Assessing treatment response to oral drugs for multiple sclerosis in real-world setting: a MAGNIMS Study.

BACKGROUND: The assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored whether a scoring system developed within the MAGNIMS (MRI in Multiple Sclerosis) network to evaluate treatment response to injectable drugs can be adopted also to oral DMTs. METHODS: A multicentre dataset of 1200 patients who started three oral DMTs (fingolimod, teriflunomide and dimethyl fumarate) was collected within the MAGNIMS network. Disease activity after the first year was classified by the 'MAGNIMS' score based on the combination of relapses (0-≥2) and/or new T2 lesions (<3 or ≥3) on brain MRI. We explored the association of this score with the following 3-year outcomes: (1) confirmed disability worsening (CDW); (2) treatment failure (TFL); (3) relapse count between years 1 and 3. The additional value of contrast-enhancing lesions (CELs) and lesion location was explored. RESULTS: At 3 years, 160 patients experienced CDW: 12% of them scored '0' (reference), 18% scored '1' (HR=1.82, 95% CI 1.20 to 2.76, p=0.005) and 37% scored '2' (HR=2.74, 95% CI 1.41 to 5.36, p=0.003) at 1 year. The analysis of other outcomes provided similar findings. Considering the location of new T2 lesions (supratentorial vs infratentorial/spinal cord) and the presence of CELs improved the prediction of CDW and TFL, respectively, in patients with minimal MRI activity alone (one or two new T2 lesions). CONCLUSIONS: Early relapses and substantial MRI activity in the first year of treatment are associated with worse short-term outcomes in patients treated with some of the oral DMTs.

Efficacy and Safety of Intravenous Immunoglobulin Treatment in Refractory Behcet's Disease with Different Organ Involvement: A Case Series.

Behçet's disease (BD) is a multi-systemic disorder of unknown etiology characterized by relapsing oral-genital ulcers, uveitis, and involvement of the articular, gastrointestinal, neurologic, and vascular systems. The choice of treatment is based on the severity of systemic involvement, clinical presentation and the site affected, and includes corticosteroids, azathioprine, interferon, cyclophosphamide, methotrexate or tumor necrosis factor-alpha and interleukin-1 blockers. We present a case series of four refractory BD patients successfully treated with intravenous immunoglobulins (IVIG). All patients fulfilled International Study Group criteria. The patients' mean age was 38.75 ± 12.09 years and mean disease duration 10.25 ± 8.5 years. Human leukocyte antigen B51 was positive in two of four patients. In addition to oral aphthosis, all patients suffered from genital ulcers and cutaneous BD-related manifestations; central nervous system involvement and arthralgia were found in two patients. Peripheral nervous system, gastrointestinal and eye involvement occurred in 25% of cases. In all patients, previously treated according to EULAR recommendations without reaching satisfactory results, IVIG induced immediate and sustained response over time without incurring any side effects. We propose IVIG administration as an additional effective and safe treatment option in patients with severe and resistant BD.

Prognostic biomarkers of IFNb therapy in multiple sclerosis patients.

BACKGROUND: Interferon beta (IFNb) reduces relapse frequency and disability progression in patients with multiple sclerosis (MS). OBJECTIVES: Early identification of prognostic biomarkers of IFNb-treated patients will allow more effective management of MS. METHODS: The IMPROVE study evaluated subcutaneous IFNb versus placebo in 180 patients with relapsing-remitting MS. Magnetic resonance imaging scans, clinical assessments, and blood samples were obtained at baseline and every 4 weeks from every participant. Thirty-nine biomarkers (32 transcripts; seven proteins) were studied in 155 patients from IMPROVE. Therapeutic response was defined by absence of new combined unique lesions, relapses, and sustained increase in Expanded Disability Status Scale over 1 year. A machine learning approach was used to examine the association between biomarker expression and treatment response. RESULTS: While baseline levels of individual genes were relatively poor predictors, combinations of three genes were able to identify subjects with sub-optimal therapeutic responses. The triplet CASP2/IRF4/IRF6, previously identified in an independent dataset, was tested among other combinations. This triplet showed acceptable predictive accuracy (0.68) and specificity (0.88), but had relatively low sensitivity (0.22) resulting in an area under the curve (AUC) of 0.63. Other combinations of biomarkers resulted in AUC of up to 0.80 (e.g. CASP2/IL10/IL12Rb1). CONCLUSIONS: Baseline expression, or induction ratios, of specific gene combinations correlate with future therapeutic response to IFNb, and have the potential to be prognostically useful.

