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Background and Objectives: Disentangling brain aging from disease-related neurodegeneration in patients with multiple sclerosis (PwMS) is increasingly topical. The brain-age paradigm offers a window into this problem but may miss disease-specific effects. In this study, we investigated whether a disease-specific model might complement the brain-age gap (BAG) by capturing aspects unique to MS., Methods: In this retrospective study, we collected 3D T1-weighted brain MRI scans of PwMS to build (1) a cross-sectional multicentric cohort for age and disease duration (DD) modeling and (2) a longitudinal single-center cohort of patients with early MS as a clinical use case. We trained and evaluated a 3D DenseNet architecture to predict DD from minimally preprocessed images while age predictions were obtained with the DeepBrainNet model. The brain-predicted DD gap (the difference between predicted and actual duration) was proposed as a DD-adjusted global measure of MS-specific brain damage. Model predictions were scrutinized to assess the influence of lesions and brain volumes while the DD gap was biologically and clinically validated within a linear model framework assessing its relationship with BAG and physical disability measured with the Expanded Disability Status Scale (EDSS)., Results: We gathered MRI scans of 4,392 PwMS (69.7% female, age: 42.8 ± 10.6 years, DD: 11.4 ± 9.3 years) from 15 centers while the early MS cohort included 749 sessions from 252 patients (64.7% female, age: 34.5 ± 8.3 years, DD: 0.7 ± 1.2 years). Our model predicted DD better than chance (mean absolute error = 5.63 years, R 2 = 0.34) and was nearly orthogonal to the brain-age model (correlation between DD and BAGs: r = 0.06 [0.00-0.13], p = 0.07). Predictions were influenced by distributed variations in brain volume and, unlike brain-predicted age, were sensitive to MS lesions (difference between unfilled and filled scans: 0.55 years [0.51-0.59], p < 0.001). DD gap significantly explained EDSS changes ( B = 0.060 [0.038-0.082], p < 0.001), adding to BAG (Δ R 2 = 0.012, p < 0.001). Longitudinally, increasing DD gap was associated with greater annualized EDSS change ( r = 0.50 [0.39-0.60], p < 0.001), with an incremental contribution in explaining disability worsening compared with changes in BAG alone (Δ R 2 = 0.064, p < 0.001)., Discussion: The brain-predicted DD gap is sensitive to MS-related lesions and brain atrophy, adds to the brain-age paradigm in explaining physical disability both cross-sectionally and longitudinally, and may be used as an MS-specific biomarker of disease severity and progression.

Progression independent of relapse activity (PIRA), a recent concept to formalize disability accrual in multiple sclerosis (MS) independent of relapses, has gained popularity as a potential clinical trial outcome. We discuss its shortcomings and appraise the challenges of implementing it in clinical settings, experimental trials, and research. The current definition of PIRA assumes that acute inflammation, which can manifest as a relapse, and neurodegeneration, manifesting as progressive disability accrual, can be disentangled by introducing specific time windows between the onset of relapses and the observed increase in disability. The term PIRMA (progression independent of relapse and MRI activity) was recently introduced to indicate disability accrual in the absence of both clinical relapses and new brain and spinal cord MRI lesions. Assessing PIRMA in clinical practice is highly challenging because it necessitates frequent clinical assessments and brain and spinal cord MRI scans. PIRA is commonly assessed using Expanded Disability Status Scale, a scale heavily weighted toward motor disability, whereas a more granular assessment of disability deterioration, including cognitive decline, using composite measures or other tools, such as digital tools, would possess greater utility. Similarly, using PIRA as an outcome measure in randomized clinical trials is also challenging and requires methodological considerations. The underpinning pathobiology of disability accumulation, that is not associated with relapses, may encompass chronic active lesions (slowly expanding lesions and paramagnetic rim lesions), cortical lesions, brain and spinal cord atrophy, particularly in the gray matter, diffuse and focal microglial activation, persistent leptomeningeal enhancement, and white matter tract damage. We propose to use PIRA to understand the main determinant of disability accrual in observational, cohort studies, where regular MRI scans are not included, and introduce the term of "advanced-PIRMA" to investigate the contributions to disability accrual of the abovementioned processes, using conventional and advanced imaging. This is supported by the knowledge that MRI reflects the MS pathogenic mechanisms better than purely clinical descriptors. Any residual disability accrual, which remains unexplained after considering all these mechanisms with imaging, will highlight future research priorities to help complete our understanding of MS pathogenesis.

