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In the last decade, ultrasound examination in neurology has been undergoing a significant expansion of its modalities. In parallel, there is an increasing demand for rapid and high-quality diagnostics in various acute diseases in the prehospital setting, the emergency room, intensive care unit, and during surgical or interventional procedures. Due to the growing need for rapid answers to clinical questions, there is particular demand for diagnostic ultrasound imaging. The Neuro-POCUS working group, a joint project by the European Academy of Neurology Scientific Panel Neurosonology, the European Society of Neurosonology and Cerebral Hemodynamics, and the European Reference Centers in Neurosonology (EAN SPN/ESNCH/ERcNsono Neuro-POCUS working group), was given the task of creating a concept for point-of-care ultrasound in neurology called "Neuro-POCUS". We introduce here a new ultrasound examination concept called point-of-care ultrasound in neurology (Neuro-POCUS) designed to streamline conclusive imaging outside of the ultrasound center, directly at the bedside. The aim of this study is to encourage neurologists to add quick and disease-oriented Neuro-POCUS to accompany the patient in the critical phase as an adjunct not a substitution for computed tomography, magnetic resonance imaging, or standard comprehensive neurosonology examination. Another goal is to avoid unwanted complications during imaging-free periods, ultimately resulting in advantages for the patient.Im letzten Jahrzehnt hat die Ultraschalldiagnostik in der Neurologie eine deutliche Ausweitung ihrer Modalitäten erfahren. Parallel dazu steigt der Bedarf an schneller und qualitativ hochwertiger Diagnostik bei verschiedenen akuten Erkrankungen sowohl im prähospitalen Umfeld, in der Notaufnahme, auf der Intensivstation und bei chirurgischen oder interventionellen Eingriffen. Die Neuro-POCUS Working Group, eine gemeinsame Aktivität des European Academy of Neurology Scientific Panel Neurosolonogy, der European Society of Neurosonology and Cerebral Hemodynamics und der European Reference Centers in Neurosonology (EAN SPN/ESNCH/ERcNsono Neuro-POCUS Working Group) hat sich zum Ziel gesetzt, ein Konzept des Point-of-Care-Ultraschalls in der Neurologie mit dem Namen „Neuro-POCUS“ zu erstellen. Die bildgebende Diagnostik wird durch den wachsenden Bedarf an schnellen Antworten auf klinische Fragen besonders herausgefordert. Wir stellen hier ein neues Konzept der Ultraschalluntersuchung vor, den sogenannten Point-of-Care-Ultraschall in der Neurologie (Neuro-POCUS), der eine aussagekräftige Diagnostik fernab des Ultraschalllabors direkt am Krankenbett ermöglichen soll. Ziel dieser Arbeit ist es, Neurologen zu ermutigen, den Patienten in der kritischen Phase mit einem schnellen und krankheitsorientierten Neuro-POCUS zu begleiten und nicht als Ersatz für die Computertomographie, die Magnetresonanztomographie oder die umfassende neurosonologische Standarduntersuchung zu dienen. Ein weiteres Ziel besteht darin, unerwünschte Komplikationen innerhalb bildgebungsfreier Zeiträume zu vermeiden und das outcome des Patienten Vorteile zu verbessern.

Transcranial color-coded duplex ultrasonography (TCCS) is a combined ultrasound technique which allows a morphological and hemodynamic investigation of the intracranial vessels as well as of pathological vascular conditions. The goal of this chapter is to describe the typical color-coded duplex ultrasonography features of cerebral arteriovenous malformations (AVM) and fistulas that may result in intracranial hemorrhage.

Mechanical thrombectomy (MT) is standard care for patients suffering from an ischemic stroke due to a large vessel occlusion. Immediate and follow-up transcranial ultrasound examinations after MT were shown to have a diagnostic benefit. However, it is unclear whether repeated extracranial ultrasound after MT has an additional diagnostic yield, that is, depicts new findings.Retrospectively, from our prospective database we identified all patients after MT who presented for a follow-up examination between January 2017 and March 2020 and who had received an ultrasound examination after MT and at follow-up. Clinical data were extracted from our database. Ultrasound images of all patients were revisited to identify new findings at follow-up compared to examination after MT.Ninety-one patients were identified appropriate for further analysis, with a mean age of 67.8 ± 16 years. Median National Institute of Health Stroke Scale at admission was 11 ± 8.5 points. At baseline ultrasound, 18 patients (19.8%) had no atherosclerotic alterations and 73 patients (82.2%) had a plaque burden of ≥1 plaque. During follow-up, in 5 patients (5.5%) a pathological finding presented in first examination evolved dynamically, that is, normalized. Vessel status of all other patients was stable, especially, in no patient a new relevant pathological finding occurred.Although sonographic normalization of pathologic findings was observed, pathologic new findings were not detected during follow-up. This study provides first data for a discussion of the role of ultrasound in a structured stroke care after MT. However, larger studies are required to improve the understanding.

The updated version of the EFSUMB guidelines on the application of non-hepatic contrast-enhanced ultrasound (CEUS) deals with the use of microbubble ultrasound contrast outside the liver in the many established and emerging applications.Die aktualisierte Version der EFSUMB-Leitlinien für die Anwendung von nicht-hepatischem kontrastverstärktem Ultraschall (CEUS) befasst sich mit der Verwendung von Mikrobläschen Ultraschall-Kontrastmitteln außerhalb der Leber in zahlreichen etablierten und neu entstehenden Einsatzbereichen.

