Pathobiology of healing response after endovascular treatment of intracranial aneurysms : Paradigm shift from lumen to wall oriented therapy

Background and Purpose: Subarachnoid hemorrhage attributable to saccular intracranial aneurysm (IA) rupture is a devastating disease leading to stroke, permanent neurological damage and death. Despite rapid advances in the development of endovascular treatment (EVT), complete and long lasting IA occlusion remains a challenge, especially in complexly shaped and large-sized aneurysms. Intraluminal thrombus induced by EVT may recanalize. The biological mechanisms predisposing IA to recanalize and grow are not yet fully understood, and the role of mural cell loss in these processes remains unclear. To elucidate these processes, animal models featuring complex aneurysm architecture and aneurysm models with different wall conditions (such as mural cell loss) are needed. Materials and Methods: Complex bilobular, bisaccular and broad-neck venous pouch aneurysms were microsurgically formed at artificially created bifurcations of both common carotid arteries in New Zealand rabbits. Sidewall aneurysms were microsurgically created on the abdominal aorta in Wistar rats. Some sidewall aneurysms were decellularized with sodium dodecyl sulfate. Thrombosis was induced using direct injection of a fibrin polymer into the aneurysm. CM-Dil-labeled syngeneic smooth muscle cells were injected into fibrin embolized aneurysms. The procedures were followed up with two-dimensional intra-arterial digital subtraction angiography, contrast-enhanced serial magnetic resonance angiographies, endoscopy, optical projection tomography, histology and immunohistochemistry. Results: Aneurysm and parent vessel patency of large aneurysms with complex angioarchitecture was 90% at one month and 86% at one year follow-up in the bifurcation rabbit model. Perioperative and one month postoperative mortality and morbidity were 0% and 9%. Mean operation time in the rat model was less than one hour and aneurysm dimensions proved to be highly standardized. Significant growth, dilatation or rupture of the experimental aneurysms was not observed, with a high overall patency rate of 86% at three week follow-up. Combined surgery-related mortality and morbidity was 9%. Decellularized aneurysms demonstrated a heterogeneous pattern of thrombosis, thrombus recanalization and growth, with ruptures in the sidewall rat model. Aneurysms with intraluminal local cell replacement at the time of thrombosis developed better neointima, showed less recurrence or growth and no ruptures. Growing and ruptured aneurysms demonstrated marked adventitial fibrosis and inflammation, complete wall disruption and increased neutrophil accumulation in unorganized luminal thrombus. Conclusions: Creation of complex venous pouch bifurcation aneurysms in the rabbit is feasible, with low morbidity, mortality and high short-term and long-term aneurysm patency. They represent a promising approach for in vivo animal testing of novel endovascular therapies. The sidewall aneurysm rat model is a quick and consistent method to create standardized aneurysms. Aneurysms missing mural cells are incapable of organizing a luminal thrombus, leading to aneurysm recanalization and increased inflammatory reactions. These, in turn, result in severe wall degeneration, aneurysm growth and eventual rupture. The results of the presented studies suggest that the biologically active luminal thrombus drives the healing process towards destructive wall remodeling and aneurysm rupture. Local smooth muscle cell transplantation compensates for mural cell loss and reduces recurrence, growth and rupture rate in a sidewall aneurysm rat model.Aivovaltimopullistuman repeämisestä johtuva lukinkalvonalinen verenvuoto (subaraknoidaalivuoto, SAV) on äkillinen ja raju kallonsisäinen verenvuoto joka tapahtuu noin tuhannelle henkilölle suomessa per vuosi. SAV aiheuttaa pysyvän neurologisen haitan tai kuoleman valtaosalle potilaista. Aivovaltimopullistumia voidaan hoitaa joko mikrokirurgisella leikkauksella tai tukkimalla pullistuma suonensisäisesti (endovaskulaarinen hoito). Suonesisäiset hoitomenetelmät ovat viime vuosikymmeninä kehittyneet merkittävästi, mutta edelleen osaa pullistumista ei voida tällä menetelmällä hoitaa ja ajoittain hoidon tulos ei ole pitkällä aikavälillä pysyvä. Suonensisäisten hoitomenetelmien jatkokehittämiseksi tarvitaan enemmän tietoa aivovaltimopullistuman seinämässä tapahtuvista biologisista mekanismeista ja realistisempiä kokeellisia malleja, mukaan lukien koe-eläinmalleja, joissa hoitomenetelmiä voidaan testata. Tässä väitöskirjassa on syvennytty tutkimaan kahta eri koe-eläinmallia, kani- ja rottamallia. Väitöskirjassa osoitetaan että mallit soveltuvat suonensisäisten hoitomenetelmien testaamiseen. Malleissa on kyetty realistisella tavalla mallintamaan todellisen aivovaltimopullistuman eri rappeutuneisuusasteita ja saatu merkittävää lisätietoa siitä miten pullistuman seinämän biologiset tapahtumat joko vahvistavat seinämää tai altistavat seinämän repeämiselle

