Objective: To review the use of transcranial Doppler ultrasonography (TCD) and transcranial color-coded sonography (TCCS) for diagnosis. Methods: The authors searched the literature for evidence of 1) if TCD provides useful information in specific clinical settings; 2) if using this information improves clinical decision making, as reflected by improved patient outcomes; and 3) if TCD is preferable to other diagnostic tests in these clinical situations. Results: TCD is of established value in the screening of children aged 2 to 16 years with sickle cell disease for stroke risk (Type A, Class I) and the detection and monitoring of angiographic vasospasm after spontaneous subarachnoid hemorrhage (Type A, Class I to II). TCD and TCCS provide important information and may have value for detection of intracranial steno-occlusive disease (Type B, Class II to III), vasomotor reactivity testing (Type B, Class II to III), detection of cerebral circulatory arrest/brain death (Type A, Class II), monitoring carotid endarterectomy (Type B, Class II to III), monitoring cerebral thrombolysis (Type B, Class II to III), and monitoring coronary artery bypass graft operations (Type B to C, Class II to III). Contrast-enhanced TCD/TCCS can also provide useful information in right-to-left cardiac/extracardiac shunts (Type A, Class II), intracranial occlusive disease (Type B, Class II to IV), and hemorrhagic cerebrovascular disease (Type B, Class II to IV), although other techniques may be preferable in these settings.

https://n.neurology.org/content/neurology/62/9/1468.full.pdf

Assessment: Transcranial Doppler ultrasonography: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

The incidence of subarachnoid haemorrhage (SAH) is 6-8 per 100 000 person years, peaking in the sixth decade. SAH, mostly due to rupture of an intracranial aneurysm, accounts for a quarter of cerebrovascular deaths. Aneurysms increase in frequency with age beyond the third decade, are 1.6 times more common in women and are associated with a number of genetic conditions. Prospective autopsy and angiographic studies indicate that between 3.6 and 6% of the population harbour an intracranial aneurysm. Studies have found an increased rate of SAH in first degree relatives of SAH patients (relative risk 3.7-6.6). In affected families, the most frequent relationship between sufferers is sibling to sibling. The rupture rate of asymptomatic aneurysms was thought to be 1-2% per annum, but the recent International Study of Unruptured Intracranial Aneurysms found that the rupture rate of small aneurysms was only 0.05% per annum in patients with no prior SAH, and 0.5% per annum for large (>10 mm diameter) aneurysms and for all aneurysms in patients with previous SAH. Non-invasive tests such as magnetic resonance angiography (MRA), computed tomographic angiography (CTA) and transcranial Doppler (TCD) have been advocated as alternatives to intra-arterial digital subtraction angiography to screen for aneurysms. Although all are promising techniques, the quality of data testing their accuracy is limited. Overall reported sensitivity for CTA and MRA (TCD is poorer) was 76-98% and specificity was 85-100%, but many subjects had an aneurysm or recent SAH, which could overestimate accuracy. CTA and MRA are much poorer methods for the detection of aneurysms <5 mm diameter, which account for up to one-third of unruptured aneurysms. Elective surgical clipping of asymptomatic aneurysms has a morbidity of 10.9% and mortality of 3. 8%. Treatment of aneurysms by Guglielmi coils, for which there is less long-term follow-up available, has a 4% morbidity and 1% mortality, but only achieves complete aneurysm occlusion in 52-78% of cases. There has been interest in screening for aneurysms, but the indication for, and cost effectiveness of screening are unclear because aneurysm prevalence varies, rupture rate is low, non-invasive imaging tests are not yet accurate enough to exclude small aneurysms and the morbidity and mortality for elective surgical treatment of unruptured aneurysms is high. There may be a limited role for investigation of high risk subgroups. Ideally, screening in such subgroups should be tested in a randomized trial. The avoidance of risk factors for aneurysms such as smoking, hypertension and hypercholesterolaemia should be part of the management of at-risk subjects.

The detection and management of unruptured intracranial aneurysms

The purpose of this study was to investigate the pathologic changes of extracorporeal ablation of human malignant tumors with high-intensity focused ultrasound (HIFU). HIFU treatment was performed in the 164 patients with liver cancer, breast cancer, malignant bone tumor, soft tissue sarcoma and other malignant tumors at focal peak intensities from 5000 W x cm(-2) to 20,000 W x cm(-2), with operating frequencies of 0.8 to 3.2 MHz. To explore the pathologic impact of extracorporeal HIFU, 30 patients with malignant carcinoma underwent surgical removal after HIFU treatment. Pathologic findings showed that the treated tissues demonstrated homogeneous coagulative necrosis with an irreversible tumor cell death and severe damage to tumor blood vessels at the level of microsvasculature within the HIFU-targeted region. Thermolesions to intervening tissue were never observed. The treated region had a sharp border comprising only several cell layers between the treated and untreated areas. The repair of lesions had the processes of necrotic tissue absorption and granulation tissue replacement. It is concluded that extracorporeal treatment of human solid malignancies with HIFU could be safe, effective and feasible. As a noninvasive therapy, HIFU would be used clinically to treat patients with solid malignancies.

