Falini A, Calabrese G, Filippi M, Origgi D, Lipari S, Colombo B, Comi G, Scotti G
AJNR Am J NeuroRadiol 1998 Feb;19(2):223-9
Univ of Milan, Scientific Institute San Raffaele Hospital, Dept of NeuroRadiology, Italy
PMID# 9504469; UI# 98162997
We determined the clinical utility of Proton MR Spectroscopy in defining the extent of disability in Benign versus Secondary/Progressive Multiple Sclerosis (MS).
Thirty patients with Clinically Definite MS, including 16 patients with Benign MS and 14 with Secondary/Progressive MS, and a group of 13 healthy volunteers were studied with combined stimulated-echo acquisition mode proton MR Spectroscopy and MR imaging (all patients received contrast material).
Acute enhancing lesions of Benign and Secondary/Progressive MS were characterized by a reduction in N-AcetylAspartate (NAA)/Choline and NAA/Creatine and an increase in Inositol compounds/Creatine as compared with Normal White Matter.
Such variations were also detected in chronic unenhancing lesions in patients with Secondary/Progressive MS, although they were not found in chronic unenhancing lesions in patients with Benign MS. Chronic lesions of the two forms of the disease have significative differences in NAA and Inositol signals.
Proton MR Spectroscopy is able to show metabolic changes occurring in the White Matter of patients with MS. Such changes differ according to the phase (acute versus chronic) and the clinical form (Benign versus Secondary/Progressive) of the disease.
Filippi M, Barker GJ, Horsfield MA, Sacares PR, MacManus DG, Thompson AJ, Tofts PS, McDonald WI, Miller DH
J Neurol 1994 Feb;241(4):246-51
Institute of Neurology, Queen Square, London, UK
PMID# 8195825; UI# 94253858
In a preliminary study, we compared by means of quantitative Magnetic Resonance Imaging (MRI) methods:
- The T2 values and the decay characteristics of chronic Brain lesions
- The T2 values of Normal-Appearing Frontal White Matter (NAWM)
- The Brain lesion volumes in patients with Benign and Secondary/Progressive Multiple Sclerosis (MS)
To evaluate the mechanisms underlying the development of Disability, eleven Clinically Definite MS patients were studied:
Fifty-two chronic lesions (identified by comparison with MRI scans obtained at least 12 months previously) were identified.
The mean T2 of large lesions (cross-sectional area greater than 41 mm2) and of the NAWM was similar in both clinical groups. However, small lesions had higher mean T2 values (P < 0.01) in the Benign group, probably at least in part because of partial volume effects.
Analysis of large lesions revealed BiExponential T2 Relaxation in 6 of 8 "Secondary/Progressive" and in 2 of 16 "Benign" lesions, perhaps indicating a greater degree of Axonal Loss in large lesions of patients with Secondary/Progressive MS.
Patients with Secondary/Progressive MS had higher (although not significant) total and InfraTentorial lesion loads than those of the Benign group.
These preliminary findings suggest, but do not establish, that variations in the extent, site and pathological nature of lesions may all contribute to different patterns of disease evolution in MS.
Filippi M, Campi A, Martinelli V, Colombo B, Scotti G, Comi G
J Neurol Sci 1996 Nov;143(1-2):143-9
Univ of Milan, Dept of Neurology, Scientific Institute, Ospedale San Raffaele, Italy
PMID# 8981313; UI# 97135776
We performed a clinical and Magnetic Resonance (MR) longitudinal study in 19 patients with Benign Multiple Sclerosis (MS) to achieve a better definition of the nature of disability in MS.
Patients with higher lesion volumes on conventional T2-weighted images at entry were those with more frequent relapses (p = 0.0004) and more new MR lesions (p = 0.003) during the follow up. However, 1/3 of these new lesions were located PeriVentricularly and about 2/3 were small or intermediate in size.
Two of the 11 patients (18%) with higher lesion volumes at entry developed progressive Neurological deficits: in these two patients the new lesions seen on conventional T2 images, had lower Magnetization Transfer Ratios (p = 0.005) than those present in patients who remained clinically stable and a marked increase in HypoIntense lesion volumes on T1-weighted images was also found.
Spinal Cord cross-sectional area at C5 and MTR values for the Seemingly Normal White Matter were similar to those found in normal controls.
