Lumen-oriented versus wall-oriented treatment strategies for intracranial aneurysms - A systematic review of suggested therapeutic concepts.

The development of new treatment strategies for intracranial aneurysms (IAs) has been and continues to be a major interest in neurovascular research. Initial treatment concepts were mainly based on a physical-mechanistic disease understanding for IA occlusion (lumen-oriented therapies). However, a growing body of literature indicates the important role of aneurysm wall biology (wall-oriented therapies) for complete IA obliteration. This systematic literature review identified studies that explored endovascular treatment strategies for aneurysm treatment in a preclinical setting. Of 5278 publications screened, 641 studies were included, categorized, and screened for eventual translation in a clinical trial. Lumen-oriented strategies included (1) enhanced intraluminal thrombus organization, (2) enhanced intraluminal packing, (3) bridging of the intraluminal space, and (4) other, alternative concepts. Wall-oriented strategies included (1) stimulation of proliferative response, (2) prevention of aneurysm wall cell injury, (3) inhibition of inflammation and oxidative stress, and (4) inhibition of extracellular matrix degradation. Overall, lumen-oriented strategies numerically still dominate over wall-oriented strategies. Among the plethora of suggested preclinical treatment strategies, only a small minority were translated into clinically applicable concepts (36 of 400 lumen-oriented and 6 of 241 wall-oriented). This systematic review provides a comprehensive overview that may provide a starting point for the development of new treatment strategies

Saccular Aneurysm Models Featuring Growth and Rupture: A Systematic Review.

BACKGROUND Most available large animal extracranial aneurysm models feature healthy non-degenerated aneurysm pouches with stable long-term follow-ups and extensive healing reactions after endovascular treatment. This review focuses on a small subgroup of extracranial aneurysm models that demonstrated growth and potential rupture during follow-up. METHODS The literature was searched in Medline/Pubmed to identify extracranial in vivo saccular aneurysm models featuring growth and rupture, using a predefined search strategy in accordance with the PRISMA guidelines. From eligible studies we extracted the following details: technique and location of aneurysm creation, aneurysm pouch characteristics, time for model creation, growth and rupture rate, time course, patency rate, histological findings, and associated morbidity and mortality. RESULTS A total of 20 articles were found to describe growth and/or rupture of an experimentally created extracranial saccular aneurysm during follow-up. Most frequent growth was reported in rats (n = 6), followed by rabbits (n = 4), dogs (n = 4), swine (n = 5), and sheep (n = 1). Except for two studies reporting growth and rupture within the abdominal cavity (abdominal aortic artery; n = 2) all other aneurysms were located at the neck of the animal. The largest growth rate, with an up to 10-fold size increase, was found in a rat abdominal aortic sidewall aneurysm model. CONCLUSIONS Extracranial saccular aneurysm models with growth and rupture are rare. Degradation of the created aneurysmal outpouch seems to be a prerequisite to allow growth, which may ultimately lead to rupture. Since it has been shown that the aneurysm wall is important for healing after endovascular therapy, it is likely that models featuring growth and rupture will gain in interest for preclinical testing of novel endovascular therapies

An unexpected intracerebral lesion - case report of a superinfected aspergillosis mimicking a brain metastasis

BACKGROUND: Invasive aspergillosis of the central nervous system is a rare but increasingly prevalent disease. We present the unusual case of an immunosuppressed patient suffering from unexpected superinfected invasive aspergillosis with cerebral, pulmonal, and adrenal manifestations, mimicking a metastasized bronchial carcinoma. This report reveals the importance of including aspergillosis in the differential diagnosis of a cerebral mass lesion in the light of unspecific clinical findings. CASE PRESENTATION: A 58-year-old immunocompromised female presented to our emergency department with a single tonic-clonic seizure. Imaging showed a ring enhancing cerebral mass with perifocal edema and evidence of two smaller additional hemorrhagic cerebral lesions. In the setting of a mass lesion in the lung, and additional nodular lesions in the left adrenal gland the diagnosis of a metastasized bronchus carcinoma was suspected and the cerebral mass resected. However, histology did not reveal any evidence for a neoplastic lesion but septate hyphae consistent with aspergillus instead and microbiological cultures confirmed concomitant staphylococcal infection. CONCLUSIONS: A high index of suspicion for aspergillus infection should be maintained in the setting of immunosuppression. Clinical and radiological findings are often unspecific and even misleading. Definite confirmation usually relies on tissue diagnosis with histochemical stains. Surgical resection is crucial for establishing the diagnosis and guiding therapy with targeted antifungal medications

Compensatory mechanisms in adult degenerative thoracolumbar spinal deformity – Radiographic patterns, their reversibility after corrective surgery, and the influence of pelvic morphology

