Is cerebral white matter involvement helpful in the diagnosis of dentatorubral-pallidoluysian atrophy?

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disease clinically characterized by the presence of cerebellar ataxia in combination with variable neurological symptoms. Cerebral white matter involvement of DRPLA is rare and reported mainly in severe, progressed cases of old-aged or juvenile-onset DRPLA. We describe three cases of genetically confirmed DRPLA that developed changes in cerebral white matter in the early stage of middle-aged patients. Our results of our study indicate that cerebral white matter changes are not rare in DRPLA and might be helpful for differentiation in ataxia patients with brainstem and cerebellum atrophy.     

Initial clinical and radiological findings in patients with SSPE: are they predictive of neurological outcome after 6 months of follow-up?

Subacute sclerosing panencephalitis (SSPE) is a progressive, devastating neurologic disorder caused by mutant measles virus. In this study we evaluated the prognostic value of neuroimaging abnormalities in SSPE. Thirty consecutive patients with SSPE were included. Diagnosis of SSPE was based on the criteria described by Dyken. Patients were followed for 6 months. Neuroimaging studies were performed at inclusion and after 6 months. Regression or progression of the disease was defined as a change of one, or more than one, stage in Jabbour’s staging system. Degree of disability was assessed using the modified Rankin scale (mRS) score. Neuroimaging abnormalities were seen in 27 patients. Dominant imaging abnormalities were cerebral atrophy, white matter signal changes, cortical grey matter abnormalities and signal change in the basal ganglia. After 6 months of follow-up, 18 (60%) patients had a poor outcome (mRS score: 3–6); one patient died. The remaining 12 patients (40%) had a stabilized clinical condition (mRS score: 0–2). On univariate analysis, predictors of death or disability were: poor mRS score at baseline (p = 0.003) and Jabbour’s clinical stage III (p = 0.019). None of the neuroimaging abnormalities were associated with a poor prognosis or clinical deterioration (p > 0.05). We conclude that we did not observe any association between cerebral neuroimaging at baseline and neurological outcome after 6 months in patients with SSPE.     

CT hypodensity on cerebral white matter in Wilson's disease.

Wilson's disease in an autosomal recessive disorder of copper metabolism where systemic manifestations are secondary to the accumulation of copper in hepatic, nervous and other tissues. In CNS, the structural lesions most commonly found by CT scan are ventricular dilatation, cortical atrophy, basal ganglia hyperdensities, and brainstem and cerebellar atrophy. Degenerative changes of cerebral white matter seen on early anatomo-pathologic studies, but were almost never found on CT scan from recently described patients. We report a case of Wilson's disease with an unusually rapid deterioration where asymmetric low-densities in the subcortical white matter were disclosed by CT scan.     

Quantitation of cerebral atrophy in preclinical and end-stage Alzheimer's disease

Morphometric analysis of standardized gross cerebral slices from 16 patients with end-stage Alzheimer's disease (AD), 14 controls without neuropathological lesions or neurological disease, and 4 neurologically intact nondemented patients with histopathological lesions of AD was used to measure cross-sectional areas of cerebral cortex, white matter, subcortical nuclei, and the ventricular system. In AD, there was global cerebral atrophy of both cortex and white matter, selective atrophy of the amygdala and hippocampus, and ex vacuo hydrocephalus. In addition, in half the cases of AD, white matter atrophy was associated with overt histopathological evidence of patchy rarefaction of fibers and gliosis. Patients with preclinical AD had prominent and selective shrinkage of white matter comparable to that observed in AD, yet their cortical areas were normal. These observations suggest that white matter degeneration is an intrinsic component of AD. Moreover, its presence in preclinical AD where cortical atrophy is not evident indicates that cytoskeletal abnormalities associated with axonal degeneration may precede and perhaps cause the cortical atrophy observed in clinically manifested AD.     

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.     

Progressive CT abnormalities despite clinical improvement in SSPE treated with inosiplex

Inosiplex has been utilized in the treatment of subacute sclerosing panencephalitis (SSPE), though without unequivocally established beneficial effect. We report a patient whose computerized tomographic (CT) scans demonstrated the development of progressive cerebral atrophy and multifocal white matter lesions despite continuous treatment with inosiplex and periods of considerable clinical improvement or stabilization. The findings suggest that inosiplex may not have altered the pathological consequences of SSPE and that clinical staging categories alone may not be reliable long-term correlates of the progression of the disease. Controlled studies utilizing assessment of brain mass by CT scan or other imaging devices in addition to clinical staging are required to evaluate the efficacy of inosiplex.     

