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Using MRI, we measured disease activity and brain atrophy in nine multiple sclerosis patients treated with autologous hematopoietic stem cell transplantation (AHSCT) for a mean follow up of 63 months. We show that AHSCT is associated to a longlasting suppression of inflammation and to a marked decrease of the rate of brain atrophy after the second year following treatment. Multiple Sclerosis 2007; 13 : 1068—1070. http://msj.sagepub.com

Eleven consecutive patients with a first episode of acute optic neuritis were evaluated, using conventional and magnetization transfer (MT) magnetic resonance imaging (MRI), in order to assess the temporal evolution of optic nerve (ON) damage and to investigate the correlation of ON damage with visual outcome and electrophysiological parameters. Patients underwent neuro-ophthalmological, neurological, electrophysiological, and MRI assessments at baseline and after three and 12 months. ON volumes were measured on coronal T1–weighted images using a local thresholding segmentation technique. MT ratio (MTR) from the ON was derived from gradient echo images. No significant volume difference was detected between affected and healthy ON, both at baseline and follow-up. At baseline, mean MTR values were significantly higher in affected ON than in healthy ON (P = 0.001), whereas at months 3 and 12, the mean MTR values were significantly reduced in the affected ON (P = 0.02 and 0.003, respectively). Mean MTR of the affected ON, corrected for healthy ON values, progressively decreased over time (P = 0.04 at month 3 and P = 0.0012 at month 12). On the contrary, MTR values of healthy ON remained stable. No correlations were found between MTR measures and clinical or electrophysiological data. This study shows the presence of subtle pathological changes, possibly due to residual demyelination and subsequent additional demyelination and impaired remyelination, in the ON of patients with a first episode of optic neuritis. In the early phase of optic neuritis, MT MRI is more sensitive than atrophy measurements in detecting disease-related changes. Multiple Sclerosis 2007; 13: 265–268. http://msj.sagepub.com

During the past 10 years, conventional magnetic resonance imaging (cMRI) has become an established tool for the assessment of patients with multiple sclerosis (MS) and to monitor treatment trials. This is mainly due to the sensitivity and reproducibility of cMRI in the detection of MS-related damage. A large effort has also been devoted to develop imaging strategies capable of providing accurate estimates of the extent of disease-related damage not only in the brain, but also in the spinal cord and optic nerve. Guidelines have been defined to integrate MR findings in the diagnostic evaluation of patients at presentation with clinically isolated syndromes suggestive of MS, and specific acquisition protocols have been offered for monitoring longitudinal changes in patients with established disease. Despite the fact that the role of cMRI in MS has been profoundly obviated by the advent of modern and quantitative MR techniques, several issues are still unresolved. Technical development in acquisition and postprocessing, as well as the introduction of high-field magnets in the clinical arena, are likely to increase our understanding of disease pathobiology, mainly through an increased ability to quantify the extent of gray matter damage.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive and simultaneous degeneration of upper and lower motor neurons. The pathological process associated to ALS, albeit more pronounced in the motor/premotor cortices and along the corticospinal tracts (CST), does not spare extra‐motor brain gray (GM) and white (WM) matter structures. However, it remains unclear whether such extra‐motor cerebral abnormalities occur with mildly disabling disease, and how irreversible tissue loss and intrinsic tissue damage are interrelated. To this end, we used an optimized version of voxel‐based morphometry (VBM) analysis to investigate the patterns of regional GM density changes and to quantify GM and WM diffusivity alterations of the entire brain from mildly disabled patients with ALS. A high‐resolution T1‐weighted 3D magnetization‐prepared rapid acquisition gradient echo and a pulsed gradient spin–echo single shot echo–planar sequence of the brain were acquired from 25 mildly disabled patients with ALS and 18 matched healthy controls. An analysis of covariance was used to compare volumetry and diffusivity measurements between patients and controls. Compared with controls, ALS patients had significant clusters of locally reduced GM density (P < 0.001) in the right premotor cortex, left inferior frontal gyrus (IFG), and superior temporal gyrus (STG), bilaterally. In ALS patients contrasted to controls, we also found significant clusters of locally increased MD (P < 0.001) in the splenium of the corpus callosum and in the WM adjacent to the IFG, STG, and middle temporal gyrus (MTG) of the right hemisphere, and in the WM adjacent to the MTG and lingual gyrus in the left hemisphere. Compared with controls, ALS patients also had significant clusters of locally decreased FA values (P < 0.001) in the CST in the midbrain and corpus callosum, bilaterally. This study supports the notion that ALS is a multisystem disorder and suggests that extra‐motor involvement may be an early feature of the disease. Hum Brain Mapp 2007. © 2007 Wiley‐Liss, Inc.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), autologous hematopoietic stem cell transplantation (AHSCT) induces a profound suppression of clinical activity and MR imaging-detectable inflammation, but it may be associated with a rapid brain volume loss in the months subsequent to treatment. The aim of this study was to assess how AHSCT affects medium-term evolution of brain atrophy in MS. MATERIALS AND METHODS: MR imaging scans of the brain from 14 patients with rapidly evolving secondary-progressive MS obtained 3 months before and every year after AHSCT for 3 years were analyzed. Baseline normalized brain volumes and longitudinal percentage of brain volume changes (PBVCs) were assessed using the Structural Image Evaluation of Normalized Atrophy software. RESULTS: The median decrease of brain volume was 1.92% over the first year after AHSCT and then declined to 1.35% at the second year and to 0.69% at the third year. The number of enhancing lesions seen on the pretreatment scans was significantly correlated with the PBVCs between baseline and month 12 (r = -0.62; P = .02); no correlation was found with the PBVCs measured over the second and third years. CONCLUSIONS: After AHSCT, the rate of brain tissue loss in patients with MS declines dramatically after the first 2 years. The initial rapid development of brain atrophy may be a late consequence of the pretransplant disease activity and/or a transient result of the intense immunoablative conditioning procedure.

