Andrew J. Ringer

Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm

Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.

Aggressive mechanical clot disruption and low-dose intra-arterial third-generation thrombolytic agent for ischemic stroke: a prospective study.

OBJECTIVE We prospectively evaluated the safety and effectiveness of aggressive mechanical disruption of clot in conjunction with intra-arterial administration of a low-dose third-generation thrombolytic agent (reteplase) to treat ischemic stroke in patients who were considered poor candidates for intravenous alteplase therapy or who failed to improve after intravenous thrombolysis. Mechanical clot disruption was used if low-dose pharmacological thrombolysis was ineffective. This strategy was adopted to increase the recanalization rate without increasing the risk of intracerebral hemorrhage. METHODS Patients were considered poor candidates for intravenous therapy because of severity of neurological deficits, interval from symptom onset to presentation of at least 3 hours, or recent major surgery. We administered a maximum total dose of 4 U of reteplase intra-arterially in 1-U increments via superselective catheterization. After the initial doses were administered, we performed mechanical angioplasty (for proximal occlusion) or snare manipulation (for distal occlusion) at the occlusion site if recanalization had not occurred. The remaining doses of thrombolytics were subsequently administered if required for further recanalization. Angiographic responses were graded using modified Thrombolysis in Myocardial Infarction (TIMI) criteria. Clinical evaluations were performed before and 24 hours, 7 to 10 days, and 1 to 3 months after treatment. RESULTS Nineteen consecutive patients were treated (mean age, 64.3 ± 16.2 yr; 10 were men). Initial National Institutes of Health Stroke Scale scores ranged from 11 to 42. Time from onset to treatment ranged from 1 to 9 hours. Occlusion sites were in the following arteries: cervical internal carotid (n = 7), intracranial internal carotid (n = 1), middle cerebral (n = 9), and basilar (n = 2). Of the 19 patients, thrombolysis alone was used in 5 patients, angioplasty was performed in 11 patients, and snare maneuvers were used in 5 patients. Complete restoration of blood flow (modified TIMI Grade 4) was observed in 12 patients, near-complete restoration of flow (modified TIMI Grade 3) in 4 patients, minimal response (modified TIMI Grade 1) in 1 patient, and no response in 2 patients (modified TIMI Grade 0). Neurological improvement at 24 hours (decline of at least 4 points in National Institutes of Health Stroke Scale score) was observed in seven patients. Five other patients experienced further improvement in National Institutes of Health Stroke Scale score at 7 to 10 days. No vessel rupture, dissection, or symptomatic intracranial hemorrhages were observed. At the time of follow-up evaluation, 7 of 19 patients were functionally independent. CONCLUSION A high rate of recanalization and clinical improvement can be observed in patients with ischemic stroke using low-dose thrombolytic agents with adjunctive mechanical disruption of clot. Moreover, this strategy may reduce the risk of intracerebral hemorrhage observed with thrombolytics.

Guidelines for the Management of Patients With Unruptured Intracranial Aneurysms A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

Purpose— The aim of this updated statement is to provide comprehensive and evidence-based recommendations for management of patients with unruptured intracranial aneurysms. Methods— Writing group members used systematic literature reviews from January 1977 up to June 2014. They also reviewed contemporary published evidence-based guidelines, personal files, and published expert opinion to summarize existing evidence, indicate gaps in current knowledge, and when appropriate, formulated recommendations using standard American Heart Association criteria. The guideline underwent extensive peer review, including review by the Stroke Council Leadership and Stroke Scientific Statement Oversight Committees, before consideration and approval by the American Heart Association Science Advisory and Coordinating Committee. Results— Evidence-based guidelines are presented for the care of patients presenting with unruptured intracranial aneurysms. The guidelines address presentation, natural history, epidemiology, risk factors, screening, diagnosis, imaging and outcomes from surgical and endovascular treatment.

Angioplasty of intracranial occlusion resistant to thrombolysis in acute ischemic stroke.

