The use of mixed reality for the treatment planning of unruptured intracranial aneurysms.

BACKGROUND: A thorough comprehension of topographic neuroanatomy is paramount in neurosurgery. In recent years, great attention has been raised towards extended reality, which comprises virtual, augmented, and mixed reality (MR) as an aid for surgery. In this paper, we describe our preliminary experience with the use of a new MR platform, aiming to assess its reliability and usefulness in the planning of surgical treatment of unruptured intracranial aneurysms. METHODS: We prospectively enrolled 5 patients, harboring a total of 8 intracranial unruptured aneurysms, undergoing elective surgical clipping. A wearable mixed-reality device (HoloLens; Microsoft Corp., Redmond, WA, USA) was used to display and interact with a holographic model during surgical planning. Afterward, a total of 10 among surgeons and residents filled in a 5-point Likert-Scale evaluation questionnaire. RESULTS: According to the participants' feedback, the main MR platform advantages were considered the educational value, its utility during patients positioning and craniotomy planning, as well as the anatomical and imaging interpretation during surgery. The graphic performance was also deemed very satisfactory. On the other hand, the device was evaluated as not easy to use and pretty uncomfortable when worn for a long time. CONCLUSIONS: We demonstrated that MR could play important role in planning the surgical treatment of intracranial aneurysms by enhancing the visualization and understanding of the patient-specific anatomy.

Distribution of Cerebrovascular Phenotypes According to Variants of the ENG and ACVRL1 Genes in Subjects with Hereditary Hemorrhagic Telangiectasia.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder caused, in more than 80% of cases, by mutations of either the endoglin (ENG) or the activin A receptor-like type 1 (ACVRL1) gene. Several hundred variants have been identified in these HHT-causing genes, including deletions, missense and nonsense mutations, splice defects, duplications, and insertions. In this study, we have analyzed retrospectively collected images of magnetic resonance angiographies (MRA) of the brain of HHT patients, followed at the HHT Center of our University Hospital, and looked for the distribution of cerebrovascular phenotypes according to specific gene variants. We found that cerebrovascular malformations were heterogeneous among HHT patients, with phenotypes that ranged from classical arteriovenous malformations (AVM) to intracranial aneurysms (IA), developmental venous anomalies (DVA), and cavernous angiomas (CA). There was also wide heterogeneity among the variants of the ENG and ACVRL1 genes, which included known pathogenic variants, variants of unknown significance, variants pending classification, and variants which had not been previously reported. The percentage of patients with cerebrovascular malformations was significantly higher among subjects with ENG variants than ACVRL1 variants (25.0% vs. 13.1%, p < 0.05). The prevalence of neurovascular anomalies was different among subjects with different gene variants, with an incidence that ranged from 3.3% among subjects with the c.1231C > T, c.200G > A, or c.1120C > T missense mutations of the ACVRL1 gene, to 75.0% among subjects with the c.1435C > T missense mutation of the ACVRL1 gene. Further studies and larger sample sizes are required to confirm these findings.

A Spotlight on the Role of Radiomics and Machine-Learning Applications in the Management of Intracranial Meningiomas: A New Perspective in Neuro-Oncology: A Review.

Background: In recent decades, the application of machine learning technologies to medical imaging has opened up new perspectives in neuro-oncology, in the so-called radiomics field. Radiomics offer new insight into glioma, aiding in clinical decision-making and patients' prognosis evaluation. Although meningiomas represent the most common primary CNS tumor and the majority of them are benign and slow-growing tumors, a minor part of them show a more aggressive behavior with an increased proliferation rate and a tendency to recur. Therefore, their treatment may represent a challenge. Methods: According to PRISMA guidelines, a systematic literature review was performed. We included selected articles (meta-analysis, review, retrospective study, and case-control study) concerning the application of radiomics method in the preoperative diagnostic and prognostic algorithm, and planning for intracranial meningiomas. We also analyzed the contribution of radiomics in differentiating meningiomas from other CNS tumors with similar radiological features. Results: In the first research stage, 273 papers were identified. After a careful screening according to inclusion/exclusion criteria, 39 articles were included in this systematic review. Conclusions: Several preoperative features have been identified to increase preoperative intracranial meningioma assessment for guiding decision-making processes. The development of valid and reliable non-invasive diagnostic and prognostic modalities could have a significant clinical impact on meningioma treatment.

The role of the craniotomy size in the surgical evacuation of acute subdural hematomas in elderly patients: a retrospective multicentric study.

