Brain White Matter Involvement in Hereditary Spastic Paraplegias: Analysis with Multiple Diffusion Tensor Indices

BACKGROUND AND PURPOSE:The hereditary spastic paraplegias are a group of genetically heterogeneous neurodegenerative disorders, characterized by progressive spasticity and weakness of the lower limbs. Although conventional brain MR imaging findings are normal in patients with pure hereditary spastic paraplegia, microstructural alteration in the cerebral WM can be revealed with DTI. Concomitant investigation of multiple intrinsic diffusivities may shed light on the neurobiologic substrate of the WM degeneration pattern in patients with pure hereditary spastic paraplegia across the whole brain.MATERIALS AND METHODS:Tract-based spatial statistics analysis was performed to compare fractional anisotropy and mean, axial, and radial diffusivities of the WM skeleton in a group of 12 patients with pure hereditary spastic paraplegia and 12 healthy volunteers. Data were analyzed counting age and sex as nuisance covariates. The threshold-free cluster-enhancement option was applied, and the family-wise error rate was controlled by using permutation tests for nonparametric statistics.RESULTS:In pure hereditary spastic paraplegia, group widespread fractional anisotropy decreases and radial diffusivity and mean diffusivity increases (P < .05, corrected) were found. No voxelwise difference was observed for the axial diffusivity map. Percentage of voxels within the WM skeleton that passed the significance threshold were 51%, 41.6%, and 11.9%, respectively, for radial diffusivity, fractional anisotropy, and mean diffusivity clusters. An anteroposterior pattern with preferential decrease of fractional anisotropy in the frontal circuitry was detected.CONCLUSIONS:In patients with pure hereditary spastic paraplegia, alterations in multiple DTI indices were found. Radial diffusivity seems more sensitive to hereditary spastic paraplegia–related WM pathology and, in line with the lack of axial diffusivity changes, might indicate a widespread loss of myelin integrity. A decrease of fractional anisotropy alone in the frontal circuitry may reflect subtle disruption of the frontal connections.

The hereditary spastic paraplegias (HSPs), also called familial spastic paraparesis or Strümpell-Lorrain disease, represent a genetically and clinically heterogeneous group of neurodegenerative disorders.¹ The main clinical feature is progressive spasticity due to slowly progressing “dying back” axonal degeneration, which is maximal in the terminal portions of the longest descending and ascending tracts.² On the basis of clinical symptoms, HSPs are classified into pure or uncomplicated, in which the spastic paraplegia is the major clinical manifestation; and complex or complicated forms, presenting with additional neurologic signs, such as intellectual disability or cognitive decline, deafness, cerebellar ataxia, epilepsy, dysarthria, peripheral neuropathy, optic atrophy, and visual dysfunction.³ Autosomal dominant, autosomal recessive, or X-linked inheritance is associated with multiple genes or loci and leads to genetic heterogeneity of this disorder. The HSP loci are designated as spastic paraplegia loci and are numbered 1–56 according to their discovery.⁴ There is scarce evidence about the epidemiology of HSP, though its prevalence is estimated at 1.27:100,000 population in Europe.⁵Findings of conventional MR imaging of the brain are usually normal in pure hereditary spastic paraplegia (pHSP). In contrast, nonspecific findings such as cortical atrophy and subcortical and periventricular WM alterations are present in complicated HSP.⁶ Distinct MR imaging findings may accompany complicated HSP; for instance, a common form of autosomal recessive HSP with SPG11 mutation (linked to the 15q13-q15 chromosome) is frequently associated with a thin corpus callosum.⁷ Optic nerve and cerebellar atrophy may be revealed when visual symptoms and cerebellar ataxia are present.⁸DTI is an efficient technique used to characterize the in vivo microstructural organization of the WM.⁹ The common DTI indices are fractional anisotropy (FA) (sensitive to microstructural changes and associated with the presence of oriented structures in tissue) and mean diffusivity (MD) (characterizes mean-square displacement of molecules and the overall presence of obstacles to diffusion).¹⁰ Other indices, axial diffusivity (AD) and radial diffusivity (RD), offer suggestive elements to differentiate axonal injury and demyelination.¹¹ To extend our knowledge of the neurobiologic basis of WM pathology, using multiple diffusivity matrices (FA, MD, RD, and AD) is recommended.¹²The present study was set up to investigate WM alterations across the whole brain in a group of patients with pHSP with SPG4, SPG5, SPG3a, and SPG10 mutations, applying tract-based spatial statistics (TBSS) analysis with multiple DTI indices.     

Microstructural Tissue Changes in Alzheimer Disease Brains: Insights from Magnetization Transfer Imaging

BACKGROUND AND PURPOSE:Reductions in magnetization transfer ratio have been associated with brain microstructural damage. We aim to compare magnetization transfer ratio in global and regional GM and WM between individuals with Alzheimer disease and healthy control participants to analyze the relationship between magnetization transfer ratio and cognitive functioning in Alzheimer disease.MATERIALS AND METHODS:In this prospective study, participants with Alzheimer disease and a group of age-matched healthy control participants underwent clinical examinations and 3T MR imaging. Magnetization transfer ratios were determined in the cortex, AD-signature regions, normal-appearing WM, and WM hyperintensities.RESULTS:Seventy-seven study participants (mean age ± SD, 72 ± 8 years; 47 female) and 77 age-matched healthy control participants (mean age ± SD, 72 ± 8 years; 44 female) were evaluated. Magnetization transfer ratio values were lower in patients with Alzheimer disease than in healthy control participants in all investigated regions. When adjusting for atrophy and extent of WM hyperintensities, significant differences were seen in the global cortex (OR = 0.47; 95% CI: 0.22, 0.97; P = .04), in Alzheimer disease–signature regions (OR = 0.31; 95% CI: 0.14, 0.67; P = .003), in normal-appearing WM (OR = 0.59; 95% CI: 0.39, 0.88; P = .01), and in WM hyperintensities (OR = 0.18; 95% CI: 0.09, 0.33; P ≤ .001). The magnetization transfer ratio in these regions was an independent determinant of AD. When correcting for atrophy and WM hyperintensity extent, lower GM magnetization transfer ratios were associated with poorer global cognition, language function, and constructional praxis.CONCLUSIONS:Alzheimer disease is associated with magnetization transfer ratio reductions in GM and WM regions of the brain. Lower magnetization transfer ratios in the entire cortex and AD-signature regions contribute to cognitive impairment independent of brain atrophy and WM damage.

Alzheimer disease (AD) represents the most common cause of dementia. Only a few neuroimaging biomarkers have been approved for clinical use, and most are still objects of research.¹ Although structural MR imaging contributes to the exclusion of other possible causes of a dementia syndrome, brain atrophy measures have only modest sensitivity and specificity for the differential diagnosis of dementia.² The role of MR imaging techniques that allow assessment of microstructural brain changes, such as DTI and magnetization transfer imaging (MTI) for detecting AD-related tissue abnormalities, is still widely unknown. Numerous DTI studies have reported loss of WM integrity in AD and related this to tau accumulation in AD-specific regions.³ Only a few studies used MTI to explore microstructural tissue abnormalities in AD.The magnetization transfer ratio (MTR), which can be derived from MTI, has been shown to be associated with axonal attenuation and myelin content.^4-6 In patients with AD, MTR reductions were reported in the whole-brain analyses,^7-9 cortical GM,^8,10 global WM,¹⁰ hippocampus,^7,11,12 and temporal lobes.⁸ In a longitudinal study of our own group, patients with AD had significantly lower global MTR values than control participants. MTR declined significantly over a follow-up period of 12 months and was paralleled by a brain tissue loss of 2.2% per year.¹³ So far, only a few studies have explored the association between regional MTR changes and cognition in patients with AD. Van der Flier et al⁹ reported a strong association between whole-brain MTR and global cognitive deterioration in patients with AD, but there was no significant relationship between regional MTR reductions and domain-specific cognitive impairment. In our previous study, we observed direct associations between MTR and Mini-Mental State Examination (MMSE) scores for the hippocampus, putamen, and thalamus. The relationship was stronger in the left than in the right hemisphere.¹³Here we extend previous work by assessing the role of MTR reductions in the GM and WM in distinguishing patients with mild to moderate AD from healthy control participants, and we investigate their associations with cognitive decline independent of atrophy and WM damage.     

