Functional characterization of variants found in Japanese patients with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant form of vascular dysplasia. Genetic diagnosis is made by identifying loss-of-function variants in genes, such as ENG and ACVRL1. However, the causal mechanisms of various variants of unknown significance remains unclear. In this study, we analyzed 12 Japanese patients from 11 families who were clinically diagnosed with HHT. Sequencing analysis identified 11 distinct variants in ACVRL1 and ENG. Three of the 11 were truncating variants, leading to a definitive diagnosis, whereas the remaining eight were splice-site and missense variants that required functional analyses. In silico splicing analyses demonstrated that three variants, c.526-3C > G and c.598C > G in ACVRL1, and c.690-1G > A in ENG, caused aberrant splicing, as confirmed by a minigene assay. The five remaining missense variants were p.Arg67Gln, p.Ile256Asn, p.Leu285Pro, and p.Pro424Leu in ACVRL and p.Pro165His in ENG. Nanoluciferase-based bioluminescence analyses demonstrated that these ACVRL1 variants impaired cell membrane trafficking, resulting in the loss of bone morphogenetic protein 9 (BMP9) signal transduction. In contrast, the ENG mutation impaired BMP9 signaling despite normal cell membrane expression. The updated functional analysis methods performed in this study will facilitate effective genetic testing and appropriate medical care for patients with HHT.

Comparison of efficacy between clazosentan and fasudil hydrochloride-based management of vasospasm after subarachnoid hemorrhage focusing on older and WFNS grade V patients: a single-center experience in Japan.

Subarachnoid hemorrhage often leads to poor outcomes owing to vasospasm, even after successful aneurysm treatment. Clazosentan, an endothelin receptor inhibitor, has been proven to be an effective treatment for vasospasms in a Japanese randomized controlled trial. However, its efficacy in older patients (≥ 75 years old) and those with World Federation of Neurosurgical Societies (WFNS) grade V has not been demonstrated. We retrospectively evaluated the efficacy of clazosentan in older patients and those with WFNS grade V, using real-world data. Patients with subarachnoid hemorrhage treated before and after the introduction of clazosentan were retrospectively evaluated. The patients were categorized into two groups (clazosentan era versus pre-clazosentan era), in which vasospasm management and outcomes were compared. Vasospasms were managed with fasudil hydrochloride-based (pre-clazosentan era) or clazosentan-based treatment (clazosentan era). Seventy-eight patients were included in this study: the clazosentan era (n = 32) and pre-clazosentan era (n = 46). Overall, clazosentan significantly reduced clinical vasospasms (clazosentan era: 31.3% versus pre-clazosentan era: 60.9%, p = 0.01), delayed cerebral ischemia (DCI) (9.4% versus 39.1%, p = 0.004), and vasospasm-related morbidity and mortality (M/M) (3.1% versus 19.6%, p = 0.03). In subgroup analysis of older patients or those with WFNS grade V, no significant difference was observed in clinical outcomes, although both DCI and vasospasm-related M/M were lower in the clazosentan era. Clazosentan was more effective than fasudil-based management in preventing DCI and reducing vasospasm-related M/M. Clazosentan could be used safely in older patients and those with WFNS grade V, although clinical outcomes in these patients were comparable to those of conventional treatment.

[Aortic Arch:Embryology and Remodeling].

A right aortic arch and aberrant subclavian artery result from an interruption in the remodeling of the pharyngeal arch arteries. We occasionally encounter this anatomical variation during angiography. Patients with disorders such as Down syndrome and congenital heart disease show a high incidence of an aberrant right subclavian artery, and this anomaly can cause symptomatic esophageal or tracheal compression. The root of the aberrant artery may show dilatation(referred to as a Kommerell diverticulum), dissection, intramural hematoma, or rupture necessitating cardiac intervention using a surgical or endovascular approach. Neurointerventionalists should have working knowledge of the anatomy to rapidly understand the anatomy and ensure a safe procedure. A left transradial approach should be considered if prior knowledge of the aberrant subclavian anatomy is available.

Postsurgical dural supply to the spinal cord arteriovenous malformation in spinal arteriovenous metameric syndrome.

Dural supply from the external carotid system in cerebral arteriovenous malformations (AVMs) is well known, but actual angiographic evidence of dural supply to spinal cord AVMs (SCAVMs) has not been reported. Here, we report a case of dural supply to the conus SCAVM in the spinal arteriovenous metameric syndrome segment 25-30. Thirteen years after spinal surgery (T12-L2 laminoplasty), spinal angiography showed multiple dural supplies from the dorsal somatic branches, prelaminar arteries, and radiculomeningeal arteries to the SCAVM at the level of the previous spinal surgery. To the best of our knowledge, this is the first reported case with dural supply to the spinal cord. This case demonstrates that the extradural and extraspinal branches can supply the spinal cord in rare instances of spinal dural adhesions following repeated hemorrhages and surgical intervention under a metameric link background.