This chapter focuses on how the immune system is thought to contribute to the multiple sclerosis (MS) process through the different disease phases, including initiation and propagation, and in different anatomical compartments. Several subsets of regulatory T-cells are capable of inhibiting activation of other T-cells, including suppression of autoimmune responses. Clinical trials of B-cell depletion with rituximab and more recently ocrelizumab have demonstrated substantial reductions in new brain lesions, and relapses in MS patients. The innate immune system rapidly senses foreign pathogen-associated structures without the need for adaptive antigen-specific recognition or memory responses. The presence of clonally expanded CD4 and CD8 T-cells persisting in the CNS, suggests that T-cells can be activated or re-activated within the central nervous system (CNS) compartment. Cellular immune responses and soluble factors can have protective and potentially growth permissive influences capable of limiting injury, as well as promoting survival and repair of neural elements.

Brain atrophy is a typical feature of many neurological conditions. Therefore, quantitative evaluation and spatial characterization of atrophy are potentially useful for monitoring the evolution of central nervous system (CNS) disorders. In this study, a method for measuring atrophy of the major white matter (WM) fiber bundles in the brain using diffusion tensor (DT) MRI data is developed. To this end, an atlas was created from sets of diffusion anisotropy images from normal subjects, and the deformations necessary to match single subject anisotropy images to this atlas were then computed. Because diffusion anisotropy images were used, this approach should be sensitive to fiber bundle volume changes in the same way that using T1-weighted images allows gray matter volume changes to be measured. The Jacobian determinant of the deformation field for each subject was then used as a measure of contraction or expansion of the tissue at each image voxel. An overview of the nonlinear registration problem is given; then an optimization of the parameters for the chosen algorithm is performed and the method for producing the atlas is described. The effectiveness of the method was then tested on data from five patients with multiple sclerosis (MS) and two patients with amyotrophic lateral sclerosis (ALS). Magn Reson Med 58:527–534, 2007. © 2007 Wiley-Liss, Inc.

There is increasing evidence that the severity of the clinical manifestations of multiple sclerosis (MS) does not simply depend on the extent of tissue destruction, but rather represents a complex balance among tissue damage, tissue repair, and cortical reorganization. Functional magnetic resonance imaging (fMRI) provides information about the extent and nature of brain plasticity, which follows MS structural injury and might have the potential to limit the clinical manifestations of the disease. An altered recruitment of regions normally devoted to the performance of a given task and/or the recruitment of additional areas, which are not typically activated by healthy people for performing that given task, have been described in patients with MS, independent of their clinical phenotype when investigating the visual, cognitive, and motor systems. These functional changes have been related to the extent and severity of brain damage within and outside T2-visible lesions and to the involvement of specific central nervous system (CNS) structures, including the spinal cord and the optic nerve. Brain functional changes have been shown to be dynamic over time, not only after an acute relapse, but also in clinically stable patients. An increased recruitment of the cerebral networks might represent a first step of cortical reorganization with the potential to maintain a normal level of function in the course of MS. The progressive failure of these mechanisms might, on the one hand, result in the activation of previously silent "second-order" compensatory areas, and, on the other, contribute to the clinical manifestations of the disease.

Several clinical trials have reported that therapies targeting programmed death-1 (PD1) and its ligand (PD-L1) improve patient outcomes, while tumor response has been related to PD-L1 expression.To investigate the prognostic role of PD-L1 expression in patients affected by renal cell carcinoma (RCC).MEDLINE/PubMed, the Cochrane Library, and ASCO University were searched for studies investigating the prognostic role of PD-L1 expression in RCC. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.Six studies and 1323 cases were included in the final analysis. PD-L1 was expressed in 24.2 % of clear cell tumors compared to 10.9 % of non-clear cell tumors (p = 0.002). In the overall population, a higher level of PD-L1 expression increased the risk of death by 81 % (HR; 1.81, 95 % CI 1.31-2.49; p 0.001). When the analysis was restricted to cases evaluated by immunohistochemistry alone, the higher expression of PD-L1 more than doubled the risk of death (HR; 2.05, 95 % CI 1.38-3.05; p 0.001). In clear cell histology, higher PD-L1 expression increased the risk of death by 53 % (HR; 1.53, 95 % CI 1.27-1.84; p 0.001), while in metastatic patients, the evaluation of PD-L1 expression on primary tumors revealed that it retains its prognostic role (HR; 1.45, 95 % CI 1.08-1.93; p = 0.01).Significant heterogeneity has been identified among the included studies. As a consequence, cautious interpretation of the results is recommended.This meta-analysis indicates that a higher level of PD-L1 expression is a negative prognostic factor in RCC. Its validation as an independent prognostic factor compared to other traditionally used clinical parameters in localized or advanced disease is recommended.

Objective To study the role of NR5A1 in cryptorchidism and male factor infertility. Mutations in NR5A1 have been initially associated with primary adrenal insufficiency and 46,XY gonadal dysgenesis and more recently with less severe phenotypes, including preliminary descriptions in severe forms of male factor infertility. Far less clear is the possible involvement of NR5A1 mutations in cryptorchidism. Design Retrospective cross-sectional cohort study and functional analysis of mutant proteins. Setting University department. Patient(s) Nine hundred fifty-nine subjects, including children with cryptorchidism and adults with different semen phenotypes associated or not associated with a history of cryptorchidism. Intervention(s) None. Main Outcome Measure(s) Mutation screening of NR5A1 by sequencing all exons. Functional analysis of mutant proteins by transactivation assays of CYP11A1 and CYP17A1 promoters. Result(s) We identified seven undescribed and one previously described missense mutation in subjects with severe spermatogenic impairment, without (4/236, 1.7%) and with (3/85, 3.5%) a history of cryptorchidism. Newborns with cryptorchidism carry NR5A1 mutations at low frequency (0.7%), whereas no mutations were found in milder forms of infertility and normozoospermia, irrespective of the presence of cryptorchidism. The mutant proteins showed impaired transactivation of gonadal promoters. A single nucleotide polymorphism (rs1110061; c.437 G→C; p.Gly146Ala) was also associated with more severe forms of spermatogenic impairment with cryptorchidism. Conclusion(s) This study, combined with what is already known about NR5A1-associated phenotypes, suggests considering mutations in this gene as a novel genetic cause of more severe forms of male factor infertility, especially when associated with a history of cryptorchidism.

e17039 Background: The need to combine cure with preservation of laryngeal functions is the challenge in laryngeal cancer treatment. We conducted a randomized phase II study with platinum induction...

