Somatic mutational landscape of extracranial arteriovenous malformations and phenotypic correlations.

BACKGROUND: Somatic genetic variants may be the cause of extracranial arteriovenous malformations, but few studies have explored these genetic anomalies, and no genotype-phenotype correlations have been identified. OBJECTIVES: The aim of the study was to characterize the somatic genetic landscape of extracranial arteriovenous malformations and correlate these findings with the phenotypic characteristics of these lesions. METHODS: This study included twenty-three patients with extracranial arteriovenous malformations that were confirmed clinically and treated by surgical resection, and for whom frozen tissue samples were available. Targeted next-generation sequencing analysis of tissues was performed using a gene panel that included vascular disease-related genes and tumour-related genes. RESULTS: We identified a pathogenic variant in 18 out of 23 samples (78.3%). Pathogenic variants were mainly located in MAP2K1 (n = 7) and KRAS (n = 6), and more rarely in BRAF (n = 2) and RASA1 (n = 3). KRAS variants were significantly (P < 0.005) associated with severe extended facial arteriovenous malformations, for which relapse after surgical resection is frequently observed, while MAP2K1 variants were significantly (P < 0.005) associated with less severe, limited arteriovenous malformations located on the lips. CONCLUSIONS: Our study highlights a high prevalence of pathogenic somatic variants, predominantly in MAP2K1 and KRAS, in extracranial arteriovenous malformations. In addition, our study identifies for the first time a correlation between the genotype, clinical severity and angiographic characteristics of extracranial arteriovenous malformations. The RAS/MAPK variants identified in this study are known to be associated with malignant tumours for which targeted therapies have already been developed. Thus, identification of these somatic variants could lead to new therapeutic options to improve the management of patients with extracranial arteriovenous malformations.

Curriculum for Vestibular Medicine (VestMed) proposed by the Bárány Society.

This document presents the initiative of the Bárány Society to improve diagnosis and care of patients presenting with vestibular symptoms worldwide.The Vestibular Medicine (VestMed) concept embraces a wide approach to the potential causes of vestibular symptoms, acknowledging that vertigo, dizziness, and unsteadiness are non-specific symptoms that may arise from a broad spectrum of disorders, spanning from the inner ear to the brainstem, cerebellum and supratentorial cerebral networks, to many disorders beyond these structures.The Bárány Society Vestibular Medicine Curriculum (BS-VestMed-Cur) is based on the concept that VestMed is practiced by different physician specialties and non-physician allied health professionals. Each profession has its characteristic disciplinary role and profile, but all work in overlapping areas. Each discipline requires good awareness of the variety of disorders that can present with vestibular symptoms, their underlying mechanisms and etiologies, diagnostic criteria and treatment options. Similarly, all disciplines require an understanding of their own limitations, the contribution to patient care from other professionals and when to involve other members of the VestMed community. Therefore, the BS-VestMed-Cur is the same for all health professionals involved, the overlaps and differences of the various relevant professions being defined by different levels of detail and depth of knowledge and skills.The BS-VestMed-Cur defines a Basic and an Expert Level Curriculum. The Basic Level Curriculum covers the VestMed topics in less detail and depth, yet still conveys the concept of the wide net approach. It is designed for health professionals as an introduction to, and first step toward, VestMed expertise. The Expert Level Curriculum defines a Focused and Broad Expert. It covers the VestMed spectrum in high detail and requires a high level of understanding. In the Basic and Expert Level Curricula, the range of topics is the same and runs from anatomy, physiology and physics of the vestibular system, to vestibular symptoms, history taking, bedside examination, ancillary testing, the various vestibular disorders, their treatment and professional attitudes. Additionally, research topics relevant to clinical practice are included in the Expert Level Curriculum. For Focused Expert proficiency, the Basic Level Curriculum is required to ensure a broad overview and additionally requires an expansion of knowledge and skills in one or a few specific topics related to the focused expertise, e.g. inner ear surgery. Broad Expert proficiency targets professionals who deal with all sorts of patients presenting with vestibular symptoms (e.g. otorhinolaryngologists, neurologists, audiovestibular physicians, physical therapists), requiring a high level of VestMed expertise across the whole spectrum. For the Broad Expert, the Expert Level Curriculum is required in which the minimum attainment targets for all the topics go beyond the Basic Level Curriculum. The minimum requirements regarding knowledge and skills vary between Broad Experts, since they are tuned to the activity profile and underlying specialty of the expert. The BS-VestMed-Cur aims to provide a basis for current and future teaching and training programs for physicians and non-physicians. The Basic Level Curriculum could also serve as a resource for inspiration for teaching VestMed to students, postgraduate generalists such as primary care physicians and undergraduate health professionals, or anybody wishing to enter VestMed. VestMed is considered a set of competences related to an area of practice of established physician specialties and non-physician health professions rather than a separate clinical specialty. This curriculum does not aim to define a new single clinical specialty. The BS-VestMed-Cur should also integrate with, facilitate and encourage translational research in the vestibular field.

