Faculty Bibliography

PURPOSE: The purpose of this study was twofold: first, to compare two different measures of lesion burden in patients with multiple sclerosis (MS), the magnetization transfer ratio (MTR) histogram and T2 lesion volume; and, second, to investigate the relationship between lesion burden and atrophy in patients with MS. METHODS: Thirty patients with MS were examined with MR imaging, including fast spin-echo T2- and proton density-weighted sequences as well as magnetization transfer sequences. The lesion burden in each subject was quantitated by MTR histographic analysis and by a computer-based method for calculating the total volume of lesions on T2-weighted images. Additionally, the CSF volume, the brain parenchymal volume, and the percentage of brain parenchymal volume were determined in all patients by using this method and were compared with measurements in eight control subjects. RESULTS: Significant loss of parenchymal volume was seen in patients with MS as determined by increased CSF volume and decreased percentage of brain parenchymal volume relative to that in age-matched control subjects. An inverse correlation was observed between the peak height of the MTR histogram and T2 lesion volume. T2 lesion volume corresponded positively with CSF volume and inversely with percentage of brain parenchymal volume. The peak height of the MTR histogram corresponded positively with percentage of brain parenchymal volume and inversely with CSF volume. CONCLUSION: MS patients sustain a significant loss of parenchymal volume (atrophy), which corresponds strongly with increasing lesion burden. T2 lesion volume and peak height of the MTR histogram show good correlation, and the peak height of the MTR histogram shows a superior correlation with measures of brain atrophy as compared with measurements of T2 lesion volume, suggesting that the MTR histogram may be a better indicator of global disease burden than is T2 lesion volume

We examined the relations between quantitative volumetric estimates of cerebral lesion load based on magnetization transfer imaging (MTI), clinical data, and measures of neuropsychological function in 44 patients with clinically diagnosed MS. In this population we assessed the correlation between several volumetric MTI measures, measures of neurologic function (Kurtzke Expanded Disability Status Scale and Ambulation Index), and disease duration using Spearman's correlation coefficient. Patients were classified on the basis of neuropsychological test performance as severely impaired, moderately impaired, and normal. We assessed differences between these groups with respect to MTI results using the Kruskal-Wallis test. MTI measures corrected for brain volume were found to correlate with disease duration (p < 0.01) and showed suggestive correlations with measures of neurologic impairment (p < 0.05). Individual neuropsychological tests correlated with MTI measures corrected and not corrected for brain volume (p < 0.001). An MTI measure not corrected for brain volume differed (p < 0.05) between severely impaired, moderately impaired, and normal patients. These preliminary results suggest that volumetric MTI analysis provides new measures that reflect more accurately the global lesion load in the brain of MS patients, and they may serve as a method to study the natural course of the disease and as an outcome measure to evaluate the effect of drugs

The predictive value of T2-weighted imaging in multiple sclerosis is only moderate, due to low specificity of high signal on such images. Among new MR techniques with acclaimed higher pathological specificity, hypointense lesions on moderately T1-weighted spin echo images show improved correlation with disability. The degree of hypointensity of so called black holes correlates with loss of magnetisation transfer, a marker of matrix destruction. Severe tissue loss is also shown histopathologically in a post-mortem MR study of black holes. In this review unresolved issues regarding black holes are discussed including standardisation of sequences, definition of hypointensity, interobserver variation in measuring lesion load with this technique, and significance of acute black holes. The role of black holes in monitoring treatment efficacy is as yet unexplored

Magnetic resonance imaging techniques based on magnetisation transfer exploit the inherent heterogeneity of tissue with respect to relaxation times T1 and T2. Contrast reflecting the interactions between distinct relaxation 'environments' may be exploited via novel quantitative analysis for potential gains in specificity of the MR examination in multiple sclerosis

We studied the frequency and location of isolated U-fiber involvement in MS and correlated these findings exploratively with physical disability and neuropsychological impairment. Fifty-three MS patients were examined. Three-millimeter-thick, fast spin-echo T2-weighted MR images and spin-echo postgadolinium T1-weighted images were obtained. Computer software that which had been validated previously for quantitation of MS lesions was used to detect lesions on the T2-weighted images. The Expanded Disability Status Scale (EDSS), Ambulation Index (AI), and a battery of neurocognitive tests were performed on each patient. Forty-two arcuate hyperintensities along the U-fiber were detected by the software in 28 patients (53%). Twenty-seven lesions (64.3%) were seen in the frontal lobe, eight (19.0%) in the temporal lobe, three (7.1%) in the parietal lobe, three (7.1%) in the occipital lobe, and one (2.4%) in both frontal and parietal lobes. Four lesions (9.5%) showed gadolinium enhancement. Seventeen lesions (40%) were hypointense on the T1-weighted images. Scores of three of the 11 neuropsychological tests reflecting performance in executive control and memory were significantly different at least at the p = 0.05 level between the eight patients with multiple, isolated U-fiber lesions and the 45 patients without any or with only a single U-fiber lesion. No significant difference was noted for EDSS or AI. Isolated U-fiber involvement is an underappreciated MR finding in MS. Our preliminary hypothesis is that U-fiber lesions may contribute to neuropsychological impairment, although our observation requires confirmation

OBJECT: This study was conducted to determine whether proton magnetic resonance spectroscopy (MRS) is a sensitive method for detecting diffuse axonal injury, which is a primary sequela of traumatic brain injury (TBI). Diffuse axonal injury is characterized by selective damage to white matter tracts that is caused in part by the severe inertial strain created by rotational acceleration and deceleration, which is often associated with motor vehicle accidents. This axonal injury is typically difficult to detect by using conventional imaging techniques because it is microscopic in nature. The splenium was selected because it is a site vulnerable to shearing forces that produce diffuse axonal injury. METHODS: The authors used proton MRS to evaluate the splenium, the posterior commissure of the corpus callosum, in normal control volunteers and in patients with TBI. Proton MRS provided an index of neuronal and axonal viability by measuring levels of N-acetyl aspartate (NAA). CONCLUSIONS: A majority of mildly brain injured patients, as well as those more severely injured, showed diminished NAA/creatine (Cr) levels in the splenium compared with normal control volunteers. The patients displaying lowered NAA/Cr in the splenium were also likely to exhibit lowered NAA/Cr in lobar white matter. Also, the levels of NAA/Cr in the splenium of normal volunteers were higher compared with those found in lobar white matter. Decreases in NAA/Cr levels in the splenium may be a marker for diffuse injury. A proton MRS examination may be particularly useful in evaluating mildly injured patients with unexplained neurological and cognitive deficits. It is concluded that MRS is a sensitive tool in detecting axonal injury

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

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

A 32 year old man with symptoms of an upper respiratory infection one week prior presented with mental status changes, diffuse hyperreflexia, and bilateral extensor plantar responses. An MRI scan showed multifocal areas of high signal intensity predominantly in the parietal and occipital white matter, unassociated with mass affect. Despite aggressive treatment, the patient's symptoms rapidly progressed and he was declared brain dead. Post-mortem examination revealed acute hemorrhagic leukoencephalopathy. The clinical and pathologic features of this disorder are reviewed