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Biomedical subjects

David H Miller

Publications and source records attributed to David H Miller.

At least 19 recordsLinked to original sources
PubMed2003

Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis. Commentary: evaluating disease modifying treatments in multiple sclerosis.

OBJECTIVE: To evaluate the cost effectiveness of four disease modifying treatments (interferon betas and glatiramer acetate) for relapsing remitting and secondary progressive multiple sclerosis in the United Kingdom. DESIGN: Modelling cost effectiveness. SETTING: UK NHS. PARTICIPANTS: Patients with relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis. MAIN OUTCOME MEASURES: Cost per quality adjusted life year gained. RESULTS: The base case cost per quality adjusted life year gained by using any of the four treatments ranged from pound 42,000 (66,469 dollars; 61,630 euro) to pound 98,000 based on efficacy information in the public domain. Uncertainty analysis suggests that the probability of any of these treatments having a cost effectiveness better than pound 20,000 at 20 years is below 20%. The key determinants of cost effectiveness were the time horizon, the progression of patients after stopping treatment, differential discount rates, and the price of the treatments. CONCLUSIONS: Cost effectiveness varied markedly between the interventions. Uncertainty around point estimates was substantial. This uncertainty could be reduced by conducting research on the true magnitude of the effect of these drugs, the progression of patients after stopping treatment, the costs of care, and the quality of life of the patients. Price was the key modifiable determinant of the cost effectiveness of these treatments.

Cost-Benefit Analysis↗
PubMed2003

A controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.

Adult↗
PubMed2003

New T2 lesions enable an earlier diagnosis of multiple sclerosis in clinically isolated syndromes.

In clinically isolated syndromes, the new McDonald criteria for multiple sclerosis diagnosis require new gadolinium-enhancing lesions for dissemination in time at a 3-month follow-up magnetic resonance imaging scan. In a cohort of 56 patients, these criteria were specific (95%) but less sensitive (58%) for clinically definite multiple sclerosis at 3 years. If new T2 lesions were allowed as an alternative for dissemination in time, sensitivity increased (74%) with maintained specificity (92%), enabling an accurate diagnosis of multiple sclerosis in more patients.

Adolescent↗
PubMed2003

Guidelines for using quantitative magnetization transfer magnetic resonance imaging for monitoring treatment of multiple sclerosis.

Quantitative evaluation of brain magnetic resonance imaging (MRI) scans is now an accepted part of the trial of new putative treatments for multiple sclerosis (MS). However, conventional MRI is not pathologically specific, and it does not reveal the details of the pathological processes that underlie the progression of the disease. Magnetization transfer (MT) imaging is a relatively new quantitative technique that appears to offer some pathological specificity, and can be used to monitor the changes over time in both individual lesions and the central nervous system as a whole. This paper considers the case for incorporating MT imaging into new clinical trials, so that the utility of MT for monitoring the modification of MS progression by treatment can be assessed. Specific guidelines for implementing MT imaging as part of a large multicenter clinical trial are given, and practical considerations when planning such a trial are detailed. It is anticipated that MT imaging will be incorporated into many new trials in the near future.

Brain↗
PubMed2003

Application of a B-spline active surface technique to the measurement of cervical cord volume in multiple sclerosis from three-dimensional MR images.

PURPOSE: To evaluate the ability of a B-spline active surface technique to detect cervical spinal cord atrophy due to multiple sclerosis (MS) compared with intensity-based contouring. MATERIALS AND METHODS: In a previously reported study, the cervical spinal cords of 28 MS patients and 13 age-matched controls were imaged with a volume-acquired inversion-prepared fast spoiled gradient echo sequence at baseline and after one year. The images were reanalyzed using the B-spline technique and the results compared with the results obtained in the original report using intensity-based contouring. RESULTS: The mean cervical spinal cord volume determined by the active surface programme was 6487 mm(3) in 28 patients compared with 7117 mm(3) in controls (P = 0.002, corrected for age and gender). The patients' cervical spinal cord volumes were associated with expanded disability status scale scores (parameter estimate = -1.21 x 10(-3), r(2) = 0.39, P = 0.001). The patients' cervical spinal cord volumes did not decrease significantly over one year, unlike the mean cervical spinal cord areas at C2/3 calculated using intensity-based contouring. CONCLUSION: The active surface technique can detect cervical spinal cord atrophy due to MS, which has functional significance. However, this methodology is less sensitive at detecting small serial changes compared with the previously reported method.

