MicroRNA-135b-5p Is a Pathologic Biomarker in the Endothelial Cells of Arteriovenous Malformations.

Arteriovenous malformations (AVMs) are congenital vascular anomalies with a poor prognosis. AVMs are considered intractable diseases, as there is no established approach for early diagnosis and treatment. Therefore, this study aimed to provide new evidence by analyzing microRNAs (miRNAs) associated with AVM. We present fundamental evidence for the early diagnosis and treatment of AVM by analyzing miRNAs in the endothelial cells of AVMs. This study performed sequencing and validation of miRNAs in endothelial cells from normal and AVM tissues. Five upregulated and two downregulated miRNAs were subsequently analyzed under hypoxia and vascular endothelial growth factor (VEGF) treatment by one-way analysis of variance (ANOVA). Under hypoxic conditions, miR-135b-5p was significantly upregulated in the AVM compared to that under normal conditions, corresponding to increased endothelial activity (p-value = 0.0238). VEGF treatment showed no significant increase in miR-135b-5p under normal conditions, however, a surge in AVM was observed. Under both hypoxia and VEGF treatment, comparison indicated a downregulation of miR-135b-5p in AVM. Therefore, miR-135b-5p was assumed to affect the pathophysiological process of AVM and might play a vital role as a potential biomarker of AVMs for application related to diagnosis and treatment.

Treatment Effectiveness and Recurrence of Extracranial Arteriovenous Malformations Following Surgical Operations: A 15-Year Retrospective Cohort Study.

BACKGROUND: At present, there is no golden standard for treatment of extracranial arteriovenous malformations (AVMs) and recurrence remains a major challenge with limited available evidence on the associated factors. This study aimed to evaluate the effectiveness of surgical treatment options, in terms of size reduction, symptoms, and early recurrence in patients treated surgically for AVMs. METHODS: A retrospective cohort study was conducted to evaluate patients with AVMs following surgical treatment in 2 centers from 2005 to 2020. Posttreatment lesion size and symptoms, as well as recurrence, were assessed. Multiple regression analysis was performed to identify factors associated with recurrence. RESULTS: Forty-four surgical treatment cases in 31 patients were assessed with a mean follow-up duration period of 67.9 ± 39.5 months. Treatment included total resection in 26 cases (59.1%) and partial resection 18 (40.9%), with free flap coverage used in 19 cases (43.2%). No acute exacerbation following treatment was observed in our cohort. Total resection significantly reduced posttreatment lesion size ( P < 0.001), symptoms ( P < 0.001), and recurrence (20.0%, P = 0.03). The recurrence rate was significantly higher after partial resection (73.7%, P = 0.03). Total resection was identified as an associated factor for significantly reduced AVM recurrence (odds ratio: 0.12; 95% confidence interval: 0.03, 0.52). However, the use of free flaps did not significantly reduce recurrence, post treatment size or improve AVM symptoms. CONCLUSIONS: Total resection is the optimal treatment for AVMs. Free flaps are useful in covering large defects but the regulative effect of free flap remains controversial.

Tumescent solution: a game changer in excising refractory arteriovenous malformation.

Arteriovenous malformations of the head and neck are rare and inborn errors of vascular morphogenesis. They pose therapeutic challenges owing to their bleeding tendency and a high chance of recurrence. Treatment modalities include digital subtraction angiography with embolisation as a primary treatment or can be done preoperatively followed by surgical excision. We present a case of recurrent arteriovenous malformation of the postauricular region in an adolescent male who was taken up for upfront surgical excision with the help of a tumescent solution, thereby eliminating the need for embolisation and drastically reduced intraoperative blood loss.

Microsurgical Treatment for Arteriovenous Malformations in the Hand.

Vascular malformations in the extremities are a common site of occurrence; arteriovenous malformations (AVMs) are the least frequent of all vascular malformations, estimated at 5% to 20%. The first step in management is to perform a thorough clinical examination. Symptoms are assessed, and staging is performed using the Schobinger classification. Next, ultrasonography and contrast-enhanced computed tomography are used to confirm the diagnosis of AVM and to confirm the extent of the malformation. Surgery is the first-line treatment and reconstruction is performed. In cases where surgery is not feasible, embolization and sclerotherapy may be used to alleviate symptoms.

Macrocheilia as an Atypical Clinical Presentation of Capillary Malformation-Arteriovenous Malformation Type 2.

This case report describes a 53-year-old man with multiple erythematous macules and papules diffusely distributed on the frontal area, cheeks, eyelids, nose, and supralabial skin.

