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.     

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.     

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.     

Subcortical Deep Gray Matter Pathology in Patients with Multiple Sclerosis Is Associated with White Matter Lesion Burden and Atrophy but Not with Cortical Atrophy: A Diffusion Tensor MRI Study

BACKGROUND AND PURPOSE:The association between subcortical deep gray matter, white matter, and cortical pathology is not well understood in MS. The aim of this study was to use DTI to investigate the subcortical deep gray matter alterations and their relationship with lesion burden, white matter, and cortical atrophy in patients with MS and healthy control patients.MATERIALS AND METHODS:A total of 210 patients with relapsing-remitting MS, 75 patients with progressive MS, and 110 healthy control patients were included in the study. DTI metrics in whole brain, normal-appearing white matter, normal-appearing gray matter, and subcortical deep gray matter structures were compared. The association between DTI metrics of the subcortical deep gray matter structures with lesion burden, normalized white matter volume, and normalized cortical volume was investigated.RESULTS:DTI measures were significantly different in whole brain, normal-appearing white matter, and normal-appearing gray matter among the groups (P < .01). Significant differences in DTI diffusivity of total subcortical deep gray matter, caudate, thalamus, and hippocampus (P < .001) were found. DTI diffusivity of total subcortical deep gray matter was significantly associated with normalized white matter volume (P < .001) and normalized cortical volume (P = .033) in healthy control patients. In both relapsing and progressive MS groups, the DTI subcortical deep gray matter measures were associated with the lesion burden and with normalized white matter volume (P < .001), but not with normalized cortical volume.CONCLUSIONS:These findings suggest that subcortical deep gray matter abnormalities are associated with white matter lesion burden and atrophy, whereas cortical atrophy is not associated with microstructural alterations of subcortical deep gray matter structures in patients with MS.

Although in the past MS has been considered an inflammatory demyelinating disease affecting primarily the white matter of the central nervous system, currently, a substantial number of studies have established that gray matter is also involved in different stages of the disease.^1–5 Cortical and subcortical deep gray matter (SDGM) atrophy occurs also in the early stages of MS, and disability progression is significantly influenced by the neuronal loss of the gray matter.^6–8Atrophy of the SDGM structures is associated with disability progression and cognitive dysfunctions and can also predict the conversion to clinically definite MS.^9–12 An increasing body of evidence suggests that the atrophy of cortical and SDGM structures is associated with white matter lesion burden,¹³ but the underlying pathophysiologic processes remain poorly understood. Secondary Wallerian degeneration is certainly implicated in neuronal damage of gray matter structures; however, it seems unlikely to be the sole cause of gray matter pathology.^4,14DTI is an advanced MR imaging technique that has been used in a number of in vivo and ex vivo studies.^15,16 DTI measures are able to identify alterations outside the focal lesions in the so-called normal-appearing white matter and normal-appearing gray matter that remain largely undetected with conventional MR imaging in patients with MS.¹⁷There is a growing interest in studying the DTI alterations of the SDGM in the different stages of the MS disease process. Previous studies suggested that SDGM DTI abnormalities are also present in patients with clinically isolated syndrome^18,19 and are associated with disability progression as well as cognitive dysfunctions in patients with MS.^20–23Although different studies have investigated the associations between white matter lesions, brain atrophy, and DTI alteration in patients with MS,^24–26 the same relationships were not extensively investigated in healthy people whose pathophysiologic alteration of the brain cannot be attributable to the inflammatory process in the central nervous system. Therefore, in the current study, we aimed to investigate volumetric and DTI global, tissue-specific, and regional brain differences in a large cohort of healthy control (HC) patients, patients with relapsing-remitting MS (RRMS), and patients with progressive MS (PMS). We hypothesized that microstructural abnormalities of SDGM structures detected by DTI techniques are associated with lesion burden, and with white matter and gray matter volume alterations in patients with MS. Another aim was to explore the same associations in the HC group.     

FLAIR2: A Combination of FLAIR and T2 for Improved MS Lesion Detection

BACKGROUND AND PURPOSE:FLAIR and double inversion recovery are important MR imaging scans for MS. The suppression of signal from CSF in FLAIR and the additional suppression of WM signal in double inversion recovery improve contrast between lesions, WM and GM, albeit at a reduced SNR. However, whether the acquisition of double inversion recovery is necessary is still debated. Here, we present an approach that allows obtaining CSF-suppressed images with improved contrast between lesions, WM and GM without strongly penalizing SNR.MATERIALS AND METHODS:3D T2-weighted and 3D-FLAIR data acquired from September 2014 to April 2015 in healthy volunteers (23.4 ± 2.4 years of age; female/male ratio, 3:2) and patients (44.1 ± 14.0 years of age; female/male ratio, 4:5) with MS were coregistered and multiplied (FLAIR²). SNR and contrast-to-noise measurements were performed for focal lesions and GM and WM. Furthermore, data from 24 subjects with relapsing-remitting and progressive MS were analyzed retrospectively (52.7 ± 8.1 years of age; female/male ratio, 14:10).RESULTS:The GM-WM contrast-to-noise ratio was by 133% higher in FLAIR² than in FLAIR and improved between lesions and WM by 31%, 93%, and 158% compared with T2, DIR, and FLAIR, respectively. Cortical and juxtacortical lesions were more conspicuous in FLAIR². Furthermore, the 3D nature of FLAIR² allowed reliable visualization of callosal and infratentorial lesions.CONCLUSIONS:We present a simple approach for obtaining CSF suppression with an improved contrast-to-noise ratio compared with conventional FLAIR and double inversion recovery without the acquisition of additional data. FLAIR² can be computed retrospectively if T2 and FLAIR scans are available.