Atrophy↗
PubMed2003

A study of the mechanisms of normal-appearing white matter damage in multiple sclerosis using diffusion tensor imaging--evidence of Wallerian degeneration.

Diffusion tensor imaging (DTI) investigates brain tissue microstructure in vivo. In multiple sclerosis (MS) Wallerian degeneration of axons traversing focal lesions is a potential mechanism of damage in normal-appearing white matter. In vivo evidence for this hypothesis is limited. The present study investigated the relationship between DTI-derived indices in the normal-appearing corpus callosum (CC) and the lesion loads (LLs) in connected cerebral regions. DTI was performed in 39 MS patients and in 21 age-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) were estimated in the genu, body and splenium of CC. Patients showed lower FA and higher MD in the CC than controls and both correlated with the total LL (r = -0.56 and r = 0.54, p < 0.0001). The LL of individual cerebral lobes correlated with both FA and MD in the corresponding callosal regions, with the body showing the strongest correlations with frontal and parietal LL (p < 0.0001). The strong correlations between DTI indices in the CC and the extent of lesions in connected brain regions support the hypothesis that Wallerian degeneration of axons transected by remote, but connected focal lesions, is an important pathogenic mechanism of damage in MS.

Adult↗
PubMed2002

A longitudinal study of abnormalities on MRI and disability from multiple sclerosis.

BACKGROUND: In patients with isolated syndromes that are clinically suggestive of multiple sclerosis, such as optic neuritis or brain-stem or spinal cord syndromes, the presence of lesions as determined by T2-weighted magnetic resonance imaging (MRI) of the brain increases the likelihood that multiple sclerosis will develop. We sought to determine the relation between early lesion volume, changes in volume, and long-term disability. METHODS: Seventy-one patients in a serial MRI study of patients with isolated syndromes were reassessed after a mean of 14.1 years. Disability was measured with the use of Kurtzke's Expanded Disability Status Scale (EDSS; possible range, 0 to 10, with a higher score indicating a greater degree of disability). RESULTS: Clinically definite multiple sclerosis developed in 44 of the 50 patients (88 percent) with abnormal results on MRI at presentation and in 4 of 21 patients (19 percent) with normal results on MRI. The median EDSS score at follow-up for those with multiple sclerosis was 3.25 (range, 0 to 10); 31 percent had an EDSS score of 6 or more (including three patients whose deaths were due to multiple sclerosis). The EDSS score at 14 years correlated moderately with lesion volume on MRI at 5 years (r=0.60) and with the increase in lesion volume over the first 5 years (r=0.61). CONCLUSIONS: In patients who first present with isolated syndromes suggestive of multiple sclerosis, the increases in the volume of the lesions seen on magnetic resonance imaging of the brain in the first five years correlate with the degree of long-term disability from multiple sclerosis. This relation is only moderate, so the volume of the lesions alone may not be an adequate basis for decisions about the use of disease-modifying treatment.

Adolescent↗
PubMed2002

Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of multiple sclerosis.

Traditionally, multiple sclerosis (MS) has been diagnosed on the basis of clinical evidence of dissemination in time and space. Previously, it could not be diagnosed in patients with single clinical episodes of demyelination known as clinically isolated syndromes. New diagnostic criteria from the International Panel of McDonald and colleagues incorporate MRI evidence of dissemination in time and space to allow a diagnosis of MS in patients with clinically isolated syndromes. From clinical and MRI examinations performed prospectively at baseline, 3 months, 1 year, and 3 years of follow-up, the frequency of developing MS was ascertained by the application of both the new McDonald criteria and the Poser criteria for clinically definite MS. The specificity, sensitivity, positive and negative predictive value, and accuracy of the new criteria for the development of clinically definite MS were assessed. At 3 months, 20 of 95 (21%) patients had MS with the McDonald criteria, whereas only 7 of 95 (7%) had developed clinically definite MS. After 1 year, the corresponding figures were 38 of 79 (48%) and 16 of 79 (20%), and after 3 years, they were 29 of 50 (58%) and 19 of 50 (38%). The development of MS with the new MRI criteria after 1 year had a high sensitivity (83%), specificity (83%), positive predicative value (75%), negative predictive value (89%), and accuracy (83%) for clinically definite MS at 3 years. Use of the new McDonald criteria more than doubled the rate of diagnosis of MS within a year of presentation with a clinically isolated syndrome. The high specificity, positive predictive value, and accuracy of the new criteria for clinically definite MS support their clinical relevance.

