MRI White Matter Abnormalities Research Articles

Brain MRI White Matter Abnormalities in Pediatric Non-Infectious Uveitis

ABSTRACT Background Childhood chronic non-infectious uveitis (cNIU) is a challenging disease whose differential diagnosis may include demyelinating diseases. We aim to describe the white matter abnormalities (WMA) in brain MRI in childhood cNIU. Methods This is a multicentric retrospective study involving children with cNIU followed at the Pediatric rheumatology units of Florence and the ophthalmology department of the UMC Utrecht who underwent a Brain MRI. Demographic, clinical, laboratory and imaging information was collected. The presence of WMA was considered as the main outcome Results Data of 123 children was collected (66 from Utrecht and 57 from Florence), of whom 51 were males, with a median uveitis onset at age 9 years (range 3–16) for the UMC Utrecht and 8.75 years (range 1.6–15.1) for Florence. We evaluated 39 children with anterior uveitis, 35 with intermediate uveitis, 1 with posterior uveitis and 48 with panuveitis. Uveitis was idiopathic in 105. On brain MRI, 33 patients (26.8%) showed WMA, and most of them had non-anterior uveitis (72.8%). WMA were more frequent in males (χ2 5.25, p = 0.02). No difference in underlying systemic disease was seen between patients with and without WMA, but 40% of patients with TINU and 27.3% of patients with idiopathic uveitis showed WMA. None of the patients received a diagnosis of demyelinating disease during follow-up. Conclusion As WMA were found in 26.8% of patients who were screened in our cohort, brain MRI might be useful in cNIU. However, the clinical significance of these WMA could not be determined in this study. An interdisciplinary evaluation is necessary to assess the appropriate management, and a longer follow up is necessary to determine the prognosis of some of these WMA.

Distinct neurological phenotypes associated with biallelic loss of NOTCH3 function: evidence for recessive inheritance.

NOTCH3 variants are known to be linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, some null NOTCH3 variants with homozygous inheritance cause neurological symptoms distinct from CADASIL. The aim of this study was to expand the clinical spectrum of this distinct condition and provide further evidence of its autosomal recessive inheritance. Whole exome sequencing (WES) was performed on a proband who exhibited livedo racemosa, ataxia, cognitive decline, seizures, and MRI white matter abnormalities without anterior temporal pole lesions. Segregation analysis was conducted with Sanger sequencing. WES of the proband identified a novel homozygous NOTCH3 null variant (c.2984delC). The consanguineous parents were confirmed as heterozygous variant carriers. In addition, three heterozygous NOTCH3 null variants were reported as incidental findings in three unrelated cases analyzed in our center. The findings of this study suggest an autosomal recessive inheritance pattern in this early-onset leukoencephalopathy, in contrast to CADASIL's dominant gain-of-function mechanism; which is a clear example of genotype-phenotype correlation. Comprehensive genetic analysis provides valuable insights into disease mechanisms and facilitates diagnosis and family planning for NOTCH3-associated neurological disorders.

Differences in brain changes between adults with childhood-onset epilepsy and controls: A prospective population-based study.

PurposeTo determine the impact of childhood‐onset uncomplicated epilepsy (COE) on brain aging over 50‐year prospective follow‐up.MethodsA population‐based cohort of 41 aging subjects with COE and their 46 matched controls participated in a detailed in‐person prospective assessment in 2012 and 2017 to characterize ongoing changes in the aging brain.ResultsThe mean age of the COE participants was 63.2 years (SD 4.14, median 63.2, range 55.8–70.6) and 63.0 years (mean, SD 4.13, median 63.3, range 56.0–69.9) years for controls. Neurologic signs were significantly more common in COE participants not in remission (p = .015), and the most frequent abnormalities were cerebellar signs (p < .001). Neurologic signs in general (p = .008) and cerebellar signs in particular (p = .018) were significantly more common in focal than in generalized epilepsies. MRI white matter abnormalities were significantly associated with absence of vocational education (p = .011), and MRI hippocampal atrophy in COE subjects was associated with arterial hypertension versus normal blood pressure (p = .017). In the combined study cohort of COE subjects and controls, presenting neurologic signs increased both in the subjects and in the controls from the 2012 to 2017 study.ConclusionsAt ultra‐long‐term follow‐up, clinical and neuroimaging findings show tendencies to brain aging that is more accelerated in COE participants with active adult childhood‐onset epilepsy, and particularly in focal epilepsy.