Traumatic Cerebral Microbleeds in the Subacute Phase Are Practical and Early Predictors of Abnormality of the Normal-Appearing White Matter in the Chronic Phase

BACKGROUND AND PURPOSE:In the chronic phase after traumatic brain injury, DTI findings reflect WM integrity. DTI interpretation in the subacute phase is less straightforward. Microbleed evaluation with SWI is straightforward in both phases. We evaluated whether the microbleed concentration in the subacute phase is associated with the integrity of normal-appearing WM in the chronic phase.MATERIALS AND METHODS:Sixty of 211 consecutive patients 18 years of age or older admitted to our emergency department ≤24 hours after moderate to severe traumatic brain injury matched the selection criteria. Standardized 3T SWI, DTI, and T1WI were obtained 3 and 26 weeks after traumatic brain injury in 31 patients and 24 healthy volunteers. At baseline, microbleed concentrations were calculated. At follow-up, mean diffusivity (MD) was calculated in the normal-appearing WM in reference to the healthy volunteers (MD_z). Through linear regression, we evaluated the relation between microbleed concentration and MD_z in predefined structures.RESULTS:In the cerebral hemispheres, MD_z at follow-up was independently associated with the microbleed concentration at baseline (left: B = 38.4 [95% CI 7.5–69.3], P = .017; right: B = 26.3 [95% CI 5.7–47.0], P = .014). No such relation was demonstrated in the central brain. MD_z in the corpus callosum was independently associated with the microbleed concentration in the structures connected by WM tracts running through the corpus callosum (B = 20.0 [95% CI 24.8–75.2], P < .000). MD_z in the central brain was independently associated with the microbleed concentration in the cerebral hemispheres (B = 25.7 [95% CI 3.9–47.5], P = .023).CONCLUSIONS:SWI-assessed microbleeds in the subacute phase are associated with DTI-based WM integrity in the chronic phase. These associations are found both within regions and between functionally connected regions.

The yearly incidence of traumatic brain injury (TBI) is around 300 per 100,000 persons.^1,2 Almost three-quarters of patients with moderate to severe TBI have traumatic axonal injury (TAI).³ TAI is a major predictor of functional outcome,^4,5 but it is mostly invisible on CT and conventional MR imaging.^6,7DTI provides direct information on WM integrity and axonal injury.^5,8 However, DTI abnormalities are neither specific for TAI nor stable over time. Possibly because of the release of mass effect and edema and resorption of blood products, the effects of concomitant (non-TAI) injury on DTI are larger in the subacute than in the chronic phase (>3 months).^4,9,10 Therefore, DTI findings are expected to reflect TAI more specifically in the chronic than in the subacute phase (1 week–3 months).⁴ Even in regions without concomitant injury, the effects of TAI on DTI are dynamic, possibly caused by degeneration and neuroplastic changes.^6,11,12 These ongoing pathophysiological processes possibly contribute to the emerging evidence that DTI findings in the chronic phase are most closely associated with the eventual functional outcome.^12,13Although DTI provides valuable information, its acquisition, postprocessing, and interpretation in individual patients are demanding. SWI, with which microbleeds can be assessed with high sensitivity, is easier to interpret and implement in clinical practice. In contrast to DTI, SWI-detected traumatic microbleeds are more stable¹ except in the hyperacute^14,15 and the late chronic phases.¹⁶ Traumatic cerebral microbleeds are commonly interpreted as signs of TAI. However, the relation is not straightforward. On the one hand, nontraumatic microbleeds may be pre-existing. On the other hand, even if traumatic in origin, microbleeds represent traumatic vascular rather than axonal injury.¹⁷ Indeed, TAI is not invariably hemorrhagic.¹⁸ Additionally, microbleeds may secondarily develop after trauma through mechanisms unrelated to axonal injury, such as secondary ischemia.¹⁸DTI is not only affected by pathophysiological changes but also by susceptibility.¹⁹ The important susceptibility-effect generated by microbleeds renders the interpretation of DTI findings at the location of microbleeds complex. In the chronic phase, mean diffusivity (MD) is the most robust marker of WM integrity.^4,6 For these reasons, we evaluated MD in the normal-appearing WM.Much TAI research focuses on the corpus callosum because it is commonly involved in TAI^5,18,20 and it can reliably be evaluated with DTI,^5,21 and TAI in the corpus callosum is related to clinical prognosis.^6,20 The corpus callosum consists of densely packed WM tracts that structurally and functionally connect left- and right-sided brain structures.²² The integrity of the corpus callosum is associated with the integrity of the brain structures it connects.²³ Therefore, microbleeds in brain structures that are connected through the corpus callosum may affect callosal DTI findings. Analogous to this, microbleeds in the cerebral hemispheres, which exert their function through WM tracts traveling through the deep brain structures and brain stem,^24,25 may affect DTI findings in the WM of the latter.Our purpose was to evaluate whether the microbleed concentration in the subacute phase is associated with the integrity of normal-appearing WM in the chronic phase. We investigated this relation within the cerebral hemispheres and the central brain and between regions that are functionally connected by WM tracts.     

NAA is a Marker of Disability in Secondary-Progressive MS: A Proton MR Spectroscopic Imaging Study

BACKGROUND AND PURPOSE:The secondary progressive phase of multiple sclerosis is characterised by disability progression due to processes that lead to neurodegeneration. Surrogate markers such as those derived from MRI are beneficial in understanding the pathophysiology that drives disease progression and its relationship to clinical disability. We undertook a 1H-MRS imaging study in a large secondary progressive MS (SPMS) cohort, to examine whether metabolic markers of brain injury are associated with measures of disability, both physical and cognitive.MATERIALS AND METHODS:A cross-sectional analysis of individuals with secondary-progressive MS was performed in 119 participants. They underwent ¹H-MR spectroscopy to obtain estimated concentrations and ratios to total Cr for total NAA, mIns, Glx, and total Cho in normal-appearing WM and GM. Clinical outcome measures chosen were the following: Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Nine-Hole Peg Test, Timed 25-foot Walk Test, and the Expanded Disability Status Scale. The relationship between these neurometabolites and clinical disability measures was initially examined using Spearman rank correlations. Significant associations were then further analyzed in multiple regression models adjusting for age, sex, disease duration, T2 lesion load, normalized brain volume, and occurrence of relapses in 2 years preceding study entry.RESULTS:Significant associations, which were then confirmed by multiple linear regression, were found in normal-appearing WM for total NAA (tNAA)/total Cr (tCr) and the Nine-Hole Peg Test (ρ = 0.23; 95% CI, 0.06–0.40); tNAA and tNAA/tCr and the Paced Auditory Serial Addition Test (ρ = 0.21; 95% CI, 0.03–0.38) (ρ = 0.19; 95% CI, 0.01–0.36); mIns/tCr and the Paced Auditory Serial Addition Test, (ρ = −0.23; 95% CI, −0.39 to −0.05); and in GM for tCho and the Paced Auditory Serial Addition Test (ρ = −0.24; 95% CI, −0.40 to −0.06). No other GM or normal-appearing WM relationships were found with any metabolite, with associations found during initial correlation testing losing significance after multiple linear regression analysis.CONCLUSIONS:This study suggests that metabolic markers of neuroaxonal integrity and astrogliosis in normal-appearing WM and membrane turnover in GM may act as markers of disability in secondary-progressive MS.

Secondary-progressive MS (SPMS) is the dominant progressive form of multiple sclerosis that is characterized by accumulating disability due to a variety of neurodegenerative processes.¹ These include microglial activation with subsequent formation of reactive oxygen species inducing mitochondrial damage, sodium channel dysfunction leading to histotoxic hypoxia and axonal energy failure, and glutaminergic excitotoxicity.^2-4Surrogate markers of brain injury are valuable in improving our understanding of the pathophysiology driving clinical disability in progressive forms of MS (PMS). Surrogate imaging-based markers such as MR imaging–based lesional and atrophy metrics can identify existing inflammatory injury and axonal loss and provide adjunctive prognostic information. Yet existing imaging based–measures are relatively limited in their ability to demonstrate metabolic or microstructural changes and show only a modest association with clinical disability outcomes in PMS.⁵ This is where advanced nonstructural MR imaging techniques such as ¹H-MR spectroscopy are attractive to further understand this neuropathology and its association with clinical disability in progressive forms of MS.By means of ¹H-MR spectroscopy, neurometabolites of interest in MS include the following: N-acetylaspartate plus N-acetylaspartylglutamate (total NAA = tNAA), a marker of neuroaxonal integrity and mitochondrial function;^6,7 Glx, the sum of the excitatory neurotransmitter glutamate and its precursor glutamine;⁴ myo-inositol (mIns), a marker of glial cell activity, most likely astrogliosis; and total choline (tCho = glycerophosphocholine and phosphocholine), a marker of membrane turnover.^7,8 Many studies have demonstrated decreases in tNAA and tNAA/tCr and increases in total creatine (tCr = creatine and phosphocreatine) and inositol in normal-appearing white matter (NAWM) and GM in SPMS.⁹ In a recent meta-analysis of ¹H-MR spectroscopy studies, effect sizes for a reduction in NAA and NAA/Cr were larger in PMS compared with relapsing-remitting MS.⁹ There have been conflicting results from studies examining disability associations in PMS: Several studies showed no association between metabolites (NAA, Glx, mIns, tCho) and the Expanded Disability Status Scale score (EDSS),^10-13 while others showed moderate associations with EDSS, the Nine-Hole Peg Test (9HPT), and the Timed 25-foot Walk Test (T25-FW) in cortical GM and NAWM.^14-16 Of the studies examining cognitive performance (including information processing speed [IPS]) in PMS, no associations were found in sample sizes ranging from 14 to 31, with only 2 of these studies containing pure SPMS cohorts.^13,14,16-18The rationale for this cross-sectional study was to further define metabolite levels and their associations with disability in a much larger sample of individuals with SPMS than has been achieved before.     

