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Recognition of multiple sclerosis (MS) attacks relies mostly on clinical assessment. However, their definition based on McDonald criteria refers mostly to timing and when dealing with clinical features is rather ambiguous: "...of the kind seen in multiple sclerosis." This is heightened in clinically isolated syndromes of the brainstem/cerebellum (CISB), where clinical manifestations can be manifold. This study aimed to describe the clinical features of patients with CISB to improve clinical recognition of patients with brainstem manifestations at the onset of their MS. To this end, we conducted a retrospective analysis of case notes of consecutively recruited patients with CISB assessed within 3 months of symptoms onset. Seventy-five patients were included. Most common brainstem-specific symptoms were: diplopia (68%), facial sensory symptoms (32%) and gait disturbance (31%). Adjusting for follow-up times, total number of symptoms and presence of other brainstem-specific symptoms, only the presence of facial sensory symptoms was predictive of (a lower risk of) conversion to clinically definite (CD) MS (Odds ratio: 0.086; p = 0.007). Neither the total number of brainstem-specific, non brainstem-specific nor the sum of both predicted conversion to CDMS. Results indicate that diplopia, facial sensory symptoms and gait disturbance occur in more than 30% of patients with CISB. Facial sensory symptoms are less associated with conversion to CDMS.

Background: A diagnosis of multiple sclerosis in patients who present for the first time with a clinically isolated syndrome (CIS) can be established with brain magnetic resonance imaging (MRI) if the MRI demonstrates demyelinating lesions with dissemination in space (DIS) and dissemination in time (DIT)., Objective: To investigate the diagnostic performance of a single MRI study obtained within the first 3 months after symptom onset in a cohort of patients with a CIS suggestive of multiple sclerosis at presentation., Design: Multicenter inception cohort with a follow-up of at least 24 months., Setting: Referral hospitals. Patients Patients with CIS onset between April 1, 1995, and September 30, 2004, who fulfilled the following criteria were included: (1) age of 14 to 50 years and (2) clinical follow-up for at least 24 months after CIS onset or until development of clinically definite multiple sclerosis (CDMS), if this occurred within 2 years. Main Outcome Measure All patients underwent 2 comparable brain MRI examinations, the first within 3 months (early) and the second between 3 and 12 months (delayed) after CIS onset. We defined DIS using several existing MRI criteria, and DIT was inferred when there were simultaneous gadolinium-enhancing and nonenhancing lesions on a single MRI., Results: Two hundred fifty patients were included in the study. The comparison of the diagnostic performance of various MRI criteria for identifying early converters to CDMS showed similar sensitivity and specificity between early and delayed MRIs. In addition, the use of less stringent criteria for DIS yielded better sensitivity and similar specificity, particularly when assessed in the first weeks after CIS onset., Conclusion: A single brain MRI study that demonstrates DIS and shows both gadolinium-enhancing and nonenhancing lesions that suggest DIT is highly specific for predicting the early development of CDMS, even when the MRI is performed within the first 3 months after the onset of a CIS.

Multiple sclerosis (MS) is considered to be a two stage disease: a first stage in which inflammatory phenomena are crucial and a later one in which degenerative processes become the hallmark. The role of magnetic resonance imaging (MRI) is nowadays of great help both to establish the diagnosis and to rule out other conditions. At the clinically isolated syndrome (CIS) stage, MRI is an important tool both to predict the appearance of a second attack or the development of disability at long term. In the relapsing-remitting (RR) phase of the disease conventional MRI is probably less helpful to predict future relapses and disability. Cross sectional and longitudinal studies have shown very weak correlations between lesion burden on brain T2 and disability in the progressive forms of MS. Regarding T2 burden of disease, a plateau effect for EDSS values greater than 4.5 has been observed. Measures related to brain or spinal cord atrophy together with MR Spectroscopy, Magnetization Transfer Imaging and Diffusion Tensor Imaging may be useful in the future to better monitor disease progression in the late degenerative phase of the condition. MRI has also been of great help in monitoring the effect of immunomodulatory drugs in CIS or RRMS clinical trials. Its role to predict treatment response is still controversial on an individual basis.

Understanding the contribution of the brain white matter pathways to declarative verbal memory processes has been hindered by the lack of an adequate model in humans. An attractive and underexplored approach to study white matter region functionality in the living human brain is through the use of non-aprioristic models which specifically search disrupted white matter pathways. For this purpose, we employed voxel-based lesion-function mapping to correlate white matter lesions on the magnetic resonance images of 46 multiple sclerosis patients with their performance on declarative verbal memory storage and retrieval. White matter correlating with storage was in the temporal lobe-particularly lateral to the hippocampus and in the anterior temporal stem-, in the thalamic region and in the anterior limb of the internal capsule, all on the left hemisphere, and also in the right anterior temporal stem. The same volumes were relevant for retrieval, but to them were added temporo-parieto-frontal paramedian bundles, particularly the cingulum and the fronto-occipital fasciculus. These 3D maps indicate the white matter regions most critically involved in declarative verbal memory in humans.