The brief repeatable battery of neuropsychological tests (BRB-N) version a: update of Italian normative data from the Italian Neuroimaging Network Initiative (INNI).

BACKGROUND: Cognitive impairment is a common clinical manifestation in people with multiple sclerosis (PwMS) and significantly impacts patients' quality life. Cognitive assessment is crucial for treatment decisions and understanding disease progression. Several neuropsychological batteries are used in MS, including the Brief Repeatable Battery of Neuropsychological Tests (BRB-N), Minimal Assessment of Cognitive Function in MS (MACFIMS), and Brief International Cognitive Assessment for MS (BICAMS). However, normative data for BRB-N version A in Italy are outdated. OBJECTIVES: To revise and update normative data for the BRB-N version A in the Italian population. METHODS: From the Italian Neuroimaging Network Initiative (INNI) database, we retrospectively selected 342 healthy subjects (172 males and 170 females) evaluated at four Italian INNI-affiliated sites (Milan, Siena, Rome, Naples). The subjects underwent neuropsychological assessment using the BRB-N version A. Regression-based method relying on scaled scores was used to calculate demographic correction procedures. RESULTS: No significant differences were found in age, education, and sex distribution among the four sites (p ≥ 0.055). Regression analysis provided normative data to calculate demographically adjusted z-scores for each BRB-N version A test. DISCUSSION: This study provides updated normative data for the BRB-N version A in the Italian population. The use of a regression-based method and scaled scores ensures consistency with other neuropsychological batteries commonly used in Italy, namely MACFIMS and BICAMS. The availability of updated normative data increases reliability of neuropsychological assessment of cognitive function in Italian PwMS and other clinical populations using BRB-N version A, providing valuable insights for both clinical and research applications.

Isoprostanes in clinically isolated syndrome and early multiple sclerosis as biomarkers of tissue damage and predictors of clinical course.

BACKGROUND: Isoprostanes (IsoP) are sensitive biomarkers of oxidative stress. Their cerebrospinal-fluid (CSF) level is increased in several neurological conditions, including multiple sclerosis (MS). In particular, in relapsing-remitting MS, IsoP have been proposed as an index of neurodegenerative processes. The mechanisms leading to neuroaxonal damage in MS are not fully understood but oxidative mechanisms play a substantial role. Although axonal loss is present in MS patients since their first clinical symptoms, IsoP levels at this early stage have not been evaluated yet. OBJECTIVES: The objectives of this study were (a) to assess IsoP levels in CSF of patients with a first clinical attack suggestive of MS; (b) to correlate IsoP levels with magnetic resonance imaging (MRI) measures of brain damage and (c) to assess IsoP value in predicting disease clinical evolution. METHODS: Thirty-nine patients with a first clinical attack suggestive of MS underwent neurological examination, lumbar puncture with IsoP levels quantification and conventional/spectroscopic-MRI. Patients were followed up for 24 months. RESULTS: CSF IsoP levels were higher in patients than controls (mean ± standard deviation (SD) 123.4 ± 185.8 vs 4.5 ± 2.9 pg/ml; p<0.0001) and inversely correlated to normalized brain volume (p=0.04) and N-acetylaspartate/choline (NAA/Cho) (p=0.01). The risk of experiencing clinical relapses differed according to IsoP level: subjects with levels higher than 95 pg/ml (a cut-off value resulting from ROC analysis) were more likely to relapse than patients with levels equal or lower than 95 pg/ml (59% vs 27% respectively; p=0.03). CONCLUSIONS: CSF IsoP might be useful biomarkers of tissue damage in MS with a predictive value of disease course.

Modelling the distribution of cortical lesions in multiple sclerosis.

Recent studies have shown the relevance of the cerebral grey matter involvement in multiple sclerosis (MS). Cortical lesions (CLs), detected by specific MRI sequences, are likely to become a new research outcome in MS studies. The aim of this study was to infer the optimal statistical model describing the distribution of CLs in patients with relapsing-remitting (RR)MS. The negative binomial model gave the best fit to the observed distribution of CLs in a group of 44 RRMS patients with one MRI scan of the brain. This observation has important implications for the statistical analysis of CLs in MS studies.