Management of Patients Presenting with Acute Subdural Hematoma due to Ruptured Intracranial Aneurysm

Acute subdural hematoma is a rare presentation of ruptured aneurysms. The rarity of the disease makes it difficult to establish reliable clinical guidelines. Many patients present comatose and differential diagnosis is complicated due to aneurysm rupture results in or mimics traumatic brain injury. Fast decision-making is required to treat this life-threatening condition. Determining initial diagnostic studies, as well as making treatment decisions, can be complicated by rapid deterioration of the patient, and the mixture of symptoms due to the subarachnoid hemorrhage or mass effect of the hematoma. This paper reviews initial clinical and radiological findings, diagnostic approaches, treatment modalities, and outcome of patients presenting with aneurysmal subarachnoid hemorrhage complicated by acute subdural hematoma. Clinical strategies used by several authors over the past 20 years are discussed and summarized in a proposed treatment flowchart

Acute subdural hematoma from ruptured cerebral aneurysm

Purpose: The combination of ruptured aneurysms with acute subdural hematomas (aSDHs) is a rare presentation. Patients with aSDH associated with aneurysmal bleeding represent a subgroup within the spectrum of aneurysmatic hemorrhage. We summarize the clinical characteristics, diagnostic evaluation, and management of a series of cases presenting with aSDH associated with aneurysmal subarachnoid hemorrhage (SAH). Methods: Medical records and surgical reports of 743 consecutive patients admitted to our institution with SAH from January 1995 to December 2007 were screened to detect cases of associated aSDH. Admission evaluations included the Glasgow Coma Scale (GCS) and the subarachnoid grade of the World Federation of Neurosurgical Societies (WFNS). Radiological assessment included computer tomography (CT) scan, CT angiography (CTA), and digital subtraction angiography (DSA). The presence and volume of SAH, intracerebral hemorrhage (ICH), and aSDH were documented. Outcome was measured in terms of Glasgow Outcome Scale (GOS) and modified Rankin Scale (mRS) at 4-8 months. Results: A total of seven cases (0.9%) presenting with aSDH (mean width: 11.2mm ± 4.8mm, range: 5-20mm) attributable to SAH were documented. Three of these patients were admitted with a suspicion of trauma. Five patients presented with WFNS grade 5, one patient with WFNS grade 3, and one patient with WFNS grade 1. All patients underwent evacuation of the aSDH. In four patients, surgical obliteration of the aneurysm was achieved in the same procedure. Two patients underwent delayed occlusion of the aneurysm: one by coiling and one by clipping. Three of the seven patients recovered completely from their neurological deficits (GOS 5, mRS 0-1), three recovered with mild disability (GOS 4, mRS 2-3), and one died within 8 h after the decompressive procedure. Conclusions: The incidence of aSDH associated with SAH is low. Most of the patients with aSDH due to a ruptured aneurysm present in exceptionally poor neurological condition. Nevertheless, rapid surgical treatment of the hematoma and aneurysm obliteration can lead to a favorable outcome. Routine CTA should be performed in all patients presenting with an aSDH associated with SAH and no clear history of traum

Preclinical extracranial aneurysm models for the study and treatment of brain aneurysms: A systematic review.