Inversion Recovery Ultrashort TE MR Imaging of Myelin is Significantly Correlated with Disability in Patients with Multiple Sclerosis

BACKGROUND AND PURPOSE:MR imaging has been widely used for the noninvasive evaluation of MS. Although clinical MR imaging sequences are highly effective in showing focal macroscopic tissue abnormalities in the brains of patients with MS, they are not specific to myelin and correlate poorly with disability. We investigated direct imaging of myelin using a 2D adiabatic inversion recovery ultrashort TE sequence to determine its value in assessing disability in MS.MATERIALS AND METHODS:The 2D inversion recovery ultrashort TE sequence was evaluated in 14 healthy volunteers and 31 patients with MS. MPRAGE and T2-FLAIR images were acquired for comparison. Advanced Normalization Tools were used to correlate inversion recovery ultrashort TE, MPRAGE, and T2-FLAIR images with disability assessed by the Expanded Disability Status Scale.RESULTS:Weak correlations were observed between normal-appearing white matter volume (R = –0.03, P = .88), lesion load (R = 0.22, P = .24), and age (R = 0.14, P = .44), and disability. The MPRAGE signal in normal-appearing white matter showed a weak correlation with age (R = –0.10, P = .49) and disability (R = –0.19, P = .31). The T2-FLAIR signal in normal-appearing white matter showed a weak correlation with age (R = 0.01, P = .93) and disability (R = 0.13, P = .49). The inversion recovery ultrashort TE signal was significantly negatively correlated with age (R = –0.38, P = .009) and disability (R = –0.44; P = .01).CONCLUSIONS:Direct imaging of myelin correlates with disability in patients with MS better than indirect imaging of long-T2 water in WM using conventional clinical sequences.

MS is the most common demyelinating disease of the brain.¹ Demyelination affects many aspects of neurologic function, including speech, balance, and cognitive awareness. Across time, this frequently leads to severe and irreversible clinical disability. MR imaging has been widely used for accurate diagnosis of MS, with current techniques focused on imaging the long-T2 water components in WM and GM.^2-4 MS lesions often appear hypointense with T1-weighted gradient recalled-echo sequences² and hyperintense with T2-weighted FSE and T2-weighted FLAIR sequences.³ Active lesions can be highlighted with gadolinium-enhanced imaging.⁴ The magnetization transfer ratio has been used as an indirect marker of myelin disorder in regions of normal-appearing WM (NAWM).⁵ There are also several other advanced imaging techniques for indirect myelin imaging via assessment of myelin water, such as multicomponent T2 or T2* analysis^6,7 and direct visualization of components with short transverse relaxation times.^8,9While conventional MR imaging sequences are highly effective in detecting focal macroscopic brain tissue abnormalities, they are not specific for pathologic substrates of MS lesions such as demyelination and remyelination, and they may not correlate well with patients'' neurologic deficits. Current MR imaging techniques correlate only modestly with disability assessed by the Expanded Disability Status Scale (EDSS).^10-15 The total lesion load showed statistically significant-but-weak correlations with the EDSS score in several large-scale studies (R = 0.1–0.3).^10-12 Composite scores including relaxation times of different tissues and/or volumetric measures generally correlate more strongly with the EDSS score, with a maximum observed correlation of R = 0.34 (P < .001).¹³ Lesions seen with gadolinium-enhanced imaging are only moderately correlated with disability in the first 6 months and are not predictive of changes in the EDSS score in the subsequent 1 or 2 years.¹⁴ A large-scale multicenter study reported very limited correlation between the EDSS score and normalized brain volume (R = –0.18), cross-sectional area (R = –0.26), magnetization transfer ratio of whole-brain tissue (R = –0.16), and GM (R = –0.17).¹⁵The poor performance of conventional MR imaging sequences in assessing disability highlights the need for novel MR imaging techniques that can directly image myelin lipid and enable direct assessment of both myelin damage and repair. However, myelin has an extremely short transverse relaxation time and is not directly detectable with conventional MR images, which typically have TEs of several milliseconds or longer. Ultrashort TE (UTE) sequences can directly detect signal from myelin with ultrashort T2 (ie, excluding water with longer T2s).^16-21 In this study, we describe imaging of WM using a 2D adiabatic inversion recovery prepared UTE (IR-UTE) sequence in healthy volunteers and patients with MS and evaluate its performance in assessing disability in patients with MS compared with 2 conventional clinical sequences.     

Automated Detection and Segmentation of Brain Metastases in Malignant Melanoma: Evaluation of a Dedicated Deep Learning Model

BACKGROUND AND PURPOSE:Malignant melanoma is an aggressive skin cancer in which brain metastases are common. Our aim was to establish and evaluate a deep learning model for fully automated detection and segmentation of brain metastases in patients with malignant melanoma using clinical routine MR imaging.MATERIALS AND METHODS:Sixty-nine patients with melanoma with a total of 135 brain metastases at initial diagnosis and available multiparametric MR imaging datasets (T1-/T2-weighted, T1-weighted gadolinium contrast-enhanced, FLAIR) were included. A previously established deep learning model architecture (3D convolutional neural network; DeepMedic) simultaneously operating on the aforementioned MR images was trained on a cohort of 55 patients with 103 metastases using 5-fold cross-validation. The efficacy of the deep learning model was evaluated using an independent test set consisting of 14 patients with 32 metastases. Manual segmentations of metastases in a voxelwise manner (T1-weighted gadolinium contrast-enhanced imaging) performed by 2 radiologists in consensus served as the ground truth.RESULTS:After training, the deep learning model detected 28 of 32 brain metastases (mean volume, 1.0 [SD, 2.4] cm³) in the test cohort correctly (sensitivity of 88%), while false-positive findings of 0.71 per scan were observed. Compared with the ground truth, automated segmentations achieved a median Dice similarity coefficient of 0.75.CONCLUSIONS:Deep learning–based automated detection and segmentation of brain metastases in malignant melanoma yields high detection and segmentation accuracy with false-positive findings of <1 per scan.

Malignant melanoma is an aggressive skin cancer associated with high mortality and morbidity rates.^1,2 Brain metastases are common in malignant melanoma,^3,4 subsequently causing potential severe neurologic impairment and worsened outcome. Therefore, it is recommended that melanoma patients with an advanced stage undergo MR imaging of the head for screening purposes to detect metastases.^5-8Owing to an increased workload of radiologists, repetitive evaluation of MR imaging scans can be tiresome, hence bearing an inherent risk of missed diagnosis for subtle lesions, with satisfaction of search effects leading to decreased sensitivity for additional lesions.^9,10 Automatization of detection could serve as an adjunct tool for lesion preselection that can support image evaluation by radiologists and clinicians.^11,12 Furthermore, automated segmentations may be used as a parameter to evaluate therapy response in oncologic follow-up imaging.^13,14 Additionally, exact lesion determination and delineation of size are required for stereotactic radiosurgery.^15,16 In clinical routine, brain lesions have to be segmented manually by the radiosurgeon. This task proves to be time-consuming, in particular if multiple metastases are present. Furthermore, manual segmentation is potentially hampered by interreader variabilities with reduced reproducibility, hence resulting in inaccuracies of lesion delineation.^17,18 In this context, accurate objective and automated segmentations of brain metastases would be highly beneficial.^17-19Recently, deep learning models (DLMs) have shown great potential in detection, segmentation and classification tasks in medical image analysis while having the potential to improve clinical workflow.^20-25 The models apply multiple processing layers that result in deep convolutional neural networks (CNNs). Training data are used to create complex feature hierarchies.^26-28 In general, a DLM includes different layers for convolution, pooling, and classification.²⁸ The required training data are supplied by manual segmentations, which usually serve as the segmentation criterion standard.^18,28,29Previous studies on brain metastases from different tumor entities have demonstrated promising results, reporting a sensitivity for automated deep learning–based detection of lesions of around 80% or higher.^17,30-32 However, the often reported relatively high number of false-positive findings questions their applicability in clinical routine.^17,30The purpose of this study was to develop and evaluate a DLM for automated detection and segmentation of brain metastases in patients with malignant melanoma using heterogeneous MR imaging data from multiple vendors and study centers.     

