Search PubMed⌕ Search

Biomedical subjects

D H Miller

Publications and source records attributed to D H Miller.

At least 199 records · Page 11Linked to original sources
PubMed1999

A direct demonstration of both structure and function in the visual system: combining diffusion tensor imaging with functional magnetic resonance imaging.

The relationships between functional activation patterns and the structural properties of brain pathways have not been widely studied. The recently developed magnetic resonance imaging technique of diffusion tensor imaging (DTI) allows a full characterization of water molecule mobility in three dimensions, providing new structural information that is not available from other in vivo imaging techniques. The directional bias of diffusion (anisotropy) may be derived from the diffusion tensor, and is related to fiber tract integrity and orientation. Since DTI and functional magnetic resonance imaging (fMRI) both require rapid (generally echoplanar) imaging it is possible to obtain geometrically matched images from the two modalities. fMRI and DTI were combined in a visual system study using photic stimulation to demonstrate the feasibility of combining the two methods and to investigate the structural properties of activated regions compared to the white matter tracts. Blood oxygenation level-dependent (BOLD) fMRI activation maps were directly overlayed upon fractional anisotropy (FA) maps, avoiding registration and spatial transformation by carefully matching acquisition parameters. Activated regions had lower FA than optic radiation white matter, supporting the hypothesis that most BOLD signal change occurs within the relatively isotropic cortical grey matter. The combination of these modalities in future studies may provide further insights into relationships between brain structure and function in both health and disease.

Adult↗
PubMed1999

Interobserver agreement for diagnostic MRI criteria in suspected multiple sclerosis.

MRI is the paraclinical test most widely used to support the diagnosis of multiple sclerosis (MS). We evaluated interobserver agreement in applying diagnostic criteria to MRI obtained at first presentation. Five experienced observers scored 25 sets of images consisting of unenhanced T2- and gadolinium-enhanced T1-weighted images (approximately half the sets were normal). We scored frontal, parietal, temporal, occipital, infratentorial and basal ganglia lesions and the total number of lesions on T2-weighted images; periventricular, callosal, juxtacortical and ovoid lesions and those > 5 mm in maximum diameter; contrast-enhancing and hypointense lesions. Based on a combination of imaging findings patients were classified as compatible or not compatible with MS according to composite criteria. Observer concordance was characterised by weighted kappa values (kappa) and mean average difference to the median (MADM) scores. Using the raw scores, there was poor agreement for the total number of lesions on T2-weighted images, and for occipital, oval, juxtacortical and hypointense lesions. Moderate agreement was found for frontal, callosal, basal ganglia and large lesions on T2 weighting. Good agreement was attained for parietal, temporal, infratentorial and periventricular lesions. After dichotomisation according to accepted cut-off values, most criteria performed better, especially the number of lesions on T2-weighted images (P < 0.05). Good agreement was found for the criteria of Paty and Fazekas and moderate agreement for those of Barkhof. While experienced observers may not agree on the total number of lesions, they show quite good agreement for commonly used cut-off points and elements in the composite criteria. This validates the use of MRI in the diagnosis of MS, and the use of dichotomised and composite criteria.

Brain↗
PubMed1999

Visual analysis of serial T2-weighted MRI in multiple sclerosis: intra- and interobserver reproducibility.

We evaluated the effect of consensus formation and training on the agreement between observers in scoring the number of new and enlarging multiple sclerosis (MS) lesions on serial T2-weighted MRI studies. The baseline and month 9 MRI studies of 16 patients with a range of MRI activity were used (dual-echo conventional spin-echo sequence, TR 2000, TE 34 and 90 ms, 5 mm contiguous slices, inplane resolution 1 mm). First, the serial studies were visually analysed for the presence of new and enlarging lesions, on two occasions, by five experienced observers, without adopting any consensus strategy and in isolation. Next, the observers met to identify the common sources of inconsistencies in reporting between observers and formulate consensus rules. Finally, a further independent reading session was performed on the same MRI dataset, this time applying the consensus rules. Agreement between observers was assessed using kappa scores. Without the consensus rules, interobserver kappa scores for the first and second reading sessions for new lesions were only 0.51 and 0.39 respectively; agreement for enlarging lesions was even worse. The mean intraobserver kappa score for new lesions was higher at 0.72, reflecting the fact that the observers were consistently applying their individual assessment strategies. Application of the consensus rules did not lead to a significant improvement in inter observer kappas; the kappa scores adopting the guidelines were 0.46 and 0.21 for new and enlarging lesions respectively. Consensus guidelines thus did not improve the reproducibility of visual analysis of serial T2-weighted MRI, and the level of agreement between observers remained only moderate. Suboptimal repositioning is likely to be a major source of residual variability and this suggests a future role for image registration strategies; until then, a single observer, or pair of observers working in consensus, should be used in MS studies.

