This study shows that transcranial B-mode sonography seems to be able qualitatively detect vascular WMLs based on MR images with a sensitivity of 91%. The combination of MR images with US images during US examination increases the detection rate of periventricular WMHs on US images in B-Mode since the MR images help to find the lesions with US. The highest sensitivity of WMHs ultrasound detection was shown at the contralateral central part and the contralateral frontal horn of the lateral ventricle and increases with WMH burden.

TCS is a well-established imaging technique in neurology to investigate brain parenchyma in various brain disorders and can complement information from other neuroimaging modalities [20, 21]. Brain CT or MR images superimposed to TCS insonation image show the almost perfect correspondence of anatomic structures intra- and extra-cranially and can aid the ultra-sonographer during the US session. Generally, the advantages of merging two imaging modalities for investigations or surgeries are common in other specialties (e.g., urology, neurosurgery) [22,23,24].

MRI-verified WMHs in periventricular location correspond to sonographic reproducible hyperechogenic structures, like double or blurred lines or hyperechogenic lesions surrounding the wall of lateral ventricles. In case of confluent deep white matter lesions, the brain parenchyma appeared more inhomogeneous in echogenicity with ultrasound in comparison to normal brain parenchyma, where the US image showed a more homogeneous echogenic pattern (Fig. 2). Maybe these change in echogenicity are more often seen on anatomical borderlines between brain parenchyma and lateral ventricle wall, and are more evident in case of WMH pathology. Especially in the control group sometimes we observed small hyperechogenic signals, like white caps, at frontal horns directly on the border of the ventricle wall and brain parenchyma, but thought as artifacts due to their inconstancy in appearance. This observation could be a reason for the low specificity.

US visualization of WMLs based on MRI. The brain lesions seen on MR images correspond on ultrasound (US) images to hyperechogenic signals, double or blurred lines or as inhomogeneous hyperechogenic signal surrounding the wall of the central part, the frontal or dorsal horns of the lateral ventricles. Left: cerebral MR FLAIR image, axial plane. Right: transcranial sonography in B-Mode. a, b: WMLs I, white arrows indicate WML at the anterior horn ipsilateral. c, d WMLs II, white arrows indicate WML at the dorsal horn contralateral. e, f WMLs III, white arrows indicate WML in the deep white matter surrounding the central part contralateral

Several US studies indicated that ionic deposits like iron, copper or manganese lead to hyper-echogenicity in different brain structures in neurodegenerative disorders [25,26,27,28]. Additionally, calcification can lead to an increased echogenicity. Petersen et al. recently reported a decrease of structural connectivity in patients with higher CSVD burden in which the frontal brain regions were prominently affected and hypothesized a disruptive effect on white matter fiber tracts [29]. Increased interstitial water content results in signal changes on MRI, typically on FLAIR and T2WI sequences [30]. Histologically in extensive WMLs decreased density of glial cells and vacuolization are the leading pathological findings, whereas subtle WMLs show a highly variable histopathology [31]. Conceivably, the loss of structural integrity, increased perivascular water content and damaged white matter fibers due to CSVD leading to a change of echogenicity with US. Further, transcranial Doppler sonography (TCD) data pointed out changes in the cerebral perfusion and vascular resistance, linked to microcirculation pathology and small vessel und capillary damage, in patients with VCI without evident dementia significantly associated with WMLs [32]. These changes might display the neurosonological correlates of microcirculatory pathology in patients with WMLs additionally to the TCS imaging findings. Contrary, some hemodynamic studies observed changes in TCD parameters in asymptomatic patients with Fabry´s disease, without any additional vascular risk factors or evident brain MRI lesions [33]. These findings have been considered to use TCD parameters as a screening method for patients at risk for both acute stroke and chronic cerebrovascular disease as well.

In newborn infants ultrasound examination of the brain is a common and reliable method. Correlation of US with MRI images in the detection of WMLs in newborns showed low reliability in subtle WMLs, while the visualization rate of severe and diffuse WMLs in the frontal and periventricular region with cranial US correlates well to hyperechogenic lesions identified on MRI [34,35,36]. These results are consistent with our observations. The highest sensitivity for WMLs US detection and inter-rater agreement was found in the frontal and central periventricular brain areas. At the posterior regions hyperintense artifacts were seen more often, mostly raising from the choroid plexus. UFI was a helpful tool to distinguish hyperechogenic artifacts from WMLs. Furthermore, the number of localizations at the CPi and the DHi is low, due to insufficient insonation angle and unreproducible depiction possibility of anatomical landmarks. Spotty lesions in the deep white matter were not visualizable with UFI as well.

The automatized quantification of echogenicity values from TCS-MRI fusion images in neurodegenerative disorders or of the insula demonstrates a high reliability using B-Mode Assist System [37, 38]. We evaluated US images without any automatized software, but constantly with the same presets. Further automatized imaging analysis should be tested to evaluate if the severity of WMLs burden could be graded with TCS.

This study has some limitations. US is known to be examiner dependent. Missing transtemporal bone window makes US examination impossible (in our study: WMLs group: 19%, control group: 8%). To apply fusion technique during TCS examination correctly, it is crucial to guarantee an almost perfect match to pre-acquired MRI images reproducibly. Therefore, standardized investigation protocols should be used. Due to anatomical variants the dorsal horn ipsi- and contra-laterally was not visualizable constantly in every patient. Also, the choroid plexus causes a hyperechogenic signal at the dorsal horn region, which sometimes makes it harder to visualize WLMs. In fact, the number in these localizations for evaluation is low. Further, the sample size is relatively low, because during the observation time of 3 months, there were no more patients who matched the inclusion criteria for this study.

Moreover, the question arises whether sonographically characteristic hints or patterns can be detected and defined to distinguish between vascular, inflammatory or degenerative white matter lesions with US, which sometimes is not fully differentiable on MR images alone. At this timepoint it is not clear if UFI/TCS is able to differentiate between vascular, demyelinating, metabolic cerebral WMLs. Further studies are necessary and planned to answer this question. The experimental insonation of white matter lesion in multiple sclerosis, performed in a few patients during study time, showed a different appearance on US images in comparison to vascular lesion. So, the hypothesis arises that this method maybe has the potential to differentiate these lesions etiologically.