Targeted embolisation for coexisting conus medullaris arteriovenous malformation and cauda equina arteriovenous fistulas with a varix on a shared drainer†.

BACKGROUND: The coexistence of vascular malformations in the conus medullaris and cauda equina has been rarely reported, and the complex angioarchitecture in multiple arteriovenous lesions remains poorly understood. CASE DESCRIPTION: A 17-year-old woman presented with a sudden-onset, stepwise worsening of weakness and pain in the bilateral legs. Angiography revealed conus medullaris arteriovenous malformation and cauda equina arteriovenous fistulas. One of the drainers was shared between the coexisting lesions and harboured a varix. Targeted embolisation of a fistulous point in the conus lesion was performed with precaution to prevent occluding the common drainage route, which led to symptom improvement with angiographical diminishment of the varix. CONCLUSIONS: Recognising that communications between drainers can be observed in multiple spinal arteriovenous lesions is important in facilitating a safe embolisation. Cautious assessment of angiogram with fusion images of cone-beam computed tomography and volumetric T2 magnetic resonance imaging can help in establishing the diagnosis and treatment strategy.

FLOW-diverted Glue Embolization to Target lesions (FLOW-GET) technique for spinal vascular diseases: A technical note.

We present and exemplify the flow-diverted glue embolization to target lesions (FLOW-GET) technique for spinal vascular diseases. In this technique, the occlusion of the posterior intercostal artery or dorsal muscular branch by coils diverts the injected glue from the segmental artery to the target lesions. This technique was applied to a ruptured retrocorporeal artery aneurysm and spinal dural arteriovenous fistulas. The FLOW-GET accomplished the complete obliteration of all lesions. This simple and useful technique can be applied to spinal vascular lesions even if a microcatheter is not placed in proper feeders or advanced close to the shunt points or aneurysms.

Simmons Angled microguidewire INsertion to the Target (SAINT) technique in neuroendovascular therapy.

Advancing appropriate microcatheters is essential for treatment. However, we still encounter inaccessible arterial branches because of the anatomical arrangement. While many successful techniques regarding microcatheters have been reported, there have been very few reports of microguidewire-shaping techniques. We developed the Simmons-Angled microguidewire INsertion to the Target (SAINT) technique for insertion of the microguidewire into inaccessible arterial branches. The SAINT technique is feasible for selection and insertion into arteries that are inaccessible with conventional methods.

[A Case of Bilateral Carotid Injury Caused by Vinyl Umbrella Penetration Successfully Treated with Endovascular Therapy].

Here, we have reported a case pertaining to a 59-year-old man with bilateral traumatic carotid artery injury caused by vinyl umbrella penetration who was successfully treated. The patient fell from the stairs while holding an umbrella, which penetrated his neck. On admission, the patient was in a comatose state and the umbrella had been removed. Active bleeding was observed on the left side of the neck. Hence, tracheal intubation was performed to support respiration. Neck and head contrast-enhanced CT revealed bilateral extravasations from the carotid arteries and right middle cerebral artery(MCA)occlusion. Left carotid angiography showed extravasation from the external carotid artery(ECA), which was treated with coil embolization. Right carotid angiography revealed bleeding from the ECA and internal carotid artery(ICA)and occlusion of the MCA. The ECA and ICA were occluded by coil and n-butyl-2-cyanoacrylate embolization. After the procedures, the patient developed a large right cerebral infarction with massive brain swelling; therefore, external decompression was performed. Subsequently, the patient became alert and was able to walk with support within a month. Bilateral carotid injury is severe and difficult to treat. Endovascular therapy may be effective for the management of bilateral carotid injuries.

Prognostic Significance of Hyponatremia in Acute Stroke: A Systematic Review and Meta-Analysis.

