Diffuse White Matter Changes Research Articles

Brain structure in asymptomatic FMR1 premutation carriers at risk for fragile X-associated tremor/ataxia syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset movement disorder affecting FMR1 premutation carriers, is associated with cerebral and cerebellar lesions. The aim of this study was to test whether computational anatomy can detect similar patterns in asymptomatic FMR1 premutation carriers (mean age 46.7 years) with qualitatively normal -appearing grey and white matter on brain MRI. We used a multimodal imaging protocol to characterize brain anatomy by automated assessment of gray matter volume and white matter properties. Structural changes in the hippocampus and in the cerebellar motor network with decreased gray matter volume in lobule VI and white matter alterations of the corresponding afferent projections through the middle cerebellar peduncles are demonstrated. Diffuse subcortical white matter changes in both hemispheres, without corresponding gray matter alterations, are only identified through age × group interactions. We interpret the hippocampal fimbria and cerebellar changes as early alterations with a possible neurodevelopmental origin. In contrast, progression of the diffuse cerebral hemispheric white matter changes suggests a neurodegenerative process, leading to late-onset lesions, which may mark the imminent onset of FXTAS.

White Matter Changes in an Untreated, Newly Diagnosed Case of Classical Homocystinuria

The authors report the case of a 4-year-old boy who developed progressive unilateral weakness and developmental delays prior to his diagnosis of classical homocystinuria. Magnetic resonance imaging (MRI) of the brain demonstrated diffuse white matter changes, raising the concern for a secondary diagnosis causing leukoencephalopathy, since classical homocystinuria is not typically associated with these changes. Other inborn errors of the transsulfuration pathway have been reported as causing these changes. Once begun on therapy for his homocystinuria, his neurologic deficits resolved and his delays rapidly improved. Repeat MRI performed one year after instating therapy showed resolution of his white matter abnormalities. This case illustrates the need to consider homocystinuria and other amino acidopathies in the differential diagnosis of childhood white matter diseases and lends weight to the hypothesis that hypermethioninemia may induce white matter changes.

Microstructural white matter changes in cognitively normal individuals at risk of amnestic MCI

Since Alzheimer disease (AD) is a slowly progressive disorder and its pathologic features are likely to be present for many years before symptoms become manifest, we investigated whether microstructural white matter changes similar to those identified in patients with AD can be detected in cognitively normal individuals without dementia destined to develop amnestic mild cognitive impairment (aMCI). We studied 193 cognitively normal individuals, of whom 173 remained cognitively stable (CN-stable) and 20 were diagnosed with aMCI (CN-aMCI converter) 2 years later. Structural MRI and diffusion tensor imaging were acquired at baseline to assess gray matter atrophy and microstructural white matter changes, respectively. At baseline, compared with CN-stable, CN-aMCI converters had substantial reductions in white matter integrity in the precuneus, parahippocampal cingulum, parahippocampal gyrus white matter, and fornix. Other diffuse white matter changes were observed in the frontal, parietal, and subcortical regions, whereas gray matter structures were relatively intact. The fractional anisotropy (FA) values of the precuneus were found to be a predictor of conversion from cognitively normal to aMCI. In addition, the FA values of the left parahippocampal gyrus white matter were predictive of subsequent episodic memory decline. Microstructural white matter changes are present in cognitively normal individuals in the pre-aMCI stage, and may serve as a potential imaging marker of early AD-related brain changes.

Neuroimaging findings in a case of fluoxetine overdose

Brain MRI and ¹⁸F-FDG PET/CT scans were performed in a patient who had survived a suicide attempt by fluoxetine overdose. The patient presented with the following clinical signs and symptoms, and neuroimaging findings: severe signs of serotonin toxicity, including comatose state, akinetic rigid syndrome and dysautonomia; bilateral globus pallidus changes consistent with extensive pallidal necrosis and subsequent reversible diffuse ischemic changes in white matter, with posterior predominance, involving the splenium of the corpus callosum on brain MRI; and marked hypometabolism in the frontal, parietal and temporal cortical regions as well as in both caudate nuclei on ¹⁸F-FDG PET/CT performed 37 days later. These findings suggest that acute severe serotonin toxicity can induce structural and long-standing functional changes in multiple cortical and subcortical brain regions that are associated with cognitive and extrapyramidal syndromes.