Adolescent↗
PubMed2002

Reproducibility of in vivo metabolite quantification with proton magnetic resonance spectroscopic imaging.

PURPOSE: To investigate intra- and interscanner in vivo reproducibility of brain metabolite quantification using 1H magnetic resonance spectroscopic imaging (1H-MRSI) (PRESS localization, TE = 30 msec, voxel volume = 2.3 mL) and the linear combination model (LCModel). MATERIALS AND METHODS: One subject had a total of nine scans on three occasions at a single site, and three subjects had single scans at two sites. Coefficients of variation (CVs) were estimated using different statistical models applied to intra- and interscanner data; therefore, only qualitative comparisons may be made between results. RESULTS: CV (intra-/interscanner) for metabolite quantifications were choline, 12.3%/10.1%; creatine, 9.9%/10.6%; glutamate + glutamine, 15.8%/13.6%; myo-inositol, 18.5%/14.7%; and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate, 6.1%/7.0%. Overall, total intra- and intersubject variability was greater than intra- and interscanner variability. CONCLUSION: When quantifying metabolic concentrations using the methods employed in this study, biological factors contribute a greater proportion to measurement variability than measurement errors. Using this technique, intra- and intersite measurement errors are of the same order.

Adult↗
PubMed2002

The reproducibility and sensitivity of brain tissue volume measurements derived from an SPM-based segmentation methodology.

PURPOSE: To investigate the reproducibility of SPM99-based whole brain, gray matter, and white matter volume measurements with and without image inhomogeneity correction, subsequently exploring age and gender effects on absolute and fractional (proportional to intra-cranial) volumes. MATERIALS AND METHODS: Twenty-seven control subjects (aged 23.2 to 55.2 years) had three-dimensional fast spoiled gradient recall scans. Ten subjects were scanned about 197 days later. RESULTS: Coefficients of variation (CV) for absolute and fractional volumes determined from images processed with inhomogeneity correction ranged from 1.2% to 0.5%. Inhomogeneity correction reduced the CV for all measures except gray matter fractional (GMF) volumes. Significantly lower white matter absolute (WM) and fractional (WMF) volumes, and higher GMF were found in females compared with males, overlying age-related reductions (in decreasing order of significance) in brain parenchymal fraction, GMF, WMF, brain parenchymal, and gray matter volumes. CONCLUSION: SPM99 segmentations are sufficiently reproducible to detect age and gender effects in limited cohorts.

Adult↗
PubMed2002

ADC mapping of the human optic nerve: increased resolution, coverage, and reliability with CSF-suppressed ZOOM-EPI.

The mean apparent diffusion coefficient (ADC) of the human optic nerve (ON) has been quantified in vivo, and mean ADC maps are shown along the complete length of the nerve from the globe to the optic chiasm. The mean ADC, over the whole nerve, is shown to be 1058 x 10(-6) mm(2) s(-1) (standard deviation (SD), over nine 3-mm slices, 101x10(-6) mm(2) s(-1); range (833-1178)x10(-6) mm(2) s(-1)). The robustness of the method relies on acquisition of high-resolution coronal images of the ON using the ZOOM-EPI technique, which makes use of a shortened echo train length for increased resolution with decreased susceptibility-induced distortions. Suppression of the cerebrospinal fluid (CSF) and fat signals from tissues that surround the ON also helps successful identification and delineation of the nerve. Averaging of magnitude images is used to compensate for the inherently low signal-to-noise ratio (SNR) of the acquired images; the effects of the Rayleigh distributed noise in such images are allowed for during ADC calculations.

Cerebrospinal Fluid↗
PubMed2002

Investigating cervical spinal cord structure using axial diffusion tensor imaging.