Neuropathology and general autopsy findings in nondemented aged subjects

A retrospective study of the essential general pathology and neuropathological features in 100 nondemented individuals aged 65 years or older (mean 81.23 ± 5.47 y) was performed using semiquantitative methods. 91% of the patients had a history of hypertension, 31% malignancies, 24% COPD, 18% myocardial infarction, and 4% stroke. Major causes of death were cardiovascular decompensation, pneumonia, acute myocardial infarction, and malignancies. General autopsy revealed severe systemic and coronary atherosclerosis in 86 and 90%, respectively, renal angioangiolosclerosis in 82%, acute or recurrent myocardial infarction in 65%, and other diseases. Neuropathology showed average brain weight of 1,163 ± 113 g, mild to moderate brain atrophy, absent to mild atherosclerosis of large cerebral arteries in 46%, mild, moderate and severe one in 31, 17, and 6%, respectively. There were considerable discrepancies in the severity between generalized/ aortic and intracranial atherosclerosis, only less than one-third being comparable. Negative Khachaturian criteria and CERAD Stage 0 were observed in 83 and 86%, respectively, only 13% with CERAD Stage A, and 1% Stage B. Braak neuritic stages ranged from 0 to II (53%), II - III (29%) to III - IV (18%), none scoring Grade V or VI. The average Braak score was 2.3 ± 0.8. Vascular pathologies were common; CAA was absent in 61%, mild or moderate in 36% and severe in 3%. Mild to severe lacunar state in basal ganglia and/or white matter was seen in 73%, hippocampal sclerosis in 3 cases, while only 9% were free of cerebrovascular lesions. Lewy bodies were observed in 5 brains involving substantia nigra (n = 3), cerebral cortex (n = 1) and medulla oblongata (n = 1), 1 case representing incidental Lewy body disease. τ pathology in brainstem was observed in 60 cases (60%). Mixed cerebral pathologies (cerebrovascular lesions and moderate neuritic Braak stages) were observed in 6 cases (mean age 89.6 y). The importance of mixed pathologies in nondemented elderly, being less frequent than in other studies, remains to be elucidated.     

Clinicophysiological study of multimodality evoked potentials and computed tomographic findings in persistent vegetative state

The auditory brainstem response (ABR), short latency somatosensory evoked potential (SSEP) and visual evoked potential (VEP) of patients in the persistent vegetative state (PVS) are reported, and the correlations between the electrophysiological findings and the CT scan findings with the three clinical grades of the PVS (transitional, incomplete and complete vegetative syndromes) are discussed. Twenty two patients in a vegetative state caused by subarachnoid hemorrhage (3), hypertensive intracerebral hemorrhage (5), cerebral infarction (6), head injury (3), cerebral anoxia (4) and brain tumor (1). Each evoked response was evaluated for the presence or absence of abnormalities and assigned a grade ranked I to III. Briefly an evoked response was assigned a grade I, II, III if it satisfied the respective criteria of normal, moderately abnormal and severely abnormal or absent electrical activity. On the other hand CT scan findings in the PVS were evaluated for abnormal low density areas, ventricular dilatation and enlargement of the sulci and cisterns indicative of atrophy of the brain parenchyma. SSEP and VEP were better correlated with the clinical grade than ABR, and upper brainstem atrophy and abnormal low density area in CT scan findings were more valuable as an index to expresses the clinical features than ventricular dilatation. On the basis of these results, it is concluded that studies of ABR, SSEP and VEP associated with CT scan findings in the PVS could be a useful diagnostic aid to evaluate the lesions of these patients.     

Microphthalmia and brain atrophy: a novel neurodegenerative disease

OBJECTIVE: To delineate the features of a novel neurodegenerative disease. METHODS: We report three children of three related families with congenital microphthalmia and blindness, and progressive spasticity, microcephaly, seizures, and profound mental retardation. RESULTS: A magnetic resonance imaging scan was normal at birth. However, follow-up studies showed progressive atrophy involving the cerebral white matter and cortex, cerebellum, brainstem, and corpus callosum. The white matter changes extended into the subcortical region leaving only small islands of remaining cortical tissue. Known metabolic conditions involving white matter degeneration were excluded. INTERPRETATION: We propose this to be a novel autosomal recessive neurodegenerative disorder to be coined MOBA (microphthalmia brain atrophy) disease.     

