Postmortem unfixed whole brains from five multiple sclerosis (MS) patients were examined by MRI using a T2- and T1-weighted spin-echo (SE) sequence and histology to investigate the histopathologic characteristics of hypointense lesions on T1-weighted SE MR images. The degree of hypointensity was scored semiquantitatively by two blinded observers in reference to normal-appearing white matter. Signal intensities of the lesions and the normal-appearing white matter were measured to obtain contrast ratios. Hematoxylin-eosin stain was used to assess degree of matrix destruction (decrease of density of the neuropil) and cellularity of a lesion, Klüver-Barrera stain for degree of demyelination, Bodian stain for axonal density, and immunostaining of glial fibrillary acid protein for reactive astrocytes and fibrillary gliosis. Nineteen lesions were selected for analysis. Nearly all lesions were compatible with the chronic MS plaque: hypocellularity, absence of myelinated axons, in the presence of reactive astrocytes. Contrast ratios of the lesions were highly correlated (R = -0.90; p < 0.01), with degree of hypointensity scored semiquantitatively. Degree of hypointensity on T1-weighted SE images did not correlate with degree of demyelination or number of reactive astrocytes, but was associated with axonal density (R = -0.71; p = 0.001). A trend was found with degree of matrix destruction (R = 0.45; p = 0.052). We conclude that, in our limited sample, hypointense lesions seen on T1-weighted SE MR images are associated histopathologically with severe tissue destruction, including axonal loss. Our results need to be substantiated in a larger study on more varied patient material to evaluate the use of hypointense lesions as a surrogate marker of persistent deficit in MS patients.

Article abstract-We identified nine children with a leukoencephalopathy of similar type according to clinical and MRI findings. The patients included three affected sibling pairs. The age range was 3 to 19 years. The onset of the disease was in childhood; the course was both chronic-progressive and episodic, There were episodes of deterioration following infections and minor head traumas, and these could result in unexplained coma. In eight patients with advanced disease, MRI revealed a diffuse cerebral hemispheric leukoencephalopathy, in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In one patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter, which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate, compatible with the presence of mainly CSF and little brain tissue. Spectra of the cortex were much better preserved. However, in addition to the normal resonances, there were signals representing lactate and glucose. MRS of the white matter in the patient whose disease was at an early stage was much less abnormal. Autopsy in one patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. Typical involve ment of pontine tegmental white matter was suggested by MRI and confirmed by autopsy. The disease probably has an autosomal recessive mode of inheritance, but the basic metabolic defect is not known. NEUROLOGY 1997;48:845-855 There is a growing number of progressive encepha lopathies identified and defined by enzyme defect, gene defect, or both.1 MRI has contributed consider ably to the detection of leukoencephalopathies,2 but a significant proportion remains unclassified.3 In some cases, MRI and magnetic resonance spectroscopy (MRS) findings are sufficiently distinct to be used as criteria for a classifying diagnosis.4As part of an ongoing study of unclassified leu koencephalopathies, we identified nine patients with a distinct disorder, as defined by clinical and MRI criteria. We describe the clinical picture, metabolic investigations, and neurophysiologic studies, as well as MRI, MRS, and autopsy findings, and provide criteria for the diagnosis. Proton ^H) MRS was performed in five patients (pa tients 3, 4, 5, 7, and 9) with the standard imaging head coil. We used single-voxel spectroscopy in order to achieve a high-quality assessment of the neurochemical composi tion of white matter versus cortex. A 2 X 2 X 2 cm3 voxel was chosen in the mid-occipital area, containing mainly occipital cortex of both hemispheres and some white mat ter and CSF. Another voxel of 2 X 2 X 2 cm3 was chosen in the parieto-occipital area, containing white matter and, at most, some ventricular CSF. The spectra were acqui...

Later onset does occur in the disease of vanishing white matter, and both MRS and histopathology are compatible with a primary axonopathy rather than primary demyelination.

Child Behavior Checklist questionnaires (Achenbach, 1992), filled in separately by mothers and fathers, were collected for an effective sample of 3501 Dutch 3-year-old twin pairs. To disentangle the child's phenotype from that of the rater, two contrasting models were fitted to the data. One model, called a Rater Bias model, is based on the assumption that both parents assess exactly the same behaviors in the child. A weaker alternative of this model, called a Psychometric model, assumes that apart from these common behavioral views, each parent also assesses a unique aspect of the child's behavior. A Psychometric model fitted the data of both Internalizing and Externalizing scales significantly better than a Rater Bias model. This implied that each parent provided unique information from his or her own perspective, apart from the common behavioral view. Using this best fitting model, the etiology of both the Internalizing and Externalizing scales was studied. Common factors (influencing behaviors similarly assessed by both parents) were more important than unique factors (influencing behaviors uniquely assessed by one parent). Common genetic factors explained about 50 % of the variance of both scales, indicating a possible inborn vulnerability to childhood psychopathology. Common environmental factors not shared between twins (free of unreliability and error) explained around 14 % of both scales, suggesting the importance of pure idiosyncratic experiences even for children as young as 3 years. Common environmental factors shared between twins (unconfounded by rater bias) were only found for the Externalizing scale, explaining 18 % of the variance. Rater bias and unreliability, if present in the data, were included in the estimates of the unique factors. Unique genetic, shared, and nonshared environmental factors each explained around 8 % of the variance for both scales. These small effects could be detected because of the large sample of twin pairs used.