Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia.

DESCRIPTION: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. METHODS: The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. RECOMMENDATIONS: The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

Transumbilical arterial embolization of a large dural arteriovenous fistula in a low-birth-weight neonate with congestive heart failure.

PURPOSE: The purpose of this study was to report transumbilical arterial embolization of a large dural arteriovenous fistula (AVF) in a low-birth-weight neonate with congestive heart failure (CHF). CASE PRESENTATION: A female neonate was delivered by cesarean section at 31 weeks of gestation. Her birth weight was 1538 g and Apgar scores were 6 at both 1 and 5 min. Because of dyspnea and retracted respiration immediately after birth, she required mechanical ventilation. Ultrasound revealed right cardiac overload and a large cystic mass at the posterior brain. Magnetic resonance imaging on day 1 showed a large dural AVF (dural sinus malformation with arteriovenous (AV) shunts) at the torcular herophili. Umbilical artery and vein catheterization were performed on the same day for neurointervention. CHF prompted emergency embolization on day 8. The transfemoral arterial route could not be used because of its small size and compromised femoral artery blood flow. Transumbilical arterial embolization shrank the AV shunts markedly, resulting in clinical improvement, thus requiring no further intervention. Follow-up angiography at 4 months confirmed no residual AVF. Her growth and development were normal at the last follow-up at age 4 years. CONCLUSION: This patient apparently was the lowest birth weight neonate with a large AVF successfully treated by embolization, which is usually performed through the transfemoral arterial route. The transumbilical arterial route is an alternative for neonates with birth weight <2000 g and very small femoral arteries.

[A Case of Cervical Spinal Dural Arteriovenous Fistula with Extradural Drainage Presenting with Subarachnoid Hemorrhage due to a Ruptured Anterior Spinal Artery Aneurysm].

We report a rare case of a cervical spinal dural arteriovenous fistula(AVF)at the C2 level presenting with subarachnoid hemorrhage(SAH)due to a ruptured anterior spinal artery aneurysm. A 61-year-old man presented with sudden onset headache. Initial computed tomography revealed SAH around the brainstem. Digital subtraction angiography(DSA)demonstrated a cervical dural AVF that was fed by the left C1 radicular, left C2 radicular, and anterior spinal arteries, and drained into the epidural plexus. An aneurysm in the branch of the cervical anterior spinal artery was considered the bleeding point. A left lateral suboccipital craniotomy and C1 hemilaminectomy were performed on day 43. The feeding arteries were clipped, followed by coagulation of the draining veins. However, the aneurysm was not clipped because we deemed that obliteration of the aneurysm would be difficult without disrupting the blood flow of the parent artery. The patient showed no neurological deterioration after the operation. Postoperative DSA revealed residual dural AVF. Therefore, a second surgery was performed. After the second open surgery, DSA showed that the dural AVF and aneurysm disappeared. The patient also showed no neurological deterioration after the second surgery.

Hereditary hemorrhagic telangiectasia in Japanese patients.

To describe clinical presentations of hereditary hemorrhagic telangiectasia (HHT) patients in Japan. There were 80 patients (40 men and 40 women, age 2-78, mean 39.4 years old), who were either genetically verified or genetically not identifiable but clinically definite HHT patients. Clinical presentations of these HHT patients were analyzed retrospectively. Radiological examinations, which included at least brain magnetic resonance imaging and lung computed tomography, were performed when indicated. Seventy-eight patients had either endoglin (ENG) or activin A receptor type II-like 1 (ACVRL1) mutation. They were 53 HHT1 patients with ENG mutation in 27 families and 25 HHT2 patients with ACVRL1 mutation in 17 families. Two other female patients were clinically definite HHT, but genetic mutation could not be identified. Nosebleeds were noted in 53/53 (100%) HHT1 and 24/25 (96%) HHT2 patients. Telangiectases were observed in 34/53 (64%) HHT1 and 18/25 (72%) HHT2 patients. Pulmonary arteriovenous malformations (AVMs) were noted in 33/52 HHT1 (63%) and 5/25 HHT2 patients (20%). Brain AVMs were detected in 12/51 HHT1 (24%) and 1/25 HHT2 (4%) patients. Hepatic AVMs were noted in 7/29 (24%) HHT1 and 16/20 (80%) HHT2 patients. The number of HHT1 patients was roughly twice as many as that of HHT2 patients in Japan. Pulmonary and brain AVMs were predominantly observed in HHT1 while hepatic AVMs were detected in HHT2. It seemed that ethnicity and regionality had minimal roles in the clinical presentation of HHT.