Longitudinal Assessment of Enhancing Foci of Abnormal Signal Intensity in Neurofibromatosis Type 1

BACKGROUND AND PURPOSE:Patients with neurofibromatosis 1 are at increased risk of developing brain tumors, and differentiation from contrast-enhancing foci of abnormal signal intensity can be challenging. We aimed to longitudinally characterize rare, enhancing foci of abnormal signal intensity based on location and demographics.MATERIALS AND METHODS:A total of 109 MR imaging datasets from 19 consecutive patients (7 male; mean age, 8.6 years; range, 2.3–16.8 years) with neurofibromatosis 1 and a total of 23 contrast-enhancing parenchymal lesions initially classified as foci of abnormal signal intensity were included. The mean follow-up period was 6.5 years (range, 1–13.8 years). Enhancing foci of abnormal signal intensity were followed up with respect to presence, location, and volume. Linear regression analysis was performed.RESULTS:Location, mean peak volume, and decrease in enhancing volume over time of the 23 lesions were as follows: 10 splenium of the corpus callosum (295 mm³, 5 decreasing, 3 completely resolving, 2 surgical intervention for change in imaging appearance later confirmed to be gangliocytoma and astrocytoma WHO II), 1 body of the corpus callosum (44 mm³, decreasing), 2 frontal lobe white matter (32 mm³, 1 completely resolving), 3 globus pallidus (50 mm³, all completely resolving), 6 cerebellum (206 mm³, 3 decreasing, 1 completely resolving), and 1 midbrain (34 mm³). On average, splenium lesions began to decrease in size at 12.2 years, posterior fossa lesions at 17.1 years, and other locations at 9.4 years of age.CONCLUSIONS:Albeit very rare, contrast-enhancing lesions in patients with neurofibromatosis 1 may regress over time. Follow-up MR imaging aids in ascertaining regression. The development of atypical features should prompt further evaluation for underlying tumors.

Neurofibromatosis type 1 (NF-1) is an autosomal dominant tumor predisposition syndrome characterized by optic pathway gliomas, neurofibromas, skin manifestations, iris hamartomas, and bone lesions, affecting approximately 1 in 3000 individuals.^1,2 Foci of abnormal signal intensity, previously known as unidentified bright objects or neurofibromatosis bright objects of the brain, are not among the diagnostic criteria but can be found in 43%–95% of pediatric patients with NF-1.^3-7 On MR imaging, FASI appear as T2/FLAIR hyperintense lesions of the brain with a predilection for the basal ganglia, cerebellum, and brain stem. Although FASI are not completely understood, myelin vacuolization is commonly considered as an underlying feature of these lesions.^1,4,5,7-9Patients with NF-1 are at an increased risk of developing low- and high-grade brain tumors, including cerebral and cerebellar astrocytomas, ependymomas, and brain stem gliomas, many of which can mimic FASI on MR imaging.^3,10-14 On the other hand, FASI are known for their dynamic properties and may increase or decrease in size or resolve over time.⁸ Although the reference standard for differentiating brain lesions is transcranial biopsy with its own inherent risks, brain signal abnormalities in patients with NF-1 are primarily followed up by MR imaging to screen for possible tumors.^15-18 Contrast enhancement after administration of a gadolinium-based contrast agent is usually considered atypical for FASI and likely to indicate the presence of a brain tumor. Reports considering contrast enhancement in FASI are sparse, limited to case reports and small numbers in cohort studies.^3,6,19-29 We therefore aimed to characterize lesions considered to represent enhancing FASI based on location, volume of enhancement, and demographics to advance the understanding of these rare lesions.     

Effects of Acquisition Parameter Modifications and Field Strength on the Reproducibility of Brain Perfusion Measurements Using Arterial Spin-Labeling

BACKGROUND AND PURPOSE:Although the added diagnostic value of arterial spin-labeling is shown in various cerebral pathologies, its use in clinical practice is limited. To encourage clinical adoption of ASL, we investigated the reproducibility of CBF measurements and the effects of variations in acquisition parameters compared to the recommended ASL implementation.MATERIALS AND METHODS:Thirty-four volunteers (mean age, 57.8 ± 17.0 years; range, 22–80 years) underwent two separate sessions (1.5T and 3T scanners from a single vendor) using a 15-channel head coil. Both sessions contained repeated 3D and 2D pseudocontinuous arterial spin-labeling scans using vendor-recommended acquisition parameters (recommendation paper–based), followed by three 3D pseudocontinuous arterial spin-labeling scans, two with postlabeling delays of 1600  and 2000 ms and one with increased spatial resolution. All scans were single postlabeling delay. Intrasession (identical acquisitions, scanned five minutes apart) and intersession (first 2D and 3D acquisitions of two sessions) reproducibility was examined as well as the effect of parameter variations on CBF.RESULTS:Intrasession CBF reproducibility was similar across image readouts and field strengths (within-subject coefficient of variation between 4.0% and 6.7%). Intersession within-subject coefficient of variation ranged from 6.6% to 14.8%. At 3T, the 3D acquisition with a higher spatial resolution resulted in less mixing of GM and WM signal, thus decreasing the bias in GM CBF between the 2D and 3D acquisitions (ΔCBF = 2.49 mL/100g/min [P < .001]). Postlabeling delay variations caused a modest bias (ΔCBF between −3.78 [P < .001] and 2.83 [P < .001] mL/100g/min).CONCLUSIONS:Arterial spin-labeling imaging is reproducible at both field strengths, and the reproducibility is not significantly correlated with age. Furthermore, 3T tolerates more acquisition parameter variations and allows more extensive optimizations so that 3D and 2D acquisitions can be compared.

Arterial spin-labeling (ASL) MR imaging has the potential to be a cost-effective and safe alternative to contrast agent–based perfusion imaging.¹ However, despite its proved clinical value,^2-4 technologic improvements,^5-7 and consensus recommendation on the implementation,⁸ clinical use of ASL remains limited to date.⁹ ASL is also regularly used in clinical and pharmaceutical trials because in these cases, the preference is to avoid the use of gadolinium-based contrast agents. In such trials, it remains a challenge to harmonize imaging protocols over different MR imaging systems, which use different readout types and ASL labeling and imaging parameters.^10-12 Overcoming these challenges is especially important in multicenter trials as well as in longitudinal studies, in which scanner hardware or software updates and subsequent sequence changes are common.Several practical limitations hamper the adoption of ASL to image CBF in clinical practice. First, the recommended use of ASL is at a field strength of 3T.⁸ However, if ASL is used as an alternative to contrast agent perfusion MR imaging to reduce the duration and cost of MR imaging examinations, it would also be preferably conducted at 1.5T, a field strength that is more widely available. Another limiting factor in clinical practice is that the sensitivity of CBF values to changes in the acquisition parameters is not well-understood.Despite the relatively large body of literature on the precision of ASL, in which studies have shown that ASL has a similar reproducibility to PET¹³ and that whole-brain (WB) reproducibility is comparable among various labeling and readout strategies,^10,14,15 investigators still question the effects of acquisition parameter changes on the precision of ASL with respect to the recommended implementation as described by the ASL consensus paper.⁸ Other challenges for clinical adoption may be that most ASL reproducibility studies were conducted in young participants and may not be applicable to the elderly population.¹⁶ Moreover, many studies apply partial volume correction (PVC) to mathematically correct for mixing of GM and WM perfusion, which is inherently present in ASL data due to the relatively large voxels and long readout durations in 3D acquisitions specifically.¹⁷ Studies are often inconsistent on the corrections applied when reporting CBF values, complicating comparison among studies.A final challenge for ASL-based perfusion imaging is that standard ASL acquisitions aim to quantify CBF from a single postlabeling delay (PLD) measurement without measuring whether the labeled blood arrived in the tissue. Therefore, it might be unclear whether a low ASL signal is due to decreased perfusion or a delay in arrival. Recently, a novel ASL parameter, which can be derived from single-PLD CBF maps, the spatial coefficient of variation (CoV), was introduced as a proxy of arterial transit time.¹⁸ Correlation of spatial CoV with clinical parameters was shown in recent studies,^19-21 but the reproducibility of this parameter has not yet been reported.To address the practical issues mentioned above and to encourage further adoption of ASL in clinical practice, this study aims to extend the knowledge on the precision of CBF and spatial CoV measurements. Specifically, this work focuses on studying ASL reproducibility with respect to three common sources of ASL signal variation: 1) age: studying healthy subjects over a large range of adult ages, focusing mostly on older adults because reproducibility studies in this age group are lacking in the literature; 2) field strength and scan parameter variations: assessing the influence of small acquisition parameter variations⁸ at both 3T and 1.5T; and 3) partial volume correction: showing the effect of partial volume correction on deriving pure GM CBF with different scan parameter variations and imaging field strengths.     

Glioma-Induced Disruption of Resting-State Functional Connectivity and Amplitude of Low-Frequency Fluctuations in the Salience Network

BACKGROUND AND PURPOSE:Cognitive challenges are prevalent in survivors of glioma, but their neurobiology is incompletely understood. The purpose of this study was to investigate the effect of glioma presence and tumor characteristics on resting-state functional connectivity and amplitude of low-frequency fluctuations of the salience network, a key neural network associated with cognition.MATERIALS AND METHODS:Sixty-nine patients with glioma (mean age, 48.74 [SD, 14.32] years) who underwent resting-state fMRI were compared with 31 healthy controls (mean age, 49.68 [SD, 15.54] years). We identified 4 salience network ROIs: left/right dorsal anterior cingulate cortex and left/right anterior insula. Average salience network resting-state functional connectivity and amplitude of low-frequency fluctuations within the 4 salience network ROIs were computed.RESULTS:Patients with gliomas showed decreased overall salience network resting-state functional connectivity (P = .001) and increased amplitude of low-frequency fluctuations in all salience network ROIs (P < .01) except in the left dorsal anterior cingulate cortex. Compared with controls, patients with left-sided gliomas showed increased amplitude of low-frequency fluctuations in the right dorsal anterior cingulate cortex (P = .002) and right anterior insula (P < .001), and patients with right-sided gliomas showed increased amplitude of low-frequency fluctuations in the left anterior insula (P = .002). Anterior tumors were associated with decreased salience network resting-state functional connectivity (P < .001) and increased amplitude of low-frequency fluctuations in the right anterior insula, left anterior insula, and right dorsal anterior cingulate cortex. Patients with high-grade gliomas had decreased salience network resting-state functional connectivity compared with healthy controls (P < .05). The right anterior insula showed increased amplitude of low-frequency fluctuations in patients with grade II and IV gliomas compared with controls (P < .01).CONCLUSIONS:By demonstrating decreased resting-state functional connectivity and an increased amplitude of low-frequency fluctuations related to the salience network in patients with glioma, this study adds to our understanding of the neurobiology underpinning observable cognitive deficits in these patients. In addition to more conventional functional connectivity, amplitude of low-frequency fluctuations is a promising functional-imaging biomarker of tumor-induced vascular and neural pathology.