"Better explanations" in multiple sclerosis diagnostic workup: A 3-year longitudinal study.

BACKGROUND: The exclusion of other diseases that can mimic multiple sclerosis (MS) is the cornerstone of current diagnostic criteria. However, data on the frequency of MS mimics in real life are incomplete. METHODS: A total of 695 patients presenting with symptoms suggestive of MS in any of the 22 RIREMS centers underwent a detailed diagnostic workup, including a brain and spinal cord MRI scan, CSF and blood examinations, and a 3-year clinical and radiologic follow-up. FINDINGS: A total of 667 patients completed the study. Alternative diagnoses were formulated in 163 (24.4%) cases, the most frequent being nonspecific neurologic symptoms in association with atypical MRI lesions of suspected vascular origin (40 patients), migraine with atypical lesions (24 patients), and neuromyelitis optica (14 patients). MS was diagnosed in 401 (60.1%) patients according to the 2017 diagnostic criteria. The multivariate analysis revealed that the absence of CSF oligoclonal immunoglobulin G bands (IgG-OB) (odds ratio [OR] 18.113), the presence of atypical MRI lesions (OR 10.977), the absence of dissemination in space (DIS) of the lesions (OR 5.164), and normal visual evoked potentials (OR 3.550) were all independent predictors of an alternative diagnosis. INTERPRETATION: This observational, unsponsored, real-life study, based on clinical practice, showed that diseases that mimicked MS were many, but more than 45% were represented by nonspecific neurologic symptoms with atypical MRI lesions of suspected vascular origin, migraine, and neuromyelitis optica. The absence of IgG-OB and DIS, the presence of atypical MRI lesions, and normal visual evoked potentials should be considered suggestive of an alternative disease and red flags for the misdiagnosis of MS.

Right-to-left shunt in CADASIL patients: prevalence and correlation with clinical and MRI findings.

BACKGROUND AND PURPOSE: A high prevalence of right-to-left shunt (RLS) was described in a family of patients with CADASIL, a rare cerebral arteriopathy attributable to Notch3 gene mutations. The aim of this study was to determine the prevalence of RLS in patients with CADASIL and possible relation to clinical phenotype and cerebral MRI lesion load. METHODS: Twenty-three CADASIL patients underwent Transcranial Doppler with gaseous contrast to asses RLS. Correlations between RLS, clinical features, and MRI lesion volume (LV) were determined. RESULTS: Large RLS was diagnosed in 47% of patients. No significant clinical or MRI differences were found between patients with and without RLS. CONCLUSIONS: We found a high prevalence of RLS in our group of CADASIL patients. This may not be a coincidence, but can be rather related to the role of the Notch receptor family in the development of cardiovascular system.

Voxel-based assessment of differences in damage and distribution of white matter lesions between patients with primary progressive and relapsing-remitting multiple sclerosis.

BACKGROUND: Several studies have reported lower focal demyelination and inflammatory activity in primary progressive multiple sclerosis (PPMS) than in relapsing-remitting MS (RRMS). However, very little is known about possible differences in damage and distribution that may occur within lesions visible on magnetic resonance imaging in the 2 forms of the disease. OBJECTIVE: To evaluate differences in spatial distribution and structural damage of focal demyelinating lesions in patients with PPMS and RRMS. DESIGN: We acquired conventional magnetic resonance and magnetization transfer images in 24 PPMS and 36 RRMS patients (matched for sex, age, and disease duration) and 23 healthy sex- and age-matched controls. In each participant, we measured T2- and T1-weighted lesion volumes and magnetization transfer ratios in lesional and nonlesional brain tissues. The spatial distribution of focal demyelination was assessed using T2- and T1-weighted lesion probability maps in each patient group. Voxel-based procedures were performed. SETTING: University hospital. RESULTS: Patients with PPMS had greater disability than those with RRMS, with 70% of PPMS patients and 11% of RRMS patients having relevant motor symptoms. The T1- and T2-weighted lesion volumes were higher in PPMS than in RRMS patients (P < .001). T1- and T2-weighted lesion probability maps showed that the maximum probability for lesions was higher in PPMS (peak probability, 45% and 29%, respectively) than in RRMS (peak probability, 33% and 19%, respectively) patients and was localized in the corona radiata. Voxelwise analysis of lesional magnetization transfer ratios gave overlapping results. CONCLUSIONS: Differences in cerebral pathologic involvement exist between RRMS and PPMS and contribute to variations in clinical disability.

