Diffuse White Matter Abnormalities Research Articles

Hereditary Ataxias

Hereditary Ataxias

Merosin and congenital muscular dystrophy

Merosin (also called as Laminin-2) is an isoform of laminin comprised of the alpha2, beta1 and gamma1 chains. In European populations, half of the patients with classical congenital muscular dystrophy have mutations of the LAMA2 gene (6q22-23) and present reduced or absence of laminin alpha2 chain. This form is generally referred to as merosin-deficient CMD. Merosin-deficient CMD is characterized by involvement of not only skeletal muscle but also central and peripheral nervous systems: Extensive brain white matter abnormalities are found by magnetic resonance imaging (MRI). However, most patients show no mental retardation. Recent case studies reported that some patients have several structural abnormalities such as abnormal cerebral cortical gyration, hypoplasia of cerebellum and pons, and dilation of ventricles. At present, functions of merosin related to muscle degeneration have not been fully elucidated. In addition, the mechanisms responsible for pathogenesis of diffuse brain white matter abnormalities remain to be determined. As mouse models for merosin-deficient CMD, three spontaneous mutants(dy, dy(2J), dy(PAS1)) and two mutants named dy(W) and dy(3K) by targeted gene disruption have been reported. These mice will help to elucidate the pathogenesis of merosin-deficient CMD and serve to develop therapy.

Magnetic resonance diffusion tensor imaging for characterizing diffuse and focal white matter abnormalities in multiple sclerosis.

High-resolution diffusion tensor imaging (DTI) was performed in 14 patients with clinically definite multiple sclerosis (MS) and the trace of the diffusion tensor (<D>) and the fractional anisotropy (FA) were determined in normal appearing white matter (NAWM) and in different types of focal MS lesions. A small but significant increase of the <D> in NAWM compared to control white matter ((840 +/- 85) x 10(-6) mm(2)/sec vs. (812 +/- 59) x 10(-6) mm(2)/sec; P < 0.01) was found. In addition, there was a significant decrease in the FA of normal-appearing regions containing well-defined white matter tracts, such as the genu of the internal capsule. In non-acute lesions, the <D> of T(1)-hypointense areas was significantly higher than that of T(1)-isointense lesions ((1198 +/- 248) x 10(-6) mm(2)/sec vs. (1006 +/- 142) x 10(-6) mm(2)/sec; P < 0. 001), and there was a corresponding inverse relation of FA. Diffusion characteristics of active lesions with different enhancement patterns were also significantly different. DTI with a phase navigated interleaved echo planar imaging technique may be used to detect abnormalities of isotropic and anisotropic diffusion in the NAWM and selected fiber tracts of patients with MS throughout the entire brain, and it demonstrates substantial differences between various types of focal lesions.

Notch3 mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a mendelian condition causing stroke and vascular dementia.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited condition whose key features include recurrent subcortical ischemic events, migraine attacks and vascular dementia in association with diffuse white-matter abnormalities seen on neuroimaging. Pathologic examination shows multiple small deep cerebral infarcts, a leukoencephalopathy and a nonatherosclerotic nonamyloid angiopathy involving mainly the media of small cerebral arteries. To progress in understanding the pathophysiological mechanisms of this condition, we undertook the identification of the mutated gene. We mapped the CADASIL gene on chromosome 19p13.1. More than 120 families have been referred to our lab. Genetic linkage analysis of 33 of these families allowed us to reduce the size of the genetic interval to less than 1 cM and to demonstrate the genetic homogeneity of this condition. In the absence of any candidate gene, we undertook positional cloning of this gene. We identified, within the CADASIL critical region, the human Notch3 gene, whose sequence analysis revealed deleterious mutations in CADASIL families co-segregating with the affected phenotype. These data establish that this gene causes CADASIL. Identification of the CADASIL gene will provide a valuable diagnostic tool for clinicians and could be used to estimate the prevalence of this underdiagnosed condition. It should help in the understanding of pathophysiological mechanisms of CADASIL and vascular dementia.

Magnetic resonance imaging in classification of congenital muscular dystrophies with brain abnormalities.