Spinal arteriovenous metameric syndrome in a neonate presenting with congestive heart failure: case report.

BACKGROUND: Spinal arteriovenous metameric syndrome (SAMS) is a combination of more than two separate vascular malformations in the same embryonic metameres. This syndrome, also known as Cobb syndrome, is rare, especially in the neonate. CASE DESCRIPTION: A neonatal girl with a birthmark in the occipital and posterior nuchal regions presented with severe heart failure on the day of birth. The large arteriovenous fistulas in the left hypoglossal canal and in the posterior nuchal region were embolized with detachable coils on the postnatal days 5 and 18, which improved heart failure markedly. The associated intramuscular arteriovenous malformation in the posterior neck was left untreated because large arteriovenous fistulas had been occluded. She grew up without any neurological deficits and developed with normal milestones until the latest follow-up of 8 years old. CONCLUSION: To our knowledge, this is the first case with SAMS in a neonate presenting with congestive heart failure. Presence of a birthmark in a neonate presenting with congestive heart failure may suggest the possible underlying high-flow vascular malformations in the same metamere.

Successful Internal Trapping of Vertebral Artery Dissecting Aneurysm Located between Double Origin of the Posterior Inferior Cerebellar Artery, Resulting in Antegrade Blood Flow: A Case Report.

Objective: The double origin of the posterior inferior cerebellar artery (DOPICA) is a rare variant of PICA. Vertebral artery dissecting aneurysm (VADA) with DOPICA is an extremely rare occurrence. Herein, we report a case of VADA located between DOPICA that was successfully treated with endovascular internal trapping. Case Presentation: A 48-year-old male, found collapsed at his workplace, was admitted to our hospital for emergency medical assistance. Head CT revealed a subarachnoid hemorrhage (Fisher group 3), and cerebral angiography revealed right VADA with DOPICA. The VADA was located distal to the proximal component of the posterior inferior cerebellar artery (PCPICA) and just proximal to the hypoplastic distal component of PICA (DCPICA). Emergency endovascular internal trapping was performed using a total of 13 coils from the distal end of the VADA to just the distal of the branching point of PCPICA. VADA was not visualized, and antegrade flow through DOPICA to the basilar artery was confirmed. Head magnetic resonance angiography (MRA) showed antegrade flow via DOPICA, and the patient was discharged home on Day 46 with a modified Rankin Scale 0. Conclusion: Endovascular internal trapping for VADA with DOPICA was considered useful, especially when VADA is distal to PCPICA and proximal to DCPICA.

Embryological consideration of the inferolateral trunk.

Inferolateral trunk (ILT), also called inferior or lateral cavernous branch, of the internal carotid artery is an important artery during neuro-intervention and neurosurgery. However, its embryological background is not well elucidated. Review of the developmental biology of this small artery indicated that the alleged nomenclatures of the remnant of the primitive maxillary artery of Sabin (1917) and primitive dorsal ophthalmic artery of Lasjaunias (1977) are misnomers because the primordium of the ILT does not nourish the maxilla or retina essentially, but it supplies the premandibular region where the premandibular (prechordal) mesoderm and its surrounding premandibular trigeminal neural crests are distributed. Thus, this embryological artery might be called the primitive premandibular artery more appropriately, and its remnant, i.e., the ILT, might be recognized as the remnant of the primitive premandibular artery.