The updated version of the EFSUMB guidelines on the application of non-hepatic contrast-enhanced ultrasound (CEUS) deals with the use of microbubble ultrasound contrast outside the liver in the many established and emerging applications.Die aktualisierte Version der EFSUMB-Leitlinien für die Anwendung von nicht-hepatischem kontrastverstärktem Ultraschall (CEUS) befasst sich mit der Verwendung von Mikrobläschen Ultraschall-Kontrastmitteln außerhalb der Leber in zahlreichen etablierten und neu entstehenden Einsatzbereichen.

BACKGROUND The clinical significance of vertebral artery hypoplasia (VAH) and the possible pathomechanism of ischemic stroke in patients with VAH are still not completely clear. METHODS In a group of 80 posterior circulation strokes (PCS) patients, we compared the location of the ischemic areas in VAH (n = 26) and non-VAH (n = 54) group. We assessed the side of VAH (diameter equal to or less than 2.5mm) with the stroke localization. RESULTS The possible morphological stroke pathomechanisms in the VAH group - “blood flow reorganization” (n = 11) and “pathway liberation for embolization” (n = 10) - were represented equally and may also act together (n = 3). In two cases, the stroke pathomechanism was unknown. The frequency of the presence of conventional risk factors - hypertension (p = 1.0), diabetes mellitus (p = 0.62), hyperlipidemia (p= 1.0) and smoking (p = 1.0) - and the stroke etiology - cardioembolism (p = 0.80), atherosclerotic changes of large (p = 0.76) and small vessels (p = 0.79) - did not differ between the two subgroups. CONCLUSION In patients with VAH, the combination of several pathomechanisms of ischemic stroke and the contribution of several risk factors can cause the clinical manifestation of PCS.

Summary Transcranial color-coded duplex ultrasonography (TCCS) enables the visualization of basal cerebral arteries through the intact skull by color-coding of blood flow velocity. The arteries of the circle of Willis can be identified by their anatomic location with respect to the brain stem structures and by the determination of the flow direction. TCCS is an important neuroimaging method due to its excellent time resolution. In addition to the diagnostics of intracranial vascular disease, this technique is valuable in intensive care and stroke units, e.g. for follow-up examinations in vasospasm after subarachnoid hemorrhage, and for intraoperative monitoring as well. In difficult anatomical conditions, the application of echo contrast agents can improve the diagnostic reliability of the examination. This paper reviews the examination technique and the clinical application of this method in routine cerebrovascular diagnostics.

Summary The aim of this preliminary study is to evaluate the hypothesis of a possible causal link between the anatomical findings of vertebral artery hypoplasia (VAH) and the incidence of posterior circulation stroke. We used full ultrasonographic examination to evaluate patients with stroke in the vertebrobasilar circulation territory over a period of 1.5 years. The diameter equal or less than 2.5 mm (in V1 and V2 segment of the vertebral artery) was set as a feature of vertebral artery hypoplasia. Magnetic resonance imaging and angiography (MRI and MRA) or computed tomography and angiography (CT and CTA) were performed to confirm the anatomic variation of hypoplasia and the site of the cerebral ischemic territory. In the group of 44 stroke patients, 9 (20%) had a hypoplastic vertebral artery and 35 (80%) were without VAH. Although vertebral artery hypoplasia in previously published literature is seldom shown as a leading risk factor for stroke in vertebrobasilar (posterior) circulation, its occurrence is not negligible and in coexistence with known risk factors of stroke may increase the negative clinical impact. Vertebral artery hypoplasia can be diagnosed non-invasively with duplex ultrasonography. It is therefore a useful method for detection of this anatomic variation and for follow-up examination.

To systematically review the ultrasonographic criteria proposed for the diagnosis of chronic cerebrospinal venous insufficiency (CCSVI). The authors analyzed the five ultrasonographic criteria, four extracranial and one intracranial, suggested for the diagnosis of CCSVI in multiple sclerosis (MS), together with the references from which these criteria were derived and the main studies that explored the physiology of cerebrospinal drainage. The proposed CCSVI criteria are questionable due to both methodological and technical errors: criteria 1 and 3 are based on a scientifically incorrect application of data obtained in a different setting; criteria 2 and 4 have never been validated before; criterion 2 is technically incorrect; criteria 3 and 5 are susceptible to so many external factors that it is difficult to state whether the data collected are pathological or a variation from the normal. It is also unclear how it was decided that two or more of these five ultrasound criteria may be used to diagnose CCSVI, since no validation of these criteria was performed by different and independent observers nor were they blindly compared with a validated gold-standard investigation. The European Society of Neurosonology and Cerebral Hemodynamics (ESNCH) has considerable concerns regarding the accuracy of the proposed criteria for CCSVI in MS. Therefore, any potentially harmful interventional treatment such as transluminal angioplasty and/or stenting should be strongly discouraged.

The purpose of this report is to describe, based on the experience with 50 patients, transcranial colour-coded duplex ultrasonography and to evaluate its practical potential in the routine examination in comparison with conventional transcranial Doppler ultrasonography. Under visual control, the Doppler angle between the ultrasonic beam and the flow direction can be adjusted. The mean angle of incidence in the middle cerebral artery was 33 degrees +/- 15 degrees, in the anterior cerebral artery 35 degrees +/- 17 degrees, in the posterior cerebral artery 45 degrees +/- 18 degrees and in the basilar artery 15 degrees +/- 14 degrees. The measurements of blood flow velocity under consideration of the angle of incidence resulted in 15%, 18%, 30% and 3% respectively higher velocity values. Examples of pathologic findings demonstrate the practical potential of this noninvasive method.

