Biomedical subjects

D H Miller

Publications and source records attributed to D H Miller.

At least 19 recordsLinked to original sources

PubMed1999

Primary and transitional progressive MS: a clinical and MRI cross-sectional study.

BACKGROUND: Ten percent of patients with MS have a progressive course from onset with no history of relapses or remissions. A smaller subgroup follow a similar progressive course but have a single relapse at some point (transitional progressive [TP] MS). To date these patients have been excluded from receiving licensed treatments for MS and from most therapeutic trials. OBJECTIVE: To document the clinical and MRI characteristics of a large cohort of progressive patients, including 158 with primary progressive (PP) MS and 33 with TPMS. Data from a small reference group of 20 patients with secondary progressive (SP) MS are also presented for reference. METHODS: Patients were recruited from six European centers. All underwent a clinical assessment including scoring on the Expanded Disability Status Scale (EDSS) and MRI of the brain and spinal cord. RESULTS: The men-to-women ratio was 81:77 (51% men) in the PP group, 14:19 (42% men) in the TP group, and 5:15 (25% men) in the SP group. The mean age at disease onset was significantly higher in the PP group than it was in the other two groups (PP 40.2 years, TP 34.9 years, SP 28.7 years). On MRI the PP group had lower mean brain T2 and T1 hypointensity lesion loads than the SP group (T2 12.02 versus 27.74 cm3, p = 0.001; T1 4.34 versus 7.04 cm3, p = 0.015). The SP and TP cohorts had significantly more T2-weighted lesions in the spinal cord than the PP patients, and the SP cohort had the greatest degree of atrophy. There was a correlation in the PP and TP patients between EDSS score and brain and spinal cord atrophy (r = 0.3, 0.2, p < or = 0.006) but not with brain lesion load. The PP and TP patients who presented with spinal cord pathology had significantly lower brain T2 and T1 lesion loads than those with non-spinal cord presentations (p = 0.002). CONCLUSIONS: The monitoring of disease progression in PPMS is difficult, although measures of atrophy correlate with the EDSS and appear most promising. This study increases our understanding of this unique patient group, which will be further expanded with the acquisition of serial data.

Adult↗

PubMed1999

Modelling MRI enhancing lesion counts in multiple sclerosis using a negative binomial model: implications for clinical trials.

In multiple sclerosis (MS) the number of new enhancing lesions seen on monthly magnetic resonance imaging (MRI) scans is the most widely used response variable in MRI-monitored studies of experimental treatments. However, no statistical model has been proposed to describe the distribution of the number of such lesions across MS patients. This article briefly summarizes the statistical models for counted data. The negative binomial (NB) model is proposed to fit the number of new enhancing lesions counted in a set of 56 untreated MS patients followed for 9 months. It is shown that the large variability present in this data set is better addressed by the NB model (residual deviance=66.6, 54 degrees of freedom) than by the Poisson model (residual deviance=1830.1, 55 degrees of freedom). Applications of the parametrization of lesion counts are discussed, and an example related to computer simulations for the sample size estimation is presented.

Adolescent↗

PubMed1999

A multicenter measurement of magnetization transfer ratio in normal white matter.

To assess the importance of intercenter variations when measuring magnetization transfer ratio (MTR) in the brain, six European centers measured MTR in normal white matter. MTR ranged from 9 to 51 percent units (25 sequences). The effective flip angle of the saturating pulse divided by the pulse repetition time (ENRsat degrees/msec) was a good predictor of MTR (MTR = 3.25 ENRsat).

Brain↗

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

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↗

PubMed1999

Correlates of executive function in multiple sclerosis: the use of magnetic resonance spectroscopy as an index of focal pathology.