Detrimental effects of cancer on cognitive function and, consequently, on the quality of life are emerging as a key focus of cancer survivorship both in research and clinical practice.^1,2 Brain tumors have been shown to affect memory, processing, and attention in patients; however, their underlying neurobiology is incompletely understood.³ Using resting-state functional MR imaging (rsfMRI) to evaluate changes in cognitive resting-state networks may provide a better understanding of the pathology underlying the observable cognitive disruptions in gliomas, the most common primary brain tumor in adults.A “triple network model” of neurocognitive pathology has been proposed, which encompasses the default mode network, involved in mind wandering; the central executive network, involved in decision-making; and the salience network (SN), implicated in modulating activation of the default mode network and central executive network by detecting the presence of salient stimuli.^4-8 While previous rsfMRI research has largely focused on tumor-induced changes in the default mode network,^9,10 our study examined the less-studied SN, a network rooted in the anterior insula and the dorsal anterior cingulate cortex.⁶Prior studies evaluating gliomas and SN resting-state functional connectivity (RSFC) provided conflicting results in small patient samples: Maesawa et al¹⁰ found no significant differences in the SN in 12 patients, while Liu et al¹¹ more recently found decreased SN connectivity in 13 patients. Gliomas impact the integrity of the neurovascular unit to varying degrees, resulting in neurovascular uncoupling that has been reported to confound fMRI interpretations in patients with brain tumors.^12-14 Additionally, research has reported neuronal plasticity manifested by structural reorganization and functional remodeling of neural networks in patients with gliomas with possible alterations in clinically observable cognitive manifestations.^15-17 An rsfMRI metric, the amplitude of low-frequency fluctuations (ALFF), has recently shown promise as a biomarker for brain plasticity and hemodynamic characterization, including neurovascular uncoupling in patients with gliomas.^15-19The purpose of this study was to investigate the effect of glioma presence and tumor characteristics on overall RSFC and regional normalized ALFF within the SN in a large patient population. We hypothesized that there would be decreased average SN RSFC and altered ALFF in patients with gliomas compared with healthy controls. Recent studies have acknowledged that gliomas have variable effects on network integrity based on lesion location and proximity to network ROIs,^20-22 and unilateral gliomas can be associated with plasticity in both the ipsilateral and contralateral hemispheres.^11,17 Research also supports differences in resting-state network reorganization in aggressive high-grade gliomas compared with slower-growing low-grade gliomas.^20,23 Therefore, we also hypothesized that there would be differences in average SN RSFC and regional ALFF in patients based on the anterior-versus-posterior location, hemispheric side, and grade of glioma.     

Neonatal Developmental Venous Anomalies: Clinicoradiologic Characterization and Follow-Up

BACKGROUND AND PURPOSE:Although developmental venous anomalies have been frequently studied in adults and occasionally in children, data regarding these entities are scarce in neonates. We aimed to characterize clinical and neuroimaging features of neonatal developmental venous anomalies and to evaluate any association between MR imaging abnormalities in their drainage territory and corresponding angioarchitectural features.MATERIALS AND METHODS:We reviewed parenchymal abnormalities and angioarchitectural features of 41 neonates with developmental venous anomalies (20 males; mean corrected age, 39.9 weeks) selected through a radiology report text search from 2135 neonates who underwent brain MR imaging between 2008 and 2019. Fetal and longitudinal MR images were also reviewed. Neurologic outcomes were collected. Statistics were performed using χ², Fisher exact, Mann-Whitney U, or t tests corrected for multiple comparisons.RESULTS:Developmental venous anomalies were detected in 1.9% of neonatal scans. These were complicated by parenchymal/ventricular abnormalities in 15/41 cases (36.6%), improving at last follow-up in 8/10 (80%), with normal neurologic outcome in 9/14 (64.2%). Multiple collectors (P = .008) and larger collector caliber (P < .001) were significantly more frequent in complicated developmental venous anomalies. At a patient level, multiplicity (P = .002) was significantly associated with the presence of ≥1 complicated developmental venous anomaly. Retrospective fetal detection was possible in 3/11 subjects (27.2%).CONCLUSIONS:One-third of neonatal developmental venous anomalies may be complicated by parenchymal abnormalities, especially with multiple and larger collectors. Neuroimaging and neurologic outcomes were favorable in most cases, suggesting a benign, self-limited nature of these vascular anomalies. A congenital origin could be confirmed in one-quarter of cases with available fetal MR imaging.

Developmental venous anomalies (DVAs) are the most frequently diagnosed intracranial vascular malformations, often encountered as incidental neuroimaging findings.^1,2 On MR imaging, DVAs are recognized on postcontrast T1WI as radially oriented veins with a “caput medusae” pattern converging into 1 (or rarely more) dilated venous collector.^3,4 These features may be also detected on precontrast MR images,^3-5 especially if T2*-weighted sequences such as high-resolution SWI are included in the protocol.⁵ In addition, DVAs may be occasionally recognized in utero using fetal MR imaging.⁶DVAs are usually considered benign anatomic variants.⁷ However, they represent areas of venous fragility that can become symptomatic through diverse pathomechanisms.^8,9 Indeed, DVA-associated brain abnormalities are frequently depicted, including-but-not limited-to sporadic cerebral cavernous malformations (CCMs).^8-16 Moreover, a higher prevalence of DVAs has been described in patients with different pathologies and/or genetic conditions.^17-21Although DVAs are widely described and characterized in adults, they remain under-reported in the pediatric population. Indeed, there are noticeably fewer studies focusing exclusively on DVAs in this age group, especially in the neonatal period.^17,18,21-24 In particular, the largest case series of neonatal DVAs described so far included 14 neonates, mostly detected using ultrasound during routine scanning for other reasons,²² with limited information on the prevalence and perinatal characteristics of these vascular abnormalities, including complications and longitudinal evolution. Moreover, additional data on neonatal and fetal DVAs would be of great interest because there is an ongoing debate regarding their congenital or postnatal etiology.²⁵In this study, we aimed to describe the pre- and postnatal appearance of DVAs and associated brain anomalies in a relatively large single-center group of neonates, providing information on their imaging and clinical follow-up. In addition, we tested a possible association between parenchymal and ventricular abnormalities in the drainage territory of neonatal DVAs and their angioarchitectural features.     

Cortical Distribution of Fragile Periventricular Anastomotic Collateral Vessels in Moyamoya Disease: An Exploratory Cross-Sectional Study of Japanese Patients with Moyamoya Disease

BACKGROUND AND PURPOSE:Collateral vessels in Moyamoya disease represent potential sources of bleeding. To test whether these cortical distributions vary among subtypes, we investigated cortical terminations using both standardized MR imaging and MRA.MATERIALS AND METHODS:Patients with Moyamoya disease who underwent MR imaging with MRA in our institution were enrolled in this study. MRA was spatially normalized to the Montreal Neurological Institute space; then, collateral vessels were measured on MRA and classified into 3 types of anastomosis according to the parent artery: lenticulostriate, thalamic, and choroidal. We also obtained the coordinates of collateral vessel outflow to the cortex. Differences in cortical terminations were compared among the 3 types of anastomosis.RESULTS:We investigated 219 patients with Moyamoya disease, and a total of 190 collateral vessels (lenticulostriate anastomosis, n = 72; thalamic anastomosis, n = 21; choroidal anastomosis, n = 97) in 46 patients met the inclusion criteria. We classified the distribution patterns of collateral anastomosis as follows: lenticulostriate collaterals outflowing anteriorly (P < .001; 95% CI, 67.0–87.0) and medially (P < .001; 95% CI, 11.0–24.0) more frequently than choroidal collaterals; lenticulostriate collaterals outflowing anteriorly more frequently than thalamic collaterals (P < .001; 95% CI, 34.0–68.0); and choroidal collaterals outflowing posteriorly more frequently than thalamic collaterals (P < .001; 95% CI, 14.0–34.0). Lenticulostriate anastomoses outflowed to the superior or inferior frontal sulcus and interhemispheric fissure. Thalamic anastomoses outflowed to the insular cortex and cortex around the central sulcus. Choroidal anastomoses outflowed to the cortex posterior to the central sulcus and the insular cortex.CONCLUSIONS:Cortical distribution patterns appear to differ markedly among the 3 types of collaterals.