Chromosomal abnormalities may cause growth failure before or since birth. 9q duplication is reported as a cause of intrauterine growth restriction, mild dysmporphism, and intellectual disabilities. We report a case of a maternally inherited 9q21.31q21.33 duplication causing prenatal and postnatal growth restriction with feeding refusal and mild facial dysmorphisms, prenatally diagnosed by single-nucleotide polymorphism array analysis. Hypothesis of the possible pathogenic mechanisms are discussed.

Aims To identify the most appropriate surgical strategy for carcinoma of the urachus. Methods Analysis of a case of adenocarcinoma of the urachus and an examination of the current literature were carried out. Conclusions Partial cystectomy is considered the most appropriate surgical strategy but the need for close follow-up is underlined.

The aims of this study were to improve, using a 3.0 Tesla (T) scanner and diffusion tensor (DT) magnetic resonance imaging (MRI) with sensitivity encoding, our understanding of: 1) the possible pathological substrates of normal-appearing white matter (NAWM) and grey matter (GM) damage in multiple sclerosis (MS) and 2) the factors associated to WM and GM atrophy in this condition. Conventional and DT MRI of the brain were acquired from 32 relapsing-remitting (RR) MS patients and 16 controls. Lesion load, WM (WMV), overall GM (GMV), and neocortical GM (NCV) volumes were measured. NAWM mean diffusivity (MD) and fractional anisotropy (FA), and GM MD were calculated. GMV and NCV were lower (por = 0.001) in MS patients than controls, whereas WMV did not differ significantly. MS patients had higher NAWM and GM average MD and lower NAWM average FA (por = 0.001) than controls. Moderate correlations were found between intrinsic lesion and tissue damage with both GM volumetric and diffusivity changes (-0.41or = ror = 0.42, por = 0.04). DT MRI and volumetry measurements at 3.0 T confirm the presence of NAWM and GM abnormalities in RRMS patients. Although histopathology was not available, axonal and neuronal damage and consequent reactive glial proliferation are the most likely substrates of the changes observed.

Functional magnetic resonance imaging (fMRI) is being widely used to study recovery of function in patients with several neurological conditions, including multiple sclerosis, stroke and Alzheimer’s disease. The application of this MR technique has shown that plastic cortical changes do occur after central nervous system (CNS) injury of different aetiology, that such changes are related to the extent of CNS damage and that they can contribute in limiting the clinical consequences of brain damage. Conversely, the failure or exhaustion of the adaptive properties of the cerebral cortex might be among the factors responsible for the accumulation of ‘fixed’ neurological deficits. New studies aimed at investigating the effect of therapies devoted to promote brain plasticity are now warranted.

Background and objective: Diffusion tensor (DT) magnetic resonance imaging (MRI) has the potential to disclose subtle abnormalities in the brain of migraine patients. This ability may be increased by the use of high field magnets. A DT MRI on a 3.0 tesla scanner was used to measure the extent of tissue damage of the brain normal appearing white (NAWM) and grey matter in migraine patients with T2 visible abnormalities. Methods: Dual echo, T1 weighted and DT MRI with diffusion gradients applied in 32 non-collinear directions were acquired from 16 patients with migraine and 15 sex and age matched controls. Lesion load on T2 weighted images was measured using a local thresholding segmentation technique, and brain atrophy assessed on T1 weighted images using SIENAx. Mean diffusivity and fractional anisotropy histograms of the NAWM and mean diffusivity histograms of the grey matter were also derived. Results: Brain atrophy did not differ between controls and patients. Compared with healthy subjects, migraine patients had significantly reduced mean diffusivity histogram peak height of the grey matter (p = 0.04). No diffusion changes were detected in patients’ NAWM. In migraine patients, no correlation was found between T2 weighted lesion load and brain DT histogram derived metrics, whereas age was significantly correlated with grey matter mean diffusivity histogram peak height (p = 0.05, r = −0.52). Conclusions: DT MRI at high field strength discloses subtle grey matter damage in migraine patients, which might be associated with cognitive changes in these patients.

Contrary to what happens in adult-onset multiple sclerosis (MS), in a previous preliminary magnetic resonance imaging (MRI) study we showed only subtle normal-appearing brain tissue changes in patients with earlyonset MS. Our objective was to evaluate the presence and extent of tissue damage in the brain normalappearing white matter (NAWM) and gray matter (GM) from a larger population of patients with earlyonset MS.Using diffusion tensor (DT) and magnetization transfer (MT) MRI, we obtained DT and MT ratio (MTR) maps of the NAWM and GM from 23 patients with early-onset MS and 16 sex- and age-matched healthy volunteers.Compared with healthy volunteers, patients with early-onset MS had significantly increased average MD (p = 0.02) and FA peak height (p = 0.007) and decreased average FA (p0.0001) of the NAWM. Brain dual-echo lesion load was significantly correlated with average FA (r = -0.48, p = 0.02) and with FA peak height (r = 0.45, p = 0.03) of the NAWM. No MTR and diffusion changes were detected in the GM.This study confirms the paucity of the 'occult' brain tissue damage in patients with earlyonset MS. It also suggests that in these patients GM is spared by the disease process and that NAWM changes are likely to be secondary to Wallerian degeneration of fibers passing through macroscopic lesions.

Background and Purpose— In migraine patients, functional imaging studies have shown changes in several brain gray matter (GM) regions. However, 1.5-T MRI has failed to detect any structural abnormality of these regions. We used a 3-T MRI scanner and voxel-based morphometry (VBM) to assess whether GM density abnormalities can be seen in patients with migraine with T2-visible abnormalities and to grade their extent. Methods— In 16 migraine patients with T2-visible abnormalities and 15 matched controls, we acquired a T2-weighted and a high-resolution T1-weighted sequence. Lesion loads were measured on T2-weighted images. An optimized version of VBM analysis was used to assess regional differences in GM densities on T1-weighted scans of patients versus controls. Statistical parametric maps were thresholded at P Results— Compared with controls, migraine patients had areas of reduced GM density, mainly located in the frontal and temporal lobes. Conversely, patients showed increased periacqueductal GM (PAG) density. Compared with patients without aura, migraine patients with aura had increased density of the PAG and of the dorsolateral pons. In migraine patients, reduced GM density was strongly related to age, disease duration, and T2-visible lesion load ( r ranging from −0.84 to −0.73). Conclusions— Structural GM abnormalities can be detected in migraine patients with brain T2-visible lesions using VBM and a high-field MRI scanner. Such GM changes comprise areas with reduced and increased density and are likely related to the pathological substrates associated with this disease.