Ruptured small cerebral aneurysm occurring at the fenestration of the A1 portion of the anterior cerebral artery, combined with accessory middle cerebral artery branching from the crus: A case report.

Background: Cerebral aneurysms arising from fenestration of the A1 portion of the anterior cerebral artery (ACA) (A1 fenestration) with the accessory middle cerebral artery (MCA) is rare. Herein, we report a ruptured cerebral aneurysm arising from A1 fenestration combined with the accessory MCA that was successfully treated with coil embolization. Case Description: A 51-year-old woman suddenly experienced a severe occipital headache and was admitted to our hospital. Detailed examination revealed subarachnoid hemorrhage due to a cerebral aneurysm arising from A1 fenestration combined with the accessory MCA. Hence, coil embolization was performed, and a favorable outcome was obtained. Conclusion: Coil embolization of the cerebral aneurysm arising from the A1 fenestration of the ACA combined with the accessory MCA is considered to be useful.

An unusual anatomical variant: A transclival artery supplying the vertebrobasilar circulation.

The persistent carotid-vertebrobasilar anastomoses are arterial communications between the anterior and posterior circulations due to the persistence of embryological connections. We here present an extremely rare instance of a transclival persistent carotid-vertebrobasilar anastomosis in a 10-month-old infant, which does not fit into any of the traditionally described categories, such as the trigeminal artery, hypoglossal artery, or proatlantal artery.

[Spontaneous cerebrospinal fluid rhinorrhea associated with long-standing overt ventriculomegaly in adults (LOVA)].

OBJECTIVE: Spontaneous cerebrospinal fluid rhinorrhea associated with aqueductal stenosis is rare. CSF diversion is reported to be a failure in the majority of cases. The combination of the repair of the skull base and CSF diversion is reported to be successful. We describe a case successfully treated by intradural repair with ventricular drainage followed by endoscopic third ventriculostomy. CLINICAL PRESENTATION: A 28-year-old woman presented with rhinorrhea, and occasional attacks of headache, vomiting, and unconsciousness for two years. She had been diagnosed as arrested hydrocephalus for 10 years. Magnetic resonance imaging revealed triventriculomegaly with ballooning of the floor of the third ventricle, tonsilar herniation, right anterior horn herniation into the cribriform plate, and bilateral temporal lobe herniation into the temporal base. INTERVENTION: A ventricular drain was inserted followed by dissection of the herniated brain and repair of the enlarged cribriform foramen with periosteal flap. Make sure that the bacterial culture negative, endoscopic third ventriculostomy has been performed. There is no recurrence of hydrocephalus and rhinorrhea for two years. CONCLUSION: Direct communication between the lateral ventricle and the nasal/paranasal sinus is a rare complication of aqueductal stenosis and LOVA. Surgical repair of the skull base followed by cerebrospinal fluid diversion with endoscopic third ventriculostomy was a safe and reliable method.

Vascular supply of the hindbrain: Basic longitudinal and axial angioarchitecture.

The basic pattern of arterial vascularization is highly conserved across vertebrates and develops under neuromeric rules. The hindbrain has an angioarchitecture that is homologous to that of the spinal cord, and the hindbrain vascular system can be analyzed at the longitudinal and axial structures. During development, there are two main longitudinal arteries: the longitudinal neural artery and primitive lateral basilovertebral anastomosis. This review discusses the basic pattern of the blood supply of the hindbrain, the development of vascularization, and the anatomical variations, with a special reference to the embryological point of view of two main longitudinal anastomoses (longitudinal neural artery and primitive lateral basilovertebral anastomosis). The formation of commonly observed variations, such as fenestration and duplication of the vertebrobasilar artery, or primitive trigeminal artery variant, can be explained by the partial persistence of the primitive lateral basilovertebral anastomosis. Understanding the pattern and the development of the blood supply of the hindbrain provides useful information of the various anomalies of the vertebrobasilar junction and cerebellar arteries.