MR imaging is important for the diagnosis and monitoring of MS. Formation of MS lesions creates a hydrophilic environment, resulting in an increase in the T2 and proton density–weighted MR signal and a signal reduction on T1-weighted scans.¹ Ovoid hyperintense areas on T2-weighted MR imaging are therefore a radiologic hallmark of MS. Lesion conspicuity is often affected by the bright CSF signal, for instance, close to the ventricles or cortical sulci. FLAIR is a T2-weighted scan that suppresses CSF selectively with an inversion pulse.² Yet, the CSF signal suppression comes at the cost of reduced SNR. Usually, FLAIR scans are acquired in 2D with sections parallel to the subcallosal line. Additional sagittal FLAIR scans are required to reliably detect corpus callosum lesions.^2,3 Furthermore, 2D-FLAIR has artifacts due to CSF and blood inflow and often provides insufficient T2-weighting,⁴ requiring additional proton density/T2-weighted images for the detection of lesions in infratentorial areas. The brain MR imaging protocol for MS studies⁵ includes proton density and T2-weighted spin-echo, axial, and sagittal FLAIR and recommends pre- and postcontrast T1-weighted spin-echo MR imaging.Apart from diagnosis, conventional MR images play an important role as outcome measures in clinical trials of new MS therapies.^5,6 New lesion activity (eg, gadolinium-enhancing lesions and new or enlarging T2-lesions) and estimates of disease burden (eg, total T2-lesion volume or count; T1-hypointense lesion volume; brain atrophy) are typical imaging end points in clinical trials.⁵ These scans are directed toward lesion identification in WM. Demyelination and the appearance of lesions is, however, not limited to the WM; it also involves the deep and cortical GM.⁷ Focal GM lesions appear in the earliest stages of MS^8,9 and are associated with physical and cognitive disability.^10,11 Moreover, cortical lesion load was shown to be a predictor of progression of clinical disability during 5 years¹² and to improve predictions for the conversion from relapsing-remitting to secondary-progressive MS compared with assessing WM lesions alone.¹³ Given the importance of cortical lesions in MS, there is great interest in their visualization. However, the cortex is thin, its myelin content is low, and inflammation is low in cortical lesions. Contrast between lesions and healthy tissue is therefore low, making the detection of cortical damage challenging.In double inversion recovery (DIR),¹⁴ both CSF and the WM signal are suppressed; this suppression results in enhanced contrast between lesions, GM and WM. T1-relaxation times of GM and WM are similar. Therefore, both tissues are affected by the inversion pulse, resulting in reduced SNR. Long data-acquisition times further limit the spatial resolution of DIR to 1 mm³ isotropic at 3T. In a postmortem study, the specificity of 3D-DIR was found to be 90%, whereas sensitivity was only 18%.¹⁵ DIR detected most leukocortical lesions; however, intracortical and subpial lesions were still missed.¹⁵ Intracortical and subpial lesions are the most common cortical lesions in patients with chronic MS, yet subpial lesions are rarely detected with DIR or other techniques.^16,17 More recently, 3D versions of MR imaging sequences for MS have become available¹⁸ but are not yet used widely in clinical imaging of MS.¹⁹ 3D sequences with isotropic voxels of 1 mm³ volume or smaller are particularly suitable for the assessment of the cortex. Moreover, these scans allow simultaneous assessment of all 3 orthogonal image planes. A drawback is the increased acquisition time per scan, in particular for DIR. Lesion detection, especially within the cortex, would benefit from a rapid 3D imaging approach with high spatial resolution, suppressed CSF, higher SNR than DIR, and a good contrast-to-noise ratio (CNR) between lesions, GM and WM.This study aims to develop and test a method that combines the good SNR of T2-weighted images with the CSF suppression of FLAIR to achieve GM-WM contrast similar to that in DIR and good contrast between lesions, healthy tissue. We compared SNR and CNR of this new approach with conventional FLAIR, T2, and DIR; and we present images acquired in patients with relapsing-remitting and progressive MS.     

Improved Lesion Detection by Using Axial T2-Weighted MRI with Full Spinal Cord Coverage in Multiple Sclerosis

BACKGROUND AND PURPOSE:Identification of lesions in specific locations gains importance in multiple sclerosis imaging diagnostic criteria. In clinical routine, axial scans are usually exclusively obtained to depict the cervical spinal cord or used to confirm suspected lesions on sagittal scans. We sought to evaluate the detection rate for MS lesions on axial T2WI scans with full spinal cord coverage in comparison with sagittal scans.MATERIALS AND METHODS:One hundred fifteen patients with definite or suspected MS underwent an MR imaging examination including 3-mm sagittal and 3.5-mm axial T2-weighted images with full spinal cord coverage. T2WI lesions were identified on axial and sagittal scans independently by 2 raters. Axial diameter, craniocaudal extension, lesion intensity, and location were analyzed.RESULTS:Four hundred forty-nine of 509 (88.2%) lesions were detected on axial and 337/509 (66.2%) on sagittal scans. Only 277/449 (61.7%) axial lesions were also detected on sagittal images. The number of lesions visible on sagittal and axial images was dependent on the axial lesion diameter (P < .001).CONCLUSIONS:Axial T2WI scans with full spinal cord coverage showed 22% more lesions in patients with MS in comparison with sagittal scans, especially for lesions with small axial diameters. We suggest including biplanar spinal MR imaging with full spinal cord coverage for lesion detection in MS in clinical routine and for clinical studies.

Multiple sclerosis is a chronic inflammatory disease, considered the most common demyelinating process involving the central nervous system.¹ The diagnosis requires typical clinical findings in addition to the evidence of lesions in the CNS disseminated in time and space seen on MR imaging of the brain or spinal cord.² While the diagnostic focus of most multiple sclerosis studies is still based on MR imaging of the brain, several studies have revealed spinal cord lesions in 75%–90% of patients with clinically diagnosed MS.^3–6 As many as 20% of spinal MS lesions are isolated, without coexisting brain lesions.¹Spinal cord abnormalities seen on MR imaging were incorporated into the McDonald Diagnostic Criteria for MS in 2005.^7,8 Since the revision of the McDonald Diagnostic Criteria for MS in 2010,⁹ they have gained even more importance because better spinal cord lesion detection potentially impacts the recognition of the dissemination of MS lesions in space.In 2006, a consortium of MS centers published consensus guidelines with a standardized MR imaging protocol for spinal cord imaging in MS, recommending a 3-plane scout; a pre- and post-contrast-enhanced sagittal T1; a pre-contrast-enhanced sagittal FSE proton-density/T2; and additionally, only in case of suspected lesions, a pre-contrast-enhanced axial FSE proton-density/T2 and a post-contrast-enhanced axial T1.¹⁰ In the clinical routine of MS diagnostics, axial scans are typically obtained exclusively with coverage of the cervical spinal cord or are used to confirm suspected lesions in sagittal scans. This is mainly due to the long scanning time of axial scans with full spinal cord coverage.So far in most MS studies, spinal cord lesions were evaluated and marked on the sagittal plane,^11,12 while some groups included axial scans covering only the cervical spine^13–15 and very few studies analyzed the axial and sagittal planes of the entire spinal cord.^3,16 Also, lesion location and size were described on sagittal scans only or on axial scans covering the cervical spinal cord exclusively.¹⁵We hypothesized that axial T2WI scans with full spinal cord coverage would detect more T2WI lesions in comparison with sagittal scans. We sought to evaluate detection rates for T2WI lesions on axial and sagittal scans in relation to the distribution and extent of spinal cord lesions in patients with MS. To our knowledge, this is the first study focusing on the clinical application of axial 3.5-mm scans with full spinal cord coverage. We used a sequence with reasonable duration, feasible in clinical routine.     