The McDonald International Panel accepted the Barkhof/Tintoré criteria for providing MRI evidence of dissemination in space to allow a diagnosis of multiple sclerosis in patients with clinically isolated syndromes (CIS). We applied these criteria in a large cohort of patients with CIS, representative of those seen in a general diagnostic setting, to assess their accuracy in predicting conversion to definite multiple sclerosis and to identify factors that affect this risk.In a collaborative study of seven centres, baseline MRI and clinical follow-up data for 532 patients with CIS were studied, with the development of a second clinical event used as the main outcome. All scans were scored for lesion counts and spatial lesion distribution to assess the fulfilment--ie, at least three out of four--of the Barkhof/Tintoré criteria. We used survival analysis and 2x2 tables to assess the test characteristics of the criteria at baseline.Overall conversion rate was 32.5% with a median survival time of 85.3 months. Fulfilment of the criteria at baseline showed, after a survival time of 2 years, a conversion rate of about 45% (95% CI 37-53) versus about 10% (6-16) in those with no asymptomatic lesions at baseline (p0.0001). For patients with a follow-up of at least 2 years, the fulfilment of the MRI criteria showed an accuracy of 68% (sensitivity 49%, specificity 79%) for predicting conversion and an increase in risk of nearly four times for conversion compared with those not fulfilling the criteria (odds ratio 3.7, 95% CI 2.3-5.9; p0.0001). Cox proportional hazards regression analysis accorded with this increased risk. No effects were recorded on the performance of the criteria by sex, presenting symptoms, or centre. Age at baseline did have a small but significant effect as predictor (hazard ratio 0.97, 0.95-0.99; p=0.002), but did not affect the prognostic value of the MRI criteria.MRI abnormalities have important prognostic value. The cut-off, based on the Barkhof/Tintoré criteria, as incorporated in the McDonald diagnostic scheme yields acceptable specificity, but could have lower sensitivity than previously reported.

This study aimed at evaluating the influence of a different slice orientation on brain magnetic resonance imaging (MRI) lesion load in multiple sclerosis (MS). Fifteen MS patients were scanned obtaining both axial and sagittal conventional spin echo (24 slices; TR 2400, TE 30/80) brain MRI. The total lesion load (TLL) was assessed twice for each scan, using a semi-automated local thresholding technique and the same marked hardcopies. The mean TLL was 22734 mm3 for axial and 22003 mm3 for sagittal scans. The mean intra-observer coefficient of variation (COV) was 4.65% for the axial acquisitions and 4.52% for the sagittal acquisitions. This difference was not statistically significant (one-way ANOVA, P> 0.1). The lesion load was significantly higher from axial MRI as compared to the intra-observer variability (two-way ANOVA, P =0.01), but the fluctuations around this average difference between axial and sagittal scan TLL were significantly large (test for interaction, P < 0.00I). Our data indicate that the use of sagittal conventional MRI scans does not seem to be worthwhile for the quantitative assessment of lesion load in MS patients.

The application of modern MRI techniques to the assessment of MS patients has considerably improved our understanding of MS pathophysiology and has provided new objective metrics that might be useful to monitor disease evolution, either in natural history studies or in treatment trials. However, none of the quantitative MR-based techniques considered, taken in isolation, is able to provide a complete picture of the complexity of the MS process and this should call for the definition of aggregates of MR quantities, thought to reflect different aspects of MS pathology, to improve our ability to monitor the disease. At present, longitudinal natural history data collected in large samples of MS patients using structural, metabolic and functional MR techniques are needed to gain additional insight into MS pathobiology and on the actual value of modern MR technologies in the management of MS.

Using fMRI, an increased recruitment of the ipsilateral primary sensorimotor cortex (SMC), supplementary motor area, and middle frontal gyrus has been detected in patients with cervical cord myelitis of possible demyelinating origin. The aim of this study was to evaluate, using fMRI, whether the level of cord involvement influences cortical reorganization by comparing patients with isolated myelitis of the cervical and the dorsal portions of the cord, and to investigate whether the extent of cortical reorganization is associated with the extent of cervical cord pathology measured using magnetization transfer (NIT) MRI. We studied 24 right-handed patients (14 with a previous involvement of the cervical cord and 10 with an involvement of the dorsal cord) in a chronic and clinically stable phase following an isolated myelitis of possible demyelinating origin and 15 sex- and age-matched healthy controls. During a single session, we obtained fMRI during repetitive flexion-extension of the last four ringers of the right and left hands and cervical cord NIT MRI. Average cord MTR was lower in patients with cervical (P < 0.0001) and dorsal (P = 0.0001) myelitis than in controls. Compared to controls and for both tasks, patients with myelitis had an increased recruitment of the ipsilateral primary SMC, which was independent of the level of cord involvement. On the contrary, patients with cervical myelitis had a more widespread recruitment of frontal and parietal regions, whereas those with dorsal myelitis had a more widespread recruitment of temporal and cerebellar regions. Strong correlations (r values ranging front -0.72 to -0.88) were found between relative activations of cortical areas and the severity of cervical cord damage. Patients with isolated myelitis have different patterns of movement-associated cortical activations according to the level of cord involvement. This "level-dependent" functional reorganization of the cortex is likely to have an adaptive role in limiting the clinical outcome of cord damage and should be considered when designing rehabilitation strategies for these patients. (c) 2005 Elsevier Inc. All rights reserved.