Objective: To evaluate in clinically isolated syndrome (CIS) and migraine with aura (MA) how the number of periventricular lesions (PVLs) detected at MRI influences diagnostic performance when the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) or the 2017 revised criteria are applied., Methods: In this retrospective study, white matter hyperintensities (WMH) of 84 patients with MA and 79 patients with CIS were assessed using manual segmentation technique. Lesion probability maps (LPMs) and voxel-wise analysis of lesion distribution by diagnosis were obtained. Furthermore, we performed a logistic regression analysis based on lesion locations and volumes., Results: Compared to patients with MA, patients with CIS showed a significant overall higher T2 WMH mean number and volume (17.9 ± 16.9 vs 6.2 ± 11.9 and 3.1 ± 4.2 vs 0.3 ± 0.6 mL; p < 0.0001) and a significantly higher T2 WMH mean number in infratentorial, periventricular, and juxtacortical areas ( p < 0.0001). LPMs identified the periventricular regions as the sites with the highest probability of detecting T2 WMH in patients with CIS. Voxel-wise analysis of lesion distribution by diagnosis revealed a statistically significant association exclusively between the diagnosis of CIS and the PVLs. MAGNIMS criteria demonstrated the highest specificity in differentiating patients with CIS from patients with MA (100% vs 87%) against a predictable lower sensitivity (63% vs 72%)., Conclusions: PVLs play a key role in the differential diagnosis between MA and CIS, particularly when there are more than 3. Future studies on multiple sclerosis criteria might reconsider the 3 PVLs to minimize the risk of misdiagnosis., Classification of Evidence: This study provides Class IV evidence that the presence at least 3 PVLs increases the specificity in distinguishing MA from CIS., (© 2019 American Academy of Neurology.)

Over the last few decades, the improved diagnostic criteria, the wide use of MRI, and the growing availability of effective pharmacologic treatments have led to substantial advances in the management of multiple sclerosis (MS). The importance of early diagnosis and treatment is now well-established, but there is still no consensus on how to define and monitor response to MS treatments. In particular, the clinical relevance of the detection of minimal MRI activity is controversial and recommendations on how to define and monitor treatment response are warranted. An expert panel of the Magnetic Resonance Imaging in MS Study Group analyzed and discussed published studies on treatment response in MS. The evolving concept of no evidence of disease activity and its effect on predicting long-term prognosis was examined, including the option of defining a more realistic target for daily clinical practice: minimal evidence of disease activity. Advantages and disadvantages associated with the use of MRI activity alone and quantitative scoring systems combining on-treatment clinical relapses and MRI active lesions to detect treatment response in the real-world setting were also discussed. While most published studies on this topic involved patients treated with interferon-β, special attention was given to more recent studies providing evidence based on treatment with other and more efficacious oral and injectable drugs. Finally, the panel identified future directions to pursue in this research field., (Copyright © 2018 American Academy of Neurology.)

Patients with the main clinical phenotypes of multiple sclerosis (MS) manifest varying degrees of brain atrophy beyond that of normal aging. Assessment of atrophy helps to distinguish clinically and cognitively deteriorating patients and predicts those who will have a less-favorable clinical outcome over the long term. Atrophy can be measured from brain MRI scans, and many technological improvements have been made over the last few years. Several software tools, with differing requirements on technical ability and levels of operator intervention, are currently available and have already been applied in research or clinical trial settings. Despite this, the measurement of atrophy in routine clinical practice remains an unmet need. After a short summary of the pathologic substrates of brain atrophy in MS, this review attempts to guide the clinician towards a better understanding of the methods currently used for quantifying brain atrophy in this condition. Important physiologic factors that affect brain volume measures are also considered. Finally, the most recent research on brain atrophy in MS is summarized, including whole brain and various compartments thereof (i.e., white matter, gray matter, selected CNS structures). Current methods provide sufficient precision for cohort studies, but are not adequate for confidently assessing changes in individual patients over the scale of months or a few years., (© 2016 American Academy of Neurology.)

Objective: To provide new insights into the role of markers of response to interferon-β therapy in multiple sclerosis (MS) in a multicenter setting, focusing on the relevance of MRI lesions in combination with clinical variables., Methods: A large multicenter clinical dataset was collected within the Magnetic Resonance Imaging in MS (MAGNIMS) network. This included a large cohort of patients with relapsing-remitting MS on interferon-β treatment, MRI and clinical assessments during the first year of treatment, and clinical follow-up of at least 2 additional years. Heterogeneity among centers was assessed before pooling the data. The association of 1-year MRI or clinical relapses with the risk of treatment failure (defined as Expanded Disability Status Scale [EDSS] worsening or treatment switch for inefficacy) and of EDSS worsening alone was evaluated using multivariate Cox models., Results: A pooled dataset of 1,280 patients with relapsing-remitting MS from 9 MAGNIMS centers was analyzed. The risk of failure had a relevant increase with 1 relapse (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.39-2.44, p < 0.001) and ≥3 new T2 lesions (HR 1.55, 95% CI 0.92-2.60, p = 0.09). In patients without relapses and less than 3 new T2 lesions, the 3-year risk of failure and EDSS worsening were 17% and 15%; in patients with 1 relapse or ≥3 new T2 lesions, the risks were 27% and 22%; in patients with both conditions or more than 1 relapse, the risks were 48% (p < 0.001) and 29% (p < 0.001)., Conclusions: Substantial MRI activity, particularly if in combination with clinical relapses, during the first year of treatment with interferon-β indicates significant risk of treatment failure and EDSS worsening in the short term., (© 2016 American Academy of Neurology.)