How Common Is Signal-Intensity Increase in Optic Nerve Segments on 3D Double Inversion Recovery Sequences in Visually Asymptomatic Patients with Multiple Sclerosis?

BACKGROUND AND PURPOSE:In postmortem studies, subclinical optic nerve demyelination is very common in patients with MS but radiologic demonstration is difficult and mainly based on STIR T2WI. Our aim was to evaluate 3D double inversion recovery MR imaging for the detection of subclinical demyelinating lesions within optic nerve segments.MATERIALS AND METHODS:The signal intensities in 4 different optic nerve segments (ie, retrobulbar, canalicular, prechiasmatic, and chiasm) were evaluated on 3D double inversion recovery MR imaging in 95 patients with MS without visual symptoms within the past 3 years and in 50 patients without optic nerve pathology. We compared the signal intensities with those of the adjacent lateral rectus muscle. The evaluation was performed by a student group and an expert neuroradiologist. Statistical evaluation (the Cohen κ test) was performed.RESULTS:On the 3D double inversion recovery sequence, optic nerve segments in the comparison group were all hypointense, and an isointense nerve sheath surrounded the retrobulbar nerve segment. At least 1 optic nerve segment was isointense or hyperintense in 68 patients (72%) in the group with MS on the basis of the results of the expert neuroradiologist. Student raters were able to correctly identify optic nerve hypersignal in 97%.CONCLUSIONS:A hypersignal in at least 1 optic nerve segment on the 3D double inversion recovery sequence compared with hyposignal in optic nerve segments in the comparison group was very common in visually asymptomatic patients with MS. The signal-intensity rating of optic nerve segments could also be performed by inexperienced student readers.

MR imaging contributes to not only the diagnosis and differential diagnosis of MS but also the monitoring and follow-up of patients.¹ T1-weighted postcontrast, T2-weighted, proton-density, FLAIR, and double inversion recovery (DIR) images are recommended to detect acute and chronic demyelinating lesions in typical locations.^1–9Acute optic neuritis is an inflammatory demyelination of the optic nerve causing acute visual loss.^10–13 After recovery, patients are often visually asymptomatic, but careful visual testing by visually evoked potentials, optical coherence tomography, and visual disability evaluation may reveal persistent slight visual deficits.^14–17 These deficits are also observed in patients without any history of previous acute optic neuritis due to a suspected subclinical disease known as subclinical optic nerve demyelination.^14–17Acute optic neuritis is easily diagnosed on MR imaging by focal nerve swelling and segmental T2-weighted hyperintensity, especially on STIR images or on fat-suppressed T2-weighted images and by segmental gadolinium enhancement on T1-weighted fat-suppressed images.^10,18–22 The enhancement is present for a mean of 30 days after the onset of visual symptoms.^21,23–31Subclinical optic nerve demyelination, however, is not easily visible on MR imaging. Routine T2-weighted images without fat suppression and contrast-enhanced T1-weighted FSE images do not show any signal abnormality in the affected optic nerve. Fat-suppressed T2-weighted FSE images, especially STIR T2-weighted images, may detect a signal-intensity abnormality in subclinical optic nerve demyelination.^23,32,33 The highly diagnostic value of fat-suppressed FLAIR images and fat-suppressed 3D DIR images in the detection of any pathologic signal intensity in the optic nerve has been evaluated in acute optic nerve demyelination.^10,34,35 In a few patients with subclinical optic nerve demyelination, signal-intensity abnormalities have been reported on 3D FLAIR.³⁴ However, there are few data about the use of the 3D DIR sequence in the evaluation of subclinical optic nerve demyelination.³⁶In our department, patients with MS are routinely and regularly monitored for disease progression by a standard protocol with 3D FLAIR, 3D DIR, T2-weighted FSE, and 3D T1-weighted postcontrast images. 3D DIR is added to our standard protocol for improved detection of juxtacortical, cortical, and infratentorial demyelinating lesions.^1–9 On the basis of postmortem and clinical studies having already shown a high percentage of subclinical optic nerve demyelination with ongoing axonal loss in patients with MS,^37–41 we wanted to test 2 hypotheses: first, that it is possible to detect signal-intensity changes in optic nerve segments on the 3D DIR sequence without the additional application of a STIR T2-weighted sequence over the orbits in patients with MS without a history of clinically obvious visual loss and without a history of acute optic neuritis during the previous 3 years; and second, that the signal-intensity changes on 3D DIR are so obvious that even inexperienced readers can detect them. This second hypothesis is important because in our department, MR imaging examinations of patients with MS are evaluated not only by trained neuroradiologists but also general radiologists. Therefore, it is desirable that the lack of neuroradiologic experience be compensated by the application of an easily readable MR image, and the 3D DIR sequence is routinely acquired in our department for the follow-up of patients with MS.For comparison, the signal intensities of normal healthy optic nerve segments in patients evaluated by the identical 3D DIR sequence for different diseases (ie, epileptic seizures and posttraumatic sequelae) were analyzed as well.     

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.     

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.     

Fellows' Journal Club: Brain MRI Findings in Neurologically Asymptomatic Patients with Infective Endocarditis

BACKGROUND AND PURPOSE:Neurologic complications in infective endocarditis are frequent and affect patient prognosis negatively. Additionally, detection of asymptomatic lesions by MR imaging could help early management of this condition. The objective of our study was to describe MR imaging characteristics of cerebral lesions in a neurologically asymptomatic population with infective endocarditis.MATERIALS AND METHODS:One hundred nine patients at the acute phase of a definite or possible infective endocarditis according to the Duke modified criteria and without neurologic manifestations according to the NIHSS were prospectively included. Each patient underwent cerebral MR imaging and MRA within 7 days of admission.RESULTS:MR imaging showed abnormalities in 78 patients (71.5%). Acute ischemic lesions (40 patients, 37%) and cerebral microbleeds (62 patients, 57%) were the most frequent lesions. Eight patients had an acute SAH, 3 patients had brain microabscesses, 3 had a small cortical hemorrhage, and 3 had a mycotic aneurysm. Acute ischemic lesions mostly appeared as multiple small infarcts disseminated in watershed territories (25/40, 62.5%) and as lesions of different ages (21/40, 52.5%). Cerebral microbleeds were preferentially distributed in cortical areas (362/539 cerebral microbleeds, 67%). No significant correlation was found among lesions, in particular between acute ischemia and cerebral microbleeds.CONCLUSIONS:Occult cerebral lesions, in particular cerebral microbleeds and acute ischemic lesions, are frequent in infective endocarditis. The MR imaging pattern of acute small infarcts of different ages predominating in watershed territories and cortical cerebral microbleeds may represent a surrogate imaging marker of infective endocarditis.

