These findings suggest that thalamic atrophy is a clinically relevant biomarker of the neurodegenerative disease process in multiple sclerosis.

Objective In the presurgical workup of MRI-negative (MRI−, or “nonlesional”) pharmacoresistant focal epilepsy (PFE) patients, discovering a previously undetected lesion can drastically change the evaluation and likely improve surgical outcome. Our study utilizes a voxel-based MRI post-processing technique, implemented in a morphometric analysis program (MAP), to facilitate detection of subtle abnormalities in a consecutive cohort of MRI− surgical candidates. Methods Included in this retrospective study was a consecutive cohort of 150 MRI-surgical patients. MAP was performed on T1-weighted MRI, with comparison to a scanner-specific normal database. Review and analysis of MAP were performed blinded to patients’ clinical information. The pertinence of MAP+ areas was confirmed by surgical outcome and pathology. Results MAP showed a 43% positive rate, sensitivity of 0.9 and specificity of 0.67. Overall, patients with MAP+ region completely resected had the best seizure outcomes, followed by the MAP− patients, and patients who had no/partial resection of the MAP+ region had the worst outcome (p<0.001). Subgroup analysis revealed that visually identified subtle findings are more likely correct if also MAP+. False-positive rate in 52 normal controls was 2%. Surgical pathology of the resected MAP+ areas contained mainly non-balloon-cell FCD. Multiple MAP+ regions were present in 7% of patients. Conclusions MAP can be a practical and valuable tool to: (1) guide the search for subtle MRI abnormalities, and (2) confirm visually identified questionable abnormalities in patients with PFE due to suspected FCD. A MAP+ region, when concordant with the patient’s electro-clinical presentation, should provide a legitimate target for surgical exploration.

Patients with magnetic-resonance-imaging (MRI)-negative (or 'nonlesional') pharmacoresistant focal epilepsy are the most challenging group undergoing presurgical evaluation. Few large-scale studies have systematically reviewed the pathological substrates underlying MRI-negative epilepsies. In the current study, histopathological specimens were retrospectively reviewed from MRI-negative epilepsy patients (n ¼ 95, mean age ¼ 30 years, 50% female subjects). Focal cortical dysplasia cases were classified according to the International League Against Epilepsy (ILAE) and Palmini et al classifications. The most common pathologies found in this MRI-negative cohort included: focal cortical dysplasia (n ¼ 43, 45%), gliosis (n ¼ 21, 22%), hamartia þ gliosis (n ¼ 12, 13%), and hippocampal sclerosis (n ¼ 9, 9%). The majority of focal cortical dysplasia were ILAE type I (n ¼ 37) or Palmini type I (n ¼ 39). Seven patients had no identifiable pathological abnormalities. The existence of positive pathology was not significantly associated with age or temporal/extratemporal resection. Follow-up data post surgery was available in 90 patients; 63 (70%) and 57 (63%) attained seizure freedom at 6 and 12 months, respectively. The finding of positive pathology was significantly associated with seizure-free outcome at 6 months (P ¼ 0.035), but not at 12 months. In subgroup analysis, the focal cortical dysplasia group was not significantly correlated with seizure-free outcome, as compared with the negative-pathology groups at either 6 or 12 months. Of note, the finding of hippocampal sclerosis had a significant positive correlation with seizurefree outcome when compared with the negative-pathology group (P ¼ 0.009 and 0.004 for 6-and 12-month outcome, respectively). Absence of a significant histopathology in the resected surgical specimen did not preclude seizure freedom. In conclusion, our study highlights the heterogeneity of epileptic pathologies in MRInegative epilepsies, with focal cortical dysplasia being the most common finding. The existence of positive pathology in surgical specimen may be a good indication for short-term good seizure outcome. There is a small subset of cases in which no pathological abnormalities are identified.

Summary:Magnetic resonance imaging (MRI) plays an everexpanding role in the evaluation of multiple sclerosis (MS). This includes its sensitivity for the diagnosis of the disease and its role in identifying patients at high risk for conversion to MS after a first presentation with selected clinically isolated syndromes. In addition, MRI is a key tool in providing primary therapeutic outcome measures for phase I/II trials and secondary outcome measures in phase III trials. The utility of MRI stems from its sensitivity to longitudinal changes including those in overt lesions and, with advanced MRI techniques, in areas affected by diffuse occult disease (the so-called normalappearing brain tissue). However, all current MRI methodology suffers from limited specificity for the underlying histopathology. Conventional MRI techniques, including lesion detection and measurement of atrophy from T1-or T2-weighted images, have been the mainstay for monitoring disease activity in clinical trials, in which the use of gadolinium with T1-weighted images adds additional sensitivity and specificity for areas of acute inflammation. Advanced imaging methods including magnetization transfer, fluid attenuated inversion recovery, diffusion, magnetic resonance spectroscopy, functional MRI, and nuclear imaging techniques have added to our understanding of the pathogenesis of MS and may provide methods to monitor therapies more sensitively in the future. However, these advanced methods are limited by their cost, availability, complexity, and lack of validation. In this article, we review the role of conventional and advanced imaging techniques with an emphasis on neurotherapeutics.