Fetal choroid plexus arteriovenous malformation, masquerading as a neoplastic lesion.

A woman in her 20s, who was pregnant, underwent a routine antenatal ultrasound revealing organised intraventricular haemorrhage and a vascular area in the left thalamic region. Fetal MRI raised suspicion of arteriovenous malformation (AVM). The baby was delivered at 36 weeks via C-section, and initial brain MRI suggested a possible neoplastic lesion.Cerebral angiography confirmed a large AVM involving the left choroid plexus with arterial feeders from the left anterior and posterior choroidal arteries and a large venous varix draining into the vein of Galen. Both arterial feeders were successfully embolised with Onyx and glue, achieving complete occlusion.Choroid plexus AVMs are rare and often lead to intraventricular or intraparenchymal haemorrhage. Surgical treatment has shown success, but endovascular management is effective, especially for small, deep-seated AVMs, offering a better prognosis.

Stereotactic radiosurgery for brain arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia.

OBJECTIVE: Brain arteriovenous malformations (AVMs) in patients with hereditary hemorrhagic telangiectasia (HHT) present different characteristics from sporadic AVMs, and they have lower initial bleeding rates. Conservative management is usually preferred for the treatment of these lesions. In this case study, we present the largest series of HHT patients treated with stereotactic radiosurgery to date. METHODS: We identified eight patients with HHT and 14 AVMs. We retrospectively collected clinical, radiographic, and treatment characteristics of the patients and each AVM. RESULTS: Most patients in our sample presented with small AVMs. The median volume of these AVMs was 0.22 cm3 (IQR 0.08-0.59). Three out of eight patients presented with initial intracerebral hemorrhage (ICH). The majority of lesions had low (12/14) Spetzler-Martin grades (I-II). Median maximum and margin doses used for treatment were 36.2 (IQR 35.25-44.4) and 20 (IQR 18-22.5) Gy, respectively. The overall obliteration rate after SRS was 11/14, and the median time to obliteration across all 11 obliterated AVMs was 35.83 months (IQR, 17-39.99). Neurological status was favorable with all patients having a mRS of 0 or 1 at the last follow-up. Symptomatic radiation-induced changes (RIC) after SRS were low (7.1%), and there were no permanent RIC. CONCLUSIONS: Patients with HHT who present with multiple brain AVMs are generally well served by SRS. Obliteration can be achieved in the majority of HHT patients and with a low complication rate. In the current study, initial hemorrhage rates prior to SRS were noticeable which supports the decision to treat these AVMs. Future studies are needed to better address the role of SRS for HHT patients harboring ruptured and unruptured AVMs.

Trans-radial artery microcatheter angiography-assisted juvenile ruptured brainstem arteriovenous malformation resection.

BACKGROUND: Due to their crucial functional location, surgical treatment of brainstem arteriovenous malformations (AVMs) has always been challenging. For unruptured AVMs, we can determine whether radiological therapy, interventional treatment, or surgical resection is feasible based on the AVM structure. However, for ruptured AVMs, microsurgical resection and interventional embolization are effective methods to prevent further rupture. In the microsurgical resection of AVMs, we usually use a hybrid operation to confirm the AVM structure and determine if the AVM is completely resected during the surgery. METHOD: We report a case of juvenile ruptured brainstem AVM resection. The right lateral position and left suboccipital retrosigmoid approach were used. We established an interventional approach via left radial artery and set a microcatheter in the feeding artery. Methylene blue injection via a microcatheter showed the AVM structure, and we totally resected the brainstem AVM under electrophysiological monitoring and navigation. Intraoperative angiography was performed to ensure complete resection without residual nidus. CONCLUSION: This case demonstrates that the trans-radial approach is convenient and safe for special positions in hybrid operations. Methylene blue injection via a microcatheter in the feeding artery provides clearer visualization of the AVM structure under the microscope.

Unilateral segmental presentation and a novel EPHB4 gene variant in capillary malformation-arteriovenous malformation type 2.

Capillary malformation-arteriovenous malformation is a rare autosomal dominant disorder associated with EPHB4 loss-of-function mutations. We report the unique presentation of a 6-year-old girl with multiple capillary malformations in a unilateral segmental distribution affecting the right hemiface, right upper chest, and right arm associated with overgrowth. Targeted next-generation sequencing on a tissue sample revealed a novel heterozygotic variant in the EPHB4 gene (NM_004444.5 (EPHB4): c.715T>A, p.[Cys239Ser]). This case highlights a distinct presentation of CM-AVM type 2 and showcases a new variant in EPHB4 not previously reported in the literature.

