Association of asymptomatic spinal cord lesions and atrophy with disability 5 years after a clinically isolated syndrome.

BACKGROUND: Spinal cord pathology is an important substrate for long-term disability in multiple sclerosis (MS). OBJECTIVE: To investigate longitudinal changes in spinal cord lesions and atrophy in patients with a non-spinal clinically isolated syndrome (CIS), and how they relate to the development of disability. METHODS: In all, 131 patients with a non-spinal CIS had brain and spinal cord imaging at the time of CIS and approximately 5 years later (median: 5.2 years, range: 3.0-7.9 years). Brain magnetic resonance imaging (MRI) measures consisted of T2-hyperintense and T1-hypointense lesion loads plus brain atrophy. Spinal cord MRI measures consisted of lesion number and the upper cervical cord cross-sectional area (UCCA). Disability was measured using the Expanded Disability Status Scale (EDSS). Multiple linear regression was used to identify independent predictors of disability after 5 years. RESULTS: During follow-up, 93 (71%) patients were diagnosed with MS. Baseline spinal cord lesion number, change in cord lesion number and change in UCCA were independently associated with EDSS ( R2 = 0.53) at follow-up. Including brain T2 lesion load and brain atrophy only modestly increased the predictive power of the model ( R2 = 0.64). CONCLUSION: Asymptomatic spinal cord lesions and spinal cord atrophy contribute to the development of MS-related disability over the first 5 years after a non-spinal CIS.

A pilot MRI study of white and grey matter involvement by multiple sclerosis spinal cord lesions.

OBJECTIVES: Spinal cord pathology is a major cause of disability in multiple sclerosis (MS) and pathology studies show multifocal demyelinating lesions in white matter (WM) tracts and central grey matter (GM). Better localisation of cord lesions by in vivo MRI may help to understand the structural-functional effects of spinal cord pathology in MS. METHODS: Three-Tesla MRI was performed on upper cervical cord in 15 MS patients and one clinically isolated syndrome. Axial 3D gradient-echo fast field echo (3D-FFE) and phase sensitive inversion recovery sequences (3D-PSIR) were acquired. Two readers reviewed images to detect and classify lesions: WM-only, mixed WM-GM or GM-only. Location of the WM component was classified: anterior (AC), lateral (LC) or posterior (PC) column. RESULTS: Fifty one lesions were identified: 32 (63%) mixed WM-GM, 19 (37%) WM-only, no GM-only. Most were in LC (n=30, 59%), followed by PC (n=18, 35%) and AC (n=3, 6%). Mean lesion areas: AC 4.3mm(2), LC 8.5mm(2), PC 11.3mm(2), corresponding to 6.1%, 12% and 16.1% of mean cord area, respectively. Mean lesion lengths: 18.3mm in AC, LC 17.6mm and PC 24.8mm. CONCLUSIONS: While there was good depiction of WM tract involvement by cord lesions, involvement of central grey matter was not as clear. Noting the important effects of spinal cord pathology in MS, further work to better depict cord lesions by in vivo imaging is warranted.

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.

Early MRI in optic neuritis: the risk for clinically definite multiple sclerosis.

MRI brain lesions at presentation with optic neuritis (ON) increase the risk for developing clinically definite (CD) multiple sclerosis (MS). More detailed early MRI findings may improve prediction of conversion. The objectives of this study were to investigate the influence of number, location and activity of lesions at presentation, new lesions at early follow-up and non-lesion MRI measures on conversion from optic neuritis (ON) to CDMS. 142/143 ON patients, prospectively recruited into a serial MRI and clinical follow-up study, were followed-up at least once. Cox regression analysis determined independent early MRI predictors of time to CDMS from: (i) baseline lesion number, location and activity measures, (ii) three-month lesion activity measures and (iii) brain atrophy, magnetization transfer ratio and spectroscopy measures. 114/142 (80%) had abnormal baseline brain or cord MRI. 57 (40%) developed CDMS (median of 16 months from clinically isolated syndrome onset). Median follow-up of the non-converters was 62 months. Multivariate analysis of baseline parameters revealed gender, periventricular and gadolinium-enhancing lesions as independent predictors of CDMS. Considering both scans together, gender, baseline periventricular and new T2 lesions at follow-up remained significant (hazard ratios 2.1, 2.4 and 4.9, respectively). No non-conventional measure predicted CDMS. It was concluded that new T2 lesions on an early follow-up scan were the strongest independent predictor of CDMS.