Background: The MRI incidental finding in asymptomatic subjects of brain white matter (WM) changes meeting the Barkhof criteria for the diagnosis of multiple sclerosis (MS) has been recently characterized as the radiologically isolated syndrome (RIS). This entity needs to be more specifically defined to allow risk stratification of these subjects. We used brain proton magnetic resonance spectroscopic imaging (1H-MRSI) to assess metabolic changes in an RIS population., Methods: Twenty-three RIS subjects who were classified according to the Okuda Criteria underwent 1H-MRSI examination with a central brain (CB) volume of interest (VOI) to measure levels of N-acetylaspartate (NAA) and choline (Cho) normalized to creatine (Cr) in the whole CB-VOI, in lesional/perilesional and normal-appearing WM regions, and in the cortical gray matter (CGM). The 1H-MRSI data were compared with those of 20 demographically matched healthy controls (HC)., Results: NAA/Cr levels were significantly lower in RIS than in HC in all regions (p < 0.005 for all). No differences in Cho/Cr levels were found in either brain region. A single-subject analysis showed that NAA/Cr levels were at least 2 SDs below the HC mean in the 44% of RIS in the normal-appearing WM and in the 61% of RIS in the CGM., Conclusion: Decreased brain NAA/Cr levels in a group of RIS subjects indicates that brain metabolic abnormalities suggestive of axonal damage can be significant even at this early disease stage. This information could be useful for stratifying RIS individuals with a high risk of progression to MS.

Objective: To test the cognitive reserve (CR) hypothesis in the model of multiple sclerosis (MS) by assessing the interactions among CR, brain atrophy, and cognitive efficiency in patients with relapsing-remitting MS., Methods: A Cognitive Reserve Index was calculated including education, premorbid leisure activities, and IQ. Brain atrophy was assessed through magnetic resonance quantitative parameters of normalized total brain volume and normalized cortical volume. Cognitive function was measured using Rao's Brief Repeatable Battery., Results: Fifty-two patients with relapsing-remitting MS were evaluated at baseline and 35 of them were reassessed after a 1.6-year follow-up period. At baseline, higher CR predicted better performance on most of the Brief Repeatable Battery tests, independent of brain atrophy and clinical and demographic characteristics (p ≤ 0.021). An interaction between CRI and normalized cortical volume predicted better cognitive performance on tasks of verbal memory and attention/information processing speed (p < 0.005). However, at the follow-up examination, progressing cortical atrophy (β = 0.45; p = 0.008) and older age (β = -0.33; p = 0.044) were the only predictors of deteriorating cognitive performance., Conclusions: Our findings suggest that higher CR in individuals with MS may mediate between cognitive performance and brain pathology. CR-related compensation may, however, fail with progression of damage. The time window of opportunity for therapeutic approaches aimed at intellectual enhancement most likely lies in the earliest disease stages.

Objective: Neuromyelitis optica and its spectrum disorder (NMOSD) can present similarly to relapsing-remitting multiple sclerosis (RRMS). Using a quantitative lesion mapping approach, this research aimed to identify differences in MRI brain lesion distribution between aquaporin-4 antibody-positive NMOSD and RRMS, and to test their diagnostic potential., Methods: Clinical brain MRI sequences for 44 patients with aquaporin-4 antibody-positive NMOSD and 50 patients with RRMS were examined for the distribution and morphology of brain lesions. T2 lesion maps were created for each subject allowing the quantitative comparison of the 2 conditions with lesion probability and voxel-wise analysis., Results: Sixty-three percent of patients with NMOSD had brain lesions and of these 27% were diagnostic of multiple sclerosis. Patients with RRMS were significantly more likely to have lesions adjacent to the body of the lateral ventricle than patients with NMOSD. Direct comparison of the probability distributions and the morphologic attributes of the lesions in each group identified criteria of "at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or the presence of a subcortical U-fiber lesion; or a Dawson's finger-type lesion," which could distinguish patients with multiple sclerosis from those with NMOSD with 92% sensitivity, 96% specificity, 98% positive predictive value, and 86% negative predictive value., Conclusion: Careful inspection of the distribution and morphology of MRI brain lesions can distinguish RRMS and NMOSD.

Objectives: To assess in a large population of patients with clinically isolated syndrome (CIS) the relevance of brain lesion location and frequency in predicting 1-year conversion to multiple sclerosis (MS)., Methods: In this multicenter, retrospective study, clinical and MRI data at onset and clinical follow-up at 1 year were collected for 1,165 patients with CIS. On T2-weighted MRI, we generated lesion probability maps of white matter (WM) lesion location and frequency. Voxelwise analyses were performed with a nonparametric permutation-based approach (p < 0.05, cluster-corrected)., Results: In CIS patients with hemispheric, multifocal, and brainstem/cerebellar onset, lesion probability map clusters were seen in clinically eloquent brain regions. Significant lesion clusters were not found in CIS patients with optic nerve and spinal cord onset. At 1 year, clinically definite MS developed in 26% of patients. The converting group, despite a greater baseline lesion load compared with the nonconverting group (7 ± 8.1 cm3 vs. 4.6 ± 6.7 cm3, p < 0.001), showed less widespread lesion distribution (18% vs. 25% of brain voxels occupied by lesions). High lesion frequency was found in the converting group in projection, association, and commissural WM tracts, with larger clusters being in the corpus callosum, corona radiata, and cingulum., Conclusions: Higher frequency of lesion occurrence in clinically eloquent WM tracts can characterize CIS subjects with different types of onset. The involvement of specific WM tracts, in particular those traversed by fibers involved in motor function and near the corpus callosum, seems to be associated with a higher risk of clinical conversion to MS in the short term.

