Intraoperative Neuromonitoring during Peripheral Arteriovenous Malformation Embolization.

PURPOSE: To evaluate whether intraoperative neuromonitoring (IONM), including pre-embolization lidocaine injection challenge ("provocative testing") is associated with reduced risk of irreversible nerve injury during embolization of peripheral arteriovenous malformations (AVMs). MATERIALS AND METHODS: Medical records of patients with peripheral AVMs who underwent embolotherapy with IONM with provocative testing between 2012 and 2021 were reviewed retrospectively. Data collected included patient demographic characteristics, AVM location and size, embolic agent used, IONM signal changes after lidocaine and embolic agent injections, postprocedural adverse events, and clinical outcomes. Decisions regarding whether embolization would proceed at specific locations were based on IONM findings after the lidocaine challenge and as embolization proceeded. RESULTS: A cohort of 17 patients (mean age, 27 years ± 19; 5 women) who underwent 59 image-guided embolization procedures with adequate IONM data was identified. No permanent neurologic deficits occurred. Transient neurologic deficits were observed in 3 patients (4 sessions), comprising skin numbness (2 patients), extremity weakness (1 patient), and extremity weakness and numbness (1 patient). All neurologic deficits resolved by postoperative day 4 without additional treatment. CONCLUSIONS: IONM, including provocative testing, during AVM embolization may minimize potential nerve injury.

[GLIOBLASTOMA MULTIFORME AFTER STEREOTACTIC RADIOSURGERY TREATMENT FOR ARTERIO-VENOUS MALFORMATION].

INTRODUCTION: Stereotactic radiosurgery (SRS) is a minimally invasive option commissioned in the treatment of intracranial arteriovenous malformations (AVMs). As long-term follow-up data became available, some late adverse effects have been reported, including SRS-induced neoplasia. However, the exact incidence of this adverse effect is unknown. In this article we present and discuss the topic with an unusual case of a young patient who was treated with SRS for AVM and developed a malignant brain tumor.

Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features.

Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, and cytoplasmic dynein-1 is an established molecular motor that is critical for neurogenesis and homeostasis. We performed whole-exome sequencing, homozygosity mapping, and chromosomal microarray studies in five individuals from three independent pedigrees and identified likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. In a consanguineous Pakistani family with three affected individuals presenting with microcephaly, severe intellectual disability, simplification of cerebral gyration, corpus callosum hypoplasia, and dysmorphic facial features, we identified a homozygous splice donor site variant (GenBank: NM_001378.2:c.607+1G>A). We report two additional individuals who have similar neurodevelopmental deficits and craniofacial features and harbor deleterious variants; one individual bears a c.740A>G (p.Tyr247Cys) change in trans with a 374 kb deletion encompassing DYNC1I2, and an unrelated individual harbors the compound-heterozygous variants c.868C>T (p.Gln290∗) and c.740A>G (p.Tyr247Cys). Zebrafish larvae subjected to CRISPR-Cas9 gene disruption or transient suppression of dync1i2a displayed significantly altered craniofacial patterning with concomitant reduction in head size. We monitored cell death and cell cycle progression in dync1i2a zebrafish models and observed significantly increased apoptosis, likely due to prolonged mitosis caused by abnormal spindle morphology, and this finding offers initial insights into the cellular basis of microcephaly. Additionally, complementation studies in zebrafish demonstrate that p.Tyr247Cys attenuates gene function, consistent with protein structural analysis. Our genetic and functional data indicate that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment.

Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.

BACKGROUND: Sporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown. METHODS: We analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase-chain-reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating KRAS mutations, which we had discovered in tissue samples. RESULTS: We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations and observed that expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased ERK (extracellular signal-regulated kinase) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK (mitogen-activated protein kinase)-ERK signaling. CONCLUSIONS: We identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of the brain that we analyzed. We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells. (Funded by the Swiss Cancer League and others.).

Safety and Effectiveness of Ethylene Vinyl Alcohol Copolymer Embolization of Peripheral High-Flow Arteriovenous Malformations: Results of a Prospective Study.

