Biomedical subjects

D H Miller

Publications and source records attributed to D H Miller.

At least 271 records · Page 15Linked to original sources

PubMed1997

Primary progressive multiple sclerosis.

Patients with multiple sclerosis who develop progressive disability from onset without relapses or remissions pose difficulties in diagnosis, monitoring of disease activity and treatment. There is a need to define the diagnostic criteria for this group more precisely and, in particular, to describe a comprehensive battery of investigations to exclude other conditions. The mechanisms underlying the development of disability and the role of MRI in monitoring disease activity in this clinical subgroup require elucidation, particularly in view of the lack of change on conventional imaging in the presence of continuing clinical deterioration. The prognosis is poor and there are currently no treatment trials for this form of the disease.

Disease Progression↗

PubMed1997

Sensitivity of contrast enhanced MRI in multiple sclerosis. Effects of gadolinium dose, magnetization transfer contrast and delayed imaging.

Although clinical end points remain the definitive measure of therapeutic efficacy in multiple sclerosis, more sensitive markers of disease activity are required to screen potential disease-modifying agents. The use of gadolinium contrast-media in MRI studies increases both the reliability and sensitivity of detecting active lesions in multiple sclerosis. We studied three potential methods for further improving sensitivity; the use of 0.3 mmol/kg (triple dose) gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA), magnetization transfer (MT) contrast imaging and the introduction of a delay between contrast-medium injection and imaging. Fifty patients were studied (seven with benign, 14 with relapsing-remitting, 10 with secondary progressive, 16 with primary progressive and three with transitional multiple sclerosis). Imaging was performed on two occasions, 24-72 h apart, with triple- and single-dose Gd-DTPA. Pairs of contrast-enhanced T 1-weighted studies, with and without MT, were obtained at three different times, i.e. within early (0-20 min), short-delay (20-40 min) and long-delay (40-60 min) time-windows. Nineteen patients did not have the full complement of studies. Seven patients suffered minor self-limiting adverse events possibly related to triple-dose Gd-DTPA. Overall, triple-dose Gd-DTPA resulted in a 75% increase in the number of enhancing lesions detected compared with the single dose (P < 0.002). The use of MT or delay alone did not significantly increase the sensitivity of either single- or triple-dose studies. The combination of MT and short delay increased the number of enhancing lesions detected with single-dose Gd-DTPA by 47% (P < 0.05) and with triple-dose Gd-DTPA by 27% (P < 0.01). Detection was not significantly further improved by a long delay. The most sensitive modality was MT imaging with a long delay following triple-dose Gd-DTPA, resulting in the detection of 126% more enhancing lesions than in standard single-dose imaging (P < 0.05). This applies to all subgroups except for primary progressive multiple sclerosis, in which none of these methods alone or in combination improved the sensitivity. We conclude that for relapsing-remitting and secondary progressive multiple sclerosis, the combination of triple-dose Gd-DTPA and delayed MT imaging more than doubles the sensitivity to contrast-enhancing lesions.

Adult↗

PubMed1997

Measurement of treatment efficacy and new trial results in multiple sclerosis.

The past 12 months have witnessed a considerable number of new publications of the results of phase I, II and III trials of new, putative disease modifying therapies in multiple sclerosis. Some important reports have appeared concerning the development and optimization of clinical and magnetic resonance imaging methods for measuring therapeutic outcome. A general sense of optimism continues to exist that there will be further progress in coming years in achieving more effective strategies for treating symptoms, and for preventing relapses and disease progression.

Clinical Trials as Topic↗

PubMed1997

Magnetisation transfer ratio of normal brain white matter: a normative database spanning four decades of life.