Objective: To evaluate cognitive changes in a cohort of radiologically isolated syndromes (RIS) suggestive of multiple sclerosis (MS) and to assess their relationship with quantitative magnetic resonance (MR) measures such as white matter (WM), lesion loads, and cerebral atrophy., Methods: We assessed the cognitive performance in a group of 29 subjects with RIS recruited from 5 Italian MS centers and in a group of 26 patients with relapsing-remitting MS (RRMS). A subgroup of 19 subjects with RIS, 26 patients with RRMS, and 21 healthy control (HC) subjects also underwent quantitative MR assessments, which included WM T1 and T2 lesion volumes and global and cortical brain volumes., Results: Cognitive impairment of the same profile as that of RRMS was found in 27.6% of our subjects with RIS. On MR scans, we found comparable levels of lesion loads and brain atrophy in subjects with RIS and well-established RRMS. In subjects with RIS, high T1 lesion volume (ρ = 0.526, p = 0.025) and low cortical volume (ρ = -0.481, p = 0.043) were associated with worse cognitive performance., Conclusions: These findings emphasize the importance of including accurate neuropsychological testing and quantitative MR metrics in subjects with RIS suggestive of MS. They can provide a better characterization of these asymptomatic subjects, potentially useful for diagnostic and therapeutic decisions.

Objective: To assess the presence of cortical lesions (CLs) as detected by MRI in subjects with radiologically isolated syndrome (RIS)., Methods: Fifteen subjects with RIS underwent an MRI examination, including a double inversion recovery sequence for CL assessment. T2-hyperintense white matter (WM) lesion volume (LV) and normalized volumes of brain and cortex were also obtained., Results: Thirty-four CLs were identified in 6 of 15 (40%) subjects with RIS and predominantly distributed in frontotemporal lobes. CLs were frequent in subjects with RIS with immunoglobulin G oligoclonal bands on CSF, cervical cord lesions, and dissemination in time on brain MRI. WM LV was higher in subjects with CLs than in those without CLs (11.5 ± 10.1 vs 3.9 ± 2.8 cm(3), p = 0.04). Indeed, CL number and volume correlated with WM LV (r = 0.57, p = 0.03 and r = 0.61, p = 0.01). All subjects with CLs were classified in a previous study as having a very high probability of having relapsing-remitting multiple sclerosis (MS) on a logistic regression analysis of quantitative MRI indices., Conclusions: We found CLs in subjects with RIS, a condition characterized by the unanticipated MRI finding of WM lesions highly suggestive of MS in the absence of a clinical scenario. CLs were mainly localized to the frontotemporal lobes and were associated with important markers of evolution to MS.

Objective: In multiple sclerosis (MS), the aim of therapies is to prevent the accumulation of irreversible disability. This is difficult to assess given the short time course of clinical trials. MRI markers and relapses are often used as surrogate of disability in MS studies, but their validity remains controversial. We sought to validate, at the individual patient level, MRI lesions and relapses as surrogates for disability progression over the course of MS trials., Methods: Individual patient data from a large, placebo-controlled trial of interferon β-1a in relapsing-remitting MS (RRMS) were analyzed. The Prentice criteria were applied to evaluate surrogacy of 1-year MRI active lesions and relapses for disability worsening (Expanded Disability Status Scale [EDSS]) over the 2-year follow-up., Results: All Prentice criteria were satisfied. Treatment reduced by 31% the odds of having EDSS worsening over 2 years, reducing the mean number of MRI lesions by 61% and the mean number of relapses by 36% over 1 year. Both 1-year MRI lesion activity and relapses, when considered independently, accounted for more than 60% of the treatment effect on 2-year EDSS worsening. A combination of 1-year MRI lesion activity and relapses explained 100% of the treatment effect on EDSS worsening over 2 years., Conclusions: A combined measure of 1-year changes in MRI lesions and relapses after interferon therapy fully estimated the corresponding effect on 2-year EDSS worsening. This short-term combined measure appears to be a surrogate for disability progression over a longer term when evaluating the effect of interferon in RRMS.

Background: The presence of cortical lesions (CLs) and their topographic distribution in the brains of patients with multiple sclerosis (MS) have been clearly shown by recent histopathologic studies. CLs can also be assessed in vivo, with less sensitivity, by using specific MRI sequences. MRI-based lesion probability maps (LPMs) may partially overcome this lack of sensitivity and provide unique information on the spatial distribution and frequency of CLs in MS., Methods: A total of 149 patients with MS (103 relapsing-remitting [RR] and 46 primary progressive [PP]) underwent an MRI examination, which included the double inversion recovery (DIR) sequence for CL assessment. CL masks were then obtained for each patient and a cortical LPM (cLPM) was created for each MS subtype., Results: CLs were mainly distributed in the frontal (RR = 51.8%; PP = 50.5%) and temporal (RR = 30.4%; PP = 35.5%) lobes, with a prominent involvement of the motor (RR = 37.8%; PP = 30.6%) and anterior cingulate (RR = 9.2%; PP = 10.6%) cortices. The extent of brain lobe affected by CLs was higher in RR than in PP patients. The frequency of CL occurrence was higher in PP than in RR patients. Both measurements, however, did not show differences between the 2 MS subtypes at voxel-wise analysis., Conclusions: Patients with RRMS and PPMS share more similarities than differences in terms of CL number, volume, topographic distribution, and frequency. The similarities between histopathologic data and the findings reported here suggest that DIR images can accurately illustrate the focal pathology occurring in the cortical regions of patients with MS, providing clinically relevant information.