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.

Early MRI in optic neuritis: the risk for disability.

BACKGROUND: MRI findings influence the risk of patients with optic neuritis (ON) developing clinically definite (CD) multiple sclerosis (MS) but their influence on future disability is less clear. OBJECTIVE: To investigate in patients with ON the influence of lesion number, location and activity, and non-lesion MRI measures obtained on early scans on disability. METHODS: A total of 106 of 143 prospectively recruited patients with ON had reached a scheduled 5-year follow-up, of whom 100 were evaluated clinically. Lesion number, location, and activity measures were analyzed at baseline (within 3 months of onset) and lesion activity measures were studied at 3-month follow-up. Brain atrophy, magnetization transfer ratio, and spectroscopy measures were also analyzed. Ordinal logistic regression assessed the association between early MRI findings and subsequent disability. RESULTS: At median 6 years follow-up, 48% had converted to CDMS and 52% remained with clinically isolated syndrome (median Expanded Disability Status Scale 2 and 1). In the final models, both the presence and the number of spinal cord lesions at baseline (odds ratios [OR] 3.30, 1.94) and new T2 lesions at follow-up (OR 7.12, 2.06) were significant independent predictors of higher disability. Disability was also predicted by the presence at baseline of gadolinium-enhancing lesions (OR 2.78) and number of infratentorial lesions (OR 1.82). Only spinal cord lesions predicted disability in patients converting to CDMS. CONCLUSION: Spinal cord, infratentorial, and gadolinium lesions within 3 months of optic neuritis onset and new T2 lesions after 3 months predicted disability after 6 years; only spinal cord lesions were predictive of disability in those developing clinically definite 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.

Is the frequency of abnormalities on magnetic resonance imaging in isolated optic neuritis related to the prevalence of multiple sclerosis? A global comparison.

The link between optic neuritis and multiple sclerosis is well established, as is the increased risk of conversion to multiple sclerosis, with lesions seen at presentation on the magnetic resonance imaging (MRI) scan of the brain. One or more asymptomatic lesions were present in 77% of the optic neuritis cohort from London, UK, a higher proportion than that reported in other large cohorts studied elsewhere, where generally lower prevalence rates for multiple sclerosis are also reported. These observations may support the hypothesis that optic neuritis is more likely to be associated with abnormalities on MRI and to be due to multiple sclerosis in geographical regions where multiple sclerosis is more common.

Ventricular enlargement in MS: one-year change at various stages of disease.

OBJECTIVES: To investigate ventricular enlargement (VE) over 1 year at three different stages of multiple sclerosis (MS). METHODS: A semi-automated technique for measuring VE was applied to MRI scans in 26 patients with clinically isolated syndromes (CIS) suggestive of MS, 30 with early relapse-onset MS of 1 year duration, 41 with established relapsing remitting (RR) MS, and 23 with secondary progressive (SP) MS. RESULTS: VE at 1 year was seen in early MS (median increase 0.3 mL [p = 0.003]), RRMS (median increase 0.5 mL [p = 0.001]), and SPMS (median increase 1.1 mL [p = 0.001]). Allowing for age there was more VE in the SPMS group (p = 0.005). No VE was observed in the CIS only group (median decrease -0.001 mL [p = 0.829]). Significant increases in T2 and T1 hypointense lesion load volume were seen in all MS subgroups: there were no differences between the groups in T2 volume increase but there was a larger increase in T1 hypointense lesion volume in the SPMS group compared with early RRMS. CONCLUSIONS: Ventricular enlargement is a sensitive measure of progressive cerebral atrophy that is seen at all stages of multiple sclerosis (MS) and is more marked in secondary progressive than relapsing remitting MS.