OBJECTIVES: To establish a normative database for magnetisation transfer ratio (MTR) measurements in the white matter of healthy adult brains. Such MTR values were evaluated for regional variation and evidence of differences associated with aging, sex, and handedness. METHODS: Forty one healthy volunteers, ranging in age from 16 to 55 years, underwent axial brain magnetisation transfer (MT) imaging on a 1.5 Tesla magnetic resonance scanner. Calculated MT images allowed evaluation of MTR from specific regions within the corpus callosum, cerebral hemispheres, and pons. RESULTS: Highest values were noted in the corpus callosum. No significant sex differences were seen for any region studied. Small but significant age related reductions in MTR were noted in the corpus callosum and other cerebral white matter regions studied. Comparing MTR values between young (16-35 years) and older (36-55 years) age groups, this was most apparent in the corpus callosum (40.82% units in the young group v 40.28% units in the older group, P < 0.05) and frontal white matter (39.65% units in the young group v 39.18% units in the older group, P < 0.005). In addition, values for MTR were analysed for evidence of hemispheric asymmetry. MTR values were higher in the left hemisphere for all regions studied, reaching significance in the centrum semiovale (37.75% units v 37.57% units, P < 0.05) and parieto-occipital white matter (37.67% units v 37.43% units, P < 0.05). No relation between such interhemispheric MTR differences and handedness was noted. CONCLUSIONS: Magnetisation transfer imaging shows significant age related changes in normal brain white matter. In addition to regional variations in MTR in the normal brain, there seem to be small but significant variations in MTR between the cerebral hemispheres. It is important to consider such normal variations when evaluating MTR in pathological states.

Adolescent↗

PubMed1997

Survey of the distribution of lesion size in multiple sclerosis: implication for the measurement of total lesion load.

OBJECTIVES: Quantitative measurement of lesion load on proton density or T2 weighted brain MRI in multiple sclerosis is a widely used marker of disease progression in treatment trials and natural history studies. However, it has proved difficult to obtain highly reproducible measurements. Several factors account for this, one of which is uncertainties in lesion identification, particularly very small white matter abnormalities. This paper aims to ascertain the significance of very small white matter abnormalities in the measurement of lesion load in multiple sclerosis. METHODS: All visible lesion areas identified by an experienced observer on proton density weighted spin echo brain MRI with 5 mm thick slices were measured by using a contouring technique in 15 patients with secondary progressive multiple sclerosis (SPMS) and 13 with relapsing remitting multiple sclerosis (RRMS). The size distribution of these lesions was analysed. RESULTS: 80% of the number of the lesions were smaller than 80 mm2. Lesions that were smaller than 10 mm2 (equivalent diameter <3.5 mm) made up nearly 20% of all lesions; their relative contribution to the total lesion load varied from 0.0-5.7% (mean=1.1%, median=0.65%) in individual patients, and was larger when the total lesion load was smaller (r = -0.65, P<0.001). Median lesion size was significantly smaller in the SPMS group than the RRMS group. CONCLUSIONS: The results suggest that it is prudent to identify and measure small lesions in evaluating treatment effects, and that measures are undertaken (for example, using thinner slices such as 3 mm) to improve their detection.

Adult↗

PubMed1997

1H magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis.

