High-Resolution 7T MR Imaging of the Motor Cortex in Amyotrophic Lateral Sclerosis

BACKGROUND AND PURPOSE:Amyotrophic lateral sclerosis is a progressive motor neuron disorder that involves degeneration of both upper and lower motor neurons. In patients with amyotrophic lateral sclerosis, pathologic studies and ex vivo high-resolution MR imaging at ultra-high field strength revealed the co-localization of iron and activated microglia distributed in the deep layers of the primary motor cortex. The aims of the study were to measure the cortical thickness and evaluate the distribution of iron-related signal changes in the primary motor cortex of patients with amyotrophic lateral sclerosis as possible in vivo biomarkers of upper motor neuron impairment.MATERIALS AND METHODS:Twenty-two patients with definite amyotrophic lateral sclerosis and 14 healthy subjects underwent a high-resolution 2D multiecho gradient-recalled sequence targeted on the primary motor cortex by using a 7T scanner. Image analysis consisted of the visual evaluation and quantitative measurement of signal intensity and cortical thickness of the primary motor cortex in patients and controls. Qualitative and quantitative MR imaging parameters were correlated with electrophysiologic and laboratory data and with clinical scores.RESULTS:Ultra-high field MR imaging revealed atrophy and signal hypointensity in the deep layers of the primary motor cortex of patients with amyotrophic lateral sclerosis with a diagnostic accuracy of 71%. Signal hypointensity of the deep layers of the primary motor cortex correlated with upper motor neuron impairment (r = −0.47; P < .001) and with disease progression rate (r = −0.60; P = .009).CONCLUSIONS:The combined high spatial resolution and sensitivity to paramagnetic substances of 7T MR imaging demonstrate in vivo signal changes of the cerebral motor cortex that resemble the distribution of activated microglia within the cortex of patients with amyotrophic lateral sclerosis. Cortical thinning and signal hypointensity of the deep layers of the primary motor cortex could constitute a marker of upper motor neuron impairment in patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disorder that entails degeneration of both upper and lower motor neurons,¹ producing fasciculation, muscle wasting and weakness, increased spasticity, and hyperreflexia.Upper motor neuron (UMN) impairment in ALS can be detected from clinical signs such as brisk reflexes and spasticity; however, the masking effect of the lower motor neuron involvement that reduces muscle strength and reflexes may make it hard to reveal clinical evidence of pyramidal involvement. Electrophysiologic investigations, such as prolongation of central motor conduction time in motor-evoked potentials in transcranial magnetic stimulation, may detect the upper motor neuron involvement, but results are conflicting and these measures are not a sensitive tool or a useful indicator of disease severity or prognosis.^2–4 Therefore, a robust in vivo biomarker of UMN impairment, though desirable,⁵ is not available.The hallmark of UMN pathology in ALS is depopulation of the Betz cells in the motor cortex and axonal loss within the descending motor pathway associated with myelin pallor and gliosis of the corticospinal tracts.⁶Conversely, also, characteristic of ALS pathology similar to that in other neurodegenerative disorders is the occurrence of a neuroinflammatory reaction, consisting of activated glial cells, mainly microglia and astrocytes, and T-cells.⁷ In transgenic mouse models of mutant SOD1-associated familial ALS, reactive microglial cells and astrocytes actively contribute to the death of motor neurons.⁷Moreover, a significant association between cortical microgliosis and UMN damage has been described by using PET with a radioligand for microglia.⁸Recently, an ex vivo study with Perls'' DAB staining detected intracellular and extracellular iron deposits in the motor cortex of patients with ALS. Iron in the form of ferritin is detected in activated microglia (CD68+) in the middle and deep layers of the motor cortex, sparing the superficial layers.⁹Gradient recalled-echo T2* sequences, which can provide signal magnitude, phase, and their combination in susceptibility-weighted imaging,¹⁰ are considered the most appropriate technique to visualize small amounts of uniformly distributed iron, such as ferritin,^11,12 and are the most sensitive sequences for detecting the low signal intensity in the precentral cortex in patients with ALS.¹³The introduction of ultra-high field (UHF) MR imaging equipment greatly increases the sensitivity to susceptibility phenomena and allows obtaining in vivo spatial resolution of approximately 200 μm, which enables determination of the cortical layers.¹⁴The aims of our study were to measure the thickness of the primary motor cortex (M1) and to describe the distribution of the iron-related signal changes in the M1 of patients with ALS as a possible in vivo biomarker of UMN impairment by using targeted high-resolution gradient recalled-echo T2* sequences at UHF.     

A distinct MR imaging phenotype in amyotrophic lateral sclerosis: correlation between T1 magnetization transfer contrast hyperintensity along the corticospinal tract and diffusion tensor imaging analysis

BACKGROUND AND PURPOSE:In the search for a diagnostic marker in ALS, we focused our attention on the hyperintense signal intensity in T1 MTC MR images along the CST, detected in some patients and not found in other patients with ALS and in control subjects. The aim of this study was to investigate the relationship between the hyperintense signal intensity in T1 MTC images and white matter damage. To this purpose, we studied potential heterogeneities in DTI values within our patients by using TBSS without a priori anatomic information.MATERIALS AND METHODS:In 43 patients with ALS and 43 healthy control subjects, the presence or absence of T1 MTC hyperintense signal intensity was evaluated. With a DTI analysis with a TBSS approach, differences in FA distribution between the 2 groups (patients with T1 MTC hyperintense signal intensity and patients without it) compared with each other and with control subjects were investigated.RESULTS:We found regional differences in white matter FA between patients with T1 MTC hyperintense signal intensity (37.2%) and patients without it. Patients with T1 MTC abnormal signal intensity showed lower FA strictly limited to the motor network and the posterior aspect of the body of the CC without extramotor FA reductions, whereas patients without this sign showed FA reductions in several confluent regions within and outside the CST and in the whole CC.CONCLUSIONS:T1 MTC hyperintense signal intensity in the CST and posterior CC, when present, is specific for ALS and represents, among patients with ALS, a possible distinct phenotype of presentation of the disease with prominent UMN involvement.

ALS is a chronic neurodegenerative disease that selectively involves the motor system. Clinically, patients present with UMN and LMN signs and symptoms. Degeneration of the UMNs in the precentral gyrus of the cerebral cortex is the main pathologic change, accompanied by degeneration of the CST from the cerebral cortex to the spinal cord.^1,2The incidence of sporadic ALS ranges between 1.5 and 2.7 per 100,000 population/year (average 1.89 per 100,000/year) in Europe and North America.^3–7In patients with ALS, MR imaging of the brain may show signal-intensity abnormalities, namely a hyperintense signal intensity in PD-T2^8–10 and FLAIR^11–14 MR images in the CST from the white matter of the precentral gyrus through the corona radiata and posterior limb of the internal capsule down to the brain stem, consistent with CST degeneration.In addition, a hypointense rim in the posterior aspect of the precentral gyrus attributed to iron accumulation has been found.^{12,13,15–17}Only a few authors have specifically studied T1^13,16,18 and T1 MTC sequences, finding either a hyperintense signal intensity¹⁸ or a reduction of MTR along the CST,^19,20 suggesting the presence of a more severe tissue damage. MTC imaging focuses on fundamental relaxation properties of water protons and is applied to augment image contrast and tissue specificity. This technique is based on the application of off-resonance radio frequency pulses before the pulse sequence to preferentially saturate immobile protons of macromolecules, which then transfer magnetization to mobile protons in free water and can be used to detect changes in the structural status of the brain tissue.²¹MT imaging of the gray matter of patients with ALS recently showed a reduction of MTR in the precentral gyrus and also in the prefrontal and temporal cortices.²²In our experience, T1 MTC hyperintense signal intensity of the CST is a characteristic but inconstant finding in patients with ALS. On the hypothesis that this feature could correspond to a specific disease phenotype, we used MT imaging of the white matter of patients with ALS, focusing our attention on the T1 MTC signal intensity along the CST. To further characterize the relationship between the hyperintense signal intensity in T1 MTC and the white matter damage, we followed a DTI approach. Among in vivo neuroimaging techniques, DTI is in fact the criterion standard method to assess the structural integrity of white matter. Diffusion anisotropy describes how variable the diffusion is in different directions and is most commonly quantified via a measure known as FA.^23,24 A decrease in FA has been shown to be related to axonal fiber degeneration and myelin breakdown.²⁵In this article, we used TBSS,²⁶ a voxel-based approach that uses extracted and skeletonized white matter tracts in the FA images of all subjects. TBSS is used in an effort to overcome the problems associated with the use of standard registration algorithms in other voxel-based approaches.Several DTI studies have reported reduced FA in the CSTs of patients with ALS, though the extent and distribution of these changes have been variable.^26–39 Reduced FA along the CST from the corona radiata through the internal capsule and into the brain stem has been reported by using both region-of-interest^27,32,36 and voxel-based approaches.^{28,33,35,38,40}In addition, some authors^28,35 described a decrease in FA, not only in the CST but also in regions outside the main motor cortices and the CST. In previous studies that used TBSS, FA reductions were found in regions outside the motor network, such as the CC and the white matter underneath the premotor, primary sensory, frontal, and prefrontal cortices.^37,38 In another DTI study by using TBSS, the authors reported FA reductions in the body and genu of the CC and corona radiata in patients with ALS compared with controls, and mean diffusivity, axial diffusivity, and radial diffusivity increased in regions outside strictly motor areas.³⁹The aim of our investigation was to explore the relationship between the hyperintense signal intensity in T1 MTC and white matter damage in a series of patients with ALS by using a TBSS approach and to establish whether there were regional differences in white matter FA between patients with T1 MTC hyperintense signal intensity and patients without it.     

Cortical Activation Through Passive-Motion Functional MRI

BACKGROUND AND PURPOSE:Functional brain mapping is an important technique for neurosurgical planning, particularly for patients with tumors or epilepsy; however, mapping has traditionally involved invasive techniques. Existing noninvasive techniques require patient compliance and may not be suitable for young children. We performed a retrospective review of our experience with passive-motion functional MR imaging in anesthetized patients to determine the diagnostic yield of this technique.MATERIALS AND METHODS:A retrospective review of patients undergoing passive-motion fMRI under general anesthesia at a single institution over a 2.5-year period was performed. Clinical records were evaluated to determine the indication for fMRI, the ability to detect cortical activation, and, if present, the location of cortical activation.RESULTS:We identified 62 studies in 56 patients in this time period. The most common indication for fMRI was epilepsy/seizures. Passive-motion fMRI identified upper-extremity cortical activation in 105 of 119 (88%) limbs evaluated, of which 90 (86%) activations were in an orthotopic location. Lower-extremity cortical activation was identified in 86 of 118 (73%) limbs evaluated, of which 73 (85%) activations were in an orthotopic location.CONCLUSIONS:Passive-motion fMRI was successful in identifying cortical activation in most of the patients. This tool can be implemented easily and can aid in surgical planning for children with tumors or candidates for epilepsy surgery, particularly those who may be too young to comply with existing noninvasive functional measures.

