MELAS with diffuse degeneration of the cerebral white matter: Report of an autopsy case

Up to now diffuse white matter demyelination of the cerebrum has been reported in only a few cases of mitochondrial encephalopathy with lactic acidosis and stroke‐like episodes (MELAS). Here we document an autopsy case with this rare neuropathology. Most MELAS cases are diagnosed antemortem by A3243G transition of mitochondrial DNA. While cerebral damage including necrotic foci in the cerebral cortex are common findings in MELAS, prominent white matter involvement best characterizes this MELAS case. There were numerous necrotic foci, varying in size and chronological stage, in the cerebral white matter. In the areas of the white matter without necrotic foci, there was diffuse fibrillary gliosis with the loss of axons and oligodendrocytes. The gliosis was dominant in the deep white matter, sparing the U‐fiber. The cerebral cortex showed diffuse cortical atrophy with few scattered necrotic foci. Distribution of the cerebral lesions does not coincide with the territory of blood supply. The vascular wall presented only slight to mild hyalinosis. We assumed a common pathogenesis to the cortical lesions and the white matter change. The pathogenesis of the present diffuse cerebral lesions may not be just secondary to circulatory disturbance but partly due to metabolic abnormality.     

MELAS with the mitochondrial DNA 3243 point mutation: a neuropathological study

We performed a neuropathological examination of the central nervous system from seven autopsied patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Five of the seven cases were confirmed to have the mitochondrial DNA (mtDNA) 3243 point mutation. In addition to the changes reported previously, diffuse atrophy of the cerebral and cerebellar cortices, diffuse gliosis of cerebral and cerebellar white matter, and cactus formation of Purkinje cells were observed. Electron microscopy revealed accumulation of mitochondria in the cactus formations. These lesions are common in MELAS with the mtDNA 3243 point mutation, but cannot be explained solely by mitochondrial angiopathy, and suggest that intrinsic mitochondrial malfunction contributes to neuronal damage in MELAS pathology. Moreover, the pathological changes observed in the cerebellum suggest that cerebellar function should be evaluated more carefully at the clinical level. Received: 3 December 1998 / Accepted: 21 April 1999     

Mitochondrial encephalomyopathy (MELAS): pathological study and successful therapy with coenzyme Q10 and idebenone

Two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes (MELAS) in one family are reported. Pathological examination of case 1 showed ragged-red fibers, with 7% of the fibers being unstained by cytochrome c oxidase stain, peripheral nerve damage, multiple areas of softening in the cerebrum and midbrain, and spongy changes in the cerebrum, optic nerve and pons. Electron microscopic examination revealed abnormal accumulations of mitochondria in the skeletal muscle, smooth muscle and cardiac muscle. The activity of cytochrome c oxidase in the brain and liver showed a tendency to decrease. In case 2 (maternal aunt of case 1), muscular weakness and peripheral nerve damage improved by treatment with coenzyme Q₁₀. By adding idebenone to the coenzyme Q₁₀ therapy, the EEG and Wechsler's Adult Intelligence Scale (WAIS) improved. Furthermore, in the cerebral spinal fluid (CSF), the protein, lactate, and pyruvate decreased, and the monoamines and monoamine metabolites increased.     

Differential white and gray matter damage in highly active multiple sclerosis: A prospective cohort study

We analyze the differential brain volume changes in highly active multiple sclerosis (HAMS) vs. non-HAMS patients during the disease onset.MethodsHAMS was defined as: a) patients with 1 relapse in the previous year and at least 1 T1 gadolinium-enhancing lesion or 9 or more T2 lesions while on therapy with other disease modifying treatment (DMD); or b) patients with 2 or more relapses in the previous year, whether on DMD or not. High-resolution T1 weighted MRI scans were acquired at onset and every 12 months for 2 years. Lesion load and brain volume measurements were determined. At onset, gray matter volume (GMV) and white matter volume (WMV) tissue volumes were calculated using the SIENAX. Longitudinal changes were estimated by using SIENA to calculate the percentage of brain volume loss. Differences between volumes per group at onset and at the end of the follow up were established.Results64 patients, mean age 38.4 years, 35 (57%) women were included. A total of 14 (21%) were classified as HAMS. At onset, HAMS patients showed lower GMV and WMV volume compared with non-HAMS patients (p = 0.003 and p = 0.01, respectively). During the follow up, HAMS patients showed a higher decrease in GM volume compared with non-HAMS patients (-0.61 vs. – 0.77, p < 0.001) independent from new lesion as well as relapse rate activity during follow up.ConclusionHAMS increased rates of GMV atrophy over 24 months compared to non-HAMS patients independent from relapse rate and new T2 lesions.     