Computed tomography (CT) in late infantile metachromatic leucodystrophy

Computed tomographic features of 7 cases of the late infantile form of MLD confirmed by sural nerve biopsy are presented. Diffuse symmetrical white matter, low attenuation of the cerebral parenchyma was the common feature. Hypodensity of the temporal lobes and the cerebellar hemispheres are 2 features which have not been reported earlier. Three patients had brainstem atrophy without evidence of cerebral atrophy. Awareness of the various CT features of MLD may help in more definitive radiological diagnosis of the disease and to differentiate it from other dysmyelinating diseases of the central nervous system.     

Electroencephalographic and imaging profile in a subacute sclerosing panencephalitis (SSPE) cohort: a correlative study.

OBJECTIVE: There are only a few studies correlating diverse radiological and EEG features of subacute sclerosing panencephalitis (SSPE). The objective of the study was to (a) describe EEG profile and (b) correlate it with the clinical and imaging data of patients with confirmed SSPE. METHODS: This study was conducted at a University teaching hospital in south India and involved 58 patients (M:F=37:21, age: 12.3, SD 4.8 years) of SSPE. Diagnosis of SSPE was based on the characteristic clinical manifestations, and raised IgG (1:625) anti-measles antibody in cerebrospinal fluid (CSF) by ELISA in all the patients. Scalp EEGs were recorded on 16 channel machines using standard parameters and procedures. The EEG, clinical and imaging data were reviewed. RESULTS: EEGs were frequently abnormal: typical (37) and atypical (21). Diffuse slowing of background activity (BGA) was noted in 46 records being asymmetrical in six. Periodic complexes were periodic (32), quasi-periodic (21) or a-periodic (4). Periodic complexes (PC) (amplitude: 370.7, SD 171.2 microV; duration - 1.7, SD 2.0 s; inter-complex interval: 8.4, SD 9.2s) were symmetrical in 39 and asymmetrical in 19. CT (32) and MRI (23) scans were normal in 16 patients while others had white matter (15), cerebral edema (8), cerebral atrophy (8), basal ganglia (2), and thalamic (2) changes. There was an independent association of frontally dominant slowing of BGA (p=0.04) and typical PCs (p=0.03) with the diffuse cerebral edema on imaging. White matter changes correlated with slowing of BGA (p=0.04), but not with typical PC (p=0.16). CONCLUSIONS: This study provides valuable insight into the structural and clinical correlates of EEG changes in SSPE. SIGNIFICANCE: Irrespective of the incidence of occurrence of SSPE in a community, a clinician should be aware of the wide spectra of EEG findings. This study also discusses the possible underlying structural and clinical correlates.     

Cranial magnetic resonance imaging findings in children with nonsyndromic mitochondrial diseases

Cranial magnetic resonance imaging findings suggestive of specific mitochondrial syndromes are reported. However, cranial magnetic resonance imaging features in children with nonsyndromic mitochondrial diseases are rarely described. From January 1992-September 2009, data from 33 patients with nonsyndromic mitochondrial diseases were collected. We investigated cranial magnetic resonance imaging features in children with nonsyndromic mitochondrial diseases, and identified potential diagnostic characteristics. Eleven of 33 patients (33.3%) demonstrated normal findings, and 22 (66.7%) demonstrated abnormal findings. The most common abnormal finding was cerebral atrophy, with or without other lesion sites (15/33; 45.5%). The second most common was bilateral basal ganglia involvement (6/33; 18.2%). Follow-up imaging was performed in 20 patients. Ten of these 20 (50.0%) demonstrated evolutionary changes, in which progressive global brain atrophy was evident. Three patients with normal results and one patient with cerebral atrophy on initial imaging demonstrated prominent signal changes over the basal ganglia, brainstem, gray matter, white matter, and bilateral cerebellar hemispheres on follow-up imaging. Imaging in children with nonsyndromic mitochondrial diseases may produce variable findings. Normal results and cerebral atrophy on the initial cranial magnetic resonance imaging are commonly evident in this patient group.     