PURPOSE: To prospectively evaluate the efficacy and safety of a new ethylene vinyl alcohol (EVOH) copolymer-based embolic agent in the treatment of symptomatic peripheral arteriovenous malformations (AVMs). MATERIALS AND METHODS: This prospective single-center study evaluated EVOH embolization with 3 different formulations of EVOH (Squid Peri 12 cP, 18 cP, and 34 cP; BALT Germany GmbH, Düsseldorf, Germany) in patients with symptomatic AVMs. Between April 2018 and October 2019, 36 embolization procedures in 21 patients (3 males and 18 females; mean age, 34.7 years) were performed (inclusion criteria: symptomatic peripheral AVM, ≥14 years of age, and elective embolization). Symptoms, technical aspects (transarterial, transvenous, or percutaneous approach; plug or balloon occlusion), clinical and technical success (defined as the improvement of symptoms and complete angiographic eradication of the AVM nidus), adverse events, and short-term outcomes were assessed. RESULTS: The mean volume of the embolic agent used per session was 3.4 mL of EVOH 34 cP (standard deviation [SD], ± 5.4), 6.2 mL ± 8.1 of EVOH 18 cP, and 4.6 mL ± 10.1 of EVOH 12 cP. Angiographic success was achieved in 18 patients (85.7%). The mean follow-up was 190 days (range, 90-538 days; median, 182 days). In the follow-up assessment, findings of magnetic resonance imaging showed that 19 patients (90.5%) had a persistent state of devascularization compared with postinterventional angiography. Amelioration or complete elimination of pain was achieved in 90.0% of the patients. One patient experienced a major adverse event; minor adverse events developed in 2 patients. CONCLUSIONS: In this study, EVOH appeared to be a safe and effective embolic agent in peripheral AVMs and had a low rate of adverse events in a limited number of patients.

High-Flow Vascular Malformations in Children.

Children can have a variety of intracranial vascular anomalies ranging from small and incidental with no clinical consequences to complex lesions that can cause substantial neurologic deficits, heart failure, or profoundly affect development. In contrast to high-flow lesions with direct arterial-to-venous shunts, low-flow lesions such as cavernous malformations are associated with a lower likelihood of substantial hemorrhage, and a more benign course. Management of vascular anomalies in children has to incorporate an understanding of how treatment strategies may affect the normal development of the central nervous system. In this review, we discuss the etiologies, epidemiology, natural history, and genetic risk factors of three high-flow vascular malformations seen in children: brain arteriovenous malformations, intracranial dural arteriovenous fistulas, and vein of Galen malformations.

Clinical Importance of the Posterior Inferior Cerebellar Artery: A Review of the Literature.

The posterior inferior cerebellar artery (PICA), with its unique anatomical complexity, is of great clinical importance and involved in many diseases including aneurysm, ischemic stroke, neurovascular compression syndrome (NVCS), arteriovenous malformation (AVM), and brain tumor. However, a comprehensive systematic review of the importance of the PICA is currently lacking. In this study, we perform a literature review of PICA by searching all the associated papers in the PUBMED database hoping to provide a better understanding of the artery. The PICA has tortuous and variable course and territory, divided into 5 segments. Various aneurysms involving PICA were not uncommon, of which the treatment is challenging. The PICA infarct typically manifests lateral medullary syndrome (LMS) and is more likely to cause mass effects. The PICA frequently compresses the medulla and the cranial nerves resulting in various neurovascular compression syndromes (NVCS). Arteriovenous malformation (AVM) fed by PICA are associated with aneurysm and dissection which have high risk of rupture and worse outcome. PICA injured by head trauma can cause fatal SAH. VA terminating in PICA probably cause Bow hunter's syndrome (BHS). The PICA supplies many brain tumors and can be used in intracerebellar chemotherapy. The PICA can be exposed and injured during surgeries especially in telovelar approach, and it also plays an important role in bypass surgeries, hinting the surgical importance of PICA. In conclusion, PICA is very important in clinical practice.

Cerebral Arteriovenous Malformations as Acquired Lesions: Case Reports and Review of the Literature.

Cerebral arteriovenous malformations (AVMs) are generally attributed to congenital lesions that arise from aberrant vasculogenesis between the fourth and eighth weeks of embryonic life. However, this dogma has been challenged by several recent observations, one of which is de novo formation of AVMs. Forty cases of de novo AVMs were published between 2000 and 2019, all of which involved a history of intracranial insult, such as vascular abnormalities or nonvascular conditions, prior to AVM diagnosis. We hereby present two unique operative cases of ruptured de novo AVMs in older adult patients. Case 1 is novel in the sense that the patient did not experience any kind of environmental trigger ("second hit") such as a previous intracranial insult, while Case 2 serves as the second report of a de novo AVM patient with a medical history of Bell's palsy. Although the exact mechanisms of AVM formation remain to be elucidated, it is likely to be a multifactorial process related to environmental and hemodynamic factors.