Objective: Loss of lumbar lordosis (LL) in degenerative deformity activates spinal compensatory mechanisms to maintain neutral C7 sagittal vertical axis (C7SVA), such as an increase in pelvic tilt (PT) and decreased thoracic kyphosis (TK). We study the extent to which PT increase and TK reduction contribute to the compensation of pelvic incidence (PI)-LL mismatch. Methods: A cohort of 43 adult patients with adult degenerative thoracolumbar deformity were included in this retrospective study. Radiographic spinopelvic measurements were obtained before and after corrective surgery. Pearson correlations were calculated. Results: Preoperative PI-LL mismatch significantly correlated with an increase in PT and a decrease in TK in the whole cohort r = +0.66 (95% confidence interval [CI] 0.44–0.8) and r = −0.67 (95% CI − 0.81–−0.47), respectively, at a relative rate of 0.37 (standard deviation [SD]: 0.07) and − 0.57 (SD: 0.09), respectively. In patients with low PI, only TK showed a significant correlation with PI-LL mismatch, r = −0.56 (95% CI − 0.8 to − 0.16), at a rate of − 0.57 (SD: 0.19). The high PI subgroup showed a significant correlation with PT, TK, and C7SVA, r = 0.62 (95% CI 0.26–0.82), r = −0.8 (95% CI − 0.9–−0.58), and r = 0.71 (95% CI 0.41–0.87) at rates of 0.48 (SD: 0.11), −0.72 (SD: 0.12), and 0.62 (SD: 1.27). Conclusions: Decreased TK represented a more consistent compensatory mechanism in patients with high and low PI when compared to an increase in PT. PI-LL mismatch induced more pronounced changes in TK than did PT in both subgroups. Patients with high PI relied more on increases in PT and a relative decrease in TK to compensate for PI-LL mismatch than patients with low PI. Keywords: Adult spinal deformity, pelvic incidence, pelvic tilt, sagittal balance, thoracolumbar deformit

Parent artery-initiated and stent-mediated neointima formation in a rat saccular side wall model.

BACKGROUND Unlike clipping that forms an immediate barrier of blood flow into intracranial aneurysms, endovascular treatments rely on thrombus organization and neointima formation. Therefore, a continuous endothelial cell layer is crucial to prevent blood flow in the former aneurysm. This study investigates the origin of endothelial cells in the neointima of endovascular treated aneurysms, specifically whether cells from the parent artery play a role in neointima formation. METHODS In male rats, decellularized and vital side wall aneurysms were treated by coil (n=16) or stent embolization (n=15). The cell tracer CM-Dil dye was injected into the clamped aorta before aneurysm suture to mark initial endothelial cells in the parent artery and enable tracking of their proliferation during follow-up. Aneurysms were analyzed for growth, thrombus formation, and recurrence. Histological evaluation followed with cell counts for specific regions-of-interest. RESULTS During follow-up, none of the 31 aneurysms ruptured. Macroscopic residual perfusion was observed in 12/16 rats after coiling and in 1/15 after stenting. Amounts of CM-Dil +cells in coiled versus stented decellularized aneurysms significantly decreased in the thrombus on day 7 (p=0.01) and neointima on day 21 (p=0.04). For vital aneurysms, the number of CM-Dil +cells in the neointima on day 21 showed no significant difference. CONCLUSIONS Healing patterns were worse in coil-treated than stent-treated aneurysms. Cell migration forming a neointima seemed mainly dependent on the adjacent vessel in decellularized aneurysms, but appeared buoyed by recruitment from aneurysm wall cells in vital aneurysms. Therefore, a cell-rich parent artery might be crucial

Topographic distribution of inflammation factors in a healing aneurysm.

BACKGROUND Healing of intracranial aneurysms following endovascular treatment relies on the organization of early thrombus into mature scar tissue and neointima formation. Activation and deactivation of the inflammation cascade plays an important role in this process. In addition to timely evolution, its topographic distribution is hypothesized to be crucial for successful aneurysm healing. METHODS Decellularized saccular sidewall aneurysms were created in Lewis rats and coiled. At follow-up (after 3 days (n = 16); 7 days (n = 19); 21 days (n = 8)), aneurysms were harvested and assessed for healing status. In situ hybridization was performed for soluble inflammatory markers (IL6, MMP2, MMP9, TNF-α, FGF23, VEGF), and immunohistochemical analysis to visualize inflammatory cells (CD45, CD3, CD20, CD31, CD163, HLA-DR). These markers were specifically documented for five regions of interest: aneurysm neck, dome, neointima, thrombus, and adjacent vessel wall. RESULTS Coiled aneurysms showed enhanced patterns of thrombus organization and neointima formation, whereas those without treatment demonstrated heterogeneous patterns of thrombosis, thrombus recanalization, and aneurysm growth (p = 0.02). In coiled aneurysms, inflammation markers tended to accumulate inside the thrombus and in the neointima (p < 0.001). Endothelial cells accumulated directly in the neointima (p < 0.0001), and their presence was associated with complete aneurysm healing. CONCLUSION The presence of proinflammatory cells plays a crucial role in aneurysm remodeling after coiling. Whereas thrombus organization is hallmarked by a pronounced intra-thrombotic inflammatory reaction, neointima maturation is characterized by direct invasion of endothelial cells. Knowledge concerning topographic distribution of regenerative inflammatory processes may pave the way for future treatment modalities which enhance aneurysm healing after endovascular therapy