Infective endocarditis is associated with symptomatic neurologic complications in 20%–40% of cases.^1–4 Among symptomatic complications, ischemic stroke is the most common manifestation, whereas hemorrhagic stroke, brain abscess, cerebral hemorrhage or SAH, and mycotic aneurysms are less frequent.² Symptomatic cerebral complications are one of the main prognostic factors in infective endocarditis (IE)^5–8 because they are significantly associated with a 3-month mortality rate.^2,3,9,10 Symptomatic neurologic complications are difficult to predict and prevent because they mostly occur in the early phase of IE and have been reported as the presenting symptom of the disease in up to 47% of cases.²Asymptomatic cerebral lesions revealed by systematic cerebral CT and/or MR imaging have been recently reported, but their impact on patient care and prognosis has not been completely assessed.^8,11–13 Our group showed that detection of cerebral asymptomatic lesions influenced diagnostic decisions in cases of suspected IE.^14,15The purposes of the present study were to extensively describe MR imaging characteristics of cerebral lesions in a neurologically asymptomatic population at the acute phase of IE, to prospectively report their respective frequencies, and to assess correlations between different MR imaging features.     

Comparison of Sagittal FSE T2, STIR,and T1-Weighted Phase-Sensitive Inversion Recovery in the Detection of Spinal Cord Lesions in MS at 3T

BACKGROUND AND PURPOSE:Determining the diagnostic accuracy of different MR sequences is essential to design MR imaging protocols. The purpose of the study was to compare 3T sagittal FSE T2, STIR, and T1-weighted phase-sensitive inversion recovery in the detection of spinal cord lesions in patients with suspected or definite MS.MATERIALS AND METHODS:We performed a retrospective analysis of 38 patients with suspected or definite MS. Involvement of the cervical and thoracic cord segments was recorded on sagittal FSE T2, STIR, and T1-weighted phase-sensitive inversion recovery sequences independently by 2 readers. A consensus criterion standard read was performed with all sequences available. Sensitivity, specificity, and interobserver agreement were calculated for each sequence.RESULTS:In the cervical cord, the sensitivity of T1-weighted phase-sensitive inversion recovery (96.2%) and STIR (89.6%) was significantly higher (P < .05) than that of FSE T2 (50.9%), but no significant difference was found between T1-weighted phase-sensitive inversion recovery and STIR. In the thoracic cord, sensitivity values were 93.8% for STIR, 71.9% for FSE T2, and 50.8% for T1-weighted phase-sensitive inversion recovery. Significant differences were found for all comparisons (P < .05). No differences were detected in specificity. Poor image quality and lower sensitivity of thoracic T1-weighted phase-sensitive inversion recovery compared with the other 2 sequences were associated with a thicker back fat pad.CONCLUSIONS:The use of an additional sagittal sequence other than FSE T2 significantly increases the detection of cervical and thoracic spinal cord lesions in patients with MS at 3T. In the cervical segment, both STIR and T1-weighted phase-sensitive inversion recovery offer high sensitivity and specificity, whereas in the thoracic spine, STIR performs better than T1-weighted phase-sensitive inversion recovery, particularly in patients with a thick dorsal fat pad.

MR imaging of the spinal cord is an important diagnostic technique in MS because the prevalence of spinal cord abnormalities in patients with clinically isolated syndrome is as high as 42%.¹ In clinically diagnosed MS, spinal cord involvement reaches 75%–92%, depending on the series.^2–4 The presence of asymptomatic cord lesions contributes to the demonstration of dissemination in space in the McDonald 2010 criteria for MS, and imaging of the spinal cord allows an increase of 18.3% in the number of patients meeting the diagnostic criteria.⁵ The presence of spinal cord lesions not only facilitates diagnosing MS but is also predictive of conversion to clinically definite MS, especially in patients with nonspinal clinically isolated syndrome who do not fulfill brain MR imaging criteria.⁶ Moreover, spinal cord lesions in MS can occur in isolation in 5% of patients, particularly in primary-progressive MS.⁷Spinal cord imaging is challenging because the spinal cord is a small and mobile structure.⁸ In addition, its anatomic location makes it prone to ghosting artifacts caused by the heart and great vessels as well as truncation artifacts. 3T MR imaging compared with 1.5T is more prone to artifacts caused by B₁ field inhomogeneity,⁹ susceptibility, vascular pulsation, and chemical shift.^10,11 In addition, 3T MR imaging has a higher energy deposit within the tissue, resulting in a higher specific absorption rate than lower field scanners. These problems can be partially solved with various technical adjustments and fast (parallel) imaging.¹²Traditionally, the spinal cord in patients with MS has been imaged by using sagittal and axial FSE T2/proton density sequences. Additional sequences, including STIR^13,14 and T1 inversion recovery,¹⁵ have shown promise by increasing lesion visibility, particularly at 3T, in which conventional FSE T2 and proton density images are frequently unsatisfactory.¹⁶ STIR has proved very useful as a complementary sequence in the detection of MS lesions but cannot be used in isolation due to its lower specificity.^13,14 Numerous studies have demonstrated the superiority of STIR over T2 at 1.5T,^{13,14,17–19} and 1 study¹⁵ also showed the advantages of STIR at 3T in the cervical cord. To our knowledge, no studies have been performed in the thoracic cord comparing sagittal FSE T2 and STIR. A recent publication showed the advantages of T1-weighted phase-sensitive inversion recovery (PSIR) for the detection of cervical spinal cord lesions in MS at 3T.¹⁶ PSIR has been shown to improve lesion localization and boundary definition over STIR in the cervical spinal cord, but it has not been tested in the thoracic cord.¹⁶The aim of our study was to compare the sensitivity and specificity of sagittal STIR, PSIR, and FSE T2 in the detection of MS spinal cord lesions at 3T, in both the cervical and thoracic segments.     