Analysis of Variance↗
PubMed1999

Problems in designing and recruiting to therapeutic trials in primary progressive multiple sclerosis.

Patients with primary progressive multiple sclerosis have atypical clinical and magnetic resonance imaging (MRI) characteristics which present unique problems in designing and recruiting to therapeutic trials. The first randomised controlled therapeutic trial specifically for primary progressive multiple sclerosis is now underway. Although only an exploratory phase II study, it has provided further insight into difficulties in diagnosis, classification and choice of clinical and MRI outcome measures. Patients with primary progressive multiple sclerosis have a wide differential diagnosis and do not readily conform to the Poser criteria. They may therefore present diagnostic uncertainty, particularly as their classification often relies on a retrospective history. This was highlighted during the recruitment to this study of interferon-beta1a. Of the 138 patients referred with a definite diagnosis of primary progressive multiple sclerosis only 50 were enrolled in the study. Of the 88 patients not included, 50% either did not have primary progressive multiple sclerosis, or the diagnosis was not secure. Outcome measures pose particular problems. Clinically the focus must be on progression, and the measure should be both responsive and reliable. In relation to MRI, the currently recommended measures for therapeutic trials in relapsing/remitting and secondary progressive multiple sclerosis show little change in primary progressive multiple sclerosis, and therefore more pathologically specific MRI measures are required. Strict clinical guidelines and further developments in clinical and MRI measures are required to facilitate future therapeutic trials in primary progressive multiple sclerosis.

Brain↗
PubMed1999

Long-term recovery and fellow eye deterioration after optic neuritis, determined by serial visual evoked potentials.

Twelve optic neuritis patients (part of a larger group in whom the effects of intravenous methylprednisolone treatment were previously reported), were followed-up 3 years from the onset of symptoms with visual evoked potentials (VEPs), contrast sensitivity and visual field examination. Findings from the previously "unaffected" eyes, none of which had had symptomatic optic neuritis, were also assessed. Between 6 months and 3 years after the onset of symptoms the VEPs of the affected eyes showed a significant shortening of mean latency (whole field, 131-123 ms; central field, 136-125 ms). Conversely, the responses of the previously unaffected eyes showed a contemporaneous latency prolongation (significant for the whole field, 110-113 ms) which exceeded the expected effect of aging. Contrast sensitivity tests showed no significant change in the affected eyes but a mild deterioration in the unaffected eyes, while the visual fields showed no overall pattern of improvement or deterioration. If the strong tendency for VEP latencies to shorten is due to ongoing remyelination, the lack of significant improvement in visual function may be because the visual deficit at 6 months is due to irreversible axonal loss rather than demyelination. The absence of functional deterioration in the affected eye, while VEPs and contrast sensitivity deteriorated in the unaffected eye, suggests that long-term remyelination may for a while counteract the effects of insidious demyelination and axonal degeneration which affect the visual pathway during clinical remission.

Adult↗
PubMed1999

Multiple sclerosis: interobserver agreement in reporting active lesions on serial brain MRI using conventional spin echo, fast spin echo, fast fluid-attenuated inversion recovery and post-contrast T1-weighted images.

Previous studies have addressed the question of the precision in assessing multiple sclerosis (MS) activity by counting enhancing lesions on gadolinium enhanced brain magnetic resonance imaging (MRI). However, counting the active lesions on serial unenhanced MRI obtained by various pulse sequences has not been yet considered. We compared the interobserver levels of agreement in reporting active MS lesions on serial enhanced and unenhanced MRI to assess whether the use of various unenhanced techniques may change the degree of interobserver measurement reproducibility. Dual-echo conventional spin echo (CSE), dual-echo fast spin echo (FSE), fast fluid-attenuated inversion recovery (FLAIR) and Gd-enhanced T1-weighted brain MRI were obtained from five MS patients at baseline and monthly for 2 months. Six experienced observers independently identified and counted active MS lesions on the two follow-up MRI scans. Active lesions were considered to be all the enhancing lesions and any new or enlarging lesion on enhanced and unenhanced scans. Interobserver levels of agreement were calculated by weighted kappa values. Very good agreement was reached only for counting total and new Gd-enhancing lesions. Good agreement was achieved for counting new lesions on the three unenhanced techniques, whereas the agreement for counting enlarging lesions was poor with all the MRI techniques. The level of agreement was significantly heterogeneous for various MRI techniques but not for various lesion sites. These results confirm that counting enhancing lesions is the most reliable method for assessing MS activity, but the use of any of the available unenhanced MRI techniques did not result in different levels of interobserver agreement when reporting new and enlarging MS lesions on serial scans.