A quantitative study of the pathological changes in white matter in multiple system atrophy

The density and spatial distribution of the vacuoles, glial cell nuclei and glial cytoplasmic inclusions (GCI) were studied in the white matter of various cortical and subcortical areas in 10 cases of multiple system atrophy (MSA). Vacuolation was more prevalent in subcortical than cortical areas and especially in the central tegmental tract. Glial cell nuclei widespread in all areas of the white matter studied; overall densities of glial cell nuclei being significantly greater in the central tegmental tract and frontal cortex compared with areas of the pons. The GCI were present most consistently in the external and internal capsules, the central tegmental tract and the white matter of the cerebellar cortex. The density of the vacuoles was greater in the MSA brains than in the control brains but glial cell density was similar in both groups. In the majority of areas, the pathological changes were distributed across the white matter randomly, uniformly, or in large diffuse clusters. In most areas, there were no spatial correlations between the vacuoles, glial cell nuclei and GCI. These results suggest: (i) there is significant degeneration of the white matter in MSA characterized by vacuolation and GCI; (ii) the central tegmental tract is affected significantly more than the cortical tracts; (iii) pathological changes are diffusely rather than topographically distributed across the white matter; and (iv) the development of the vacuoles and GCI appear to be unrelated phenomena.     

Unraveling the cerebellar cortex: Cytology and cellular physiology of large-sized interneurons in the granular layer

Neuronal network behaviors emerge from complex interactions between excitatory relay cells, principal cells and inhibitory interneurons. Therefore, characterizing homogeneous cell types and their properties is an essential step towards understanding information processing in the brain. The cerebellar cortex is generally described as a repetitive circuit composed of only five cell types. However, recent studies have revealed an unexpected diversity in the morphological, neurochemical and electrophysiological properties of the large-sized granular layer interneurons. These data are reviewed here with an emphasis on the synaptic interactions of the different cell types within the cerebellar cortex. The existence of a complex network of excitatory and inhibitory interneurons controlling the spatial and temporal pattern of granule cell firing is documented, providing insights into the cellular and synaptic processes underlying oscillations and synchronization in the cerebellar cortex.     

The clinical, pathological and genetic aspects of sporadic late onset cerebellar ataxia: observations on a series of ten patients

Ten patients with sporadic late onset cerebellar ataxia (LOCA) are described. The mean age of onset was 50.4 +/- 7.13 years. The important clinical features were gait ataxia, poor coordination of hands, intention tremors, exaggerated deep tendon reflexes, extrapyramidal symptoms and extensor plantar responses. Computerised tomography (CT) scanning in one patient showed a low density mid-line lesion, suggesting early cerebellar atrophy. Histopathological examination in one patient, clinically diagnosed as multiple sclerosis, revealed complete loss of Purkinje cells from the cerebellar folia with gliosis in the molecular layer and loss of small granular neurones. A marked loss of the neurones from the olivary nuclei with astrocytic proliferation was also seen. The disorder is probably genetically determined although a single Mendelian inheritance is unlikely in the absence of recurrence in the first degree relatives. Recurrence risks for gentic counselling are suggested.     