Autoimmune Comorbidities Are Associated with Brain Injury in Multiple Sclerosis

BACKGROUND AND PURPOSE:The effect of comorbidities on disease severity in MS has not been extensively characterized. We determined the association of comorbidities with MR imaging disease severity outcomes in MS.MATERIALS AND METHODS:Demographic and clinical history of 9 autoimmune comorbidities confirmed by retrospective chart review and quantitative MR imaging data were obtained in 815 patients with MS. The patients were categorized on the basis of the presence/absence of total and specific comorbidities. We analyzed the MR imaging findings, adjusting for key covariates and correcting for multiple comparisons.RESULTS:Two hundred forty-one (29.6%) study subjects presented with comorbidities. Thyroid disease had the highest frequency (n = 97, 11.9%), followed by asthma (n = 41, 5%), type 2 diabetes mellitus (n = 40, 4.9%), psoriasis (n = 33, 4%), and rheumatoid arthritis (n = 22, 2.7%). Patients with MS with comorbidities showed decreased whole-brain and cortical volumes (P < .001), gray matter volume and magnetization transfer ratio of normal-appearing brain tissue (P < .01), and magnetization transfer ratio of gray matter (P < .05). Psoriasis, thyroid disease, and type 2 diabetes mellitus comorbidities were associated with decreased whole-brain, cortical, and gray matter volumes (P < .05). Psoriasis was associated with a decreased magnetization transfer ratio of normal-appearing brain tissue (P < .05), while type 2 diabetes mellitus was associated with increased mean diffusivity (P < .01).CONCLUSIONS:The presence of comorbidities in patients with MS is associated with brain injury on MR imaging. Psoriasis, thyroid disease, and type 2 diabetes mellitus comorbidities were associated with more severe nonconventional MR imaging outcomes.

MS is a chronic immune-mediated disorder that affects the CNS and is characterized by specific clinical and MR imaging findings.¹ Studies have suggested genetic, environmental, and infectious agents as interacting factors influencing the risk for development of MS.^2,3Epidemiologic evidence from the North American Research Committee on Multiple Sclerosis, the large registry containing patient self-reported data, suggests an increased risk for disability progression in individuals with MS who have additional comorbidities.⁴ An increased prevalence of autoimmune- and nonimmune-mediated comorbidities was reported in patients with MS compared with the general population.^5–14 Examples of the most frequent comorbidities or secondary disorders that co-occur with MS include thyroid disease, rheumatoid arthritis, psoriasis, cardiovascular disorders, depression and anxiety, diabetes mellitus, chronic lung disease, and irritable bowel syndrome, among others.^{4–6,8–10,14,15} The pathogenesis of these associations with MS is unclear at this time but may be linked to a genetic predisposition,^5,16,17 the presence of a chronic inflammatory condition,¹⁰ environmental factors,¹⁸ and the use of disease-modifying therapy.¹⁹It has been postulated that CD4+ T-cells of the Th1 phenotype, CD8+ T-cells, and B-cells play a key role in focal and diffuse destruction of the CNS in patients with MS.²⁰ The immune deviation of CD 4+ T-cells into Th1 and Th2 phenotypes has been the subject of many immunologic and epidemiologic studies in MS.^21,22 In particular, it has been reported that Th1 responses associated with autoimmunity may be attenuated by a Th2 shift.¹³ Several studies reported a positive association of comorbidities in patients with MS when explored from the Th1/Th2 point of view.^13,22,23 However, some other studies suggested that these associations were related more to a demographic selection bias than a true sharing of immunologic and pathologic processes.¹⁴Conventional MR imaging examines visible focal inflammatory changes within the CNS. However, it does not capture the true extent of diffuse GM and WM pathology that is mostly undetected in patients with MS and responsible for long-term development of disability progression.²⁴ On the other hand, nonconventional MR imaging techniques are more sensitive biomarkers for measuring these nonfocal pathologic processes associated with tissue damage in the GM and WM and that are better associated with disease severity.²⁴ Some of these techniques include measures of brain atrophy, magnetization transfer imaging, DWI and DTI, MR spectroscopy, and functional MR imaging.It has been shown that patients with MS with ≥1 cardiovascular risk factor have increased lesion burden and more advanced brain atrophy on MR imaging.^25,26 However, it is not clear whether the presence of other comorbidities may also influence the severity of conventional and nonconventional MR imaging measures in patients with MS. Therefore, in this large-cohort MS study, we aimed to investigate the impact of autoimmune comorbidities on the severity of conventional and nonconventional MR imaging outcomes in patients with MS.     

Frontotemporal Cortical Thinning in Amyotrophic Lateral Sclerosis

BACKGROUND AND PURPOSE:The extensive application of advanced MR imaging techniques has undoubtedly improved our knowledge of the pathophysiology of amyotrophic lateral sclerosis. Nevertheless, the precise extent of neurodegeneration throughout the central nervous system is not fully understood. In the present study, we assessed the spatial distribution of cortical damage in amyotrophic lateral sclerosis by using a cortical thickness measurement approach.MATERIALS AND METHODS:Surface-based morphometry was performed on 20 patients with amyotrophic lateral sclerosis and 18 age- and sex-matched healthy control participants. Clinical scores of disability and disease progression were correlated with measures of cortical thickness.RESULTS:The patients with amyotrophic lateral sclerosis showed a significant cortical thinning in multiple motor and extramotor cortical areas when compared with healthy control participants. Gray matter loss was significantly related to disease disability in the left lateral orbitofrontal cortex (P = .04), to disease duration in the right premotor cortex (P = .007), and to disease progression rate in the left parahippocampal cortex (P = .03).CONCLUSIONS:Cortical thinning of the motor cortex might reflect upper motor neuron impairment, whereas the extramotor involvement seems to be related to disease disability, progression, and duration. The cortical pattern of neurodegeneration depicted resembles what has already been described in frontotemporal dementia, thereby providing further structural evidence of a continuum between amyotrophic lateral sclerosis and frontotemporal dementia.