Magnetic resonance imaging (MRI) plays an ever-expanding role in the evaluation of multiple sclerosis (MS). This includes its sensitivity for the diagnosis of the disease and its role in identifying patients at high risk for conversion to MS after a first presentation with selected clinically isolated syndromes. In addition, MRI is a key tool in providing primary therapeutic outcome measures for phase I/II trials and secondary outcome measures in phase III trials. The utility of MRI stems from its sensitivity to longitudinal changes including those in overt lesions and, with advanced MRI techniques, in areas affected by diffuse occult disease (the so-called normal-appearing brain tissue). However, all current MRI methodology suffers from limited specificity for the underlying histopathology. Conventional MRI techniques, including lesion detection and measurement of atrophy from T1- or T2-weighted images, have been the mainstay for monitoring disease activity in clinical trials, in which the use of gadolinium with T1-weighted images adds additional sensitivity and specificity for areas of acute inflammation. Advanced imaging methods including magnetization transfer, fluid attenuated inversion recovery, diffusion, magnetic resonance spectroscopy, functional MRI, and nuclear imaging techniques have added to our understanding of the pathogenesis of MS and may provide methods to monitor therapies more sensitively in the future. However, these advanced methods are limited by their cost, availability, complexity, and lack of validation. In this article, we review the role of conventional and advanced imaging techniques with an emphasis on neurotherapeutics.

We found prolonged MTT values in lesions and surrounding NAWM of patients with acute and chronic ischemic stroke when compared to MS patients. The use of PWI is a promising tool for differential diagnosis between acute ischemic and acute demyelinating lesions. The results of this study contribute to a better understanding of the extent of hemodynamic abnormalities in lesions and surrounding NAWM in patients with MS.

Management of MRI-negative patients with intractable focal epilepsy after failed surgery is particularly challenging. In this study, we aim to investigate whether MRI post-processing could identify relevant targets for the re-evaluation of MRI-negative patients who failed the initial resective surgery. We examined a consecutive series of 56 MRI-negative patients who underwent resective surgery and had recurring seizures at 1-year follow-up. T1-weighted volumetric sequence from the pre-surgical MRI was used for voxel-based MRI post-processing which was implemented in a morphometric analysis program (MAP). MAP was positive in 15 of the 56 patients included in this study. In 5 patients, the MAP+ regions were fully resected. In 10 patients, the MAP+ regions were not or partially resected: two out of the 10 patients had a second surgery including the unresected MAP+ region, and both became seizure-free; the remaining 8 patients did not undergo further surgery, but the unresected MAP+ regions were concordant with more than one noninvasive modality in 7. In the 8 patients who had unresected MAP+ regions and intracranial-EEG before the previous surgery, the unresected MAP+ regions were concordant with ictal onset in 6. Our data suggest that scrutiny of the presurgical MRI guided by MRI post-processing may reveal relevant targets for reoperation in nonlesional epilepsies. MAP findings, when concordant with the patient's other noninvasive data, should be considered when planning invasive evaluation/reoperation for this most challenging group of patients.

The perfusion/diffusion 'mismatch model' in acute ischemic stroke provides the potential to more accurately understand the consequences of thrombolytic therapy on an individual patient basis. Few methods exist to quantify mismatch extent (ischemic penumbra) and none have shown a robust ability to predict infarcted tissue outcome. Hidden Markov random field (HMRF) approaches have been used successfully in many other applications. The aim of the study was to develop a method for rapid and reliable identification and quantification of perfusion/diffusion mismatch using an HMRF approach. An HMRF model was used in combination with automated contralateral identification to segment normal tissue from non-infarcted tissue with perfusion abnormality. The infarct was used as a seed point to initialize segmentation, along with the contralateral mirror tissue. The two seeds were then allowed to compete for ownership of all unclassified tissue. In addition, a novel method was presented for quantifying tissue salvageability by weighting the volume with the degree of hypoperfusion, allowing the penumbra voxels to contribute unequal potential damage estimates. Simulated and in vivo datasets were processed and compared with results from a conventional thresholding approach. Both simulated and in vivo experiments demonstrated a dramatic improvement in accuracy with the proposed technique. For the simulated dataset, the mean absolute error decreased from 171.9% with conventional thresholding to 2.9% for the delay-weighted HMRF approach. For the in vivo dataset, the mean absolute error decreased from 564.6% for thresholding to 34.2% for the delay-weighted HMRF approach. The described method represents a significant improvement over thresholding techniques.