Adult onset leukodystrophy with neuroaxonal spheroids and demyelinating plaque‐like lesions

Adult onset leukodystrophy with neuroaxonal spheroids is an uncommon cause of dementia. Both hereditary (autosomal dominant) and sporadic cases have been described. A 41‐year‐old African woman presented with inappropriate behavior and personality change consistent with frontal lobe dysfunction. MRI demonstrated diffuse frontoparietal white matter signal abnormality and volume loss, as well as focal enhancing white matter lesions, while CT scan showed white matter calcifications. She had been gradually deteriorating over the last 5 years, diagnosed as having progressive demyelinating illness. She died of recurrent chest infections. There was no familial history. The brain showed prominent symmetrical white matter changes with greyish discolorization mainly affecting the frontal and parietal lobes, with less involvement of the temporal lobe and only mildly affecting the occipital white matter. Histology revealed deep white matter atrophy with many neuroaxonal spheroids labelled by neurofilament and β‐amyloid precursor protein. In addition, scattered inactive demyelinating plaque‐like lesions were found in the periventricular areas, brainstem and the cervical spinal cord. This case had typical features of an adult onset leukodystrophy with neuroaxonal spheroids. However, we also demonstrated demyelinating plaque‐like lesions, which has not been previously described. The possibility of a demyelinating origin contributing to the changes may be considered in the pathogenesis of this condition.     

Brain atrophy in Werdnig-Hoffmann disease

CT scan imaging of the brain was done in eight children with Werdnig-Hoffmann Disease. Seven of them showed generalized cerebral cortical atrophy and one had low attenuated, non-enhancing areas in the white matter involving both frontal lobes. These changes could be due to repeated episodes of hypoxic injury.     

Significance of white matter lucencies in posthypoxic-ischemic encephalopathy: comparison of clinical status and of computed and positron emission tomographic findings.

The clinical status and the computed and positron tomographic findings were compared in 10 patients with sequelae of hypoxic-ischemic encephalopathy after cardiopulmonary arrest and successful resuscitation. Conscious patients with moderate neuropsychiatric deficits had no significant computed tomography (CT) scan changes and normal values of regional cerebral blood flow and oxygen consumption, while patients in vegetative state had definite cerebral atrophy on CT scan and a severe and widespread decrease of regional cerebral blood flow and oxygen consumption. This decrease was even more pronounced in vegetative patients with the worst neurological score and with CT scans demonstrating additional diffuse white matter lucencies and hypodensities in the basal ganglia. In this group of patients increased regional oxygen extraction rates mainly in the white matter indicated the occurrence of delayed ischemic changes. The positron emission tomography and CT findings correlated well with the degree of posthypoxic-ischemic damage and the clinical status of the studied subjects.     

Clinical and magnetic resonance imaging features of elderly onset dentatorubral–pallidoluysian atrophy

Dentatorubral–pallidoluysian atrophy (DRPLA) is an autosomal dominant spinocerebellar ataxia caused by CAG triplet expansion in atrophin 1 and is frequently associated with cerebral white matter lesions. To elucidate the clinical features of elderly onset DRPLA and the key radiological findings for differentiating DRPLA from physiological white matter lesions in healthy elderly subjects, we reviewed the clinical and magnetic resonance imaging (MRI) features of ten patients with elderly onset genetically confirmed DRPLA (> 60 years) and compared their MRI findings with those of age- and sex-matched ten healthy subjects with asymptomatic cerebral white matter lesions. The initial symptom was cerebellar ataxia in all DRPLA patients, and five of them did not have any symptoms other than ataxia at the time of MRI examination. Atrophy of the brainstem, superior cerebellar peduncle, and cerebellum was detected in all DRPLA patients and none of the healthy subjects. Abnormal signals in the brainstem (inferior olive, pons, and midbrain), thalamus, and cerebellar white matter were frequently observed in elderly onset DRPLA patients but not in healthy subjects. In conclusion, elderly onset DRPLA presents as cerebellar ataxia alone in the early stage of disease. Atrophy of the brainstem, superior cerebellar peduncle, and cerebellum and abnormal signals in the brainstem, cerebellum, and thalamus are key findings for differentiating elderly onset DRPLA from asymptomatic cerebral white matter lesions in healthy subjects.     

1H and 31P magnetic resonance spectroscopy of the brain in degenerative cerebral disorders.

Proton and phosphorus magnetic resonance spectroscopy of the brain was performed in 35 patients with degenerative cerebral disorders: 24 patients had demyelinating (white matter) disorders and 11 patients had neuronal (gray matter) disorders. Four grades of demyelination and three grades of cerebral atrophy were distinguished by magnetic resonance imaging criteria. The spectroscopic data were compared with normal values previously obtained. With increasing degrees of demyelination, lower ratios of phosphodiesters to beta-ATP were found. This trend was statistically significant. Decreased phosphodiester-beta-ATP ratios occurred simultaneously with imaging abnormalities. The decrease in phosphodiester-beta-ATP ratio in demyelinated areas is attributed to white matter rarefaction. Increasing cerebral atrophy was accompanied by lower ratios of N-acetyl aspartate to creatine. This trend was statistically significant. The decrease in the N-acetyl aspartate-creatine ratio was demonstrated before the magnetic resonance images showed signs of cerebral atrophy in patients with neuronal disorders. As N-acetyl aspartate is located exclusively in neurons and their branches, a decrease of the N-acetyl aspartate-creatine ratio can be attributed to neuronal and axonal damage and loss.     