Mouse intermittent hypoxia mimicking apnoea of prematurity: effects on myelinogenesis and axonal maturation

Premature babies are at high risk for both infantile apnoea and long-term neurobehavioural deficits. Recent studies suggest that diffuse structural changes in brain white matter are a positive predictor of poor cognitive outcomes. Since oligodendrocyte maturation, myelination, axon development, and synapse formation mainly occur in the third trimester of gestation and first postnatal year, infantile apnoea could lead to and/or exaggerate white matter impairments in preterm neonates. Therefore, we investigated oligodendroglia and axon development in a neonatal mouse model of intermittent hypoxia between postnatal days 2 and 10. During critical phases of central nervous system development, intermittent hypoxia induced hypomyelination in the corpus callosum, striatum, fornix, and cerebellum, but not in the pons or spinal cord. Intermittent hypoxia-elicited alterations in myelin-forming processes were reflected by decreased expression of myelin proteins, including MBP, PLP, MAG, and CNPase, possibly due to arrested maturation of oligodendrocytes. Ultrastructural abnormalities were apparent in the myelin sheath and axon. Immature oligodendrocytes were more vulnerable to neonatal intermittent hypoxia exposures than developing axons, suggesting that hypomyelination may contribute, at least partially, to axonal deficits. Insufficient neurofilament synthesis with anomalous components of neurofilament subunits, β-tubulin, and MAP2 isoforms indicated immaturity of axons in intermittent hypoxia-exposed mouse brains. In addition, down-regulation of synapsin I, synaptophysin, and Gap-43 phosphorylation suggested a potential stunt in axonogenesis and synaptogenesis. The region-selective and complex impairment in brain white matter induced by intermittent hypoxia was further associated with electrophysiological changes that may underlie long-term neurobehavioural sequelae.

A combination of extraglandular manifestations of Sjögren’s syndrome

A combination of extraglandular manifestations of Sjögren’s syndrome

Measles-Vaccinated Israeli Boy With Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis is a rare neurologic disorder of childhood and adolescence. We describe a 16-year-old boy who manifested the disease despite proper vaccinations. He was hospitalized because of bedwetting, involuntary limb movements, abnormal speech, and balance disturbances. Immunoglobulin G antibodies against measles were strongly positive, with a high relative cerebrospinal fluid/serum ratio. Polymerase chain reaction for measles produced negative results. Electroencephalography registered slow activity with high voltage discharges every few seconds, and with triphasic complex morphology. Magnetic resonance imaging revealed diffuse white matter changes, mostly around the posterior regions and lateral ventricles. Treatment with valproic acid, levetiracetam, carbamazepine, and intravenous immunoglobulin G was ineffective. Inosiplex and interferon-β-1a were also administrated. The patient became comatose, with generalized myoclonic jerks, and died 1 year later. An autopsy was not performed. This patient illustrates that subacute sclerosing panencephalitis should be suspected among young vaccinated subjects.

Unusual MRI findings in an immunocompetent patient with EBV encephalitis: a case report

BlackgroundIt is well-known that Epstein-Barr virus (EBV) can affect the central nervous system (CNS).Case presentationHerein the authors report unusual timely Magnetic Resonance Imaging (MRI) brain scan findings in an immunocompetent patient with EBV encephalitis.Diffusion weighted MRI sequence performed during the acute phase of the disease was normal, whereas the Fast Relaxation Fast Spin Echo T2 image showed diffuse signal intensity changes in white matter. The enhancement pattern suggested an inflammatory response restricted to the brain microcirculation. Acyclovir and corticosteroid therapy was administered. After three weeks, all signal intensities returned to normal and the patient showed clinical recovery.ConclusionThis report demonstrates that EBV in an immunocompetent adult can present with diffuse, reversible brain white matter involvement in the acute phase of mononucleosis. Moreover, our case suggests that a negative DWI sequence is associated with a favorable improvement in severe EBV CNS infection. More extensive studies are needed to assess what other instrumental data can help to distinguish viral lesions from other causes in the acute phase of disease.