Modification of MRI criteria for multiple sclerosis in patients with clinically isolated syndromes.

BACKGROUND: The McDonald criteria include MRI evidence for dissemination in space and dissemination in time for the diagnosis of multiple sclerosis in young adult patients who present with clinically isolated syndromes (CIS) typical of the disease. Although a major advance, the criteria have limited sensitivity for making an early diagnosis. OBJECTIVE: To compare the performance of McDonald criteria and modified McDonald criteria for dissemination in space and time for assessing the development of clinically definite multiple sclerosis. METHODS: McDonald criteria were modified using the combination of a less stringent definition for dissemination in space and allowing a new T2 lesion per se after three months as evidence for dissemination in time. Modified and McDonald criteria were applied in 90 CIS patients at baseline and at three month follow up scans. RESULTS: Both criteria were highly specific (>90%) but the modified criteria were more sensitive (77% v 46%) and more accurate (86% v 73%). CONCLUSIONS: These modified criteria should be evaluated in other CIS cohorts.

Magnetization transfer histograms in clinically isolated syndromes suggestive of multiple sclerosis.

In established multiple sclerosis, magnetization transfer ratio (MTR) histograms reveal abnormalities of normal-appearing white matter (NAWM) and grey matter (NAGM). The aim of this study was to investigate for such abnormalities in a large cohort of patients presenting with clinically isolated syndromes suggestive of multiple sclerosis. Magnetization transfer imaging was performed on 100 patients (67 women, 33 men, median age 32 years) a mean of 19 weeks (SD 3.8, range 12-33 weeks) after symptom onset with a clinically isolated syndrome and in 50 healthy controls (34 women, 16 men, median age 32.5 years). SPM99 software was used to generate segmented NAWM and NAGM MTR maps. The volumes of T2 lesions, white matter and grey matter were calculated. Eighty-one patients were followed up clinically and with conventional MRI after 3 years (n = 61) or until they developed multiple sclerosis if this occurred sooner (n = 20). Multiple regression analysis was used to investigate differences between patients and controls with age, gender and volume measures as covariates to control for potential confounding effects. The MTR histograms for both NAWM and NAGM showed a reduction in the mean (NAWM, 38.14 versus 38.33, P = 0.001; NAGM 32.29 versus 32.50, P = 0.009; units in pu) and peak location, with a left shift in the histogram. Mean NAWM and NAGM MTR were also reduced in the patients who developed clinically definite multiple sclerosis and multiple sclerosis according to the McDonald criteria but not in the 24 patients with normal T2-weighted brain magnetic resonance imaging (MRI). MTR abnormalities occur in the NAWM and NAGM at the earliest clinical stages of multiple sclerosis.

Chronic inflammatory demyelinating polyradiculoneuropathy: MRI study of brain and spinal cord.

CNS demyelinating lesions have been reported in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). There are no studies of cord atrophy in CIDP. Ten patients with CIDP underwent brain and spinal cord MRI to investigate CNS demyelination and cord atrophy. No CNS demyelination was found, but the mean cervical cord area was significantly smaller in CIDP patients vs control subjects. Spinal cord atrophy may be related to degeneration secondary to axonal loss.

The optic nerve sheath on MRI in acute optic neuritis.

Optic nerve sheath dilatation or gadolinium-enhancement on magnetic resonance imaging in acute optic neuritis have been previously reported but have been thought to be rare occurrences. This study recruited 33 patients with acute unilateral optic neuritis. All had their optic nerves imaged with fat-saturated fast spin-echo (FSE) imaging, and 28 had imaging before and after triple-dose gadolinium-enhanced fat-saturated T(1)-weighted imaging. Follow-up imaging was performed on 20 patients (15 following gadolinium). A dilated subarachnoid space at the anterior end of the symptomatic optic nerve on FSE imaging was seen in 15/33 cases. In three of these cases, dilatation was visible on short-term follow-up. Optic nerve sheath enhancement was seen in 21/28 cases acutely: seven at the anterior end of the lesion only, five at the posterior end only and nine at both ends. Optic sheath enhancement was seen in 13 patients on follow-up. This study suggests that optic nerve sheath dilatation on FSE images and optic nerve sheath enhancement on triple-dose gadolinium-enhanced images are common findings in acute optic neuritis. Optic nerve sheath dilatation may be due to inflammation of the optic nerve, with its associated swelling, interrupting the communication between the subarachnoid space of the diseased optic nerve and the chiasmal cistern. Optic nerve sheath enhancement suggests that meningeal inflammation occurs in optic neuritis, in agreement with pathological studies of both optic neuritis and multiple sclerosis.