Alexithymia in multiple sclerosis: Clinical and radiological correlations

BackgroundAlexithymia, meaning no words for emotions is a common problem that could affect up to 53% of patients in multiple sclerosis (MS).ObjectivesTo determine the frequency of alexithymia in MS and investigate MS-related abnormalities in structural magnetic resonance imaging (MRI) and their associations with fatigue and cognitive functions.MethodsNinety-five patients at all stages of the disease were examined: 21 with clinically isolated syndromes (CIS), 30 with relapsing-remitting MS (RRMS), 21 with primary (PP) and 23 with secondary progressive MS (SPMS). Alexithymia was measured with the Toronto alexithymia scale (TAS-20) and correlated to cognitive functions, depression, and fatigue. Voxel-based morphometry MRI was analyzed to determine lesion load, cerebral and regional atrophy.ResultsFifty-seven of patients had alexithymia with no significant difference between the clinical phenotypes. Alexithymic patients differed from non-alexithymic patients on fatigue, depression and information processing speed. Compared to non-alexithymic patients, alexithymic patients had decreased volumes of cerebral and cerebellar white matter and there was a significant relationship between alexithymia and decreased brainstem, thalamic and corpus callosum volume.ConclusionRegardless of the phenotype of MS, alexithymia is associated with atrophy of cerebral and cerebellar white matter, brainstem, corpus callosum, and thalami.     

Adult polyglucosan body disease (APBD)

Three patients aged 63, 63 and 74 years had various combinations of progressive lower and upper motor neuron dysfunction, sensory loss, urinary incontinence and dementia. Postmortem examinations in two cases showed moderate cerebral and spinal atrophy, ill-defined areas of incomplete myelin loss in white matter and small necrotic foci in the white matter of gyri, around the basal ganglia and near the dentate nuclei. The main microscopic abnormality was a massive accumulation of PAS-positive polyglucosan bodies (PB) of various sizes and shapes in the cerebral hemispheres, brainstem, cerebellum, spinal cord, nerve roots and nerves. These PB were found in the processes of nerve cells and astrocytes, but not in their perikarya. Similar PB were present in peripheral nerves and in the lungs, heart, liver and kidneys. In the third case, a nerve biopsy revealed several, unusually large, PB in the axons of myelinated fibers. These clinicopathologic features are consistent with adult polyglucosan body disease (APBD) and are distinctive from other conditions in which PB may accumulate. Twelve similar cases have been reported previously. The diagnosis can be made by nerve biopsy. The pathogenesis of APBD is not known, but it may be a polysaccharide storage disease.     

Computerized tomography of brain and optic nerve in multiple sclerosis: Observations in 100 patients,including serial studies in 16

Computerized tomography (CT) of the brain was carried out in 100 patients with established or suspected multiple sclerosis (MS). The optic nerves were also examined in 53 of these patients. Areas compatible with demyelinating lesions were found in the cerebral hemisphere white matter and less frequently in the brain stem in 47% of cases. The hemisphere lesions were commonly multiple, typically situated in the deep white matter and periventricular regions, and were often asymptomatic. Small areas with unduly low attenuation coefficients were found in one or both optic nerves in 52% of patients in whom the optic nerves were examined. While these areas may represent demyelinating lesions their significance remains uncertain in view of poor correlation with clinical and electrophysiological parameters of optic nerve damage. Cerebral cortical atrophy and/or ventricular dilatation was found in 44% of cases, the frequency and severity of atrophy increasing with age and duration of disease.Serial studies after intervals of up to 21 months were performed in 16 patients, providing the opportunity to study the natural history of the cerebral lesions. While in some cases no significant change occurred, in others white matter lesions underwent an increase, or a reduction in size, and in some cases new lesions appeared. In some patients minor degrees of atrophy became apparent over the period of the study.The value of CT in the investigation of patients with suspected MS and as a means of studying the natural history of the disease is discussed.