BACKGROUND: Elderly patients operated for an acute subdural hematoma (ASDH) frequently have a poor outcome, with a high frequency of death, vegetative status, or severe disability (Glasgow Outcome Score, GOS, 1-3). Minicraniotomy has been proposed as a minimally invasive surgical treatment to reduce the impact of surgery in the elderly population. The present study aimed to compare the influence of the size of the craniotomy on the functional outcome in patients undergoing surgical treatment for ASDH. METHODS: We selected patients ≥70 years old admitted to 5 Italian tertiary referral neurosurgical for the treatment of a post-traumatic ASDH between January 1st 2016 and December 31st 2019. We collected demographic data, clinical data (GCS, GOS, Charlson Comorbidity Index-CCI, antiplatelet/anticoagulant therapy, neurological deficits, seizure, pupillary size, length of stay), surgical data (craniotomy size, dividing the patients into 3 groups based on the corresponding tertile, and surgery duration), radiological data (ASDH side and thickness, midline shift, other post-traumatic lesions, extent of ASDH evacuation) and we assessed the functional outcome at hospital discharge and 6-month follow-up considering GOS=1-3 as a poor outcome. ANOVA and Chi-squared tests and logistic regression models were used to assess differences in and associations between clinicalradiological characteristics and functional outcomes. RESULTS: We included 136 patients (76 males) with a mean age of 78±6 years. Forty-five patients underwent a small craniotomy, 47 a medium size, and 44 a large craniotomy. Among the different craniotomy size groups, there were no differences in gender, anticoagulant/antithrombotic therapy, CCI, side of ASDH, ASDH thickness, preoperative GCS, focal deficits, seizures, and presence of other posttraumatic lesions. Patients undergoing small craniotomies were older than patients undergoing medium-large craniotomies; ASDH treated with medium size craniotomy were thinner than the others; patients undergoing large craniotomies showed greater midline shift and a higher rate of anisocoria. The three groups did not differ for functional outcome and postoperative midline shift, but the length of surgery and the rate of >50% of ASDH evacuation were lower in the small craniotomy group. CONCLUSIONS: A small craniotomy was not inferior to larger craniotomies in determining functional outcomes in the treatment of ASDH in the elderly.

The clinical challenge of subarachnoid hemorrhage associated with multiple aneurysms when the bleeding source is not certainly identifiable.

BACKGROUND: Multiple intracranial aneurysms (IAs) are encountered in 20-30% of the subarachnoid hemorrhages (SAH). Neuroimaging and clinical examination are usually sufficient to detect the bleeding source, but sometimes it can be misdiagnosed with catastrophic consequences. METHODS: We reviewed our diagnostic work-up for all patients admitted from January 2016 to December 2020 for SAH with multiple IAs accounting for our rate of diagnostic failure. Then, we grouped the patients into 4 categories according to aneurysms topography and described our operative protocol in case of uncertain bleeding origin. RESULTS: Sixty-two patients harboring 161 IAs were included. The bleeding source was identified in 56 patients (90.3%), who harbored other 81 bystander aneurysms. In 6 cases (9.7%) with a total of 24 aneurysms we failed the bleeding source identification. According to IAs topography, we grouped the IAs multiplicity in: a) anterior plus posterior circulation IAs; b) multiple posterior circulation IAs; c) bilateral anterior circulation IAs; d) multiple ipsilateral anterior circulation IAs. In case of unidentified bleeding source, key-elements favoring the simultaneous multiple IAs treatment were their number, morphology, topography, clinicians' experience, and management modality as endovascular treatment allows a faster exclusion of multiple IAs distant one each other compared with surgery. MCA involvement represented the more frequent reason to prefer multiple clipping rather than multiple coiling. CONCLUSIONS: In a small percentage of patients with SAH with multiple IAs, bleeding source identification can be difficult. Until the routinely availability of new tools such as vessel wall imaging or computational fluid dynamics, an experienced neurovascular team and strategies aiming to simultaneously exclude multiple IAs remain mandatory.

Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo.

Abnormalities in arterial versus venous endothelial cell identity and dysregulation of angiogenesis are deemed important in the pathophysiology of brain arteriovenous malformations (AVMs). The Sonic hedgehog (Shh) pathway is crucial for both angiogenesis and arterial versus venous differentiation of endothelial cells, through its dual role on the vascular endothelial growth factor/Notch signaling and the nuclear orphan receptor COUP-TFII. In this study, we show that Shh, Gli1 (the main transcription factor of the Shh pathway), and COUP-TFII (a target of the non-canonical Shh pathway) are aberrantly expressed in human brain AVMs. We also show that implantation of pellets containing Shh in the cornea of Efnb2/LacZ mice induces growth of distinct arteries and veins, interconnected by complex sets of arteriovenous shunts, without an interposed capillary bed, as seen in AVMs. We also demonstrate that injection in the rat brain of a plasmid containing the human Shh gene induces the growth of tangles of tortuous and dilated vessels, in part positive and in part negative for the arterial marker αSMA, with direct connections between αSMA-positive and -negative vessels. In summary, we show that the Shh pathway is active in human brain AVMs and that Shh-induced angiogenesis has characteristics reminiscent of those seen in AVMs in humans.