Clinical correlation of brain MRI and MRS abnormalities in patients with Wilson disease.

BACKGROUND: The progression of Wilson disease (WD), a disorder of copper metabolism, can be arrested by chelation therapy. However, neurologic deficits may persist despite adequate treatment. MRI is used to assess patients with WD, but previous attempts to correlate clinical progression with the investigation findings have often been unsuccessful. OBJECTIVE: To identify MR visible markers that could help stratify disease severity and to clarify the mechanism of persistent neurologic deficit after treatment. METHODS: MRI and proton MR spectroscopy (1H-MRS) were performed in 17 patients with WD. MRI was assessed semiquantitatively and used to locate volumes of interest (voxels) in the striatum for 1H-MRS. RESULTS: MRI showed abnormalities predominantly confined to those patients with neurologic features of WD. The 1H spectra demonstrated a reduction of N-acetylaspartate and N-acetylaspartylglutamate (2.05 mM; p < 0.01) in those patients with neurologic features but not in patients without clinical neurologic involvement (0.42 mM; p > 0.1) in comparison with age-matched normal control subjects. Choline was also reduced in both patient groups (0.08 mM; p < 0.01) compared with age-matched controls. CONCLUSIONS: There may be a biochemical correlate of tissue-specific dysfunction in patients with Wilson disease who develop neurologic features. These changes appear to be present despite prior clinical improvement and may imply a need for additional treatment.

Elevated white matter myo-inositol in clinically isolated syndromes suggestive of multiple sclerosis.

Normal-appearing white matter (NAWM) in established multiple sclerosis has been shown to be abnormal using a variety of magnetic resonance (MR) techniques, including proton MR spectroscopy ((1)H-MRS), although the stage at which these changes first appear is less clear. Using a 1.5 T scanner and single-voxel (1)H-MRS [TR 3000 ms, TE 30 ms, point-resolved spectroscopy (PRESS) localization], we determined NAWM metabolite concentrations in 96 patients a mean of 19 weeks (range 12-28 weeks) after onset of a clinically isolated syndrome (CIS) suggestive of multiple sclerosis and in 44 healthy control subjects. Absolute concentrations of N-acetyl-aspartate, total creatine and phosphocreatine (Cr), choline-containing compounds, glutamate plus glutamine, and myo-inositol (Ins) were estimated automatically using the LCModel. Compared with control subjects, the concentration of Ins was elevated in CIS NAWM (mean 3.31 mM, SD 0.86 versus mean 3.82 mM, SD 1.06; P = 0.001). The increase in Ins was also seen in the patient subgroup with abnormal T2-weighted MRI (mean 3.88 mM, SD 1.10; P = 0.001) and in those who satisfied the McDonald criteria for multiple sclerosis (mean 4.04 mM, SD 1.31; P = 0.001). An increase in Cr was also observed in CIS NAWM (P = 0.023), but other metabolites did not significantly differ between the whole CIS group and control subjects. There was no significant correlation between NAWM Ins and T2 lesion load. The early increase in Ins may reflect a process of pathogenic importance in multiple sclerosis NAWM. Follow-up studies will investigate whether the increase in NAWM Ins is of prognostic importance for future relapses and disability.

Serial magnetization transfer imaging in acute optic neuritis.