A survey was performed of magnetic resonance imaging (MRI) findings in 21 patients with congenital muscular dystrophy (CMD) with cerebral abnormalities to evaluate the contribution of MRI to the classification of CMD patients. In 5 patients with Walker-Warburg syndrome (WWS), MRI showed hydrocephalus due to aqueduct stenosis, generalized cerebral cortical agyric or pachygyric polymicrogyria, diffuse cerebral hemispheric white matter abnormalities, and malformations of posterior fossa structures. In 4 patients with muscle-eye-brain disease, MRI showed cortical dysplasia, but less severe than in WWS. The cerebral white matter either was normal or contained multiple focal abnormalities. Malformations of posterior fossa structures were present. Eight patients, classified as having classic merosin-deficient CMD (MD-CMD), had diffuse cerebral hemispheric white matter abnormalities, no other abnormalities. One patient with MD-CMD had only a few, focal white matter abnormalities. Three CMD patients had occipital agyria, otherwise normal gyration, multifocal or more diffuse cerebral white matter changes, and variable hypoplasia of pons and vermis. Two of the 3 patients had negative muscle merosin staining. The conclusion of the study is that MRI is an important adjunct in the classification of CMD patients. CMD with occipital agyria can be regarded as a newly recognized, separate CMD subtype.

Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.

Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.

Magnetic resonance imaging and magnetic resonance angiography in long term survivors of acute lymphoblastic leukemia treated with cranial irradiation

Successful treatment of acute lymphoblastic leukemia (ALL) has resulted in an increasing number of patients whose disease is cured. This treatment includes cranial irradiation as prophylaxis against central nervous system relapse. The late effects of irradiation are well documented, but their incidence is unknown. The authors investigated the late effects of this treatment modality further by scanning 35 long term survivors of ALL who received cranial irradiation. Thirty-five survivors of ALL with no known complication of treatment were included in this study. They were examined with magnetic resonance imaging (MRI) of the brain and magnetic resonance angiography (MRA) of the circle of Willis. A control group of 24 patients who were cured of other childhood malignancies without exposure to cranial irradiation also were scanned. Fifteen of 35 (43%) abnormalities were found in the study group versus 4/24 (17%) in the control group. Excluding minor atrophic changes that are known to be produced by irradiation and chemotherapy, there were 9/35 (26%) abnormalities in the study group and 1/24 (4%) in the control group (P < 0.05). These abnormalities included three tumors, a meningioma, a paranasal sinus rhabdomyosarcoma, and an anaplastic astrocytoma. In addition, there were two cases of large vessel vasculopathy, two small cystic infarcts, one diffuse white matter abnormality, and one cryptic vascular malformation. The abnormal control patient had a cerebellar infarct. Complications of cranial irradiation in the treatment of ALL appear to be more frequent than currently are appreciated. That these complications include tumors that are potentially treatable suggests that screening may be valuable for these patients.

Magnetic Resonance Imaging Findings in Japanese Encephalitis

Ten patients with Japanese encephalitis diagnosed by serological criteria underwent magnetic resonance imaging (MRI) in axial and coronal sections. In 6, a second MRI study was done. The MRI findings were compared with the clinical outcome. Four patients died within several months of onset, 2 had sequelae such as hemiparesis and dementia, and the remaining 4 had no sequelae. In 9 of 10 patients, either diffuse or patchy white matter lesions were observed bilaterally, together with abnormalities in areas such as the thalamus, basal ganglia, and brainstem. For 3 patients who died or remained demented, the second MRI revealed extensive, diffuse white matter abnormalities. This study indicates that Japanese encephalitis can produce white matter involvement, although gray matter structures such as the thalamus, basal ganglia, and brainstem are more severely affected. The severity of these MRI lesions correlated with the clinical outcome.

Callosal atrophy in patients with lacunar infarction and extensive leukoaraiosis. An indicator of cognitive impairment.