[Diagnostic criteria for Menière's disease according to the Classification Committee of the Bárány Society]. / M. Menière: Diagnostische Kriterien des Internationalen Klassifikationskomitees der Bárány-Gesellschaft.

This paper presents diagnostic criteria for Menière's disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes two categories: definite Menière's disease and probable Menière's disease. The diagnosis of definite Menière's disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low- to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 min and 12 h. Probable Menière's disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 min to 24 h.

Visuo-proprioceptive interactions in degenerative cervical spine diseases requiring surgery.

Cervical proprioception plays a key role in postural control, but its specific contribution is controversial. Postural impairment was shown in whiplash injuries without demonstrating the sole involvement of the cervical spine. The consequences of degenerative cervical spine diseases are underreported in posture-related scientific literature in spite of their high prevalence. No report has focused on the two different mechanisms underlying cervicobrachial pain: herniated discs and spondylosis. This study aimed to evaluate postural control of two groups of patients with degenerative cervical spine diseases with or without optokinetic stimulation before and after surgical treatment. Seventeen patients with radiculopathy were recruited and divided into two groups according to the spondylotic or discal origin of the nerve compression. All patients and a control population of 31 healthy individuals underwent a static posturographic test with 12 recordings; the first four recordings with the head in 0° position: eyes closed, eyes open without optokinetic stimulation, with clockwise and counter clockwise optokinetic stimulations. These four sensorial situations were repeated with the head rotated 30° to the left and to the right. Patients repeated these 12 recordings 6weeks postoperatively. None of the patients reported vertigo or balance disorders before or after surgery. Prior to surgery, in the eyes closed condition, the herniated disc group was more stable than the spondylosis group. After surgery, the contribution of visual input to postural control in a dynamic visual environment was reduced in both cervical spine diseases whereas in a stable visual environment visual contribution was reduced only in the spondylosis group. The relative importance of visual and proprioceptive inputs to postural control varies according to the type of pathology and surgery tends to reduce visual contribution mostly in the spondylosis group.

Klippel-Trenaunay syndrome and spinal arteriovenous malformations: an erroneous association.

BACKGROUND AND PURPOSE: KTS is a rare limb overgrowth disorder with slow-flow vascular anomalies. This study examines the presumed association between KTS and spinal AVMs. MATERIALS AND METHODS: We performed a MEDLINE search of articles and reviewed textbooks of spinal diseases to study the association between KTS and spinal AVM. Our goal was to ascertain the basis on which the diagnosis of KTS was established and to evaluate the evidence of its association with spinal AVMs. In addition, the data base of the Vascular Anomalies Center at Children's Hospital Boston was queried for patients with KTS, and the association with spinal AVM was investigated. RESULTS: Twenty-four published reports on spinal AVMs in 31 patients with KTS were reviewed. None of these references provided solid evidence of the diagnosis of KTS in any patient. Clinical data were either incompatible with the diagnosis of KTS or were inadequate to establish the diagnosis. Alternative possible diagnoses (CLOVES syndrome and CM-AVM) were suggested by the first author for 9 of the patients reported in these articles. The medical records of 208 patients with the diagnosis of KTS were analyzed; not a single patient had clinical or radiologic evidence of a spinal AVM. CONCLUSIONS: An association between KTS and spinal AVM, as posited in numerous references, is most likely erroneous. The association has neither been reliably proved in the limited published literature nor encountered in a large cohort.

[Pregnancy follow-up and outcome in women with superficial vascular malformations]. / Malformations vasculaires superficielles : impact sur le suivi de grossesse et prise en charge à l'accouchement.

Superficial vascular malformations (MAV), so far called "superficial angioma", are uncommon and often unknown. The last classification, done by the "International Society for the Study of Vascular Anomalies", is essential to avoid diagnostic and therapeutic mistakes. Extramedullar localisations are rare. The coexistence of a pregnancy and a MAV states two problems: the medical and paraclinic supervision of the volume of the MAV and its risk of thrombosis with the choice of thrombosis prevention, and the mode of delivery and type of anaesthesia depending on its anatomical location. We revised the management of pregnant women with a MAV illustrating possible troubles to deal with. We reported the cases of two women having for the first one a pharyngolaryngeal MAV, the second a cutaneous MAV located on the leg and needing a multidisciplinary management with obstetricians, anaesthesists, hematologists, dermatologists, ENT, radiologists and pediatricians.

Intracranial vascular anomalies in patients with periorbital lymphatic and lymphaticovenous malformations.

