Diffuse White Matter Disease Research Articles

Understanding White Matter Disease

Most strokes are covert and observed incidentally on brain scans, but their presence increases risk of overt stroke and dementia. Amyloid angiopathy, associated with Alzheimer Disease (AD) causes stroke, and when even small strokes coexist with AD, they lower the threshold for dementia. Diffuse ischemic white matter disease impairs executive functioning, information processing speed, and gait. Neuroimaging techniques, such as tissue segmentation, Diffusion Tensor Imaging, MR Spectroscopy, functional MRI and amyloid PET, probe microstructural integrity, molecular biology, and activation patterns, providing new insights into brain-behavior relationships. MR-pathological studies of periventricular hyperintensity (leukoaraiosis) in aging and dementia reveal arteriolar tortuosity, reduced vessel density, and occlusive venous collagenosis which causes venous insufficiency and vasogenic edema. Activated microglia, oligodendroglial apoptosis, clasmatodendritic astrocytosis, and upregulated hypoxia-markers are seen on immunohistochemistry. Further research is needed to understand and treat this chronic subcortical vascular disease, which is epidemic in our aging population.

Diagnostic Criteria of Dementia

In the past two decades there has been a tremendous effort among clinicians and searchers to improve the diagnostic criteria of the dementias on the basis of the differential neurological and neuropsychological profiles. This was an obligatory requirement for clinical trials and the development of treatments. Over the years it became rapidly evident that the cohorts of patients in studies had some degree of heterogeneity, making it difficult to interpret the results of some studies, particularly in the vascular dementias and the mild cognitive impairment (MCI) group. For example, many sub-types of the vascular group were included in clinical trials, such as the cortical strokes, the lacunar states and the diffuse white matter disease cases, and some of the patients might have had also mixed pathology. In addition, the standard DSM IV criteria for dementia no longer represent our present knowledge of the clinical profile of some of the dementias such as vascular dementia (VaD) and fronto-temporal dementia where the memory impairment is not necessarily the first requirement. To improve the validity of clinical trials and eventually help developing more appropriate treatments, we revised the present diagnostic criteria and made recommendations for some changes in the context of the 2nd Canadian Conference on the Development of Antidementia Therapies, held in 2004 and reviewed in the light of the recent literature as of early 2006. It is expected that in the near future, these dementia criteria for clinical trials will have to be revised again in order to include specific subtypes of the dementias as well as biomarkers, structural and functional imaging.

Positional Nystagmus of Central Origin

Audiometric, electrophysiologic, and radiographic findings for a 68-year-old male with an "imbalance" concern are presented. This paper has a two-fold purpose: (1) to present an unusual electronystagmography case study and (2) to highlight the importance of test conditions in lesion localization. The specific disease pathophysiology remains obscure. Repeated hearing tests documented a known hearing impairment with worsening word-recognition ability of the right ear. An initial electronystagmographic exam was normal except for a mild ageotropic direction-changing positional nystagmus with eyes open and fixed. No repeatable click-evoked auditory brainstem response waveforms could be collected. A magnetic resonance imaging of the brain documents diffuse ischemic white matter disease. A repeated vestibular examination some months later supports the initial findings. The case illustrates the importance of following diagnostic protocol, of repeated measures, and of using both a visual fixation and a nonfixation condition for select electronystagmographic subtests.

Delayed Neurotoxicity in Primary Central Nervous System Lymphoma

Treatment for primary central nervous lymphoma (PCNSL) with chemotherapy and radiotherapy has resulted in improved survival, but some patients develop neurologic deterioration that represents a treatment-related toxic effect. This delayed neurotoxicity has been poorly defined in the literature, and the underlying mechanisms are unknown. To describe the clinical findings, time course, and pathophysiologic mechanisms associated with neurotoxicity in an attempt to generate hypotheses for future studies that address prevention and treatment of this complication of successful PCNSL therapy. Retrospective review. Department of Neurology, Memorial Sloan-Kettering Cancer Center. One hundred eighty-five patients treated for PCNSL, including 43 who developed neurotoxicity. Potential risk factors, clinical course, and neuropsychological, neuroimaging, and histologic findings. The 5-year cumulative incidence of neurotoxicity was 24%; this incidence increases over time. Neurotoxicity presented as a rapidly progressive subcortical dementia characterized by psychomotor slowing, executive and memory dysfunction, behavioral changes, gait ataxia, and incontinence. Imaging findings revealed diffuse white matter disease and cortical-subcortical atrophy. Available autopsy data showed white matter damage with gliosis, thickening of small vessels, and demyelination. Statistical analyses were performed, accounting for death as a competing risk. Older age (P = .01), mental status changes at diagnosis (P = .04), female sex (P = .05), and radiotherapy (P<.001) predicted neurotoxicity on univariate analysis, but only radiotherapy remained significant in the multivariate setting. These findings suggest that the core pathophysiologic mechanism is the interruption of frontal-subcortical circuits mediated by radiation damage, possibly caused by progressive microvascular alterations, loss of oligodendrocyte progenitors, or oxidative stress.