Left Thalamus Arteriovenous Malformation Secondary to Radiation Therapy of Original Vermian Arteriovenous Malformation: Case Report.

A 70-year-old gentleman with history of hypothyroidism, hyperlipidemia, hypertension, and right superior cerebellar aneurysm presented to the neurosurgery service in 2008 with vertigo. Diagnostic cerebral angiography performed that year demonstrated a vermian arteriovenous malformations (AVM). The patient underwent stereotactic proton beam radiosurgery, which resulted in a decrease in flow and size of the lesion, and the patient was lost to follow-up. Now at the age of 80, the patient presented with acute gait instability. Cerebral angiogram demonstrated his stable vermian AVM and a new 1.1 cm AVM nidus in the region of the left posterior thalamus. Although AVMs are often described as congenital lesions, there is a growing body of literature suggesting that AVMs can grow, spontaneously regress, and even arise de novo in response to some insult. Understanding what leads to the growth, remodeling, regression, and hemorrhage of AVMs is crucial in order to better direct therapeutic endeavors. We would argue that this patient's AVM is secondary to endothelial cell damage from radiation therapy. Radiation can cause endothelial cell injury and upregulation of factors, such as vascular endothelial growth factor and transforming growth factor beta expression, which are implicated in AVM development pathways. We believe that this patient's new AVM is secondary to entrance radiation dosing affecting the thalamus during radiation therapy for the original vermian AVM.

De novo brain arteriovenous malformation after tumor resection: case report and literature review.

The congenital origin of brain arteriovenous malformations (bAVMs) has been increasingly challenged by reports of de novo bAVMs in patients previously confirmed to have no vascular malformation. We describe the oldest patient reported in the English language literature harboring a de novo bAVM. An uneventful frontal convexity meningioma resection was performed for a 60-year-old woman, and at 67 years of age, a bAVM was detected by MRI and confirmed by digital subtraction angiography at the site of the previous meningioma resection. This case adds to the growing literature that the etiology of bAVMs is most likely multifactorial.

Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels.

Arteriovenous (AV) malformation (AVM) is a devastating condition characterized by focal lesions of enlarged, tangled vessels that shunt blood from arteries directly to veins. AVMs can form anywhere in the body and can cause debilitating ischemia and life-threatening hemorrhagic stroke. The mechanisms that underlie AVM formation remain poorly understood. Here, we examined the cellular and hemodynamic changes at the earliest stages of brain AVM formation by time-lapse two-photon imaging through cranial windows of mice expressing constitutively active Notch4 (Notch4*). AVMs arose from enlargement of preexisting microvessels with capillary diameter and blood flow and no smooth muscle cell coverage. AV shunting began promptly after Notch4* expression in endothelial cells (ECs), accompanied by increased individual EC areas, rather than increased EC number or proliferation. Alterations in Notch signaling in ECs of all vessels, but not arteries alone, affected AVM formation, suggesting that Notch functions in the microvasculature and/or veins to induce AVM. Increased Notch signaling interfered with the normal biological control of hemodynamics, permitting a positive feedback loop of increasing blood flow and vessel diameter and driving focal AVM growth from AV connections with higher blood velocity at the expense of adjacent AV connections with lower velocity. Endothelial expression of constitutively active Notch1 also led to brain AVMs in mice. Our data shed light on cellular and hemodynamic mechanisms underlying AVM pathogenesis elicited by increased Notch signaling in the endothelium.

Intracranial papillary endothelial hyperplasia (Masson's tumour) following gamma knife radiosurgery for temporal lobe epilepsy.

We present a rare case of intracranial papillary endothelial hyperplasia, or 'Masson's tumour,' following gamma knife radiosurgery for epilepsy. A 59-year-old woman presented with a 4-month history of escalating headaches and progressive neurological deficit. MR scan of brain showed enlargement of an enhancing right temporal lobe lesion, midline shift and obstructive hydrocephalus. She had previously undergone non-curative gamma knife radiosurgery at the age of 44 years for medically refractory complex partial seizures. Postprocedure imaging had shown signal change and enhancement within the right temporal lobe consistent with radiation necrosis, which remained stable over the next decade. Now, 15 years following radiosurgery, we suspected an intrinsic high-grade neoplasm, but surgical excision instead found a benign pseudoneoplasm. Papillary endothelial hyperplasia should be considered in the differential diagnosis for mass lesions following gamma knife radiosurgery, particularly as resection can be curative. Remarkably, she has become seizure free.

