Severe cerebral white matter involvement in a case of dentatorubropallidoluysian atrophy studied at autopsy

BACKGROUND: The pathophysiology of white matter involvement in dentatorubropallidoluysian atrophy (DRPLA) is controversial. Moreover, the clinical repercussions and evolution of these lesions have not been well documented. OBJECTIVE: To describe a case of DRPLA with severe cerebellar white matter involvement. DESIGN: Case report.Patient A 62-year-old woman with DRPLA. RESULTS: When the genetic diagnosis was made, the patient manifested severe ataxia, slight dysarthria, and subcortical cognitive impairment. Cranial magnetic resonance imaging showed atrophy of the cerebellum and brainstem and moderate high-intensity signal alterations in the periventricular cerebral white matter in T2-weighted sequences. In the following 5 years, she developed uncontrolled head movements associated with severe bruxism and tetraparesis, and became deeply demented. New magnetic resonance imaging showed severe diffuse cerebral white matter alterations in T2 sequences with only slight progression of brainstem and cerebellar atrophy. After her death at 67 years of age, the autopsy study showed diffuse myelin pallor, axonal preservation, and reactive astrogliosis in the cerebral white matter, with only mild atherosclerotic changes, and moderate neuronal loss in the cerebellum and brainstem. CONCLUSIONS: Leukoencephalopathy could be a prominent finding in some patients with DRPLA, explaining, at least in part, their clinical evolution. In our case, the disproportion between the severity of white matter damage and vascular changes does not support a cardinal role for ischemic mechanisms in leukoencephalopathy.     

Age exacerbates HIV-associated white matter abnormalities

Both HIV disease and advanced age have been associated with alterations to cerebral white matter, as measured with white matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), and more recently with diffusion tensor imaging (DTI). This study investigates the combined effects of age and HIV serostatus on WMH and DTI measures, as well as the relationships between these white matter measures, in 88 HIV seropositive (HIV+) and 49 seronegative (HIV?) individuals aged 23–79 years. A whole-brain volumetric measure of WMH was quantified from FLAIR images using a semi-automated process, while fractional anisotropy (FA) was calculated for 15 regions of a whole-brain white matter skeleton generated using tract-based spatial statistics (TBSS). An age by HIV interaction was found indicating a significant association between WMH and older age in HIV+ participants only. Similarly, significant age by HIV interactions were found indicating stronger associations between older age and decreased FA in the posterior limbs of the internal capsules, cerebral peduncles, and anterior corona radiata in HIV+ vs. HIV? participants. The interactive effects of HIV and age were stronger with respect to whole-brain WMH than for any of the FA measures. Among HIV+ participants, greater WMH and lower anterior corona radiata FA were associated with active hepatitis C virus infection, a history of AIDS, and higher current CD4 cell count. Results indicate that age exacerbates HIV-associated abnormalities of whole-brain WMH and fronto-subcortical white matter integrity.     

Neuronal apoptosis in HIV infection in adults

Productive infection of the central nervous system by HIV predominantly involves the white matter and basal ganglia. Involvement of the cerebral cortex with neuronal loss is also described in AIDS patients but not in asymptomatic HIV-positive patients. The mechanism of neuronal damage is unknown. To enquire whether neuronal loss in AIDS may be due to an apoptotic process, we examined the cerebral cortex from 12 patients who died from AIDS using two different methods: in situ end labelling and gel electrophoresis of DNA to demonstrate DNA fragmentation. None of the patients had cerebral opportunistic infection or tumour. Four patients had no significant neuropathological changes, eight patients had variable cerebral atrophy and four of them also had productive HIV infection of the brain. These patients were compared with four HIV-positive asymptomatic patients, five seronegative asymptomatic controls, and two seronegative patients with Alzheimer's disease. We demonstrated neuronal apoptosis in the cortex in all AIDS patients, as well as in the Alzheimer's patients. Apoptosis was not observed in the asymptomatic cases whether seropositive or seronegative. Neuronal apoptosis was more severe in atrophic brains, and did not directly correlate with productive HIV infection, suggesting an indirect mechanism of neuronal damage is most likely.     