Objective: To assess the time course of brain atrophy and the difference across clinical subtypes in multiple sclerosis (MS)., Methods: The percent brain volume change (PBVC) was computed on existing longitudinal (2 time points) T1-weighted MRI from untreated (trial and nontrial) patients with MS. Patients (n = 963) were classified as clinically isolated syndromes suggestive of MS (CIS, 16%), relapsing-remitting (RR, 60%), secondary progressive (SP, 15%), and primary progressive (9%) MS. The median length of follow-up was 14 months (range 12-68)., Results: There was marked heterogeneity of the annualized PBVC (PBVC/y) across MS subtypes (p = 0.003), with higher PBVC/y in SP than in CIS (p = 0.003). However, this heterogeneity disappeared when data were corrected for the baseline normalized brain volume. When the MS population was divided into trial and nontrial subjects, the heterogeneity of PBVC/y across MS subtypes was present only in the second group, due to the higher PBVC/y values found in trial data in CIS (p = 0.01) and RR (p < 0.001). The estimation of the sample sizes required for demonstrating a reduction of brain atrophy in patients in a placebo-controlled trial showed that this was larger in patients with early MS than in those with the progressive forms of the disease., Conclusions: This first large study in untreated patients with multiple sclerosis (MS) with different disease subtypes shows that brain atrophy proceeds relentlessly throughout the course of MS, with a rate that seems largely independent of the MS subtype, when adjusting for baseline brain volume.

In recent years, criteria for the diagnosis of multiple sclerosis (MS) have changed, mainly due to the incorporation of new MRI criteria. While the new criteria are a logical step forward, they are complex and-not surprisingly-a good working knowledge of them is not always evident among neurologists and neuroradiologists. In some circumstances, several MRI examinations are needed to achieve an accurate and prompt diagnosis. This provides an incentive for continued efforts to refine the incorporation of MRI-derived information into the diagnostic workup of patients presenting with a clinically isolated syndrome. Within the European multicenter collaborative research network that studies MRI in MS (MAGNIMS), a workshop was held in London in November 2007 to review information that may simplify the existing MS diagnostic criteria, while maintaining a high specificity that is essential to minimize false positive diagnoses. New data that are now published were reviewed and discussed and together with a new proposal are integrated in this position paper.

Objective: To assess whether neuropsychological tests and MRI measures could be used as predictors of short-term disease evolution in a population of patients with benign multiple sclerosis (B-MS)., Background: The definition of B-MS is controversial. Recent data suggest that neuropsychological tests and MRI measures can provide valuable information for a more correct definition and interpretation of B-MS., Methods: Sixty-three patients with B-MS (Expanded Disability Status Scale [EDSS] < or =3.0 and disease duration > or =15 years) underwent neuropsychological assessment using the Rao's Brief Repeatable Neuropsychological Battery and the Stroop Test. At that time, conventional brain MRI and magnetization transfer (MT) imaging was performed. White matter lesion load, global and regional brain volumes, and MT ratio in lesions and normal-appearing brain were measured. After a mean follow-up of 5 years, patients still having an EDSS score < or =3.5 were classified as still benign, whereas patients who had developed a secondary progressive course or who had an EDSS score > or =4.0 were defined as no longer benign (NLB)., Results: At end of follow-up, 29% of patients were classified as NLB. Male gender (hazard ratio [HR] = 2.9; 95% confidence interval [CI] 1.2-7.5; p = 0.02), number of neuropsychological tests failed (HR = 1.4; 95% CI 1.1-1.7; p = 0.003), and T1-weighted lesions (HR = 1.3; 95% CI 1.1-1.5; p = 0.002) were related to NLB status. In a model including these 3 variables, the NLB status was predicted with an accuracy of 82%., Conclusions: Cognitive assessment and MRI metrics can predict short-term disease evolution in benign multiple sclerosis (B-MS). This information can be useful to correctly identify patients with B-MS.

It is well known that the current classification of patients with benign multiple sclerosis (BMS), i.e., those with absent or minimal locomotor disability several years after disease onset, suffers from not having any prognostic value for the subsequent evolution of multiple sclerosis (MS). The identification of markers predictive of the longer-term course of MS will help define BMS more reliably and would allow better counseling of patients, particularly when advising on the initiation of a disease-modifying treatment. MRI-based evidence suggests that there are three potential, but not mutually exclusive, explanations for the scarce clinical impact of BMS: 1) the paucity of tissue damage within and outside MS lesions; 2) the relative sparing of clinically eloquent regions; and 3) the presence of effective compensatory mechanisms. In addition, the results of correlative MRI/neuropsychology studies underpin the need for a new definition of BMS, which should consider the maintenance of a normal cognitive profile as an additional criterion.