Cardiac autonomic nervous system and risk of arrhythmias in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited systemic microangiopathy with prevalently cerebral manifestations. Among the causes of death, sudden unexpected death seems to occur in a significant number of CADASIL patients. Because potential causes of sudden unexpected death may include cardiac arrhythmias and myocardial infarction, we evaluated risk factors for life-threatening arrhythmias, such as reduced heart rate variability, sympathetic overactivity and QT interval (QTc) prolongation, in 23 CADASIL patients. The relationship of these changes with brain MRI pattern was also investigated. METHODS: Frequency domain measures of heart rate variability (10 minutes recordings) and QTc interval were recorded in 23 CADASIL patients (17 males, 6 females) and 22 healthy age- and sex-matched control subjects. The following heart rate variability spectral parameters were considered at rest during spontaneous and controlled breathing (Cb): total power, very-low-frequency component, low-frequency component, high-frequency component, low-frequency/high-frequency ratio, and Cb-total power, Cb-very-low-frequency component, Cb-low-frequency component, Cb-high-frequency component, Cb-low-frequency/high-frequency ratio. R-to-R wave and QTc interval were also analyzed. All data were statistically compared between CADASIL and control subjects. Conventional brain MRI was performed in patients with CADASIL and T1-weighted and T2-weighted lesion volumes, and were compared with each spectral component of the tachogram. RESULTS: During spontaneous and controlled breathing, total power spectrum and all spectral components (very low frequency component, high-frequency component, low-frequency component) of heart rate variability were significantly reduced in CADASIL patients with respect to controls (P<0.05). The low-frequency/high-frequency component ratio was significantly higher in CADASIL patients than in controls. No significant correlation between heart rate variability spectral parameters and other variables including total brain T2-weighted and T1-weighted lesion volumes were observed in CADASIL subjects. CONCLUSIONS: We found a statistically significant reduction in all frequency domain parameters of heart rate variability associated with a higher low frequency/high frequency ratio for CADASIL patients with respect to normal subjects. These data are consistent with autonomic derangement and suggests that CADASIL patients may be at risk for life-threatening arrhythmias. This could at least in part explain their higher recurrence of sudden unexpected death and should be taken into account in planning therapy.

Cortical damage in brains of patients with adult-form of myotonic dystrophy type 1 and no or minimal MRI abnormalities.

OBJECTIVE: To evaluate, by using quantitative MRI metrics, subtle cortical changes in brains of patients with the adult form of myotonic dystrophy type I (DM1) who showed no or minimal abnormalities on MRI. BACKGROUND: DM1 is an autosomal dominant multisystem disorder caused by the expansion of CTG repeats in the myotonic dystrophy-protein kinase gene. Mild to severe involvement of the CNS can be part of the clinical features of the disease. Several MRI studies have demonstrated that both focal white matter (WM) lesions and diffuse grey matter atrophy can be found in the brains of DM1 patients. However, whether these two processes are related or may occur independently is not clear. DESIGN/METHODS: Ten genetically-proven DM1 patients who showed no or minimal abnormalities on MRI underwent a new brain MRI examination to obtain computerized measures of total and regional brain volumes normalized to head size and regional measurements of the magnetization transfer ratio (MTr). RESULTS: Normalized brain volumes (NBV) were significantly (p < 0.0001) lower in DM1 subjects than in a group of age- and sex-matched normal controls. Normalized cortical volumes (NCV) also were lower (p = 0.003) in DM1 subjects than in normal controls, whereas normalized WM volumes were not different between the two groups (p = 0.3). In agreement with this, values of MTr in the neocortex (cortical-MTr) were significantly (p = 0.006) lower in DM1 patients than in normal controls and this difference was not found in the WM tissue (p = 0.8). CONCLUSIONS: Neocortical damage seems to be evident in the absence of visible WM lesions suggesting that a neocortical pathology, unrelated to WM lesion formation, occurs in DM1 brains.