Matrix metalloproteinase-9 (MMP-9) is involved in blood-brain barrier (BBB) disruption in active multiple sclerosis (MS), while MMP-2 seems to be associated with the chronic progressive phase of the disease. Recombinant interferon beta-1a (rIFNβ-1a) is effective in restoring the BBB. We studied the relationships between serum MMP-9, MMP-2, TIMP-1 and TIMP-2 and different magnetic resonance imaging (MRI) measures of disease activity in MS patients during treatment with rIFNβ-1a. Twenty-one relapsing-remitting (RR) MS patients underwent longitudinally simultaneous blood withdrawals and MRI (before and after standard dose (SD) and triple dose (TD) of gadolinium (Gd)) examinations before and during 48 weeks of rIFNβ-1a (Rebif® 22 mcg three times a week) treatment. Serum MMP-9, MMP-2, TIMP-1 and TIMP-2 were measured, MMP-9 to TIMP-1 and MMP-2 to TIMP-2 ratios were calculated and the numbers of Gd-SD, Gd-TD, new-Gd-SD, new-Gd-TD and new-T2 lesions counted. Serum MMP-9/TIMP-1 ratio (P< 0.0001), as well as the numbers of ‘active’ lesions (P ranging from 0.0004 to 0.005) decreased during treatment. Moreover, serum MMP-9/TIMP-1 ratio proved to be a good positive predictor (estimate= 0.85; P> 0.05) of the numbers of MRI Gd-TD active lesions. These data confirm that serum MMP-9/TIMP-1 ratio may be viewed as a reliable marker and may be predictive of MRI activity in RR MS.

Background: In patients with migraine, functional changes have been described in the red nucleus (RN), substantia nigra (SN) and periaqueductal gray matter (PAG). Purpose: To evaluate whether and at which frequency these structures are involved by MRI-detectable structural abnormalities in migraineurs and to investigate the pathogenic role of these abnormalities by assessing their frequency and extent in patients with multiple sclerosis (MS) and migraine. Methods: On brain dual-echo scans obtained from 58 migraineurs (40 without and 18 with aura), 37 MS patients with migraine without aura and 42 MS patients without migraine, the presence of hyperintense lesions involving the brainstem structures was recorded. A test of heterogeneity between groups was used to compare the presence of lesions among patient groups. Results: Lesions of RN, SN and PAG were found in all patient groups, with frequency from 57.5% to 86.5%. Significant between-group differences for all these regions were found. No difference was found between migraine patients with and without aura. Compared with MS patients without migraine, MS patients with migraine had more significant involvement of the SN (p = 0.02) and RN (p < 0.0001). Compared with migraine patients, MS patients with migraine had more significant involvement of the SN and PAG (p ranging from 0.009 to 0.02). Conclusions: T2-visible lesions in the brainstem are frequent in patients with migraine, but do not seem to be associated with the presence of aura. Demyelinating lesions in the RN, SN and PAG might be among the factors responsible for the presence of migraine in patients with MS

Functional cortical changes have been demonstrated in patients with several neurological conditions, including stroke, tumors and MS. The correlation found between the extent of fMRI activations and the extent and severity of brain structural damage suggests an adaptive role of these functional changes. In this study, we assess, using fMRI, the brain pattern of movement-associated cortical activations in neuropsychiatric systemic lupus erythematosus (NPSLE) patients and investigate whether the extent of cortical reorganization is associated with the extent of brain pathology, measured on dual-echo and diffusion tensor (DT) MR images. From 14 right-handed NPSLE patients and 14 matched controls, we obtained: (a) fMRI during the performance of repetitive flexion-extension of the last four fingers of the right hand; (b) dual-echo and (c) pulsed-gradient spin-echo echo-planar sequence to calculate DT MRI maps of the normal-appearing white (NAWM) and gray (NAGM) matter. Brain T2-visible abnormalities were detected in I I NPSLE patients. Compared with controls, NPSLE patients had significantly higher NAWM fractional anisotropy histogram peak height (P = 0.005), and more significant activations of the contralateral primary sensorimotor cortex, putamen and dentate nucleus. They also had more significant activations of several regions located in the frontal and parietal lobes as well as of MT/V5 and the middle occipital gyrus, bilaterally. Strong correlations (r values ranging from 0.79 to 0.87) were found between relative activations of sensorimotor areas and the extent and severity of brain damage. Movement-associated functional cortical changes do occur in patients with NPSLE and might contribute to the maintenance of their normal functional capacities. (c) 2005 Elsevier Inc. All rights reserved.

Multiple sclerosis (MS) is a chronic, demyelinating disease of the central nervous system (CNS) with the onset of symptoms typically occurring between the age of 20 and 40 years. However, in about 3% to 12% of the cases, the onset of the disease is before 16 years of age. This review summarizes the main results obtained by the application of conventional and non-conventional MRI techniques to the assessment of patients with early-onset MS, which showed that the overall amount of CNS damage in these subjects is mild, compared to that typically detected in the adult-form of the disease. This fits with the notion that an early onset of the disease is associated with a more favourable clinical evolution.

The classical view of MS as a chronic inflammatory demyelinating disease leading to the formation of focal central nervous system (CNS) white matter (WM) lesions has been recently challenged by pathological studies and by the extensive application of modern MRI-based techniques. There is now overwhelming evidence supporting the following statements: MS causes widespread tissue damage in the normal-appearing white matter (NAWM) of the brain and spinal cord, whose extent and severity is more strictly associated to the clinical manifestations of the disease than the extent of focal pathology. Discrete, macroscopic lesions are just the tip of the iceberg of MS pathology. Grey matter (GM) damage is a consistent feature of all MS phenotypes, which is progressive from the start of the relapsing-remitting phase of the disease. As is the case for WM, GM damage is also a mixture of focal lesions and diffuse pathology. High-field strength MR scanners are improving our ability to image focal GM lesions and modern MR-based techniques are enabling us to quantify in vivo the extent and severity of GM pathology, which have been shown to correlate only moderately with the amount of WM changes. At least part of GM pathology in MS is not secondary to retrograde degeneration of fibers traversing WM lesions. The neurodegenerative component of the disease is not a late phenomenon and it is not completely driven by inflammatory demyelination. In fact, neurodegeneration occurs very early in the course of MS and the correlation between MRI measures of inflammation and neurodegeneration is weak in all disease phases. The interplay of inflammation and neurodegeneration is a complex and still poorly understood phenomenon. At least part of MS-related neurodegeneration is not directly driven by Wallerian degeneration. Functional cortical changes can be seen in virtually all MS patients and are likely to play a central role in the ability of the MS brain to respond to tissue injury and, hence, limit the functional consequences of structural damage. MS disability is not just the result of tissue destruction but rather a balance between tissue destruction, tissue repair and adaptive cortical reorganization. All of this calls for the concept of MS as a focal, inflammatory demyelinating, WM disease to be reexamined and to start viewing MS as a diffuse CNS disease with an important neurodegenerative component. This is central for identifying novel and effective treatment strategies.