Rates of progression vary widely in primary progressive multiple sclerosis. This multicenter study aimed to identify predictors of progression over 10 years. A total of 101 patients who had been imaged at baseline and 2 years were scored on the expanded disability status scale after 10 years. Ordinal logistic regression identified the following independent variables that predicted progression: male sex, shorter disease duration, and slower timed walk test at baseline (best overall predictor), and deterioration in expanded disability status scale score and reduction in brain volume over 2 years. These predictors of long-term disability provide some insight into disease progression.

Although the mechanisms underlying the accumulation of disability in primary progressive (PP) multiple sclerosis (MS) are still unclear, a major role seems to be played by 'occult' tissue damage. We investigated whether conventional and magnetization transfer (MT) MRI may provide complementary information for the assessment of PPMS severity. Conventional and MT MRI scans from 226 PPMS patients and 84 healthy controls were collected for centralized analysis. The expanded disability status scale (EDSS) score was rated at the time of MRI acquisition. T2 lesion volume, normalized brain volume (NBV) and cervical cord cross-sectional area (CSA) were measured. Magnetization transfer ratio (MTR) histograms from whole brain tissue, normal-appearing white matter and grey matter (NAGM) were also obtained. Mean NBV, CSA and MTR histogram-derived metrics showed significant inter-centre heterogeneity. After correcting for the acquisition centre, pooled average MTR and histogram peak height values were different between PPMS patients and controls for all tissue classes (P-values between 0.03 and 0.0001). More severe brain and cord atrophy and MT MRI-detectable NAGM damage were found in patients who required walking aids than in those who did not (P-values: 0.03, 0.001 and 0.016). A composite score of NBV, CSA, whole brain and NAGM MTR histogram peak height z-scores was correlated with patients' EDSS (r = 0.37, P 0.001). Magnetization transfer MRI might provide information complementary to that given by conventional MRI when assessing PPMS severity. Sequence-related variability of measurements makes the standardization of MT MRI acquisition essential for the design of multicentre studies.

Objective: To investigate whether patients with early primary progressive multiple sclerosis show changes in T1 relaxation time (T1-RT) in normal-appearing white matter (NAWM) and normal-appearing gray matter (NAGM) during 2 years and whether T1-RT at baseline predicts disability., Methods: Twenty-one patients and 12 control subjects were studied at baseline and after 2 years. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores were assessed. T1 relaxation time histograms of NAWM and NAGM were obtained in all subjects, and mean, peak height, and peak location of the histograms were measured. Paired t tests were used to compare baseline and 2-year histogram values in patients and control subjects. To investigate whether T1-RT predicted clinical changes, multiple linear regression analysis was used., Results: Patients showed increases in NAWM and NAGM T1-RT mean and peak location during follow-up, and significant decreases in NAWM and NAGM peak height. Baseline NAWM T1-RT mean values and peak height predicted disability at 2 years, as measured with the Multiple Sclerosis Functional Composite score., Conclusion: T1 relaxometry is a good marker of disease progression and has prognostic potential in primary progressive multiple sclerosis.

Background: Gray matter (GM) atrophy has been reported in multiple sclerosis (MS). However, little is known about its regional distribution., Objective: To investigate the regional distribution of GM atrophy in clinically early primary progressive MS (PPMS)., Design and Patients: Thirty-one patients with PPMS within 5 years of symptom onset (mean age, 43.2 years; median Expanded Disability Status Scale score, 4.5) and 15 healthy control subjects (mean age, 43.7 years) were studied. All subjects underwent a 3-dimensional inversion-recovery fast spoiled gradient-recalled echo sequence that was repeated after 1 year in patients only. Magnetic resonance images underwent an optimized voxel-based morphometric analysis that segments magnetic resonance data volumes in a normalized space and quantifies tissue atrophy on a voxel-by-voxel basis. A lesion mask was created for each patient and used in normalization and segmentation steps to minimize bias from lesions. A multisubject design was used in the cross-sectional study to compare patients with PPMS and controls. A 1-way analysis of variance (within-subjects) design was used in the longitudinal study., Results: At baseline, patients with PPMS displayed bilateral thalamic atrophy compared with controls. In addition, a significant association between lesion load and decreased GM volume was found for the thalami. Loss of GM in the putamen, caudate, thalami, and cortical and infratentorial areas was observed in patients after 1 year of follow-up., Conclusions: Atrophy is most obvious in deep GM in clinically early PPMS. This may reflect increased sensitivity of these regions to neurodegeneration. Cortical and infratentorial atrophy developed as the disease evolved.