Differences in brain volumes among males and female hormone-therapy users and nonusers

Numerous studies have shown gender differences in the brain volumes of elderly adults. Some evidence shows that higher estrogen levels may be neuroprotective, suggesting that hormone therapy (HT) may in part be responsible for these gender differences; however, few studies have examined the relation between HT and brain volumes. Brain volumes of caudate, putamen, hippocampus, gray matter, white matter, white-matter lesions, and cerebrospinal fluid were measured on magnetic resonance imaging scans. A comprehensive neuropsychological battery was administered. Women were separated into two groups based on HT use, and we used multiple regression analyses to compare these groups with one another and with men. Results of brain-volume measurements showed that HT users had significantly less gray matter and more cerebrospinal fluid than nonusers. Results of the neuropsychological testing showed that HT users performed better on the Shipley Vocabulary Test than males did.     

Assessment of the impact of the removal of cerebrospinal fluid on cerebral tissue volumes by advanced volumetric 3D-MRI in posthaemorrhagic hydrocephalus in a premature infant

Current clinical practice in the premature infant with posthaemorrhagic ventricular dilatation (PHVD) includes drainage of cerebrospinal fluid (CSF). This case study used advanced volumetric three dimensional magnetic resonance imaging to document the impact of CSF removal on the volume of regional brain tissues in a premature infant with PHVD. The removal of a large volume of CSF was associated with an identical reduction in CSF volume, but more dramatically with a significant increase in the regional volumes of cortical grey matter and myelinated white matter. The alterations in cerebral cortical grey matter and myelinated white matter volumes may provide insight into the established association of PHVD with deficits in cognitive and motor functions.     

Cerebral tissue alterations and daily life stress experience in psychosis

OBJECTIVE: To examine whether the total volumes of cerebrospinal fluid (CSF), cerebral grey matter and white matter were correlated with the experience of environmental stress in daily life situations. METHOD: Twenty-seven patients with psychosis underwent magnetic resonance imaging scanning and a random time-sampling self-assessment technique (Experience Sampling Method) to determine subjective daily life stress experiences. Total cerebral tissue volumes were derived from an automated segmentation procedure. RESULTS: CSF volume was positively associated with daily life event-related stress (beta=0.016, P=0.002), while the association with total white matter was negative (beta=-0.013, P=0.005). The effects were independent of each other and of total cerebral volume and other confounders. No large or significant association was found with grey matter volume. CONCLUSION: Subjective stress experience in daily life is associated with increased CSF and reduced white matter volumes in patients with psychosis, suggesting functional significance of these cerebral measures.     

Evidence of subtle gray-matter pathologic changes in healthy elderly individuals with nonspecific white-matter hyperintensities

OBJECTIVE: To investigate whether additional "occult" tissue changes can be detected in the normal-appearing white matter and gray matter of otherwise normal elderly individuals with nonspecific white-matter hyperintensities on conventional magnetic resonance images of the brain. METHODS: Conventional and magnetization transfer magnetic resonance images were obtained from 12 otherwise normal elderly subjects with white-matter hyperintensities and 11 age- and sex-matched normal individuals. After automatic tissue segmentation, image coregistration, and masking of T2-visible lesions, we obtained magnetization transfer ratio histograms of the normal-appearing white matter and gray matter. For each histogram, the average magnetization transfer ratio, the peak height, and the peak position were measured. We also calculated the percentages of gray-matter and white-matter volumes normalized over the total volume of the intracranial content and the total normalized brain volumes. RESULTS: Average magnetization transfer ratio (P =.03) and mean peak position (P =.01) of the gray-matter histograms from elderly individuals with white-matter hyperintensities were significantly lower than the corresponding quantities from those without white-matter hyperintensities. The normalized percentages of gray and white matter and normalized brain volume did not differ between the 2 groups. The average gray-matter magnetization transfer ratio was correlated with the average lesion magnetization transfer ratio (r = 0.68; P<.01). CONCLUSIONS: This study shows that brain abnormalities in otherwise normal elderly subjects with nonspecific white-matter hyperintensities extend beyond the macroscopic white-matter lesions visualized on conventional magnetic resonance images.     