44 White Matter Abnormality is Associated with Volume Reduction in Deep Grey Nuclei Following Preterm Birth

Background. Diffuse white matter disease, which can be seen on MRI as Diffuse Excessive High Signal Intensity (DEHSI) and quantified using apparent diffusion coefficient (ADC) values is the most common abnormality in preterm infants at term equivalent age. We used a computational anatomic approach to survey the brain for structural alterations associated diffuse white matter disease.Methods. Subjects: 62 preterm infants without parenchymal cerebral lesions, born at median 29.7 weeks GA were studied at term equivalent age (median 40.4 weeks GA) together with 12 term born controls. Image acquisition: A 1.5 Tesla MR system was used to acquire high resolution T1-weighted volume datasets with a voxel size 1x1x1.6mm, in addition to conventional and diffusion weighted imaging. Diffuse white matter disease was defined as ADC values > 2 standard deviations above the mean of the control group in one or more white matter region. Image processing: non-rigid image registration was used to transform all images to a reference subject, and voxel-wise volume change values extracted from transformations were analysed with a correction for multiple comparisons.Results. Preterm infants showed volume loss within lentiform and thalamic nuclei (p<0.05), particularly among infants with diffuse white matter disease (p<0.05) and with increasing prematurity at birth (p<0.05), but ADC values in the thalamus and lentiform nuclei were similar to controls.Conclusions. Growth failure within deep grey nuclei occurs in association with diffuse white matter disease and without evidence of acute injury. This suggests deep grey matter connectivity is altered by preterm birth.

Neuropathological Substrates of Dementia and Depression in Vascular Dementia, with a Particular Focus on Cases with Small Infarct Volumes

The neuropathological substrates of dementia and depression were evaluated in 30 patients with cerebrovascular disease and significant cognitive impairment (VaD), with a particular focus on patients with small infarct volumes (<15 ml). VaD patients with small infarct volumes had a similar degree of cognitive impairment to those with larger infarct volumes (>15 ml) but were significantly more likely to be depressed and to have areas of microinfarction. A review of individual cases with small infarct volumes suggested that the combination of microinfarction, diffuse white matter disease and perivascular changes, or the overlap of neurodegenerative pathologies and microvascular changes were particularly important. Microinfarction was also significantly associated with major depression.

Idiopathic granulomatous angiitis of the CNS manifesting as diffuse white matter disease

Idiopathic granulomatous angiitis of the CNS manifesting as diffuse white matter disease

CADASIL in a North American family: clinical, pathologic, and radiologic findings.

To expand the reported phenotypic range of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Despite numerous patient reports, our knowledge of the phenotypic range of CADASIL remains incomplete. We performed clinical, pathologic, and radiologic examinations on members of a family with CADASIL. The proband is a 61-year-old man with a history of migraine and depression who has experienced multiple subcortical infarctions resulting in a stepwise decline. Neuropsychological testing documented a dementia syndrome with frontal lobe features and neurologic examination noted a left hemiparesis and a right-sided palmomental reflex. Brain biopsy with light microscopy revealed a nonatherosclerotic small-vessel angiopathy with periodic acid-Schiff positive granular changes in the media and white matter gliosis, with unremarkable cortex. Genetic testing confirmed a Notch3 mutation. The proband's first cousin has a history of depression, one seizure possibly resulting from an acute stroke, and a learning disorder. Neuropsychological testing demonstrated deficits in executive function and neurologic examination noted persistent extraneous adventitial movements, poor coordination, and primitive reflexes. Skin biopsy with electron microscopy demonstrated granular osmiophilic material within the basement membrane of vascular smooth muscle cells, which is considered to be pathognomonic of CADASIL. The proband's older son and younger son have histories of migraine and depression, respectively, and both also had learning disorders. MRI revealed diffuse white matter disease extending into the temporal lobes, and lacunar infarctions in these four nonhypertensive patients. Other family members have experienced migraine, recurrent stroke, dementia, and depression. CADASIL is a genetic basis for vascular dementia that may be manifest earlier in life than previously reported.