The criterion standard for presurgical brain mapping has typically been intraoperative cortical stimulation mapping and the Wada test.^1–4 Both methods are invasive procedures, and their efficacy and superiority over other mapping procedures have become less clear with advances in noninvasive brain-mapping techniques,^4–12 with some studies showing that these alternative methods are comparable to stand-alone and/or adjunct techniques.^9–18 Blood oxygen level–dependent functional MR imaging is an increasingly used imaging technique in the clinical setting. Since the early 1990s, it has been used to study brain function in healthy individuals and particularly for surgical planning in patients with brain tumors or epilepsy.^{2,4,17,19–22} This imaging technique maps areas of cortical activation via changes in blood flow to metabolically active brain regions during cortical activation, typically secondary to specific motor, language, and visual tasks. fMRI provides a number of benefits: it is noninvasive, it is a useful tool for presurgical evaluation for invasive procedures that involve high risk,^{2,4,17,19,20,23,24} and it can also assess the current function of patients with brain lesions or previous brain surgery.^20,25 Clinically, it is performed as a task-based technique that requires the patient to cooperate and keep all other body movements to a minimum. Incomplete compliance limits the utility of this technology and introduces risk for spurious results. Compliance with the tasks and remaining still is a particular concern in young children and patients with developmental or acquired cognitive deficits.^26,27 Even children who can perform the task during training sessions may not be able to comply in the MR imaging scanner.²⁷A strategy that allows this information to be obtained from subjects who are unable to cooperate is to perform a similar fMRI task under sedation. fMRI of sedated patients performed with passive motion of the extremities has been successful in some reports.^{15,23,24,28,29} The goal is to map the motor cortex while removing the need for task compliance and reducing or eliminating concerns for patient motion.^23,24,28 We performed a retrospective review of our institution''s 2.5-year experience with passive-motion fMRI to assess the feasibility and reliability of this imaging technique.     

Manual Segmentation of MS Cortical Lesions Using MRI: A Comparison of 3 MRI Reading Protocols

BACKGROUND AND PURPOSE:Double inversion recovery has been suggested as the MR imaging contrast of choice for segmenting cortical lesions in patients with multiple sclerosis. In this study, we sought to determine the utility of double inversion recovery for cortical lesion identification by comparing 3 MR imaging reading protocols that combine different MR imaging contrasts.MATERIALS AND METHODS:Twenty-five patients with relapsing-remitting MS and 3 with secondary-progressive MS were imaged with 3T MR imaging by using double inversion recovery, dual fast spin-echo proton-density/T2-weighted, 3D FLAIR, and 3D T1-weighted imaging sequences. Lesions affecting the cortex were manually segmented by using the following 3 MR imaging reading protocols: Protocol 1 (P1) used all available MR imaging contrasts; protocol 2 (P2) used all the available contrasts except for double inversion recovery; and protocol 3(P3) used only double inversion recovery.RESULTS:Six hundred forty-three cortical lesions were identified with P1 (mean = 22.96); 633, with P2 (mean = 22.6); and 280, with P3 (mean = 10). The counts obtained by using P1 and P2 were not significantly different (P = .93). The counts obtained by using P3 were significantly smaller than those obtained by using either P1 (P < .001) or P2 (P < .001). The intraclass correlation coefficients were P1 versus P2 = 0.989, P1 versus P3 = 0.615, and P2 versus P3 = 0.588.CONCLUSIONS:MR imaging cortical lesion segmentation can be performed by using 3D T1-weighted and 3D FLAIR images acquired with a 1-mm isotropic voxel size, supported by conventional T2-weighted and proton-density images with 3-mm-thick sections. Inclusion of double inversion recovery in this multimodal reading protocol did not significantly improve the cortical lesion identification rate. A multimodal approach is superior to using double inversion recovery alone.

Multiple sclerosis is an inflammatory and neurodegenerative disease that affects both the white matter and gray matter of the central nervous system. Postmortem immunohistochemical characterization of cortical lesions (CLs) has allowed the identification of a substantial burden of cortical GM lesions in patients with long-standing MS.^1–5 However, the prevalence of cortical lesions at earlier stages of MS is underexplored.⁶ As a result, an efficient, standardized MR imaging protocol for segmentation of CLs in early-stage MS has become an important research goal. Double inversion recovery (DIR) MR imaging has generally been selected because it enhances the conspicuity of GM by suppressing unwanted signal from both WM and CSF. However, DIR images have a low signal-to-noise ratio due to the application of 2 inversion pulses. They are also prone to hyperintense vascular artifacts, which can confound CL identification.^7–14In 2011, an international panel of experts formulated consensus recommendations for scoring CLs at 1.5T and 3T by using DIR.¹¹ As part of the recommendations, they noted that in the future, the additional use of other MR imaging contrasts (T1-weighted, T2-weighted, or fluid-attenuated inversion recovery images) in combination with DIR could improve the detection of cortical lesions by reducing the number of false-positives and false-negatives. Several groups have since reported on such multicontrast approaches for segmenting CLs. Examples include the following: 1) CL segmentation performed by using a single MR imaging contrast followed by subsequent verification of lesion labels on other contrasts¹³; 2) CL segmentation performed independently by using 2 different MR imaging contrasts, where a tight correlation between the counts is considered evidence that each MR imaging contrast yields counts proportional to the real lesion load¹⁵; 3) CL segmentation performed by using a single MR imaging contrast with the results subsequently reviewed by a second (more experienced) rater who uses other contrasts to resolve ambiguities/potential false-positives¹⁶; and 4) CL segmentation performed independently for each independent contrast, and then each count compared with the counts obtained from the other MR imaging contrasts to determine which one detects the highest number of lesions.¹⁷ The variability among these methods has led to difficulty in developing a standardized CL segmentation protocol.¹¹ Consequently, a major goal of this work was to identify a robust, multicontrast CL segmentation protocol that could be used with more generally available MR imaging pulse sequences at clinically accessible magnetic field strengths.According to the consensus recommendations, only type I leukocortical and type II intracortical lesions should be considered for radiologic scoring¹¹ in MS. However, type I lesions affecting both the cortex and the juxtacortical white matter are often difficult to differentiate from purely juxtacortical lesions. Consequently, these lesions can be misclassified. Type II lesions are the smallest and affect the cortex without reaching either the pial or white matter boundaries. These lesions are also challenging to detect visually by using 1.5T or 3T MR imaging. Subpial lesions (type III and IV), extending from the pial boundary down to the white matter surface, are not considered within the consensus guidelines for MR imaging at 1.5 and 3T due to their low detectability at these clinical field strengths. Even with these simplifying assumptions in place, CL identification has been highly variable.^10,13,18,19 The prevalence of MR imaging–identified intracortical lesions ranges from 8.2% to 46% across different published reports.^{10,12,13,18,19} This variability may partially reflect the variable sensitivity of current MR imaging protocols but also may indicate the inherent variability of cortical lesion involvement across MS disease stages and individual patients. Support for this hypothesis is provided by histology studies in which the percentage of intracortical lesions (type II) also shows a wide range: 7%–31% and 17%–71% when we consider types I and type II combined.^{1–6,19,20,21}A significant aim of our study was to simplify and improve the process of manual cortical lesion segmentation when using multiple MR imaging contrasts derived from 3T MR imaging. We specifically strived to identify a lesion-segmentation method with reduced variability and reduced false-positive identifications. To do this, we avoided classification of cortical lesions into subtypes.     

Associations between Measures of Structural Morphometry and Sensorimotor Performance in Individuals with Nonspecific Low Back Pain

BACKGROUND AND PURPOSE:To date, most structural brain imaging studies in individuals with nonspecific low back pain have evaluated volumetric changes. These alterations are particularly found in sensorimotor-related areas. Although it is suggested that specific measures, such as cortical surface area and cortical thickness, reflect different underlying neural architectures, the literature regarding these different measures in individuals with nonspecific low back pain is limited. Therefore, the current study was designed to investigate the association between the performance on a sensorimotor task, more specifically the sit-to-stand-to-sit task, and cortical surface area and cortical thickness in individuals with nonspecific low back pain and healthy controls.MATERIALS AND METHODS:Seventeen individuals with nonspecific low back pain and 17 healthy controls were instructed to perform 5 consecutive sit-to-stand-to-sit movements as fast as possible. In addition, T1-weighted anatomic scans of the brain were acquired and analyzed with FreeSurfer.RESULTS:Compared with healthy controls, individuals with nonspecific low back pain needed significantly more time to perform 5 sit-to-stand-to-sit movements (P < .05). Brain morphometric analyses revealed that cortical thickness of the ventrolateral prefrontal cortical regions was increased in patients with nonspecific low back pain compared with controls. Furthermore, decreased cortical thickness of the rostral anterior cingulate cortex was associated with lower sit-to-stand-to-sit performance on an unstable support surface in individuals with nonspecific low back pain and healthy controls (r = −0.47, P < .007). In addition, a positive correlation was found between perceived pain intensity and cortical thickness of the superior frontal gyrus (r = 0.70, P < .002) and the pars opercularis of the inferior ventrolateral prefrontal cortex (r = 0.67, P < .004). Hence, increased cortical thickness was associated with increased levels of pain intensity in individuals with nonspecific low back pain. No associations were found between cortical surface area and the pain characteristics in this group.CONCLUSIONS:The current study suggests that cortical thickness may contribute to different aspects of sit-to-stand-to-sit performance and perceived pain intensity in individuals with nonspecific low back pain.