MRI evaluation of thalamic volume differentiates MS from common mimics.

Objective:To determine whether MRI evaluation of thalamic volume differentiates MS from other disorders that cause MRI white matter abnormalities.Methods:There were 40 study participants: 10 participants with MS without additional comorbidities for white matter abnormalities (MS − c); 10 participants with MS with additional comorbidities for white matter abnormalities (MS + c); 10 participants with migraine, MRI white matter abnormalities, and no additional comorbidities for white matter abnormalities (Mig − c); and 10 participants previously incorrectly diagnosed with MS (Misdx). T1-magnetization-prepared rapid gradient-echo and T2-weighted three-dimensional fluid attenuation inversion recovery sequences were acquired on a Phillips Achieva d-Stream 3T MRI, and scans were randomly ordered and de-identified for a blinded reviewer who performed MRI segmentation using LesionTOADS.Results:Mean normalized thalamic volume differed among the 4 cohorts (analysis of variance, p = 0.005) and was smaller in the 20 MS participants compared with the 20 non-MS participants (p < 0.001), smaller in MS − c compared with Mig − c (p = 0.03), and smaller in MS + c compared with Misdx (p = 0.006). The sensitivity and specificity were both 0.75 for diagnosis of MS with a thalamic volume <0.0077.Conclusions:MRI volumetric evaluation of the thalamus, but not other deep gray-matter structures, differentiated MS from other diseases that cause white matter abnormalities and are often mistaken for MS. Evaluation for thalamic atrophy may improve accuracy for diagnosis of MS as an adjunct to additional radiologic criteria. Thalamic volumetric assessment by MRI in larger cohorts of patients undergoing evaluation for MS is needed, along with the development of automated and easily applied volumetric assessment tools for future clinical application.Classification of evidence:This study provides Class III evidence that MRI evaluation of thalamic volume differentiates MS from other diseases that cause white matter abnormalities.

An advanced white matter tract analysis in frontotemporal dementia and early-onset Alzheimer's disease.

Cortical and subcortical nuclei degenerate in the dementias, but less is known about changes in the white matter tracts that connect them. To better understand white matter changes in behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer’s disease (EOAD), we used a novel approach to extract full 3D profiles of fiber bundles from diffusion-weighted MRI (DWI) and map white matter abnormalities onto detailed models of each pathway. The result is a spatially complex picture of tract-by-tract microstructural changes. Our atlas of tracts for each disease consists of 21 anatomically clustered and recognizable white matter tracts generated from whole-brain tractography in 20 patients with bvFTD, 23 with age-matched EOAD, and 33 healthy elderly controls. To analyze the landscape of white matter abnormalities, we used a point-wise tract correspondence method along the 3D profiles of the tracts and quantified the pathway disruptions using common diffusion metrics – fractional anisotropy, mean, radial, and axial diffusivity. We tested the hypothesis that bvFTD and EOAD are associated with preferential degeneration in specific neural networks. We mapped axonal tract damage that was best detected with mean and radial diffusivity metrics, supporting our network hypothesis, highly statistically significant and more sensitive than widely studied fractional anisotropy reductions. From white matter diffusivity, we identified abnormalities in bvFTD in all 21 tracts of interest but especially in the bilateral uncinate fasciculus, frontal callosum, anterior thalamic radiations, cingulum bundles and left superior longitudinal fasciculus. This network of white matter alterations extends beyond the most commonly studied tracts, showing greater white matter abnormalities in bvFTD versus controls and EOAD patients. In EOAD, network alterations involved more posterior white matter – the parietal sector of the corpus callosum and parahipoccampal cingulum bilaterally. Widespread but distinctive white matter alterations are a key feature of the pathophysiology of these two forms of dementia.Electronic supplementary materialThe online version of this article (doi:10.1007/s11682-015-9458-5) contains supplementary material, which is available to authorized users.

