The classical ultrasound modalities used nowadays in clinical routine for imaging of the brain and its vasculature were pioneered in the 1960s (B-mode) and 1980s (color Doppler) [1]
[2]
[3]
[4]
[5]
[6]
[7], however, became part of clinical standard recommendations and guidelines not before the late 1990s [8]
[9]
[10]
[11]
[12]. An important reason for the delay in transferring transcranial B-mode sonography (TCS) and transcranial color-coded duplex sonography (TCCS) into clinical routine was the competition with the in-parallel evolving CT and MRI techniques that enable complete brain and (static) vasculature scans in short time and highly reproducible manner, unlike transcranial ultrasound [13]. The limitation of ultrasound image quality by the cranial bone accounted for the relatively long dominance of one-dimensional echo-encephalography (A-scan) over two-dimensional (B-mode) scan, and of conventional transcranial Doppler sonography over TCCS, despite their early availability and comparative evaluation [14]
[15]
[16]. This is different in infants in whom the intracranial structures can be visualized ultrasonically with high image resolution through open fontanelles, allowing even for the assessment of cerebral cortex and bridging veins as is elegantly demonstrated using a 14-MHz transducer in the case reported by K.H. Deeg in the present issue of Ultraschall in der Medizin
[17]. Also, cranial bone surface can well be assessed with high-frequency ultrasound, as is nicely shown using a 11-MHz transducer in the study of Pogliani et al. (this issue) [18]. Transcranial sonography, however, requires lower ultrasound frequencies of around 2.5 MHz in adolescents and adults to penetrate the bone which limits image resolution. Despite this drawback, image resolution on TCS reached a remarkable level already in the 2000s thanks to technological advances, allowing for relatively high resolution of echogenic deep brain structures in the focal zone of transducer [19]. The recent boom of therapeutic transcranial focused ultrasound (tFUS), applied e. g. for the treatment of essential tremor, has boosted the efforts in individualized optimization of transcranial ultrasound penetration which may also benefit the diagnostic TCS and TCCS technologies in near future [20].
Using the “old” B-mode and color Doppler techniques, continuously refined through technological progress, many clinical routine questions can be answered today, and still novel and trend-setting findings are made. This is underpinned in several articles in the present issue of Ultraschall in der Medizin. The current standard applications of TCCS in clinical neurology and neuro-intensive care are concisely presented in the CME article of Gröschel et al. (this issue) [21]. Pinto et al. (this issue) investigated the clinical relevance of TCCS in the detection of intracranial vasospasms in patients with posterior reversible encephalopathy syndrome and/or reversible cerebral vasoconstriction syndrome [22]. These diseases share pathophysiological mechanisms and may co-occur, however the knowledge on outcome-related factors is still limited. Pinto and co-workers demonstrate that TCCS-detected intracranial vasospasms are clearly related to a worse outcome in these entities [22]. K.H. Deeg (this issue) presents the diagnostic potential of high-resolution trans-fontanellar ultrasound in shaken baby syndrome [17]. In the study of Kozel et al. (this issue) classical diagnostic TCS of deep brain structures is combined with the recent technology of real-time fusion imaging of the brain, allowing here for the accurate detection and digitized echogenicity quantification of caudate and lenticular nucleus in patients with Huntington’s disease [23]. With this, the authors were able to prove and quantify the increase of basal ganglia hyperechogenicity in this progressive disease, reported in earlier studies only as a visually rated semi-quantitative finding. Their findings may open the door to a refined TCS-based disease monitoring in Huntington’s disease.
What about the transfer of newer brain ultrasound technologies into clinical standard application?
Contrast-enhanced ultrasound (CEUS) has been first applied in humans in the 1980s to improve assessment of vessels and parenchyma [24]
[25] ([Table 1]). Shortly after invention of the first specifically designed ultrasound contrast agent with stability during pulmonary transit, Bogdahn et al. (1993) investigated contrast-enhanced TCCS and demonstrated marked improvement of intracranial vessel visualization [25]. However, despite the many subsequent studies in the field of neurovascular medicine (reviewed in [26]), CEUS is nowadays only occasionally used in neurosonology, mostly for the assessment of intracranial vessels if the transcranial bone window is insufficient. The under-usage is caused on the one hand by the broad availability of CT- and MR-angiography, and on the other hand by the restricted availability of well-trained specialists who are familiar with using transcranial CEUS. This might change if ongoing studies can prove the value of CEUS for detecting acute large intracranial vessel occlusion in the pre-hospital emergency care setting [27]. Nevertheless, CEUS-TCCS was early included in a guideline on neurovascular imaging [10], and a special indication, i. e. the proof of cerebral circulatory arrest [28], made the way into a guideline in 2015 [29]. The application of CEUS to visualize vessels (e. g. vascular malformations, arterial aneurysms) during open brain surgery has been described by Prada et al. (2015) [30], however is still at an experimental stage. CEUS of brain parenchyma using low-mechanical index contrast-harmonic imaging, first reported by Postert et al. (1998) [31], has been evaluated in adults mainly for the transcranial assessment of acute ischemic stroke lesions and brain tumors [32]
[33]. Because of the limitation to usually one imaging plane, this technique has not reached the clinical routine application in neurology, and its potential in the emergency stroke management remains to be proven [34]. Also, CEUS of brain parenchyma in open-brain surgery and trans-fontanellar CEUS, both introduced in the past decade, are far from being routinely used [35]
[36]