Proton magnetic resonance spectroscopy (MRS) was performed in a group of patients with multiple sclerosis (MS) and matched control subjects to examine the relationship between frontal lobe pathology and performance on tests of executive function. The N-acetyl aspartate/creatine ratio (NAA/Cr) was significantly reduced in frontal lesions and/or normal-appearing white matter in the patient group compared with the control group, but choline/creatine ratios did not differ. Although MRS abnormalities and executive deficits were not correlated for MS patients as a group, a few patients with more severe abnormalities of NAA/Cr ratio performed worse than other patients on the spatial working memory test, suggesting that subtle frontal neuropathological abnormalities detected by MRS may contribute to executive deficits. Further investigation is warranted to determine the value of MRS as an index of the pathophysiological processes leading to cognitive deficit.

Adult↗

PubMed1999

Quantitative MRI in patients with clinically isolated syndromes suggestive of demyelination.

OBJECTIVE: To assess the long-term predictive value of quantitative lesion load measurement on brain MRIs in patients after a 10-year follow-up who presented initially with a clinically isolated syndrome of the optic nerve, brainstem, or spinal cord. BACKGROUND: Quantitative MRI measurement is being used in treatment trials as a surrogate marker in MS, but there is a lack of long-term MRI follow-up data in assessing the natural course of the disease from the earliest stages. METHODS: Using a semiautomated threshold technique, the total lesion volume (TLV), the course of the disease, and disability were assessed in 58 patients at onset and after 5 and 10 years. RESULTS: The TLV at presentation correlated significantly (r = 0.81, p = 0.0001) with the TLV and also with the Expanded Disability Status Scale (EDSS) score (r = 0.45, p = 0.001) at 10-year follow-up. In contrast there was no correlation of the TLV at 5 years with subsequent change in EDSS score over the next 5 years (r = 0.18, p = 0.12). The change in TLV over the first 5 years in patients who developed clinically definite MS (CDMS) differed significantly according to the type of disease course (relapsing-remitting with disability, secondary progressive, or benign) manifesting at 10-year follow-up. CONCLUSION: Quantification of changes detected by T2-weighted brain MRI at the earliest clinical stages is strongly predictive of the subsequent development of CDMS as well as the clinical course and level of disability 10 years later.

Adolescent↗

PubMed1998

Correlations between monthly enhanced MRI lesion rate and changes in T2 lesion volume in multiple sclerosis.

Magnetic resonance imaging (MRI) provides a powerful tool for assessing disease activity in multiple sclerosis (MS), and its role as a surrogate marker for monitoring treatment efficacy is now becoming established. The most commonly used MRI parameters in treatment trials are (1) monthly gadolinium-enhanced MRI, with the number of active lesions serving as the outcome measure, and (2) annual lesion load quantification, in which change in MS lesion volume provides the MRI endpoint. We evaluated clinical/MRI correlations and the relationship between these two markers of disease activity in 73 patients with clinically definite MS. Quantification of T2 lesion load was performed at study entry and exit, with a median study duration of 11 months (range, 9 to 14 months). Monthly postgadolinium T1-weighted images were acquired between these time points. Lesion load at study entry was significantly correlated with the baseline Expanded Disability Status Scale (EDSS) score, but no significant longitudinal correlation was demonstrated. The number of enhancing lesions on the entry scan was predictive of subsequent relapse rate over the study duration and also correlated with the subsequent enhancing lesion activity over the study period. A significant correlation was found between change in lesion load and disease activity on the monthly scans. Our results suggest that annual lesion load quantification provides an efficient measure of ongoing disease activity, and this supports its application as a surrogate marker of disease evolution in phase III treatment trials.

Adolescent↗

PubMed1998

Guidelines for using quantitative measures of brain magnetic resonance imaging abnormalities in monitoring the treatment of multiple sclerosis.