OBJECTIVEThrombolysis has been demonstrated to improve revascularization and outcome in patients with acute ischemic stroke. Many centers now apply thrombolytic therapy locally via intra-arterial infusion. One therapeutic benefit is the ability to cross soft clots with a guidewire and to perform mechanical thrombolysis. In some instances, reopened arteries reocclude as a result of either thrombosis or vasospasm. We report the use of balloon angioplasty during thrombolysis for acute stroke. METHODSFrom June 1995 through June 1999, 49 patients underwent intra-arterial therapy for acute stroke. In this group, nine patients (seven men and two women) were treated with balloon angioplasty after inadequate recanalization with thrombolytic infusion. The mean age of these patients was 67.9 years. Nine matched control patients who underwent thrombolysis alone without angioplasty were chosen for comparison. RESULTSIn the group of nine patients who had angioplasty, the mean National Institutes of Health Stroke Scale score at presentation was 21.8 ± 5.4. Four patients had residual distal occlusion after angioplasty, and one patient had a hemorrhagic conversion. Of the five patients in which recanalization was successful, none had reocclusion of the balloon-dilated vessel. The mean score at 30 days for the five survivors was 12.6 ± 14.9, for an improvement of 7.0 ± 14.2. Among the nine control patients, the mean score at presentation was 20.3 ± 5.2; the mean score at 30 days for the five survivors was 19.4 ± 7.7, for an improvement of 4.2 ± 7.8. CONCLUSIONIn our experience, balloon angioplasty is a safe, effective adjuvant therapy in patients who are resistant to intra-arterial thrombolysis. The use of balloon angioplasty may prevent reocclusion in a stenotic artery and permit distal infusion of thrombolytic agents.

Intra-arterial Third-generation Recombinant Tissue Plasminogen Activator (Reteplase) for Acute Ischemic Stroke

OBJECTIVEWe prospectively evaluated the safety and recanalization efficacy of intra-arterially administered reteplase, a third-generation recombinant tissue plasminogen activator, for treating ischemic stroke in patients considered poor candidates for intravenously administered alteplase therapy. METHODSPatients were considered poor candidates for intravenously administered therapy because of severity of neurological deficits, interval from onset of symptoms to presentation of 3 hours or more, or recent major surgery. We administered a maximum total dose of 8 U of reteplase intra-arterially in 1-U increments via superselective catheterization. Adjunctive angioplasty of the occluded artery was performed in seven patients. Angiographic evidence of perfusion and thrombus was graded by use of modified Thrombolysis in Myocardial Infarction (TIMI) criteria. Neurological examinations were performed before and 24 hours and 7 to 10 days after treatment. RESULTSSixteen consecutive patients were treated (mean age, 64.1 ± 16.4 yr; seven were men). Initial National Institutes of Health Stroke Scale scores ranged from 10 to 26. Time from onset of symptoms to treatment ranged from 2 to 9 hours. Occlusion sites were the cervical internal carotid artery (n = 4), intracranial internal carotid artery (n = 4), middle cerebral artery (n = 6), and vertebrobasilar artery (n = 2). Complete or near-complete perfusion (TIMI Grade 3 or 4) was achieved in the arteries in 14 patients (88%), with partial recanalization (TIMI Grade 2) or minimal response (TIMI Grade 1) in the arteries in one patient each. Neurological improvement (defined as decrease of four or more points in National Institutes of Health Stroke Scale score) was observed in 7 (44%) of the 16 patients at 24 hours. Symptomatic intracerebral hemorrhage occurred in one patient; three other patients experienced intracerebral hemorrhages that did not result in neurological worsening. The overall mortality during hospitalization was 56%, related to massive ischemic stroke (n = 7), withdrawal of care at the family’s request after the development of aspiration pneumonia and renal failure (n = 1), and a combination of intracerebral hemorrhage and massive ischemic stroke (n = 1). CONCLUSIONIn this study, intra-arterially administered reteplase in doses up to 8 U with or without angioplasty resulted in a high rate of recanalization. This strategy should be considered in treating patients considered poor candidates for intravenous thrombolysis.