Background: The definition of benign multiple sclerosis (B-MS) is still controversial. This mainly takes into account the subject's motor ability, with little or no relevance to other important features such as cognition. Moreover, no paraclinical markers are currently available to reliably identify patients who will remain benign in the long term., Objectives: To assess, by using quantitative magnetic resonance (MR) metrics, differences in tissue damage between B-MS patients after dividing them into two groups on the basis of their cognitive performance., Methods: Forty-seven B-MS patients (Expanded Disability Status Scale score /=15 years) underwent neuropsychological assessment through the Rao Brief Repeatable Battery and the Stroop Test. At that time, B-MS patients underwent conventional brain MR and magnetization transfer (MT) imaging. White matter lesion load, global and regional brain volumes, and MT ratio (MTr) in lesions and normal-appearing brain were measured. Quantitative MR measures were compared in cognitively impaired (CI-MS) and cognitively preserved (CP-MS) patients and in 24 demographically matched healthy controls. Test performance was correlated with MR changes in specific cortical regions., Results: Eleven patients were classified as CI-MS, and 36 were classified as CP-MS. Both T2-weighted and T1-weighted lesion loads were higher (p = 0.05 and 0.001) in CI-MS than in CP-MS patients. Furthermore, CI-MS patients were characterized by more pronounced decrease in neocortical volume (p = 0.005) and cortical MTr (p = 0.02) values than CP-MS patients. Finally, test performance correlated significantly with MR changes in relevant cortical regions., Conclusions: Cognitive assessment and quantitative magnetic resonance can help to reliably identify benign multiple sclerosis patients.

Proton MR spectroscopy (MRS) allows noninvasive characterization of chemical-pathologic changes in the brain. In patients with multiple sclerosis (MS), proton MRS reveals chemical pathology in focal inflammatory lesions as well as in regions of the brain that are not associated with structural abnormalities on conventional MRI. In MS studies, it has been particularly useful as a method for the assessment of neurodegeneration based on decreases in the levels of the neuro-axonal marker compound, N-acetylaspartate. Also, MRS has provided evidence of chemical pathology and repair involving non-neuronal brain cells based on changes in metabolites, including choline, myo-inositol, glutamate, and GABA. Despite its greater pathologic specificity for axonal integrity compared to conventional MRI, MRS has been used only infrequently in clinical trials. This prompted us to review current MRS clinical applications in MS, discuss the potential and limitations of the technique, and suggest recommendations for the application of MRS to clinical trials.

Background: Cerebral involvement is usually absent in pure adrenomyeloneuropathy (AMN). Recently, nonconventional MR studies have reported brain abnormalities in patients with pure AMN, providing evidence that occult cerebral involvement may occur in this disease. It remains unclear, however, whether these brain abnormalities reflect centripetal extension of spinal cord long-tract axonopathy or can be the expression of a pathologic process largely involving the brain., Methods: Conventional MRI and proton MR spectroscopic imaging (1H-MRSI) data of four patients with pure AMN were compared to those of four men with spinal cord injury (SCI) and 10 age-matched healthy men (HM). Resonance intensity areas of N-acetylaspartate (NAA) and choline were calculated as ratios to creatine (Cr) in voxels located in white matter (WM) regions. Functional MRI (fMRI) data during simple motor task were obtained in a separate session in three patients with AMN and three age-matched HM., Results: Conventional MRI examinations were normal in all patients. On 1H-MRSI, NAA/Cr values were lower in all WM regions of patients with AMN than in those of patients with SCI (p < 0.05) and HM (p < 0.01). In contrast, patients with SCI showed NAA/Cr values lower than HM only in the periventricular WM (p = 0.04). At fMRI, patients with AMN showed a more pronounced activation than HM in all movement-associated cortical regions contralateral to the hand moved and an exclusive voxel activation of the primary motor, somatosensory, and posterior parietal cortices ipsilateral to the hand moved., Conclusions: CNS damage in pure adrenomyeloneuropathy is not confined exclusively to spinal cord and seems to primarily involve the brain.

The authors describe an infant with vanishing white matter disease with demyelinating peripheral neuropathy. Sequence analysis of EIF2B5 gene showed that the patient was a double heterozygote, with novel missense mutation CGA-->CAA in codon 269 of exon 6, resulting in the replacement of an arginine residue with glutamine.