Nonspecific low back pain (NSLBP) refers to low back pain that is not attributable to a specific cause. This category of low back pain disorders includes almost all low back pain symptoms.^1–3 Despite much effort in the development of treatment strategies for this large population,⁴ the effects of current NSLBP interventions are rather small. Therefore, understanding the underlying neural basis of NSLBP is crucial.Previous imaging studies showed structural alterations in cortical and subcortical brain regions in individuals with NSLBP. However, mixed findings were obtained. Both increases and decreases in gray matter volume in different brain regions were found in individuals with NSLBP compared with healthy controls. Volumetric alterations in individuals with NSLBP were observed, for example, in the dorsolateral prefrontal cortex,^5–7 in the somatosensory cortex,^6,8,9 in the temporal lobes,^6,8 and in the thalamus.^5–7 Together, most gray matter alterations in NSLBP, either reduced or increased, are observed in areas related to sensorimotor control. These alterations in sensorimotor-related areas are indicative of impaired sensorimotor performance, as observed in individuals with NSLBP with behavioral measures.^10–12 For example, individuals with NSLBP need notably more time to perform 5 consecutive sit-to-stand-to-sit (STSTS) movements compared with healthy controls.¹³ This STSTS task necessitates optimal sensorimotor control, which requires an efficient processing of sensory and motor information across the brain.¹⁴ However, nearly all structural brain imaging studies in NSLBP and in sensorimotor control have evaluated volumetric changes.^5–9 Only 1 study in patients with Parkinson disease investigated how structural morphometry was associated with motor performance, showing an association between cortical thinning of the sensory parietotemporal areas and motor deficits.¹⁵ However, in NSLBP, cortical thickness and cortical surface area have been relatively understudied, while these 2 aspects of brain structure may be crucial to functional connectivity.Cortical thickness and cortical surface area have a distinct genetic origin,^16,17 a contrasting phylogeny,¹⁸ and different developmental trajectories.¹⁹ In addition, it is suggested that cortical thickness and cortical surface area reflect different aspects of the underlying neural architecture.²⁰ More specifically, cortical surface area is primarily determined by the number of columns within a cortical region, whereas cortical thickness is thought to reflect the number of cells within these cortical columns.^18,21 Therefore, evaluation of cortical surface area and cortical thickness as separate measures can provide interesting additional knowledge on the neural mechanisms of NSLBP and sensorimotor tasks. These measures of structural morphometry can be computed by a surface-based analysis method called FreeSurfer (http://surfer.nmr.mgh.harvard.edu).²²With the FreeSurfer analysis suite, 2 recent studies^23,24 have provided evidence for alterations in cortical thickness in individuals with NSLBP compared with healthy controls. Although, Kong et al,²³ found increased cortical thickness in the bilateral primary somatosensory cortex, somatotopically associated with the lower back, in individuals with NSLBP, Dolman et al,²⁴ demonstrated that the differences in cortical thickness between individuals with NSLBP and healthy controls disappeared when controlling for age. Nevertheless, little research has been done on the associations with sensorimotor control and pain by using both surface area and cortical thickness. Therefore, this study was designed to investigate the distinct relation between the STSTS performance and the cortical surface area and cortical thickness in individuals with NSLBP and healthy controls. An association between cortical thinning of sensorimotor brain areas and a longer duration to perform 5 consecutive STSTS movements was hypothesized. This correlation analysis was performed to reveal the potential different contributions of the 2 nonvolumetric parameters to sensorimotor control. In addition, considering recent findings,^23,24 we hypothesized subtle cortical thinning in both sensorimotor- and pain-related brain regions in individuals with NSLBP compared with healthy controls.     

Heterogeneity of Cortical Lesion Susceptibility Mapping in Multiple Sclerosis

BACKGROUND AND PURPOSE:Quantitative susceptibility mapping has been used to characterize iron and myelin content in the deep gray matter of patients with multiple sclerosis. Our aim was to characterize the susceptibility mapping of cortical lesions in patients with MS and compare it with neuropathologic observations.MATERIALS AND METHODS:The pattern of microglial activation was studied in postmortem brain tissues from 16 patients with secondary-progressive MS and 5 age-matched controls. Thirty-six patients with MS underwent 3T MR imaging, including 3D double inversion recovery and 3D-echo-planar SWI.RESULTS:Neuropathologic analysis revealed the presence of an intense band of microglia activation close to the pial membrane in subpial cortical lesions or to the WM border of leukocortical cortical lesions. The quantitative susceptibility mapping analysis revealed 131 cortical lesions classified as hyperintense; 33, as isointense; and 84, as hypointense. Quantitative susceptibility mapping hyperintensity edge found in the proximity of the pial surface or at the white matter/gray matter interface in some of the quantitative susceptibility mapping–hyperintense cortical lesions accurately mirrors the microglia activation observed in the neuropathology analysis.CONCLUSIONS:Cortical lesion susceptibility maps are highly heterogeneous, even at individual levels. Quantitative susceptibility mapping hyperintensity edge found in proximity to the pial surface might be due to the subpial gradient of microglial activation.

In recent years, it has become increasingly clear that cortical and deep gray matter are not spared in multiple sclerosis.^1,2 Several neuropathologic studies have consistently demonstrated that cortical gray matter lesions (CLs) are frequent in MS and that their accumulation strongly correlates with long-term disability measures.³ These observations have been confirmed and extended by imaging studies showing that CLs correlate with both physical and cognitive disability.^4,5 Unfortunately, despite these data, little is known about the pathogenetic mechanisms underlying CL development.Neuropathologic studies have highlighted the lack of substantial focal immune infiltrates, complement deposition, and blood-brain barrier damage in MS CLs^6,7 and have suggested that meningeal inflammation and activated microglia may have a key role in GM damage.^3,8 In particular, most of the examined CLs in postmortem brain samples exhibit a chronic inflammatory phenotype and rims of activated microglia close to the pial surface or the lesion edge.^3,8,9In a previous MR imaging/histopathologic combined study,¹⁰ hypointense rings on T2*, representing activated microglia or macrophages, were observed at the edge of chronic active CLs. Similar rings have been reported in white matter lesions by using T2* phase imaging.¹¹ These results, in line with those by Kooi et al,¹² showed that some patients with MS had rims of activated microglia at the border of the CLs, whereas others did not. More recently, a study on ultra-high-field MR imaging on postmortem specimens of 2 patients with MS¹³ did not find rings of activated iron-laden microglia within CLs, and all CLs appeared darker in R2* images and brighter in magnitude images.Magnetic susceptibility is a fundamental physical tissue property, which is known to reflect clinically relevant tissue characteristics, such as tissue iron content. During the last decades, phase imaging,¹⁴ SWI,¹⁵ and T2* imaging¹⁶ have been used to qualitatively assess magnetic susceptibility variations in cerebral tissue, including deep and cortical gray matter.¹⁷ Increased paramagnetic susceptibility-weighted filtered phase values were observed in the putamen in patients with clinically isolated syndrome compared with healthy controls.¹⁸ Thus, this finding suggests that susceptibility is sensitive to MS even in the early phase of the disease. In this context, quantitative susceptibility mapping (QSM),¹⁹ which overcomes several nonlocal restrictions of susceptibility-weighted and phase imaging, could shed some light on the pathologic process taking place in the cortical GM of patients with MS. A recent study has investigated MS, using QSM in the basal ganglia,²⁰ showing that iron accumulation correlated with disease progression even in a patient with clinically isolated syndrome. Moreover, another group showed how WM MS lesions could be investigated longitudinally with QSM; the investigation could provide insight into the pathogenesis of those lesions.²¹ However, limited quantitative susceptibility data of cortical GM and, especially, of CLs are available. Indeed, only a recent study at 7T showed,²² in a restricted cohort of patients with MS, heterogeneity in CLs, with a predominant iron loss hypothesis.In the present study, the characteristics of CLs were first determined with an analysis of microglial/macrophage activity in the postmortem MS brain, followed by the analysis of similar lesions in patients. 3D echo-planar imaging, which uses phase data to quantify local tissue susceptibility, was combined with a 3D double inversion recovery (DIR) at 3T to characterize the in vivo susceptibility of CLs in patients with MS.     

Reduced cortical thickness in children with new-onset seizures

BACKGROUND AND PURPOSE:Children with new-onset seizures may have antecedent neurobiologic alterations that predispose them to developing seizures. Our aim was to evaluate hippocampal and thalamic volumes and lobar cortical thickness of children with new-onset seizures.MATERIALS AND METHODS:Twenty-nine children with new-onset seizures and normal MR imaging findings were recruited. Ten patients had generalized seizures, 19 had partial seizures, and 15 were on antiepileptic medications. Twenty-three age-matched healthy controls were also recruited. Hippocampal and thalamic volumes and lobar cortical thickness, including frontal, medial temporal, lateral temporal, parietal, cingulate, and occipital cortical thickness, were assessed by using volumetric T1-weighted imaging and were compared between patients and controls.RESULTS:There were no significant differences in hippocampal and thalamic volumes of patients with new-onset seizures, including the subgroups with generalized and partial seizures and those on and off antiepileptic medications, compared with controls (P > .01). There was significant reduction in cortical thickness in right cingulate (P = .004), right medial temporal (P = .006), and left frontal (P = .007) cortices in patients with new-onset seizures. Patients with generalized seizures did not demonstrate a significant reduction in cortical thickness (P > .01). Patients with partial seizures demonstrated a significant reduction in cortical thickness in the right frontal (P = .008), right parietal (P = .003), and left frontal (P = .007) cortices. There were no significant differences in cortical thickness among patients on or off antiepileptic medications (P > .01).CONCLUSIONS:We found reduced cortical thickness in children with new-onset seizures. Further studies are necessary to elucidate the neurobiologic relevance of these structural changes.

Patients with chronic localization-related epilepsy, including adults and children, have demonstrated structural abnormalities, including cortical thickness and volume reduction and reduced hippocampal volume.^1–7 Volumetric abnormalities have been reported in neuronal regions involved in the generation and propagation of seizures, including the hippocampus,^8–11 amygdala,¹² entorhinal cortex,¹³ thalamus,¹⁴ and also extratemporal regions^15,16 in patients with chronic temporal lobe epilepsy. Children with idiopathic generalized epilepsies have also shown distributed patterns of abnormality affecting the thalamus and frontal lobe.^17–21 It is not known whether the structural alterations developed during a vulnerable phase of cerebral development or are the cumulative effects of recurrent seizures²² or are a combination of these factors acting synergistically.¹¹ To determine whether antecedent neurobiologic alterations are present, assessment could be performed in a population of patients with new-onset seizures, which would exclude the confounding effects of recurrent seizures and long-term antiepileptic medications on the brain.Children with new-onset seizures or new-onset epilepsy are known to have neuropsychological deficits and academic underachievement,^23–26 even when they are intellectually healthy. It is possible that there is an antecedent neurobiologic alteration that predisposes to both seizures and neuropsychological deficits. Volumetric imaging of the brain has been used to quantify total and lobar gray and white matter volumes in children with new-onset epilepsy but did not identify overall differences in total cerebral or lobar gray and white matter volumes.²⁴ It is possible that voxel-based morphometry of total and lobar volumes is not sufficiently sensitive to assess subtle changes in brain structures. Alternatively, other structures such as the hippocampi or thalami could be more susceptible to the neurobiologic alterations and are, therefore, more likely to manifest structural changes. In this study, we evaluated the hippocampal and thalamic volumes and lobar cortical thickness of the cerebral hemispheres of children with new-onset seizures. Our hypothesis was that antecedent structural alterations, including changes in cortical thickness and other gray matter structures, were present in children with new-onset seizures, which predisposed the patients to seizures.     