OBJECTIVES: To test the hypothesis that irrecoverable neurological deficit in multiple sclerosis is associated with axonal loss. METHODS: 1H magnetic resonance spectroscopy (MRS) was carried out in a group of patients with clinically definite multiple sclerosis (n=31). Using this technique, the apparent concentration of NA ([NA] the sum of N-acetyl aspartate (NAA), a neuronal marker, and N-acetylaspartylglutamate has been compared in four groups of patients with multiple sclerosis classified as relapsing-remitting, secondary progressive, primary progressive, benign, and a control group. RESULTS: In the patients with relapsing-remitting disease (n=9) there was a highly significant reduction of apparent NA (median 8.73 mM, range 6.86 mM-10.74 mM, P=0.0008) from an area of high signal compared with the control group (median 11.97 mM, range 10.55 mM-14.5 mM). In the patients with secondary progressive disease (n=10), there was again a highly significant reduction of apparent NA (median 7.82 mM, range 3.5 mM-10.3 mM, P=0.0003) from an area of high signal compared with the control group. In the patients with primary progressive disease (n=6) there was once again a highly significant reduction of apparent NA (median 8.83 mM, range 6.95 mM-9.89 mM, P<0.002) from an area of high signal compared with the control group. In the patients with benign disease, however, there was no significant difference in the apparent NA (median 10.5 mM, range 8.53 mM-12.8 mM, P>0.05) from an area of high signal compared with the control group. In the patients with benign disease (n=5) there was also no significant difference in the apparent NA (median 10.74 mM, range 8.58 mM-13.4 mM, P>0.3) from an area of normal appearing white matter compared with the control group. In the patients with primary progressive disease, however, there was a significant reduction of apparent NA from an area of normal appearing white matter (median 8.78 mM, range 8.7 mM-12.38 mM, P< 0.025) compared with the control group. There was a significant inverse correlation between [NA] from lesions in the patients with multiple sclerosis and disability as measured on the Kurtzke expanded disability scale score (r= -0.364, 0.05>P>0.02). CONCLUSION: These findings support the hypothesis that axonal loss is important in the development of disability in multiple sclerosis. They also provide evidence for axonal loss in normal appearing white matter in patients with primary progressive disease.

Adolescent↗

PubMed1997

Lymphocyte-endothelial cell interactions in multiple sclerosis: disease specificity and relationship to circulating tumour necrosis factor-alpha and soluble adhesion molecules.

This study addressed two questions; first, whether the supranormal adherence of blood lymphocytes from patients with multiple sclerosis (MS) to endothelial cell monolayers treated with tumour necrosis factor-alpha (TNF alpha) was a feature common to other inflammatory disorders; and second, whether the adherence properties of blood lymphocytes from MS patients were related to changes in disease activity and to levels of circulating TNF alpha and soluble adhesion molecules. In the first part of the investigation, lymphocytes from 14 patients with MS were more adherent to TNF alpha-treated endothelial cells (P < 0.01) than those from healthy controls, whereas the adherence properties of lymphocytes from 12 patients with rheumatoid arthritis, eight patients with psoriasis and ten patients with neurological diseases other than MS were normal. In the second phase of the work, measurement of the adhesive properties of lymphocytes isolated at monthly intervals from a further six MS patients over a 5-8 month period, found that changes in binding to TNF alpha-treated endothelial cells, directly paralleled changes in circulating levels of TNF alpha (r = 0.77; P < 0.001) and soluble vascular cell adhesion molecule-I (sVCAM-1) r = 0.67; P = 0.001). An increase in disease activity, measured by T2-weighted and gadolinium-enhanced magnetic resonance imaging of the central nervous system (CNS), occurred in two patients and was associated with heightened lymphocyte adhesiveness and a rise in serum TNF alpha levels. Further analysis of the 34 serum samples from the six MS patients revealed a direct relationship between the concentration of sL-selectin and soluble intercellular adhesion molecule-I (sICAM-I) (r = 0.65; P < 0.001) and between sL-selectin and sTNF alpha (r = 0.42; P < 0.02). These findings support the view that disease activity in MS is associated with an increased adhesive interaction of blood lymphocytes with vascular endothelium at inflammatory sites within the CNS.

Adult↗

PubMed1997

Inter-rater variability in reporting enhancing lesions present on standard and triple dose gadolinium scans of patients with multiple sclerosis.