Collateral vessels in Moyamoya disease develop as the disease progresses.¹ Lenticulostriate arteries (LSAs), perforators from the posterior communicating artery (PcomA), and anterior and posterior choroidal arteries (choAs) are representative collateral vessels that supply the cortex.^2-4 Development of such collateral vessels represents a risk factor for intracerebral hemorrhage,^3,5-7 and these vessels have frequently been considered as the vessels responsible for bleeding in recent reports.^8-10 These collateral vessels connect with medullary arteries near the lateral ventricle and thus supply the cortex via the medullary arteries.^3,4 However, no reports have addressed the cortical distributions of these collateral vessels.Bypass surgery reduces the risk of rebleeding in patients with hemorrhagic onset of Moyamoya disease^7,11-13 and also shrinks collateral vessels in Moyamoya disease.^7,12,14,15 Augmentation of cerebral blood flow via bypass seems to decrease the necessity for development of collateral flow and shrinks existing collaterals.¹⁵ To shrink risky collateral vessels effectively and prevent hemorrhage, well-designed and planned bypass surgeries may be required.¹⁶ Comprehension of the nature and cortical distribution of collateral vessels may thus be clinically useful.MRA performed using a 3T scanner has proved useful for detecting the abnormally extended collateral vessels in Moyamoya disease.² We investigated the cortical distribution of collateral vessels using 3T MR imaging and MRA to clarify whether cortical distributions vary among anastomotic subtypes and to better understand collateral networks.     

Intra-Arterial Thrombolysis after Unsuccessful Mechanical Thrombectomy in the STRATIS Registry

BACKGROUND AND PURPOSE:Recent data suggest that intra-arterial thrombolytics may be a safe rescue therapy for patients with acute ischemic stroke after unsuccessful mechanical thrombectomy; however, safety and efficacy remain unclear. Here, we evaluate the use of intra-arterial rtPA as a rescue therapy in the Systematic Evaluation of Patients Treated with Neurothrombectomy Devices for Acute Ischemic Stroke (STRATIS) registry.MATERIALS AND METHODS:STRATIS was a prospective, multicenter, observational study of patients with acute ischemic stroke with large-vessel occlusions treated with the Solitaire stent retriever as the first-line therapy within 8 hours from symptom onset. Clinical and angiographic outcomes were compared in patients having rescue therapy treated with and without intra-arterial rtPA. Unsuccessful mechanical thrombectomy was defined as any use of rescue therapy.RESULTS:A total of 212/984 (21.5%) patients received rescue therapy, of which 83 (39.2%) and 129 (60.8%) were in the no intra-arterial rtPA and intra-arterial rtPA groups, respectively. Most occlusions were M1, with 43.4% in the no intra-arterial rtPA group and 55.0% in the intra-arterial rtPA group (P = .12). The median intra-arterial rtPA dose was 4 mg (interquartile range = 2–12 mg). A trend toward higher rates of substantial reperfusion (modified TICI  ≥ 2b) (84.7% versus 73.0%, P = .08), good functional outcome (59.2% versus 46.6%, P = .10), and lower rates of mortality (13.3% versus 23.3%, P = .08) was seen in the intra-arterial rtPA cohort. Rates of symptomatic intracranial hemorrhage did not differ (0% versus 1.6%, P = .54).CONCLUSIONS:Use of intra-arterial rtPA as a rescue therapy after unsuccessful mechanical thrombectomy was not associated with an increased risk of symptomatic intracranial hemorrhage or mortality. Randomized clinical trials are needed to understand the safety and efficacy of intra-arterial thrombolysis as a rescue therapy after mechanical thrombectomy.

Mechanical thrombectomy (MT) is a powerful therapy for patients with acute ischemic stroke with large-vessel occlusions. However, despite its proved success,^1-5 most patients do not achieve complete reperfusion^6-9 and only about half of all patients treated with MT achieve a good clinical outcome at 3 months.⁶ Because patients with complete reperfusion are 2 times more likely to have favorable outcomes than those with near-complete reperfusion,¹⁰ exploration of adjunctive or rescue therapies (RTs) to augment MT complete reperfusion is warranted.The role of intra-arterial (IA) thrombolysis has evolved from a primary therapy^11-17 to an adjunctive or RT to MT. Recently, a US survey indicated that 60.6% of neurointerventionalists use IA lytics in their practice, with the most common approach as an RT after MT.¹⁸ Previous studies on the use of IA rtPA in the context of MT either as an RT or adjunctive therapy have yielded promising data, but these studies are limited by their small sample sizes and retrospective design.^19-21 Here, in this subanalysis, we retrospectively evaluate the use of IA rtPA as an RT after unsuccessful MT in the multicenter, prospective, Systematic Evaluation of Patients Treated with Neurothrombectomy Devices for Acute Ischemic Stroke (STRATIS) registry (https://www.clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT02239640","term_id":"NCT02239640"}}NCT02239640?term=STRATIS&draw=2&rank=7).     

Neck Location on the Outer Convexity is a Predictor of Incomplete Occlusion in Treatment with the Pipeline Embolization Device: Clinical and Angiographic Outcomes

BACKGROUND AND PURPOSE:With the increasing use of the Pipeline Embolization Device for the treatment of aneurysms, predictors of clinical and angiographic outcomes are needed. This study aimed to identify predictors of incomplete occlusion at last angiographic follow-up.MATERIALS AND METHODS:In our retrospective, single-center cohort study, 105 ICA aneurysms in 89 subjects were treated with Pipeline Embolization Devices. Patients were followed per standardized protocol. Clinical and angiographic outcomes were analyzed. We introduced a new morphologic classification based on the included angle of the parent artery against the neck location: outer convexity type (included angle,  <160°), inner convexity type (included angle,  >200°), and lateral wall type (160° ≤ included angle  ≤200°). This classification reflects the metal coverage rate and flow dynamics.RESULTS:Imaging data were acquired in 95.3% of aneurysms persistent at 6 months. Complete occlusion was achieved in 70.5%, and incomplete occlusion, in 29.5% at last follow-up. Multivariable regression analysis revealed that 60 years of age or older (OR, 5.70; P = .001), aneurysms with the branching artery from the dome (OR, 10.56; P = .002), fusiform aneurysms (OR, 10.2; P = .009), and outer convexity–type saccular aneurysms (versus inner convexity type: OR, 30.3; P < .001; versus lateral wall type: OR, 9.71; P = .001) were independently associated with a higher rate of incomplete occlusion at the last follow-up. No permanent neurologic deficits or rupture were observed in the follow-up period.CONCLUSIONS:The aneurysm neck located on the outer convexity is a new, incomplete occlusion predictor, joining older age, fusiform aneurysms, and aneurysms with the branching artery from the dome. No permanent neurologic deficits or rupture was observed in the follow-up, even with incomplete occlusion.

Flow-diversion stents with the Pipeline Embolization Device (PED; Medtronic) were first reported in 2008.¹ Since then, multiple trials^2-6 and retrospective studies^3,7,8 have reported the safety and efficacy of the PED in the treatment of intracranial aneurysms. Long-term follow-up data showed a 95.2% occlusion rate at 5 years after treatment^3,8 and no evidence of recanalization of previously occluded aneurysms.³ Angiographic and clinical long-term follow-up data are important because incomplete occlusion leads to retreatment or rerupture in coil embolization.⁹Several factors such as age, sex, smoking, fusiform-type aneurysms, small aspect ratios, and dome-neck ratios have been reported to be predictors of incomplete or complete occlusion.^10-17 However, there is debate about outcomes when using these factors because of limited analysis of the confounding factors. Moreover, the follow-up imaging rate of incomplete occlusion is sometimes insufficient (around 50% at 6 months).¹ Additionally, the same morphologic indices used in coil embolization were used in previous PED studies, even though the 2 methods are different in their treatment mechanism for aneurysms. The metal coverage ratio (MCR)^18-20 is an important metric of PED treatment.Although the MCR correlates with the occlusion rate,¹⁹ it is calculated after treatment and additional work-up is needed to acquire it. Therefore, in this study, we introduced a new classification based on the included angle of the parent artery against the neck location for the aneurysm, which can be measured before the PED treatment and complements the MCR: outer convexity type, inner convexity type, and lateral wall type. In addition, we clarified factors, including our new classification, affecting incomplete occlusion and clinical outcome in PED treatment, on the basis of data with a high follow-up rate.     