Phase White Matter Signal Abnormalities in Patients with Clinically Isolated Syndrome and Other Neurologic Disorders

BACKGROUND AND PURPOSE:Identifying MRI biomarkers that can differentiate multiple sclerosis patients from other neurological disorders is a subject of intense research. Our aim was to investigate phase WM signal abnormalities for their presence, prevalence, location, and diagnostic value among patients with clinically isolated syndrome and other neurologic disorders and age-, sex-, and group-matched healthy controls.MATERIALS AND METHODS:Forty-eight patients with clinically isolated syndrome and 30 patients with other neurologic diseases and a healthy control group (n = 47) were included in the study. Subjects were scanned at 3T by using SWI-filtered phase and T2WI, with WM signal abnormalities ≥3 mm being classified.RESULTS:Patients with clinically isolated syndrome had significantly more phase and T2 WM signal abnormalities than healthy controls (P < .001). Phase WM signal abnormalities were more prevalent among patients with clinically isolated syndrome compared with patients with other neurologic disorders (4:1 ratio), whereas T2 WM signal abnormalities were more ubiquitous with a 2:1 ratio. The presence of phase WM signal abnormalities was sensitive for clinically isolated syndrome (70.8%) and achieved a moderate-to-high specificity for differentiating patients with clinically isolated syndrome and healthy controls, patients with other neurologic disorders, and patients with other neurologic disorders of other autoimmune origin (specificity, 70%–76.7%). Combining the presence of ≥2 phase lesions with the McDonald 2005 and 2010 criteria for dissemination in space improved the specificity (90%), but not the accuracy, in differentiating patients with clinically isolated syndrome from those with other neurologic disorders. In subanalyses among patients with clinically isolated syndrome who converted to clinically definite multiple sclerosis versus those who did not within a 3-year follow-up period, converters had significantly more phase (P = .008) but not T2 or T1 WM signal abnormalities.CONCLUSIONS:Phase WM signal abnormalities are prevalent among patients with clinically isolated syndrome. The presence of (multiple) phase WM signal abnormalities tended to be more predictive of conversion to clinically definite multiple sclerosis and was specific in differentiating patients with clinically isolated syndrome and other neurologic disorders, compared with T2 WM signal abnormalities; however, the accuracy remains similar to that of the current McDonald criteria.

The occurrence of WM signal abnormalities (SAs) is a hallmark feature of multiple sclerosis, yet the clinical relevance of the pathologic substrate of WM-SAs is disappointing.^1–4 WM-SAs observed on T2WI and T1WI represent focal pathology and are thought to be caused by inflammation, edema, demyelination, or gliosis.² They are usually secondary to active inflammation, imaged by using postcontrast T1WI gadolinium-enhanced scanning.⁵ Even though T2 WM-SAs are present at the first demyelinating episode, the poor specificity of conventional MR imaging^1,6 and comparable MR imaging features at disease onset compared with ischemic, autoimmune diseases or aging limits their predictive value.Previously, differential diagnosis between MS and other conditions was considered by using brain and spinal cord MR imaging and incorporating number, location, and morphology of T2 WM-SAs in the diagnostic criteria of MS⁷ or by using different nonconventional MR imaging techniques.^6,8–10 It is important to further investigate the value of nonconventional MR imaging techniques in the MS differential diagnosis, for example by using SWI-filtered phase to identify early focal brain pathology indicative of MS, especially in patients with clinically isolated syndrome (CIS).Recent studies have confirmed histologically that WM-SAs visible on MR imaging phase and R^2* correspond to focal iron deposits, whereas T2 and T1 WM-SAs are influenced by water content.¹¹ A substantial subset of MS WM-SAs has phase shifts^11,12 and morphologic differences.^11–15 However, factors other than nonheme iron may influence the observed WM-SA signal, such as changes in myelin, deoxyhemoglobin, and inflammation.^11,16–19 Therefore, because there are a multitude of effects, it is not fully known to what extent they each individually influence SWI-filtered phase changes.Phase changes may signal early WM-SA development^17,20 in that these phase WM-SAs may appear initially but then disappear as the pathology advances.¹⁷ Considering that the distinct pathologies influencing phase shift (eg, cellular/myelin destruction, iron levels, microstructural changes) in WM-SAs are most likely intricately related and are observed in MS and related disorders,^{12,14,15,21–23} the inquiry into pathology visible on SWI-filtered phase remains important regardless of the causative factors.SWI-filtered phase work has mostly focused on patients with MS,^{11,13–15,24} high-field-strength imaging,^11,13,24 or histologically validating phase WM-SAs.^11,25 Regardless of what pathology phase WM-SAs represent, it is imperative to identify whether their presence has diagnostic value. In the present study, we assessed WM-SAs visible on T2WI and SWI-filtered phase among patients with CIS and patients with other neurologic disorders (OND) to investigate their prevalence, location, and ability to differentiate disease groups.     

Ultra-High-Field MR Imaging in Polymicrogyria and Epilepsy

BACKGROUND AND PURPOSE:Polymicrogyria is a malformation of cortical development that is often identified in children with epilepsy or delayed development. We investigated in vivo the potential of 7T imaging in characterizing polymicrogyria to determine whether additional features could be identified.MATERIALS AND METHODS:Ten adult patients with polymicrogyria previously diagnosed by using 3T MR imaging underwent additional imaging at 7T. We assessed polymicrogyria according to topographic pattern, extent, symmetry, and morphology. Additional imaging sequences at 7T included 3D T2* susceptibility-weighted angiography and 2D tissue border enhancement FSE inversion recovery. Minimum intensity projections were used to assess the potential of the susceptibility-weighted angiography sequence for depiction of cerebral veins.RESULTS:At 7T, we observed perisylvian polymicrogyria that was bilateral in 6 patients, unilateral in 3, and diffuse in 1. Four of the 6 bilateral abnormalities had been considered unilateral at 3T. While 3T imaging revealed 2 morphologic categories (coarse, delicate), 7T susceptibility-weighted angiography images disclosed a uniform ribbonlike pattern. Susceptibility-weighted angiography revealed numerous dilated superficial veins in all polymicrogyric areas. Tissue border enhancement imaging depicted a hypointense line corresponding to the gray-white interface, providing a high definition of the borders and, thereby, improving detection of the polymicrogyric cortex.CONCLUSIONS:7T imaging reveals more anatomic details of polymicrogyria compared with 3T conventional sequences, with potential implications for diagnosis, genetic studies, and surgical treatment of associated epilepsy. Abnormalities of cortical veins may suggest a role for vascular dysgenesis in pathogenesis.

Polymicrogyria is a malformation of the cerebral cortex secondary to abnormal migration and postmigrational development.¹ It is characterized by an excessive number of abnormally small gyri separated by shallow sulci, associated with fusion of the overlying molecular layer (layer 1) of the cerebral cortex.² This combination of features produces a characteristic appearance of irregularity at both the cortical surface and cortical–white matter junction.^3,4 Its pathogenesis is still poorly understood, and its histopathology, clinical features, topographic distribution, and imaging appearance are heterogeneous. Deficiencies in the understanding of this malformation result from both causal heterogeneity (causative factors include destructive events such as congenital infections,^5,6 in utero ischemia,⁷ metabolic disorders, and several gene mutations and copy number variations^1,8,9) and the limited number of postmortem examinations available.The topographic distribution of polymicrogyria may be focal, multifocal, or diffuse; unilateral or bilateral; and symmetric or asymmetric.^10–15 Polymicrogyria can occur as an isolated disorder or can be associated with other brain abnormalities such as corpus callosum dysgenesis, cerebellar hypoplasia, schizencephaly, and periventricular and subcortical heterotopia.^16,17Clinical manifestations of patients with polymicrogyria have a large spectrum, ranging from isolated selective impairment of cognitive function¹⁸ to severe encephalopathy and intractable epilepsy.¹⁹ The severity of neurologic manifestations and the age at presentation are, in part, influenced by the extent and location of the cortical malformation but may also depend on its specific etiology.Neuroimaging has a primary role in the diagnosis and classification of polymicrogyria due to its noninvasive nature. Imaging findings are variable and are primarily determined by the morphology of the malformed cortex itself but also by the maturity of myelination and imaging-related technical factors (section thickness, gray-white matter contrast).²⁰ In addition, polymicrogyria-like patterns can be seen in certain malformations, such as tubulinopathies²¹ and cobblestone malformations^22–24; these have different histologic appearances but similar MR imaging appearances to polymicrogyria, which can lead to false diagnoses.On the basis of morphologic characteristics, Barkovich^2,20 described the variable appearance of polymicrogyria on MR imaging and suggested that the gyral-sulcal dysmorphisms may be roughly divided into 3 main categories: coarse with a thick, bumpy cortex and irregular surface on both the pial and gray-white junction sides; delicate with multiple small, fine gyri of thin cortex that remains thin even after myelination; and sawtooth, composed of thin microgyri separated by deep sulci (primarily seen in diffuse polymicrogyria and before myelination develops). However, numerous gradations of morphology exist within these groups. To date, neither functional nor etiologic associations have been inferred on the basis of this imaging categorization of a polymicrogyric cortex.Over the past several years, ultra-high-field 7T MR imaging has been available for in vivo human brain imaging. In vivo 7T MR imaging can provide greater tissue-type identification than that obtained in vitro without stains.²⁵ As a result of an increased signal-to-noise ratio, enhanced image contrast, and improved resolution, MR imaging at 7T can visualize small anatomic structures not previously appreciated at lower fields.^25–28 Because 7T MR imaging has already provided diagnostic benefits in different pathologies²⁸ such as multiple sclerosis,²⁹ cerebrovascular diseases (strokes, microbleeds),^30,31 aneurysms,³² cavernous malformations,³³ brain tumors,³⁴ and degenerative brain diseases like dementia and Parkinson disease,^35,36 we tested the added value of 7T MR imaging in providing details of structural changes and their extent in 10 patients with polymicrogyria with respect to conventional 3T imaging. We also addressed the limitations we encountered while exploring the polymicrogyric brain with 7T.     