Objective: To investigate the extent and severity of cervical cord damage using diffusion tensor MRI (DT-MRI) and histogram analysis in patients with primary progressive MS (PPMS). Methods: Diffusion-weighted sensitivity-encoded (SENSE) echoplanar images of the cervical cord and brain dual-echo and diffusion-weighted scans were acquired from 24 patients with PPMS and 13 healthy controls. Cord and brain mean diffusivity and fractional anisotropy histograms were produced. An analysis of variance model, adjusting for cord volume, was used to compare cord DT-MRI parameters from controls and patients. Results: Compared to healthy controls, PPMS patients had reduced cervical cord cross-sectional area and average cord fractional anisotropy ( p = 0.007), and increased cord mean diffusivity ( p = 0.024). No correlations were found between DT-MRI metrics of the cord and quantities obtained from conventional and DT-MRI of the brain. Conclusions: DT-MRI of the cervical cord can quantify the extent of diffuse cord pathology in patients with PPMS. Such cord diffusivity changes in patients with PPMS are likely to reflect irreversible axonal injury and reactive gliosis and seem to be independent of brain damage.

Although multiple sclerosis (MS) frequently involves the optic nerves, imaging this structure is not yet performed routinely in clinical practice. The recent improvement of magnetic resonance (MR) technology and the development of new MR strategies, capable of providing an, in vivo, overall assessment of MS pathology has allowed objective metrics to be obtained for monitoring disease evolution, essentially in the brain. However, despite this progress, the correlation between brain MR metrics of the disease and clinical disability are still disappointing. An objective and accurate estimate of the presence and extent of optic nerve involvement might help to overcome this clinical/MRI paradox. This review summarizes the main results obtained from the application of conventional and modern MR-based techniques for the evaluation of optic nerve damage in MS.

This chapter discusses the main results obtained by the application of modern magnetic resonance (MR) technology to the study of multiple sclerosis (MS), with the ultimate goal of highlighting how they are changing the understanding of MS, which is now viewed as a diffuse condition affecting both white and gray matter of the central nervous system (CNS) and which causes irreversible clinical disability mainly through axonal or neuronal damage. Axonal or neuronal loss is an important feature of MS pathology, and it is likely to represent one of the main factors responsible for the accumulation of irreversible disability. The application of modern MR techniques to the in vivo study of MS is providing important insights into the pathophysiology of the disease, and it is establishing new markers to understand and monitor MS evolution. However, none of the quantitative MR-based techniques taken in isolation is likely to be able to provide a complete picture of the complexity of the MS process, and this should call for the definition of aggregates of MR measurements thought to reflect different aspects of MS pathology. This approach is likely to enhance our ability to monitor the disease and to improve the correlation between MRI metrics and disability.

Summary Mucosal leishmaniasis of the upper respiratory tract is usually associated with the visceral form or is found in immunosuppressed individuals. This report presents a case of isolated mucosal leishmaniasis in an immunocompetent patient, whose diagnosis mainly rested on histology and positive polymerase chain reaction result for Leishmania donovani in the laryngeal tissue. A 59-year-old man, who never lived outside Italy, showed a subglottic mucosal polypoid-like lesion. The typical morphological picture and positive polymerase chain reaction result for L donovani by DNA extracted from laryngeal biopsy specimens allowed the diagnosis of mucosal leishmaniasis. Specific amphotericin B therapy was started, resulting in clinical and endoscopic improvement. Increased knowledge about the histological and molecular tissue analysis of Leishmania enhances the diagnostic testing for mucosal leishmaniasis, as primary mucosal leishmaniasis may occur in both immunosuppresed and immunocompetent patients who travel to or reside in areas endemic for Leishmania .

The aim of this study was to investigate whether neurological symptoms related to a specific axonal fiber tract in brain white matter were associated with a higher degree of tissue damage in that region, in patients at presentation with clinically isolated syndromes (CIS) suggestive of multiple sclerosis. To this end, a magnetic resonance imaging (MRI) method to segment and evaluate the fiber bundle of interest was implemented, taking care to circumvent the problems caused by pathology. Diffusion tensor (DT) MRI tractography was used to construct, from healthy volunteer data, a probability map for the pyramidal tract (PYT), and this map was applied to patients to calculate DT-derived metrics inside the PYT. In CIS patients with clinical symptoms related to motor function, the DT-derived mean diffusivity and the lesion volume in the PYT were found to be increased, while the fractional anisotropy was no different, when compared to those patients without motor symptoms. These results may be explained by several microstructural changes in the damaged tissue, such as changes in the permeability of axonal cell membranes, decreases of axonal density and edema. The approach taken to analyze a specific fiber tract was possible because the axons in the tract have a high orientational coherence, allowing tissue structure changes to be isolated from the tissue architecture. Its extension to other white matter fiber bundles is therefore limited to bundles with high orientational coherence.

Background Early-onset multiple sclerosis (MS) typically has a more favorable course than adult-onset disease. Objective To assess the extent of microscopic tissue damage in the brain and cervical cord of patients with early-onset MS. Design During a single magnetic resonance imaging session, images of the brain and spinal cord were obtained using diffusion tensor and magnetization transfer magnetic resonance imaging. Patients We studied 13 patients with early-onset MS and 10 healthy volunteers. Results Compared with control subjects, patients with early-onset MS showed only a slight increase of the average mean diffusivity of the normal-appearing brain tissue. Conclusion The relatively modest central nervous system damage detected in these patients might explain why early-onset MS typically has a more favorable clinical course than adult-onset MS.

This is a multiparametric MR study of the first reported patient with adult-onset genetically confirmed vanishing white matter (VWM) disease. It shows that, despite the presence of a severe and diffuse damage of the brain WM, brain gray matter, and cervical cord tissue, the cortical adaptive capacities were relatively preserved. Interpatient variability of brain plasticity may contribute to the known phenotypic variation of patients with VWM disease.