AIM To assess the diagnostic potential of duplex color-flow imaging in the evaluation of extracranial vertebral artery dissection. In 15 of 20 patients (75%), the dissection was related to trauma. METHOD Over the last six years, we evaluated 20 consecutive patients aged 18 to 59 years with 24 extracranial vertebral artery dissections (four occurring bilaterally). The examinations were performed with a color Doppler imaging system using a 7 MHz transducer. Angiography was done in 18 patients, confirming the diagnosis. RESULTS In 15 patients, the diagnosis was primarily established with ultrasonography. Six vertebral arteries were dissected at the origin or in the proximal V1 segment, one in the distal V2 segment and one at the atlas loop. Most dissections occurred in the region between the V1 and V2 segments (n = 16), most often at the entrance of the artery into the transverse foramen of the C6 vertebra (n = 11). Typical ultrasonographic findings were irregular stenosis, dissecting membrane with true and false lumen, localized increase in diameter of the artery, pseudoaneurysm, intramural hematoma and tapering stenosis with distal occlusion. The diagnosis of dissection in the V3 segment was based on indirect signs such as high resistance flow pattern and decreased diastolic flow velocity. In follow-up examinations, marked resolution of pathological findings were found in 17 cases (70.8%). Two occlusions were completely recanalized. CONCLUSION Duplex color-flow imaging is a valuable noninvasive method for early diagnosis of extracranial vertebral artery dissection and for follow-up examinations.

In 60 patients the vertebral arteries were investigated to determine whether color Doppler imaging has advantages over conventional duplex ultrasonography. The vertebral artery was easily identified in the midcervical course (V1-V2 segment) with both methods. Visualization at the atlas loop (V3 segment) was rarely successful with duplex scanning, however, color Doppler imaging enabled good documentation of vertebral artery flow in 87% on the right and in 85% on the left side. Color Doppler imaging provided better evaluation of the vertebral origin (V0 segment). Although visualization of the ostium with duplex scanning was more difficult and time consuming, it was possible in 80% on the right and in 65% on the left side. Color Doppler imaging allowed more rapid identification of the origin in 88% on the right and in 73% on the left side. The special problems of visualization of vertebral arteries with both methods and characteristic color-coded Doppler sonographic features of pathological findings are discussed.

Background and Purpose— Glycohemoglobin (hemoglobin A 1c [HbA 1c ]) and high-sensitivity C-reactive protein (hsCRP) are risk indicators for atherosclerosis. Limited information exists regarding the combined effects of inflammation and hyperglycemia. We investigated the joint effects of both parameters on early carotid atherosclerosis progression and major vascular events in diabetic and nondiabetic subjects. Methods— We analyzed the data of INVADE (Intervention Project on Cerebrovascular Diseases and Dementia in the Community of Ebersberg, Bavaria), a prospective, population-based study conducted in 3534 subjects (mean age, 69 years). In addition to common risk factors, measurements of carotid intima-media thickness (IMT), hsCRP, and HbA 1c were performed at baseline and after 2 years of follow-up. Results— For the entire population, IMT progression was significantly related to HbA 1c ( P =0.003) but not to hsCRP ( P =0.06) after risk factor adjustment. The interaction hsCRP×HbA 1c was highly significant ( P =0.001), and the most pronounced IMT progression was seen in subjects with both parameters in the fourth quartiles compared with subjects with both parameters in the first quartiles (0.028 [0.025, 0.031] versus 0.012 mm/year [0.007, 0.019]; P =0.0013). We observed a significant joint effect of HbA 1c and hsCRP on IMT progression in the diabetic (n=882) as well as the nondiabetic subgroup (n=2652). Subjects with HbA 1c and hsCRP in the upper 2 quartiles had an increased risk for new vascular events (adjusted hazard ratio in diabetics: 4.3 [1.8, 7.3]; P =0.001; nondiabetics: 2.9 [1.6, 4.7]; P =0.001). Conclusions— The combination of hyperglycemia and inflammation is associated with an advanced early carotid atherosclerosis progression and an increased risk of new vascular events in diabetic as well as nondiabetic subjects.

Introduction Dissection of a cervical artery supplying the brain is a major cause of stroke in young adults. It can occur spontaneously, in connection with an underlying disorder such as fi bromuscular dysplasia, 1 -antitrypsin defi ciency, hypertension, migraine, atherosclerosis, arteritis or Marfan’s disease [1, 2] . More often, it is related to a neck trauma. In the case of a vertebral artery dissection, a vessel wall can be injured through abrupt or continuous neck movements, regardless of visible outward signs of neck trauma. The fi rst clinical symptoms – occipital headache, neck pain and vertigo – can be associated with focal neurological defi cits of varying severity, from transient ischemic attacks up to complete ischemia in the vertebrobasilar territory [3] . Dissection of the vertebral arteries is most accurately diagnosed with conventional digital subtraction angiography (DSA). In recent years, this procedure is being increasingly replaced by noninvasive techniques, such as magnetic resonance imaging (MRI), MR angiography and duplex ultrasonography [4–7] . We describe a traumatic dissection of the left vertebral artery in the distal V2 segment which was initially not recognized using extracranial duplex sonography – although the examination had been carried out with a view to this very possibility.