It is unclear why only some patients with lacunar infarction and radiological evidence of diffuse white matter abnormalities have dementia. The purpose of this study is to investigate the value of callosal atrophy as an indicator of cognitive impairment. We used magnetic resonance imaging to evaluate 11 right-handed male patients with lacunar infarction and extensive white matter hypodensities on computed tomography (8 with dementia and 3 without dementia). The midsagittal corpus callosum area on T1-weighted images was compared with the IQ determined by the Wechsler Adult Intelligence Scale. The relation between these parameters and cerebral oxygen metabolism measured with positron emission tomography was also evaluated in the 8 patients with dementia. All patients showed diffuse high-intensity areas in the bilateral hemispheric white matter on T2-weighted images. Compared with 19 age- and sex-matched right-handed normal control subjects, the patients had a significantly smaller callosal area. The severity of callosal atrophy, which varied from mild to severe, was significantly related to the total IQ. In the 8 demented patients, the total callosal area was significantly correlated with the mean level of oxygen metabolism in the cerebral white matter. In patients with lacunar infarction and diffuse white matter abnormalities, the presence of callosal atrophy may indicate cognitive impairment. Callosal atrophy may reflect the severity and extent of white matter damage associated with a decrease in oxygen metabolism, which may determine the severity of intellectual decline.

Deficiency in complex II of the respiratory chain, presenting as a leukodystrophy in two sisters with leigh syndrome

We report 2 sisters with a degenerative neurological disorder presenting clinically as a leukodystrophy. CT scan and MRI demonstrated small symmetrical foci of necrosis in the substentia nigra and in the basal ganglia typical of Leigh syndrome and diffuse cerebral white matter abnormalities. In these patients a deficiency in complex II of the respiratory chain was demonstrated in isolated mitochondria from muscle, as well as in fibroblasts and lymphocytes.

Very-low-birth-weight, preterm infants with or without intracranial hemorrhage. Neurologic, cognitive and cranial MRI correlations at 4-8-year follow-up.

Fourteen very-low-birth-weight (VLBW) preterm infants with and without intracranial hemorrhage (ICH) were prospectively followed from birth to 4 to 8 years for the purpose of determining neurologic and cognitive sequelae associated with ICH severity and to correlate outcomes with brain morphology as determined by Magnetic Resonance Imaging (MRI). Intracranial hemorrhage was documented by cranial ultrasonography performed in early life. Follow-up assessments included neurologic and psychometric examinations and cranial MRI scans. Of six children with no ICH, five had normal results on all three follow-up measures. Three children with Grade I-II ICH had mild to moderate neurologic and cognitive sequelae with focal white matter MRI abnormalities. Five children with Grade III-IV ICH had severe neurologic, cognitive, and MRI deficits, including MRI regional and diffuse white matter abnormalities and/or cortical atrophy. Focal and diffuse neurologic deficits correlated with the extent of MRI morphologic abnormalities. Results of this study indicate that ICH severity correlated with outcomes in children at follow-up; the more severe the ICH, the more adverse the neurologic, cognitive, and MRI results. MRI white matter abnormalities were present in all children with any degree ICH, while ventriculomegaly was seen only in severe ICH (Grade III-IV ICH). Neurologic deficits correlated with MRI structural abnormalities.

Leukoencephalopathy in Patients Treated with Amphotericin B Methyl Ester

Clinical and autopsy studies of 14 patients treated with amphotericin B methyl ester (AME) for focal, disseminated, and nervous system mycotic infections revealed a high incidence of progressive neurologic dysfunction (dementia, akinesia, mutism, hyperreflexia, and tremor) and diffuse white matter degeneration. All of seven patients who received greater than 9.8 g of AME intravenously developed severe neurologic and neuropathologic changes. Two of three patients given 5-7.2 g of AME developed less severe neurologic symptoms; all three had mild diffuse white matter gliosis. Four patients given less than 1.5 g of AME had no bran abnormalities except those related to coccidioidal meningitis. Thirty-one control patients who died on untreated or amphotericin B-treated coccidioidal meningitis showed no diffuse white matter abnormalities. These findings indicate that prolonged administration of AME and/or other contaminating polyenes injures human white matter. Long-term animal studies, with particular attention to nervous system histology, must precede human use of other polyene derivatives.