Succinate in dystrophic white matter: a proton magnetic resonance spectroscopy finding characteristic for complex II deficiency

A deficiency of succinate dehydrogenase is a rare cause of mitochondrial encephalomyopathy. Three patients, 2 sisters and 1 boy from an unrelated family, presented with symptoms and magnetic resonance imaging signs of leukoencephalopathy. Localized proton magnetic resonance spectroscopy indicated a prominent singlet at 2.40ppm in cerebral and cerebellar white matter not present in gray matter or basal ganglia. The signal was also elevated in cerebrospinal fluid and could be identified as originating from the two equivalent methylene groups of succinate. Subsequently, an isolated deficiency of complex II (succinate:ubiquinone oxidoreductase) was demonstrated in 2 patients in muscle and fibroblasts. One of the sisters died at the age of 18 months. Postmortem examination showed the neuropathological characteristics of Leigh syndrome. Her younger sister, now 12 months old, is also severely affected; the boy, now 6 years old, follows a milder, fluctuating clinical course. Magnetic resonance spectroscopy provides a characteristic pattern in succinate dehydrogenase deficiency.     

Clinical correlates of white-matter abnormalities on head magnetic resonance imaging

We undertook this study to investigate the relationship between white-matter abnormalities (seen on brain magnetic resonance imaging [MRI]) and muscle tone and muscle stretch reflexes on clinical examination. We identified all patients less than 5 years of age who had undergone cranial MRI studies at Riley Hospital for Children between June 30, 1999, and July 1, 2000, whose scans were read as showing white-matter abnormalities. We measured two ratios and the thickness of the corpus callosum as indicators of the quantity of cerebral white matter. The ratios were R1, the ratio of the thickness of the white matter at the level just above the body of the lateral ventricle compared with the width of the hemisphere, and R2, the ratio of the thickness of the white matter to the width of the hemisphere at the level of the trigone of the lateral ventricle. The thickness of the corpus callosum was measured at the junction of the anterior two thirds and the posterior third. We also evaluated the signal intensity of the cerebral white matter by reviewing the fluid-attenuated inversion-recovery images and grading the signal as normal to severely abnormal depending on the degree and extent of high signal intensity seen (0 = normal to 4+). Thirty-eight children less than 5 years of age who underwent MRI scans between June and August 2000 and who were found to have normal tone prospectively and normal MRI scan on review served as a control group. We identified 215 patients who had white-matter abnormalities; of these, only 142 (66%) had documented tone assessments in their medical record. Our study group was divided into three groups: increased (n = 35), decreased (n = 53), and normal tone (n = 54). All three measurements of white matter in each of the three study groups were significantly below values for control children. The children with white-matter abnormalities and decreased tone had significantly less signal intensity abnormality than the other study groups. Children with white-matter abnormalities and increased tone had a greater frequency of increased reflexes and tended to have more signal abnormalities than the other groups. The group of children with white-matter abnormalities and normal tone had the least amount of cerebral white-matter deficiency of the three study groups. In patients with strikingly decreased quantities of cerebral white matter, those with normal signal-intensity white matter are likely to be hypotonic with normal reflexes and those with increased signal intensity in the white matter are likely to be spastic.     

Clinical factors related to brain structure in HIV: the CHARTER study

Despite the widening use of combination antiretroviral therapy (ART), neurocognitive impairment remains common among HIV-infected (HIV+) individuals. Associations between HIV-related neuromedical variables and magnetic resonance imaging indices of brain structural integrity may provide insight into the neural bases for these symptoms. A diverse HIV+ sample (n?=?251) was studied through the CNS HIV Antiretroviral Therapy Effects Research initiative. Multi-channel image analysis produced volumes of ventricular and sulcal cerebrospinal fluid (CSF), cortical and subcortical gray matter, total cerebral white matter, and abnormal white matter. Cross-sectional analyses employed a series of multiple linear regressions to model each structural volume as a function of severity of prior immunosuppression (CD4 nadir), current CD4 count, presence of detectable CSF HIV RNA, and presence of HCV antibodies; secondary analyses examined plasma HIV RNA, estimated duration of HIV infection, and cumulative exposure to ART. Lower CD4 nadir was related to most measures of the structural brain damage. Higher current CD4, unexpectedly, correlated with lower white and subcortical gray and increased CSF. Detectable CSF HIV RNA was related to less total white matter. HCV coinfection was associated with more abnormal white matter. Longer exposure to ART was associated with lower white matter and higher sulcal CSF. HIV neuromedical factors, including lower nadir, higher current CD4 levels, and detectable HIV RNA, were associated with white matter damage and variability in subcortical volumes. Brain structural integrity in HIV likely reflects dynamic effects of current immune status and HIV replication, superimposed on residual effects associated with severe prior immunosuppression.     