Brain↗
PubMed1999

Correlation of magnetic resonance imaging parameters with clinical disability in multiple sclerosis: a preliminary study.

Magnetic resonance imaging (MRI) is frequently used to monitor new treatments in multiple sclerosis (MS), but its role is limited by the uncertain relationship between MRI parameters and clinical disability. A brain MRI study using nine MRI parameters was undertaken in 15 MS patients with a wide spectrum of disability to evaluate the relationship between each parameter and disability. A strong correlation was found between disability (measured using Kurtzke's EDSS) and total lesion load on both proton density (PD; r = 0.79) and T1 (r = 0.71) weighted sequences. There was also a strong correlation of disability with average lesion magnetisation transfer ratio (MTR; r = -0.74) and calculated T1 (r = 0.71) but not with calculated T2 or the average signal intensity of lesions on the conventional T1-weighted, PD-weighted and heavily T2-weighted images. Thus, four parameters which measured either the extent of lesions (PD lesion load) or their pathological severity (MTR, calculated T1, hypointense T1-lesion load) were correlated significantly with disability. While this suggests that such parameters will be useful in treatment trial monitoring, further multi-parameter MRI studies, of larger cohorts and using a wider range of techniques, are indicated.

Adult↗
PubMed1999

1H magnetic resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis.

Recent magnetic resonance imaging (MRI) and pathological studies have indicated that axonal loss is a major contributor to disease progression in multiple sclerosis. 1H magnetic resonance spectroscopy (MRS), through measurement of N-acetyl aspartate (NAA), a neuronal marker, provides a unique tool to investigate this. Patients with primary progressive multiple sclerosis have few lesions on conventional MRI, suggesting that changes in normal appearing white matter (NAWM), such as axonal loss, may be particularly relevant to disease progression in this group. To test this hypothesis NAWM was studied with MRS, measuring the concentration of N-acetyl derived groups (NA, the sum of NAA and N-acetyl aspartyl glutamate). Single-voxel MRS using a water-suppressed PRESS sequence was carried out in 24 patients with primary progressive multiple sclerosis and in 16 age-matched controls. Ratios of metabolite to creatine concentration (Cr) were calculated in all subjects, and absolute concentrations were measured in 18 patients and all controls. NA/Cr (median 1.40, range 0.86-1.91) was significantly lower in NAWM in patients than in controls (median 1.70, range 1.27-2.14; P = 0.006), as was the absolute concentration of NA (patients, median 6.90 mM, range 4.62-10.38 mM; controls, median 7.77 mM, range 6.60-9.71 mM; P = 0.032). There was no significant difference in the absolute concentration of creatine between the groups. This study supports the hypothesis that axonal loss occurs in NAWM in primary progressive multiple sclerosis and may well be a mechanism for disease progression in this group.

Adult↗
PubMed1999

The sensitivity of thin-slice fast spin echo, fast FLAIR and gadolinium-enhanced T1-weighted MRI sequences in detecting new lesion activity in multiple sclerosis.

Fast fluid-attenuated inversion-recovery (FLAIR) and proton density/T2-weighted fast spin echo (FSE) brain images with 3-mm slices were acquired monthly for 7 months in 37 multiple sclerosis patients. New and enlarging lesions were counted and compared according to the site of lesions seen with each sequence. In addition, the number of new enhancing lesions seen on gadolinium-enhanced T1-weighted brain magnetic resonance imaging at the same time points was counted. All sequences used 3-mm contiguous axial slices. Overall, 126 new or enlarging lesions were seen on FSE and 135 on fast FLAIR (P = 0.25, Wilcoxon signed ranks test). Regional comparisons revealed significantly more fast FLAIR lesions only in the cortical/subcortical areas. There was a total of 295 new enhancing lesions over the same period -- a gain in the number of 'active lesions' of 234% seen with FSE and 218% with FLAIR. It is concluded that serial thin slice fast FLAIR is only slightly superior to FSE in detecting new and enlarging multiple sclerosis lesions but the difference is not sufficient to recommend that FLAIR should replace FSE in short-term, exploratory trials in MS using monthly scanning. Gadolinium-enhanced imaging is more then twice as sensitive as either FSE or fast FLAIR to new multiple sclerosis lesion activity, and enhancing lesions should provide the primary outcome measure in such studies.