OBJECTIVE: Hyponatremia is a common electrolyte disorder in patients with stroke, which leads to various fatal complications. We performed a systematic review and meta-analysis to investigate the outcomes of acute stroke patients with hyponatremia. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library databases for relevant literature in English published up to March 2020. Two review authors independently screened and selected the studies by assessing the eligibility and validity based on the inclusion criteria. Mortality at 90 days was set as the primary end point, and in-hospital mortality and length of hospital stay were set as the secondary end points. We conducted the data synthesis and analyzed the outcomes by calculating the odds ratio (OR) and mean difference. RESULTS: Of 835 studies, 15 studies met the inclusion criteria (n = 10,745). The prevalence rate of stroke patients with hyponatremia was 7.0-59.2%. They had significantly higher 90-day mortality (OR, 1.73; 95% confidence interval (CI), 1.24-2.42) and longer length of hospital stay (mean difference, 10.68 days; 95% CI, 7.14-14.22) than patients without hyponatremia. Patients with hyponatremia had a higher tendency of in-hospital mortality than those without hyponatremia (OR, 1.61; 95% CI, 0.97-2.69). CONCLUSIONS: The development of hyponatremia in the clinical course of stroke is associated with higher short-term mortality and a longer hospital stay. Although the causal relationship is unclear, hyponatremia could be a significant predictor of poor outcomes after stroke.

Japanese clinical practice guidelines for vascular anomalies 2017.

The objective was to prepare guidelines to perform the current optimum treatment by organizing effective and efficient treatments of hemangiomas and vascular malformations, confirming the safety, and systematizing treatment, employing evidence-based medicine (EBM) techniques and aimed at improvement of the outcomes. Clinical questions (CQs) were decided based on the important clinical issues. For document retrieval, key words for literature searches were set for each CQ and literature published from 1980 to the end of September 2014 was searched in Pubmed, Cochrane Library, and Japana Centra Revuo Medicina (JCRM). The strengths of evidence and recommendations acquired by systematic reviews were determined following the Medical Information Network Distribution System (MINDS) technique. A total of 33 CQs were used to compile recommendations and the subjects included efficacy of resection, sclerotherapy/embolization, drug therapy, laser therapy, radiotherapy, and other conservative treatment, differences in appropriate treatment due to the location of lesions and among symptoms, appropriate timing of treatment and tests, and pathological diagnosis deciding the diagnosis. Thus, the Japanese Clinical Practice Guidelines for Vascular Anomalies 2017 have been prepared as the evidence-based guidelines for the management of vascular anomalies.

Clinical Course and Management of Vein of Galen Varix of the Neonate: A Case Report and Literature Review.

A 28-year-old pregnant woman underwent an emergency caesarian section after 39 weeks of gestation because of decreased fetal movement and baseline fetal heart rate variability. The neonate was diagnosed with neonatal asphyxia and presented with right cardiac failure due to pulmonary hypertension. The neonate presented convulsion, and plane computed tomography (CT) showed dilation of the vein of Galen and sinuses on day 3. Magnetic resonance imaging and CT with contrast were performed after cardiac failure subsided, and there was no evidence of arteriovenous shunt and normalization of the vein of Galen. The patient was diagnosed with vein of Galen varix (VGV). In the previous literature, only 3 cases of VGV have been reported. VGV is considered to be caused by right cardiac failure without the presence of an arteriovenous shunt and requires treatment only for cardiac failure and its cause. Therefore, it is important to differentiate VGV from vein of Galen aneurysmal malformation.

Risk Factors for Acute Heart Failure and Impact on In-Hospital Mortality after Stroke.

BACKGROUND: In the acute phase of stroke, some patients develop cardiac events. It could be fatal in their clinical courses. We aimed to investigate acute heart failure after stroke onset and stratify the patients by establishing a predictive model. METHODS: This single-center, observational study included stroke patients diagnosed at the Department of Neurology and Neurosurgery from January 2013 to December 2014. Baseline characteristics and clinical findings on admission were analyzed for acute heart failure after stroke. We assessed risk factors using multivariable logistic regression, and set a risk score to evaluate the association with poor outcomes. RESULTS: Of 532 stroke patients, 27 (5%) developed acute heart failure within the 7 days after admission. We identified 4 risk factors for acute heart failure after stroke: atrial fibrillation (odds ratio [OR], 5.9; 95% confidence interval [CI], 2.5-14.0; P < .001), history of cardiac disease (OR, 3.6; 95% CI, 1.3-9.1; P = .01), Glasgow Coma Scale score ≤ 8 (OR, 4.5; 95% CI, 1.7-12.0; P = .003), and serum albumin < 35 g/L (OR, 3.4; 95% CI, 1.4-8.4; P = .008). Furthermore in-hospital mortality rate was higher (37% [n = 10/27] versus 9.9% [n = 50/505], P = .001) in patients with poststroke heart failure. Higher predictive scores were associated with increased mortality. CONCLUSIONS: Acute heart failure can develop in the early phase of stroke and lead to poor outcomes. It is foreseeable and preventable by stratifying and monitoring high-risk patients.