Accessible online at: www.karger.com/ene The last two decades have witnessed an increased effort in understanding the mechanisms responsible for the accumulation of irreversible disability in multiple sclerosis (MS). In this context, the clinical application of magnetic resonance imaging (MRI) techniques has progressively increased our ability to achieve an accurate quantification of the overall burden of the disease and to monitor its course objectively. More recently, the use of functional MRI in the assessment of MS patients has shown a modified recruitment of cortical areas during motor, cognitive and sensory tasks in MS patients [1]. Functional cortical changes have been demonstrated during the acute phase of the disease [2] and in clinically stable patients with different disease phenotype and clinical impairment [1]. It has also been shown that cortical adaptive changes might be elicited and/or modulated by different substrates, including the extent of T2-visible lesions and the severity of their intrinsic damage, the amount of normal-appearing white matter and gray matter damage, the extent of axonal loss/dysfunction and the severity of spinal cord involvement [1]. Up to now, the role of brain atrophy on cortical functional changes has not been fully elucidated yet. Conversely, this variable has been carefully controlled in all the previous studies in order to avoid a possible bias in functional MRI results. The single case report of Roelcke et al. [3] presented in this issue may be considered as a preliminary view on this important topic. The progressive development of brain atrophy is a well-known feature of MS patients [4]. Using different measurement techniques, many studies have shown that atrophy of the brain is present from the earliest stages of the disease and tends to progress with disease evolution [4]. In their report, Roelke et al. [3] compared the movement-associated pattern of cortical activations between the atrophic and the normal hemisphere in an MS patient with unilateral brain atrophy and found no differences in the location, extent and significance of the cluster of activations between the two hemispheres. In some longitudinal follow-up studies of MS patients with a subcortical lesion affecting the corticospinal tracts, we invariably found during self-paced movements an increased activation of the contralateral primary motor cortex associated with increased activation of the supplementary motor area and ipsilateral primary motor cortex. During the follow-up, the overactivation both in the contralateral and ipsilateral areas always decreased if a good recovery of motor function was achieved. However, also in patients with good recovery, some increased activation of cortical motor areas persisted, indicating that cortical reorganization contributed to the recovery. Interestingly enough, in the more advanced phases of the disease, in patients with severe motor deficits, the overactivation of cortical motor areas (both contralateral and ipsilateral) disappeared, suggesting that the decrease in motor ability

Using magnetization transfer (MT) and diffusion tensor (DT) MRI, the authors assessed the extent of tissue damage of the brain normal-appearing white and gray matter (NAGM) in patients with neuromyelitis optica (NMO). Compared to healthy controls, patients with NMO showed reduced MT ratio and increased mean diffusivity of the NAGM. This challenges the classic notion of a sparing of the brain tissue in the course of NMO.

Devic’s neuromyelitis optica (NMO) is a neurological condition characterized by a severe involvement of the optic nerves and spinal cord in a mono- or multi-phasic manner. Recent pathologic, cerebrospinal fluid and conventional magnetic resonance imaging (MRI) studies have shown abnormalities which might help in differentiating patients with NMO from those with multiple sclerosis. This review article summarizes the main results obtained using conventional MRI in NMO, which has contributed to the definition of internationally-accepted diagnostic criteria, and those obtained from the application of modern quantitative MR techniques which are significantly changing our views on NMO pathobiology.

Using functional magnetic resonance imaging (fMRI), we investigated whether movement‐associated functional changes of the brain are present in patients who are, most likely, at the earliest stage of multiple sclerosis (MS). Functional MRI exams were obtained from 16 patients at presentation with clinically isolated syndromes (CIS) suggestive of MS and 15 sex‐ and age‐matched healthy volunteers during the performance of three simple and one more complex motor tasks with fully normal functioning extremities. fMRI analysis was performed using statistical parametric mapping (SPM99). Compared to healthy volunteers, CIS patients had increased activations of the contralateral primary sensorimotor cortex (SMC), secondary somatosensory cortex (SII), and inferior frontal gyrus (IFG), when performing a simple motor task with the dominant hand. The increased recruitment of the contralateral primary SMC was also found during the performance of the same motor task with the non‐dominant hand and with the dominant foot. In this latter case, an anterior shift of the center of activation of this region was detected. During the performance of a complex motor task with the dominant upper and lower limbs, CIS patients had an increased recruitment of a widespread network (including the frontal lobe, the insula, the thalamus), usually considered to function in motor, sensory, and multimodal integration processing. The comparison of brain activations during the performance of simple vs. complex motor tasks showed that the movement‐associated somatotopic organization of the cerebral and cerebellar cortices was retained in patients with CIS. Cortical reorganization occurs in patients at presentation with CIS highly suggestive of MS. Local synaptic reorganization, recruitment of parallel existing pathways, and reorganization of distant sites are all likely to contribute to the observed functional changes. Hum. Brain Mapping 21:106–115, 2004. © 2003 Wiley‐Liss, Inc.

Cortical functional changes, with the potential to limit the functional consequences of tissue injury, have been shown in patients with multiple sclerosis (MS). In this study, we assessed the influence of MS-related tissue damage of the brain portion of the left pyramidal tract on the corresponding movement-associated patterns of cortical recruitment in a large sample of MS patients when performing a simple motor task with their fully normal functioning right upper limbs. We investigated 76 right-handed patients with definite MS. In each subject, functional magnetic resonance imaging (fMRI) was acquired during the performance of a simple motor task with the dominant, right upper limb. During the same session, dual-echo, magnetization transfer (MT) and diffusion tensor (DT) MRI sequences were also obtained to quantify the extent and the severity of pyramidal tract damage. Lesions along the left pyramidal tract were identified in 43 patients. Compared to patients without pyramidal tract lesions, patients with such lesions had more significant activations of the contralateral primary sensorimotor cortex (SMC), secondary sensorimotor cortex (SII), inferior central sulcus, and cingulate motor area (CMA). They also showed more significant activations of several regions of the ipsilateral hemisphere, including the primary SMC and the precuneus. In these patients, T2 lesion load of left pyramidal tract was correlated with the extent of activation of the contralateral primary SMC (r(2) = 0.25, P < 0.0001), whereas no correlations were found between the extent of fMRI activations and the severity of intrinsic lesion damage, as well as with left pyramidal tract normal-appearing white matter damage. This study shows that, in patients with MS, following injury of the motor pathways, there is an increased recruitment of a widespread sensorimotor network, which is likely to contribute to limit the appearance of overt clinical deficits. (C) 2004 Elsevier Inc. All rights reserved.