Objective: To assess neocortical changes and their relevance to cognitive impairment in early relapsing-remitting (RR) multiple sclerosis (MS)., Methods: Conventional MR was acquired in 41 patients with RR MS and 16 demographically matched normal control subjects (NCs). An automated analysis tool was used with conventional T1-weighted MRI to obtain measures of cortical brain volumes normalized for head size. Neuropsychological performance of MS patients was assessed using the Rao Brief Repeatable Battery. Relationship between volumetric MR measures and neuropsychological scores was assessed., Results: Neuropsychological assessment allowed for the identification of 18 cognitively preserved (MS-cp) and 23 cognitively impaired (MS-ci) MS patients. The whole MS sample showed lower values of normalized cortical volumes (NCVs) than did the NC group (p = 0.01). Upon grouping of MS patients according to cognitive performance, NCV values were lower (p = 0.02) in MS-ci patients than in both MS-cp patients and NCs. Moreover, there were positive correlations between NCV values and measures of verbal memory (r = 0.51, p = 0.02), verbal fluency (r = 0.51, p = 0.01), and attention/concentration (r = 0.65, p < 0.001) in MS-ci patients. Furthermore, NCV values were decreased in patients who scored lower on a greater number of tests (r = -0.58, p < 0.01) in the MS-ci group. None of the neuropsychological measures correlated to NCV values in the MS-cp patient group., Conclusions: Cortical atrophy was found only in cognitively impaired patients and was significantly correlated with a poorer performance on tests of verbal memory, attention/concentration, and verbal fluency. Gray matter pathology may contribute to the development of cognitive impairment in MS from the earliest stages of the disease.

Reported are the clinical, neuroradiologic, and molecular findings in 18 patients with megalencephalic leukoencephalopathy and subcortical cysts (MLC) syndrome. Marked clinical intrafamilial and interfamilial variability in mutation-proven cases was found. A broad spectrum of pathogenetic mutations (missense, splice site, insertion, and deletions) were identified in the MLC1 gene, enlarging the spectrum of allelic variants without a straightforward genotype-phenotype correlation. Five patients did not harbor mutations in MLC1, supporting the existence of at least one other MLC locus.

Objective: To assess cortical gray matter (GM) changes in MS and establish their relevance to clinical disability and to inflammatory changes of white matter (WM) in patients with the relapsing-remitting (RR) and primary progressive (PP) forms of the disease., Methods: Conventional MRI examinations were obtained in patients with definite MS who had either the RR or the PP form of the disease. An automated analysis tool was used with conventional T1-weighted MR images to obtain total and cortical brain volumes normalized for head size. Total brain lesion load was estimated on conventional proton density and T2-weighted MR images. The relationship between volumetric MR measures and scores of clinical disability was assessed., Results: Normalized cortical volumes (NCV) were lower for both RR and PP MS patients than for normal control subjects (p < 0.001) but were similar between the two patient groups (p > 0.5). NCV decreases in both patients groups were detected even in those patients with short disease duration (<5 years; p < 0.001 in RR MS and p < 0.05 in PP MS) and minimal brain lesion volume (<5 mL; p < 0.0001 in RR MS and p < 0.005 in PP MS). Measures of NCV in individual patients were negatively correlated with T2-weighted lesion volume (r = -0.47, p < 0.001) and disease duration (r = -0.25, p < 0.05) only in the patients with RR MS. NCV correlated with Expanded Disability Status Scale scores across all of the patients, but the strength of the correlation was stronger (p < 0.05) for PP (r = -0.64, p < 0.0001) than for RR (r = -0.27, p = 0.04) MS patients., Conclusions: These data confirm substantial neocortical volume loss in MS patients and suggest that neocortical GM pathology may occur early in the course of the disease in both RR and PP MS patients and contribute significantly to neurologic impairment. Although a proportion of this neocortical pathology may be secondary to WM inflammation, the extent of the changes suggests that, especially in patients with PP MS, an independent neurodegenerative process also is active.

Objective: To characterize the clinical features of a new type of X-linked mental retardation associated with MECP2 mutation in the index family., Background: MECP2 mutations, originally described in a high percentage of patients with classic Rett syndrome, were considered lethal in men. The authors recently described a novel A140V MECP2 missense mutation in an Italian family with X-linked semidominant mental retardation., Methods: The neurologic features of six symptomatic relatives (two women and four men) carrying the mutation were compiled. Laboratory investigations included EEG, EMG, conduction velocity (CV) of peripheral nerves, brain MRI, and (1)H-MR spectroscopy., Results: Mental retardation and signs of neurologic impairment were present in all the affected members, but more pronounced in men. Neurologic features included slowly progressive spastic paraparesis/pyramidal signs (6/6), distal atrophy of the legs (6/6), ataxia (2/6), and postural tremor of the hands (3/6). Speech was preserved (6/6) but was dysarthric in the oldest brothers (2/6). Mild dysmorphic features were present in all cases., Conclusion: The neurologic disorder associated with A140V MECP2 mutation is not necessarily lethal in men, but they are more severely affected than women of the same family.

Objectives: To assess the magnitude of the correlations between disability and composite MRI scores in patients with MS., Methods: T2- and T1-weighted MRI, magnetization transfer imaging, diffusion tensor imaging, and MRS imaging scans of the brain from 23 patients with MS were obtained. T2 lesion volume, T1 lesion volume, brain magnetization transfer ratio, average brain diffusivity (D), and brain N-acetylaspartate/creatine ratio were measured., Results: The correlations between the Expanded Disability Status Scale (EDSS) score and each of the MR quantities taken in isolation were not significant, with the exception of the correlation between EDSS and the NAA/creatine ratio (r = -0.50; p = 0.01). In contrast, three of the composite MR scores computed using regression models were strongly correlated with the EDSS scores (r range, 0.58 to 0.73; p range, 0.004 to 0.0001). The model that included T2 and T1 lesion volumes and brain D explained 34% of the EDSS variance; the model that included T2 and T1 lesion volumes and brain N-acetylaspartate/creatine ratio explained 36% of the EDSS variance; the model that included T1 lesion volume, brain D, and brain N-acetylaspartate/creatine ratio explained 53% of the EDSS variance., Conclusions: The results suggest that multiparametric MR models have the potential to provide powerful measures to monitor MS evolution.