Juxtacortical Lesions and Cortical Thinning in Multiple Sclerosis

BACKGROUND AND PURPOSE:The role of juxtacortical lesions in brain volume loss in multiple sclerosis has not been fully clarified. The aim of this study was to explore the role of juxtacortical lesions on cortical atrophy and to investigate whether the presence of juxtacortical lesions is related to local cortical thinning in the early stages of MS.MATERIALS AND METHODS:A total of 131 patients with clinically isolated syndrome or with relapsing-remitting MS were scanned on a 3T system. Patients with clinically isolated syndrome were classified into 3 groups based on the presence and topography of brain lesions: no lesions (n = 24), only non–juxtacortical lesions (n = 33), and juxtacortical lesions and non–juxtacortical lesions (n = 34). Patients with relapsing-remitting MS were classified into 2 groups: only non–juxtacortical lesions (n = 10) and with non–juxtacortical lesions and juxtacortical lesions (n = 30). A juxtacortical lesion probability map was generated, and cortical thickness was measured by using FreeSurfer.RESULTS:Juxtacortical lesion volume in relapsing-remitting MS was double that of patients with clinically isolated syndrome. The insula showed the highest density of juxtacortical lesions, followed by the temporal, parietal, frontal, and occipital lobes. Patients with relapsing-remitting MS with juxtacortical lesions showed significantly thinner cortices overall and in the parietal and temporal lobes compared with those with clinically isolated syndrome with normal brain MR imaging. The volume of subcortical structures (thalamus, pallidum, putamen, and accumbens) was significantly decreased in relapsing-remitting MS with juxtacortical lesions compared with clinically isolated syndrome with normal brain MR imaging. The spatial distribution of juxtacortical lesions was not found to overlap with areas of cortical thinning.CONCLUSIONS:Cortical thinning and subcortical gray matter volume loss in patients with a clinically isolated syndrome or relapsing-remitting MS was related to the presence of juxtacortical lesions, though the cortical areas with the most marked thinning did not correspond to those with the largest number of juxtacortical lesions.

Multiple sclerosis is a chronic, persistent inflammatory-demyelinating disease of the central nervous system, characterized pathologically by focal areas of inflammation, demyelination, axonal loss, and gliosis. Brain MR imaging typically shows multifocal lesions, mainly in white matter regions,¹ though focal cortical demyelinated plaques are also a prominent feature, even in the earliest phases of the disease.² Unfortunately, conventional MR imaging has limited sensitivity for detecting cortical lesions because of their small size, the poor contrast resolution, and the partial volume effects of the subarachnoid spaces and surrounding cortex.^3,4 Thus, histopathologic studies are the only way to describe, quantify, and classify gray matter lesions according to their position in relation to the gray-white matter surface (leukocortical or juxtacortical; intracortical and subpial).^5,6 Despite the limited sensitivity of MR imaging for detecting cortical lesions in MS, results of several studies showed that cross-sectional cortical lesion volume and its increase over time are associated with progression of disability and cognitive impairment in MS.^7–10Brain atrophy, which is also frequently detected by MR from the earliest stages of MS, is associated with irreversible neurologic disability, including cognitive impairment.^11–14 Whole-brain atrophy has emerged as a clinically relevant component of disease progression, and results of several studies showed that this parameter correlates better with disability and, in particular, with cognitive impairment than with focal lesions.¹⁵ Although most brain atrophy measurements are based on global or regional (gray and white matter) brain volume assessment, cortical thickness has recently emerged as a new way to assess cortical gray matter atrophy because decreased thickness is related to fatigue, disability in general, and cognitive impairment in particular.^13,16 This measurement seems to be dependent on focal white matter lesion volume,¹⁷ but a potential relationship between the presence and location of demyelinating juxtacortical lesions (JLs) and cortical atrophy has not been elucidated. Therefore, the aim of this study was to explore the role of JLs on cortical atrophy and to investigate whether their presence is related to local cortical thinning in the early stages of MS.     

Early-Stage Glioblastomas: MR Imaging–Based Classification and Imaging Evidence of Progressive Growth

BACKGROUND AND PURPOSE:The serial imaging changes describing the growth of glioblastomas from small to large tumors are seldom reported. Our aim was to classify the imaging patterns of early-stage glioblastomas and to define the order of appearance of different imaging patterns that occur during the growth of small glioblastomas.MATERIALS AND METHODS:Medical records and preoperative MR imaging studies of patients diagnosed with glioblastoma between 2006 and 2013 were reviewed. Patients were included if their MR imaging studies showed early-stage glioblastomas, defined as small MR imaging lesions detected early in the course of the disease, demonstrating abnormal signal intensity but the absence of classic imaging findings of glioblastoma. Each lesion was reviewed by 2 neuroradiologists independently for location, signal intensity, involvement of GM and/or WM, and contrast-enhancement pattern on MR imaging.RESULTS:Twenty-six patients with 31 preoperative MR imaging studies met the inclusion criteria. Early-stage glioblastomas were classified into 3 types and were all hyperintense on FLAIR/T2-weighted images. Type I lesions predominantly involved cortical GM (n = 3). Type II (n = 12) and III (n = 16) lesions involved both cortical GM and subcortical WM. Focal contrast enhancement was present only in type III lesions at the gray-white junction. Interobserver agreement was excellent (κ = 0.95; P < .001) for lesion-type classification. Transformations of lesions from type I to type II and type II to type III were observed on follow-up MR imaging studies. The early-stage glioblastomas of 16 patients were pathologically confirmed after imaging progression to classic glioblastoma.CONCLUSIONS:Cortical lesions may be the earliest MR imaging–detectable abnormality in some human glioblastomas. These cortical tumors may progress to involve WM.

Glioblastoma (GB) is the most common primary malignant brain tumor. It typically appears as a large mass with necrosis, prominent edema, mass effect, and strong heterogeneous contrast enhancement when diagnosed. MR imaging, a noninvasive diagnostic tool with excellent tissue contrast, has the potential to detect small GBs. However, it is uncommon to detect small GBs clinically, probably due to nonspecific or absent symptoms. The serial imaging changes depicting the growth of GBs from small to large tumors are seldom reported.Some reports described small MR imaging lesions that subsequently progressed to GBs.^1–11 These are often described as ill-defined, FLAIR or T2-weighted hyperintensities without discernable mass effect that typically involve both the cortex and subcortical WM, but occasionally appear as only cortical lesions.^2,4,8 Contrast enhancement is not a consistent feature and tends to be focal and nodular when present.^6–8 The commonly affected brain areas include frontal (n = 4),^2,3,6,8 parietal (n = 2),^7,10 occipital (n = 1),¹¹ temporal (n = 5),^2,3,6,7,11 hippocampal (n = 3),^1,2,9 and insular (n = 1)⁹ regions. Because these MR imaging lesions were detected early in the course of the disease, they were frequently referred to as early-stage GBs.^3,5–8,11We have noticed different imaging patterns in early-stage GBs. An imaging classification for early-stage GB, however, is not available because most previous studies included only a few such cases. It is important for radiologists to be familiar with early imaging findings and growth patterns of GBs because familiarity may help diagnose small tumors that are symptomatic or incidentally found. Early diagnosis of GB may lead to a higher extent of tumor resection, which has been demonstrated to correlate with patient survival.¹² In this study, we aimed to classify the imaging patterns of early-stage GBs and to the define the order of appearance of different imaging patterns that occur during the growth of these tumors.     

Symptom Differences and Pretreatment Asymptomatic Interval Affect Outcomes of Stenting for Intracranial Atherosclerotic Disease

BACKGROUND AND PURPOSE:Different types of symptomatic intracranial stenosis may respond differently to interventional therapy. We investigated symptomatic and pathophysiologic factors that may influence clinical outcomes of patients with intracranial atherosclerotic disease who were treated with stents.MATERIALS AND METHODS:A retrospective analysis was performed of patients treated with stents for intracranial atherosclerosis at 4 centers. Patient demographics and comorbidities, lesion features, treatment features, and preprocedural and postprocedural functional status were noted. χ² univariate and multivariate logistic regression analysis was performed to assess technical results and clinical outcomes.RESULTS:One hundred forty-two lesions in 131 patients were analyzed. Lesions causing hypoperfusion ischemic symptoms were associated with fewer strokes by last contact [χ² (1, n = 63) = 5.41, P = .019]. Nonhypoperfusion lesions causing symptoms during the 14 days before treatment had more strokes by last contact [χ² (1, n = 136), 4.21, P = .047]. Patients treated with stents designed for intracranial deployment were more likely to have had a stroke by last contact (OR, 4.63; P = .032), and patients treated with percutaneous balloon angioplasty in addition to deployment of a self-expanding stent were less likely to be stroke free at point of last contact (OR, 0.60; P = .034).CONCLUSIONS:More favorable outcomes may occur after stent placement for lesions causing hypoperfusion symptoms and when delaying stent placement 7–14 days after most recent symptoms for lesions suspected to cause embolic disease or perforator ischemia. Angioplasty performed in addition to self-expanding stent deployment may lead to worse outcomes, as may use of self-expanding stents rather than balloon-mounted stents.

Intracranial atherosclerotic disease (ICAD) causes considerable morbidity and mortality, accounting for up to one-third of ischemic strokes in some series, particularly in certain populations.^1–3 Some lesions prove recalcitrant to first-line medical management, and, in recent decades, endovascular treatments have emerged and evolved as complementary therapies.^4,5 Early series demonstrated technical feasibility and acceptable safety for percutaneous transluminal angioplasty (PTA) and then stent placement of lesions in ICAD.^5–17 Initially, intracranial procedures were performed with devices designed and approved for coronary interventions, with subsequent release of angioplasty balloons specifically engineered for intracranial use.^5,12,17–33 In 2005, the Wingspan stent system with Gateway PTA balloon catheter (Stryker, Kalamazoo, Michigan) became the first stent approved for treatment of ICAD in the United States.^{5,12,18–22,25,34} Numerous studies reported progressively improved outcomes and low complication rates, but randomized data proving efficacy were lacking.^{5,12,18,20,24,25,35,36} In 2011, enrollment in the first randomized, controlled trial to evaluate stent placement versus medical management of ICAD, the Stent placement and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, was halted early due to high complication rates in the stent placement group as compared with the medical management group.⁴The results of SAMMPRIS have elicited strong responses from both proponents and detractors of stent placement, with clinical decisions now changing.⁵ This current study retrospectively analyzes results of stent placement procedures performed for ICAD at 4 centers, with attention given to factors not specifically assessed in SAMMPRIS that may help guide further investigations of endovascular ICAD management.     