An autopsy case of lymphomatosis cerebri showing pathological changes of intravascular large B-cell lymphoma in visceral organs

We describe the case of a 61-year-old man presenting with subacute encephalopathy. The clinical manifestations included progressive dementia and pyramidal and extrapyramidal tract signs. Brain CT scan and MRI showed diffuse bilateral white matter changes in the cerebral hemispheres, basal ganglia, thalamus and brainstem. No contrast-enhanced lesion was observed. Peripheral blood studies, CSF analysis, and brain and muscle biopsies were nonspecific and failed to reveal diagnostic evidence of any specific disease. The patient was diagnosed with and treated for a cerebral demyelinating disorder. Post mortem examination showed diffuse infiltration of lymphoma cells without mass lesions in the extensive cerebral white and gray matter with minimal intravascular patterns, particularly in the perivascular and periventricular spaces. These findings were consistent with lymphomatosis cerebri (LC). In other visceral organs such as the lungs, liver, kidneys and adrenal glands, blood vessels were plugged by numerous neoplastic cells which were morphologically and immunohistochemically similar to those observed in the CNS, consistent with intravascular malignant lymphoma (IVL). To our knowledge, this is the first autopsy report showing the coexistence of LC and IVL. This case suggests a possible link between LC and IVL.

Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL): From Discovery to Gene Identification

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a single-gene disorder directly affecting the cerebral small blood vessels, that is caused by mutations in the HTRA1 gene encoding HtrA serine peptidase/protease 1 (HTRA1). CARASIL is the second known genetic form of ischemic, nonhypertensive, cerebral small-vessel disease with an identified gene, along with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The exact prevalence of CARASIL is currently unknown, and to date approximately 50 patients have been reported, most of them from Japan and two from China. Genetically, no founder haplotype has been identified, and thus the disease is expected to be found more widely. The main clinical manifestations of CARASIL are ischemic stroke or stepwise deterioration in brain functions, progressive dementia, premature baldness, and attacks of severe low back pain or spondylosis deformans/disk herniation. The most characteristic findings on brain magnetic resonance imaging are diffuse white matter changes and multiple lacunar infarctions in the basal ganglia and thalamus. Histopathologically, CARASIL is characterized by intense arteriosclerosis, mainly in the small penetrating arteries, without granular osmiophilic materials or amyloid deposition. CARASIL is a prototype single-gene disorder of cerebral small vessels secondary to and distinct from CADASIL. CARASIL-associated mutant HTRA1 exhibited decreased protease activity and failed to repress transforming growth factor-β family signaling, indicating that the increased signaling causes arteriopathy in CARASIL. Therefore, HTRA1 represents another new gene to be considered in future studies of cerebral small-vessel diseases, as well as alopecia and degenerative vertebral/disk diseases.

Treatment of Dural Arteriovenous Fistula Presenting as Typical Symptoms of Hydrocephalus Caused by Venous Congestion -Case Report-

A 76-year-old woman presented with a dural arteriovenous fistula (DAVF) manifesting as typical symptoms of normal pressure hydrocephalus such as progressive dementia, gait disturbances, and urinary incontinence. The cerebrospinal fluid pressure during lumbar puncture was 120 mmH(2)O. Computed tomography and magnetic resonance imaging showed ventricular dilation and diffuse white matter changes, which were consistent with the symptoms of hydrocephalus. Cerebral angiography revealed a DAVF in the transverse-sigmoid sinuses with severe cortical venous reflux into the superior sagittal sinus. Transarterial embolization of the feeding arteries reduced the venous flow from the cortical veins into the superior sagittal sinus. Her symptoms improved with reduction in ventricle size. However, she suffered recurrence of the same symptoms several months later. Computed tomography and magnetic resonance imaging demonstrated ventricular dilation associated with hydrocephalus. Angiography revealed a fistulous channel in the left transverse-sigmoid junction. Transvenous embolization was performed resulting in complete obliteration of the fistula. Magnetic resonance image findings such as ventricular dilation and diffuse white matter disappeared and the symptoms of hydrocephalus improved. Although DAVFs often present as venous hypertensive encephalopathy, this case presented with ventricular dilation and diffuse white matter changes, which are the typical neurological signs of normal-pressure hydrocephalus. Venous hypertension associated with the DAVF in the transverse-sigmoid sinuses may have been caused by normal pressure hydrocephalus.