Distribution of cerebello‐olivary degeneration in idiopathic late cortical cerebellar atrophy: Clinicopathological study of four autopsy cases

Late cortical cerebellar atrophy (LCCA) is a neurodegenerative disease which presents with slowly progressive cerebellar ataxia as a prominent symptom and is characterized neuropathologically by a limited main lesion to the cerebellar cortex and inferior olivary nucleus. To elucidate the features of lesions in the cerebellar cortex and inferior olivary nucleus, four autopsy cases suffering from idiopathic LCCA without other cortical cerebellar atrophies, such as alcoholic cerebellar degeneration, phenytoin intoxication, or hereditary cerebellar atrophy including spinocerebellar ataxia type 6, were examined. All affected patients had identical distinct features of cerebellar cortical lesions. In all four cases, the most obvious pathological finding throughout the cerebellum was loss of Purkinje cells, but the rarefaction of granular cell layers was observed only where loss of Purkinje cells was very severe, and thinning of the molecular layer was seen only where the rarefaction of granular cell layers was moderate to severe. Two patients presented with vermis dominant cerebellar cortical lesions, but the other two patients showed hemispheric dominant pathological changes. Neuronal loss of the inferior olivary nucleus was observed in the three autopsy cases. Two of the three cases had a prominent lesion in the dorsal part of the inferior olive and the cerebellar cortical lesion disclosed the vermis dominance, but the other patient, showing prominent neuronal loss in the ventral olivary nucleus, had a cerebellar hemisphere dominant lesion. The patient without neuronal loss in the inferior olivary nucleus had suffered from a shorter period of disease than the others and the rarefaction of granular cell layers and narrowing of the molecular layer of the cerebellar cortex were mild. Therefore, it is obvious that there are two types of cerebellar cortex lesions in idiopathic LCCA; one is vermis dominant and the other is cerebellar hemispheric dominant. The lesion of the inferior olivary nucleus occurs as a secondary degeneration after rarefaction of the granular cell layer and thinning of the molecular layer of the cerebellar cortex progresses. Furthermore, the distribution of the degeneration in the inferior olivary nucleus depends on the distribution of the cerebellar cortex lesions.     

新型脑白质病变动物模型及其脑小血管的病理学研究

目的建立一个新型的具有高血压及脑小血管病理改变的脑白质病变(white matter lesions,WMLs)动物模型。方法 13只雄性Sprague-Dawley大鼠,随机分为假手术组(n=6)与易卒中型肾血管性高血压-改良的2VO组(stroke-prone renovascular hypertensive rat-modified 2 vessel occlusion RHRSP/Modified 2VO)(n=7),RHRSP/Modified 2VO组先行双肾双夹术制作RHRSP模型,12周后间隔1周先后夹闭双侧颈总动脉。双肾双夹术后20周对大鼠进行水迷宫试验观察大鼠是否存在空间记忆功能的受损,组织病理学检测观察是否存在脑白质病变及相应的脑小血管病理学改变。结果双肾双夹术后12周,RHRSP/Modified 2VO组7只大鼠收缩压均大于180 mm Hg;水迷宫实验:RHRSP/Modified 2VO组的逃避潜伏期较假手术组明显升高(P0.05),穿越平台次数及原平台象限停留时间比较假手术组明显降低[(2.5±1.05 vs.5±1.67);(28.04%±14.13%vs.49.69%±13.12%)],差异具有统计学意义(P0.05);RHRSP/Modified 2VO组脑白质病变的分级明显高于假手术组(2.17±0.75 vs.0.33±0.52),差异具有统计学意义(P0.05),且RHRSP/Modified 2VO大鼠存在脑小血管的病理改变(小动脉管壁增厚、血脑屏障破坏及静脉胶原沉积)。结论 RHRSP/Modified 2VO是适用的WMLs动物模型,可用于探究WMLs的发病机制及治疗靶点。     

Rapidly progressive aphasia and motor neuron disease: a clinical, radiological, and pathological study of an autopsy case with circumscribed lobar atrophy