This study describes a new technique for Diffusion Tensor Imaging (DTI) that acquires axial (transverse) images of the cervical spinal cord. The DTI images depict axonal fiber orientation, enable quantification of diffusion characteristics along the spinal cord, and have the potential to demonstrate the connectivity of cord white matter tracts. Because of the high sensitivity to motion of diffusion-weighted magnetic resonance imaging and the small size of the spinal cord, a fast imaging method with high in-plane resolution was developed. Images were acquired with a single-shot EPI technique, named ZOOM-EPI (zonally magnified oblique multislice echo planar imaging), which selects localized areas and reduces artefacts caused by susceptibility changes between soft tissue and the adjacent vertebrae. Cardiac gating was used to reduce pulsatile flow artefacts from the surrounding cerebrospinal fluid. Voxel resolution was 1.25 x 1.25 mm(2) in-plane with 5-mm slice thickness. Both the mean diffusivity (MD) and the fractional anisotropy (FA) indices of the cervical spinal cord were measured. The FA index demonstrated high anisotropy of the spinal cord with an average value of 0.61 +/- 0.05 (highest value of 0.66 +/- 0.03 at C3), comparable to white matter tracts in the brain. The diffusivity components parallel and orthogonal to the longitudinal axes of the cord were lambda( parallel) = (1648 +/- 123) x 10(-6) mm(2)s(-1) and lambda( perpendicular) = (570 +/- 47) x 10(-6) mm(2) s(-1), respectively. The high axial resolution allowed preliminary evaluation of fiber connectivity using the fast-marching tractography algorithm, which generated traces of fiber paths consistent with the well-known cord anatomy.

Algorithms↗
PubMed2002

Disability and lesion load in MS: a reassessment with MS functional composite score and 3D fast FLAIR.

The correlation between T2 lesion load (LL) detected on conventional MR sequences and disability assessed by the Expanded Disability Status Scale (EDSS) in multiple sclerosis (MS) is, at best, moderate. The present study was performed to determine whether the correlation between disability and LL is improved by (i) use of the more sensitive three-dimensional fast fluid-attenuated inversion recovery (3D-fast FLAIR) sequence; (ii) application of the newly devised MS functional composite (MSFC) score. Forty-one patients with clinically definite or probable MS were studied. All had been followed prospectively for 14 years since their first symptom. EDSS and MSFC score were assessed. Imaging was performed with 3D-fFLAIR, fast spin-echo (FSE), and T1 weighted SE sequences. 3D-fFLAIR detected a 34% higher LL than FSE, but did not improve the correlation between T2 LL and EDSS (r = 0.51 and r = 0.53); the correlation was stronger with T1 LL (r = 0.57). The MSFC score did not significantly correlate with T2 LL or T1 LL. The robust correlation in this cohort between T2 LL and EDSS may reflect the homogeneous disease duration and the wide spread of disability. This correlation was not improved by the increased detection of T2 lesions with the 3D-fFLAIR sequence. The stronger correlation between T1 LL with EDSS is consistent with the finding that this subgroup of lesions represent areas of more severe tissue damage. The MSFC score did not improve the clinico-radiological paradox that is found in MS, despite including information on cognitive function.

Adolescent↗
PubMed2002

Monitoring disease activity and progression in primary progressive multiple sclerosis using MRI: sub-voxel registration to identify lesion changes and to detect cerebral atrophy.

OBJECTIVE: To explore the potential usefulness of two new magnetic resonance imaging (MRI) analysis techniques for assessment of progressive cerebral atrophy and T2 lesion activity in primary progressive multiple sclerosis (PPMS), and thereby assess the relationship between MRI activity and atrophy in this patient group. BACKGROUND: Measurements of cerebral atrophy and net change in T2 lesion volumes are currently used as surrogate markers of disease progression in multiple sclerosis (MS). However, manual implementation of these techniques is time-consuming and the pathological specificity of T2 lesion change is low. Advances in serial scan registration have facilitated the development of a new, fully-automated technique to measure cerebral volume (SIENA; Structural Image Evaluation, using Normalisation, of Atrophy), and a technique to measure the total new T2 lesion volume selectively (MRI difference imaging). METHOD: SIENA measures changes in cerebral size based on sub-voxel detection of shifts in edge contours. The lesion difference imaging method measures differences in lesion volumes over time as defined by a semi-automated outlining technique. The two new methods were validated against the T2 lesion volume contour technique and a previously described measure of partial brain volume (which uses six slices centred on the presumed area of greatest change around the lateral ventricles). All were applied to serially acquired MR images from a cohort of 39 patients with PPMS, who also underwent scoring on the expanded disability status scale (EDSS) twice, two years apart. RESULTS: The two measures reflecting cerebral atrophy correlated strongly (r = 0.58, p < 0.001). T2 lesion load measurements using the two techniques correlated very highly (r = 0.999, p < 0.001). 91% of the total new T2 lesion volume was from enlargement of pre-existent lesions and only 9 % from new, discrete, lesions. No relationship was seen between the traditional measure of net gain in T2 lesion load and either measure of atrophy. However, the fully-automated measure of total new T2 load correlated with both measures of atrophy (SIENA technique, r= -0.37, p= 0.02; six slice measure, r = -0.41, p = 0.01). There was no relationship between the MRI measures and changes in the EDSS. CONCLUSION: Both of the new image analysis techniques appear to be promising as sensitive markers for disease progression in PPMS. The correlation of total new T2 lesion volume with the progression of cerebral atrophy (which is known to be a consequence of axonal loss in progressive disease), compared with a lack of correlation with the traditional net gain in T2 lesion load is interesting and suggests that the total new T2 lesion volume may ultimately be the most useful measure.