Hashimoto Encephalopathy

Hashimoto encephalopathy (HE) is an immune-mediated encephalopathy associated with Hashimoto thyroiditis. Most patients with HE respond to corticosteroids. Diffuse or focal white matter changes suggesting primary demyelination on magnetic resonance imaging (MRI) has been reported in only a few patients with HE. Follow-up imaging studies have been sparse. We report the case of a 48-year-old woman who presented with progressively declining cognitive function over 6 weeks without neurologic focal deficit on clinical examination. Her Mini-Mental State Examination Score was 3/30, and the MRI showed cortical and subcortical white matter demyelination. Biologic and radiologic investigations did not reveal an infective, vasculitic, or neoplastic etiology. Although her thyroid function tests were normal, thyroid antibodies were detected in high titers in her serum. A diagnosis of HE was made, and the patient was treated with high-dose corticosteroids. Over the next 8 weeks, her Mini-Mental State Examination Score improved to 24/30. The MRI changes showed resolution paralleling her clinical improvement. This case illustrates the importance of considering rare but treatable causes of encephalopathy in a patient presenting with acute or subacute cognitive decline.

Paraparésie et surdité progressives avec leuco-encéphalopathie révélant une neurobrucellose chronique

Brucellosis is a rare disease with variable neurological and imaging manifestations. A 54-year-old woman presented with progressive paraparesis and sensorineural hearing loss over 18months. The presence of diffuse white matter changes on brain magnetic resonance imaging (MRI) and cerebrospinal fluid findings led to the diagnosis of neurobrucellosis. Spinal MRI did not show any lesion that could explain the paraparesis that was finally attributed to the leukoencephalopathic lesions. The patient improved clinically after three months of antibiotic treatment but no significant changes were noticed on brain imaging. Neurobrucellosis is a treatable disease which should be discussed when a patient presents with the triade progressive paraparesis, sensorineural hearing loss and leukoencephalopathy on MRI. Outcome can be favorable if adapted treatment is given early.

O.4 Mouse model of LMNA-congenital muscular dystrophy shows severe skeletal and cardiac muscle maturation defects associated with major metabolic defects leading to early death

LMNA gene encodes for lamins A/C, ubiquitous proteins of the nuclear envelope. Lamins A/C are thought to have structural but also essential regulatory roles in various signalization pathways by interaction with transcription factors such as Sterol Regulatory Element Binding Protein 1 (SREBP1). LMNA mutations are responsible for more than 10 different disorders affecting various tissues in isolated or systemic fashion. Among those the LMNA-related congenital muscular dystrophy (L-CMD) is characterized by early onset of muscle weakness and joint contractures.

O.3 Satellite cell loss is the pathomechanism leading to muscle atrophy in selenoprotein N deficiency

zygous for the RT insertion mutation, five of whom carried a novel intronic mutation that activates a pseudoexon between exons 5 and 6 (c.647 + 2084G > T). Compared with individuals that were homozygous for the RT insertion mutation, the seven heterozygotes for the RT insertion mutation, including five patients with the novel pseudoexon mutation, exhibited a more severe clinical phenotype in terms of motor abilities and more extensive brain MRI abnormalities (i.e., a wider distribution of cortical malformation, pons and cerebellar hypoplasia, and more frequent diffuse white matter changes and ventricular dilatation). Conclusions FKTN mutations are the most common genetic cause of CMD with defective a-DG glycosylation in Korea. Compound heterozygosity of the RT insertion and the novel pseudoexon mutation is the most prevalent genotype in Korea and is associated with a more severe clinical phenotype and a wider extent of brain MRI abnormalities compared with homozygosity for the RT insertion mutation.