The change of brain lesion load, measured on T2-weighted magnetic resonance imaging (MRI) using computer-assisted techniques, is a widely used secondary endpoint for phase III clinical trials in multiple sclerosis (MS). Collection, transfer, and analysis of the electronic data across multiple centers have all proved challenging and give rise to potential errors. However, many new acquisition schemes and postprocessing techniques have been developed; these may reduce scan times and result in better lesion conspicuity or lessen the human interaction needed for data analysis. This review considers many aspects of the use of MRI in clinical trials for MS and provides international consensus guidelines, derived from a task force of the European Magnetic Resonance Networks in Multiple Sclerosis (MAGNIMS) together with a group of North American experts. The main points considered are the organization of correctly powered trials and selection of participating sites; the appropriate choice of pulse sequences and image acquisition protocol given the current state of technology; quality assurance for data acquisition and analysis; accuracy and reproducibility of lesion load assessments; and the potential for the application of quantitative methods to other MRI-derived measures of disease burden.

Brain↗

PubMed1998

Correction for variations in MRI scanner sensitivity in brain studies with histogram matching.

Quantitative comparisons of abnormalities in MRI scans between patients or within patients serially are affected by variations in MR scanner performance. A histogram matching method is proposed to correct for variation in scanner sensitivity. It is demonstrated that this histogram matching method reduced the variation in white matter intensities across normal subjects from 7.5 to 2.5% and provided a method to remove the threshold dependency in lesion volume measurement with global thresholding in patients with multiple sclerosis (MS). The effectiveness of the method was compared with three other possible correction schemes. The histogram matching method was shown to be 2 to 5 times better.

Algorithms↗

PubMed1998

Optimisation of unenhanced MRI for detection of lesions in multiple sclerosis: a comparison of five pulse sequences with variable slice thickness.

We used five MRI sequences in six patients with multiple sclerosis (MS): conventional spin-echo (CSE) with 5-mm slices; 2D fast spin-echo (FSE) with 2-mm slices; multishot T2*-weighted echo-planar imaging (EPI) with 5-mm slices; fast fluid-attenuated inversion recovery (fFLAIR) with 2-mm slices; and 3D fast spin-echo with 1.5-mm-thick slices. A total of 225 lesions were detected on CSE, 274 on 2D FSE, 137 on EPI, 385 on fFLAIR and 320 on 3D FSE. The EPI sequence was clearly the least sensitive and susceptibility artefact was a problem, particularly in the brain stem and temporal lobes. Fast FLAIR displayed a much higher number of supratentorial lesions (380) than 3D FSE (297), 2D FSE (264) or CSE (211). However, in the posterior cranial fossa 3D FSE was the most sensitive sequence (23 lesions), followed by CSE (14) and 2D FSE (10), while fFLAIR (5) was extremely insensitive.

Adult↗

PubMed1998

Improved imaging of the spinal cord in multiple sclerosis using three-dimensional fast spin echo.

We report assessment of a new three-dimensional fast spin echo (3D FSE) sequence in ten patients with clinically definite multiple sclerosis, comparing it with standard 2D FSE, and in ten normal controls. We saw 29 focal lesions on the 2D images and 53 on the 3D FSE images (P = 0.05); none were seen in controls. Lesion length was significantly smaller on the 3D FSE than on to the 2D FSE images (3D: 1.36; 2D 2.0; P = 0.03). This may relate in part to separation into several lesions on the 3D images of confluent abnormal signal seen on 2D and in part to detection of small lesions missed by the thicker 2D FSE slices (3 mm compared to 1.5 mm). The 3D FSE sequence looks promising in improving spinal cord imaging.

Adult↗

PubMed1998

The effect of repositioning on brain MRI lesion load assessment in multiple sclerosis: reliability of subjective quality criteria.