In this study we evaluated and compared the inter-rater variabilities in detecting enhancing lesions in patients with MS after injection of a standard dose (s.d.) and a triple dose (TD) of gadolinium (Gd). Enhanced magnetic resonance imaging (MRI) were obtained in 15 patients, consisting of T1-weighted images 5 to 7 min after the injection of the s.d. (0.1 mmol/kg) of Gd and, after an interval of 6 to 24 h, 5 to 7 min after the injection of the TD (0.3 mmol/kg). An additional scan 1 h after the TD injection (delayed scanning-DS) was obtained in 11 patients. The scans were independently evaluated in a random order by four observers. Lesions were counted and scored according to size and location. The level of inter-observer observer concordance was very high for reporting the total numbers of enhancing lesions, their sizes and sites for the three experimental conditions. No significant differences were found in inter-observer variability in reporting the total number of enhancing lesions and their location in different brain sites in the three conditions. Our data indicate that the gain in sensitivity in detecting enhancing lesions in MS with the TD is not counteracted by a loss in reproducibility. This is important in planning clinical trials in which the number of enhancing lesions is used as a measure of outcome.

Brain↗

PubMed1997

Effects of anti-CD4 antibody treatment on lymphocyte subsets and stimulated tumor necrosis factor alpha production: a study of 29 multiple sclerosis patients entered into a clinical trial of cM-T412.

T lymphocytes may play a central role in MS. The search for more targeted immunosuppression than is currently available has led to recent clinical trials of novel therapeutics. We studied 29 patients in a double-blind placebo-controlled trial of the chimeric monoclonal anti-CD4 antibody, cM-T412 (Centocor, Leiden, Holland) over a period of 18 months. Total and differential WBC counts; T, B, and natural killer lymphocytes; CD4+ and CD8+ T cells; CD4+ and CD4- naive cells; CD4+ and CD4- memory cells; interleukin-2 receptor- and major histocompatibility class II-positive T cells; serum tumor necrosis factor alpha (TNF-alpha); and PHA (phytohemagglutinin)/LPS (lipopolysaccharide)-stimulated whole blood TNF-alpha production were all examined serially in peripheral blood for the duration of the trial. In addition, for the first two treatment cycles, the above variables were tested 1 and 7 days after treatment. The results demonstrated significant long-term reductions, lasting up to 12 months after the last treatment cycle in all CD4+ subsets studied, but with a relative preservation of CD4+ memory cells as opposed to CD4+ naive cells. CD4- subsets also showed significant reductions after treatment but returned to baseline levels within 7 days. Monocyte counts were unaffected by cM-T412. Serum TNF-alpha and 2- and 18-hour PHA/LPS-stimulated TNF-alpha levels were also unchanged in the long term, although significant increases were observed in the 2- and 18-hour PHA/LPS-stimulated TNF-alpha levels the day immediately after treatment. There was no significant correlation between any of the immunologic markers studied and MRI measures of disease activity.

Adult↗

PubMed1997

Longitudinal study of soluble adhesion molecules in multiple sclerosis: correlation with gadolinium enhanced magnetic resonance imaging.

OBJECTIVE: To assess whether serial serum levels of soluble forms of intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) are useful as surrogate markers of disease activity in multiple sclerosis (MS). BACKGROUND: Increased levels of sICAM-1 and sVCAM-1 have been described in cross-sectional, but not longitudinal, studies of patients with MS. Although they appear to correlate with clinical and MRI markers of disease activity, their role as potential surrogate markers remains undefined. METHODS: Serial serum levels of sICAM-1 and sVCAM-1 were measured in patients with MS undergoing monthly gadolinium-enhanced MRI studies of the brain (462 gadolinium-enhanced MRI in 57 patients) and in 12 normal control subjects. Ten patients had primary progressive (PP), 22 relapsing remitting (RR), and 25 secondary progressive (SP) disease. RESULTS: Levels of sICAM-1 and sVCAM-1 were increased intermittently in patients with all subtypes of MS. Median levels of sICAM-1 were elevated in patients with MS compared with normal controls (normal controls median [interquartile range] = 176[119-209] compared with PP = 502[194-1768], RR = 419[158-481], and SP = 352[196-469] ng/mL; p = 0.04). After excluding patients with PP MS, patients with high sICAM-1 levels had a greater number of gadolinium-enhancing lesions per study (1.9[0.9-4.3]) than patients with normal levels (0.4[0-2.7], p = 0.03), and patients with MRI studies with no gadolinium-enhancing lesions had lower associated sICAM-1 levels (200 ng/mL[85-561]) than patients with only persistent (349 ng/mL[82-615]) or new enhancing lesions (497 ng/mL[108-667], p = 0.03). Patients with RR or SP disease that progressed clinically during the study had a greater number of gadolinium-enhancing lesions per MRI study (3.5[0.4-5.5]) than did patients in whom disease did not progress (1.2 [0.3-2.7], p = 0.03). The patients with progressive disease tended to have higher sICAM-1 levels (469 ng/mL [196-1019]) than patients in whom disease did not progress (353 ng/mL [171-469], p = 0.07). Although MS patients tended to have higher sVCAM-1 levels than did normal controls, this finding was not significant. No correlation could be found between levels of sVCAM-1 and gadolinium enhancement on MRI. CONCLUSIONS: Patients with MS have elevated levels of sICAM-1, which correlate with gadolinium enhancement on MRI and possibly short-term disease progression. Soluble ICAM-1, and not sVCAM-1, may therefore be suitable as a long-term surrogate marker of disease activity in MS.

