Brain lesion location and clinical status 20 years after a diagnosis of clinically isolated syndrome suggestive of multiple sclerosis.

BACKGROUND/OBJECTIVES: The objective of this study was to investigate associations between the spatial distribution of brain lesions and clinical outcomes in a cohort of people followed up 20 years after presentation with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). METHODS: Brain lesion probability maps (LPMs) of T1 and T2 lesions were generated from 74 people who underwent magnetic resonance imaging (MRI) and clinical assessment a mean of 19.9 years following a CIS. One-tailed t-test statistics were used to compare LPMs between the following groups: clinically definite (CD) MS and those who remained with CIS, with an abnormal MRI; people with MS and an Expanded Disability Status Scale (EDSS) ≤3 and >3; people with relapsing-remitting (RR) and secondary progressive (SP) MS. The probability of each voxel being lesional was analysed adjusting for age and gender using a multiple linear regression model. RESULTS: People with CDMS were significantly more likely than those with CIS and abnormal scan 20 years after onset to have T1 and T2 lesions in the corona radiata, optic radiation, and splenium of the corpus callosum (periventricularly) and T2 lesions in the right fronto-occipital fasciculus. People with MS EDSS >3, compared with those with EDSS ≤3, were more likely to have optic radiation and left internal capsule T2 lesions. No significant difference in lesion distribution was noted between RRMS and SPMS. CONCLUSION: This work demonstrates that lesion location characteristics are associated with CDMS and disability after long-term follow-up following a CIS. The lack of lesion spatial distribution differences between RRMS and SPMS suggests focal pathology affects similar regions in both subgroups.

MRI only conversion to multiple sclerosis following a clinically isolated syndrome.

OBJECTIVES: Using current diagnostic criteria, patients who present with a clinically isolated syndrome (CIS) may develop multiple sclerosis (MS) by subsequently exhibiting dissemination in space and time on clinical (clinically definite (CD) MS) or radiological (MRI) grounds. This study investigated the frequency of radiological without clinical conversion to MS after long term follow-up as this has not previously been defined. METHODS: Two cohorts who underwent serial clinical and MRI studies from presentation with a CIS and who were followed-up over a mean of 6 and 20 years were investigated. The distribution and formation of lesions visible on brain MRI were assessed using the revised McDonald criteria (2005). Radiologically defined (RD) MS was determined by fulfilment of the MRI but not the CDMS criteria. RESULTS: 105 people were followed-up for 6 years after a CIS, of whom 51% developed CDMS, 15% RDMS and the remainder were classified as still having had a CIS. 70 people were followed-up at 20 years, of whom 61% and 11% had developed CDMS and RDMS, respectively. CONCLUSION: About 10-15% of CIS patients may develop MS on MRI criteria only, without further clinical events for up to two decades.

Hippocampal atrophy in relapsing-remitting and primary progressive MS: a comparative study.

BACKGROUND: In multiple sclerosis (MS), demyelination and neuroaxonal damage are seen in the hippocampus, and MRI has revealed hippocampal atrophy. OBJECTIVES: To investigate and compare hippocampal volume loss in patients with relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) using manual volumetry, and explore its association with memory dysfunction. METHODS: Hippocampi were manually delineated on volumetric MRI of 34 patients with RRMS, 23 patients with PPMS and 18 controls. Patients underwent neuropsychological tests of verbal and visuospatial recall memory. Linear regression was used to compare hippocampal volumes between subject groups, and to assess the association with memory function. RESULTS: Hippocampal volumes were smaller in MS patients compared with controls, and were similar in patients with RRMS and PPMS. The mean decrease in hippocampal volume in MS patients was 317 mm(3) (9.4%; 95% CI 86 to 549; p = 0.008) on the right and 284 mm(3) (8.9%; 95% CI 61 to 508; p = 0.013) on the left. A borderline association of hippocampal volume with memory performance was observed only in patients with PPMS. CONCLUSION: Hippocampal atrophy occurs in patients with RRMS and PPMS. Factors additional to hippocampal atrophy may impact on memory performance.

MRI measures show significant cerebellar gray matter volume loss in multiple sclerosis and are associated with cerebellar dysfunction.