This study suggests that patients with Benign MS have two different patterns of disease evolution, one characterized by very low clinical and MR activities, the other in which the lack of disabling symptomatology might be related to factors like site, size and nature of lesions.
It also indicates that in patients with Benign MS and high MR lesion loads, the risk of developing a Secondary/Progressive form of the disease is still present even after many years after onset.
Flachenecker P, Hartung HP
Nervenarzt 1996 Jun;67(6):435-43
Klinische Forschungsgruppe fur Multiple Sklerose und NeuroImmunologie, Neurologische Klinik und Poliklinik, Julius-Maximilians-Universitat, Wurzburg
PMID# 8767197; UI# 96302735
This review summarizes the natural history of Multiple Sclerosis (MS) in terms of disease type, survival, relapse rate and recovery as well as disability.
The course of MS is highly variable and individually difficult to predict. In Epidemiological studies, the most common type of MS is the Relapsing/Remitting form.
However, after 10-15 years of disease duration, 30-40% of patients will develop Chronic/Progressive MS.
Survival of all MS patients is only mildly affected, but markedly decreased in severely disabled patients mainly due to secondary complications. Suicide is more frequent in MS patients than in normals, especially within the first 5 years of the disease.
The mean relapse rate ranges from approximately 0.5 to 0.8 relapses per year and decreases with time. Most patients will recover from relapses within 4 weeks. 50% of patients will require some form of walking aid within 15-18 years from onset.
20-40% of patients have, *Benign* MS, i.e. no or only mild Disability after 10 years of MS.
Optic Neuritis As The First Sign Of Multiple Sclerosis
Szilasiova J, Klimova E, Vesela D
Cesk Slov Oftalmol 2002 Jul;58(4):259-64
Neurologicka klinika, LF UPJS a FNsP, Kosice
Optic Neuritis (ON) is as the initial manifestation of Multiple Sclerosis (MS) a favorable prognostic factor during the subsequent course.
To assess the ratio of ON at the onset of MS in the authors patients and to assess according to clinical criteria the form of disease and degree of functional inability, expressed by Kurtzke s EDSS scale.
Patients And Methods
In a retrospective analysis of patients with clinically defined and Probable MS (Poser's Criteria) hospitalized at the Neurological clinic in 1987-2000 the authors investigated the incidence of ON in relation to the course and form of MS.
In individual patients they evaluated the age at the onset of the first manifestations of MS, the form, duration and degree of functional inability in EDSS.
These findings were compared in groups of patients with incipient ON and without ON at the onset of MS (non-ON).
ON as an isolated initial symptom of MS was present in 29 (18.2%) of the total number of 159 patients.
The mean age at the time of the initial ON was 27.9 years, which is as compared with the non-ON group of MS patients by 2.8 years or less.
Patients with isolated ON at the onset had the resulting general affection by 2 grades EDSS lower than the non-ON and it was recorded in 73% cases with a Relapsing/Remitting course of MS.
The Secondary/Progressive form of the disease accounted for 27% and the Primary/Progressive form was not found.
ON as the initial manifestation of MS is a favorable prognostic factor during the subsequent clinical course of the disease.
A Clinical Longitudinal Study Of Multiple Sclerosis In Cantabria, Spain
Moris G, Berciano J, Miro J
Neurologia 2003 Dec;18(10):723-30
Univeesity Hospital Marques de Valdecilla University of Cantabria, Service of Neurology, Santander, Spain
There are many studies that analyze the clinical course of Multiple Sclerosis (MS), but only a few of them observed patients from their first episode.
We report a MS series of patients longitudinally evaluated from the onset of the disease and compare outcome between ImmunoSuppressive treatment and non-treatment groups.
Patients And Methods
Patients were included when their follow-up was at least three years and serial examination was available. Poser's Criteria were used for diagnosis.
We measured Neurological Impairment according to Kurtzke's Expanded Disability Status Scale (EDSS).
Fifty-five MS patients were followed-up. Forty-six had Clinically Defined and nine Clinically Probable MS.
Thirty-three patients had Relapsing/Remitting, 11 had Secondary/Progressive and 11 had Primary/Progressive MS. Mean age of onset of the disease was 31.1 years and mean duration of follow-up was seven years.