In serial studies of multiple sclerosis lesions, reductions in magnetization transfer ratio (MTR) are thought to be due to demyelination and axonal loss, with later rises due to remyelination. This study followed serial changes in MTR in acute optic neuritis in combination with clinical and electrophysiological measurements to determine if the MTR changes over time mirror the picture in multiple sclerosis lesions, further validating MTR as a marker of tissue integrity. Twenty-nine patients were recruited who had acute optic neuritis for a median of 13 days (range 7-24 days) since the onset of visual symptoms. A clinical examination and measurement of visual evoked potentials (VEP) was performed on each patient. Their optic nerves were imaged with a fat-saturated fast spin echo (FSE) sequence and a magnetization transfer sequence. Twenty-one had multiple subsequent examinations over the course of 1 year. In addition, 27 control subjects had their optic nerves imaged up to three times over 1 year. A blinded observer segmented the optic nerves from the MTR maps. Lesions were defined on the acute FSE images and, from the coordinates, the ratio of mean lesion MTR : healthy nerve MTR (lesion ratio) was calculated for each dataset. The time-averaged mean MTR in control optic nerves was 47.7 per cent units (pu). In diseased optic nerves, baseline mean MTR was 47.3 pu, with a mean lesion ratio of 0.98. The diseased optic nerve MTR and lesion ratio declined over time with a nadir at about 240 days at a mean MTR value of 44.2 pu and mean lesion ratio of 0.91. Subsequently, diseased optic nerve MTR appeared to rise; after 1 year the diseased optic nerve mean MTR was 45.1 pu (mean lesion ratio 0.93), although the difference was not significant compared with the nadir value. For each 0.01 increase in time-averaged lesion ratio logMAR visual acuity recovery improved by 0.03 (95% CI, 0.002, 0.08, P = 0.02). Time-averaged VEP central field latency was shorter by 6.1 ms (95% CI 1.5, 10.7, P = 0.012) per 1 pu rise in time-averaged diseased optic nerve MTR. The early fall in diseased optic nerve MTR is consistent with demyelination and Wallerian degeneration of transected axons. The late nadir compared with studies of multiple sclerosis lesions may have been due to slow clearance of myelin debris. Remyelination may have influenced subsequent MTR changes. The observations support using MTR to monitor symptomatic demyelinating lesions.

Spinal cord MRI in clinically isolated optic neuritis.

BACKGROUND/METHODS: One hundred and fifteen patients with clinically isolated optic neuritis underwent magnetic resonance imaging (MRI) of the brain and spinal cord within 3 months of the onset of symptoms. RESULTS: Eighty one (70%) patients had brain lesions and 31 (27%) had cord lesions. Cord lesions were seen in 12% with a normal brain MRI, 21% with between one and eight brain lesions, and 45% with nine or more brain lesions. When the new diagnostic criteria for MS were applied, MRI cord imaging used for evidence of dissemination in time and space allowed a diagnosis of MS in only one additional asymptomatic patient at 1 year, two additional asymptomatic patients at 3 years. CONCLUSIONS: Using existing criteria, spinal cord imaging rarely contributes to the diagnosis in patients with clinically isolated optic neuritis.

Progressive ventricular enlargement in patients with clinically isolated syndromes is associated with the early development of multiple sclerosis.

BACKGROUND: In patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS), the extent of brain magnetic resonance imaging (MRI) lesion load influences the probability and time to development of clinically definite MS. Cerebral atrophy is recognised in established MS, but its time of onset and whether, in early disease, it is related to MRI lesion load or clinical outcome is less certain. OBJECTIVES: This study investigated ventricular enlargement over one year in CIS patients and explored its relation with lesion load and clinical outcome. METHODS: A semi-automated thresholding technique for measuring ventricular volume (MIDAS) was applied to MRI scans in a cohort of 55 patients with CIS, recruited consecutively and imaged within three months of the onset of symptoms and again after one year. RESULTS: Clinical MS had developed after one year in 16 of 40 patients with an abnormal baseline T2 scan and 2 of 15 with a normal scan. Significant ventricular enlargement was seen in 27 of 55 patients who fulfilled the new McDonald MRI criteria for MS using all available MRI at clinical follow up (median increase 0.3 cm(3), p=0.005) Significant increase in ventricular volume was also seen in the 18 of 55 patients who developed clinical MS over the follow up period (median increase 0.5 cm(3), p=0.006). There were significant but modest correlations between baseline lesion measures and subsequent ventricular enlargement. CONCLUSIONS: (1) Lesions and atrophy are both associated with early relapse leading to a diagnosis of clinical MS; (2) while lesions contribute to the development of atrophy, atrophy may also develop by other mechanisms. This suggests that MR measures have a complementary role in monitoring the course of MS, even from the earliest clinical stage.