Objective. The clinical value of transcranial color-coded duplex sonography (TCCS) in the evaluation of arteriovenous malformations (AVMs) has not yet been fully investigated. In this study, 54 intracranial AVMs confirmedby angiography were prospectively examined over 6 years. The purpose of the study was to describe their typical sonographic features and to define sensitivity for diagnosis with regard to the location of an AVM. Methods. Transcranial color-coded duplex sonographic findings for 54 patients with intracranial AVMs are presented. The vessels of the circle of Willis were identified by location, course, and direction of flow on color flow images. Results. In accordance with digital subtraction angiography, the intracranial AVMs could be visualized in 42 cases (sensitivity, 77.8%). The pathologic vessels were coded in different shades of blue and red, corresponding to varying blood flow directions in the AVM. The major feeding vessels could be easily identified. Hemodynamic parameters showing increased systolic and diastolic flow velocities and a decreased pulsatility index were better attainable with TCCS than with conventional transcranial Doppler sonography. Arteriovenus malformations located near the cortex, that is, in the parietal, frontal, occipital, and cerebellar regions of the brain, could not be visualized. In contrast, AVMs located in the basal regions were very easy to image (sensitivity, 88.9%). Additionally, TCCS proved useful for follow-up examinations postoperatively or after embolization. Conclusions. Transcranial color-coded duplex sonography is a valuable noninvasive method for the diagnosis and long-term follow-up of intracranial AVMs. Arteriovenous malformations located in the axial imaging plane can be more easily detected. Nevertheless, TCCS should not be used as a screening method.

Summary Contrast Enhanced Carotid Ultrasonography (CCU) is capable of detecting angiogenesis within the carotid plaque as a potential index of plaque vulnerability. However, due to a lack of standard of examination technique and documentation, results are not sufficiently, reliably comparable. To improve this situation and in order to support wide acceptance of this promising technique, experts in this field met in the Consensus conference in May 22, 2011, held during the 16th ESNCH Meeting (20–23 May 2011) in Munich, Germany, to discuss the limitations and problems and to determine guidelines for its proper use in scientific investigations and clinical practice. The main results of this conference are presented here. The discussion is still in progress and individual conclusions may not reflect the opinion of all participants. It aims to provide a basis for a later comprehensive consensus statement.

The clinical significance of vertebral artery hypoplasia (VAH) and the possible pathomechanism of ischemic stroke in patients with VAH are still not completely clear.In a group of 80 posterior circulation strokes (PCS) patients, we compared the location of the ischemic areas in VAH (n = 26) and non-VAH (n = 54) group. We assessed the side of VAH (diameter equal to or less than 2.5 mm) with the stroke localization.The possible morphological stroke pathomechanisms in the VAH group--"blood flow reorganization" (n = 11) and "pathway liberation for embolization" (n = 10) - were represented equally and may also act together (n = 3). In two cases, the stroke pathomechanism was unknown. The frequency of the presence of conventional risk factors--hypertension (p = 1.0), diabetes mellitus (p = 0.62), hyperlipidemia (p= 1.0) and smoking (p = 1.0)--and the stroke etiology--cardioembolism (p = 0.80), atherosclerotic changes of large (p = 0.76) and small vessels (p = 0.79)--did not differ between the two subgroups.In patients with VAH, the combination of several pathomechanisms of ischemic stroke and the contribution of several risk factors can cause the clinical manifestation of PCS.

Midiendo la fuerza de contracción isométrica en la musculatura somática de Ascaris, se encontró que los receptores catecolamínicos y muscarínicos son regulatorios, no causan aumento de la respuesta a la acetilcolina, al contrario la inhiben, la dopamina impide que se alcance la respuesta máxima y los muscarínicos modifican el umbral.

Transcranial duplex color-flow imaging is a new diagnostic method that allows visual display of blood flow in the basal cerebral arteries. This method allows determination of and correction for the Doppler angle of insonation. Conventional transcranial Doppler sonography has no imaging component and assumes a 0-degree Doppler angle for the calculation of flow velocities. The magnitude of the angle of insonation and the effect on flow velocity estimates have not been clearly defined. In order to evaluate the angle of insonation and the effect of angle correction on velocity readings, 50 patients referred for evaluation of cerebrovascular disease were studied. The mean age was 45 years (range, 24-62 yr). All were examined with conventional transcranial Doppler and transcranial duplex color-flow imaging. Specific vessels of the circle of Willis were identified by location, course, and direction of flow on color-flow images and by depth, direction of flow, and transducer orientation with conventional Doppler sonography. Visually controlled measurements of the Doppler angle of insonation were made by color-flow imaging. The data show that the mean angle of insonation was 33 degrees (+/- 15) in the middle cerebral artery, 35 degrees (+/- 17) in the anterior cerebral artery, 45 degrees (+/- 18) in the posterior cerebral artery, and 15 degrees (+/- 14) in the basilar artery. Angle-corrected peak systolic flow velocities were higher in all vessel segments (middle cerebral = 15%, anterior cerebral = 18%, posterior cerebral = 30%, and basilar = 3%), compared to uncorrected velocity readings by conventional Doppler sonography.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of the vertebral arteries is often difficult with conventional duplex ultrasonography. This study of 60 patients aimed to determine the potential advantages of color Doppler imaging over conventional duplex ultrasonography in the evaluation of vertebral arteries, specifically three extracranial segments of these vessels. Both methods allowed visualization of the vertebral artery in the midcervical course (V2 and distal V1 segments) in all subjects. Color Doppler imaging appeared more effective for visualization of the V0 and the proximal V1 segments (on the right side in 88% of patients and on the left side in 73%). Conventional duplex ultrasonography imaged the ostium on the right side in 80% of patients and on the left side in 65%, but was difficult and time-consuming. Visualization at the atlas loop (V3 segment) was rarely successful with duplex sonography, whereas color Doppler imaging visualized the vertebral artery on the right side in 87% of patients and on the left side in 85%. Color Doppler imaging allows better visualization of the proximal and distal segments of the vertebral arteries, compared to conventional duplex ultrasonography.