Retinal nerve fiber thickness and MRI white matter abnormalities in healthy relatives of multiple sclerosis patients

ObjectivesTo compare retinal nerve fiber (RNFL) thickness and conventional and non-conventional MRI characteristics of healthy controls (HCs) from the general population (non-fHC) to healthy relatives of multiple sclerosis (MS) patients (fHC). MethodsSixty-eight (68) HCs underwent optical coherence tomography (OCT) and 3T MRI examination. Subjects were classified based on whether or not there was a family history of MS. The study enrolled 40 non-fHC who had no relatives with MS and 28 fHC with at least one relative affected with MS. The associations between OCT parameters and conventional and non-conventional MRI measures were investigated. ResultsThere were no significant OCT or conventional and non-conventional MRI measureable differences between the non-fHC and fHC groups. Periventricular localization and total volume of white matter (WM) signal abnormalities (SA) were more common in the fHC group but the differences did not reach a level of significance. A significant association between decreased RNFL thickness with increased volume (p=0.001), number (p=0.003) and frequency of ≥9 T2 (p=0.003) WM SAs on MRI was found in the fHC group. No association between OCT and MRI parameters was detected in the non-fHC group. ConclusionThere is an association between decreased RNFL thickness on OCT and increased WM injury in healthy relatives of MS patients. Further studies should explore the pathophysiology of these findings.

Hypertension and lower walking speed in the elderly: the Three-City study

The brain is one of the main targets of hypertension. However, little is known about the relation between hypertension and motor performances. We studied the association between hypertension and walking speed in a cohort of elderly people. Analyses are based on participants (65-85 years) from the Dijon (France) center of the Three-City study (n = 3604), followed every 2 years. Persistent hypertension was defined by the use of antihypertensive drugs at baseline or at first follow-up, or by high blood pressure (> or =140/90 mmHg) at baseline and first follow-up. Walking speed was measured over 6 m, at baseline and fourth follow-up (n = 1774) after a mean (SD) duration of 7.0 (0.5) years. Brain MRI was performed in 1590 participants. Generalized linear models were used to assess the relation between hypertension and baseline walking speed or walking speed change. At baseline, mean (SD) walking speed (m/s) was lower in hypertensive patients [1.51 (0.31)] than in nonhypertensive individuals [1.59 (0.30), P < 0.001]. During follow-up, hypertensive patients had a higher mean annual decline in walking speed [cm/s per year; 2.30 (3.4)] than nonhypertensive individuals [1.87 (3.3), P = 0.004]. The number of antihypertensive drugs was associated with lower walking speed at baseline and higher walking speed decline. Adjustment for MRI white matter abnormalities attenuated these relations. Persistent hypertension was associated with both lower walking speed and higher decline in walking speed in the elderly. These results may be partly explained by white matter abnormalities and support the hypothesis of a contribution of vascular risk factors to motor dysfunction.

Subcortical vascular dementia

Research criteria for subcortical vascular dementia are based on radiologic evidence of vascular pathology and greater impairment on tests of executive control than memory. The relationship(s) between neuroradiological evidence of subcortical vascular disease and neuropsychological impairments has not been specified. To define these research criteria, the authors rated the severity of MRI white matter abnormalities (WMAs) and neuropsychological data from patients with dementia. Sixty-nine outpatients who met the criteria for dementia were studied with neuropsychological tests that assessed executive (mental) control, declarative memory, visuoconstruction (clock drawing), and language (semantic category fluency). MRI-WMAs were rated using a leukoaraiosis (LA) scale (range 0 to 40). First, regression analyses demonstrated that neuropsychological measures accounted for 60.7% of the variance in WMA severity (47.3% of this variance attributable to executive/visuoconstructive test performance, 13.4% attributable to memory/language test performance). Second, patients were grouped according to the severity of WMAs (i.e., low, moderate, and severe white matter groups). Only patients with mild WMA (mean LA = 3.61 +/- 2.63, approximately 2.4 to 15.6% of the subcortical white matter) presented with greater impairment on memory/language tests vs executive control/visuoconstructive tests, a neuropsychological profile typically associated with Alzheimer disease. Patients with moderate WMA (mean LA = 12.76 +/- 2.49, approximately 25.6 to 38.1% of the subcortical white matter) presented with equal impairment on executive/visuoconstructional vs memory/language tests. Patients with severe WMA (mean LA = 21.76 +/- 2.97, approximately 46.9 to 62.4% of the subcortical white matter) displayed a profile of greater executive/visuoconstructional impairment relative to memory/language disabilities. A profile of equal impairment on tests of executive control and memory along with radiologic evidence involving about one-fourth of the cerebral white matter as measured by the Leukoaraiosis Scale may be sufficient for a diagnosis of subcortical vascular dementia.