Krabbe's disease presenting as a peripheral neuropathy

A 13-year-old female initially presented with scoliosis and pes cavus. Initial examination revealed distal lower extremity weakness and sensory loss, as well as greater auricular nerve hypertrophy. There was a Babinski sign on the right. Nerve conduction velocities were consistent with a demyelinating neuropathy. Four years after initial presentation she developed lower extremity spasticity and bilateral Babinski signs. Magnetic resonance imaging of the brain showed diffuse white matter disease. Laboratory evaluation revealed an abnormally low galactocerebroside beta-galactosidase level. Nerve biopsy demonstrated inclusions consisting of globoid clusters and evidence of demyelination. DNA analysis was used to identify mutations consistent with Krabbe's disease. Patients presenting with an atypical peripheral neuropathy should be evaluated for Krabbe's disease. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20: 1024–1028, 1997

HIV-related metabolic abnormalities in the brain: depiction with proton MR spectroscopy with short echo times.

To analyze brain metabolite changes in human immunodeficiency virus (HIV)-positive neurologically asymptomatic patients and patients with acquired immunodeficiency syndrome (AIDS) dementia complex (ADC). Twelve ADC patients, 11 HIV-positive asymptomatic patients, and 10 healthy control subjects underwent magnetic resonance (MR) imaging and proton MR spectroscopy with short echo times. Changes in N-acetyl aspartate (NAA), choline (Cho), myoinositol (MI), and creatine (Cr) were presented as ratios with Cr as the reference. Statistically significant (P < .05) differences were noted. In ADC patients, all with MR findings of brain atrophy and diffuse white matter disease, NA/Cr decreased (white matter, -31.8%; gray matter, -22.3%), MI/Cr increased (white matter, +42.5%; gray matter, +51.8%), and Cho/Cr increased (white matter, +20.6%; gray matter, +51.7%) compared with healthy control subjects. In HIV-positive asymptomatic patients, NA/Cr decreased slightly (white matter, -6.9%; gray matter, -5.1%), MI/Cr increased slightly (white matter, +13.7%; gray matter, +10.7%), and Cho/Cr did not change. ADC has a uniform pathologic metabolic pattern that affects NAA, MI, and Cho. Proton MR spectroscopy with short echo times helps detect early abnormalities in clinically asymptomatic patients.

Vascular pathology in three cases of progressive cognitive deterioration

The clinical condition known as vascular dementia remains poorly defined. Few studies have attempted a correlative link between the clinical syndrome and the structural abnormalities of the brain. Classically the clinical progression of the vascular dementing process is thought to be a multi-step process punctated by repeated episodes of ischemia, that are clinically expressed as strokes. In most instances it has been assumed that the substrate of vascular dementias consists of atherothrombotic infarcts. The objective of this report is to illustrate 3 cases of progressive (rather than stepwise) cognitive deterioration without clinical evidence of stroke, evolving over a period of several years, in which there were prominent vascular lesions. A complete autopsy and detailed neuropathologic examination demonstrated cerebral vascular lesions involving small arterial vessels (< 200 μm in diameter). The lesions consisted of moderate-to-severe arteriolosclerosis in two cases, and mild-to-moderate arteriolosclerosis in a case of Alzheimer's disease with severe cerebral amyloid angiopathy. Parenchymal lesions consisted of small cortical and subcortical infarcts, most of them smaller than 0.1 cm in average diameter, and subcortical leukoencephalopathy severe in two cases and mild-to-moderate in the third case. Severe atherosclerosis not accompanied by large infarcts was also present in one case. Arterial changes affecting small, distal branches causing sometimes small parenchymal lesions in association with diffuse cerebral white matter disease, appear to be the anatomical substrate that accompanies progressive cognitive impairment in some patients who are frequently diagnosed with Alzheimer's disease because in their clinical records there is neither history of strokes nor stepwise progression of symptoms.

Recurrent Ischemic Events and Diffuse White Matter Disease in Patients with Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum (PXE) is a rare hereditary disorder of elastic tissue with prominent dermatologic, ocular, and vascular manifestations. Although PXE has been associated with ischemic stroke, the clinical and radiologic features have not been fully characterized. We describe two women with PXE, hypertension, and progressive motor and intellectual deterioration related to multiple strokes and transient ischemic attacks beginning at ages 50 and 56. Magnetic resonance imaging in both patients showed widespread and multiple punctate ischemic vascular lesions with diffuse white matter involvement. Although brain infarction in PXE may result from a variety of mechanisms, our patients show the association of this disorder with severe, predominantly small-vessel occlusive disease.

Ophthalmic Involvement in Myo-neuro-gastrointestinal Encephalopathy Syndrome

We studied the clinical, histopathologic, neuroradiologic, biochemical, and genetic profile of a patient with the myo-neuro-gastrointestinal encephalopathy syndrome, a recently described multisystem mitochondriopathy characterized by blepharoptosis and ophthalmoparesis. The patient had severe intestinal pseudo-obstruction and a mixed demyelinating and axonal neuropathy. Abnormal collections of mitochondria in nerve and muscle as well as diffuse white matter disease were present. Cytochrome oxidase activity in muscle mitochondria was reduced. No mitochondrial DNA deletions were detected.