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency.

Cerebral arteriovenous malformations (AVMs) are common vascular malformations, which may result in hemorrhagic strokes and neurological deficits. Bone morphogenetic protein (BMP) and Notch signaling are both involved in the development of cerebral AVMs, but the cross-talk between the two signaling pathways is poorly understood. Here, we show that deficiency of matrix Gla protein (MGP), a BMP inhibitor, causes induction of Notch ligands, dysregulation of endothelial differentiation, and the development of cerebral AVMs in MGP null (Mgp(-/-)) mice. Increased BMP activity due to the lack of MGP induces expression of the activin receptor-like kinase 1, a BMP type I receptor, in cerebrovascular endothelium. Subsequent activation of activin receptor-like kinase 1 enhances expression of Notch ligands Jagged 1 and 2, which increases Notch activity and alters the expression of Ephrin B2 and Ephrin receptor B4, arterial and venous endothelial markers, respectively. Reducing the expression of Jagged 1 and 2 in the Mgp(-/-) mice by crossing them with Jagged 1 or 2 deficient mice reduces Notch activity, normalizes endothelial differentiation, and prevents cerebral AVMs, but not pulmonary or renal AVMs. Our results suggest that Notch signaling mediates and can modulate changes in BMP signaling that lead to cerebral AVMs.

How to manage patients with hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia is a rare systemic autosomal dominantly inherited disorder of the fibrovascular tissue with a wide variety of clinical manifestations. Diagnosis is based on the clinical Curaçao criteria or molecular genetic testing. Dilated vessels can develop into telangiectases or larger vascular malformations in various organs, calling for an interdisciplinary approach. Epistaxis and gastrointestinal bleeding can result from these vascular defects. Various conservative and interventional treatments have been described for these conditions. However, no optimal therapy exists. Treatment can become especially difficult due to progressive anaemia or when anticoagulant or anti-thrombotic therapy becomes necessary. Screening for pulmonary arteriovenous malformations (PAVM) should be performed in all confirmed and suspected patients. Treatment by percutaneous transcatheter embolotherapy and antibiotic prophylaxis is normally effective for PAVM. Cerebral or hepatic vascular malformations and rare manifestations need to be evaluated on a case-by-case basis to determine the best course of action for treatment.

Extensive Intracranial Arteriovenous Malformation in a Child with Aplasia Cutis Congenita.

We report on a child with multiple lesions of membranous aplasia cutis congenita of the scalp since birth who developed an extensive intracranial arteriovenous malformation several years later. Even in the absence of other clues to suggest intracranial anomalies, children with multiple scalp defects should be carefully surveyed and followed up in the long term.

De novo cerebral arteriovenous malformations: is epileptic seizure a potential trigger?

MATERIAL AND METHODS: The pathogenesis of cerebral arteriovenous malformations (cAVMs) is still not well understood. Generally, cAVMs are thought to be congenital lesions originating prenatally. We report a 7-year-old boy diagnosed with a de novo cAVM after 3 years of recurrent epileptic seizures. RESULTS: MR imaging at 4 years of age was normal. Follow-up MR imaging 3 years later demonstrated a de novo 2-cm cAVM in the right occipital lobe, confirmed by conventional angiography. We reviewed five previously reported cases of de novo cAVMs who did not have a previous neurovascular abnormality. Including our case, recurrent epileptic seizures are the major presentation (83.3 %) before de novo cAVM occurrence. CONCLUSION: We suggest that epileptic seizure is a potential trigger of de novo cAVMs.

Vascular compactness of unruptured brain arteriovenous malformation predicts risk of hemorrhage after stereotactic radiosurgery.