The aim of this study was to assess the variability of lesion load measurements for repeated brain magnetic resonance imaging (MRI) scans judged to have either poor or good repositioning quality on the basis of subjective criteria used for clinical trials in multiple sclerosis (MS). Scan-rescan variability was also compared with the intra-observer variability assessed from three repeated volume measurements of the same scan. Nine patients with MS were studied; each of them underwent the scan-rescan procedure on the same day. Five scans were considered to have poor and four scans to have good repositioning. Between these two groups there were no differences in either the mean lesion loads or the measurement variance. For the whole group of patients, the intra-observer variability of repeated measurements gave a significantly lower coefficient of variation (COV = 4.9%) than the variability owing to repositioning (COV = 8.9%, P < 0.01, F test). Our results confirm that the effect of repositioning on brain MRI lesion load assessment is stronger than that owing to the intra-observer variability for repeated measurements and indicate that the simple visual judgment about the scan repositioning quality seems unable to predict the scan-rescan reproducibility.

Adult↗

PubMed1998

Multiple sclerosis: use of MRI in evaluating new therapies.

Although definitive evaluation of new therapies should be based on clinically meaningful outcomes, there are major difficulties to overcome when conducting treatment trials with clinical endpoints such as relapse rate or progression in disability. The variable and unpredictable natural history of MS necessitates large studies (hundreds of patients) of long duration (2-3 years), with an active treatment group being compared to a control group. It is thus not surprising that there has been much effort to identify alternative laboratory markers of disease activity to monitor treatment efficacy. To be an effective replacement (or surrogate, as it is often called) of clinical outcomes the laboratory measure of disease activity needs to be objective, sensitive and cost effective, accurate, reproducible, and most importantly, predictive of clinical outcome. Magnetic resonance imaging (MRI) is currently the only widely used surrogate outcome. This article reviews its status as a surrogate, and proposes MRI trial designs to address specific therapeutic questions.

Clinical Trials as Topic↗

PubMed1998

The role of magnetic resonance techniques in understanding and managing multiple sclerosis.

Magnetic resonance (MR) techniques have had a major impact in the last 10-15 years in understanding and managing multiple sclerosis. This review summarizes the current uses of MR in multiple sclerosis, based on the proceedings of a recent international workshop, under four headings: (i) technical issues; (ii) role in diagnosis; (iii) natural history studies in understanding the disease; (iv) application in clinical trials. The theory and methodology of relevant technical issues is outlined, in order to provide a framework with which to understand the potential and limitations of MR in addressing biological and clinical questions in multiple sclerosis. The principles underlying signal-to-noise and contrast-to-noise ratio are discussed, along with the techniques and clinical results for conventional and fast spin echo T2-weighted imaging, fluid-attenuated inversion recovery, detection of blood-brain barrier break down and hypointense lesions on T1-weighted images, magnetization transfer, T2 decay-curve analysis, MR spectroscopy, spinal cord imaging, diffusion imaging, and quantification of lesion load and atrophy. MRI has an extremely valuable role in confirming the clinical diagnosis of multiple sclerosis. T2-weighted brain imaging remains the standard diagnostic tool, but in some instances it is usefully complemented with gadolinium enhancement and spinal imaging. The caveat that the diagnosis of multiple sclerosis remains primarily a clinical one cannot be over-emphasized. Serial MRI studies have added much to our understanding of the natural history and pathophysiology of the disease. Blood-brain barrier breakdown is a consistent early feature of new lesion development in relapsing-remitting and secondary progressive multiple, sclerosis, and this usually correlates with active inflammation and myelin breakdown. A number of the acute MR changes are reversible, but chronic persistent abnormalities in a number of MR parameters, such as reduced N-acetyl aspartate, low magnetization transfer ratios, atrophy and T1-hypointensity, suggest the presence of demyelination and/or axonal degeneration in many chronic lesions. The presence and extent of T2-weighted MRI abnormalities at first presentation with a clinically isolated syndrome suggestive of demyelination strongly predicts the risk of developing clinically definite multiple sclerosis in the next few years. In established multiple sclerosis, however, the correlations between T2 abnormalities and disability are modest. This poor relationship partly relates to the discrepancy between lesion site and function in attempting to correlate locomotor disability with brain MRI findings. However, the correlations between brain lesion load and cognitive dysfunction in multiple sclerosis, whilst more evident, are still modest. A more important limitation is the low pathological specificity of abnormalities seen on T2-weighted images. Stronger correlations have been found between disability and new putative MR markers for demyelination and/or axonal degeneration. Serial studies using multiple MR techniques are now needed to further clarify pathophysiological mechanisms in multiple sclerosis. Serial MR has become an important tool in monitoring treatment efficacy. It provides data which can be readily analysed in a blinded fashion and which directly inspects the pathological evolution; it also enables a rapid and sensitive measure of treatment outcome in early relapsing-remitting and secondary progressive disease. Because of the modest clinical correlations it is, however, still appropriate that the definitive determinant of treatment efficacy remains a clinical one. Further work is needed to address issues of quality control in serial studies, statistical calculation of appropriate sample sizes, and optimization of the nature and frequency of MR outcomes measured.