Pyramidal Weakness, and Sensory symptoms were the most common initial manifestations. Median time to reach EDSS-3 and EDSS-6 from onset was 4.5 and 7.5 years, respectively.
From a total of 23 patients with follow-up of 10 or more years, 11 (48 %) had Benign MS. The average time from onset of MS to Secondary/Progressive was 6.1 years. There were no significant differences between treatment and non-treatment patients.
Longitudinal studies starting from early clinical course of MS are most useful in determining its semeiology, clinical pattern and outcome. Our results call for caution in initiating early ImmunoSuppressive or ImmunoModulatory therapy.
The Topographical Distribution Of Tissue Injury In Benign MS: A 3T MultiParametric MRI Study
Ceccarelli A, Rocca MA, Pagani E, Ghezzi A, Capra R, Falini A, Scotti G, Comi G, Filippi M
NeuroImage 2008 Feb 15;39(4):1499-509
Scientific Institute and University Ospedale San Raffaele, NeuroImaging Research Unit, Milan, Italy
We compared the global and regional distribution of White Matter (WM) and Gray Matter (GM) damage and T2-visible lesion between patients with Benign (B) and Relapsing/Remitting (RR) Multiple Sclerosis (MS).
BMS and RRMS patients did not differ in terms of global volumes and Diffusion Tensor (DT) MRI metrics of the WM and GM.
Compared to controls, BMS and RRMS patients had Bilateral Thalamic loss.
Compared to controls, BMS and RRMS patients had lower WM Fractional Anisotropy (FA) in the Corpus Callosum (CC) and in several regions of Temporal and Occipital Lobes.
BMS also had a decreased WM FA in the Parietal Lobes. RRMS patients had also lower WM FA in several regions of the Frontal Lobes.
Compared to BMS, RRMS patients had decreased WM FA in the Frontal Lobes, while the opposite comparison showed lower WM FA in the CC, the Temporal Lobes and the Cuneus in BMS.
Contrasted to controls, both MS groups showed several regions of increased MD in WM and GM, but no difference was found between MS sub-groups.
T2-visible lesions were mainly located in the posterior regions of the Brain in BMS patients, while they involved also regions in the Frontal Lobes, in RRMS patients.
BMS and RRMS patients differ in terms of the topographical distribution of WM damage rather than in the overall extent of Brain structural changes.
The less prominent involvement of the Frontal Lobe WM and of the NAWM in general in BMS might be associated to their favorable clinical status.
Predictive Value Of Clinical Characteristics For 'Benign' Multiple Sclerosis
Ramsaransing GS, De Keyser J
Eur J Neurol 2007 Aug;14(8):885-9
University Medical Center Groningen, University of Groningen, Department of Neurology, Groningen, The Netherlands
We studied a cohort of 496 patients who had Multiple Sclerosis (MS) for at least 10 years. Ten years after disease onset.
151 had Benign defined as an Extended Disability Status Scale (EDSS) < or =3. Between Benign and Non-Benign patients we compared:
gender, age at clinical onset, Relapsing-/Remitting or Primary/Progressive, symptoms at onset, recovery from first relapse, time between first and second relapse, number of relapses in the first 5 years, use of ImmunoModulatory Drugs, and EDSS scores at 2, 5 and 10 years.
A multivariate regression analysis showed that a Relapsing/Remitting course, a low EDSS score at 5 years, and a low number of relapses in the first 5 years were predictive for Benign MS at 10 years.
Other factors had no additional value.
Thirty-five of the 51 patients (69%) with Benign MS at 10 years were still Benign at 20 years. A low 10-year EDSS score was the only clinical variable associated with a Benign course at 20 years.
Our results suggest that within the first 5 years from onset it is not possible to predict a Benign course. Disease course, EDSS score and relapse rate at 5 years are predictors for Benign at 10 years.
A Magnetic Resonance Imaging Voxel-Based Morphometry Study Of Regional Gray Matter Atrophy In Patients With Benign Multiple Sclerosis
Mesaros S, Rovaris M, Pagani E, Pulizzi A, Caputo D, Ghezzi A, Bertolotto A, Capra R, Falautano M, Martinelli V, Comi G, Filippi M
Arch Neurol 2008 Sep;65(9):1223-30
Scientific Institute and University Ospedale San Raffaele, NeuroImaging Research Unit, via Olgettina 60, 20132 Milan, Italy
Evidence is accumulating that indicates that a selected assessment of Gray Matter (GM) damage is able to provide strong paraclinical correlates of Multiple Sclerosis (MS) severity.