Arteriovenous malformation with hair collar sign.

We report the case of a newborn who was noted at birth to have an occipital scalp nodule presenting with a hair collar sign (HCS). The nodule had enlarged since birth. An MRI revealed a soft tissue mass on the occipital scalp without deep extension or cranial bone involvement. A biopsy of the nodule led to a diagnosis of arteriovenous malformation (AVM). A vascular malformation with HCS has not been reported before in North America. This case highlights the complexity of diagnosing a lesion with a hair collar sign.

Neurotropism of SARS-CoV-2: A Pathological Examination of Neurosurgical Specimens.

BACKGROUND AND OBJECTIVES: Neurological manifestations may occur in more than 80% of patients hospitalized with COVID-19 infection, including severe disruptions of the central nervous system (CNS), such as strokes, encephalitis, or seizures. Although the primary pathophysiological mechanism for the effects of COVID-19 in CNS remains unknown, evidence exists for both direct injury from neuroinvasion and indirect effects from disruptions in systemic inflammatory and coagulation pathways. In this study, we analyzed CNS tissue from living patients to better understand these processes. METHODS: With institutional review board approval and patient consent, samples that would be otherwise discarded from patients with active or recent (within 6 days of surgery) COVID-19 infection undergoing neurosurgical intervention were collected and tested for the presence of SARS-CoV-2 using immunohistochemistry, in situ hybridization, electron microscopy, and reverse transcription polymerase chain reaction. RESULTS: Five patients with perioperative mild-to-moderate COVID-19 infection met inclusion criteria (2 male, 3 female; mean age 38.8 ± 13.5 years). Neurosurgical diagnoses included a glioblastoma, a ruptured arteriovenous malformation, a ruptured posterior inferior cerebellar artery aneurysm, a middle cerebral artery occlusion, and a hemorrhagic pontine cavernous malformation. Samples analyzed included the frontal lobe cortex, olfactory nerve, arteriovenous malformation/temporal lobe parenchyma, middle cerebral artery, cerebellum, and cavernous malformation/brainstem parenchyma. Testing for the presence of SARS-CoV-2 was negative in all samples. CONCLUSION: The CNS is likely not a significant viral reservoir during mild-to-moderate COVID-19 infection, although direct neuroinvasion is not definitively excluded. Additional testing to help elucidate the relative contributions of direct and indirect pathways for CNS injury from COVID is warranted.

[Episodic bleeding events due to arteriovenous malformation (AVM) in the region of the distal ileum in a young male patient]. / Episodenhafte Blutungsereignisse bei arteriovenöser Malformation (AVM) im Bereich des distalen Ileums beim jungen Patienten.

We report the case of a 32-year-old male patient who presented with episodic, self-limiting gastrointestinal bleeding events. After both esophagogastroduodenoscopy (EGD) and colonoscopy remained unremarkable, capsule endoscopy revealed an unexplained mucosal lesion that presented as an ulcerated process on spiral enteroscopy. Appropriate enteroscopic ink marking was followed by surgical partial resection of the distal ileum, with histopathology revealing evidence of an arteriovenous malformation (AVM). This case emphasizes the importance of deep enteroscopy both in the diagnosis and to facilitate therapeutic resection in rare gastrointestinal bleeding events affecting young people.

Targeting the microenvironment in the treatment of arteriovenous malformations.

Extracranial arteriovenous malformations (AVMs) are regarded as rare diseases and are prone to complications such as pain, bleeding, relentless growth, and high volume of shunted blood. Due to the high vascular pressure endothelial cells of AVMs are exposed to mechanical stress. To control symptoms and lesion growth pharmacological treatment strategies are urgently needed in addition to surgery and interventional radiology. AVM cells were isolated from three patients and exposed to cyclic mechanical stretching for 24 h. Thalidomide and bevacizumab, both VEGF inhibitors, were tested for their ability to prevent the formation of circular networks and proliferation of CD31+ endothelial AVM cells. Furthermore, the effect of thalidomide and bevacizumab on stretched endothelial AVM cells was evaluated. In response to mechanical stress, VEGF gene and protein expression increased in patient AVM endothelial cells. Thalidomide and bevacizumab reduced endothelial AVM cell proliferation. Bevacizumab inhibited circular network formation of endothelial AVM cells and lowered VEGF gene and protein expression, even though the cells were exposed to mechanical stress. With promising in vitro results, bevacizumab was used to treat three patients with unresectable AVMs or to prevent regrowth after incomplete resection. Bevacizumab controlled bleeding, pulsation, and pain over the follow up of eight months with no patient-reported side effects. Overall, mechanical stress increases VEGF expression in the microenvironment of AVM cells. The monoclonal VEGF antibody bevacizumab alleviates this effect, prevents circular network formation and proliferation of AVM endothelial cells in vitro. The clinical application of bevacizumab in AVM treatment demonstrates effective symptom control with no side effects.