Pathological changes in human malignant carcinoma treated with high-intensity focused ultrasound.

Summary Over the past 15 years the use of transcranial B-mode sonography to assess brainstem and subcortical brain structures has become an important tool for the diagnosis and differential diagnosis of various movement disorders. The most widely recognised finding for movement disorders has been an increase in echogenicity of the substantia nigra, an area of the midbrain that is affected in idiopathic Parkinson's disease (PD). This finding has enabled the reliable diagnosis of PD with high predictive values. Other sonographic features, such as hypoechogenicity of the brainstem midline and hyperechogenicity of the lentiform nucleus, might help the differential diagnosis of PD and other movement disorders. This Review provides detailed information about the advantages and limitations of this novel neuroimaging method, including guidelines for the scanning procedure and considerations on the origin of ultrasound abnormalities. We discuss the use of transcranial sonography for early and preclinical diagnosis and for differential diagnosis of PD and other movement disorders, and we compare this method with other functional neuroimaging strategies. Transcranial B-mode sonography is a reliable, non-invasive, commonly available, easily applicable, and inexpensive method, which provides new information about the morphology of the brain to help the diagnosis of various movement disorders. Thus, this neuroimaging method could be recommended for general application in the diagnosis and differential diagnosis of PD.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(08)70239-4.pdf

Transcranial sonography in movement disorders

We investigated the diagnostic potential of transcranial color-coded real-time sonography in 52 individuals using a phased-array ultrasound system with color-coded blood flow representation. Ultrasound scans in the axial and coronal planes were feasible through temporal acoustic bone windows in 49 subjects, enabling depiction of the main parenchymal and vascular structures as well as the ventricular system. Color-coded representation of blood flow in the cerebral vessels allowed unequivocal identification of the circle of Willis within the anatomic black-and-white B-mode image of the parenchymal structures. In Doppler mode, vascular blood flow phenomena may be analyzed semiquantitatively using the Doppler frequency spectrum. This noninvasive, serially applicable, mobile beside method may complement conventional neuroradiologic imaging methods, allowing on-line studies of functional processes within the adult brain.

Transcranial color-coded real-time sonography in adults.

Transcranial color-coded real-time sonography (TCCS) was performed in 57 patients with primary intracranial brain tumors (n = 49) or arteriovenous malformations (n = 8) to evaluate its diagnostic potential. In 46 patients (81%), lesions could be identified employing this technique. In 7 patients, transcranial ultrasound examination was not feasible because of bone thickness; in the remaining 4 patients, the tumor was indistinguishable from adjacent brain tissue despite sufficient insonation, suggesting that these neoplasms are isoechogenic. The sonographic features of brain tumors were very similar: a hyperechogenic matrix of the lesion was interspersed by hypoechogenic pixels. Larger hypoechogenic areas (0.5-1 cm) gave evidence of tumor necrosis. Differences between the findings of TCCS and computed tomography concerning tumor size were found in 7 patients, in whom TCCS revealed an area of smaller extension within the corresponding hypodense area on the computed tomographic scan. Perifocal brain edema could not be detected by ultrasound examination. In 13 patients, a thin, hypoechogenic peritumoral halo was disclosed that did not correlate with perifocal brain edema identified by computed tomography and that may have been due to compression of adjacent parenchyma. In patients with arteriovenous malformations, TCCS permitted the identification of the main feeders, the nidus, and the draining venous system by color-coded depiction of intravascular blood flow. In conclusion, TCCS is an additional method for initial diagnosis and highly suitable for follow-up in tumor patients and provides valuable information about tissue characteristics and blood flow.

Transcranial color-coded real-time sonography in the evaluation of intracranial neoplasms and arteriovenous malformations.