BACKGROUND: Regional atrophy measures may offer useful information about the causes of specific clinical deficits in multiple sclerosis (MS). OBJECTIVE: To determine the magnitude of cerebellar gray and white matter (GM and WM) atrophy in patients with clinically isolated syndromes (CIS) and MS, and their role in clinical manifestations of cerebellar damage. METHODS: T1-weighted volumetric magnetic resonance imaging (MRI) of 73 patients [29 CIS, 33 relapsing-remitting MS (RRMS), 11 secondary progressive MS (SPMS)] was compared with 25 controls. GM and WM regions were generated using SPM5 and cerebellar regions delineated. Linear regression was used to investigate differences in tissue-specific cerebellar volumes between groups and the association with clinical measures. RESULTS: Mean cerebellar GM volume (CGMV) was 100.1 cm(3) in controls, 96.4 cm(3) in CIS patients, 91.8 cm(3) in RRMS patients, and 88.8 cm(3) in SPMS patients. Mean cerebellar WM volumes (CWMV) were 21.3 cm(3), 20.4 cm(3), 19.9 cm(3), and 18.8 cm(3), respectively. CGMV was reduced by 4.8 cm(3) (P = 0.054) in RRMS patients, and 8.5 cm(3) (P = 0.012) in SPMS patients, relative to controls. Only patients with SPMS showed a borderline significant reduction in CWMV compared with controls (mean 2.1 cm(3), P = 0.053). CGMV was significantly smaller in patients assessed as having cerebellar dysfunction compared with patients who had normal cerebellar function. Significant associations of CGMV and CWMV with performance on the nine-hole peg test were also observed. CONCLUSION: Clinically relevant GM atrophy occurs in the cerebellum of MS patients and is more prominent than WM atrophy. As such, it may provide complementary data to other regional atrophy and intrinsic tissue measures.

Magnetization transfer ratio abnormalities reflect clinically relevant grey matter damage in multiple sclerosis.

BACKGROUND: In multiple sclerosis, grey matter (GM) damage appears more clinically relevant than either white matter damage or lesion load. OBJECTIVE: We investigated if normal-appearing white matter (NAWM) and grey matter tissue changes assessed by magnetization transfer ratio were associated with long-term disability. METHODS: Sixty-nine people were assessed 20 years after presentation with a clinically isolated syndrome (CIS) [28 still CIS, 31 relapsing-remitting multiple sclerosis, 10 secondary progressive multiple sclerosis], along with 19 healthy subjects. Mean magnetization transfer ratio, peak height (PH) and peak location of the normalized magnetization transfer ratio histograms were determined in NAWM and grey matter, as well as, white matter and GM Fraction (GMF) and T(2)-weighted lesion load. RESULTS: Median expanded disability status scale for multiple sclerosis patients was 2.5 (range 1-8). GM-PH, and less so, NAWM mean and peak location, were lower in multiple sclerosis patients (P = 0.009) versus controls, relapsing-remitting multiple sclerosis versus CIS (P = 0.008) and secondary progressive multiple sclerosis versus relapsing-remitting multiple sclerosis (P = 0.002). GM-PH (as well as GMF) correlated with expanded disability status scale (r(s) = -0.49; P = 0.001) and multiple sclerosis functional score (r(s) = 0.51; P = 0.001). GM-PH independently predicted disability with similar strength to the associations of GMF with clinical measures. CONCLUSION: Grey matter damage was related to long-term disability in multiple sclerosis cohort with a relatively low median expanded disability status scale. Markers of intrinsic grey matter damage (magnetization transfer ratio) and tissue loss offer clinically relevant information in multiple sclerosis.

Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis.

Clinically isolated syndromes (CIS), such as optic neuritis, brainstem or spinal cord syndromes are frequently the first clinical presentations of multiple sclerosis. However, not all CIS patients develop multiple sclerosis and in those who do, disability is highly variable. In previous follow-up studies, brain lesions on T2-weighted MRI are associated with increased risk of multiple sclerosis and to an extent disability. We evaluated the longitudinal relationships between the MRI lesions and clinical course over a period of 20 years. CIS patients were recruited between 1984 and 1987 and previously followed up after 1, 5, 10 and 14 years. Of the 140 subjects who were initially recruited with a CIS for a baseline MRI study, we followed up 107 patients after a mean of 20.2 years (range 18-27.7). Multiple sclerosis was diagnosed as clinically definite on clinical grounds only and disability determined using the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) score. Clinically definite multiple sclerosis developed in 67 out of 107 (63%) overall: 60 out of 73 (82%) with abnormal and 7 out of 34 (21%) with normal baseline MRI. Multiple sclerosis was still relapsing-remitting in 39 (58%)--including 26 (39%) with a 'benign' course (EDSS < or = 3)--whilst 28 (42%) had developed secondary progression. T2 lesion volume at all time-points correlated moderately with 20-year EDSS (r(s) values 0.48 to 0.67; P < 0.001) and MSFC z-score [r(s) values (-0.50) to (-0.61); P < 0.001]. In those developing multiple sclerosis, a concurrent correlation of change in T2 lesion volume with change in EDSS was most evident in years 0-5 (r(s) = 0.69, P < 0.001). The estimated rate of lesion growth over 20 years was 0.80 cm3/year in those who retained a relapsing remitting multiple sclerosis course, and 2.89 cm3/year in those who developed secondary progressive multiple sclerosis, a difference of 2.09 cm3/year (95% CI: 0.77, 2.96; P < 0.001). This study extends previous follow-up of CIS patients and sheds new light on how the lesions evolve according to the natural history. Baseline MRI findings are predictive for development of clinically definite multiple sclerosis. Lesion volume and its change at earlier time points are correlated with disability after 20 years. Lesion volume increases for at least 20 years in relapse-onset multiple sclerosis and the rate of lesion growth is three times higher in those who develop secondary progressive than in those who remain relapsing remitting multiple sclerosis.