Aspirin treatment prevents inflammation in experimental bifurcation aneurysms in New Zealand White rabbits.

BACKGROUND Aneurysm wall degeneration is linked to growth and rupture. To address the effect of aspirin (ASA) on aneurysm formation under various wall conditions, this issue was analyzed in a novel rabbit bifurcation model. METHODS Bifurcation aneurysms created in 45 New Zealand White rabbits were randomized to vital (n=15), decellularized (n=13), or elastase-degraded (n=17) wall groups; each group was assigned to a study arm with or without ASA. At follow-up 28 days later, aneurysms were evaluated for patency, growth, and wall inflammation at macroscopic and histological levels. RESULTS 36 rabbits survived to follow-up at the end of the trial. None of the aneurysms had ruptured. Patency was visualized in all aneurysms by intraoperative fluorescence angiography and confirmed in 33 (92%) of 36 aneurysms by MRI/MRA. Aneurysm size was significantly increased in the vital (without ASA) and elastase-degraded (with and without ASA) groups. Aneurysm thrombosis was considered complete in three (50%) of six decellularized aneurysms without ASA by MRI/MRA. Locoregional inflammation of the aneurysm complex was significantly reduced in histological analysis among all groups treated with ASA. CONCLUSION ASA intake prevented inflammation of both the periadventitial tissue and aneurysm wall, irrespective of initial wall condition. Although ASA prevented significant growth in aneurysms with vital walls, this preventive effect did not have an important role in elastase-degraded pouches. In possible translation to the clinical situation, ASA might exert a potential preventive effect during early phases of aneurysm formation in patients with healthy vessels but not in those with highly degenerative aneurysm walls

Testing bioresorbable stent feasibility in a rat aneurysm model.

BACKGROUND Advances in stent-assisted coiling have incrementally expanded endovascular treatment options for complex cerebral aneurysms. After successful coil consolidation and aneurysm occlusion, endovascular scaffolds are no longer needed. Thus, bioresorbable stents that disappear after aneurysm healing could avoid future risks of in-stent thrombosis and the need for lifelong antiplatelet therapy. OBJECTIVE To assess the applicability and compatibility of a bioresorbable magnesium- alloy stent (brMAS) for assisted coiling. METHODS Saccular sidewall aneurysms were created in 84 male Wistar rats and treated with brMAS alone, brMAS + aspirin, or brMAS + coils + aspirin. Control groups included no treatment (natural course), solely aspirin treatment, or conventional cobalt-chromium stent + coils + aspirin treatment. After 1 and 4 weeks, aneurysm specimens were harvested and macroscopically, histologically, and molecularly examined for healing, parent artery perfusion status, and inflammatory reactions. Stent degradation was monitored for up to 6 months with micro-computed and optical coherence tomography. RESULTS Aneurysms treated with brMAS showed advanced healing, neointima formation, and subsequent stent degradation. Additional administration of aspirin sustained aneurysm healing while reducing stent-induced intraluminal and periadventitial inflammatory responses. No negative interaction was detected between platinum coils and brMAS. Progressive brMAS degradation was confirmed. CONCLUSIONS brMAS induced appropriate healing in this sidewall aneurysm model. The concept of using bioresorbable materials to promote complete aneurysm healing and subsequent stent degradation seems promising. These results should encourage further device refinements and clinical evaluation of this treatment strategy for cerebrovascular aneurysms

Growing fat tissue after grafting for dural sealing.

We report on a young patient with a growing retroauricular benign fat tissue tumour after juvenile fat grafting for dural sealing of a placed ventriculoperitoneal shunt. The clinical images indicates fat tissue rather than a cerebrospinal fluid (CSF) leak due to potential shunt malfunction suspected on plain radiography. Human adipose tissue is a source of stem cells that can replicate rather than undergo necrosis, in particular when transplanted during development