Objectives: The concentration in plasma of the brain-specific cholesterol metabolite cerebrosterol has been proposed as a biomarker of neurodegeneration in multiple sclerosis (MS) and other neurological diseases. It is unknown, however, which pathophysiological process in MS best accounts for variations in plasma cerebrosterol., Patients and Methods: In this study, we related plasma cerebrosterol concentrations in 46 MS patients - 27 with a relapsing-remitting (RR) disease course and 19 with a primary progressive (PP) course - to three conventional magnetic resonance imaging measures: on T(1)-weighted brain scans, volume of gadolinium-enhanced lesions (a marker of active inflammation) and hypointense lesions (a marker of edema or axonal loss) and on T(2)-weighted scans, volume of hyperintense lesions (a marker of disease extent)., Results: By multiple-regression analysis, we uncovered negative correlations between the cerebrosterol-cholesterol ratio in plasma and both age at sampling (beta=-0.35 and p=0.079 in RRMS; beta=-0.76 and p=0.006 in PPMS) and volume of T(2)-weighted lesions (beta=-0.52 and p=0.078 in RRMS; beta=-0.50 and p=0.247 in PPMS)., Conclusion: We hypothesize that decreases in plasma cerebrosterol may reflect the total spatiotemporal burden of MS-the cumulative effects of its dissemination in space and its duration in time.

We have recently reported brain atrophy in the early stages of primary progressive multiple sclerosis (PPMS), affecting both grey and white matter (GM and WM). However, to date no clinical or radiological predictors of GM and WM atrophy have been identified. The aim was to investigate short-term changes in GM and WM volumes and to assess the predictive value of demographic, clinical and radiological variables in order to gain a better understanding of the pathological substrate underlying these changes. Thirty-one subjects with PPMS within 5 years of symptom onset were studied at baseline and after 1 year. At baseline, patients underwent neurological examination and were scored on the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite. They had 3D inversion-prepared fast spoiled gradient recalled (FSPGR), dual-echo and triple-dose post-contrast T1-weighted spin echo MRI scans. Proton density and enhancing lesion loads were determined. The 3DFSPGR sequence was repeated after 1 year and brain volume changes were calculated using two techniques, SPM99 (statistical parametric mapping) and SIENA (structural image evaluation, using normalization, of atrophy). Stepwise linear regression models were applied to baseline variables to identify independent predictors of atrophy development. Using SPM99, a decrease in brain parenchymal fraction (-1.03%; P < 0.001) and GM fraction (-1.49%; P < 0.001) was observed. The number of enhancing lesions independently predicted decrease in brain parenchymal fraction (P = 0.019) and decrease in WM fraction (P = 0.002). No independent predictors of GM fraction decrease were found. A mean brain volume change of -0.63% (range -4.27% to +1.18%; P = 0.002) was observed using SIENA, which was independently predicted by EDSS (P = 0.004). Global and GM atrophy can be detected over a 1-year period in early PPMS. The former may be predicted by the degree of inflammation, while the latter seems to be independent of it. SIENA and SPM-based methods appear to provide complementary information.

Background: Intravenous methylprednisolone (IVMP) has been shown to hasten recovery from attacks of multiple sclerosis (MS) without altering the long term evolution of the condition; however, there is little evidence available to suggest which patients are more likely to benefit from IVMP treatment., Objective: To measure clinical change after IVMP treatment and to identify predictors of good outcome., Methods: Retrospective open-label study of medical records from 51 patients with clinically isolated syndromes or relapsing-remitting MS treated with IVMP for an acute attack (54 attacks)., Results: A measurable neurological improvement was observed at one month in 44% of these attacks; the only predictor of Expanded Disability Status Scale (EDSS) change at one month was the severity of the attack., Conclusion: Attack severity predicts good response to IVMP when measured by means of EDSS.