Adult↗
PubMed1999

Reproducibility of magnetic resonance imaging measurements of spinal cord atrophy: the role of quality assurance.

A sensitive magnetic resonance imaging (MRI) method to measure spinal cord cross-sectional area with the potential to monitor disease progression has recently been developed. As changes in cord area due to disease are usually small, assessment of the reliability of the methodology is essential in serial studies of spinal cord atrophy. The aim of this study was to institute and evaluate a protocol of quality assurance to determine long-term reproducibility of serial studies. Serial MRI of the spinal cord was carried out in five healthy volunteer controls over 1 year. Cross-sectional spinal cord areas were measured in a total of 46 scans. The mean coefficient of variation of all subjects over one year was 1.35%. The intra-observer coefficient of variation for same scan analysis was 0.63%. This study has confirmed high reliability of our serial data over one year and the on-going quality assurance protocol enables continuing evaluation of the reproducibility of results in serial studies. Quality assurance is an essential and practical component of all serial MRI studies, without which the clinical implications of change cannot be reliably evaluated.

Atrophy↗
PubMed1999

Comparison of multiple sclerosis clinical subgroups using navigated spin echo diffusion-weighted imaging.

The apparent diffusion coefficient (ADC) of tissue provides an indication of the size, shape, and orientation of the water spaces in tissue. Thus, pathologic differences between lesions in multiple sclerosis (MS) patients with different clinical courses may be reflected by changes in ADC measurements in lesions and white matter. Twelve healthy subjects and 35 MS patients with a relapsing-remitting (n = 10), benign (n = 8), secondary progressive (n = 8) and primary progressive (n = 9) clinical course were studied. T2-weighted and post-gadolinium T1-weighted images were obtained using a 1.5 T Signa Echospeed magnetic resonance imaging (MRI) system. Diffusion-weighted imaging was implemented using a pulsed gradient spin echo (PGSE) sequence with diffusion gradients applied in turn along three orthogonal directions in order to obtain the average apparent diffusion coefficient (ADCav). Navigator echo correction and cardiac gating were used to reduce motion artifact. ADC maps were derived using a two point calculation based on the Stejskal-Tanner formula. Diffusion anisotropy was estimated using the van Gelderen formula to calculate an anisotropy index. MS lesions had a higher ADC and reduced anisotropy compared with normal appearing white matter. Highest ADC values were found in gadolinium enhancing lesions and non-enhancing hypointense lesions on T1-weighted imaging. MS white matter had a slightly higher ADC and lower anisotropy than white matter of healthy subjects. Lesion and white matter ADC values did not differ between patients with different clinical courses of MS. There was no correlation between lesion ADC and disability. Diffusion-weighted imaging with measurement of ADC using the PGSE method provides quantitative information on acute edematous MS lesions and chronic lesions associated with demyelination and axonal loss but does not distinguish between clinical subtypes of MS.

Brain↗
PubMed1999

Spatial mapping of T2 and gadolinium-enhancing T1 lesion volumes in multiple sclerosis: evidence for distinct mechanisms of lesion genesis?

It is generally believed that most T2-weighted (T2) lesions in the central white matter of patients with multiple sclerosis begin with a variable period of T1-weighted (T1) gadolinium (Gd) enhancement and that T1 Gd-enhancing and T2 lesions represent stages of a single pathological process. Lesion probability maps can be used to test this hypothesis by providing a quantitative description of the spatial distribution of these two types of lesions across a patient population. The simplest prediction of this hypothesis would be that the spatial distributions of T1 Gd-enhancing and T2 lesions are identical. We generated T1 Gd-enhancing and T2 lesion probability maps from 19 patients with relapsing-remitting multiple sclerosis. There was a significantly higher probability (P = 0.001) for T2 lesions to be found in the central relative to the peripheral white matter (risk ratio 4.5), although the relative distribution of T1 Gd-enhancing lesions was not significantly different (P = 0.7) between central and peripheral white matter regions (risk ratio 0.6). Longitudinal data on the same population were used to demonstrate a similar distribution asymmetry between new T1 Gd-enhancing and new T2 lesions that developed over the course of 1 year. Alternative hypotheses to explain this observation were tested. We found no spatial difference in the likelihood of development of persistent T2 lesions following T1 Gd enhancement. The relative distribution of T1 Gd-enhancing lesions was shown to be independent of the dose of Gd contrast agent and the frequency of scanning. Our findings suggest that a proportion of the periventricular T2 lesion volume may arise from mechanisms other than those associated with early breakdown of the blood-brain barrier leading to T1 Gd enhancement.