The aim of this study was to evaluate a deficit in cerebral perfusion after administration of the contrast agent SonoVue (Bracco Altana Pharma, Konstanz, Germany) in patients with intracranial space-occupying lesions.We used transcranial duplex sonography to examine 10 healthy volunteers and 4 patients. Of the patients, one 55-year-old woman had an intracranial glioblastoma; one 54-year-old woman had an intracranial hemorrhage; and one 49-year-old woman and one 69-year-old man had a malignant middle cerebral artery infarction. A decompressive craniectomy was performed in the 2 patients with malignant middle cerebral artery infarction. Triggered images with pulsing intervals of 1000 milliseconds were used for the evaluation of time-intensity curves in several regions of interest. The mechanical index was set at 1.6; in patients with a craniectomy, the mechanical index was set at 1.1.In all patients, the perfusion deficit could be recognized in the ipsilateral hemisphere. The superimposition of the sonographic images with those from computed tomography or magnetic resonance imaging showed a good correspondence in shape and size in patients with a craniectomy. In patients without a craniectomy, a rough correspondence with findings from magnetic resonance imaging or computed tomography could be recognized.By using contrast-enhanced transcranial duplex sonography, it is possible to image the perfusion deficit in cerebral microcirculation in patients with intracranial space-occupying lesions. These results should be confirmed by more pathologic cases and correlated with magnetic resonance imaging and other neuroimaging techniques. Additionally, further technical development in sonographic systems is necessary to improve the diagnostics of cerebral perfusion deficit.

Dissection of cervical arteries causes ischemic stroke in young adults. This reports the clinical, ultrasonographic, and neuroradiological findings in 24 patients with 28 vertebral artery dissections in the neck (4 occurring bilaterally). In 20 patients (83%), the dissection was temporally related to trauma. No patients had an underlying vascular disease, for example, atherosclerosis or fibromuscular dysplasia. In all, the major initial manifestation was pain in the occipital or neck region. The next most common symptoms were vertigo and nausea (in 17 patients). Clinical manifestations were vertebrobasilar transient ischemic attack (TIA) (5 patients: in 2 patients vestibulocerebellar TIA, in 1 patient visual TIA, in 1 patient motor TIA, and in 1 patient brain stem TIA with perioral paresthesia), cerebellar infarction (10 patients, in 4 patients bilateral), brainstem infarction (5 patients), posterior cerebral artery territory infarction (1 patient), and multiple vertebrobasilar ischemic lesions (3 patients). Typical angiographic findings were irregular narrowing of the vessel lumen or a tapering stenosis with distal occlusion. Magnetic resonance imaging showed a thickened vessel wall with hematoma signal at the site of the dissection. Duplex color-flow imaging was valuable for the early diagnosis of extracranial vertebral artery dissection and for follow-up examinations. The distal V1- and the proximal V2-segment (at the level of C6 vertebra) was the most frequent localization of dissections (in 43%). The outcome was favorable except for 2 patients with basilar artery occlusion. Embolism to the basilar artery may be avoided by early administration of anticoagulants.

Transcranial color-coded duplex ultrasonography (TCCS) makes possible the visualization of basal cerebral arteries through color-coding the flow velocity information. This method is well established in the clinical routine for the diagnostics of pathological processes in cerebrovascular disease. The present review describes the examination technique, normal and pathological findings, such as stenosis and occlusion of intracranial arteries, as well as intracranial vascular malformations focussing on the advantages of the examination in the axial imaging planes.

Background and Purpose We describe the diagnostic potential of duplex color-flow imaging in the evaluation of extracranial vertebral artery dissection. Methods Twenty patients with 24 extracranial vertebral artery dissections (four bilateral) were examined with duplex ultrasonography over a period of 6 years. Color-flow imaging was carried out in 16 of these patients. In 15 patients (75%), the dissection was temporally related to trauma. Angiography was available in 18 patients, confirming the diagnosis. Results In 15 patients, the diagnosis was primarily established with ultrasonography. Five patients with a dissection were referred for follow-up color-flow examinations. Six vertebral arteries were dissected at the origin or in the proximal V1 segment, one in the distal V2 segment, and one at the atlas loop. In contrast to other studies, the most frequent localization of the dissection in our patients was the region between the V1 and V2 segments (n=16), where the most typical dissection site was the entrance of the artery into the transverse foramen of the C6 vertebra (n=11). Typical ultrasonographic findings were irregular stenosis, dissecting membrane with true and false lumen, localized increase in diameter of the artery, pseudoaneurysm, intramural hematoma, and tapering stenosis with distal occlusion. In follow-up examination, a good regression of pathological findings was found in 17 dissections (70.8%). Two occlusions were completely recanalized. Conclusions Extracranial vertebral artery dissections can be diagnosed noninvasively with duplex color-flow imaging. It is therefore a useful method for early diagnosis and follow-up examination.