Identification and clinical impact of multiple sclerosis cortical lesions as assessed by routine 3T MR imaging

BACKGROUND AND PURPOSE:Histopathologic studies have reported widespread cortical lesions in MS; however, in vivo detection by using routinely available pulse sequences is challenging. We investigated the relative frequency and subtypes of cortical lesions and their relationships to white matter lesions and cognitive and physical disability.MATERIALS AND METHODS:Cortical lesions were identified and classified on the basis of concurrent review of 3D FLAIR and 3D T1-weighted IR-SPGR 3T MR images in 26 patients with MS. Twenty-five patients completed the MACFIMS battery. White matter lesion volume, cortical lesion number, and cortical lesion volume were assessed.RESULTS:Overall, 249 cortical lesions were detected. Cortical lesions were present in 24/26 patients (92.3%) (range per patient, 0–30; mean, 9.6 ± 8.8). Most (94.4%, n = 235) cortical lesions were classified as mixed cortical-subcortical (type I); the remaining 5.6% (n = 14) were classified as purely intracortical (type II). Subpial cortical lesions (type III) were not detected. White matter lesion volume correlated with cortical lesion number and cortical lesion volume (r_S = 0.652, r_S = 0.705, respectively; both P < .001). After controlling for age, depression, and premorbid intelligence, we found that all MR imaging variables (cortical lesion number, cortical lesion volume, white matter lesion volume) correlated with the SDMT score (R² = 0.513, R² = 0.449, R² = 0.418, respectively; P < .014); cortical lesion number also correlated with the CVLT-II scores (R² = 0.542–0.461, P < .043). The EDSS scores correlated with cortical lesion number and cortical lesion volume (r_S = 0.472, r_S = 0.404, respectively; P < .05), but not with white matter lesion volume.CONCLUSIONS:Our routinely available imaging method detected many cortical lesions in patients with MS and was useful in their precise topographic characterization in the context of the gray matter−white matter junction. Routinely detectable cortical lesions were related to physical disability and cognitive impairment.

MS is a chronic progressive disease, characterized by a broad range of sensory-motor, cognitive, and neuropsychiatric symptoms. Pathologically, MS affects the central nervous system with multifocal and diffuse inflammatory and neurodegenerative changes, but their exact etiology and pathogenesis remain uncertain.¹ While early pathologic investigations describe involvement of both white matter and gray matter,^2,3 white matter involvement has been studied more extensively. Recent advances in both histopathologic and imaging techniques have renewed the appreciation of gray matter involvement in MS.⁴ New histopathologic methods have found demyelinating lesions in significant portions of the cortex.^5–10 In addition, neuroimaging techniques have detected structural and functional changes in the gray matter.⁴ Visualization of cortical lesions by MR imaging is challenging.^8,10–12 Recently, novel MR imaging methods have been used to address these challenges, including novel pulse sequences, multichannel and high-resolution imaging, and ultra-high magnetic field strength.^13–19 None of these techniques have demonstrated broad clinical applicability or vendor dissemination as applied to routine 3T MS imaging. In vivo assessment of cortical lesions is of great significance because the pathologic processes that have taken place in the gray matter and their relationship to white matter pathology and gray matter atrophy and clinical outcomes will improve our understanding of MS pathogenesis.^20,21In the present study, we used a high-resolution 3T brain MR imaging protocol that combined a multiplanar display of 3D FLAIR and T1-weighted 3D IR-SPGR sequences. This approach took advantage of the high contrast sensitivity of FLAIR for imaging cortical lesions combined with IR-SPGR to delineate the boundary between the cortex and white matter. These sequences are widely available on clinical scanners from multiple vendors and can be integrated in clinical routine with reasonable scanning time. We aimed to evaluate the ability of this standard protocol to depict cortical lesions and their different subtypes and to explore the relationships between cortical lesions versus white matter lesion load, cognitive dysfunction, and physical disability in MS.     

Influence of Resting-State Network on Lateralization of Functional Connectivity in Mesial Temporal Lobe Epilepsy

BACKGROUND AND PURPOSE:Although most studies on epilepsy have focused on the epileptogenic zone, epilepsy is a system-level disease characterized by aberrant neuronal synchronization among groups of neurons. Increasingly, studies have indicated that mesial temporal lobe epilepsy may be a network-level disease; however, few investigations have examined resting-state functional connectivity of the entire brain, particularly in patients with mesial temporal lobe epilepsy and hippocampal sclerosis. This study primarily investigated whole-brain resting-state functional connectivity abnormality in patients with mesial temporal lobe epilepsy and right hippocampal sclerosis during the interictal period.MATERIALS AND METHODS:We investigated resting-state functional connectivity of 21 patients with mesial temporal lobe epilepsy with right hippocampal sclerosis and 21 neurologically healthy controls. A multivariate pattern analysis was used to identify the functional connections that most clearly differentiated patients with mesial temporal lobe epilepsy with right hippocampal sclerosis from controls.RESULTS:Discriminative analysis of functional connections indicated that the patients with mesial temporal lobe epilepsy with right hippocampal sclerosis exhibited decreased resting-state functional connectivity within the right hemisphere and increased resting-state functional connectivity within the left hemisphere. Resting-state network analysis suggested that the internetwork connections typically obey the hemispheric lateralization trend and most of the functional connections that disturb the lateralization trend are the intranetwork ones.CONCLUSIONS:The current findings suggest that weakening of the resting-state functional connectivity associated with the right hemisphere appears to strengthen resting-state functional connectivity on the contralateral side, which may be related to the seizure-induced damage and underlying compensatory mechanisms. Resting-state network–based analysis indicated that the compensatory mechanism among different resting-state networks may disturb the hemispheric lateralization.

Up to 0.1% of the human population worldwide has temporal lobe epilepsy (TLE), and 60%–70% of these cases are classified as mesial temporal lobe epilepsy (mTLE).¹ mTLE is a drug-refractory form of human epilepsy that is typically characterized by hippocampal sclerosis (HS). Surgical intervention can prevent temporal lobe seizure recurrence in patients with mTLE.² Aberrant neuronal synchronization is believed to be as important as abnormal excitability with respect to epileptic seizure occurrences,^3,4 and resting-state functional connectivity (RS-FC) analysis is an effective approach for examining neural synchronization.Debilitating mTLE seizures are believed to originate primarily from specific anatomic divisions of the temporal lobe.² However, investigations involving large-scale network analysis have challenged this traditional conceptualization.^3,5–7 Furthermore, several studies have reported an mTLE-related decrease in basal RS-FC in the epileptogenic hemisphere in brains of patients with mTLE, accompanied by contralateral compensatory mechanisms.^8,9Many mTLE studies have focused on the epileptogenic zone, and most analyses that have investigated regions outside the hippocampus have focused on structural imaging technology.^1,10,11 In contrast, few whole-brain functional network analyses of mTLE have been conducted. Structural MRI or electroencephalography or both incompletely measure temporal changes during the disease process,⁵ while resting-state fMRI takes serial images during a time period that can capture the dynamic and evolving changes related to epilepsy.¹² The RS-FC derived from the fMRI images reflects functional aberrations and offers a network perspective on the psychiatric and cognitive complications of mTLE.^7,13 We hypothesized that mesial temporal lobe epilepsy with right hippocampal sclerosis (R-mTLE) is a functional disease involving disturbances of RS-FC over the entire brain rather than a local disease that is confined to the temporal lobe. To test this hypothesis, we applied the multivariate pattern analysis method in this study.¹⁴     

Extensive White Matter Dysfunction in Cognitively Impaired Patients with Secondary-Progressive Multiple Sclerosis

BACKGROUND AND PURPOSE:Cognitive impairment is a common, disabling symptom of MS. We investigated the association between cognitive impairment and WM dysfunction in secondary-progressive multiple sclerosis using DTI.MATERIALS AND METHODS:Cognitive performance was assessed with a standard neuropsychological battery, the Minimal Assessment of Cognitive Function in Multiple Sclerosis. Cognitive impairment was defined as scoring >1.5 standard deviations below healthy controls on ≥2 subtests. Fractional anisotropy maps were compared against cognitive status using tract-based spatial statistics with threshold-free cluster enhancement.RESULTS:Forty-five patients with secondary-progressive multiple sclerosis (median age: 55 years, female/male: 27/18, median Expanded Disability Status Scale Score: 6.5) were prospectively recruited. Cognitively impaired patients (25/45) displayed significantly less normalized global GM and WM volumes (P = .001, P = .024), more normalized T2-weighted and T1-weighted WM lesion volumes (P = .002, P = .006), and lower WM skeleton fractional anisotropy (P < .001) than non-impaired patients. Impaired patients also had significantly lower fractional anisotropy (p_corr < .05) in over 50% of voxels within every major WM tract. The most extensively impinged tracts were the left posterior thalamic radiation (100.0%), corpus callosum (97.8%), and right sagittal stratum (97.5%). No WM voxels had significantly higher fractional anisotropy in patients with cognitive impairment compared with their non-impaired counterparts (p_corr > .05). After the inclusion of confounders in a multivariate logistic regression, only fractional anisotropy remained a significant predictor of cognitive status.CONCLUSIONS:Cognitively impaired patients with secondary-progressive multiple sclerosis exhibited extensive WM dysfunction, though preferential involvement of WM tracts associated with cognition, such as the corpus callosum, was apparent. Multivariate analysis revealed that only WM skeleton fractional anisotropy was a significant predictor of cognitive status.

Cognitive impairment is a prevalent symptom of MS and has been estimated to occur in 43%–65% of patients.¹ Those with secondary-progressive multiple sclerosis (SPMS) exhibit the highest frequency of impairment.² Prior neuroimaging studies have almost exclusively investigated such impairment by assessing discrete cognitive domains, such as information processing speed or working memory, with neuropsychological tests that have established domain specificity. Such an approach is apparent in studies that examined both brain and lesion volumetry^3–6 and WM integrity.^7–11 Domain-specific cognitive tests are powerful tools that can assess the impact of MS pathology on individual cognitive domains and specific neuronal pathways, but cannot investigate cognition as a multidomain entity. Few studies of cognitive impairment in MS have adopted this broader perspective, and patients with MS with multiple domain impairment may exhibit considerably different structural brain damage from their counterparts with single domain impairment.MS has been traditionally viewed as a disease predominantly affecting WM, though only modest associations between T2-weighted hyperintense or T1-weighted hypointense white matter lesion (WML) load and cognitive test performance have been reported.¹² Normal-appearing white matter is being increasingly examined, particularly through DTI techniques.^7–11,13,14 These studies have most frequently used fractional anisotropy (FA) as their primary outcome,^8–11,13,14 whereas mean diffusivity has been investigated to a lesser extent.⁷ Radial diffusivity and axial diffusivity have been examined as secondary outcomes.^11,14 Given the recent emphasis on the role of GM pathology both in the etiology of MS and related cognitive dysfunction, FA was considered in the context of GM volume using multivariate regression.^15–17 Normal-appearing white matter has also been investigated using magnetization transfer ratio.¹⁸Tract-based spatial statistics (TBSS) is being increasingly utilized in DTI studies of MS and cognition.^8,9,11,13 TBSS has improved on traditional voxel-based morphometry by thinning WM to invariant tracts common to all patients.¹⁹ The voxel-based morphometry approach suffers from deficiencies related to spatial alignment and smoothing, which are mitigated by TBSS. Several prior TBSS studies have concluded that cognitive impairment in MS is because of the selective disruption of specific WM tracts associated with cognition, such as the cingulum and corpus callosum (CC).^8,9,11 It should be noted that this spatial specificity has a physiologic basis and is not mediated by the cognitive nature of these tracts. These studies correlated FA values with performance on individual cognitive tests and examined cohorts primarily or solely comprising patients with relapsing-remitting MS (RRMS). DTI outcomes in patients with SPMS with and without cognitive impairment have not been well investigated, yet 65% of patients with RRMS will progress to SPMS.²⁰ While WM injury is initially selective for specific tracts associated with impaired cognition in RRMS, DTI abnormalities are expected to become significantly more widespread and generalized with greater impairment and disease severity progression.We hypothesized that patients with SPMS with impairment spanning multiple cognitive domains should exhibit extensive WM dysfunction not restricted to tracts implicated in cognition, such as the cingulum and CC.     