O.2 Fukutin mutations in congenital muscular dystrophies with defective glycosylation of dystroglycan in Korea

Background: The aim of this study was to identify Fukutin (FKTN)-related congenital muscular dystrophies (CMD) with defective α-dystroglycan (α-DG) glycosylation in Korea and to discuss their genotype–phenotype spectrum focusing on detailed brain magnetic resonance imaging (MRI) findings. Methods: Twelve patients were analyzed. Eleven patients were confirmed as having hypoglycosylation of α-DG on muscle biopsy and one patient was highly suggestive of CMD with defective glycosylation, based on clinical features alone. Results: FKTN mutations were found in nine of the 12 patients (75%). Two patients were homozygous for the Japanese founder retrotransposal (RT) insertion mutation. Seven patients were heterozygous for the RT insertion mutation, five of whom carried a novel intronic mutation that activates a pseudoexon between exons 5 and 6 (c.647 + 2084G > T). Compared with individuals that were homozygous for the RT insertion mutation, the seven heterozygotes for the RT insertion mutation, including five patients with the novel pseudoexon mutation, exhibited a more severe clinical phenotype in terms of motor abilities and more extensive brain MRI abnormalities (i.e., a wider distribution of cortical malformation, pons and cerebellar hypoplasia, and more frequent diffuse white matter changes and ventricular dilatation). Conclusions FKTN mutations are the most common genetic cause of CMD with defective α-DG glycosylation in Korea. Compound heterozygosity of the RT insertion and the novel pseudoexon mutation is the most prevalent genotype in Korea and is associated with a more severe clinical phenotype and a wider extent of brain MRI abnormalities compared with homozygosity for the RT insertion mutation.

Non-enhancing primary CNS lymphoma

Primary central system lymphomas (PCNSL) are highly proliferative tumors that require aggressive treatment, e.g. using high-dose methotrexate-based chemotherapy. Early histological diagnosis is crucial for proper management of PCNSL. Histological diagnosis is obtained through stereotactic biopsy which is usually performed upon demonstration of the typical hallmarks of PCNSL on MRI. This includes large, preferentially periventricular, homogenously contrast-enhancing lesions [1]. Although the MRI presentation of PCNSL is relatively uniform regarding the appearance as homogenously contrast-enhancing lesion(s), the MRI presentation of PCNSL may very rarely be atypical [2, 3] and may lead to significant delay in diagnosis and therapy initiation in such patients. We here present a patient with the rare case of a PCNSL without contrastenhancement. An 81-year-old patient presented with a 5-week history of rapidly progressive dementia. On examination, he was disoriented and showed psychomotor slowing and gait difficulty. The Mini Mental state examination (MMSE) revealed 16/30 points. He was HIV negative and all serological and biochemical tests were normal. The CSF examination showed just a slight increase in protein content (556 mg/l), no pleocytosis and no atypical cells. The MRI of the brain taken without prior steroid treatment revealed diffuse white matter changes involving both hemispheres. No pathological contrast-enhancement could be detected (Fig. 1). A diagnosis of gliomatosis cerebri was initially suspected. A biopsy was taken from the right frontal lobe. Histological examination revealed a diffuse large cell lymphoma (non-Hodgkin’s lymphoma of germinal B cell origin; Fig. 2). The present case highlights the fact that, in very rare cases, PCNSL may present as a non-enhancing lesion. Non-enhancing presentation was found in 1% of patients in a large series of immunocompetent patients [1] and is just one form of atypical MRI presentation of PCNSL. Another atypical form is the presentation with a central nonenhancing necrosis; this is found in 6–17% of immunocompetent PCNSL patients [1]. PCNSL without contrast uptake are usually caused by angiotropic large cell lymphoma or intravascular lymphomatosis [4]. In contrast, the present case did not show a particular angiotropic pattern but had the typical pattern of a diffuse large cell lymphoma with some perivascular accentuation (Fig. 2c). Unusual non-enhancing presentation may lead to substantial prolongation of definitive diagnosis and start of therapy. This underlines that PCNSL without contrast-enhancement has to be kept in the differential diagnosis of diffuse white matter disorders. Also, it further supports the importance of histologic verification before the onset of therapy. Since histological diagnosis of PCNSL may be greatly hampered by the use of lympholytic steroids prior to biopsy, it M. L. Lachenmayer and E. Blasius contributed equally.