Early postmarket results after treatment of intracranial aneurysms with the pipeline embolization device: A US multicenter experience

BACKGROUND The pipeline embolization device (PED) is the latest technology available for intracranial aneurysm treatment. OBJECTIVE To report early postmarket results with the PED. METHODS This study was a prospective registry of patients treated with PEDs at 7 American neurosurgical centers subsequent to Food and Drug Administration approval of this device. Data collected included clinical presentation, aneurysm characteristics, treatment details, and periprocedural events. Follow-up data included degree of aneurysm occlusion and delayed (> 30 days after the procedure) complications. RESULTS Sixty-two PED procedures were performed to treat 58 aneurysms in 56 patients. Thirty-seven of the aneurysms (64%) treated were located from the cavernous to the superior hypophyseal artery segment of the internal carotid artery; 22% were distal to that segment, and 14% were in the vertebrobasilar system. A total of 123 PEDs were deployed with an average of 2 implanted per aneurysm treated. Six devices were incompletely deployed; in these cases, rescue balloon angioplasty was required. Six periprocedural (during the procedure/within 30 days after the procedure) thromboembolic events occurred, of which 5 were in patients with vertebrobasilar aneurysms. There were 4 fatal postprocedural hemorrhages (from 2 giant basilar trunk and 2 large ophthalmic artery aneurysms). The major complication rate (permanent disability/death resulting from perioperative/delayed complication) was 8.5%. Among 19 patients with 3-month follow-up angiography, 68% (13 patients) had complete aneurysm occlusion. Two patients presented with delayed flow-limiting in-stent stenosis that was successfully treated with angioplasty. CONCLUSION Unlike conventional coil embolization, aneurysm occlusion with PED is not immediate. Early complications include both thromboembolic and hemorrhagic events and appear to be significantly more frequent in association with treatment of vertebrobasilar aneurysms.

Long-term results of enterprise stent-assisted coiling of cerebral aneurysms.

BACKGROUND The Enterprise Vascular Reconstruction Device and Delivery System (Cordis; the Enterprise stent) was approved for use in conjunction with coiling of wide-necked aneurysms in 2007. No published long-term aneurysm occlusion or complication data exist for the Enterprise system. OBJECTIVE We compiled data on consecutive patients treated with Enterprise stent-assisted coiling of aneurysms from 9 high-volume neurointerventional centers. METHODS A 9 center registry was created to evaluate large volume data on the delayed safety and efficacy of the Enterprise stent system. Pooled data were compiled for consecutive patients undergoing Enterprise stent-assisted coiling at each institution prior to May 2009. RESULTS Two-hundred twenty-nine patients with 229 aneurysms, 32 of which were ruptured aneurysms, were included in the study. Mean clinical and angiographic follow-up was 619.6 ± 26.4 days and 655.7 ± 25.2 days, respectively. Mean aneurysm size was 9.2 ± 0.4 mm. Fifty-nine percent of patients demonstrated 100% coil obliteration and 81% had 90% or higher occlusion at last follow-up angiography. A total of 19 patients (8.3%) underwent retreatment of their aneurysms during the follow-up period. Angiographic in-stent stenosis was seen in 3.4% and thromboembolic events occurred in 4.4%. Overall, 90% of patients who underwent Enterprise-assisted coiling had a modified Rankin Scale score of 2 or less at last follow-up. A poor modified Rankin Scale score was strongly associated with rupture status (P < .001). CONCLUSION Although this study is limited by its retrospective nature, the Enterprise stent system appears to be an effective, safe, and durable treatment for intracranial aneurysms when used in conjunction with coiling.

Transradial cerebral angiography: an alternative route.

INTRODUCTION The transradial approach has been well described for arteriography of the coronary vessels. To assess the safety and success rate of the transradial approach for three-vessel or four-vessel diagnostic cerebral arteriography, we reviewed the experience at our institution and compared our complication rates with those found in the literature for transfemoral cerebral angiography and transradial coronary angiography. METHODS We reviewed the electronic medical records of 129 consecutive patients in whom 132 cerebral angiographic studies were performed by use of a transradial approach between December 1999 and June 2001. A total of 54 selective catheterizations were performed, of which 39 were of the vertebral artery, 11 of the internal carotid artery, and 4 of the external carotid artery. Records were reviewed for periprocedural and delayed complications, indications for diagnostic angiography, and requirement of conversion to a femoral approach. Records were reviewed prospectively for the first 55 procedures and retrospectively for the next 77 procedures. RESULTS The mean time to initial clinical follow-up was 1.5 months (median, 0.5 mo). The combined rate of periprocedural and delayed complications was 9%, and there were no major complications. Minor periprocedural complications included transient radial artery spasm (four patients), failure to access the brachial artery (two patients), severe pain (one patient), skin desquamation (one patient), and hematoma (one patient). There were no major complications. At the time of follow-up evaluation, these patients were without deficits related to cannulation of the radial artery. CONCLUSION The transradial approach for cerebral angiography is a safe alternative to the transfemoral route. After transradial cerebral angiography, patients require a shorter observation period and are not restricted to bed rest. As technological developments generate smaller, more pliable endovascular surgical devices, future endovascular surgery may be performed transradially.