Adult↗
PubMed2002

The relationship between lesion and normal appearing brain tissue abnormalities in early relapsing remitting multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), pathological changes have been found both in macroscopic lesions and normal appearing tissue. Magnetisation transfer ratio (MTR) and T1 relaxation time are abnormal in normal appearing tissues in established MS. This study used these MR techniques in early MS to study normal appearing tissues and lesions. The purpose was to determine whether abnormalities are already detectable in normal appearing tissues in early MS, and if so how they correlate with lesion characteristics. METHODS: Twenty two patients with early relapsing remitting (RR) MS (median disease duration 2 years, range 7 months-3 years) and 11 age-matched controls were studied. MTR and T1 relaxation times were measured in 9 regions of normal appearing white matter (NAWM) and 7 of normal appearing grey matter (NAGM). Gadolinium enhancing, T1-hypointense and T2 lesion loads were measured in all patients. RESULTS: When all regions were combined, there was a significant difference between patient and control NAWM for both T1 and MTR; T1 was abnormal in 6/9 and MTR in 3/9 NAWM regions. Global assessment of NAGM revealed a significant difference between patients and controls for Ti but not for MTR; T1 was significantly abnormal only in frontal NAGM. There was no significant correlation between NAWM T1 or MTR and any of the lesion load measurements. CONCLUSIONS: This study reveals quantitative MR abnormalities in both NAWM and NAGM in early RR MS, with more extensive changes in the former. The lack of correlation between NAWM and lesion abnormalities suggests that they have developed by at least partly independent mechanisms. T1 may be more sensitive than MTR in detecting subtle pathological changes in NAWM and NAGM.

Adult↗
PubMed2002

Image registration and subtraction to detect active T(2) lesions in MS: an interobserver study.

Serial MRI studies are used to analyse change in multiple sclerosis (MS) lesion volume in clinical trials. As such an evaluation is very time consuming and subject to quantification errors, one might assess only the change in number or size of lesions using subtracted images. The advantage of subtracted images is that both new and/or enlarging and resolving and/or shrinking lesions can be evaluated, resulting in a more precise volume change than a net volume change. We studied the interobserver agreement in the detection of active MS lesions using paired dual-echo T(2)-weighted spin-echo studies (3-mm slices) of 30 MS patients with a range of MS disease activity on MRI from treatment trials. Using an automatic matching algorithm based on mutual information, the follow-up scan was registered to baseline, after which subtracted images were obtained. After a training session with formulation of guidelines, six observers identified new, enlarging, resolving and shrinking lesions on subtracted images. Weighted kappa (kappa) values were calculated to assess interobserver agreement. Good agreement was found for new lesions (kappa 0.69 +/- 0.08), while moderate agreement was found for enlarging lesions (kappa 0.52 +/- 0.06). When new and enlarging lesions were combined, good agreement was found for "positive" activity (kappa 0.71 +/-0.06). The interobserver agreement was poor for resolving lesions (kappa 0.31 +/- 0.07), and moderate for shrinking lesions (kappa 0.53 +/- 0.08). In conclusion, the use of subtracted images in the visual detection of new T(2) lesions resulted in a good level of interobserver agreement for "positive" disease activity. Subtraction of registered images is a reliable, time efficient method to assess disease progression in MS.

Adult↗