Brain magnetic resonance imaging findings in 49,XXXXY syndrome

Klinefelter syndrome is a chromosomal disorder characterized by one or more supernumerary X chromosomes, in addition to the normal 46,XY male karyotype. Whereas classic Klinefelter syndrome (47,XXY) occurs in 1:400 births, the most severe Klinefelter variant (49,XXXXY) occurs in only 1:85,000 births. The degree of cognitive impairment, specific skeletal changes, and genital abnormalities in Klinefelter syndrome variants is thought to correlate with the number of additional X-chromosomes present. Magnetic resonance imaging studies in individuals with classic Klinefelter syndrome show smaller brain volumes, but magnetic resonance imaging data are lacking for individuals with rarer and more severe Klinefelter variants. We present case reports and magnetic resonance imaging studies on 3 individuals with 49,XXXXY. All 3 patients exhibited varying degrees of volume loss and abnormalities in white matter. Changes in white matter may represent a specific finding in patients with severe Klinefelter variants such as 49,XXXXY, and karyotype analysis should be considered in patients with unexplained white-matter disease, especially when developmental delay or genital abnormalities are present.     

Gender Effects on HIV-Associated White Matter Alterations: A Voxel-Wise DTI Study

Sexual dimorphisms within the human brain are well-documented. Human immunodeficiency virus (HIV) infection is associated with atrophy and microstructural white matter alterations, yet sex-specific dimorphic brain alterations in persons living with HIV have not been systematically examined. To address this issue, we evaluated regional differences in normal-appearing white matter (NAWM) in adults with and without HIV utilizing diffusion tensor imaging. Through a voxel-by-voxel analytic approach, sexual dimorphisms in NAWM anisotropy and diffusivity were identified. In comparison to seronegative men and women, HIV infection contributed to a decline in the distribution of anisotropic differences between the sexes. Alterations in diffusivity were more complex, with seropositive women demonstrating an increase in regional diffusivity, while seropositive men demonstrated a reduction in regional differences. Sex by serostatus interactions within the left frontal lobe and bilateral thalamic region were identified. These results suggest that HIV contributes to sex-specific microstructural NAWM alterations, such that sex and serostatus differentially alter the integrity of the neuronal matrix. References marked with an asterisk indicate HIV-associated studies reviewed for gender distributions.     

Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes

Cerebral metabolite disturbances occur among human immunodeficiency virus (HIV)-infected people, and are thought to reflect neuropathology, including proinflammatory processes, and neuronal loss. HIV-associated cortical atrophy continues to occur, though its basis is not well understood, and the relationship of cerebral metabolic disturbance to structural brain abnormalities in HIV has not been well delineated. We hypothesized that metabolite disturbances would be associated with reduced cortical and subcortical volumes. Cerebral volumes were measured in 67 HIV-infected people, including 10 people with mild dementia (acquired immunodeficiency syndrome [AIDS] dimentia complex [ADC] stage >1) via automated magnetic resonance imaging (MRI) segmentation. Magnetic resonance spectroscopy (MRS) was used to measure levels of cerebral metabolites N-acetylaspartate (NAA), myo-inositol (MI), choline-containing compounds (Cho), glutamate/glutamine (Glx), and creatine (Cr) from three brain regions (frontal gray matter, frontal white matter, basal ganglia). Analyses were conducted to examine the associations between MRS and cerebral volumetric measures using both absolute and relative metabolite concentrations. NAA in the mid-frontal gray matter was most consistently associated with cortical (global, frontal, and parietal), ventricular, and caudate volumes based on analysis of absolute metabolite levels, whereas temporal lobe volume was associated with basal ganglia NAA and Glx, and Cho concentrations in the frontal cortex and basal ganglia. Hippocampal volume was associated with frontal white matter NAA, whereas thalamic volume was associated with both frontal white matter NAA and basal ganglia Glx. Analyses of relative metabolite concentrations (referenced to Cr) yielded weaker effects, although more metabolites were retained as significant predictors in the models than the analysis of absolute concentrations. These findings demonstrate that reduced cortical and subcortical volumes, which have been previously found to be linked to HIV status and history, are also strongly associated with the degree of cerebral metabolite disturbance observed via MRS. Reduced cortical and hippocampal volumes were most strongly associated with decreased NAA, though reduced Glx also tended to be associated with reduced cortical and subcortical volumes (caudate and thalamus) as well, suggesting both neuronal and glial disturbances. Interestingly, metabolite-volumetric relationships were not limited to the cortical region from which MRS was measured, possibly reflecting shared pathophysiological processes. The relationships between Cho and volumetric measures suggest a complicated relationship possibly related to the effects of inflammatory processes on brain volume. The findings demonstrate the relationship between MRI-derived measures of cerebral metabolite disturbances and structural brain integrity, which has implication in understanding HIV-associated neuropathological mechanisms.     

Toluene abuse causes diffuse central nervous system white matter changes

We describe the findings of magnetic resonance imaging (MRI) of the brain in 6 chronic toluene vapor abusers and the neuropathological findings in 1 abuser not studied by MRI. MRI in 6 chronic toluene abusers revealed the following abnormalities: (1) diffuse cerebral, cerebellar, and brainstem atrophy; (2) loss of differentiation between the gray and white matter throughout the central nervous system; and (3) increased periventricular white matter signal intensity on T2-weighted images. Another chronic toluene abuser (MRI not performed) died as a result of acute toluene overdose. The brain displayed diffuse, ill-defined myelin pallor, maximal in cerebellar, periventricular, and deep cerebral white matter. Neurons were preserved throughout, axonal swelling or beading was not seen, gliosis was minimal, and occasional, scant perivascular macrophage collections were seen. Taken in concert, these findings suggest that the pathological and MRI abnormalities are due to either increased water content of the white matter or subtle toluene-induced metabolic changes in myelin.     

Clinical correlates of white-matter changes on magnetic resonance imaging scans of the brain

We report our observations on the clinical and radiologic correlates of changes in cerebral white matter based on 94 subjects undergoing magnetic resonance imaging in a prospective study of dementia. Periventricular hyperintensity occurred twice as often in patients with Alzheimer's disease as in healthy control subjects. Within the control group, the presence of periventricular hyperintensity correlated significantly with one measure of cerebral atrophy and with the presence of changes in the adjoining deep white matter. The significance of white-matter changes distinct from the ventricles (leuko-araiosis) remains unsettled. Leuko-araiosis on the magnetic resonance imaging scan, unlike its correlate on the computed tomographic scan, was not shown to relate to cognitive decline or to the presence of focal abnormalities on neurologic examination. This is likely to reflect the heterogeneity of the changes detected with magnetic resonance imaging and their limited extent in our subjects.     

Brain integrity and cerebral atrophy in Vietnam combat veterans with and without posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is associated with decreased hippocampal volume, but the relationship between trauma and brain morphology in the absence of PTSD is less clear. In this study, measures of brain integrity were determined by estimating gray and white matter regional brain volumes using structural magnetic resonance imaging in six patients with PTSD and in five controls with comparable trauma exposure but without clinical evidence of PTSD. The only statistically significant volume difference between groups was observed multivariately in the white matter of the right temporal lobe (superior temporal gyrus, fusiform gyrus, parahippocampal gyrus, white-matter stem, middle temporal gyrus, and inferior temporal gyrus), although small sample sizes limit the power to detect between-group differences. Both groups showed heterogeneity in cerebral atrophy.     