Follow-up of stented carotid arteries by Doppler ultrasound.

OBJECTIVE Blood flow velocity (BFV) in the carotid artery is altered by stent placement. The significance of these alterations is unknown. In our experience, both standard BFV criteria for stenosis and customized criteria recommended by other authors have led to high rates of false-positive studies. We reviewed our experience with Doppler ultrasonography immediately after extracranial carotid artery stent placement to define criteria for restenosis by BFV. METHODS Complete carotid angiograms and BFV results were available for 114 patients treated between January 1998 and December 1999. Angiographic images obtained immediately after stent placement and at follow-up were measured for residual or recurrent stenosis by a blinded reviewer according to the North American Symptomatic Carotid Endarterectomy Trial method. Results of BFV studies obtained within 1 week of stent placement were interpreted by using two standard criteria (A, peak in-stent systolic velocity greater than 125 cm/s;B, internal carotid artery-to-common carotid artery ratio greater than 3.0) and two customized criteria (C, peak in-stent velocity greater than 170 cm/s;D, internal carotid artery-to-common carotid artery ratio greater than 2.0). The results of follow-up angiography and the most recent Doppler study were compared for nine patients. RESULTS On the basis of an examination of Doppler studies obtained immediately after stent placement, 36 patients met Criterion A for stenosis according to measured BFV (corresponding mean angiographic stenosis, 14.73 ± 18.45%), 3 patients met Criterion B (mean stenosis, 1.67 ± 2.89%), 8 patients met Criterion C (mean stenosis, 12.61 ± 13.18%), and 14 met Criterion D (mean stenosis, 7.98 ± 21.74%). No patient with Doppler criteria for significant stenosis had more than 50% residual stenosis. Three of nine patients who underwent follow-up angiography had stenosis of 50% or more; of these three patients, two underwent second angioplasty procedures. The peak in-stent systolic velocity or internal carotid artery-to-common carotid artery BFV ratio for each of the three patients with restenosis, but not for the six other patients, had increased by more than 80% since the immediate post-stenting Doppler study. CONCLUSION Strict BFV criteria for restenosis after carotid artery stenting are less reliable than change in BFV over time. An immediate post-stenting Doppler study must be obtained to serve as a reference value for future follow-up evaluation.

Decompressive hemicraniectomy for malignant middle cerebral artery territory infarction: is life worth living?

OBJECT Although decompressive hemicraniectomy has been shown to reduce death and improve functional outcome following malignant middle cerebral artery territory infarction, there is ongoing debate as to whether surgery should be routinely performed, considering the very high rates of disability and functional dependence in survivors. Through a systematic review of the literature, the authors sought to determine the outcome from a patients perspective. METHODS In September 2010, a MEDLINE search of the English-language literature was performed using various combinations of 12 key words. A total of 16 papers were reviewed and individual study data were extracted. RESULTS There was significant variability in study design, patient eligibility criteria, timing of surgery, and methods of outcome assessment. There were 382 patients (59% male, 41% female) with a mean age of 50 years, 25% with dominant-hemisphere infarction. The mortality rate was 24% and the mean follow-up in survivors was 19 months (range 3-114 months). Of 156 survivors with available modified Rankin Scale (mRS) scores, 41% had favorable functional outcome (mRS Score ≤ 3), whereas 47% had moderately severe disability (mRS Score 4). Among 157 survivors with quality of life assessment, the mean overall reduction was 45%: 67% for physical aspect and 37% for psychosocial aspect. Of 114 screened survivors, depression affected 56% and was moderate or severe in 25%. Most patients and/or caregivers (77% of the 209 interviewed) were satisfied and would give consent again for the procedure. CONCLUSIONS Despite high rates of physical disability and depression, the vast majority of patients are satisfied with life and do not regret having undergone surgery.