This report concerns an autopsy case of rapidly progressive aphasia and motor neuron disease. The patient was a Japanese woman who was 75 years old at the time of death. The family history did not reveal hereditary burden. She developed language disturbances and difficulty in swallowing at age 74. Neurological examination 1 month after the disease onset revealed motor aphasia without dementia and bulbar sign, followed by muscle weakness of the four extremities. Neuroradiological examination revealed progressive atrophy of the anterior part of the left temporal lobe. She died of respiratory difficulty 10 months after the disease onset. Macroscopically, neuropathological examination showed circumscribed atrophy of the left perisylvian region and, histologically, neuronal loss in the cerebral cortex, including the primary motor area, substantia nigra, brain stem motor nuclei, and anterior horns of the spinal cord, in addition to obvious degeneration of the pyramidal tracts and presence of Bunina bodies. Ubiquitin-immunoreactive neuronal inclusions were present in the hippocampal dentate granular cells and frontotemporal cortical layer II neurons. Based on these clinicopathological findings and a review of the literature, we concluded that our case is the first reported case of amyotrophic lateral sclerosis with dementia that clinically showed rapidly progressive aphasia. Received: 1 March 1999 / Revised, accepted: 11 May 1999     

Dentatorubral-pallidoluysian atrophy (DRPLA): clinical, genetic, and neuroradiologic studies in a family

The clinical, genetic, and neuroradiologic characteristics of dentatorubral-pallidoluysian atrophy (DRPLA) are delineated in six patients from three generations of a Japanese family. The clinical characteristics of the disease varied, the age at onset depending on patients with juvenile-onset were characterized by myoclonus, epilepsy, and mental retardation whereas cerebellar ataxia, choreoathetosis, and dementia were typical of adult- and senile-onset patients. All affected individuals showed one expanded allele with the repeat number of CAG at the DRPLA locus, ranging from 58 to 82, and a normal allele, ranging from 10 to 21. The most severely affected patient, a case of maternal transmission and with the largest allele, became bedridden in a vegetative state by age 12. On the CT and MRI, varying degrees of brain atrophy were present in all patients. T2-weighted MRI in patients with senile-onset showed symmetric high-signal lesions in the cerebral white matter, globus pallidus, thalamus, midbrain, and pons. However, MRI in younger patients revealed no such lesions and CT failed to demonstrate lesions in the globus pallidus and brain stem. Thus, intrafamilial heterogeneity of DRPLA was also evident on MRI. High-signal lesions involving both, subcortical white matter and thalamus may be characteristics of senile-onset patients and may correlate with their dementia.     

Subclinical white matter lesions and medial temporal lobe atrophy are associated with EEG slowing in a memory clinic cohort

Objective

The aim of the study was to describe the relationship between electroencephalographic (EEG) findings obtained by standardized visual analysis, subclinical white matter lesions (WML) and brain atrophy in a large memory clinic population.

Disrupted thalamocortical connectivity in PSP: a resting-state fMRI, DTI, and VBM study

Progressive supranuclear palsy (PSP) is associated with pathological changes along the dentatorubrothalamic tract and in premotor cortex. We aimed to assess whether functional neural connectivity is disrupted along this pathway in PSP, and to determine how functional changes relate to changes in structure and diffusion. Eighteen probable PSP subjects and 18 controls had resting-state (task-free) fMRI, diffusion tensor imaging and structural MRI. Functional connectivity was assessed between thalamus and the rest of the brain, and within the basal ganglia, salience and default mode networks (DMN). Patterns of atrophy were assessed using voxel-based morphometry, and patterns of white matter tract degeneration were assessed using tract-based spatial statistics. Reduced in-phase functional connectivity was observed between the thalamus and premotor cortex including supplemental motor area (SMA), striatum, thalamus and cerebellum in PSP. Reduced connectivity in premotor cortex, striatum and thalamus were observed in the basal ganglia network and DMN, with subcortical salience network reductions. Tract degeneration was observed between cerebellum and thalamus and in superior longitudinal fasciculus, with grey matter loss in frontal lobe, premotor cortex, SMA and caudate nucleus. SMA functional connectivity correlated with SMA volume and measures of cognitive and motor dysfunction, while thalamic connectivity correlated with degeneration of superior cerebellar peduncles. PSP is therefore associated with disrupted thalamocortical connectivity that is associated with degeneration of the dentatorubrothalamic tract and the presence of cortical atrophy.     