Value of Emergent Neurovascular Imaging for “Seat Belt Injury”: A Multi-institutional Study

BACKGROUND AND PURPOSE:Screening for blunt cerebrovascular injury in patients after motor vehicle collision (MVC) solely based on the presence of cervical seat belt sign has been debated in the literature without consensus. Our aim was to assess the value of emergent neurovascular imaging in patients after an MVC who present with a seat belt sign through a large-scale multi-institutional study.MATERIALS AND METHODS:The electronic medical records of patients admitted to the emergency department with CTA/MRAs performed with an indication of seat belt injury of the neck were retrospectively reviewed at 5 participating institutions. Logistic regression analysis was used to determine the association among age, sex, and additional trauma-related findings with blunt cerebrovascular injury.RESULTS:Five hundred thirty-five adult and 32 pediatric patients from June 2003 until March 2020 were identified. CTA findings were positive in 12/567 (2.1%) patients for the presence of blunt cerebrovascular injury of the vertebral (n = 8) or internal carotid artery (n = 4) in the setting of acute trauma with the seat belt sign. Nine of 12 patients had symptoms, signs, or risk factors for cervical blunt cerebrovascular injury other than the seat belt sign. The remaining 3 patients (3/567, 0.5%) had Biffl grades I–II vascular injury with no neurologic sequelae. The presence of at least 1 additional traumatic finding or the development of a new neurologic deficit was significantly associated with the presence of blunt cerebrovascular injury among adult patients, with a risk ratio of 11.7 (P = .001). No children had blunt cerebrovascular injury.CONCLUSIONS:The risk of vascular injury in the presence of the cervical seat belt sign is small, and most patients diagnosed with blunt cerebrovascular injury have other associated findings. Therefore, CTA based solely on this sign has limited value (3/567 =  a 0.5% positivity rate). We suggest that in the absence of other clinical findings, the seat belt sign does not independently justify neck CTA in patients after trauma.

Motor vehicle collision (MVC) is a major cause of blunt cerebrovascular injury (BCVI).¹ Historically, the incidence of BCVI was reported to be as low as 0.1%–0.67% among patients with blunt trauma.^2,3 However, implementation of more rigorous screening protocols in trauma centers has revealed a 10-fold higher rate of BCVI, as high as 2.7%, among severely injured patients.^4-6 Although uncommon, the neurologic sequelae of BCVI are potentially serious. Many patients do not manifest stroke symptoms until hours to days after the injury,⁷ and when not treated in a timely fashion, up to 80% develop permanent neurologic sequelae with an estimated 40% mortality rate.^3,8,9 Thus, screening CTA or MRA for BCVI has become commonplace in the management of patients after an MVC.^10,11 However, the selection of which patients to screen has been a controversial topic during the past 4 decades.⁶Various screening algorithms, including the modified Memphis and Denver criteria or the Western Trauma Association algorithm, may be used as guidelines (Online Supplemental Data). These guidelines, developed on the basis of observational studies and expert opinion, have adopted a liberal approach to imaging patients with possible BCVI.^7,12,13 Although this approach helps avoid missing occult injuries, it may lead to unnecessary imaging, discovery of incidental findings, increased radiation exposure, and low-value health care expenditures.^14-17 Many believe that advanced imaging studies are being overused in many medical centers, in part, due to a “defensive medicine” mentality. It is estimated that up to 50% of ordered studies lead to no improvement in patient welfare.^15,18One of the controversial indications for BCVI is the physical sign of neck abrasion or contusion caused by a seat belt, the so-called cervical seat belt sign. Screening for BCVI solely based on the presence of this sign has been debated in the literature without consensus.^19-22 The existing guidelines also recommend contradictory approaches regarding the use of the seat belt sign as a sole indicator to stratify patients for screening (Online Supplemental Data). Despite some single-center studies suggesting that discoloration of the skin from the seat belt is not a reliable indicator of risk to the cervical vessels,^23-25 many trauma centers persist in ordering emergent CTAs to exclude BCVI in patients with this finding because of continued debate as to the validity of the seat belt sign as an indicator of vascular injury. To address this controversy, we aimed to assess the value of emergent neurovascular imaging in patients with a seat belt sign after an MVC through a large-scale multi-institutional study that would identify the situations in which the seat belt sign may be predictive of cervical vascular injury. We hypothesized that cervical CTA performed solely on the basis of a seat belt sign has limited value.     

Brain and Lung Imaging Correlation in Patients with COVID-19: Could the Severity of Lung Disease Reflect the Prevalence of Acute Abnormalities on Neuroimaging? A Global Multicenter Observational Study

PURPOSE:Our aim was to study the association between abnormal findings on chest and brain imaging in patients with coronavirus disease 2019 (COVID-19) and neurologic symptoms.MATERIALS AND METHODS:In this retrospective, international multicenter study, we reviewed the electronic medical records and imaging of hospitalized patients with COVID-19 from March 3, 2020, to June 25, 2020. Our inclusion criteria were patients diagnosed with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection with acute neurologic manifestations and available chest CT and brain imaging. The 5 lobes of the lungs were individually scored on a scale of 0–5 (0 corresponded to no involvement and 5 corresponded to >75% involvement). A CT lung severity score was determined as the sum of lung involvement, ranging from 0 (no involvement) to 25 (maximum involvement).RESULTS:A total of 135 patients met the inclusion criteria with 132 brain CT, 36 brain MR imaging, 7 MRA of the head and neck, and 135 chest CT studies. Compared with 86 (64%) patients without acute abnormal findings on neuroimaging, 49 (36%) patients with these findings had a significantly higher mean CT lung severity score (9.9 versus 5.8, P < .001). These patients were more likely to present with ischemic stroke (40 [82%] versus 11 [13%], P < .0001) and were more likely to have either ground-glass opacities or consolidation (46 [94%] versus 73 [84%], P = .01) in the lungs. A threshold of the CT lung severity score of >8 was found to be 74% sensitive and 65% specific for acute abnormal findings on neuroimaging. The neuroimaging hallmarks of these patients were acute ischemic infarct (28%), intracranial hemorrhage (10%) including microhemorrhages (19%), and leukoencephalopathy with and/or without restricted diffusion (11%). The predominant CT chest findings were peripheral ground-glass opacities with or without consolidation.CONCLUSIONS:The CT lung disease severity score may be predictive of acute abnormalities on neuroimaging in patients with COVID-19 with neurologic manifestations. This can be used as a predictive tool in patient management to improve clinical outcome.

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) began in Wuhan, China, in December 2019 and has rapidly spread around the world to become a pandemic.¹ Extensive studies have described chest and brain imaging characteristics associated with coronavirus disease 2019 (COVID-19).^2-13 The hallmarks of COVID-19 infection on chest imaging are now well-established, including bilateral and peripheral ground-glass and consolidative pulmonary opacities.^2-5 COVID-19-related brain imaging findings such as ischemic infarcts, hemorrhages, and multiple patterns of leukoencephalopathy^6-13 are also well-known. The clinical symptomatology has been linked to the imaging findings with up to 47% of patients with COVID-19 with neurologic symptoms demonstrating acute neuroimaging findings⁶ and patients with high lung severity scores being admitted to the intensive care unit.³ The incidence of neurologic symptoms is higher in patients with more severe respiratory disease.^10,13 There is increasing evidence that patients with acute lung injury are at risk of brain injury through hypoxemia and/or proinflammatory mediators that connect both the brain and the lungs.^14-17 However, little information is available on the potential association between the prevalence of neuroimaging abnormalities and the severity of CT lung findings in patients with COVID-19. The objective of this study was to examine the association between chest and brain imaging abnormalities in patients with COVID-19. We hypothesized that the severity of lung disease may predict acute abnormalities on neuroimaging in patients with COVID-19 with neurologic symptoms.     

CTA-Based Patient-Tailored Femoral or Radial Frontline Access Reduces the Rate of Catheterization Failure in Chronic Subdural Hematoma Embolization

BACKGROUND AND PURPOSE:Chronic subdural hematoma embolization, an apparently simple procedure, can prove to be challenging because of the advanced age of the target population. The aim of this study was to compare 2 arterial-access strategies, femoral versus patient-tailored CTA-based frontline access selection, in chronic subdural hematoma embolization procedures.MATERIALS AND METHODS:This was a monocentric retrospective study. From the March 15, 2018, to the February 14, 2019 (period 1), frontline femoral access was used. Between February 15, 2019, and March 30, 2020 (period 2), the choice of the frontline access, femoral or radial, was based on the CTA recommended as part of the preoperative work-up during both above-mentioned periods. The primary end point was the rate of catheterization failure. The secondary end points were the rate of access site conversion and fluoroscopy duration.RESULTS:During the study period, 124 patients (with 143 chronic subdural hematomas) underwent an embolization procedure (mean age, 74 [SD, 13] years). Forty-eight chronic subdural hematomas (43 patients) were included during period 1 and were compared with 95 chronic subdural hematomas (81 patients) during period 2. During the first period, 5/48 (10%) chronic subdural hematoma embolizations were aborted due to failed catheterization, significantly more than during period 2 (1/95, 1%; P = .009). The rates of femoral-to-radial (P = .55) and total conversion (P = .86) did not differ between the 2 periods. No significant difference was found regarding the duration of fluoroscopy (P = .62).CONCLUSIONS:A CTA-based patient-tailored choice of frontline arterial access reduces the rate of catheterization failure in chronic subdural hematoma embolization procedures.