Biomarkers↗

PubMed1998

Secondary progressive multiple sclerosis: the relationship between short-term MRI activity and clinical features.

We report the findings in 60 patients with secondary progressive multiple sclerosis who had monthly brain MRI studies for 4 months (one baseline and three follow-up scans). The purpose was to define the short-term MRI natural history in a large cohort with secondary progressive disease and to ascertain its relationship with other clinical and MRI features. The patients were participating in either a natural history study or the placebo arm or non-treatment phase of a therapeutic trial. The cohort had clinical features typical of secondary progressive disease: thus, all had moderate or severe locomotor disabilities [Expanded Disability Status Scale (EDSS), score 3.5-8], with a median disease duration of 12 years. There was equal representation of males and females. During the 3 months of follow-up there was a total of 362 new enhancing lesions seen in 42 patients, and there were 24 relapses in 20 patients. There was no correlation between new enhancing lesions and age at study entry, age of disease onset, gender disease duration or EDSS, but there was a strong correlation with the number of enhancing lesions on the baseline scan (r = 0.65, P < 0.0001) and subsequent activity. There was a non-significant trend for higher numbers of new enhancing lesions in those having relapses during the 3 months of scanning (P = 0.14) or in the preceding 6 months (P = 0.06). The 34 patients who did not relapse in either period had significantly fewer new active lesions (P = 0.02) than those who relapsed at some stage during the 9 months. Nevertheless, considerable activity was seen in the non-relapsing cohorts: there was a mean of 3.5 (median 2) new enhancing lesions in those not relapsing during the 3 month study, and 5.5 (median 2) in those not relapsing in the previous 6 months. We conclude that short-term MRI activity is generally high in secondary progressive disease, confirming a useful role for the technique in exploratory trials. Further work should concentrate on elucidating the mechanisms of secondary progression by longer term follow-up studies of larger cohorts using multiple MRI and clinical measurements.

Adult↗

PubMed1998

Status dystonicus: the syndrome and its management.

Patients with dystonic syndromes sometimes develop increasingly frequent and relentless episodes of devastating generalized dystonia which we call status dystonicus. Twelve cases of status dystonicus, of various underlying aetiologies, are presented. Possible precipitating factors were identified in only five cases: intercurrent infection (one); discontinuation of lithium (one) and tetrabenazine (one); and the introduction of clonazepam (two). Nine patients required mechanical ventilation and three others were sedated with intravenous chlormethiazole. Drug therapy used included benzhexol, tetrabenazine, pimozide, baclofen, chlorpromazine, haloperidol, carbamazepine and acetozolamide. Two patients underwent thalamotomies, one of whom improved. Two patients died, five returned to their pre-status dystonicus condition, two eventually made a full recovery and three were worse. Patients with status dystonicus should be managed on an intensive care unit as they may develop bulbar and respiratory complications which may require ventilation. Metabolic problems encountered can include rhabdomyolysis with acute renal failure. Drug therapy with benzhexol, tetrabenazine and pimozide or haloperidol may be beneficial in some cases.

Adolescent↗