Risk of intracranial bleeding in patients with primary brain cancer receiving therapeutic anticoagulation for venous thromboembolism: A meta-analysis.

INTRODUCTION: Venous thromboembolism (VTE) is common in glioma patients. Also, spontaneous intracerebral hemorrhage (ICH) is frequently observed in subjects with primary brain tumors. Thus, the management of anticoagulant therapy for VTE is challenging and controversial in these patients. We performed a meta-analysis to clarify the risk of ICH in glioma patients treated with anticoagulant therapy for VTE compared to glioma patients without VTE. MATERIALS AND METHODS: A systematic search of the literature was conducted using PubMed, Scopus, and EMBASE databases between January 1980 and January 2019 without language restrictions. Summary statistics for ICH were obtained by calculating the odds ratio (OR) using a random effects model, and heterogeneity across studies was estimated by the I2 statistic. The Newcastle-Ottawa Scale was used to evaluate the quality of studies. RESULTS: A total of 368 studies were initially identified. Of these, 346 were excluded after title review. The remaining 22 studies were reviewed in detail. According to the PICO criteria, 15 studies were excluded. Finally, 7 studies were included in the meta-analysis. The OR for ICH in glioma patients receiving therapeutic anticoagulation for VTE versus those who did not receive anticoagulation was 3.66 (95% confidence interval [CI], 1.84-7.29; I2  = 31%). CONCLUSIONS: This meta-analysis demonstrates that anticoagulation for VTE increases the risk of ICH in subjects with malignant brain tumors. Future studies are warranted to fully understand the best medical treatment of VTE in glioma patients.

Intracranial aneurysms of the posterior circulation associated with a fenestration: a systematic review.

INTRODUCTION: A fenestration is an anatomical variation that most commonly involves vessels of the posterior circulation, which can predispose the formation of aneurysms and represents a further technical challenge for treatment. There are no large series and the incidence of complications is unknown. This paper is a systematic review on this topic. EVIDENCE ACQUISITION: The relevant English literature was reviewed and the data was extracted for each patient and collected in a pool. Demographics, localization of fenestration, morphology and aneurysm topography, admission and follow-up clinical status, treatments, complications and occlusion rate were recorded. EVIDENCE SYNTHESIS: We analyzed 62 articles published between 1992 and 2016 including 120/133 patients/aneurysms. The most commonly involved segment was the vertebro-basilar junction (82.5%), followed by the basilar trunk (10%). About 96.6% of reported aneurysms were saccular and 80.3% were ruptured. The preferred treatment was endovascular (86.67%) and a surgical clipping was reported in just over 13% of patients. A complete/almost complete occlusion was obtained in about 80% of cases, with a global rate of complications of 12.5%. A serious clinical condition at onset has been independently associated with poor outcome at multivariate analysis (P<0.001). CONCLUSIONS: This systematic review has shown that endovascular occlusion is the treatment of choice for posterior circulation aneurysms associated with fenestrations, being highly effective, with an occlusion rate of about 80%, unchanged at follow-up. Although the presence of a fenestration can make more complex the aneurysm occlusion, and the occurrence of complications is not negligible, it is not considered a limiting condition for treatment.

Genome-wide association study of sporadic brain arteriovenous malformations.

BACKGROUND: The pathogenesis of sporadic brain arteriovenous malformations (BAVMs) remains unknown, but studies suggest a genetic component. We estimated the heritability of sporadic BAVM and performed a genome-wide association study (GWAS) to investigate association of common single nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicentre Genetics of Arteriovenous Malformation (GEN-AVM) consortium. METHODS: The Caucasian discovery cohort included 515 BAVM cases and 1191 controls genotyped using Affymetrix genome-wide SNP arrays. Genotype data were imputed to 1000 Genomes Project data, and well-imputed SNPs (>0.01 minor allele frequency) were analysed for association with BAVM. 57 top BAVM-associated SNPs (51 SNPs with p<10(-05) or p<10(-04) in candidate pathway genes, and 6 candidate BAVM SNPs) were tested in a replication cohort including 608 BAVM cases and 744 controls. RESULTS: The estimated heritability of BAVM was 17.6% (SE 8.9%, age and sex-adjusted p=0.015). None of the SNPs were significantly associated with BAVM in the replication cohort after correction for multiple testing. 6 SNPs had a nominal p<0.1 in the replication cohort and map to introns in EGFEM1P, SP4 and CDKAL1 or near JAG1 and BNC2. Of the 6 candidate SNPs, 2 in ACVRL1 and MMP3 had a nominal p<0.05 in the replication cohort. CONCLUSIONS: We performed the first GWAS of sporadic BAVM in the largest BAVM cohort assembled to date. No GWAS SNPs were replicated, suggesting that common SNPs do not contribute strongly to BAVM susceptibility. However, heritability estimates suggest a modest but significant genetic contribution.