[Supratentorial Meningeal Melanoma with Nevus of Ota:A Case Report].

We present a rare case of supratentorial meningeal melanoma associated with ipsilateral nevus of Ota, and a review of the literature. The patient was a 32-year-old man with a right-sided nevus of Ota, presenting with unconsciousness. His CT and MRI scans revealed an extra axial tumor with dural tail signs; no lesion was detected on systemic examination. Intraoperatively, the tumor demonstrated black hyperpigmentation and was histologically diagnosed as malignant melanoma. Following surgery, he received radiotherapy and chemotherapy. For over a year and a half, the patient has shown no recurrence of the lesion.

Angiographic and Clinical Characteristics of Thoracolumbar Spinal Epidural and Dural Arteriovenous Fistulas.

BACKGROUND AND PURPOSE: The purpose of this study is to compare the angiographic and clinical characteristics of spinal epidural arteriovenous fistulas (SEAVFs) and spinal dural arteriovenous fistulas (SDAVFs) of the thoracolumbar spine. METHODS: A total of 168 cases diagnosed as spinal dural or extradural arteriovenous fistulas of the thoracolumbar spine were collected from 31 centers. Angiography and clinical findings, including symptoms, sex, and history of spinal surgery/trauma, were retrospectively reviewed. Angiographic images were evaluated, with a special interest in spinal levels, feeders, shunt points, a shunted epidural pouch and its location, and drainage pattern, by 6 readers to reach a consensus. RESULTS: The consensus diagnoses by the 6 readers were SDAVFs in 108 cases, SEAVFs in 59 cases, and paravertebral arteriovenous fistulas in 1 case. Twenty-nine of 59 cases (49%) of SEAVFs were incorrectly diagnosed as SDAVFs at the individual centers. The thoracic spine was involved in SDAVFs (87%) more often than SEAVFs (17%). Both types of arteriovenous fistulas were predominant in men (82% and 73%) and frequently showed progressive myelopathy (97% and 92%). A history of spinal injury/surgery was more frequently found in SEAVFs (36%) than in SDAVFs (12%; P=0.001). The shunt points of SDAVFs were medial to the medial interpedicle line in 77%, suggesting that SDAVFs commonly shunt to the bridging vein. All SEAVFs formed an epidural shunted pouch, which was frequently located in the ventral epidural space (88%) and drained into the perimedullary vein (75%), the paravertebral veins (10%), or both (15%). CONCLUSIONS: SDAVFs and SEAVFs showed similar symptoms and male predominance. SDAVFs frequently involve the thoracic spine and shunt into the bridging vein. SEAVFs frequently involve the lumbar spine and form a shunted pouch in the ventral epidural space draining into the perimedullary vein.

Endovascular treatment of pediatric intracranial arteriovenous shunt.

Intracranial arteriovenous shunts (ICAVS) in young children are characterized by frequent high-flow fistulas. In association with high-flow fistulas and the physiological condition of the developing brain and heart, each ICAVS type tends to present at a certain age with unique symptoms. Vein of Galen aneurysmal malformation (VGAM) and dural sinus malformation with arteriovenous (AV) shunt tend to present in the neonate with high output cardiac failure. In infancy, VGAM, pial arteriovenous fistula (AVF) and infantile dural AVF (DAVF) tend to present with hydrodynamic disorder such as macrocephaly, ventriculomegaly, prominent facial veins, and developmental delay. Pial AVF, AV malformation, and infantile DAVF can present with focal neurological signs such as seizure or hemorrhage at older ages. Endovascular treatment is currently the first choice of treatment for most pediatric ICAVS. The treatment goal should be defined on a patient-by-patient basis, according to the unique physiological condition of the child.

Basilar dolichoectasia and the spontaneous intradural vertebral artery dissection.

OBJECT: Basilar dolichoectasia (BD) is an atherosclerotic, a distinct arteriopathy or a chronic-phase dissection characterized by elongation and dilation of the basilar artery. Spontaneous intradural vertebral artery dissection (siVAD) is an important cause of stroke in young and middle-aged people. It is hypothesized that the BD and the siVAD might partially share aetiologies and this study aimed to examine the relationship. METHODS: This study compared clinical and radiological characteristics in 93 patients with siVAD with 93 controls. Ectasia was defined as basilar artery diameter >4.5 mm and dolichosis, as either basilar artery bifurcation above the suprasellar cistern or lateral to the margin of the clivus or dorsum sellae. The BD was defined if both ectasia and dolichosis were simultaneously observed. Multivariate logistic regression analysis was performed using variables that were marginally or significantly associated with siVAD on univariate analysis (p < 0.20). RESULTS: Multivariate analysis showed siVAD patients have higher proportions of hypertension (OR = 2.4; 95% CI = 1.3-4.6; p = 0.007) and BD (OR = 3.7; 95% CI = 1.1-12; p = 0.036). CONCLUSIONS: The present study suggested that BD was related to the siVAD. A randomized study from multi-institutions with an adequate sample size is needed to make a strong argument about the association between BD and siVAD.