Despite the common view of amyotrophic lateral sclerosis (ALS) as a neurodegenerative disease that exclusively affects motor functions, convincing evidence supports the notion that ALS is a multisystem disease also affecting behavior, language, and cognition.^1–6 Indeed, among patients with ALS, as many as 15% meet criteria for frontotemporal dementia (FTD), whereas up to 35% show a mild to moderate cognitive impairment.^5,7 From the histochemical and genetic points of view, recent findings suggest that ALS may belong to a broader clinicopathologic spectrum, known as transactivating responsive sequence DNA-binding protein 43-kDa (TDP-43) proteinopathy, which also includes FTD.^8–10Structural and functional MR imaging studies have corroborated the theory of a relevant frontotemporal impairment in ALS with approximately half of the patients displaying at least mild abnormalities.^11–20The development of advanced automated imaging analysis techniques, on the basis of construction of statistical parametric maps, has allowed detailed anatomic studies of brain morphometry. Voxel-based morphometry (VBM) allows a fully automated whole-brain measurement of regional brain atrophy by voxelwise comparison of GM and WM volumes between groups of participants.²¹ The most consistent finding of VBM studies in ALS involves GM atrophy in several regions of the frontal (ie, anterior cingulate, middle and inferior frontal gyrus) and temporal lobes (ie, temporal poles, superior temporal gyrus, temporal isthmus, hippocampus),^{11–13,16,17,19} reporting significant correlations between GM atrophy and cognitive dysfunction mainly in patients with an ALS-plus syndrome (ie, ALS with cognitive and behavioral symptoms).²⁰ However, the lack of agreement on cortical atrophy distribution²² has prompted the application of other advanced MR imaging approaches. Surface-based morphometry (SBM), allowing cortical thickness (CTh) measurements,²³ has shown several advantages compared with VBM in reconstructing the cortical surface. This technique, indeed, allows decomposition of cortical volume into both thickness and surface area, respecting the cortical topology and enhancing reliability and sensitivity.²⁴ Therefore, mainly to identify a more sensitive marker of upper motor neuron (UMN) degeneration, CTh analysis has been applied to the study of ALS, revealing cortical thinning not only in the precentral gyrus,^18,25–27 but also within the numerous frontotemporal, parietal, and occipital areas.^26–28 It is noteworthy that, so far, the correlation between regional cortical thinning and clinical features has not been fully assessed. On this background, we aimed to further investigate—without any a priori hypothesis—the pattern of both motor and extramotor cortical involvement in patients with sporadic ALS and to explore the relationship between MR imaging data and clinical and neuropsychological features.     

Incidence of Radiologically Isolated Syndrome: A Population-Based Study

BACKGROUND AND PURPOSE:Incidental MR imaging findings resembling MS in asymptomatic individuals, fulfilling the Okuda criteria, are termed “radiologically isolated syndrome.” Those with radiologically isolated syndrome are at high risk of their condition converting to MS. The epidemiology of radiologically isolated syndrome remains largely unknown, and there are no population-based studies, to our knowledge. Our aim was to study the population-based incidence of radiologically isolated syndrome in a high-incidence region for MS and to evaluate the effect on radiologically isolated syndrome incidence when revising the original radiologically isolated syndrome criteria by using the latest radiologic classification for dissemination in space.MATERIALS AND METHODS:All 2272 brain MR imaging scans in 1907 persons obtained during 2013 in the Swedish county of Västmanland, with a population of 259,000 inhabitants, were blindly evaluated by a senior radiologist and a senior neuroradiologist. The Okuda criteria for radiologically isolated syndrome were applied by using both the Barkhof and Swanton classifications for dissemination in space. Assessments of clinical data were performed by a radiology resident and a senior neurologist.RESULTS:The cumulative incidence of radiologically isolated syndrome was 2 patients (0.1%), equaling an incidence rate of 0.8 cases per 100,000 person-years, in a region with an incidence rate of MS of 10.2 cases per 100,000 person-years. There was no difference in the radiologically isolated syndrome incidence rate when applying a modified version of the Okuda criteria by using the newer Swanton classification for dissemination in space.CONCLUSIONS:Radiologically isolated syndrome is uncommon in a high-incidence region for MS. Adapting the Okuda criteria to use the dissemination in space–Swanton classification may be feasible. Future studies on radiologically isolated syndrome may benefit from a collaborative approach to ensure adequate numbers of participants.

Due to the increased sensitivity, availability, and use of MR imaging, incidental findings have increased during the past decade.^1,2 Incidental MR imaging findings resembling MS, termed “radiologically isolated syndrome” (RIS), are 1 consequence of the increased use and sensitivity of MR imaging.³ RIS was introduced in 2009 by Okuda et al,³ to categorize incidental WM lesions suggestive of demyelinating disease in patients without typical MS symptoms and no better explanation for the MR imaging anomalies.⁴ RIS has, since its emergence, been debated, and the risk of RIS evolving into MS has been investigated.⁵ Nonconventional MR imaging methods and neuropsychological testing have revealed similar findings in RIS and MS.^6–10 One-third of patients with RIS develop MS in 5 years, implying that RIS, in some cases, constitutes a preclinical stage or subclinical form of MS. These results suggest that the McDonald criteria lack some degree of sensitivity in detecting MS in its earliest phases. This interpretation raises questions about the early pathophysiology of MS and motivates us to investigate to what extent it is possible to detect MR imaging findings before the symptomatic onset of MS. It is therefore of further interest to determine the frequency of RIS in clinical practice.^3,5,11–18However, despite the interest in RIS, its epidemiology remains largely unclear. Postmortem studies have shown a prevalence of incidental MS findings ranging from 0.06% to 0.7%.^5,19–21 The hospital-based incidence has been estimated between 0.05% and 0.7%.^17,22 Our aim was to study the population-based incidence of RIS in a country with a high incidence (10.2 per 100,000 person-years) and prevalence (189/100,000) of MS.^23,24 This was done by retrospectively re-evaluating all MR imaging brain examinations performed during 2013 in the Swedish county of Västmanland, with approximately 259,000 inhabitants.²⁵ We secondarily aimed to evaluate how implementing the newer Swanton classification for dissemination in space (DIS), from the 2010 McDonald criteria for MS, would affect the incidence of RIS.^3,4,26,27     

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.     