Dentatorubropallidoluysian atrophy in a spanish family: a clinical, radiological, pathological, and genetic study

The object was to describe the clinical, radiological, pathological, and genetic findings in a Spanish family with dentatorubropallidoluysian atrophy (DRPLA). This is an inherited neurodegenerative disease, well recognised in Japan, but with few cases reported from Europe and America and no cases published from Spain. The clinical misdiagnosis of Huntington's disease is not infrequent. Pedigree analysis and clinical data of a family were collected. A genetic study was performed in two patients. Pathological information was obtained from the necropsy of one patient. RESULTS: Pedigree analysis showed an autosomal dominant pattern of inheritance. Age at onset varied from 5 to 55 years. Ataxia and chorea were present in most of the members. Some of these had a long course disease with late dementia. Four patients had seizures and early mental impairment. In one patient, cranial MRI showed cortical, brain stem and cerebellar atrophy, and white matter changes. In another patient, necropsy showed atrophy of the globus pallidus and lipofuscin deposits in dentate and pallidal neuronal cells. Genetic study showed an abnormal CAG triplet expansion in the B37 gene on chromosome 12. As in other cases previously reported, Spanish cases of DRPLA show intrafamilial phenotypic heterogeneity. Clinical and MRI data could differentiate DRPLA from Huntington's disease but definitive diagnosis requires molecular studies. Pathological studies are still necessary to correlate DRPLA brain involvement with the clinical and molecular findings.     

Familial amyotrophic lateral sclerosis with onset in bulbar sign, benign clinical course, and Bunina bodies: a clinical, genetic, and pathological study of a Japanese family

We report a Japanese family with autosomal dominant adult-onset amyotrophic lateral sclerosis (FALS) with onset in the bulbar musculature, clinically benign course, absence of the Cu/Zn superoxide dismutase-1 (SOD 1) gene mutation, and many Bunina bodies, in addition to involvement of the upper and lower motor neurons. The proband was a Japanese woman who was 66 years old at the time of death. Family history disclosed five patients with FALS over three generations. She developed dysarthria at age 57, followed by dysphagia, muscle weakness of the upper extremities, and difficulty in respiration. She could walk without support until her death. The elder sister of the proband developed dysarthria at age 48 and died at age 58. A genetic study of the nephew of the proband showed the absence of a mutation in the SOD 1 gene. Neuropathological examination of the proband disclosed neuronal loss in the upper and lower motor neurons, and numerous Bunina bodies in the lower motor neurons without Lewy body-like inclusions or ubiquitin-immunoreactive neuronal inclusions. No degeneration of the Clarke’s column, middle root zone of the posterior column, or posterior spinocerebellar tract was present. Review of the literature revealed that only patients with FALS with a long survival period of over 5 years had pathological findings consistent with FALS with posterior column involvement. This study contributes to the elucidation of the clinicopathological heterogeneity of FALS. Received: 8 November 1999 / Accepted: 7 March 2000     

屏状核与其周围白质纤维束关系的显微解剖学研究

目的 对屏状核及其周围的白质纤维束进行显微解剖学关系研究,并分析其功能意义.方法 在4～25倍手术显微镜下,运用Klingler纤维剥离技术,解剖剥离10例被10％甲醛固定的成人尸头,观察屏状核及其周围白质的解剖结构.结果 屏状核分为两部分:位于后上的背侧屏状核及位于前下的腹侧屏状核.屏状核是一位于岛叶深部、为众多白质所包绕的不规则薄层状灰质,屏状核内侧和背侧是外囊纤维,外侧为最外囊纤维,腹侧是钩状束及枕额下束,后下为内囊的豆核下部纤维由内向外穿出.其中来自钩状束、枕额下束的纤维进入或横贯腹侧部屏状核,来自外囊的纤维起始或终止于背侧屏状核,来自最外囊的部分纤维起始或终止于背侧屏状核,来自内囊豆核下部的部分纤维进入或横贯屏状核后下极.结论 通过研究屏状核周围白质纤维束的解剖功能学或许可以为屏状核的功能研究提供一条新的思路.     