Cumulative Dose of Macrocyclic Gadolinium-Based Contrast Agent Improves Detection of Enhancing Lesions in Patients with Multiple Sclerosis

BACKGROUND AND PURPOSE:Gadolinium-enhanced MR imaging is currently the reference standard for detecting active inflammatory lesions in patients with multiple sclerosis. The sensitivity of MR imaging for this purpose may vary according to the physicochemical characteristics of the contrast agent used and the acquisition strategy. The purpose of this study was to compare detection of gadolinium-enhancing lesions or active disease following a single or cumulative dose of a macrocyclic gadolinium-based contrast agent with different image acquisition delays in patients with clinically isolated syndrome or relapsing multiple sclerosis.MATERIALS AND METHODS:All patients received a first dose (0.1 mmol/kg) of gadobutrol and, 20 minutes later, a second dose (0.1 mmol/kg), with a cumulative dose of 0.2 mmol/kg. Two contrast-enhanced T1-weighted sequences were performed at 5 and 15 minutes after the first contrast administration, and 2 additional T1-weighted sequences at 5 and 15 minutes after the second contrast administration with a 3T magnet.RESULTS:One hundred fifteen patients were considered evaluable. A significantly larger number of lesions were detected in scans obtained at 5 and 15 minutes after the second contrast injection compared with scans obtained at 5 and 15 minutes after the first injection (P < .001). The number of patients with active lesions on MR imaging was significantly higher after the second dose administration (52.0%, first dose versus 59.2%, second dose; P < .001).CONCLUSIONS:Cumulative dosing of a macrocyclic gadolinium-based contrast agent increases detection of enhancing lesions and patients with active lesions. These data could be considered in the design of MR imaging protocols aimed at detecting active multiple sclerosis lesions.

Gadolinium-enhanced MR imaging is currently the reference standard for detecting inflammatory demyelinating lesions associated with increased permeability of the blood-brain barrier in patients with multiple sclerosis, and is commonly used as a marker of acute focal inflammatory activity.^1,2 The sensitivity of the technique for this purpose may vary according to the physicochemical characteristics of the contrast agent used and the acquisition strategy (eg, delay between injection and image acquisition, contrast dose, field strength, and parameters of the postinjection T1-weighted sequence).^3–12 A large body of evidence has indicated that various approaches can increase the visibility of contrast-enhancing lesions and lead to a notable improvement in sensitivity.^{3,4,8,9,12–15} One potential strategy that has not yet been explored is the combination of an increased contrast dose and a longer delay time at 3T MR imaging with a 2D gradient recalled-echo (GRE) T1-weighted sequence. To examine this option, we designed the present open-label, prospective study to assess the advantages of combining a high-field-strength MR imaging magnet (3T) and a cumulative gadolinium dose (0.1 mmol/kg + 0.1 mmol/kg) at different delay times compared with a single dose (0.1 mmol/kg) to detect active lesions in patients with clinically isolated syndrome (CIS) or relapsing MS. The hypothesis was that the combined advantages of a cumulative gadolinium dose and a longer delay time would significantly increase the detection rate of active lesions and the percentage of patients showing disease activity, measures that have a strong impact for the diagnosis of the disease, therapy optimization, and predicting disease course and treatment response.^1,2,16     

Identifying Corticothalamic Network Epicenters in Patients with Idiopathic Generalized Epilepsy

BACKGROUND AND PURPOSE:Corticothalamic networks are considered core pathologic substrates for idiopathic generalized epilepsy; however, the predominant epileptogenic epicenters within these networks are still largely unknown. The current study aims to identify these epicenters by resting-state functional connectivity.MATERIALS AND METHODS:To identify epicenters within the corticothalamic networks in idiopathic generalized epilepsy, we retrospectively studied a large cohort of patients with this condition (n = 97) along with healthy controls (n = 123) by resting-state functional MR imaging. The thalamus was functionally divided into subregions corresponding to distinct cortical lobes for 5 parallel corticothalamic networks. The functional connectivity between each voxel in the cortical lobe and the corresponding thalamic subregion was calculated, and functional connectivity strength was used to evaluate the interconnectivity of voxels in the cortex and thalamus.RESULTS:The projection of 5 cortical lobes to the thalamus is consistent with previous histologic findings in humans. Compared with controls, patients with idiopathic generalized epilepsy showed increased functional connectivity strength in 4 corticothalamic networks: 1) the supplementary motor area, pulvinar, and ventral anterior nucleus in the prefrontal-thalamic network; 2) the premotor cortex and ventrolateral nucleus in motor/premotor-thalamic networks; 3) the visual cortex, posterior default mode regions, and pulvinar in parietal/occipital-thalamic networks; and 4) the middle temporal gyrus in the temporal-thalamic network.CONCLUSIONS:Several key nodes were distinguished in 4 corticothalamic networks. The identification of these epicenters refines the corticothalamic network theory and provides insight into the pathophysiology of idiopathic generalized epilepsy.

Idiopathic generalized epilepsy (IGE) is a common subtype of epilepsy involving abnormally synchronized generalized spike-wave discharges (GSWDs) rapidly propagating to distributed networks.¹ Various theories have been proposed to explain the origin and mechanism of generalized seizures²; the corticothalamic network has been suggested as a preferred target for the modification or elimination of seizure discharges.^3,4There is substantial evidence that dysfunction in the corticothalamic circuitry contributes to the pathogenesis of generalized seizures.^3,4 Hemodynamic changes associated with GSWDs have been consistently observed in the thalamus and default mode areas.⁵ Recently, corticothalamic interactions in generalized epilepsy have been characterized by morphometric covariance,⁶ functional and anatomic connectivity,^7,8 and causal influence.⁹ In particular, corticothalamic connections (parcellated through probabilistic tractography) showed abnormal functional connectivity in juvenile myoclonic epilepsy.⁷ However, little attention has been paid to the functional topographic pathways linking distinct cortical areas and specific thalamic nuclei.^10,11 These projections likely have distinct roles in the mechanism of GSWDs,¹² so it is essential to investigate corticothalamic functional networks in generalized epilepsy. More precisely, characterizing epicenters within each network may facilitate the development of targeted surgical interventions (eg, deep brain stimulation) that selectively disrupt seizures and ultimately improve the clinical treatment of IGE.⁴It was recently demonstrated that resting-state functional connectivity can reveal distinct corticothalamic networks¹³ analogous to classic histologic parcellation.¹⁰ As in previous investigations,^14–16 a similar approach was adopted here to identify corticothalamic networks. We hypothesized that the functional synchronization of corticothalamic networks is altered in patients with IGE. To localize epicenters within these networks, we conducted a voxelwise comparison of network functional connectivity between patients and controls.     

Quantifying the Cerebral Hemodynamics of Dural Arteriovenous Fistula in Transverse Sigmoid Sinus Complicated by Sinus Stenosis: A Retrospective Cohort Study

BACKGROUND AND PURPOSE:Sinus stenosis occasionally occurs in dural arteriovenous fistulas. Sinus stenosis impedes venous outflow and aggravates intracranial hypertension by reversing cortical venous drainage. This study aimed to analyze the likelihood of sinus stenosis and its impact on cerebral hemodynamics of various types of dural arteriovenous fistulas.MATERIALS AND METHODS:Forty-three cases of dural arteriovenous fistula in the transverse-sigmoid sinus were reviewed and divided into 3 groups: Cognard type I, type IIa, and types with cortical venous drainage. Sinus stenosis and the double peak sign (occurrence of 2 peaks in the time-density curve of the ipsilateral drainage of the internal jugular vein) in dural arteriovenous fistula were evaluated. “TTP” was defined as the time at which a selected angiographic point reached maximum concentration. TTP of the vein of Labbé, TTP of the ipsilateral normal transverse sinus, trans-fistula time, and trans-stenotic time were compared across the 3 groups.RESULTS:Thirty-six percent of type I, 100% of type IIa, and 84% of types with cortical venous drainage had sinus stenosis. All sinus stenosis cases demonstrated loss of the double peak sign that occurs in dural arteriovenous fistula. Trans-fistula time (2.09 seconds) and trans-stenotic time (0.67 seconds) in types with cortical venous drainage were the most prolonged, followed by those in type IIa and type I. TTP of the vein of Labbé was significantly shorter in types with cortical venous drainage. Six patients with types with cortical venous drainage underwent venoplasty and stent placement, and 4 were downgraded to type IIa.CONCLUSIONS:Sinus stenosis indicated dysfunction of venous drainage and is more often encountered in dural arteriovenous fistula with more aggressive types. Venoplasty ameliorates cortical venous drainage in dural arteriovenous fistulas and serves as a bridge treatment to stereotactic radiosurgery in most cases.