Cephalic/cardiac neural crest cell and moyamoya disease.

BACKGROUND: The neural crest is a transient structure present in early embryogenesis. Cephalic neural crest cells migrate into the pharyngeal arches and the frontonasal process that becomes the forehead and midfacial structures. They also contribute to forming the media of the arteries of the circle of Willis and their branches. The cardiac neural crest produces vascular smooth muscle cells in the ascending aorta, cardiac septum and coronary arteries. METHODS: In this review, we evaluate the role of the neural crest in moyamoya disease and the pathological implications from the concurrence of moyamoya disease and cardiovascular diseases from the point of view of neural crest cell distributions. RESULTS: Midline craniofacial and central nervous system anomalies with eye anomalies, morning glory disc anomaly in patients with moyamoya disease can both be explained as a subtype of cephalic neurocristopathy. Further, the association between moyamoya disease and cardiac manifestations (congenital cardiac defects and coronary artery disease) have also been reported. Both the cephalic neural crest and cardiac neural crest contribute to these concurrent arterial diseases, as cardio-cephalic neurocristopathy. CONCLUSION: The concept of cephalic/cardio-cephalic neurocristopathy provides a new perspective to understanding the underlying aetiological associations and to developing future therapeutic approaches for concomitant moyamoya disease and cardiovascular diseases.

Embryological Lateral Striate Artery Variants : Revised Concept of Recurrent Artery of Heubner, the Perforators to the Anterior Perforated Substance and Middle Cerebral Artery Variants.

PURPOSE: The anterior perforating arteries are a group of arteries that enter the brain through the anterior perforated substance (APS). Because the lenticulostriate artery, the recurrent artery of Heubner (RAH) and the perforators from A1 of anterior cerebral artery (ACA) penetrate the APS and supply the basal ganglia, these arteries can be considered as having a common embryological origin. RESULTS: During development, the lateral striate arteries are divided from the lateral olfactory artery and divided into the RAH and middle cerebral artery (MCA). The RAH is a fascinating artery for its early development and variations of origin and course. The MCA has also several variations, such as the duplicated MCA, accessory MCA, and fenestration. CONCLUSION: We provide a review of embryologic development and anatomical variations of the RAH, the perforators to the APS and MCA as a group of the lateral striate artery.

Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder characterized by recurrent epistaxis, skin/mucocutaneous telangiectasia, and organ/visceral arteriovenous malformations (AVM). HHT is mostly caused by mutations either in the ENG or ACVRL1 genes, and there are regional differences in the breakdown of causative genes. The clinical presentation is also variable between populations suggesting the influence of environmental or genetic backgrounds. In this study, we report the largest series of mutational and clinical analyses for East Asians. METHODS: Using DNAs derived from peripheral blood leukocytes of 281 Japanese HHT patients from 150 families, all exons and exon-intron boundaries of the ENG, ACVRL1, and SMAD4 genes were sequenced either by Sanger sequencing or by the next-generation sequencing. Deletions/amplifications were analyzed by the multiplex ligation-dependent probe amplification analyses. Clinical information was obtained by chart review. RESULTS: In total, 80 and 59 pathogenic/likely pathogenic variants were identified in the ENG and ACVRL1 genes, respectively. No pathogenic variants were identified in the SMAD4 gene. In the ENG gene, the majority (60/80) of the pathogenic variants were private mutations unique to a single family, and the variants were widely distributed without any distinct hot spots. In the ACVRL1 gene, the variants were more commonly found in exons 5-10 which encompasses the serine/threonine kinase domain. Of these, 25/59 variants were unique to a single family while those in exons 8-10 tended to be shared by multiple (2-7) families. Pulmonary and cerebral AVMs were more commonly found in ENG-HHT (69.1 vs. 14.4%, 34.0 vs. 5.2%) while hepatic AVM was more common in ACVRL1-HHT (31.5 vs. 73.2%). Notable differences include an increased incidence of cerebral (34.0% in ENG-HHT and 5.2% in ACVRL1-HHT), spinal (2.5% in ENG-HHT and 1.0% in ACVL1-HHT), and gastric AVM (13.0% in ENG-HHT, 26.8% in ACVRL1-HHT) in our cohort. Intrafamilial phenotypic heterogeneity not related to the age of examination was observed in 71.4% and 24.1% of ENG- and ACVRL1-HHT, respectively. CONCLUSIONS: In a large Japanese cohort, ENG-HHT was 1.35 times more common than ACVRL1-HHT. The phenotypic presentations were similar to the previous reports although the cerebral, spinal, and gastric AVMs were more common.