Effectiveness of the Combined Use of Distal Filter Protection Device and Mo.Ma Ultra: Technical Note.

BACKGROUND: Although Mo.Ma Ultra is an embolic protection device for interrupting the anterograde blood flow to the internal carotid artery, incomplete blood stagnation is often observed. We report the effectiveness of the combined use of a distal filter protection device and Mo.Ma Ultra (Medtronic, Minneapolis, MN). MATERIALS AND METHODS: Our case series comprises 10 consecutive patients (11 carotid arteries) who underwent carotid artery stenting (CAS) using Mo.Ma Ultra and FilterWire EZ (Boston Scientific, Natick, MA). RESULTS: The superior thyroid artery originated from the proximal side of the bifurcation of the common carotid artery, except for 1 artery. Although complete blood stagnation was observed in 6 arteries, filter debris was detected in 3 of these 6 arteries. Positive postoperative findings on diffusion-weighted magnetic resonance imaging were observed in 3 cases (3 arteries). Only 1 patient had transient neurological deficits. CONCLUSION: The combined use of a distal filter protection device and Mo.Ma Ultra could provide a more reliable embolic protection in CAS.

Inverse Relationship between Coffee Consumption and Cerebral Microbleeds in Men, but Not Women.

BACKGROUND: Studies evaluating the association between coffee consumption and neurovascular diseases have frequently yielded contradictory results. The aim of this study was to investigate the association of coffee consumption with small-vessel disease (SVD) incidence in a healthy urban population while accounting for multiple demographic and lifestyle risk factors. METHODS: This prospective study conducted from May 2013 through March 2014 included 455 participants (314 men and 141 women) aged 25 to 92 years. All subjects completed a questionnaire on coffee consumption and received a comprehensive neurologic examination, including magnetic resonance imaging, at St. Luke's International Hospital (Tokyo, Japan). RESULTS: Incidence of SVD was lower in male daily coffee drinkers than male nondrinkers and occasional drinkers, whereas incidence of white matter lesions was lower in female daily coffee drinkers than female nondrinkers or occasional drinkers. In multivariate analyses including age, sex, smoking status, and BMI, as well as coffee consumption, incidence of microbleeds was significantly lower in male daily coffee drinkers compared to nondrinkers. CONCLUSIONS: Daily coffee consumption is associated with reduced risk of cerebral microbleeds in men.

Basilar extension and posterior inferior cerebellar artery involvement as risk factors for progression of the unruptured spontaneous intradural vertebral artery dissection.

BACKGROUND AND PURPOSE: Spontaneous intradural vertebral artery dissection (siVAD) primarily causes stroke in young and middle-aged individuals; however, data on the relationship between vertebrobasilar morphology and the progression of siVAD are limited. METHODS: We retrospectively reviewed the data of 77 adult patients who were diagnosed with unruptured siVAD and treated conservatively. We analysed the clinical characteristics, vertebrobasilar morphologies and progression. Progression was defined as siVAD-induced stroke or morphological worsening of the siVAD. RESULTS: Twenty patients experienced progression. Recurrent ischaemic events that occurred in the vertebrobasilar territory were seen in three patients (3.9%). Two of these three patients and other 17 patients showed morphological worsening. None of the patients presented with subarachnoid haemorrhage. The log-rank test showed male sex, migraine, basilar extension and the posterior inferior cerebellar artery involvement were associated with the progression. Multivariate analysis using the Cox proportional hazards model showed that only basilar extension and the posterior inferior cerebellar artery involvement were significantly related to the progression (p=0.012 and 0.019). In addition, patients with these two vertebrobasilar morphologies had a significantly shorter period of progression of siVAD than those without these morphologies (both, median 242 days; one of two, median 1292 days; none, median 2445 days). CONCLUSIONS: Thus, some vertebrobasilar morphologies might be markers of the progression of unruptured siVAD. Although all unruptured siVAD patients should be closely monitored, those with basilar extension and posterior inferior cerebellar artery involvement should perhaps be more carefully followed than those without such morphologies.