Dural arteriovenous fistulas (DAVFs) account for 10%–15% of intracranial vascular malformations.^1,2 The most common location of an intracranial DAVF is the cavernous sinus, followed by the transverse-sigmoid sinus.^1–3 Major DAVF classification systems, such as the Cognard and Borden systems, grade DAVFs on the basis of venous drainage patterns, in which the presence of retrograde cortical venous drainage (CVD) indicates a higher risk of hemorrhage.^4–7 Cases of venous outlet obstruction playing a role in transforming benign (without CVD) into malignant DAVFs (with CVD) have been reported in the literature.⁸ Sinus stenosis (SS) is frequently associated with idiopathic intracranial hypertension.^9,10 Nevertheless, the incidence of SS and its association with DAVFs have not been thoroughly explored. SS can be found in DAVFs with retrograde or antegrade sinus flow, but its impact on cerebral hemodynamics has rarely been discussed. Theoretically, stenotic and thrombosed sinuses impede the venous outflow, and a DAVF itself increases overall blood volume in the affected sinus; the combination of the 2 hemodynamic disorders adversely affects venous flow and subsequently increases intracranial pressure and the risk of intracranial hemorrhage.Current treatment strategies for DAVFs in the transverse sinus include microsurgery, endovascular treatment, stereotactic radiosurgery (SRS), or their combinations.^11–13 Endovascular treatment has been the treatment of choice for DAVFs with CVD because it provides immediate curative results and minimizes the risk of hemorrhage.^14–16 Nevertheless, the complication rate of endovascular treatment is higher than that of SRS.^14,17,18 By contrast, SRS has hardly any periprocedural risks and achieves DAVF cure rates of between 58% and 73%. Although SRS can reduce the bleeding rate from 20% to 2% after shunting has been totally closed,¹⁹ the latent period for SRS ranges from 1 to 3 years and carries a 4.1% hemorrhagic rate in DAVFs with CVD.^3,20 Therefore, SRS is usually preferred for cases without CVD, and endovascular treatment is more suitable for immediately minimizing the risk of hemorrhage.Several studies have proposed a reconstructive method by using venoplasty and stent placement in combination with transarterial embolization to ameliorate or even cure DAVFs with venous outlet obstruction.^21–23 We wondered whether this approach could downgrade DAVFs with CVD—that is, to restore their normal cortical venous drainage and make them eligible for SRS, thereby minimizing the risk of hemorrhage during the latent period. Therefore, the purpose of the current study was to clarify the following: 1) the incidence of SS in different grades of DAVF in the transverse sigmoid sinus, 2) the impact of SS on DAVF hemodynamics by using quantitative DSA, and 3) the initial treatment results of venoplasty and/or stent placement followed by SRS.     

Gray Matter Volume Reduction Is Associated with Cognitive Impairment in Neuromyelitis Optica

BACKGROUND AND PURPOSE:Whether gray matter impairment occurs in neuromyelitis optica is a matter of ongoing debate, and the association of gray matter impairment with cognitive deficits remains largely unknown. The purpose of this study was to investigate gray matter volume reductions and their association with cognitive decline in patients with neuromyelitis optica.MATERIALS AND METHODS:This study included 50 patients with neuromyelitis optica and 50 sex-, age-, handedness-, and education-matched healthy subjects who underwent high-resolution structural MR imaging examinations and a battery of cognitive assessments. Gray matter volume and cognitive differences were compared between the 2 groups. The correlations of the regional gray matter volume with cognitive scores and clinical variables were explored in the patients with neuromyelitis optica.RESULTS:Compared with healthy controls (635.9 ± 51.18 mL), patients with neuromyelitis optica (602.8 ± 51.03 mL) had a 5.21% decrease in the mean gray matter volume of the whole brain (P < .001). The significant gray matter volume reduction in neuromyelitis optica affected the frontal and temporal cortices and the right thalamus (false discovery rate correction, P < .05). The regional gray matter volumes in the frontal and temporal cortices were negatively correlated with disease severity in patients with neuromyelitis optica (Alphasim correction, P < .05). Patients with neuromyelitis optica had impairments in memory, information processing speed, and verbal fluency (P < .05), which were correlated with gray matter volume reductions in the medial prefrontal cortex and thalamus (Alphasim correction, P < .05).CONCLUSIONS:Gray matter volume reduction is present in patients with neuromyelitis optica and is associated with cognitive impairment and disease severity in this group.

Neuromyelitis optica (NMO) is an idiopathic, severe, demyelinating disease of the central nervous system that is characterized by optic neuritis and myelitis.^1,2 Although the brain is traditionally considered to be spared in NMO,³ recent studies have identified brain lesions in 60% of patients with this condition.⁴ In 10% of patients with NMO, the site of brain lesions on MR imaging coincides with high concentrations of the water channel aquaporin 4,^5,6 the target of NMO immunoglobulin G (NMO-IgG).Although several investigations have revealed gray matter impairment in NMO by comparing intergroup differences in the regional homogeneity,⁷ amplitude of low-frequency fluctuation,⁸ diffusivity,^9–11 perfusion,¹² and magnetization transfer ratio,¹³ whether GM structural impairment is a feature of NMO is an ongoing debate. Several studies have identified reductions in GM volume (GMV)^14–16 or cortical thickness¹⁷ in patients with NMO; however, 3 additional studies have failed to demonstrate reductions in the GMV^18,19 or cortical thickness in patients.²⁰ These conflicting outcomes may result from the low statistical power of the relatively small sample sizes (15–30 patients with NMO in previous studies). Studies with a large sample of patients with NMO may help clarify this issue.Cognitive impairment has been repeatedly reported in patients with NMO^{10,17,18,21–24} and is characterized by deficits in multiple cognitive domains, including memory, attention, and speed of information processing. The neural correlates of the cognitive impairment in NMO have been attributed to focal reductions in white matter volume and integrity.^10,18 A recent study found no correlation between cognitive impairment and cortical thinning in 23 patients with NMO.¹⁷ However, it remains unknown whether GMV reduction is associated with cognitive impairment in these patients.By recruiting a large sample of patients with NMO (n = 50), we aimed to clarify the GMV changes in NMO and the correlations of GMV changes with cognitive impairment and clinical variables in these patients.     

Measurement of Cortical Thickness and Volume of Subcortical Structures in Multiple Sclerosis: Agreement between 2D Spin-Echo and 3D MPRAGE T1-Weighted Images

BACKGROUND AND PURPOSE:Gray matter pathology is known to occur in multiple sclerosis and is related to disease outcomes. FreeSurfer and the FMRIB Integrated Registration and Segmentation Tool (FIRST) have been developed for measuring cortical and subcortical gray matter in 3D-gradient-echo T1-weighted images. Unfortunately, most historical MS cohorts do not have 3D-gradient-echo, but 2D-spin-echo images instead. We aimed to evaluate whether cortical thickness and the volume of subcortical structures measured with FreeSurfer and FIRST could be reliably measured in 2D-spin-echo images and to investigate the strength and direction of clinicoradiologic correlations.MATERIALS AND METHODS:Thirty-eight patients with MS and 2D-spin-echo and 3D-gradient-echo T1-weighted images obtained at the same time were analyzed by using FreeSurfer and FIRST. The intraclass correlation coefficient between the estimates was obtained. Correlation coefficients were used to investigate clinicoradiologic associations.RESULTS:Subcortical volumes obtained with both FreeSurfer and FIRST showed good agreement between 2D-spin-echo and 3D-gradient-echo images, with 68.8%–76.2% of the structures having either a substantial or almost perfect agreement. Nevertheless, with FIRST with 2D-spin-echo, 18% of patients had mis-segmentation. Cortical thickness had the lowest intraclass correlation coefficient values, with only 1 structure (1.4%) having substantial agreement. Disease duration and the Expanded Disability Status Scale showed a moderate correlation with most of the subcortical structures measured with 3D-gradient-echo images, but some correlations lost significance with 2D-spin-echo images, especially with FIRST.CONCLUSIONS:Cortical thickness estimates with FreeSurfer on 2D-spin-echo images are inaccurate. Subcortical volume estimates obtained with FreeSurfer and FIRST on 2D-spin-echo images seem to be reliable, with acceptable clinicoradiologic correlations for FreeSurfer.

Gray matter pathology in patients with multiple sclerosis is present from the very early stages of the disease and has been related to long-term disability.^1,2 Therefore, in recent years, research has focused on obtaining accurate markers of GM damage, and different software packages have been developed or optimized for measuring it in MS. FreeSurfer software (http://surfer.nmr.mgh.harvard.edu)^3,4 allows automatic calculation of cortical thickness and the volume of subcortical GM structures by using 3D T1-weighted images. Briefly, the image-processing pipeline includes Talairach transformation of the 3D T1-weighted images and segmentation of the subcortical white matter and deep GM structures, relying on the gray and white matter boundaries and pial surfaces. The FMRIB Integrated Registration and Segmentation Tool (FIRST; http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FIRST) software package⁵ automatically segments subcortical GM structures also on the basis of 3D T1-weighted images. Briefly, FIRST is a model-based segmentation and registration program that uses shape and appearance models constructed from manually segmented images. On the basis of the learned models, FIRST searches through linear combinations of shape modes of variation for the most probable shape instance, given the observed intensities in the 3D T1-weighted input images. Both software packages have been shown to be accurate and reproducible.^6–11The study of cortical pathology in patients with MS by using FreeSurfer has shown cortical thinning in patients with MS compared with healthy controls,^12,13 which has been related to lesion volume, disease duration, disability,¹² and cognitive impairment.¹⁴ Also, cortical thinning of the superior frontal gyrus, thalamus, and cerebellum significantly predicted conversion to MS in patients presenting with clinically isolated syndromes,¹⁵ and global cortical thinning for 6 years was significantly associated with a more aggressive disease evolution.¹⁶ The volume of deep GM structures (measured with both FreeSurfer and FIRST) has also been shown to be lower in patients with MS compared with healthy controls,^17–19 and it has been related to different clinical disease outcomes such as fatigue,²⁰ cognitive impairment,^17–19,21 disability,¹⁹ and walking function.²²Both FreeSurfer and FIRST have been optimized for 3D T1-weighted gradient-echo images that incorporate a magnetization-prepared inversion pulse that increases the T1-weighting.²³ Unfortunately, for most of the historical MS cohorts with long-term clinical and radiologic follow-up, only 2D spin-echo (2D-SE) T1-weighted images were acquired, a sequence that does not provide an optimal contrast between gray and white matter, particularly when acquired with high-field magnets.²⁴ The objectives of this work were the following: 1) to evaluate whether cortical thickness and subcortical volumes obtained with FreeSurfer could be reliably measured with 2D-SE T1-weighted images by using as the criterion standard the same measures obtained with 3D gradient-echo (3D-GE) T1-weighted sequences, 2) to investigate whether subcortical volumes obtained with FIRST could be reliably measured in 2D-SE T1-weighted images by using as the criterion standard the same measures obtained with 3D-GE T1-weighted images, and 3) to assess whether the correlations between clinical outcomes and subcortical normalized volumes obtained with 3D-GE and 2D-SE T1-weighted images had a similar strength and direction.