The aim of the study was to investigate whether morphology (i.e. compact/diffuse) of brain arteriovenous malformations (bAVMs) correlates with the incidence of hemorrhagic events in patients receiving Stereotactic Radiosurgery (SRS) for unruptured bAVMs. This retrospective study included 262 adult patients with unruptured bAVMs who underwent upfront SRS. Hemorrhagic events were defined as evidence of blood on CT or MRI. The morphology of bAVMs was evaluated using automated segmentation which calculated the proportion of vessel, brain tissue, and cerebrospinal fluid in bAVMs on T2-weighted MRI. Compactness index, defined as the ratio of vessel to brain tissue, categorized bAVMs into compact and diffuse types based on the optimal cutoff. Cox proportional hazard model was used to identify the independent factors for post-SRS hemorrhage. The median clinical follow-ups was 62.1 months. Post-SRS hemorrhage occurred in 13 (5.0%) patients and one of them had two bleeds, resulting in an annual bleeding rate of 0.8%. Multivariable analysis revealed bAVM morphology (compact versus diffuse), bAVM volume, and prescribed margin dose were significant predictors. The post-SRS hemorrhage rate increased with larger bAVM volume only among the diffuse nidi (1.7 versus 14.9 versus 30.6 hemorrhage per 1000 person-years in bAVM volume < 20 cm3 versus 20-40 cm3 versus > 40 cm3; p = 0.022). The significantly higher post-SRS hemorrhage rate of Spetzler-Martin grade IV-V compared with grade I-III bAVMs (20.0 versus 3.3 hemorrhages per 1000 person-years; p = 0.001) mainly originated from the diffuse bAVMs rather than the compact subgroup (30.9 versus 4.8 hemorrhages per 1000 person-years; p = 0.035). Compact and smaller bAVMs, with higher prescribed margin dose harbor lower risks of post-SRS hemorrhage. The post-SRS hemorrhage rate exceeded 2.2% annually within the diffuse and large (> 40 cm3) bAVMs and the diffuse Spetzler-Martin IV-V bAVMs. These findings may help guide patient selection of SRS for the unruptured bAVMs.

Platelet-derived growth factor C deficiency in C57BL/6 mice leads to abnormal cerebral vascularization, loss of neuroependymal integrity, and ventricular abnormalities.

Platelet-derived growth factors (PDGFs) and their tyrosine kinase receptors (PDGFRs) are known to play important roles during development of the lungs, central nervous system (CNS), and skeleton and in several diseases. PDGF-C is a ligand for the tyrosine kinase receptor PDGFRα. Mutations in the gene encoding PDGF-C have been linked to clefts of the lip and/or palate in humans, and ablation of PDGF-C in 129/Sv background mice results in death during the perinatal period. In this study, we report that ablation of PDGF-C in C57BL/6 mice results in a milder phenotype than in 129/Sv mice, and we present a phenotypic characterization of PDGF-C deficiency in the adult murine CNS. Multiple congenital defects were observed in the CNS of PDGF-C-null C57BL/6 mice, including cerebral vascular abnormalities with abnormal vascular smooth muscle cell coverage. In vivo imaging of mice deficient in PDGF-C also revealed cerebral ventricular abnormalities, such as asymmetry of the lateral ventricles and hypoplasia of the septum, reminiscent of cavum septum pellucidum in humans. We further noted that PDGF-C-deficient mice displayed a distorted ependymal lining of the lateral ventricles, and we found evidence of misplaced neurons in the ventricular lining. We conclude that PDGF-C plays a critical role in the development of normal cerebral ventricles and neuroependymal integrity as well as in normal cerebral vascularization.

Vascular malformations of the brain.

Vascular malformations of the brain are a heterogeneous group of disorders involving the blood vessels of the brain. These entities are relatively rare; therefore, most primary care physicians are somewhat unfamiliar with their clinical implications and management. Vascular malformations of the brain range from the completely benign capillary telangiectasia to the potentially fatal arterio-venous malformation. This article reviews the distinct natural histories, etiologies and treatments of four major types of malformations: capillary telangiectasia, developmental venous anomaly, cavernous malformation and arteriovenous malformation.

Capillary malformation-arteriovenous malformation syndrome: a report of 2 cases, diagnostic criteria, and management.

Capillary malformation-arteriovenous malformation syndrome is a rare type of vascular malformation first described in 2003. It is an autosomal dominant inherited disorder that has been reported in association with heterozygous mutations in the RASA1 gene, which encodes the protein RASp21. The clinical picture is characterized by multiple small capillary malformations which are associated with either arteriovenous malformations or arteriovenous fistulas in both the affected individual and other members of their family. We describe 2 new familial cases of this syndrome that were clinically and genetically diagnosed and studied in our hospital.