Association of CETP polymorphisms with the risk of vascular dementia and white matter lesions

Cholesteryl ester transfer protein (CETP), a component of the high density lipoprotein (HDL), plays a central role in reverse cholesterol transport. We investigated the association of two putative functional CETP polymorphisms (C-629A and I405V) with the risk of vascular dementia (VD) and tested if this association is influenced by the presence of APOE4 allele. Our study included 163 VD patients (mean age: 74.25 ± 7.9 years) and 452 cognitively healthy probands (mean age: 70.81 ± 7.9 years). As a biological correlate, the association of CETP gene variants with white matter lesion (WML) load was investigated. Neither the C-629A (P = 0.169) nor the I405V (P = 0.840) polymorphism was associated with VD risk in the whole sample. However, in non-carriers of the APOE4 allele, homozygote carriers of the CETP C-629A A allele presented with an increased risk of VD (P = 0.01). Whereas in APOE4 carriers, no association of CETP polymorphisms with VD risk was detected. In addition, carriers of the CETP C-629A AA genotype presented with decreased WML load in the frontal brain (P = 0.009). Our results suggest that CETP gene polymorphisms might influence WML load and the risk of VD, the latter in non-carriers of the APOE4 allele.     

On the white matter lesions of the Creutzfeldt-Jakob disease: Can a new subentity be recognized in man?

One case of CJD with severe involvement of the white matter is discussed. The patient was admitted after a 3-month clinical course with rapidly increasing mental deterioration, coma vigil-like state, myoclonic twitching of the limbs and of the facial muscles. The EEG showed the typical features of CJD. The first CT scan, performed 3 months after onset, revealed only a mild cortical and subcortical atrophy of the brain. The second CT scan, 12 months later, showed a considerable cortical and subcortical atrophy of the brain. The patient died 18 months after onset. Neuropathological examination showed a severe degeneration in the gray matter, with spongiosis, loss of neurones and hypertrophic glial reaction. The white matter was also involved with severe spongiosis, demyelination and hypertrophic glial proliferation.The case is discussed in relation to the data in the literature. It is argued that cases of CJD with severe involvement of the white matter should be classified as a new neuropathological subentity of CJD.     

Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum

Three unrelated Japanese patients who presented with ataxia and mild mental retardation were examined in this study. Early development was normal in two patients and slightly delayed in one. All could walk independently, but were unstable due to cerebellar ataxia. They had mild intellectual retardation and displayed slow, progressive, and mild clinical courses. Two patients lost the ability to walk at 12 and 25 years of age. Brain MRI of the three patients revealed diffuse cerebral hypomyelination, moderate cerebellar cortical atrophy, and hypoplasia of the corpus callosum, which were seen in other diffuse hypomyelination syndrome. No known abnormalities were found in biochemical and genetic studies. Auditory brainstem responses and nerve conduction studies were normal. A definite diagnosis could not be made because of the lack of hypodontia, hypogonadism, cataracts, or basal ganglia atrophy. Based on common MRI findings and the relatively mild clinical courses, we believe that these patients may have another subset form of diffuse hypomyelination syndrome involving the cerebral white matter and cerebellum.     

Regression of white matter hypodensities with age in Aicardi–Goutierés syndrome: a case report

Background Aicardi–Goutierés syndrome (AGS) is a severe and progressive familial encephalopathy that is characterized by acquired microcephaly, intracranial calcification, white matter lesions, and chronic lymphocytosis with elevated levels of interferon-α in the cerebrospinal fluid. Although the degree of calcification and the severity of brain atrophy are variable, typically, the brain lesions appear to progress on successive examinations.Case report We report a 7-year-old male patient who showed relative regression of white matter lesions with nonprogression of basal ganglia calcification and atrophy on follow-up magnetic resonance imaging and computed tomography scans.Results Magnetic resonance spectroscopy findings were normal. This, to our knowledge, is the first case report, which describes relative regression of the white matter changes in AGS.