Are parenchymal AVMs congenital lesions?

A long-held dogma in neurosurgery is that parenchymal arteriovenous malformations (AVMs) are congenital. However, there is no strong evidence supporting this theory. An increasing number of documented cases of de novo formation of parenchymal AVMs cast doubt on their congenital nature and suggest that indeed the majority of these lesions may form after birth. Further evidence suggesting the postnatal development of parenchymal AVMs comes from the exceedingly rare diagnosis of these lesions in utero despite the widespread availability of high-resolution imaging modalities such as ultrasound and fetal MRI. The exact mechanism of AVM formation has yet to be elucidated, but most likely involves genetic susceptibility and environmental triggering factors. In this review, the authors report 2 cases of de novo AVM formation and analyze the evidence suggesting that they represent an acquired condition.

Endovascular treatment of intracranial aneurysms in elderly patients: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Use of endovascular coiling for treatment of ruptured and unruptured intracranial aneurysms (IAs) in the elderly is increasing. We performed a meta-analysis of the literature examining clinical and angiographic outcomes for treatment of IAs in the elderly. METHODS: We performed a comprehensive review of the literature from 1995 to 2012, reporting series of patients ≥65 years of age with ruptured or unruptured IAs treated with endovascular approach. Event rates were pooled across studies using random effects meta-analysis. RESULTS: A total of 21 studies reporting on 1511 patients were included. Long-term aneurysm occlusion rates were 79% (95% confidence interval [CI], 70%-85%). Perioperative stroke occurred in 4% (95% CI, 3%-6%), with similar rates between patients with ruptured (5%; 95% CI, 3%-7%) and unruptured aneurysms (4%; 95% CI, 1%-14%; P=0.68). Intraprocedural rupture occurred in 1% (95% CI, 0%-3%) and 4% (95% CI, 2-6%; P=0.04) of patients with unruptured and ruptured aneurysms, respectively. Perioperative mortality rate for patients with ruptured aneurysms was 23% (95% CI, 17%-30%) and 1% (95% CI, 0%-6%) for patients with unruptured aneurysms (P<0.01). Rates of good clinical outcome at 1 year were 93% (95% CI, 88%-96%) and 66% (95% CI, 59%-72%) in patients with unruptured and ruptured aneurysms, respectively. CONCLUSIONS: This study suggests that endovascular treatment of IAs in the elderly is associated with high long-term occlusion rates. Given the morbidity and mortality associated with endovascular treatment of IAs in the elderly, careful patient selection, especially in the case of patients with unruptured aneurysm, is recommended.

Calcified extra-axial cavernoma involving lower cranial nerves: technical case report.

OBJECTIVE: Extra-axial cavernomas involving cranial nerves (CNs) are uncommon vascular malformations and may cause neurological deficits. We report what is, to our knowledge, a unique case of a calcified extra-axial cerebellopontine angle (CPA) cavernoma involving the lower CNs. CLINICAL PRESENTATION: A 48-year-old man was admitted to our department with a 5-month history of gait instability and loss in tone of voice. A clinical examination documented gait disturbances and hoarseness but was otherwise unremarkable. Neuroradiological studies revealed a calcified mass in the lower third of the CPA cistern that was angiographically occult. It was associated with 3 additional lesions with a radiological appearance suggestive of multiple cavernomas. INTERVENTION: The patient underwent a retrosigmoid approach, and the calcified mass, tightly adherent to the lower CNs, was gently removed. The histopathological examination was consistent with a cavernoma. The postoperative course was characterized by a further lowering in the patient's tone of voice. At the 3-month follow-up examination, the patient showed significant improvement. CONCLUSION: CPA cavernomas are an extremely rare entity. Symptoms are generally related to CN compression, and subarachnoid hemorrhage is a very rare occurrence. The clinical and radiological appearance may mimic that of other CPA tumors (meningiomas, schwannomas). In spite of the benign nature and the very low risk of hemorrhage, we believe, with support from the literature, that surgical treatment is mandatory to prevent significant neurological deficits owing to the chronic CN compression.