1. Histrionicotoxin (HTX) at low concentrations of 5–10µM blocks the postsynaptic potential of the electroplax ofElectrophorus electricus. 2. At 100-fold higher concentrations, HTX blocks the directly evoked action potentials of the conducting membrane. 3. The pH dependence of the blockade by HTX at synaptic channels is different from that at the conducting membrane. At the synapse HTX is more potent at acid pH, while at the conducting membrane it is more potent at basic pH. 4. HTX at high concentrations antagonizes the effects of batrachotoxin, indicative of an effect on the batrachotoxin-sensitive sodium channels involved in action potential generation. 5. While the effects of HTX on the synaptic channels are concentration, time, and pH dependent, the effects on the channels of the conducting membrane are, in addition, use dependent, suggesting interactions of HTX with the activated forms of these channels.

Batrachotoxin under certain conditions has a strong depolarizing effect on the innervated membrane of the monocellular electroplax preparation from the electric eel, El-ectrophorus electricus. No effect is observed when the toxin (50-200 nM) is applied to the resting membrane for periods up to 1 hr. However, if the membrane is exposed to batrachotoxin and the cell is subjected to stimulation at a stimulus voltage slightly above the threshold for action potential firing, a progressive prolongation of the action potential and concomitant progressive depolarization of the innervated membrane is observed. When the membrane is depolarized by 15-20 mV, a further abrupt all-or-none depolarization occurs, and the potential attains a steady-state value between 0 and -10 mV. Brief stimulation of a cell in the presence of batrachotoxin is sufficient to define a batrachotoxin-treated cell, even though negligible depolarization occurs. If depolarizing agents such as carbamoylcholine or potassium chloride are introduced to such a cell in concentrations that normally produce a 20-30 mV depolarization, the abrupt all-or-none depolarization immediately occurs. All-or-none depolarizations arising from either electrical stimulation or depolarizing agents are unaffected by d-tubocurarine but are completely reversed by tetrodotoxin. Batrachotoxin thus appears to activate only the action potential sodium channels. In the batrachotoxin-treated membrane, these channels can attain stable steady states in either a closed configuration at the normal resting potential or in an open configuration after complete depolarization. A striking hysteresis cycle thus can be generated, which is strongly indicative of a voltage-dependent interaction of the toxin with the action potential sodium channels.

The effects of acetylcholine, local anesthetics and intermediary forms on the excitable membrane of the monocellular electroplax preparation have been investigated. It has been shown that small modifications of structure may markedly modify the effects on the electrical parameters and transform the activator into an inhibitor. 1. 1. Acetylcholine (2.5 μM) has a strong depolarizing action. This action is, however, limited to the synaptic membrane. The depolarization of the conducting membrane is known to be a spread of depolarization from the synapse; the compound does not reach the conducting membrane even in high concentrations. 2. 2. If the methyl on the carbon of the carbonyl group is replaced by cyclohexyl (hexahydrobenzoylcholine), the depolarizing action is markedly decreased, by a factor of 200, but the fundamental properties are still similar to acetylcholine. Combined with carbamylcholine in low concentration it has an additive effect. 3. 3. If the methyl is replaced by a phenyl radical (benzoylcholine) a marked change of the properties of the molecule in regard to its action on the excitable membrane is observed. The depolarizing action is similar to that of hexahydrobenzoylcholine, but it also exhibits some inhibitory effects. It counteracts the depolarizing action of carbamylcholine. Moreover, in contrast to acetylcholine and hexahydrobenzoylcholine, benzoylcholine blocks the directly evoked action potential in the presence of curare. The presence of the phenyl radical but not its saturated analog enables the compound to penetrate the barriers surrounding the conducting membrane. The compound may be considered as the transitory form between acetylcholine and the local anesthetics. 4. 4. The tertiary analogue of benzoylcholine has no depolarizing effect but only a weak inhibitory action on the synaptic membrane. 5. 5. Replacing the phenyl by a p-aminophenyl radical (procaine, tetracaine, etc.) deprives the compound of its depolarizing action. These compounds are receptor inhibitors. Their ability to penetrate through the barriers protecting the conducting membrane is greatly increased. These compounds block all excitable membranes, but without depolarization, hence their usefulness as local anesthetics. These studies offer a further elucidation of the mode of action of local anesthetics and their close relationship to acetylcholine.

Pretreatment of the electroplax of Electrophorus electricus with irreversible inhibitors of cholinesterase (ChE) (diisopropyl phosphorofluoridate, paraoxon or phospholine) increases the sensitivity of the membrane to acetylcholine (ACh). After washing with inhibitor-free Ringer's solution, this effect disappears rapidly. Reapplication of either of the inhibitors restores the initial sensitivity to ACh. Simultaneous measurements of ChE activity show an initial inhibition which is followed by recovery of enzyme activity. The rate of reactivation of the irreversibly inhibited enzyme is highest with paraoxon and lowest with DFP. The return of enzyme activity may be responsible for the loss of ACh action on the membrane of electroplax.

