MAb)) remain constant at higher D. To identify factors prone to limit productivity in perfusion, a detailed kinetic analysis was carried out on a series of cultures operated within a D range of 0.48/4.34 vvd (volumes of medium/reactor volume/day) in two different suspension-based systems. In the Celligen/vortex-flow filter system, significant reductions in Y(Xv/D) and q(MAb) resulting from the use of gas sparging were observed at D > 1.57 vvd (X(v) > 15 x 10(6) cells/mL). Through glucose supplementation, we have shown that the decrease in Y(Xv/D) encountered in presence of sparging was not resulting from increased cellular destruction or reduced cell growth, but rather from glucose limitation. Thus, increases in hydrodynamic shear stress imparted to the culture via intensification of gas sparging resulted in a gradual increase in specific glucose consumption (q(glc)) and lactate production rates (q(lac)), while no variations were observed in glutamine-consumption rates. As a result, while glutamine was the sole limiting-nutrient under non-sparging conditions, both glutamine and glucose became limiting under sparging conditions. Although a reduction in q(MAb) was observed at high-sparging rates, inhibition of MAb synthesis did not result from direct impact of bubbles, but was rather associated with elevated lactate levels (25-30 mM), resulting from shear stress-induced increases in q(lac), q(glc), and Y(lac/glc). Deleterious effects of sparging on Y(Xv/D) and q(MAb) encountered in the Celligen/vortex-flow filter system were eliminated in the sparging-free low-shear environment of the Chemap-HRI/ultrasonic filter system, allowing for the maintenance of up to 37 x 10(6) viable cells/mL. A strategy aimed at reducing requirements for sparging in large-scale perfusion cultures by way of a reduction in the oxygen demand using cellular engineering is discussed.

Use of the Centritech Lab centrifuge for perfusion culture of hybridoma cells in protein-free medium.

As part of an effort to develop a suspension-culture perfusion-based process with high flow rate without the fouling and antibody retention inherent to filter-based cell-separation devices, we have evaluated and contributed to the development of the Centritech Lab centrifuge for the perfusion culture of hybridoma cells in protein-free medium. Culture start-ups showed that cell growth and monoclonal-antibody (MAb) production rates were similar in both a spinner flask and continuous centrifugation coupled to a bioreactor. The centrifuge efficiently separated viable cells from dead ones. Viable-cell recoveries were never below 98%, whereas dead-cell recoveries were usually around 80%. The cell content of the centrifuge supernatant and concentrate was strongly determined by the total amount of cells, viable and dead, in the culture broth, but an influence of the centrifugation parameters (feed rate, times of separation and discharge, and rotor speed) was observed. This understanding of the separation process inside the centrifuge is important and may apply to other similar devices. Monoclonal antibodies were not retained in the bioreactor during centrifugation perfusion. However, whereas similar growth rates were obtained in perfusion cultures using either continuous centrifugation or filtration, MAb concentrations were 35% lower in the former case. Utilization of the centrifuge in an intermittent fashion decreased the daily cell residence time outside the bioreactor, the daily pelleted-cell residence time in the centrifuge, and the frequency of cell passage to the centrifuge. This led to higher viable-cell numbers in the bioreactor and an accompanying increase in MAb concentrations, 225-250 mg of IgM L-1, equal to the performance of filter-based perfusion systems with the same cell line. It was hypothesized that having cells periodically packed at the bottom of the centrifuge insert (up to 800 x 10(6) cells mL-1) is deleterious to the culture by exposing the pelleted cells to prolonged nutrient limitations.