Background Magnetization transfer magnetic resonance imaging (MT MRI) can provide in vivo markers reflecting the severity of multiple sclerosis–related brain damage occurring within and outside T2-visible lesions. Objective To investigate the effect of intravenous immunoglobulin (IVIG) treatment on the accumulation of brain damage in patients with secondary progressive multiple sclerosis (SPMS), measured using MT MRI. Design, Patients, and Intervention Seventy patients with SPMS participating in the European, multicenter, randomized, double-blind, placebo-controlled trial of IVIG in SPMS underwent brain T2-weighted and MT MRI at baseline and after 12 and 24 months. The MT MRI scans were post-processed and analyzed to obtain MT ratio values from T2-visible lesions and MT ratio histograms from the normal-appearing brain tissue (NABT). Results At baseline, a significant difference was found for NABT MT ratio histogram peak height ( P = .003) between treated patients and patients receiving placebo. No significant differences between treated patients and those receiving placebo were found for any of the considered MT MRI–derived metrics in terms of treatment × time interaction. Nevertheless, over the 24-month period, the placebo patients experienced a 6.75% reduction of the NABT MT ratio histogram peak height, whereas treated patients experienced only a 0.92% reduction of the NABT MT ratio histogram peak height. Conclusions This study did not show any statistically significant effect of IVIG on MT MRI quantities. Nevertheless, the markedly different percentage change of the NABT MT ratio histogram peak height over time between patients receiving placebo and treated patients suggests a possible role of IVIG treatment in preventing the loss of “truly” normal brain tissue in SPMS patients.

Recent functional magnetic resonance imaging (fMRI) work has suggested that cortical reorganisation might have an adaptive role in limiting the clinical impact of multiple sclerosis (MS) structural damage. In this study, we investigated whether, in patients with MS, the presence and extent of structural damage of the normal-appearing brain tissue are associated with the extent of the movement-associated pattern of cortical activations. Using fMRI and a general search method, we assessed the patterns of brain activations associated with simple motor tasks in 12 right-handed patients with clinically definite MS and nonspecific T2-weighted abnormalities on conventional MRI scans of the brain and compared them with those from 12 sex- and age-matched right- handed healthy controls. Also investigated were the extent to which the fMRI changes correlated with normal-appearing white matter and grey matter (GM) pathology, measured using diffusion tensor MRI. When performing the simple motor task with the dominant hand, MS patients had more significant activations of the ipsilateral supplementary motor area (SMA), the ipsilateral superior frontal sulcus, the contralateral superior temporal gyrus, and the thalamus than controls. On the contrary, healthy subjects showed more significant activations of the medial part of the contralateral parieto-occipital fissure and the ipsilateral primary sensorimotor cortex (SMC) than patients with MS. In patients with MS, the relative activation of the ipsilateral SMA was correlated with the peak height (r = -0.88, P < 0.001) and position (r = 0.87, P < 0.001) of the GM mean diffusivity histogram. This study shows that cortical reorganisation occurs over a rather distributed sensorimotor network even in patients with MS and nonspecific abnormalities on conventional brain MRI scans. This suggests that, in patients with MS, an increased recruitment of movement-associated cortical network can be elicited by the presence of normal-appearing tissue pathology, which is independent of macroscopic T2-weighted abnormalities. (C) 2003 Elsevier Science (USA). All rights reserved.

Movement-associated cortical changes have been shown in several neurological conditions and were found to be associated to the extent of brain and cord damage. Devic's neuromyelitis optica (DNO) is characterized by a severe involvement of the cord and optic nerve, with sparing of the brain. To assess the actual role of cord pathology on the pattern of movement-associated cortical recruitment, we obtained functional magnetic resonance imaging (fMRI) from patients with DNO and investigated whether the extent of brain activation is correlated with the extent of cervical cord damage. We studied 10 right-handed DNO patients and 15 sex- and age-matched healthy controls. The MRI assessment consisted of the following: (a) fMRI during repetitive flexion extension of the last four ringers of the right and left hand, (b) brain and cervical cord conventional MRI, and (c) cervical cord magnetization transfer (MT) MRI. Compared to controls and for both tasks, DNO patients had an increased recruitment of several regions of the sensorimotor network (primary sensorimotor cortex, postcentral gyros, middle frontal gyros, rolandic operculum, secondary sensorimotor cortex, precuneus, and cerebellum) and of several other regions mainly in the temporal and occipital lobes, such as MT/V5, the fusiform gyrus, the cuneus, and the parahippocampal gyrus. For both tasks, strong correlations (r values ranging from -0.76 to -0.85) were found between relative activations of cortical sensorimotor areas and the severity of cervical cord damage. This study shows an abnormal pattern of movement-associated cortical activations in patients with DNO, which extends beyond the 'classical' sensorimotor network and also involves visual areas devoted to motion processing. The correlation found between fMRI changes and the extent of cord damage suggests that such functional cortical changes might have an adaptive role in limiting the clinical outcome of DNO structural pathology. (C) 2003 Elsevier Inc. All rights reserved.

This review is intended to provide an up-to-date summary of the main functional magnetic resonance imaging studies conducted in patients with multiple sclerosis, and to show how such studies are changing our views on the ability of the multiple sclerosis brain to limit the clinical consequences of irreversible structural tissue damage.Brain cortical reorganization is a common phenomenon occurring in patients with multiple sclerosis, independent of disease duration and clinical phenotype, which can be elicited by macroscopic lesions, as well as by the presence of 'occult' multiple sclerosis-related damage of the brain and cervical cord. An increased recruitment of the cerebral networks involved in the performance of given tasks might represent a first step in cortical reorganization with the potential to maintain a normal level of function in the course of multiple sclerosis. The progressive failure of these mechanisms, because of accumulating tissue damage, might, on the one hand, result in the activation of previously silent 'second-order' compensatory areas, and, on the other, contribute to the accumulation of irreversible disability.Functional magnetic resonance imaging has the potential to provide important information about cortical reorganization following multiple sclerosis-related tissue damage, which should improve our understanding of the factors associated with the accumulation of irreversible disability in this disease. The enhancement of any beneficial effects of this cortical adaptive plasticity should be considered as a potential target of therapy for multiple sclerosis.