The annual incidence of chronic subdural hematomas (CSDHs), 14 to 20 per 100,000 individuals, means that the condition is one of the most frequently managed by neurosurgery departments.^1,2 CSDHs are thought to be sentinel health events, akin to hip fractures, with important reduction in life expectancy for patients compared with age-matched controls.³ The condition is, moreover, associated with far-from-negligible rates of morbidity and mortality, around 11% and 4%, respectively.⁴Standard management of symptomatic CSDHs includes surgical evacuation, mostly through twist drill or burr-hole craniostomy with closed-system drainage.^4-6 Recently, middle meningeal artery (MMA) embolization has emerged as a possible treatment of CSDHs.^7,8 The procedure is simple in appearance but can prove to be challenging in a subset of patients because of tortuous vasculature. Indeed, CSDH is mostly a disease of the elderly with two-thirds of cases accounted for in patients older than 65 years of age.¹ In the elderly, several factors, including peripheral vascular disease and vascular anatomy, can complicate or even preclude cervical vessel navigation by a traditional transfemoral approach.^9,10The transradial approach has recently emerged as an alternative to transfemoral access in interventional neuroradiology, with the stated aim of reducing access-related complications and patient discomfort.¹¹ It has also been envisioned that radial access may facilitate anterior circulation navigation in some patients.^10,11 The aim of this study was to compare 2 arterial-access strategies, frontline femoral versus patient-tailored frontline access selection (femoral or radial), based on a preoperative CTA, in CSDH embolization procedures.     

Impact of Kidney Function on CNS Gadolinium Deposition in Patients Receiving Repeated Doses of Gadobutrol

BACKGROUND AND PURPOSE:Studies associate repeat gadolinium-based contrast agent administration with T1 shortening in the dentate nucleus and globus pallidus, indicating CNS gadolinium deposition, most strongly with linear agents but also reportedly with macrocyclics. Renal impairment effects on long-term CNS gadolinium deposition remain underexplored. We investigated the relationship between signal intensity changes and renal function in patients who received ≥10 administrations of the macrocyclic agent gadobutrol.MATERIALS AND METHODS:Patients who underwent ≥10 brain MR imaging examinations with administration of intravenous gadobutrol between February 1, 2014, and January 1, 2018, were included in this retrospective study. Dentate nucleus-to-pons and globus pallidus-to-thalamus signal intensity ratios were calculated, and correlations were calculated between the estimated glomerular filtration rate (minimum and mean) and the percentage change in signal intensity ratios from the first to last scan. Partial correlations were calculated to control for potential confounders.RESULTS:One hundred thirty-one patients (73 women; mean age at last scan, 55.9 years) showed a mean percentage change of the dentate nucleus-to-pons of 0.31%, a mean percentage change of the globus pallidus-to-thalamus of 0.15%, a mean minimum estimated glomerular filtration rate of 69.65 (range, 10.16–132.26), and a mean average estimated glomerular filtration rate at 89.48 (range, 38.24–145.93). No significant association was found between the estimated glomerular filtration rate and percentage change of the dentate nucleus-to-pons (minimum estimated glomerular filtration rate, r = –0.09, P = .28; average estimated glomerular filtration rate, r = –0.09, P = .30,) or percentage change of the globus pallidus-to-thalamus (r = 0.07, P = .43; r = 0.07, P = .40). When we controlled for age, sex, number of scans, and total dose, there were no significant associations between the estimated glomerular filtration rate and the percentage change of the dentate nucleus-to-pons (r = 0.16, P = .07; r = 0.15, P = .08) or percentage change of the globus pallidus-to-thalamus (r = –0.14, P = .12; r = –0.15, P = .09).CONCLUSIONS:In patients receiving an average of 12 intravenous gadobutrol administrations, no correlation was found between renal function and signal intensity ratio changes, even in those with mild or moderate renal impairment.

Gadolinium-based contrast agents (GBCAs) are commonly used in imaging to increase conspicuity and reveal enhancement characteristics of lesions. GBCAs can have either a macrocyclic or a linear molecular structure. Recent studies investigating CNS gadolinium deposition following repeat GBCA administrations showed measurable T1 shortening in the dentate nucleus and globus pallidus in patients who received GBCAs with a linear molecular structure.^1-12 Postmortem studies in patients who received linear agents have documented gadolinium deposition in the CNS, again most prominently in the dentate nucleus and globus pallidus, lending further credibility to imaging findings.^13-15The underlying mechanism of gadolinium retention remains unknown, as does the chemical formulation of the accumulated gadolinium. Despite these unknown mechanisms, gadolinium deposition is thought to involve dissociation of gadolinium from its chelating ligand, so macrocyclic agents are thought to be more stable than linear GBCAs due to their lower dissociation constants.¹⁶ Although the CNS deposition of linear GBCAs has been demonstrated previously, most studies failed to show increased signal intensity in the dentate nucleus and globus pallidus^2-10,17-27 after the use of macrocyclic GBCAs. Nevertheless, a few studies do report increased signal in the brain,^20,27-29 including a postmortem study that detected brain gadolinium, even in the setting of macrocyclic GBCA use.³⁰ On the other hand, two studies using highly sensitive inductively coupled plasma mass spectrometry to measure gadolinium in the brain in animal models did not find significant deposition with macrocyclic agents in the parenchyma, so the picture remains mixed.^31,32GBCAs undergo primary renal clearance;³³ hence, determining whether renal impairment could predispose a patient to gadolinium deposition is important. Patients on hemodialysis receiving a linear GBCA have a greater increase in dentate nucleus signal intensity (SI) compared with controls not on dialysis.¹¹ In 2017, Lee et al²⁰ showed that in a subgroup of 28 patients, there was a significant change in SI ratios in patients with estimated glomerular filtration rates (eGFR) between 45 and 60 mL/min/m² who received the macrocyclic agent gadoterate meglumine. Although much has been discussed regarding nephrogenic systemic fibrosis in the context of renal impairment, there is surprisingly little known regarding the potential effects of abnormal renal function on long-term CNS gadolinium deposition.The purpose of this study was to specifically investigate whether a relationship exists between SI and renal function in patients receiving a large number (≥10) of administrations of the macrocyclic GBCA gadobutrol.     

Quantitative T1ρ MRI of the Head and Neck Discriminates Carcinoma and Benign Hyperplasia in the Nasopharynx

BACKGROUND AND PURPOSE:T1ρ imaging is a new quantitative MR imaging pulse sequence with the potential to discriminate between malignant and benign tissue. In this study, we evaluated the capability of T1ρ imaging to characterize tissue by applying T1ρ imaging to malignant and benign tissue in the nasopharynx and to normal tissue in the head and neck.MATERIALS AND METHODS:Participants with undifferentiated nasopharyngeal carcinoma and benign hyperplasia of the nasopharynx prospectively underwent T1ρ imaging. T1ρ measurements obtained from the histogram analysis for nasopharyngeal carcinoma in 43 participants were compared with those for benign hyperplasia and for normal tissue (brain, muscle, and parotid glands) in 41 participants using the Mann-Whitney U test. The area under the curve of significant T1ρ measurements was calculated and compared using receiver operating characteristic analysis and the Delong test, respectively. A P < . 05 indicated statistical significance.RESULTS:There were significant differences in T1ρ measurements between nasopharyngeal carcinoma and benign hyperplasia and between nasopharyngeal carcinoma and normal tissue (all, P < . 05). Compared with benign hyperplasia, nasopharyngeal carcinoma showed a lower T1ρ mean (62.14 versus 65.45 × ms), SD (12.60 versus 17.73 × ms), and skewness (0.61 versus 0.76) (all P < .05), but no difference in kurtosis (P = . 18). The T1ρ SD showed the highest area under the curve of 0.95 compared with the T1ρ mean (area under the curve  = 0.72) and T1ρ skewness (area under the curve  = 0.72) for discriminating nasopharyngeal carcinoma and benign hyperplasia (all, P < .05).CONCLUSIONS:Quantitative T1ρ imaging has the potential to discriminate malignant from benign and normal tissue in the head and neck.

The spin-lattice relaxation time in the rotating frame known as T1ρ is sensitive to biologic processes associated with alterations in the macromolecular content of tissue. Quantitative T1ρ imaging has been used to study normal tissue and nonmalignant diseases in cartilage, discs, and ligaments,^1-3 brain,^4-7 liver,^8,9 heart,¹⁰ muscles,¹¹ and parotid glands.^11-13 However, T1ρ imaging also has the potential to characterize benign and malignant processes, but only a few studies have preliminarily evaluated T1ρ for human cancer imaging. These studies showed differences of T1ρ values between high- and low-grade gliomas¹⁴ and between benign and malignant tissue in the brain,^15,16 breast,¹⁷ and prostate.¹⁸We are interested in quantitative MR imaging sequences that can be used to discriminate nasopharyngeal carcinoma (NPC) from benign hyperplasia in the nasopharynx because these entities may overlap on anatomic MR imaging sequences.^19,20 Our hypothesis is that the T1ρ value of malignancy is different from that of benign tissue and can be used to discriminate these 2 entities. In this preliminary study, we also applied T1ρ imaging to a range of normal tissue in the head and neck (brain, pterygoid muscle, and parotid gland) to compare the T1ρ values of normal tissue with those of NPC.