Animal models make an important contribution to our basic understanding of the pathobiology of human brain aneurysms, are indispensable in testing novel treatment approaches, and are essential for training interventional neuroradiologists and neurosurgeons. Researchers are confronted with a broad diversity of models and techniques in various species. This systematic review aims to summarize and categorize extracranial aneurysm models and their characteristics, discuss advantages and disadvantages, and suggest the best use of each model. We searched the electronical Medline/PubMed database between 1950 and 2020 to identify main models and their refinements and technical modifications for creation of extracranial aneurysms. Each study included was assessed for aneurysm-specific characteristics, technical details of aneurysm creation, and histological findings. Among more than 4000 titles and abstracts screened, 473 studies underwent full-text analysis. From those, 68 different techniques/models in five different species were identified, analyzed in detail, and then grouped into one of the five main groups of experimental models as sidewall, terminal, stump, bifurcation, or complex aneurysm models. This systematic review provides a compact guide for investigators in selecting the most appropriate model from a range of techniques to best suit their experimental goals, practical considerations, and laboratory environment

Is the use of antibiotic-impregnated external ventricular drainage beneficial in the management of iatrogenic ventriculitis?

Background: Profound evidence substantiates significantly reduced risk of catheter-related infections with prophylactic use of rifampin- and clindamycin-impregnated silicone catheters (Bactiseal®, Codman Johnson & Johnson, Raynham, MA, USA) for external ventricular drainage (EVD). However, whether Bactiseal®-EVD (B-EVD) influences the treatment of EVD-related ventriculitis remains controversial. Methods: We performed a retrospective analysis of patients who developed ventriculitis after EVD or ventriculoperitoneal (VP) shunt placement and consequently underwent either placement of B-EVD (group 1) or a standard non-antibiotic-impregnated EVD (group 2). Analyzed parameters included demographic and clinical data, hospitalization time, time until remission of the infection parameters, detection of new bacterial resistance on antibiograms, and clinical outcome in terms of the modified Rankin scale (mRS). Results: Time until remission of cerebrospinal fluid (CSF) pleocytosis was significantly longer in patients undergoing B-EVD (8 ± 3.8days; n = 15; group 1) than in patients who underwent standard EVD (5.1 ± 1.8days; n = 10; group 2). There was no significant difference between both groups for the time until polymorphonuclear cells dropped below 50% of peak value (5.8 ± 1.6 vs. 4.1 ± 2.9days), CRP dropped below 10mg/l (4.2 ± 3.5 vs. 5.6 ± 3.3days), the time of plasma neutrophil remission (5.7 ± 2.6 vs. 5.3 ± 3.2days) and hospitalization time (28 ± 12.5 vs. 35 ± 19.4days). The mRS for both groups was 2. Development of new antibiotic resistance did not occur in either group. Conclusions: This retrospective pilot study indicates that B-EVD might have no major advantage in the management of EVD or VP-shunt-related ventriculitis. Based on published reports and the results of this study, data support only the prophylactic use of B-EVD for prevention of EVD-related infections. Prospective randomized clinical trials are warranted to further evaluate the role of B-EVD in the treatment of ventriculiti

Preclinical Intracranial Aneurysm Models: A Systematic Review.

Intracranial aneurysms (IA) are characterized by weakened cerebral vessel walls that may lead to rupture and subarachnoid hemorrhage. The mechanisms behind their formation and progression are yet unclear and warrant preclinical studies. This systematic review aims to provide a comprehensive, systematic overview of available animal models for the study of IA pathobiology. We conducted a systematic literature search using the PubMed database to identify preclinical studies employing IA animal models. Suitable articles were selected based on predefined eligibility criteria following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Included studies were reviewed and categorized according to the experimental animal and aneurysm model. Of 4266 returned results, 3930 articles were excluded based on the title and/or abstract and further articles after screening the full text, leaving 123 studies for detailed analysis. A total of 20 different models were found in rats (nine), mice (five), rabbits (four), and dogs (two). Rat models constituted the most frequently employed intracranial experimental aneurysm model (79 studies), followed by mice (31 studies), rabbits (12 studies), and two studies in dogs. The most common techniques to induce cerebral aneurysms were surgical ligation of the common carotid artery with subsequent induction of hypertension by ligation of the renal arteries, followed by elastase-induced creation of IAs in combination with corticosterone- or angiotensin-induced hypertension. This review provides a comprehensive summary of the multitude of available IA models to study various aspects of aneurysm formation, growth, and rupture. It will serve as a useful reference for researchers by facilitating the selection of the most appropriate model and technique to answer their scientific question