Adult↗

PubMed1997

Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial.

We report the results of a randomized, double-blind, placebo-controlled exploratory trial of the chimeric monoclonal anti-CD4 antibody cM-T412 in 71 patients suffering from active relapsing-remitting and secondary progressive multiple sclerosis. Infusion of the antibody produced frequent but usually minor side effects and resulted in a long-lasting reduction of circulating CD4-positive T cells. There was no significant effect on the primary measure of efficacy, the number of active lesions on monthly gadolinium-enhanced MRI over 9 months. Further statistical evaluation provided evidence that the degree of depletion of CD4-positive cells was important with regard to treatment efficacy; using CD4 counts as a covariate there was a statistically significant effect on the number of active lesions over 18 months (p = 0.04). There was a statistically significant reduction of 41% in the number of clinical relapses (a secondary efficacy parameter) after 9 months (p = 0.02), which was still present after 18 months, but this finding may be partly due to physician unblinding. Other secondary efficacy parameters (Expanded Disability Status Scale progression, number of courses of methylprednisolone) were not influenced by anti-CD4 treatment. We conclude that intravenous treatment with the monoclonal antibody cM-T412 in the dosage we used results in a substantial and sustained reduction of the number of circulating CD4-positive cells, but is not able to reduce MS activity as measured by monthly gadolinium-enhanced MRI, and is therefore unlikely to have a beneficial effect on the clinical disease course. We found preliminary evidence suggesting that more aggressive depletion of CD4-positive cells might lead to a more substantial reduction in MRI activity.

Adult↗

PubMed1997

Multiple sclerosis lesion detection in the brain: a comparison of fast fluid-attenuated inversion recovery and conventional T2-weighted dual spin echo.

We performed fast fluid-attenuated inversion recovery (fFLAIR) and conventional spin echo (CSE) brain MRI in 32 multiple sclerosis (MS) patients (eight each benign, relapsing-remitting, primary progressive, and secondary progressive). We compared number and site of lesions detected on each sequence. With initial separate assessment, we identified a total of 3,668 lesions-2,892 by CSE and 2,943 by fFLAIR. Following simultaneous review of the sequences, we identified an additional 217 lesions on fFLAIR and 229 on CSE. fFLAIR detected fewer lesions in the posterior fossa (66 versus 138, p = 0.001), fewer small (< 5 mm) discrete cerebral white matter lesions (671 versus 829, p = 0.0002), more subcortical lesions (542 versus 306, p < 0.0001), and more large discrete lesions (419 versus 385, p = 0.0006). Its relatively poor detection of posterior fossa lesions makes it premature for fFLAIR to replace CSE as the primary sequence for detecting MS lesions in clinical trials.

Adult↗

PubMed1997

Interscanner variation in brain MRI lesion load measurements in MS: implications for clinical trials.