To investigate the pattern of Regional GM Atrophy in patients with Benign MS (BMS) vs those with Secondary/Progressive MS (SPMS) to better elucidate the factors associated with a favorable status in patients with MS.
Design, Setting & Patients
Cross-sectional survey from January 2006 to August 2007. Referral, hospital-based MS clinics. Sixty patients with BMS, 35 patients with SPMS, and 21 healthy volunteers.
Main Outcome Measures
NeuroPsychological tests exploring Memory, Attention, and Frontal Lobe Cognitive Domains were administered to BMS patients.
A voxel-based morphometry analysis of GM concentration was performed using statistical parametric mapping and a threshold of 0.05, corrected for multiple comparisons.
Twelve BMS patients (20%) had an abnormal performance on 3 or more NeuroPsychological tests.
Compared with healthy individuals, BMS patients had a reduced GM Volume in the SubCortical and FrontoParietal Regions.
Compared with BMS patients, those with SPMS had a significant GM loss in the Cerebellum.
No differences between BMS and SPMS patients were found when only BMS patients with Cognitive Impairment or those with shorter disease duration (15-19 years) and higher Expanded Disability Status Scale scores (> 2.0) were considered.
Cerebellar GM Atrophy seems to be a major determinant of irreversible locomotor disability in MS.
The absence of Cognitive Impairment and a longer disease duration or lower Expanded Disability Status Scale score may identify those BMS patients with the potential for a favorable disease evolution.
Cognitive Impairment And Structural Brain Damage In Benign Multiple Sclerosis
Rovaris M, Riccitelli G, Judica E, Possa F, Caputo D, Ghezzi A, Bertolotto A, Capra R, Falautano M, Mattioli F, Martinelli V, Comi G, Filippi M
Neurology 2008 Sep 24
From the NeuroImaging Research Unit (M.R., G.R., M. Filippi) and Department of Neurology (M.R., E.J., F.P., M. Falautano, V.M., G.C., M. Filippi), Scientific Institute and University Ospedale San Raffaele, Milan; Department of Neurology (D.C.), Scientific Institute Don Gnocchi, Milan; Multiple Sclerosis Center (A.G.), Ospedale di Gallarate, Gallarate; Multiple Sclerosis Center (A.B.), Ospedale di Orbassano, Orbassano; and Multiple Sclerosis Center (R.C., F.M.), Spedali Civili, Brescia, Italy
Although in Benign Multiple Sclerosis (BMS) locomotor disability is absent or only minimal, subclinical Cognitive Impairment seems to occur in many cases.
Diffusion Tensor (DT) MRI enables us to quantify the extent of "actual" tissue damage, which goes undetected when using conventional MRI.
Against this background, we investigated the extent of structural Brain damage underlying Cognitive Dysfunction in BMS, with the ultimate aim to move a first step toward a more reliable definition of this disease phenotype.
Conventional and DT MRI scans of the Brain were acquired from 62 BMS patients. Thirty-six Secondary/Progressive Multiple Sclerosis (SPMS) patients and 19 healthy subjects served as controls.
In BMS patients, NeuroPsychological tests exploring Memory, Attention, and Frontal Lobe functions were administered.
Normalized Brain Volume (NBV), Mean Diffusivity (MD), and Fractional Anisotropy (FA) of the Normal-Appearing White Matter (NAWM) and MD of the Gray Matter (GM) were computed.
Twelve BMS patients (19%) fulfilled predefined criteria for Cognitive Impairment. BMS patients had abnormal MD and FA values from both NAWM and GM.
Whereas BMS patients without Cognitive Impairment had lower T2 LV (p = 0.03), higher NBV (p = 0.006), and lower average GM MD (p = 0.03) than SPMS patients, BMS patients with Cognitive Impairment did not significantly differ from SPMS patients for any MRI-derived metric.
In Benign Multiple Sclerosis (BMS), Cognitive Dysfunction is associated with severe structural Brain damage, which resembles that of patients with a much more disabling disease course.
A reliable definition of BMS should, therefore, include the preservation of Cognitive functioning as an additional requisite.