Background: There is little information available on grey and white matter (GM and WM) atrophy in primary progressive multiple sclerosis (PPMS) and on their relationships with clinical and other magnetic resonance imaging (MRI) measures., Aim: To evaluate disease progression in the early phase of PPMS, focusing on axonal loss as assessed by volumetric MRI measures of WM and GM, and to determine their relationships with clinical outcomes and lesion load measures., Methods: Forty-three patients with PPMS within 5 years of symptom onset and 45 control subjects were studied. Three-dimensional brain scans were acquired and segmented into WM, GM, and cerebrospinal fluid (CSF) using SPM99. Brain parenchymal (BPF), WM (WMF), and GM fractions (GMF) normalized against total intracranial volumes were estimated. T2-weighted (T2) and enhancing lesion loads were also determined. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores were recorded in all patients., Results: There were significant differences between patients and controls in BPF, WMF, and GMF values (P < 0.001). BPF (r = -0.469; P = 0.002) and WMF (r = -0.532; P < 0.001) but not GMF (r = -0.195; P = 0.2) correlated with EDSS scores. BPF (r = 0.518; P = 0.001), WMF (r = 0.483; P = 0.001), and GMF (r = 0.337; P = 0.031) correlated with MSFC scores. Correlations with enhancing lesion and T2 loads were only significant for BPF and WMF., Conclusions: Brain atrophy is seen in the early stages of PPMS and affects both GM and WM. WM atrophy appears more closely related to clinical outcome and WM focal damage than GM atrophy in this patient group.

Background: Barkhof criteria have been adopted to demonstrate dissemination in space in the new multiple sclerosis diagnostic criteria because of their high specificity for predicting conversion to multiple sclerosis. One of the 4 Barkhof criteria is the presence of an infratentorial lesion. In clinically isolated syndromes (CIS) of the brainstem (CISB), the infratentorial criterion does not demonstrate dissemination in space, raising the possibility that the criteria may be less specific in CISB, as compared with specificity in other CIS, in which all 4 criteria demonstrate dissemination in space., Objective: To compare the validity indices of Barkhof criteria in CISB with those in other CIS., Design: Inception cohort with median follow-up of 34 months for CISB and 40 months for other CIS., Setting: Institutional ambulatory referral center., Patients: A sample of 51 patients with CISB and 102 patients with other CIS (46 with myelitis and 56 with optic neuritis) was analyzed. Barkhof criteria, with a cutoff of 3 of 4, were applied to magnetic resonance imaging performed at baseline. Four combinations each containing 3 parameters were also applied, with a cutoff of 2 of 3., Main Outcome Measure: Specificity of unmodified Barkhof criteria and of the 4 combinations to predict conversion to clinically definite multiple sclerosis., Results: The specificity of the criteria in CISB was 61% against 73% in other CIS. The combinations that retained the infratentorial lesion parameter had lower specificities in the CISB group; in analysis of the group with other CIS, no such differences were found., Conclusion: The infratentorial lesion criterion is responsible for the lower specificity of Barkhof criteria in CISB.

Background: The use of unconventional therapies is growing in western countries. Few studies on their frequency and rationale among multiple sclerosis (MS) patients have been carried out in Europe., Objective: To assess the frequency of use of unconventional therapies among MS patients and to explore associated clinical variables., Methods: Structured questionnaires were given to 380 consecutive patients seen at two hospital-based MS clinics in Barcelona. Clinical and demographical data were recorded at the same time. The questionnaire inquired about demographical features, education, income, use of unconventional therapies for MS and satisfaction with conventional medicine both in general and specifically in MS., Results: The response rate was 50.78%. Forty-one per cent of patients admitted using unconventional therapies during the previous year. Low levels of satisfaction with conventional medicine in general and for MS, and higher Expanded Disability Status Scale (EDSS) scores (EDSS mean: 4.43 in users versus 3.48 in nonusers) were significantly associated with use of unconventional therapies., Conclusion: Use of unconventional therapies is not rare among MS patients, and it is associated with high disability levels and dissatisfaction with conventional medicine.

The HLA-DR2 haplotype (DRB1*1501, DQB1*0602) on chromosome 6p21 has consistently demonstrated both association and linkage with multiple sclerosis (MS) in case-control and family studies, particularly in Caucasians of Northern European descent. However, the role of a gene within this region in determining clinical features or response to immunotherapy remains largely unknown. A new familial MS data set from the Mediterranean Spanish Basin was collected according to rigorous ascertainment criteria. We confirm, primarily in the cohort originating from Continental Spain, that similar to other high-risk groups, there was a significant association with HLA-DR2. No other DR or DQ alleles were found to be associated with disease susceptibility nor were alleles at the class I A and B loci. Overall, the effect of HLA appears to be less substantial than that observed in a reference US population with a higher disease incidence. No effect of the HLA-DR2 haplotype on age of onset, initial clinical symptoms and disease course was observed. Similarly, no difference in the distribution of responders and nonresponders to interferon-beta (IFNB) therapy, as defined by primary and secondary end points, was observed when individuals were stratified according to HLA-DR2 status.