Patients with the trisomy 9p syndrome and CNS abnormalities have been poorly assessed. We report a patient with trisomy 9p who showed band heterotopia on MRI. Abnormal neuronal migration is sufficiently frequent in patients with the trisomy 9p syndrome that brain MRI should be routinely considered in all patients with this syndrome.

We studied the physiologic adaptation of patients with mitochondrial myopathies to aerobic training. Ten patients underwent individually supervised, moderate-intensity aerobic training on a treadmill for 8 weeks. Biochemical and functional measures improved with training. Estimated aerobic capacity increased by 30%. Blood lactate concentrations at rest and after exercise decreased by 30%. Muscle phosphorus magnetic resonance spectroscopy measurements of adenosine diphosphate recovery after exercise improved by more than 60%. Fatigue and tolerance to daily activities also improved. Although the improvement in exercise tolerance may be due in part to reversal of the effects of secondary deconditioning, this uncontrolled clinical trial suggests that aerobic training can benefit patients with mitochondrial myopathies.

In a 6-year longitudinal study of a patient with relapsing progressive multiple sclerosis (MS), we used proton magnetic resonance spectroscopy to assess N-acetylaspartate (NAA) from a large central brain volume to evaluate the relationship between this marker of neuronal integrity and clinical disability. During the follow-up period, there was one major relapse and its subsequent partial remission. Changes in the brain NAA to creatine ratio correlated strongly with clinical disability (Spearman rank coefficient = -0.73, p < 0.001). We interpret this as evidence that axonal dysfunction or loss contributes to functional impairment of patients with MS. Because the NAA signal in the large volume of interest originated predominantly from white matter that appeared normal on conventional MRI, these results also suggest that some degree of axonal dysfunction may be widespread in acute, severe relapses.

There is no generally effective therapy for mitochondrial myopathies. In this study, we measured responses to combined aerobic training and oral dichloroacetate (DCA) therapy in a 25-year-old woman with a mitochondrial myopathy caused by cytochrome oxidase deficiency. The patient trained for 14 weeks, and DCA therapy was begun after 8 weeks. Independent indices of aerobic capacity and oxidative metabolism showed substantial improvement. Venous lactate concentrations at rest, and after a constant amount of work, decreased by approximately 50% after 8 weeks of aerobic training, and by more than 70% with the combination of training and DCA treatment. Heart rate at rest and after a constant amount of submaximal work decreased progressively. Aerobic capacity on a graded submaximal exercise test improved by 71% from baseline by the end of the treatment period. 31P magnetic resonance spectroscopy measurements of rate constants for recovery of muscle phosphocreatine increased 1.7-fold and metabolically active adenine diphosphate increased 2.8-fold after 8 weeks of training alone, and 4.5-fold and 23.0-fold after 14 weeks of training plus DCA treatment. Responses to the SF-36 Health Survey suggested a marked reduction in handicap. Thus, in this open study of a patient with cytochrome oxidase deficiency, a combination of aerobic training and DCA treatment resulted in substantial improvements in biochemical indices, exercise performance, and handicap. We conclude that exercise limitation in patients with mitochondrial myopathy may arise from effects of chronic deconditioning in addition to the effects of primary mitochondrial dysfunction and may be partially reversed by training and administration of DCA.

We performed a short-term, double-blind, placebo-controlled, crossover trial of sodium dichloroacetate (DCA) therapy in 11 patients affected by various primary mitochondrial disorders. Independent measures of oxidative metabolism (venous blood metabolites, exercise testing, phosphorus magnetic resonance [MR] spectroscopy of muscle, and proton MR spectroscopy of brain) were used in order to monitor metabolic responses to the drug. One week of DCA treatment produced significant decreases (p < 0.05) in blood lactate, pyruvate, and alanine at rest and after bicycle exercise. Proton MR spectra collected from a supraventricular volume of interest in brain of seven of 11 patients also showed significant changes. Brain lactate/creatine ratio decreased by 42% during DCA treatment (p < 0.05). Brain choline/creatine ratio (which is low in patients with myelinopathies) increased by 18% (p < 0.01) after therapy. N-Acetylaspartate/creatine ratio (an index of neuronal damage or loss) increased by 8% after treatment (p < 0.05). Proton MR spectra collected in two of 11 patients from a volume of interest including the basal ganglia showed similar results (decrease of 36.6% in lactate/creatine; increases of 16% in choline/creatine and 4.5% in N-acetylaspartate/creatine). Phosphorus MR spectroscopy of muscle and self-assessed clinical disability were unchanged. Our study indicates that short-term DCA treatment not only lowers blood lactate but also improves indices of both brain oxidative metabolism and neuronal and glial density or function.