Frederik Barkhof

Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis

BACKGROUNDnReliable prognostic factors are lacking for multiple sclerosis (MS). Gadolinium enhancement in magnetic resonance imaging (MRI) of the brain detects with high sensitivity disturbance of the blood-brain barrier, an early event in the development of inflammatory lesions in MS. To investigate the prognostic value of gadolinium-enhanced MRI, we did a meta-analysis of longitudinal MRI studies.nnnMETHODSnFrom the members of MAGNIMS (European Magnetic Resonance Network in Multiple Sclerosis) and additional centres in the USA, we collected data from five natural-course studies and four placebo groups of clinical trials completed between 1992 and 1995. We included a total of 307 patients, 237 with relapsing disease course and 70 with secondary progressive disease course. We investigated by regression analysis the relation between initial count of gadolinium-enhancing lesions and subsequent worsening of disability or impairment as measured by the expanded disability status scale (EDSS) and relapse rate.nnnFINDINGSnThe relapse rate in the first year was predicted with moderate ability by the mean number of gadolinium-enhancing lesions in monthly scans during the first 6 months (relative risk per five lesions 1.13, p=0.023). The predictive value of the number of gadolinium-enhancing lesions in one baseline scan was less strong. The best predictor for relapse rate was the variation (SD) of lesion counts in the first six monthly scans which allowed an estimate of relapse in the first year (relative risk 1.2, p=0.020) and in the second year (risk ratio=1.59, p=0.010). Neither the initial scan nor monthly scans over six months were predictive of change in the EDSS in the subsequent 12 months or 24 months. The mean of gadolinium-enhancing-lesion counts in the first six monthly scans was weakly predictive of EDSS change after 1 year (odds ratio=1.34, p=0.082) and 2 years (odds ratio=1.65, p=0.049).nnnINTERPRETATIONnAlthough disturbance of the blood-brain barrier as shown by gadolinium enhancement in MRI is a predictor of the occurrence of relapses, it is not a strong predictor of the development of cumulative impairment or disability. This discrepancy supports the idea that variant pathogenetic mechanisms are operative in the occurrence of relapses and in the development of long-term disability in MS.

Diagnostic criteria for primary progressive multiple sclerosis: a position paper.

The unique clinical characteristics of primary progressive multiple sclerosis (PPMS) pose particular diagnostic difficulties, both in excluding other causes of progressive syndromes and in confirming the diagnosis of MS, which is not adequately addressed by current diagnostic criteria. This article presents new diagnostic criteria developed by a group of investigators on the basis of a review of their considerable experience with PPMS. (We conclude that at least 1 year of clinical progression must be documented before a diagnosis of PPMS is made.) Three levels of diagnostic certainty have been defined—definite, probable, and possible—based on clinical findings, abnormal cerebrospinal fluid, abnormalities on magnetic resonance imaging (MRI) of the brain and spinal cord, and evoked potentials. In definite PPMS, evidence of intrathecal synthesis of immunoglobulin G together with one of the following three MRI criteria is required: (1) nine brain lesions, (2) two spinal cord lesions, or (3) four to eight brain lesions and one spinal cord lesion. Preliminary testing of these criteria was carried out on a cohort of 156 patients participating in a European natural history study of PPMS: 64% fulfilled the criteria for definite PPMS, 35% for probable PPMS, and only 1% for possible PPMS. These criteria now require prospective validation in a cohort of newly diagnosed patients and by postmortem examination. Ann Neurol 2000;47:831–835

Spinal-cord MRI in multiple sclerosis

The potential of MRI of the spinal cord as a diagnostic tool in MS has recently gained much interest. Dual echo spin echo MRI is most sensitive for the detection of spinal-cord abnormalities, which range from multiple focal lesions to confluent areas of high signal intensity. In some patients, commonly those with primary progressive disease, diffuse areas of slightly increased signal intensity are found. Disappointingly, the relation between MRI findings and clinical disability is weak. Studies relating MRI findings with histopathology have revealed substantial axonal loss in the spinal cords of patients with MS, whether focal lesions are present of not. Further, diffuse cord atrophy is found in advanced MS, which may reflect axonal loss. In the diagnostic setting, spinal-cord imaging is valuable. First, asymptomatic spinal-cord lesions are very rare in disorders other than MS. For example, in a patient with equivocal brain findings such as an elderly patient with vascular-ischaemic lesions, a normal spinal-cord examination can help rule out MS. Second, presence of asymptomatic spinal lesions may help confirm a diagnosis of MS when few or no brain lesions are present.

Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement

Gadolinium-DTPA (Gd-DTPA) is routinely used as a marker for inflammation in MRI to visualize breakdown of the blood-brain barrier (BBB) in multiple sclerosis. Recent data suggest that ultra-small superparamagnetic particles of iron oxide (USPIO) can be used to visualize cellular infiltration, another aspect of inflammation. This project aimed to compare the novel USPIO particle SHU555C to the longitudinal pattern of Gd-DTPA enhancement in multiple sclerosis. Nineteen relapsing-remitting patients were screened monthly using Gd-enhanced MRI. In case of new enhancing lesions, USPIO were injected and 24 h later, MRI was performed and blood was collected to confirm USPIO loading of circulating monocytes. Lesion development was monitored by 3 monthly Gd-DTPA-enhanced scans and a final scan 7-11 months after injection. USPIO-enhancement was observed as hyperintensity on T1-weighted images, whereas no signal changes were observed on T2-weighted-gradient-echo images. In 14 patients with disease activity, 188 USPIO-positive lesions were seen, 144 of which were Gd-negative. By contrast, there were a total of 59 Gd-positive lesions, 15 of which were USPIO negative. Three patterns of USPIO-enhancement were seen: (i) focal enhancement; (ii) ring-like enhancement and (iii) return to isointensity of a previously hypointense lesion. The latter pattern was most frequently observed for lesions that turned out to be transiently hypointense on follow-up scans, and ring-enhancing lesions were less likely to evolve into black holes at follow-up than lesions without ring-like USPIO-enhancement; we speculate this to be associated with repair. In 4% of the USPIO-positive/Gd negative lesions, USPIO-enhancement preceded Gd-enhancement by 1 month. USPIO-enhancement remained visible for up to 3 months in 1.5% of all USPIO-positive lesions. In 29% of the lesions enhancing with both contrast agents, USPIO-enhancement persisted whereas Gd-enhancement had already resolved. In conclusion, the new nano-particle SHU555C provides complementary information to Gd-enhanced MRI, probably related to monocyte infiltration. The use of USPIO-enhanced MRI is likely to lead to more insight in the pluriformity of inflammation in multiple sclerosis.

Modelling new enhancing MRI lesion counts in multiple sclerosis

Magnetic resonance imaging (MRI) has been established as the most relevant paraclinical tool for diagnosing and monitoring multiple sclerosis (MS). In this context, counting the number of new enhancing lesions on monthly MRI scans is widely used as a surrogate marker of MS activity when evaluating the effect of treatments. In this study, we investigated whether parametric models based on mixed Poisson distributions (the Negative Binomial (NB) and the Poisson-Inverse Gaussian (P-IG) distributions) were able to provide adequate fitting of new enhancing lesion counts in MS. We found that the NB model gave good approximations in relapsing7remitting and secondary progressive MS patients not selected for baseline MRI activity, whereas the P-IG distribution modelled better new enhancing lesion counts in relapsing-remitting MS patients selected for baseline activity. This study shows that parametric modelling for MS new enhancing lesion counts is feasible. This approach should provide more targeted tools for the design and the analysis of MRI monitored clinical trials in MS.

T2 lesion location really matters: a 10-year follow-up study in primary-progressive MS

Objectives Prediction of long term clinical outcome in patients with primary progressive multiple sclerosis (PPMS) using imaging has important clinical implications, but remains challenging. We aimed to determine whether spatial location of T2 and T1 brain lesions predicts clinical progression during a 10-year follow-up in PPMS. Methods Lesion probability maps of the T2 and T1 brain lesions were generated using the baseline scans of 80 patients with PPMS who were clinically assessed at baseline and then after 1, 2, 5 and 10u2005years. For each patient, the time (in years) taken before bilateral support was required to walk (time to event (TTE)) was used as a measure of progression rate. The probability of each voxel being ‘lesional’ was correlated with TTE, adjusting for age, gender, disease duration, centre and spinal cord cross sectional area, using a multiple linear regression model. To identify the best, independent predictor of progression, a Cox regression model was used. Results A significant correlation between a shorter TTE and a higher probability of a voxel being lesional on T2 scans was found in the bilateral corticospinal tract and superior longitudinal fasciculus, and in the right inferior fronto-occipital fasciculus (p<0.05). The best predictor of progression rate was the T2 lesion load measured along the right inferior fronto-occipital fasciculus (p=0.016, hazard ratio 1.00652, 95% CI 1.00121 to 1.01186). Conclusion Our results suggest that the location of T2 brain lesions in the motor and associative tracts is an important contributor to the progression of disability in PPMS, and is independent of spinal cord involvement.

Determination of individual stimulus-response curves in the visual cortex

Activation in the visual cortex is typically studied using group average changes in an on–off paradigm for a single flicker frequency. We used functional magnetic resonance imaging (fMRI) to characterize the stimulus–response curve in the visual cortex as a function of flicker frequency in individual subjects, using LED goggles with 17 frequency steps between 0 and 30 Hz. Ten healthy young individuals were studied on two different occasions (mean interval; 22 days). In all but one subject, a third‐order polynomial curve could be fitted to the data. From the response curve we calculated the peak response (the frequency where the response amplitude was maximal), the percentage change (relative difference) of the response amplitudes between 8 Hz and the peak frequency, and the average slope of response (towards the peak). On both occasions we could determine a peak response for each subject with small within‐subject variability. The average absolute difference in peak response between both sessions was 1.37 Hz (range, 0.2–4.3 Hz), indicating that the peak frequency is rather stable for a given individual. In conclusion, our study illustrates the ability of fMRI to examine the stimulus–response curve in individual subjects in the visual cortex. Based on our findings, the peak response and the slope of response seem highly reproducible within subjects. A similar analysis of the stimulus–response curve may be applicable to other types of stimuli. Hum. Brain Mapping 17:245–251, 2002.