Serial pathogenesis study of SIV brain infection

A serial study of early SIV brain infection revealed initial involvement of leptomeninges, followed by perivascular infection of brain parenchyma. Severity of SIV encephalitis correlated with severity of systemic disease rather than with length of infection. Diffuse white matter disease was not observed, and there was little evidence of SIV infection of brain endothelial cells. SIV infection of leptomeninges is separate from infection of the brain, which appears to be due to transvascular spread of infected monocytes/macrophages.

Encephalitis caused by human immunodeficiency virus: CT and MR imaging manifestations with clinical and pathologic correlation.

To determine the computed tomographic (CT) and magnetic resonance (MR) imaging manifestations of central nervous system (CNS) infection by the human immunodeficiency virus (HIV), the authors analyzed the results of imaging of the CNS in 24 patients with HIV encephalitis confirmed at autopsy. Careful pathologic correlation demonstrated that neither CT nor MR imaging enabled detection of microglial nodules with multinucleated giant cells, the hallmark of HIV encephalitis seen in all 24 affected patients. The most common abnormality observed on images of the CNS was atrophy, demonstrated in 18 patients. Demyelination and vacuolation of white matter tracts accompanying severe HIV infection caused hypoattenuation on CT scans and hyperintensity on T2-weighted MR images. These lesions had no mass effect. MR imaging was more sensitive than CT in the detection of lesions caused by HIV or other superimposed infectious agents. Although it is often difficult to attribute any radiologic appearance to a single etiologic agent in patients with acquired immunodeficiency syndrome, the combination of atrophy and symmetric, periventricular or diffuse white matter disease suggests HIV encephalitis.

Magnetic resonance imaging and computed tomography in Pelizaeus-Merzbacher disease

Six patients with the classical form of Pelizaeus-Merzbacher disease (PMD) were studied with computed tomography (CT) and magnetic resonance imaging (MRI) of the brain. While final diagnosis of PMD should be made on the basis of histopathologic findings in the brain, findings in this group support the fact that MRI can be used for tentative early diagnosis when computer tomographic examination is normal or nondiagnostic. All patients had MRI findings reflecting a pattern of diffuse white matter disease that can be considered characteristic in the appropriate clinical setting.

MRI appearance of AIDS subacute encephalopathy

A case of biopsy documented subacute encephalopathy of AIDS was evaluated by CT and MRI. CT scanning revealed ventriculomegaly and ill-defined nonspecific periventricular white matter hypodensities. MRI, however, demonstrated extensive unequivocal diffuse white matter disease as the cause of the ventriculomegaly. MRI findings in this patient support the preliminary suggestion that MRI is more useful than computed tomography (CT) in demonstrating AIDS subacute encephalopathy.

152 EXCESSIVE GLYCEROL EXCRETION IN A MALE INFAHT WITH PSYCHOMOTOR RETARDATION; ADRENOCORTICAL INSUFFICIENCY AND EARLY DEATH

A male, newborn infant (3480g, 54cm) presented with vomiting, slightly dysmorphic facial features, and serum electrolytes compatible with adrenocortical insufficiency. Although the vomiting disappeared after hormone replacement, the infant failed to thrive. Psychomotor retardation was noted, and he gradually developed spasticity. There was “diffuse white matter disease” by cerebral computer tomography. Chromosome analysis showed normal karyotype. Metabolic screening at 6 months of age revealed by sugar chromatography a marked spot with Rf-value 1.5 compared with glucose. By gas chromatography /mass spectrometry this substance was identified as glycerol. The glycerol excretion(1.0-1.5g/24h) was unrelated to diet or drugs. The patient died 12 months old, during a respiratory tract infection. Fibroblasts for glycerol kinase determination were not obtained.Glyceroluria, with or without demonstrated glycerol kinase deficiency, is an inborn error of metabolism of unknown incidence. The phenotypic expression is variable. Screening may easily be done by urine chromatography(ethyl acetate:pyridine:H2O; 13:5:4) on paper or thin layer, and visualized by silver nitrate/acetone.

Diffuse white-matter disease in the geriatric population. A clinical, neuropathological, and CT study.

CT findings in 6 autopsy cases of subcortical arteriosclerotic encephalopathy (SAE) are reported. A diffuse area of nonhomogeneous decreased density was observed in the deep white matter of both cerebral hemispheres, together with moderate dilatation of the lateral ventricles and ragged margins. The most characteristic pathological findings at autopsy were a diffuse area of incomplete infarction containing multiple small infarcts as well as cyst formation and marked stenotic atherosclerotic changes in the medullary arteries. Clinical features included patchy mental lapses, frontal-lobe syndromes, minor motor signs, and hypertension. The authors feel that SAE or a similar disease might occur in most cases of multi-infarct dementia.