BACKGROUND AND PURPOSE: The purpose of this study was to determine the nature, incidence, and radiologic appearance of intracranial vascular anomalies that occur in association with periorbital lymphatic malformation (LM) and lymphaticovenous malformation (LVM). MATERIALS AND METHODS: We retrospectively reviewed clinical records and imaging studies of 33 patients ranging in age from the neonatal period to 39 years (mean age, 5.1 years; median age, 1.0 year) who were evaluated for orbital LM or LVM at our institution between 1953 and 2002. Imaging studies, including CT, MR imaging, and cerebral angiograms, were evaluated by 2 radiologists to determine morphologic features of orbital LM and to identify associated noncontiguous intracranial vascular and parenchymal anomalies, including arteriovenous malformations (AVM), cerebral cavernous malformations (CCM), developmental venous anomalies (DVA), dural arteriovenous malformations (DAVM), and sinus pericranii (SP). RESULTS: The malformation was left-sided in 70% of patients. Twenty-two patients (70%) had intracranial vascular anomalies: DVA (n = 20; 61%), CCM (n = 2; 6%), DAVM (n = 4; 12%), pial AVM (n = 1; 3%), and SP (n = 1; 3%). Arterial shunts were present in the soft tissues in 2 patients (6%). Three patients had jugular venous anomalies. Three patients (9%) had cerebral hemiatrophy, 2 (6%) had focal cerebral atrophy, and 2 had Chiari I malformation. CONCLUSIONS: Intracranial vascular anomalies, some of which are potentially symptomatic and require treatment, are present in more than two thirds of patients with periorbital LM. Initial imaging of patients with orbital LM should include the brain as well as the orbit.

Facial infantile hemangiopericytoma resembling an arteriovenous malformation.

Malignant highly vascularized tumors such as hemangiopericytomas (HPC) may mimic a benign arteriovenous malformation (AVM) which is sometimes still referred to as "angioma". We describe the clinical and radiological findings of a facial hemangiopericytoma in comparison to an AVM in order to avoid misdiagnosis between these two pathologies since evolution and therapeutic management are completely different. Because hemangiopericytomas in children show malignant behavior requiring aggressive management, early and accurate diagnosis is of significant importance for the clinical outcome.

Subjective postural vertical in peripheral and central vestibular disorders.

The perception of subjective postural vertical was assessed in normals and patients with peripheral and central vestibular disorders and spasmodic torticollis. The subjects were seated in a motorized gimbal with the head and torso restrained and their eyes closed. The gimbal executed 7-10 cycles of tilt around the vertical at 1.5 degrees/s in either pitch or roll. Subjects indicated when they began to feel upright and again when they began to feel tilted by an analogous 3-position joystick. Normal subjects felt upright within a sector of 5-6 degrees around vertical in pitch and roll. Five patients with absent vestibular function, 25 torticollis patients and 3 patients with acute unilateral peripheral vestibular lesions showed a significant increase of the sector in pitch and roll, but only the latter had a mild directional bias. Two patients with long standing complete unilateral vestibular deficit and 8 patients with up or downbeat nystagmus in the vicinity of upright had abnormally large sectors within which they felt to be upright. The results suggest that vestibular function is important for the accurate perception of the postural vertical and that a directional asymmetry in vestibulo-ocular function or a head tilt does not necessarily correlate with a directional bias of subjective verticality.

Mathematical modelling of metabolic pathways affected by an enzyme deficiency. A mathematical model of glycolysis in normal and pyruvate-kinase-deficient red blood cells.

A mathematical model of glycolysis in human erythrocytes is proposed to study the influence of a pyruvate kinase deficiency on the energy metabolism. The model takes into account the main regulatory properties of the non-equilibrium enzymes and the magnesium-complex formation by the adenine nucleotides and by 2,3-bisphosphoglycerate. In the normal case (no enzyme defect) the calculated flux rates and metabolite concentrations are in a good agreement with experimental data. It is shown that a severe pyruvate kinase deficiency manifested in a tenfold diminished activity of that enzyme leads to a remarkable decrease of the glycolytic flux and the ATP concentration of about 50% of the normal values. On the other hand a lowering of the pyruvate kinase activity to half of the normal value, characteristic for the heterozygotes, gives no significant alterations of the metabolite concentrations and the flux rates compared with the normal case which is in accordance with the lack of clinical symptoms for a metabolic disease of these probands. For three patients with known alterations of their pyruvate kinase mutants the calculated metabolite concentrations and the control characteristics permit estimation of the degree of disorder of the glycolytic pathway. The resulting classification corresponds well to other independent experimental and clinical findings. In particular, the calculation demonstrates that there is no simple correlation between the lowered enzyme activity and the reduced flux rate through the affected pathway.