Diffuse structural and metabolic brain changes in Fabry disease.

OBJECTIVES: To assess structural and metabolic brain changes in subjects affected by Fabry disease (FD) or carrying the disease mutation. BACKGROUND: FD is an X-linked metabolic disorder due to alpha-galactosidase A deficiency, which leads to storage of glycosphingolipids in many tissues and organs. Previous MR studies have shown structural and metabolic brain abnormalities in FD patients. It is not clear, however, whether tissue damage can be seen in both the brains of hemizygous and heterozygous and whether quantitative MR metrics are useful to monitor disease evolution. DESIGN/METHODS: We studied 4 males and 4 females with FD. Each subject underwent brain proton MRI/MR spectroscopic imaging (MRSI) examinations to obtain measures of total brain volumes, total brain lesion volumes, magnetization transfer ratios (MTr) in WM and central brain levels of N-acetylaspartate (NAA) to creatine (Cr). A second MR examination was performed in five subjects after 2 years. RESULTS: Focal WM lesions were found in 2 males and 1 female. The MTr values were always low in the WM lesions of FD subjects (p < 0.001) and also were low in the normal-appearing WM of 2 affected males. Total brain volumes were never decreased in FD subjects. Brain NAA/Cr values were significantly (p = 0.005) lower in FD subjects than in normal controls and correlated closely with Rankin scale measures (r = -0.79). On follow-up examinations, no significant MR changes were found. However, the small changes in NAA/Cr correlated closely with changes in Rankin scores (r = -0.86). CONCLUSIONS: Subtle structural and metabolic tissue damage can extend beyond WM lesions in FD subjects. Diffuse brain NAA/Cr decrease can be found in FD subjects in relation to the degree of their CNS involvement and its evolution over time.

Diffuse metabolic changes in the brain of patients with familial amyloid polyneuropathy. A proton MRSI study.

OBJECTIVES: To assess brain metabolic abnormalities in patients with familial amyloid polyneuropathy (FAP) due to the transthyretin (TTR) gene mutations. BACKGROUND: The TTR-FAP has variable phenotypic expression, which includes abnormalities of the central nervous system (CNS). Several conventional MRI studies have shown brain abnormalities, probably secondary to amyloid accumulation in leptomeningeal and subarachnoid vessels. However, TTR-related amyloid deposits do not seem to significantly affect the brain parenchyma and a prominent CNS impairment is considered to be rare in TTR amyloidosis. METHODS: We performed proton MR spectroscopic imaging (1H-MRSI) in the central brain of four unrelated TTR-FAP patients with either minimal or no signs of neurological involvement and eight age- and sex-matched normal controls (NC). Metabolic changes were assessed in the entire volume of interest (VOI) and in the frontal, periventricular and posterior white matter (WM). RESULTS: Conventional MRI was normal in 2 patients and showed minimal WM lesions in the remaining 2 patients. 1H-MRSI showed N-acetylaspartate to creatine ratio (NAA/Cr) decreases in the central brain VOI in all TTR-FAP patients (p < 0.005). These NAA/Cr decreases were homogeneous in all WM regions (p < 0.05 for all). CONCLUSIONS: 1H-MRSI findings suggest that diffuse metabolic changes, probably related to axonal damage, are present in brains of TTR-FAP patients even when they have no or minimal clinical and MRI signs of CNS involvement. The mechanism leading to sub-clinical metabolic brain changes needs to be identified.

Magnetic resonance spectroscopy as a measure of brain damage in multiple sclerosis.

Recent MR studies have emphasised the importance of neuronal and axonal damage in multiple sclerosis. In this respect, proton MR spectroscopy (by monitoring levels of N-acetylaspartate, a putative marker of axonal integrity) has been particularly illuminating by showing indirect evidence of neurodegeneration in both lesional and non-lesional brain tissues from the earliest stages of the disease. The importance of these changes to patients' clinical disability argues for the primary role of neuronal pathology in the pathogenesis of the disease.

MR evidence of structural and metabolic changes in brains of patients with Werner's syndrome.