Measurement of spinal cord area in clinically isolated syndromes suggestive of multiple sclerosis.

Atrophy of the spinal cord is known to occur in multiple sclerosis but the cause and the timing of its onset are not clear. Recent evidence suggests that atrophy may start to occur early in the disease. The aim was to determine whether atrophy of the spinal cord could be detected in vivo using MRI techniques, in patients presenting with a clinically isolated syndrome, which in many cases is the earliest clinical stage of multiple sclerosis. The cross sectional area of the spinal cord was measured in 43 patients presenting with a clinically isolated syndrome and 15 matched controls. T2 weighted imaging of the brain was also performed to determine the number and volume of high signal lesions consistent with disseminated demyelination. Both patients and controls were restudied after 1 year. The spinal cord area was significantly smaller in the 74% of patients with an abnormal brain MRI at presentation than in controls (mean areas 73.9 mm(2) and 78.1 mm(2) respectively, p=0.03). No significant difference was found in the spinal cord area between controls and patients with normal baseline brain imaging. The annual rate of change in patients did not differ significantly from controls. In conclusion, the finding of a smaller cord area in the subgroup of patients with clinically isolated syndrome with the highest risk of developing multiple sclerosis-that is, with an abnormal brain MRI, suggests that atrophy has developed in some patients with multiple sclerosis even before their first clinical symptoms. However, the lack of a detectable change in cord area over 1 year of follow up contrasts strikingly with the results of an earlier study of patients with relapsing-remitting multiple sclerosis, suggesting that the rate of atrophy increases as the disease becomes more established.

Assessing the risk of early multiple sclerosis in patients with clinically isolated syndromes: the role of a follow up MRI.

OBJECTIVES: With increasing evidence that permanent tissue damage occurs early in the course of multiple sclerosis, it is important that treatment trials include patients in the earliest stages of the disease. For many patients with multiple sclerosis the first presentation is a clinically isolated syndrome. Not all patients with a clinically isolated syndrome develop multiple sclerosis, however, and treatment of all such patients would be unwarranted. A single abnormal brain MRI identifies patients at a higher risk for the early development of multiple sclerosis, but current criteria are limited by either poor specificity (T2 lesions) or sensitivity (contrast enhancing lesions). The aim of the study was to assess the positive predictive value, sensitivity, and specificity of MRI indices for the development of multiple sclerosis after 1 year from two MRI examinations obtained 3 months apart. METHODS: MRI examinations were performed in 68 patients with a clinically isolated syndrome, with a clinical assessment after 1 year. RESULTS: Contrast enhancing lesions at both time points were the most predictive indices for developing multiple sclerosis (positive predictive value 70%) but had low sensitivity (39%). The combination of T2 lesions at baseline with new T2 lesions at follow up had the best overall positive predictive value (53%), sensitivity (83%), and specificity (76%). In patients with T2 lesions at baseline, the presence or absence of new T2 lesions at follow up significantly altered the risk of multiple sclerosis within 1 year (55% and 5% respectively, p<0.001). Multiple sclerosis also developed in 10% of patients with a normal baseline MRI. CONCLUSIONS: Serial imaging in patients with clinically isolated syndromes improved the positive predictive value, sensitivity, and specificity of MRI for the development of early multiple sclerosis and also identified patients at a lower risk of early multiple sclerosis than would have been expected from their abnormal baseline MRI. Selection of patients with clinically isolated syndromes for therapeutic intervention or clinical trials may benefit from serial MRI, to target those at greatest risk of early development of multiple sclerosis.