Brain Integrity and Cerebral Atrophy in Vietnam Combat Veterans with and without Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is associated with decreased hippocampal volume, but the relationship between trauma and brain morphology in the absence of PTSD is less clear. In this study, measures of brain integrity were determined by estimating gray and white matter regional brain volumes using structural magnetic resonance imaging in six patients with PTSD and in five controls with comparable trauma exposure but without clinical evidence of PTSD. The only statistically significant volume difference between groups was observed multivariately in the white matter of the right temporal lobe (superior temporal gyrus, fusiform gyrus, parahippocampal gyrus, white-matter stem, middle temporal gyrus, and inferior temporal gyrus), although small sample sizes limit the power to detect between-group differences. Both groups showed heterogeneity in cerebral atrophy.     

Deterioration on magnetic resonance imaging despite good clinical recovery after viral encephalitis

We present a 2-year-old patient who showed progressive widespread white-matter abnormalities on magnetic resonance imaging 1 month after viral encephalitis, despite her good clinical recovery. These lesions on magnetic resonance imaging had not responded to therapies commonly used to treat secondary immune-mediated demyelinating lesions, as observed in acute disseminated encephalomyelitis. Acute viral encephalitis caused cortical blindness, but no other clinical signs developed during her clinical course. The progressive white-matter lesion in our case was different from the exacerbation of viral encephalitis or secondary immune-mediated encephalitis. A year later, magnetic resonance imaging-demonstrated brain atrophy with cystic changes in the bilateral occipital area, with remarkably reduced white-matter lesions. We hypothesize that the progressive white-matter changes resulted from the process of atrophy, degeneration, and cystic formation after viral encephalitis, rather than from the immune-mediated demyelinating process.     

Superior temporal gyrus volumes in maltreated children and adolescents with PTSD.

BACKGROUND: The structure and function of the superior temporal gyrus (STG), a structure involved in receptive and nonverbal auditory and language processing, is understudied in posttraumatic stress disorder (PTSD). Event-related potential abnormalities were previously reported in PTSD, implicating the existence of dysfunction in the primary auditory cortex and adjacent anterior auditory cortex of the STG in adult PTSD. METHODS: Anatomic magnetic resonance imaging (MRI) volumetric analysis of the superior temporal gyrus were performed in 43 maltreated children and adolescents with PTSD and 61 nonmaltreated healthy control subjects. RESULTS: Unadjusted STG gray matter volumes were larger in maltreated subjects with PTSD than in control subjects, whereas STG white matter volumes were smaller in maltreated subjects with PTSD than in control subjects. After adjusting for differences in cerebral volume, right, left, and total superior temporal gyrus volumes were relatively larger in PTSD subjects compared with control subjects. After covarying for differences in cerebral gray matter volumes, regression analysis showed that PTSD subjects had significantly greater STG gray matter volumes in most, and in particularly right-sided STG measurements. Furthermore, findings of significant side-by-diagnosis interactions for STG and STG gray but not white matter STG volumes suggest that there is a more pronounced right > left asymmetry in total and posterior STG volumes but a loss of the left > right asymmetry seen in total, anterior, and posterior STG gray matter volumes in PTSD subjects compared with control subjects. CONCLUSIONS: These STG findings may suggest developmental alterations in maltreatment-related pediatric PTSD.     

Acute disseminated encephalomyelitis after Japanese B encephalitis vaccination.

A 6-year-old girl (Patient 1) and a 5-year-old boy (Patient 2) with acute disseminated encephalomyelitis after Japanese B encephalitis vaccination are reported. Drowsiness, paresthesias, and gait disturbance were observed at 14 days (Patient 1) and 17 days (Patient 2) after the vaccination; however, transient impairment of visual acuity was only found in Patient 1. Laboratory examinations revealed slow theta waves on electroencephalography and elevated myelin basic protein in the cerebrospinal fluid in both patients. The most striking feature on magnetic resonance imaging was the combination of white matter lesions and abnormal intensity signals of the thalamus. The administration of oral prednisolone (2 mg/kg/day) markedly improved the clinical findings and abnormal magnetic resonance imaging findings. A similar magnetic resonance imaging finding of abnormal intensity of the thalamus with deep white matter lesions has been reported in patients with Japanese B encephalitis; therefore, thalamic lesions may be related to the naturally occurring encephalitis.