Prevalence of Radiologically Isolated Syndrome and White Matter Signal Abnormalities in Healthy Relatives of Patients with Multiple Sclerosis

BACKGROUND AND PURPOSE:The exact prevalence of WM signal abnormalities in healthy relatives of MS patients and their impact on disease development has not been fully elucidated. The purpose of this study was to compare WM signal abnormality characteristics and the prevalence of radiologically isolated syndrome in healthy control subjects selected randomly from the population with the healthy relatives of patients with MS.MATERIALS AND METHODS:Healthy control subjects (n = 150) underwent physical and 3T MR imaging examinations. Healthy control subjects were classified as non-familial healthy control subjects (n = 82) if they had no family history of MS or as healthy relatives of patients with MS (n = 68) if they had ≥1 relative affected with MS. The presence of radiologically isolated syndrome was evaluated according to the Okuda criteria; dissemination in space on MR imaging and fulfillment of radiologically isolated syndrome criteria were also evaluated according to Swanton criteria.RESULTS:There was a significantly higher total volume of WM signal abnormality in the healthy relatives of patients with MS compared with the non-familial healthy control subjects (P = .024 for signal abnormality ≥3 mm in size and P = .025 for all sizes). Periventricular localization and the number of lesions in all groups (P = .034 and P = .043) were significantly higher in the healthy relatives of patients with MS; 8.8% of the healthy relatives of patients with MS and 4.9% of non-familial healthy control subjects showed ≥9 WM signal abnormalities; 2.9% of subjects in the healthy relatives of patients with MS group and 2.4% of non-familial healthy control subjects fulfilled radiologically isolated syndrome according to the Okuda criteria, whereas 10.3% and 3.7% of subjects fulfilled radiologically isolated syndrome according to the Swanton criteria. In the healthy relatives of patients with MS, smoking was associated with the presence of WM signal abnormalities, whereas obesity was related to the presence of ≥9 WM signal abnormalities and to fulfillment of radiologically isolated syndrome according to the Swanton criteria.CONCLUSIONS:The frequency of WM signal abnormalities and radiologically isolated syndrome is higher in the healthy relatives of patients with multiple sclerosis patients compared with non-familial healthy control subjects.

Multiple sclerosis is an inflammatory autoimmune demyelinating disorder of the CNS.¹ Although MS is predominantly a sporadic disease, a genetic predisposition to developing familial MS is well accepted.² Although the exact definition of familial MS is not yet established, familial patients with MS are considered to be those with ≥1 first-degree relative affected with MS,² although some authors use a definition that is based on the presence of 2 first-degree relatives.³ In a recent meta-analysis, the risk of development of MS was 18.2% for monozygotic twins of patients with MS, 4.6% for dizygotic twins, and 2.7% for siblings.⁴ The risk of development of MS in a first-degree relative of the affected patient is 30- to 50-fold higher than in the general population,⁵ whereas second- and third-degree relatives also showed an increased risk for development of MS.⁶Whether familial or non-familial MS are different forms of the disease is not fully elucidated yet.⁷ Differences in disease progression in familial MS were observed in several studies demonstrating earlier age of onset and increased probability of a progressive clinical course.⁸ However, other studies did not show clinical differences among familial and non-familial healthy control subject (non-fMS) forms.^2,9 Nevertheless, MR imaging studies by use of nonconventional techniques showed MR imaging differences between familial and non-familial MS.^10–12In 2009, Okuda et al¹³ introduced the term “radiologically isolated syndrome” (RIS) to describe subjects who show incidental brain MR imaging WM lesions suggestive of MS and who fulfill Barkhof criteria for dissemination in space (DIS)¹⁴ but have no signs or symptoms of the disease. Overall, the prevalence of RIS is, according to postmortem studies, in a range of 0.06–0.7%, with an age range of 16–70.^13,15 However, the McDonald 2010 criteria for DIS¹⁶ substituted Barkhof criteria¹⁴ with the Swanton criteria for DIS.¹⁷ Swanton DIS criteria require the presence of ≥1 WM lesion in ≥2 of the brain regions (juxtracortical, periventricular, or infratentorial) or in the spinal cord.¹⁷ The value of the Swanton criteria for DIS¹⁷ was not evaluated with respect to the diagnosis of RIS.Previous MR imaging studies showed that asymptomatic relatives of patients with MS display significant magnetization transfer ratio changes in CNS WM signal abnormality, indicative of MS pathology,^3,18 though some other studies showed no differences in the magnetization transfer ratio of WM in the siblings of patients with MS.¹⁹ Studies with the use of conventional brain MR imaging showed WM signal abnormalities consistent with MS in the healthy relatives of patients with MS,^20–22 with 4% of non-familial healthy control subjects (non-fHC) and 10% of healthy control subjects with familial MS (HC) fulfilling Barkhof criteria¹⁴ for DIS.²⁰ However, these studies had several limitations including the number of enrolled subjects, strength of the MR imaging field, and use of more conservative criteria for RIS.¹³ As a result, the exact prevalence of RIS and the WM signal abnormalities in asymptomatic MS relatives is not yet fully defined.The aim of this pilot study was to compare WM signal abnormality characteristics in a large cohort of non-fHCs and healthy relatives of patients with MS by use of 3T MR imaging. We also determined the prevalence of RIS in HC groups, according to both the Barkhof¹⁴ and Swanton¹⁷ MR imaging criteria for DIS and investigated association between the presence of vascular risk factors and RIS.     

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.     

Thalamic Iron Differentiates Primary-Progressive and Relapsing-Remitting Multiple Sclerosis

BACKGROUND AND PURPOSE:Potential differences between primary progressive and relapsing remitting multiple sclerosis are the subject of ongoing controversial discussions. The aim of this work was to determine whether and how primary-progressive and relapsing-remitting multiple sclerosis subtypes differ regarding conventional MR imaging parameters, cerebral iron deposits, and their association with clinical status.MATERIALS AND METHODS:We analyzed 24 patients with primary-progressive MS, 80 with relapsing-remitting MS, and 20 healthy controls with 1.5T MR imaging for assessment of the conventional quantitative parameters: T2 lesion load, T1 lesion load, brain parenchymal fraction, and corpus callosum volume. Quantitative susceptibility mapping was performed to estimate iron concentration in the deep gray matter.RESULTS:Decreased susceptibility within the thalamus in relapsing-remitting MS compared with primary-progressive MS was the only significant MR imaging difference between these MS subtypes. In the relapsing-remitting MS subgroup, the Expanded Disability Status Scale score was positively associated with conventional parameters reflecting white matter lesions and brain atrophy and with iron in the putamen and caudate nucleus. A positive association with putaminal iron and the Expanded Disability Status Scale score was found in primary-progressive MS.CONCLUSIONS:Susceptibility in the thalamus might provide additional support for the differentiation between primary-progressive and relapsing-remitting MS. That the Expanded Disability Status Scale score was associated with conventional MR imaging parameters and iron concentrations in several deep gray matter regions in relapsing-remitting MS, while only a weak association with putaminal iron was observed in primary-progressive MS suggests different driving forces of disability in these MS subtypes.