We evaluated the effect of interscanner variation on brain MRI-measured lesion volumes and measurement reproducibility in MS. Twenty clinically definite MS patients were each scanned on two or three scanners (a total of 14 scanners were used). In addition, a formalin-fixed MS brain was studied on eight scanners from different manufacturers and with different field strengths. For the formalin-fixed MS brain, on each machine we obtained two scans with slice thicknesses of 5 and 3 mm. Only 5-mm-thick slices were obtained from patients. The lesion volume present on each scan was evaluated three times by a single observer in random order, using a local thresholding technique. In two groups of eight patients scanned on machines with different field strengths, the mean lesion volumes present on scans obtained at 1.5 T were significantly higher than those measured on scans obtained with machines operating at 0.5 and 1.0 T (p < 0.01). When a single observer repeatedly evaluated the same scan, a median introbserver agreement of 98.7% (95% CI, 97.9 to 99.1) was achieved. However, when the observer evaluated the scans from different MRI scanners, the agreement (an interscanner agreement) fell to 91.1% (CI, 90.2 to 94.1). When only scanners operating at 1.5 T were considered, the median interscanner agreement was 96.7% (CI, 95 to 97.5). Also, for the formalin-fixed MS brain, the intraobserver agreements obtained with both slice thicknesses were significantly higher than the corresponding interscanner agreements. The interscanner agreement, but not the intraobserver agreement, obtained with a slice thickness of 3 mm was higher than that obtained with a slice thickness of 5 mm. Our results indicate that lesion volume measurements in MS are influenced significantly by the use of different MR scanners and that a patient included in a serial study should be always scanned with the same MR machine using 3-mm thick slices.

Adult↗

PubMed1997

Trigeminal neuralgia in patients with multiple sclerosis: lesion localization with magnetic resonance imaging.

We performed conventional T2-weighted brain MRI examinations in six patients with multiple sclerosis (MS) and trigeminal neuralgia. In all patients brainstem lesions in positions expected to involve trigeminal fibers, particularly the entry zone of sensory fibers, were demonstrated. Compression of the trigeminal nerve by ectatic vessels, a recognized cause of idiopathic trigeminal neuralgia, was not observed. We conclude that in MS trigeminal neuralgia is usually caused by demyelinating lesions affecting pontine trigeminal pathways.

Adult↗

PubMed1997

Improving interobserver variation in reporting gadolinium-enhanced MRI lesions in multiple sclerosis.

Gadolinium-enhanced MRI is a sensitive and objective means to monitor disease activity in multiple sclerosis (MS). We evaluated the interobserver agreement and the value of observer training in reporting enhancing lesions from serial MRI. Scans of 16 MS patients were evaluated by five inexperienced and five experienced observers before and after consensus formation and training. The number of lesions at baseline, and the number of new and persistent lesions at follow-up were scored. For each condition, weighted kappa values (kappa) and the mean average difference to the median (MADM) scores were calculated. Without training, the experienced readers showed good agreement on number of lesions at baseline and new lesions at follow-up, and moderate agreement for persistent lesions. The inexperienced readers showed poor agreement for baseline and persistent lesions, and moderate agreement for new lesions. After training, both groups reported lower absolute numbers of lesions, especially the inexperienced readers. The experienced readers showed good agreement for all lesion types, the inexperienced readers showed agreement for baseline and new lesions, and agreement was moderate for persistent lesions. In both groups MADM scores were < 0.72 for baseline and new lesions, but > 1.2 for persistent lesions. Interobserver agreement is improved by training, especially in inexperienced readers. Interobserver agreement in reporting gadolinium-enhanced lesions is high, which validates the use of serial, enhanced MRI as an outcome parameter in treatment trials in MS.

Analysis of Variance↗

PubMed1997

Single-dose gadolinium with magnetization transfer versus triple-dose gadolinium in the MR detection of multiple sclerosis lesions.