Transcranial color-coded real-time sonography was applied to 20 patients with ischemic stroke and 28 patients with spontaneous intracerebral hemorrhage In all patients the sonographic diagnosis corresponded closely to cranial computed tomography findings Recent hemorrhages were visualized as a hyperechodense mass The high contrast to minor echodense adjacent parenchyma led to a clear sonographic distinction Older clots were characterized by a continuous decrease of echodensity and subsequently were interspersed by hypoechodense zones In the acute stage of ischemic infarction, the vessel occlusion (17/20) and collateral vascular supply (10/20) could be depicted in the color-B-mode in two perpendicular planes and further verified by the Doppler mode Brain edema was not visualized Although in the acute stage no change of echo texture was observed within the infarction, hyperechodense regions (7/11) could be observed in some patients during the time course Complications of intracerebral hemorrhage and ischemic stroke, such as disturbance of cerebrospinal fluid circulation, midline shift, and compression of adjacent territories, were depicted by transcranial color-coded sonography These preliminary results illustrate that transcranial color-coded real-time sonography may be helpful in the early noninvasive differential diagnosis as well as long-term follow-up in patients with cerebrovascular disorders

Differentiation between ischemic and hemorrhagic stroke by transcranial color-coded real-time sonography.

Thirty-six patients with acute spontaneous subarachnoid hemorrhage (26 caused by rupture of an aneurysm) were examined by transcranial color-coded real-time sonography by using a 2.25-MHz ultrasound transducer. In 20 of these 26 patients (76%), the aneurysm could be identified by a characteristic abnormal blood flow pattern within the aneurysm in coronal and axial scanning planes by transcranial color-coded real-time sonography. Blood within the basal cisterns, on top of the tentorium, and within the ventricles and parenchyma was sonographically detected by increased echodensity in 75%. In addition, cerebrospinal fluid circulation disturbances and cerebral vasospasm were detected in two-dimensional B-mode images in 85% and 100%, respectively. In Doppler mode, intravascular blood flow velocity could be quantified. We conclude that transcranial color-coded real-time sonography, a new, noninvasive method for diagnosis and follow-up of patients with subarachnoid hemorrhage, allows detection of the primary vascular lesion and monitoring of complications.

Diagnosis and monitoring of subarachnoid hemorrhage by transcranial color-coded real-time sonography.

The cell lines of three neuroectodermal tumors, two glioblastomas (HTZ-146, HTZ-17) and one melanoma (HTZ-19) were established and screened for the expression of growth factors by northern blotting and immunochemical methods. All three tumors were positive for platelet-derived growth factor- (PDGF-) A-, -B-chain, and basic fibroblast growth factor (bFGF) messenger ribonucleic acids. Cultured cells as well as original tumor material were also positive for PDGF-AA-, PDGF-BB, and bFGF protein, as shown by immunochemistry. To investigate the possible pathophysiological role of PDGF and bFGF, antisense technology was employed with chemically modified nuclease-stable 14-mer phosphorothioate oligodeoxynucleotides. Proliferation of all three tumors was reduced to a different extent with antisense phosphorothioate oligodeoxynucleotides in vitro, targeted against PDGF-A-chain-, -B-chain-, and -bFGF-messenger ribonucleic acid. These data indicate autocrine stimulatory loops for PDGF and bFGF, which may be blocked, may have different relevance in neuroectodermal tumors in vitro, and may have conceivable future therapeutic implications.

Autocrine growth regulation in neuroectodermal tumors as detected with oligodeoxynucleotide antisense molecules.

Transcranial color-coded real-time sonography (TCCS) is a new diagnostic method allowing the non-invasive imaging of parenchymal and vascular structures of the adult brain through the intact skull. A description of the sonographic findings in two patients presenting with a radiologically ascertained arterio-venous malformation is provided. The AVM's can be depicted in the two-dimensional B-mode image as echodense areas interspersed with zones of lower echodensity. Their extension correlated with corresponding MRI images. The color-coded illustration of intravascular flow phenomena allowed the distinct identification of the major afferent feeding vessels, the venous drainage and of the vascular convolution of both AVM's. Information on hemodynamics, as e.g. the blood supply of the angioma by the contralateral internal carotid artery, are obtained by color-coded identification of intravascular flow direction including analysis of the Doppler frequency spectrrum. All findings obtained by TCCS complied with those established by angiography. We conclude, that TCCS is a suitable method for early diagnosis and long term follow up of cerebral AVM's.

J. Winkler

Papers

Transcranial color-coded real-time sonography in the evaluation of intracranial neoplasms and arteriovenous malformations.

Differentiation between ischemic and hemorrhagic stroke by transcranial color-coded real-time sonography.

Diagnosis and monitoring of subarachnoid hemorrhage by transcranial color-coded real-time sonography.

Autocrine growth regulation in neuroectodermal tumors as detected with oligodeoxynucleotide antisense molecules.

Imaging of cerebral arterio-venous malformations by transcranial colour-coded real-time sonography