[37]. Three-dimensional ultrasound surface rendering, established in the 1990s in clinical medicine [38], has been first used for trans-fontanellar brain imaging in 2007 [39]. A 3D transcranial brain surface rendering method using an 1–8 MHz abdominal volumetric transducer, applied in fetuses prenatally, recently allowed for excellent display of brain sulci and gyri [40], and could potentially be usable also in children and adults. This might enable, for example, the quantification and monitoring of temporal lobe atrophy in Alzheimer dementia, which is currently only indirectly possible with ultrasound [41]. Real-time ultrasound fusion imaging is another example of a novel technology, invented for brain imaging in the 2000s [42]
[43], which is still performed clinically with hesitation and mainly employed in the neurosurgery setting [44]
[45]. Reasons for this are (i) the ongoing need of improvement of the image fusion technology, which currently requires visual-manual fine tuning in high-precision applications [46], that should aim at a more precise automatic image fusion and the correction for imaging artifacts [45], and (ii) the shortage of operators trained with this new imaging technology. Also, relevant indications in clinical neurology and neuropediatrics are to be established for this new modality. Shear wave elastography (SWE) has been used in clinical medicine since the 2000s [47]. Chan et al. (2014) reported the first clinical application of cerebral two-dimensional SWE (2D-SWE) during open brain surgery, to detect an MRI-negative epileptogenic brain lesion [48]. Subsequently the results of a first prospective study were published demonstrating the use of SWE to differentiate healthy brain tissue from tumor tissue in open brain surgery [49]. First trans-fontanellar applications in neonates for the assessment of altered brain stiffness associated with hydrocephalus or prematurity were published in 2017 [50]
[51]. Still, however, biological safety aspects need to be assessed in studies before routine application in neonates and infants is considered [52]. If 2D-SWE is used in neonates, scan time should be carefully monitored and kept at a minimum [53]. More recently, SWE reference data have been reported for transcranial 2D-SWE of the brain in healthy adults at various ages [54]. The same group was able to show that transcranial SWE may discriminate between brain hematoma and brain infarction 1–2 days after the insult [55]. However, there is still a need of methodological standardization, and the elucidation of dynamic changes of brain elasticity [56]. Once safety and methodological issues are better defined, prospective investigations are desired demonstrating the predictive value of this brain imaging modality in investigator-blinded studies, e. g. on imaging-naïve patients with hyper-acute stroke. Advanced microvascular imaging (AMI) is a recently introduced new ultrasound imaging modality which allows the superior detection of low-velocity flow with high resolution and high frame rates [57]. First application of AMI in open brain tumor surgery was reported by Ishikawa et al. (2017) [58], and subsequently trans-fontanellar brain AMI by Goeral et al. (2019) [59]. So far, there are no reports of transcranial AMI.
Table 1
Timeline of establishment of ultrasound technologies for brain and intracranial vessel imaging.
|
Ultrasound imaging modality
|
Application In humans (any clinical)
|
Transfontanellar or open-skull imaging
|
Transcranial imaging (postnatal)
|
Clinical standard (guideline-listed transcranial imaging)
|
Reasons for delay
|
|
B-mode
|
1960s
|
1975 [2]
|
1960s [1]
|
2002 [9]
1
|
C, T
|
|
2013 [12]
2
|
C, R
|
|
Color Doppler
|
1980s
|
1988 [4]
|
1988 [4]
|
2004 [10]
3
|
C
|
|
CEUS-angiography
|
1980s
|
2015 [33]
|
1993 [25]
|
2004 [10]
3
|
C
|
|
2015 [29]
4
|
C, E
|
|
CEUS-parenchyma
|
1980s
|
2014 [35]
|
1998 [34]
|
–
|
C, R
|
|
3D surface rendering
|
1990s
|
2007 [39]
|
–
|
–
|
C, I
|
|
RT fusion imaging
|
2000s
|
2003 [42]
|
2011 [43]
|
–
|
T, R, (I)
|
|
SW elastography
|
2000s
|
2014 [48]
|
2018 [54]
|
–
|
C, I, S
|
|
AMI
|
2010s
|
2017 [58]
|
–
|
–
|
E
|
AMI = advanced microvascular imaging; C = concurrence of other neuroimaging modalities (for details, see text); CEUS = contrast-enhanced ultrasound; E = missing/late evaluation; I = missing clinical indication; T = technological immaturity in the first years; R = limited resources (qualified sonographers, time resources), RT = real time; S = safety concerns; SW = shear wave
1 transcranial B-mode sonography (TCS) implicitly recommended with reference to studies applying transtemporal scan of neonatal brain
2 the first guideline recommendation of transcranial B-mode sonography (TCS) in adults (diagnosis of Parkinson’s disease)
3 the first guideline recommendation of transcranial color-coded sonography (TCCS) and CEUS-TCCS (evaluation and monitoring of patients with ischemic cerebrovascular disease)
4 guideline-recommended CEUS-TCCS (optional) in the diagnosis of cerebral circulatory arrest
How can the time between the introduction of new ultrasonic brain imaging modalities and their inclusion in clinical guidelines be shortened?
Helpful would surely be a higher number of well designed, prospective multi-center studies proving the advantages of innovative ultrasonic imaging with respect to costs and patients outcome. To promote this, the European Society of Neurosonology and Cerebral Hemodynamics (ESNCH) and the European Academy of Neurology (EAN) started several years ago a joint initiative of certification of European Reference Centers in Neurosonology (ERcNsono). The results of a first ERcNsono project have been reported recently [60]. In the coming years multi-center studies are being expected to be coordinated in this collaborative network. Efforts to educate and train students and physicians in performing ultrasound should also be enhanced. The ESNCH has recently collected and analyzed the data of a multi-national survey on education, training, practice requirements, and fields of application of neurosonology (Barracchini et al., submitted for publication). The results may help in further international harmonization and improvement of neurosonology training. And of course, every one of the experienced sonographers should keep on with personally sharing her/his enthusiasm, knowledge and practice with physician trainees!