Adult↗
PubMed1999

Cognitive function in primary progressive and transitional progressive multiple sclerosis: a controlled study with MRI correlates.

The relative rarity of primary progressive (PP) and transitional progressive (TP) multiple sclerosis has meant that little documentation of cognitive function in such patients is currently available. The aim of this study was to investigate the cognitive skills of patients with PP and TP multiple sclerosis relative to matched healthy controls, and to examine the relationship of this impairment to MRI parameters. Sixty-three patients (43 PP, 20 TP) were individually matched with healthy controls, who undertook the same cognitive tasks as the patient group. The neuropsychological assessment comprised Rao's brief repeatable battery, a reasoning test, and a measure of depression. Patients also underwent T1- and T2-weighted brain MRI. These patients were taken from a larger cohort (158 PP, 33 TP) in whom it had been demonstrated that the re were no significant differences between the mean scores of the PP and TP groups on any of the cognitive variables. The 63 patients were therefore taken as one group for comparison with the healthy controls. These patients performed significantly worse than the controls in tests of verbal memory, attention, verbal fluency and spatial reasoning. An impairment index was constructed and applied to the patient data. This correlated modestly with T2-lesion load (r = 0.45, P = 0.01), T1-hypointensity load (r = 0.45, P = 0.01) and cerebral volume (r = -0.35, P = 0.01). Thus, PP and TP multiple sclerosis patients demonstrate significant cognitive dysfunction when compared with matched healthy controls. The relationship between this impairment and MRI parameters is moderate, suggesting that cognitive dysfunction in PP and TP multiple sclerosis has a complex and multifactorial aetiology, which is not adequately explained by pathology as demonstrated on conventional MRI.

Adult↗
PubMed1999

Central nervous system sarcoidosis--diagnosis and management.

A series of 68 patients with neurosarcoidosis is reported, with particular emphasis on clinical aspects, diagnosis and treatment. A classification system based on clinical diagnostic probability is proposed, consisting of probable and definite disease, the latter being dependent on finding sarcoid granulomas on nervous system histology, which was obtained in 12 patients (18%). The role of investigations, including magnetic resonance imaging (MRI), chest radiography, Kveim skin test, Gallium 67 isotope scanning and cerebrospinal fluid (CSF) studies, is considered. Sixty-two percent of patients presented with nervous system disease, most commonly affecting the optic nerve and chiasm. Other common presentations included cranial nerve palsies, spinal cord and brainstem manifestations. Investigations yielding most diagnostic information included the Kveim test (41/48, 85% positive), raised CSF protein and/or cells (50/62, 81%) and gallium 67 scan (14/31, 45%). Eleven out of 29 patients (38%) patients showed meningeal enhancement on MRI scanning and 43% of scans demonstrated multiple white-matter lesions. Mean follow-up for the group was 4.6 years. Forty-seven patients were seen for > 18 months, and over half of these patients progressed despite corticosteroid and other immunosuppressive therapies. The benefit of a large patient database prospectively studied, with extended follow-up is discussed in order to learn more about prognosis and advance therapy in neurosarcoidosis.

Adrenal Cortex Hormones↗
PubMed1999

Statistical power of MRI monitored trials in multiple sclerosis: new data and comparison with previous results.

OBJECTIVES: To evaluate the durations of the follow up and the reference population sizes needed to achieve optimal and stable statistical powers for two period cross over and parallel group design clinical trials in multiple sclerosis, when using the numbers of new enhancing lesions and the numbers of active scans as end point variables. METHODS: The statistical power was calculated by means of computer simulations performed using MRI data obtained from 65 untreated relapsing-remitting or secondary progressive patients who were scanned monthly for 9 months. The statistical power was calculated for follow up durations of 2, 3, 6, and 9 months and for sample sizes of 40-100 patients for parallel group and of 20-80 patients for two period cross over design studies. The stability of the estimated powers was evaluated by applying the same procedure on random subsets of the original data. RESULTS: When using the number of new enhancing lesions as the end point, the statistical power increased for all the simulated treatment effects with the duration of the follow up until 3 months for the parallel group design and until 6 months for the two period cross over design. Using the number of active scans as the end point, the statistical power steadily increased until 6 months for the parallel group design and until 9 months for the two period cross over design. The power estimates in the present sample and the comparisons of these results with those obtained by previous studies with smaller patient cohorts suggest that statistical power is significantly overestimated when the size of the reference data set decreases for parallel group design studies or the duration of the follow up decreases for two period cross over studies. CONCLUSIONS: These results should be used to determine the duration of the follow up and the sample size needed when planning MRI monitored clinical trials in multiple sclerosis.

Adolescent↗