Pathogenesis of non-hereditary brain arteriovenous malformation and therapeutic implications.

Brain arteriovenous malformations have a high risk of intracranial hemorrhage, which is a substantial cause of morbidity and mortality in patients with brain arteriovenous malformations. Although a variety of genetic factors leading to hereditary brain arteriovenous malformations have been extensively investigated, their pathogenesis is still not well elucidated, especially in sporadic brain arteriovenous malformations. The authors have reviewed the updated data of not only the genetic aspects of sporadic brain arteriovenous malformations, but also the architecture of microvasculature, the roles of the angiogenic factors, and the signaling pathways. This knowledge may allow us to infer the pathogenesis of sporadic brain arteriovenous malformations and develop pre-emptive treatments for them.

Sumo-Associated Traumatic Vertebral Artery Dissection Precipitating Subarachnoid Hemorrhage in Association with Bifid Origins of the Posterior Inferior Cerebellar Artery.

BACKGROUND: Traumatic vertebral artery dissection (tVAD) is frequently accompanied by cerebellar infarction, but subarachnoid hemorrhage (SAH) is rare. CASE DESCRIPTION: We report a unique case of tVAD precipitating SAH, from which the patient fully recovered, most likely because of the protective effects of an anomalously duplicated posterior inferior cerebellar artery (PICA) origin. A 17-year-old Sumo wrestler experienced a brief loss of consciousness after an attack by an opponent to his neck. Head computed tomography imaging demonstrated diffuse posterior fossa SAH; cerebral angiography demonstrated left vertebral artery (VA) occlusion, which was thought to be most likely attributable to tVAD. Angiography revealed distal PICA reconstitution, supplied by collateral arterial flow from the meningeal branch of the proximal ipsilateral VA. An external ventricular drain was placed acutely for treatment of SAH-induced hydrocephalus; however, the patient had an otherwise uneventful course, and remained without clinical evidence of ischemic infarct. A repeat imaging confirming a probable duplicated PICA origin from the VA, distal to the tVAD-associated thrombosis. CONCLUSIONS: Of particular interest, the patient's abnormal anatomy may have been a mixed blessing, with a more fragile bifid PICA potentially underlying the unexpected development of SAH, whereas the sister branch simultaneously spared him a potentially catastrophic infarction via arterial collateralization.

[A Suspected Case of Hemorrhagic Hereditary Telangiectasia Presented with Cerebral Hemorrhage in Infancy].

Hereditary hemorrhagic telangiectasia (HHT) is characterized by telangiectasias in multiple organs. We experienced an infant with cerebral hemorrhaging and suspected HHT based on his family history of HHT. Computed tomography angiography confirmed a cerebral arteriovenous fistula. The onset of cerebral arteriovenous fistulas associated with HHT is relatively early, and the incidence of bleeding is relatively common. When HHT is suspected based on a family history, early imaging screening is recommended to improve the neurological prognosis, even in asymptomatic cases. (Received April 7, 2020; Accepted May 7, 2020; Published August 1, 2020).