— Cottonmouth moccasin snake venom (SV) was applied to the innervated membrane of the isolated single cell of the Sachs electric organ (electroplax) of the electric eel, Electrophorus electricus. Concentrations as low as 0.05 μg/ml irreversibly antagonized depolarization by carbamylcholine, whereas concentrations of 0.1 mg/ml or higher were required to directly and irreversibly depolarize and block electrical excitation. The active component of the venom was stable to boiling at acid pH, destroyed by boiling at alkaline pH and nondialyzable and corresponded to those fractions containing maximum phospholipase A activity demonstrable when isolated by paper electrophoresis and Sephadex filtration. Phospholipase C and lysolecithin in concentrations of 1 mg/ml and 0.2 mg/ml, respectively, depolarized and blocked electrical excitation, whereas lower concentrations did not antagonize depolarization by carbamylcholine. Triton X-100 (0.01 mg/ml) antagonized carbamylcholine, whereas 10-fold higher concentrations directly blocked electrical excitation. Hyaluronidase had no effect on resting or action potential but decreased the depolarizing response to carbamylcholine. At minimal concentrations which blocked the depolarizing response to carbamylcholine, SV caused only slight splitting of phospholipids in single cells of the Sachs organ. A concentration (1 mg/ml) of SV which blocked electrical excitation caused 80–100 per cent splitting of lecithin, phosphatidylethanolamine and phosphatidylserine, the three principal phospholipids of the electric tissue. Similar percentages of splitting of the latter two phospholipids but only about one-third of the lecithin occurred at SV concentration of 0.1 mg/ml. These results indicate that electrical excitability in the eel electroplax can be maintained in the presence of extensive phospholipid splitting. Depolarization and block of electrical excitation by relatively high concentrations of SV may have resulted from splitting of phospholipids, especially lecithin, or may have reflected action of lysophosphatide detergents produced as a result of the action of phospholipase A upon membranal phospholipids.

The organophosphates—DFP, phospholine, and Paraoxon, long known to be potent inhibitors of acetylcholine (AcCh)-esterase—have been applied to the monocellular electroplax preparation. The experiments show that the compounds act at high concentrations as inhibitors of the AcCh-receptor. The effects are rapidly reversible. At low concentrations the organophosphates potentiate the action of AcCh. Occasionally they may cause spontaneous depolarizations of the electroplax membrane. These effects are due to the inhibition of AcCh-esterase, since they are rapidly reversed by pyridine-2-aldoxime methiodide, a potent and specific reactivator of phosphorylated enzyme. A reversal takes place also in Ringer's solution, but much more slowly. Ambenonium, a bisquaternary nitrogen derivative and a potent inhibitor of AcCh-esterase, also causes spontaneous depolarizations. It potentiates the action of AcCh, but to a lesser extent than the organophosphates.

Electrical stimulation, either cathodal or anodal, of the monocellular electroplax preparation in Ca-free Ringer's solution results in a sustained depolarization which is determined by the amount of current passed through the cell. The membrane potential recovers only when Ca is added again. These changes take place at the innervated side of the electroplax only. This depolarization of the membrane is pH-dependent; it depolarizes more at pH 6.0 than at pH 9.0. The membrane does not depolarize and the action potential is not blocked within an hour in Ca-free solution unless the cell is stimulated. The sustained depolarization is not prevented or reversed by curare, tetracaine, physostigmine, tetrodotoxin, and tetraethylammonium. After stimulation, the outward K current remains unchanged regardless of whether Ca is present. In contrast, the inward current is dependent on Ca in the outside solution on the innervated membrane; in the absence of Ca following stimulation, the inward K current is decreased. The depolarization by carbamylcholine is reduced in Ca-free and increased in Mgfree Ringer's solution. In contrast to the depolarization induced by electrical stimulation, these carbamylcholine depolarizations may be reversed by washing with Ca-free or Ca- and Mg-free Ringer's solution.

1. A new and improved method has been developed for recording the electrical characteristics of a monocellular electroplax preparation. By means of a switching device, transmembrane potentials across the two faces of the electroplax may be recorded separately; also the transcellular potential may be determined. 2. The depolarizing action of acetylcholine and related compounds is much stronger and more rapid in onset than appeared from previous work. 3. The block of the propagated spike by acetylcholine and related compounds is associated with the simultaneous development of a transcellular potential and a depolarization of the membrane. 4. Earlier results showing competition between tetracaine and carbamylcholine for the acetylcholine receptor have been confirmed.

p -Nitrobenzene diazonium fluoroborate (NDF) is a potent inhibitor of the carbamylcholine-induced depolarization of the electroplax and of acetylcholinesterase. It probably forms covalent bonds with the acetylcholine-receptor and -esterase at the active site of the proteins. Its inhibitory strength is at least the same as that of trimethylammonium diazonium fluoroborate (TDF). The p -acetoxy analog, with its weaker electron-withdrawing group, is about ten times weaker as an inhibitor than the trimethylammonium or p -nitro analogs, both of which have strong electron-withdrawing groups. After treatment of the electroplax preparation with dithiothreitol, NDF remains an irreversible receptor-inhibitor, while TDF becomes a potent reversible receptor-activator. TDF is self-inhibitory: applied before reduction, it no longer depolarizes. Although the first observations on TDF suggested that the compound labels both proteins by virtue of the steric complementary of its trimethylammonium group to a negative subsite in the proteins, the present study indicates that it is the positively charged diazonium group that reacts with the active sites of the proteins to form a covalent bond with an appropriate amino-acid residue.