PURPOSE: To compare the efficacy of single-dose gadolinium with magnetization transfer contrast (MTC) with that of triple-dose gadolinium in detecting enhancing multiple sclerosis lesions. METHODS: Twenty-one patients with multiple sclerosis were examined with MR imaging first with 0.1 mmol/kg gadolinium (single dose) and then, after 24 to 72 hours, with 0.3 mmol/kg gadolinium (triple dose). T2-weighted fast spin-echo and T1-weighted spin-echo MR images with and without MTC were obtained before contrast administration followed by either T1-weighted spin-echo images with MTC (single dose) or conventional T1-weighted spin-echo images (triple dose), starting 5, 17, and 29 minutes after contrast administration. All images were evaluated in a blinded fashion and scored in random order by two readers. Outcome parameters included number of enhancing lesions, number of active MR examinations (those containing at least one enhancing lesion), contrast ratio (signal intensity of enhancing lesion divided by signal intensity of normal-appearing white matter), and size of enhancing lesions. RESULTS: Eighty-one percent more enhancing lesions and 49% more active MR examinations were detected when a triple dose of gadolinium was used as compared with a single dose. The level of agreement between readers as to the number of enhancing lesions was significantly higher for triple-dose than for single-dose gadolinium. With triple-dose gadolinium, contrast ratios and areas of enhancement increased by 10% and 33%, respectively. Delayed imaging increased the size of the lesion by 11% on single-dose MTC images and by 18% on triple-dose images. CONCLUSION: Triple-dose gadolinium is more effective (higher sensitivity and interobserver agreement) than single-dose gadolinium in combination with MTC in detecting enhancing multiple sclerosis lesions.

Adult↗

PubMed1996

Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis. US National MS Society Task Force.

Because of the major difficulties in measuring clinical end points in multiple sclerosis (MS) treatment trials, there has been much enthusiasm for using magnetic resonance imaging (MRI) findings as an alternative outcome. To provide international consensus guidelines for the use of MRI in MS clinical trials, a task force of the US National MS Society was convened. The recommendations of the task force are presented in this review. Given the high sensitivity for detecting pathological activity in relapsing-remitting and secondary progressive MS, monthly T2-weighted and gadolinium-enhanced brain MRI is an excellent tool for short-term exploratory trials of new agents where it serves as the primary end point; in particular, failure to demonstrate a reduction in lesion activity avoids the time, cost, and risks of a larger clinical end point study. However, conventional MRI findings have a limited correlation with disability in established MS. The primary end point of a definitive trial should therefore be clinical, although serial MRI at 6- to 12-month intervals is a useful secondary end point in providing an index of pathological progression. In trials of patients presenting with clinically isolated syndromes suggestive of MS, MRI findings can be used in the entry criteria, and as a secondary outcome measure, but conversion to clinically definite MS should be the primary outcome. The pathological substrates of irreversible disability are demyelination and axonal loss. Putative magnetic resonance markers for these processes include decreased N-acetylaspartate on proton magnetic resonance spectroscopy, decreased magnetization transfer ratios, hypointensity on T1-weighted images, and loss of short T2 water fractions, some of which relate more closely to disability than conventional MRI findings. Further technical developments should lead to more accurate quantitation, greater pathological specificity, and stronger clinical correlations.

Clinical Trials as Topic↗

PubMed1996

Brainstem encephalopathy with stimulus-sensitive myoclonus leading to respiratory arrest, but with recovery: a description of two cases and review of the literature.

Two unrelated patients developed bulbar symptoms, followed within several weeks by spontaneous myoclonus and painful, generalized, stimulus-sensitive jerks triggered by unexpected noises and cutaneous stimuli. They progressed to respiratory arrest and required mechanical ventilation, but both patients subsequently made an almost full recovery. These cases stress the importance of persevering with supportive treatment despite rapid progression of this severe generalized movement disorder. The relationship of brainstem reflex myoclonus to hyperekplexia, progressive encephalomyelitis with rigidity, and the stiff-man syndrome is discussed.

Adult↗