Pathologic cerebral iron accumulation in multiple sclerosis is a consistent finding in MR imaging and neuropathologic studies. Abnormal iron deposits were detected particularly in the deep gray matter (DGM)—that is, in the putamen, caudate nucleus (CN), and globus pallidus (GP) with iron-sensitive MR imaging techniques such as R2* relaxometry, magnetic field correlation imaging, phase imaging, and quantitative susceptibility mapping (QSM).^1–8 Neuropathologic studies in MS confirmed increased iron content in both glial cells and neurons in DGM associated with degenerative changes,⁹ while overall iron loss was observed in normal-appearing white matter.¹⁰ An increase in iron concentration appears to be an early phenomenon, with the highest amounts of accumulation occurring during the transitions from clinically isolated syndrome to definite MS.¹¹Currently, little information is available on the differences in iron content in various MS subtypes. Primary-progressive MS (PPMS) is a subtype characterized by a steady progression without relapses and worse response to immunosuppressant drugs. It has been postulated that underlying mechanisms and measures of disability progression in PPMS may be different from those in relapsing-remitting MS (RRMS). In particular, inflammation may be less prominent compared with neurodegeneration in the PPMS subtype. However, neuroimaging studies supporting this theory are lacking. It remains unclear whether PPMS and RRMS subtypes differ in iron accumulation in the DGM. Differences in demographic and clinical data cause difficulties in the comparison of these 2 subtypes. PPMS affects older age groups than RRMS, with a peak incidence in the fifth and sixth decades; the male-to-female ratio is typically 1:1 compared with 1:3 reported in most RRMS trials. Additionally, the Expanded Disability Status Scale (EDSS) score is higher in patients with PPMS than in those with RRMS, with the same disease duration indicating faster disease progression in PPMS.¹²The primary goal of this study was to compare iron content and conventional MR imaging parameters such as T2 lesion load (T2LL), T1 lesion load (T1LL), brain parenchymal fraction (BPF), and corpus callosum volume (CCV) in RRMS and PPMS. We were particularly interested in whether these MS subtypes differ in iron concentration and whether iron accumulation has a different impact on disability in PPMS compared with RRMS. From several MR imaging–based techniques enabling the assessment of iron concentration in the brain,¹³ we chose quantitative susceptibility mapping (QSM). Postmortem validation studies have demonstrated that QSM in the DGM is tightly correlated with iron concentration.¹⁴ QSM has been shown to correlate with R2 and R2* relaxometry, but compared with these techniques, it does not require multiecho data, has a higher dynamic range, and might be more sensitive to smaller tissue-susceptibility changes.^15–18The secondary goal was to investigate the correlation between quantitative MR imaging parameters and clinical disability measured by the EDSS in both MS subtypes.     

Ultra-High-Field MRI Visualization of Cortical Multiple Sclerosis Lesions with T2 and T2*: A Postmortem MRI and Histopathology Study

BACKGROUND AND PURPOSE:At 7T MR imaging, T2*-weighted gradient echo has been shown to provide high-resolution anatomic images of gray matter lesions. However, few studies have verified T2*WI lesions histopathologically or compared them with more standard techniques at ultra-high-field strength. This study aimed to determine the sensitivity of T2WI and T2*WI sequences for detecting cortical GM lesions in MS.MATERIALS AND METHODS:At 7T, 2D multiecho spin-echo T2WI and 3D gradient-echo T2*WI were acquired from 27 formalin-fixed coronal hemispheric brain sections of 15 patients and 4 healthy controls. Proteolipid-stained tissue sections (8 μm) were matched to the corresponding MR images, and lesions were manually scored on both MR imaging sequences (blinded to histopathology) and tissue sections (blinded to MR imaging). The sensitivity of MR imaging sequences for GM lesion types and white matter lesions was calculated. An unblinded retrospective scoring was also performed.RESULTS:If all cortical GM lesions were taken into account, the T2WI sequence detected slightly more lesions than the T2*WI sequence: 28% and 16%, respectively (P = .054). This difference disappeared when only intracortical lesions were considered. When histopathologic information (type, location) was revealed to the reader, the sensitivity went up to 84% (T2WI) and 85% (T2*WI) (not significant). Furthermore, the false-positive rate was 8.6% for the T2WI and 10.5% for the T2*WI sequence.CONCLUSIONS:There is no strong advantage of the T2*WI sequence compared with a conventional T2WI sequence in the detection of cortical lesions at 7T. Retrospectively, a high percentage of lesions could be detected with both sequences. However, many lesions are still missed prospectively. This could possibly be minimized with better a priori observer training.

Multiple sclerosis is traditionally regarded as a chronic inflammatory demyelinating disease of the white matter with a variable clinical course; primary-progressive or relapsing-remitting with possible conversion to secondary-progressive. Pathologic, immunologic, and imaging studies have confirmed that tissue damage in the gray matter is also a key component of the disease process.^1–4 GM pathology occurs frequently, already early in the disease course, and explains cognitive and clinical disability better than white matter lesions.^5,6 Nevertheless, visualizing these GM abnormalities has been challenging due to their small size, absence of inflammation, and partial volume effect from adjacent CSF and WM. The introduction of ultra-high-field MR imaging scanners and specific MR imaging pulse sequences has improved the detection of GM lesions due to a higher signal-to-noise ratio and better spatial resolution.^7–9 7T T2*-weighted gradient-echo MR imaging has been shown to provide high-resolution anatomic images of GM lesions, and it has even been suggested that this sequence be used as the new criterion standard for GM lesion detection.¹⁰ It was reported to be 44% more sensitive than 1.5T MR imaging in detecting lesions with cortical involvement¹¹ and up to 69% more sensitive than 3T double inversion recovery (DIR) imaging in detecting subpial lesions.¹⁰Few groups have had the opportunity to study GM lesions that were visualized with 7T T2*WI in terms of histopathology. Therefore, little information is available on the exact sensitivity of T2*WI and/or whether certain lesion types are more visible than others with this sequence. One postmortem study that did look at T2*WI sensitivity showed a 48% prospective sensitivity but made no distinction among lesion types.¹² Another 7T study found that 46% of cortical lesions could be prospectively detected by using T2*WI and a similar 43% could be detected by using a WM-attenuated turbo field echo.¹³ However, the 2 sequences studied were suboptimally matched in terms of image resolution, which may explain the relative absence of differences between them. The current study aimed to determine the sensitivity of a standard T2WI and a T2*WI sequence, by using the same image resolution, for detecting MS GM lesion types in postmortem MS tissue.     

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.