Electrical characteristics of a monocellular electroplax preparation were recorded with intracellular electrodes. 1. 1.|Acetylcholine, carbamylcholine and neostigmine, activators of the receptor protein, rapidly and reversibly block electrical activity in low concentrations with simultaneous depolarization. Tetracaine, physostigmine, the tertiary analogue of neostigmine and curare, inhibitors of the receptor protein, block electrical activity without depolarizing the membrane. 2. 2.|The cell depolarized by acetylcholine is repolarized by curare even in the presence of acetylcholine. Both compounds act primarily on the synaptic membrane. The response to direct stimulation, as postulated by theory, is restored by curare even in the presence of acetylcholine. 3. 3.|In low concentration, 5·10 −5 M , physostigmine, due to its high affinity to cholinesterase, acts as an enzyme inhibitor. In high concentrations, 5·10 −3 M , physostigmine prevents depolarization due to acetylcholine through its action as a receptor inihibitor. 4. 4.|Tetracaine, in 2.5·10 −5 M , reverses the depolarizing action of acetylcholine 2.5·10 −6 M in the presence of the ester and physostigmine. The response to direct stimulation does not return in contrast to curare. 5. 5.|The depolizing action of carbamylcholine in 5·19 −5 M is also overcome by tetracaine 1·10 −4 M . On increasing the concentration of carbamylcholine to 5·10 −4 M the cell was again depolarized. 6. 6.|Puffer fish poison 7·10 −8 M blocks electrical activity by a non-competitive action without depolarization. Even in ten times higher concentration it does not prevent the depolarizing action of acetylcholine in its minumally active concentration.

The effects of various compounds acting on the acetylcholine-receptor or on the acetylcholine-esterase, or on both in the synaptic membrane of the monocellular electroplax preparation have been analyzed. Additional evidence has been obtained that the active sites of these two components are different. Physostigmine, 5 × 10 −5 M, potentiates the action of acetylcholine (ACh) to its maximal effect. At higher concentrations of physostigmine the action of ACh is antagonized, thus suggesting that the two compounds compete for the active site of the receptor. In the presence of physostigmine, 5 × 10 −5 M, strong spontaneous depolarizations of the membrane are triggered by indirect stimulation of 10 pulses/sec, due apparently to intramembraneous accumulation of ACh. The depolarizing effects of acetyl-, propionyl-, and butyrylcholine are about equally strong, although butyrylcholine is a much poorer substrate of ACh-esterase than the two other esters. Dimethylcarbamate is a more potent receptor activator than monomethylcarbamate. This is in contrast to their strengths as enzyme inhibitors. The depolarizing action of neostigmine has been compared with that of some of its analogs. The potency of these compounds as receptor activators changes in a direction opposite to their strength as inhibitors of ACh-esterase in solution. The d - and l -isomers of acetyl-β-methylcholine do not depolarize the membrane of the electroplax, but act as weak receptor inhibitors. The l -isomer is about 5 times as potent as the d -isomer. The lowest concentration of the d -isomer at which an inhibition of the response to carbamylcholine is observed is 7·5 × 10 −4 M.

Two photochromic activators of the electrogenic membrane of the electroplax of Electrophorus electricus are described. Trans -3,3′-bis[α-(trimethylammonium)methyl]azobenzene dibromide (Bis-Q), one of the most potent ever reported, is active at concentrations of less than 10 -7 M. Its cis isomer, which is obtained from the trans by exposure to light of 330 nm, is practically devoid of activity. Photoregulation of the potential of the membrane takes place in the presence of Bis-Q, presumably because of the conversion of the active trans isomer to the inactive cis isomer in the single-cell electroplax system. The second activator, 3-(α-bromomethyl)-3′-[α-(trimethylammonium)methyl]azobenzene bromide (QBr) can be covalently attached to the electroplax membrane after reduction of the membrane with dithiothreitol. Activation of the membrane is induced by the covalently linked reagent. Its cis isomer, obtained from the trans by exposure to light of 330 nm, is, like cis -Bis-Q, of very low activity. Both isomers of Bis-Q are equally active as inhibitors of acetylcholinesterase, 50% inhibition occurring at a concentration of 10 -5 M. The possibility of using trans -Bis-Q and trans -QBr to characterize and isolate the receptor protein is discussed.

Due to recent improvements of recording techniques the isolated single-electroplax preparation offers a most sensitive and favorable material for studies of structure-activity relationships. Modifications of the nitrogen group of acetylcholine have been analyzed in terms of their effects on the various electrical characteristics. 1. 1. The blocking effect of acetylcholine on the electrical activity is inseparable from its depolarizing action: within 30 sec both resting and action potential, by low concentrations (5·10−6M), are quite markedly reduced. 2. 2. Removal of one methyl group from the nitrogen decreases the potency by a factor of 200, but in all other respects the action is the same as that of acetylcholine. The strong difference in potency can hardly be explained in terms of binding of the methyl group to the protein; it supports the assumption of a change of the protein during the interaction. Removal of the second methyl group decreases the potency by another factor of 25. The effect is, moreover, qualitatively different: depolarization is either small or absent. 3. 3. Replacement of the N by S reduces the potency by a factor of 10, but qualitatively the action seems to be comparable to that of acetylcholine. The As-analogue is still less potent, only 1/25 of that of acetylcholine. Again, there seems no qualitative difference. Substitution of the three methyl groups on the nitrogen by three ethyl groups reduces the potency by a factor of more than 2000. 4. 4. The similarity of the mode of action of acetylcholine and its tertiary analogue is further supported by the similarity of the competitive effects of curare and tetracaine and the noncompetitive effects of clam poison: these effects parallel those obtained previously with acetylcholine and carbamyl choline, except that higher concentrations of the tertiary analogue are required. Both curare and tetracaine which are receptor inhibitors, repolarize the cell. On addition of curare the direct response reappears, but as expected not on the addition of tetracaine.