OBJECTIVE: To assess CNS abnormalities in patients with Werner's syndrome (WS) using MR metrics specific for tissue damage. BACKGROUND: WS is a rare autosomal recessive disorder that causes premature aging. The CNS involvement in this disease is still debated. METHODS: Two siblings who showed signs of neurological involvement underwent MR spectroscopic imaging (MRSI) and magnetization transfer (MT) imaging. Also, on conventional T1-weighted MR images, measurements of total brain volume were performed. RESULTS: Conventional MR images of both WS patients did not show abnormalities on visual inspection. However, both WS patients showed significantly lower values of normalized total brain volume and MT ratio in the white matter than age-matched normal controls. Also, proton MRSI showed significantly lower values of central brain NAA/Cr in WS patients than in normal controls. CONCLUSIONS: Our findings suggest that, despite normal appearance on conventional MRI, diffuse structural and metabolic tissue damage can be demonstrated in WS brains by means of sensitive MR methods even in patients with moderate or subclinical CNS involvement.

Voxel-wise assessment of progression of regional brain atrophy in relapsing-remitting multiple sclerosis.

OBJECTIVE: To perform voxel-wise assessments of regional brain atrophy state and rate in subjects with relapsing-remitting (RR) multiple sclerosis (MS). BACKGROUND: Recently, attention has focused on defining the tissue compartments and regions within which brain atrophy occurs. These regional measures of brain volume changes may help to better define the nature of the pathology underlying MS. In this context, specific regional measures of grey matter (GM) volume changes can be obtained by using the voxel-based morphometry (VBM) approach. METHODS: Fifty-nine subjects with RR MS underwent conventional MRI at baseline and after a mean follow-up period of 3 years. Cross-sectionally, two VBM analyses (SPM-VBM, based on the Statistical Parametric Mapping software package, and FSL-VBM, based on the FMRIB Software Library tools) were performed to assess cortical GM volumes in RR MS patients compared to 25 age- and sex-matched normal controls (NC). Longitudinally, FSL-VBM and the regional extension of the SIENA method (SIENAr) were both used to assess regional brain atrophy rate in the RR MS patients and its relationship with increases in T(2)-weighted white matter (WM) lesion volume over the follow-up period. RESULTS: Widespread decrease in cortical GM volume was found in the RR MS patients compared to NC. Both SPM-VBM and FSL-VBM showed similar involvement of cortical regions (frontal, temporal, parietal, occipital lobes and insula), with a close correlation between the numbers of significant voxels obtained with the two different procedures (r=0.73, p<0.001). After 3-year follow-up, both FSL-VBM and SIENAr showed a further significant reduction in GM volume in the lateral frontal and parietal cortices, bilaterally. Regional volume changes also appeared significantly pronounced in correspondence to the increase in T(2)-weighted WM lesion volume over the follow-up period. CONCLUSIONS: By using different methodologies, we showed similar widespread tissue loss in the cerebral cortex of patients with RR MS. This brain tissue loss further progresses over time, particularly in the fronto-parietal cortex and seems to be partially dependent upon the increase of lesion load.

Imaging brain damage in first-degree relatives of sporadic and familial multiple sclerosis.

OBJECTIVE: Our objective was to assess brain damage in first-degree relatives of patients with sporadic and familial multiple sclerosis (MS). METHODS: Asymptomatic first-degree relatives of sporadic (sMS, n = 152) and familial MS (fMS, n = 88) and healthy volunteers (NC, n = 56) underwent brain MRI and magnetization transfer (MT) imaging on a mobile MR scan. On MR examinations, we visually assessed white matter (WM) lesions and quantified WM lesion volumes, brain volumes, and MT ratio (MTr) in lesions and normal-appearing WM (NAWM). RESULTS: A lesional MR pattern similar to that of MS patients was found in 4% sMS and 10% fMS. In these WM lesions, MTr was lower (p < 0.0001) than in the WM of NC. In contrast, there was no difference in NAWM-MTr and brain volume values between the three groups. INTERPRETATION: Focal brain abnormalities indistinguishable from those of MS occur in asymptomatic first-degree relatives of MS patients. These are twice more frequent in fMS than in sMS but do not lead to the widespread tissue damage commonly found in MS patients. Although there is a genetic susceptibility to develop brain abnormalities suggestive of focal demyelination in first-degree relatives of MS patients, other factors are probably critical for the development of a diffuse, clinically relevant, pathology.