P22 Clinical and pathological heterogeneity in partial merosin deficiency

P22 Clinical and pathological heterogeneity in partial merosin deficiency

Magnetic resonance imaging evaluation of radiation: Cranial radiation therapy-induced diffuse white matter injury

e13033 Background: To study the value of MRI in detection and grading of diffuse white matter injury induced by cranial radiation therapy for brain tumors and to evaluate the influence of various risk factors for its development. Methods: This study included 60 patients who had primary brain tumors and received external beam conventionally fractionated radiotherapy. Twenty-three out of 60 patients received chemotherapy after radiotherapy. Post radiotherapy follow-up MRI examination was performed for all patients at 6 weeks, 3, 6, 9, 12 months, and at more than 1 year from completion of radiotherapy. MR imaging was performed with T2-weighted turbo spin echo, fast fluid-attenuated inversion- recovery (FLAIR), T1-weighted spin-echo, and T1-weighted post-contrast spin-echo sequences. Results: Twenty-one of 60 patients (35%) developed diffuse white matter injury at a mean of 15.3 + 7.6 months from the completion of radiotherapy (range, 5–36 months). Radiation-related diffuse white matter changes were characterized as diffuse high signal intensity in the periventricular deep white matter on T2WI and FLAIR sequences. The MRI grading system of these periventricular hyperintensity (PVH) were as follow: 39 patients (65%) had no WMI (grade 0), four had grade 1 changes, three patients had grade 2 changes, nine patients had grade 3, and five patients had grade 4. They were symmetrical in 13 of 21 patients (61.9%), and asymmetrical in eight out of 21 patients (38.1%). The prevalence of diffuse matter injury found to be significantly related to the volume of irradiation (p = 0.02), fraction size (p = 0.008), and concomitant use of chemotherapy (p > 0.02)Conclusions: Diffuse white matter injury is a known consequence of radiation therapy, and the capability of detecting and grading such damage is optimally provided by MRI. No significant financial relationships to disclose.

Silent embolic infarcts on computed tomography brain scans and risk of ipsilateral hemispheric events in patients with asymptomatic internal carotid artery stenosis

This study tested the hypothesis that silent embolic infarcts on computed tomography (CT) brain scans can predict ipsilateral neurologic hemispheric events and stroke in patients with asymptomatic internal carotid artery stenosis. In a prospective multicenter natural history study, 821 patients with asymptomatic carotid stenosis graded with duplex scanning who had CT brain scans were monitored every 6 months for a maximum of 8 years. Duplex scans were reported centrally, and stenosis was expressed as a percentage in relation to the normal distal internal carotid criteria used by the North American Symptomatic Carotid Endarterectomy Trialists. CT brain scans were reported centrally by a neuroradiologist. In 146 patients (17.8%), 8 large cortical, 15 small cortical, 72 discrete subcortical, and 51 basal ganglia ipsilateral infarcts were present; these were considered likely to be embolic and were classified as such. Other infarct types, lacunes (n = 15), watershed (n = 9), and the presence of diffuse white matter changes (n = 95) were not considered to be embolic. During a mean follow-up of 44.6 months (range, 6 months-8 years), 102 ipsilateral hemispheric neurologic events (amaurosis fugax in 16, 38 transient ischemic attacks [TIAs], and 47 strokes) occurred, 138 patients died, and 24 were lost to follow-up. In 462 patients with 60% to 99% stenosis, the cumulative event-free rate at 8 years was 0.81 (2.4% annual event rate) when embolic infarcts were absent and 0.63 (4.6% annual event rate) when present (log-rank P = .032). In 359 patients with <60% stenosis, embolic infarcts were not associated with increased risk (log-rank P = .65). In patients with 60% to 99% stenosis, the cumulative stroke-free rate was 0.92 (1.0% annual stroke rate) when embolic infarcts were absent and 0.71 (3.6% annual stroke rate) when present (log-rank P = .002). In the subgroup of 216 with moderate 60% to 79% stenosis, the cumulative TIA or stroke-free rate in the absence and presence of embolic infarcts was 0.90 (1.3% annual rate) and 0.65 (4.4% annual rate), respectively (log-rank P = .005). The presence of silent embolic infarcts can identify a high-risk group for ipsilateral hemispheric neurologic events and stroke and may prove useful in the management of patients with moderate asymptomatic carotid stenosis.