Arteriovenous malformations as a presenting sign of PTEN hamartoma tumor syndrome: A case series.

High-flow vascular malformations have been associated with multiple syndromes including capillary malformation-arteriovenous malformation (CM-AVM) syndrome, hereditary hemorrhagic telangiectasia syndrome, and less commonly, phosphatase and tensin homolog hamartoma tumor syndrome (PHTS). We present a series of three patients with clinically challenging complex AVMs who were found to have underlying PHTS. In all patients, diagnosis was delayed, and the presence of the AVM prompted sampling and genetic testing for PHTS in the absence of other clinical features of the condition. This series highlights the importance of screening for PHTS in the setting of high-flow vascular malformations.

Induced Endothelial Cell Cycle Arrest Prevents Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: Distinct endothelial cell cycle states (early G1 versus late G1) provide different "windows of opportunity" to enable the differential expression of genes that regulate venous versus arterial specification, respectively. Endothelial cell cycle control and arteriovenous identities are disrupted in vascular malformations including arteriovenous shunts, the hallmark of hereditary hemorrhagic telangiectasia (HHT). To date, the mechanistic link between endothelial cell cycle regulation and the development of arteriovenous malformations (AVMs) in HHT is not known. METHODS: We used BMP (bone morphogenetic protein) 9/10 blocking antibodies and endothelial-specific deletion of activin A receptor like type 1 (Alk1) to induce HHT in Fucci (fluorescent ubiquitination-based cell cycle indicator) 2 mice to assess endothelial cell cycle states in AVMs. We also assessed the therapeutic potential of inducing endothelial cell cycle G1 state in HHT to prevent AVMs by repurposing the Food and Drug Administration-approved CDK (cyclin-dependent kinase) 4/6 inhibitor (CDK4/6i) palbociclib. RESULTS: We found that endothelial cell cycle state and associated gene expressions are dysregulated during the pathogenesis of vascular malformations in HHT. We also showed that palbociclib treatment prevented AVM development induced by BMP9/10 inhibition and Alk1 genetic deletion. Mechanistically, endothelial cell late G1 state induced by palbociclib modulates the expression of genes regulating arteriovenous identity, endothelial cell migration, metabolism, and VEGF-A (vascular endothelial growth factor A) and BMP9 signaling that collectively contribute to the prevention of vascular malformations. CONCLUSIONS: This study provides new insights into molecular mechanisms leading to HHT by defining how endothelial cell cycle is dysregulated in AVMs because of BMP9/10 and Alk1 signaling deficiencies, and how restoration of endothelial cell cycle control may be used to treat AVMs in patients with HHT.

Endoscopic endonasal transclival clipping of a cerebellar arteriovenous malformation feeding vessel and associated aneurysm; a 2D operative video.

Positioned along the ventral surface of the pons, proximal superior cerebellar artery (SCA) aneurysms account for only 1.7% of all intracranial aneurysms [1]. Unlike more commonly encountered basilar artery aneurysms, patients often experience good outcomes when treated via endovascular coiling or surgical clipping [1,2]. These lesions frequently have a lateral projection and paucity of perforator arteries [2]. With further development of endoscopic endonasal techniques, access to this region is possible via a direct frontal exposure to the ventral brainstem, basilar artery and branching vessels. To date, there are only a limited number of reports describing an endoscopic endonasal transclival (EETC) approach for surgical clipping [3-5]. In this operative video, we detail the surgical clipping of a cerebellar arteriovenous malformation feeding vessel and an associated aneurysm using the EETC approach in a 59-year-old woman who presented with sudden onset of a severe headache. The feeding vessel and aneurysm's midline location, just below the take-off of the SCA made it a good candidate for this surgery. Major steps included in this video include 1) transsphenoidal exposure of and subsequent drilling of the clivus, 2) dural opening into the pre-pontine cistern and dissection of the aneurysm, 3) clipping of the aneurysm, and 4) multi-layered closure of the skull base defect. Overall, the patient tolerated the procedure well and was found to have no residual filling of the aneurysm or the AVM feeding vessel at 2-year follow-up. EETC is a viable surgical option for the treatment of aneurysm located along the midline of the pre-pontine cistern.