Gray matter networks and clinical progression in subjects with predementia Alzheimer's disease

We studied whether gray matter network parameters are associated with rate of clinical progression in nondemented subjects who have abnormal amyloid markers in the cerebrospinal fluid (CSF), that is, predementia Alzheimers disease. Nondemented subjects (62 with subjective cognitive decline; 160 with mild cognitive impairment (MCI); agexa0= 68 ± 8xa0years; Mini-Mental State Examination (MMSE)xa0= 28 ± 2.4) were selected from the Amsterdam Dementia Cohort when they had abnormal amyloid in CSF (<640 pg/mL). Networks were extracted from gray matter structural magnetic resonance imaging (MRI), and 9xa0parameters were calculated. Cox proportional hazards models were used to test associations between each connectivity predictor and rate of progression to MCI or dementia. After a median time of 2.2xa0years, 122 (55%) subjects showed clinical progression. Lower network parameter values were associated with increased risk for progression, with the strongest hazard ratio of 0.29 for clustering (95% confidence intervalxa0= 0.12-0.70; p < 0.01). Results remained after correcting for tau, hippocampal volume, and MMSE scores. Our results suggest that at predementia stages, gray matter network parameters may have use to identify subjects who will show fast clinical progression.

Whole-brain T1-relaxation time measurements in multiple sclerosis

Magnetic resonance imaging (MRI) is widely applied to ascertain the diagnosis in patients suspected of multiple sclerosis (MS). Its diagnostic sensitivity reflects the ability to identify clinically silent lesions, which, when studied sequentially, display a dynamic pattern of waxing and waning. These new silent lesions can be used to monitor treatment efficacy, and are often used as the primary outcome measure in exploratory (“proof-ofconcept”) phase II studies. The association between clinical disability and radiological extent of involvement generally is poor, which in part reflects the limited histopathological specificity of T2-weighted images. While the extent of T2 signal increase and demyelination correlates nicely, the degree of axonal pathology, the correlate of persistent neurological deficit, remains largely undetermined using T2-weighted images [1]. By contrast, T2-weighted MRI is so sensitive that even (p)reactive lesions, consisting of an accumulation of activated microglia and oedema, are able to return abnormal signal, in the absence of frank demyelination [2]. Persistently hypointense lesions (black holes) on T1weighted MRI have been shown earlier to reflect lesions with considerable matrix destruction and axonal loss in post-mortem tissue [3] and using MR spectroscopy in vivo [4]. In a recent biopsy study [1 ] T1-hypointensity also predicted axonal loss, whereas lesion with little axonal loss and signs of remyelination showed a tendency to return to isointensity. Consistent with the greater amount of axonal damage, black holes are found more often in secondary progressive patients and higher EDSS strata. Increasingly, the volume of T1-hypointense lesions is being used to monitor treatment efficacy in phase III clinical trials [5]. While the identification of black holes increases the histopathological specificity in focal lesions, the overall gain in predictive value is moderate. This reflects the inability to monitor non-focal, diffuse damage to the normal appearing white matter (NAWM) and general brain atrophy. In the NAWM, a wide variety of quantitative MRI techniques show subtle, but definite abnormalities in MS patients, which may even be evident already at first clinical presentation. Apart from magnetic resonance spectroscopy, quantitative MRI techniques sensitive to NAWM pathology include diffusion tensor imaging, magnetization transfer imaging, and relaxation time mapping. In the current issue of the Journal of Neurology, two reports detail the findings from T1-relaxation time mapping [6, 7]. Measurement of T1 relaxation time can be performed using several MR techniques: either by varying the repetition time TR (saturation recovery), the inversion time TI,or the flip angle of the exciting radio frequency pulse. In general, inversion recovery methods are preferred over saturation recovery techniques, since they can be run at long TRs, allowing full relaxation of the longitudinal magnetization between excitations. Until recently, T1 relaxation time measurements suffered from one major disadvantage: acquisition times tended to be very long, which limited the application in the clinical setting to the analysis of single slices [8]. Since more rapid acquisition techniques have become available, this probJO N 35 Received: 13 March 2002 Accepted: 17 April 2002

The hippocampus in multiple sclerosis

Some of the clinical manifestations of multiple sclerosis, such as memory impairment and depression, are, at least partly, related to involvement of the hippocampus. Pathological studies have shown extensive demyelination, neuronal damage, and synaptic abnormalities in the hippocampus of patients with multiple sclerosis, and improvements in MRI technology have provided novel ways to assess hippocampal involvement in vivo. It is now accepted that clinical manifestations related to the hippocampus are due not only to focal hippocampal damage, but also to disconnection of the hippocampus from several brain networks. Evidence suggests anatomical and functional subspecialisation of the different hippocampal subfields, resulting in variability between regions in the extent to which damage and repair occur. The hippocampus also has important roles in plasticity and neurogenesis, both of which potentially contribute to functional preservation and restoration. These findings underline the importance of evaluation of the hippocampus not only to improve understanding of the clinical manifestations of multiple sclerosis, but also as a potential future target for treatment.