Accrual of MRI white matter abnormalities in elderly with normal and impaired mobility

White matter signal abnormality (WMSA) is often present in the MRIs of older persons with mobility impairment. We examined the relationship between impaired mobility and the progressive accrual of WMSA. Mobility was assessed with the Short Physical Performance Battery (SPPB) and quantitative measures of gait and balance. Fourteen subjects had baseline and follow-up MRI scans performed 20 months apart. WMSA was detected and quantified using automated computer algorithms. In the control subjects, WMSA volume increased by 0.02±0.05% ICCV (percent intracranial cavity volume)/year while the WMSA of mobility impaired subjects increased five-times faster (0.10±0.10 ICCV/year, p=0.03). WMSA volume was related to some of the mobility measures and was sensitive to change which was not true of the other MRI variables. The study demonstrates the sensitivity of longitudinal automated volumetric analysis of WMSA to differentiate differences in the accrual rate of WMSA in groups selected on the basis of mobility. Based on these results, we propose that a subset of subjects with mobility impairment have accelerated, disease related WMSA accrual, thus explaining the rapid progression of mobility impairment in some older persons without apparent cause. This study demonstrates that quantitative MRI and performance measures can provide valuable insight into the rate of progression and pathophysiologic abnormalities underlying mobility impairment.

Molecular findings in symptomatic and pre-symptomatic Alexander disease patients.

Alexander disease is a slowly progressive CNS disorder that most commonly occurs in children. Until recently, the diagnosis could only be established by the histologic finding of Rosenthal fibers in brain specimens. Mutations in the glial fibrillary acidic protein (GFAP) gene have now been shown in a number of biopsy- or autopsy-proven patients with Alexander disease. A prospective study on patients suspected to have Alexander disease was conducted to determine the extent to which clinical and MRI criteria could accurately diagnose affected individuals, using GFAP gene sequencing as the confirmatory assay. Patients who showed MRI white matter abnormalities consistent with Alexander disease, unremarkable family history, normal karyotype, and normal metabolic screening were included in this study. Genomic DNA from patients was screened for mutations in the entire coding region, including the exon-intron boundaries, of the GFAP gene. Twelve of 13 patients (approximately 90%) were found to have mutations in GFAP. Seven of those 12 patients presented in infancy with seizures and megalencephaly. Five were juvenile-onset patients with more variable symptoms. Two patients in the latter group were asymptomatic or minimally affected at the time of their initial MRI scan. The mutations were distributed throughout the gene, and all involved sporadic single amino acid heterozygous changes that changed the charge of the mutant protein. Four of the nine changes were novel mutations. In symptomatic and asymptomatic patients with a predominantly frontal leukoencephalopathy by MRI, GFAP gene mutation analysis should be included in the initial diagnostic evaluation process for Alexander disease.

Practice parameter: the role of corticosteroids in the management of acute monosymptomatic optic neuritis. Report of the Quality Standards Subcommittee of the American Academy of Neurology.

Optic neuritis (ON) is an inflammatory disorder of the optic nerve. Most cases are idiopathic or associated with MS. ON can be associated with a variety of systemic or ocular disorders and is the most common acute optic neuropathy in adults younger than 46 years. Among high-risk populations for MS, the incidence of ON is about 3 per 100,000 population per year, whereas in other areas the incidence is about 1 per 100,000 population per year.1-13 Acute ON often presents as an isolated clinical event without contributory systemic abnormalities (monosymptomatic ON). Clinical features include periocular pain, abnormal visual acuity and fields, reduced color vision, a relative afferent pupillary defect, and abnormal visual evoked potentials. The fundus may appear normal or demonstrate edema of the optic nerve head (papillitis).12-18 MRI white matter abnormalities identical to those seen in MS are found in 50 to 70% of monosymptomatic ON cases.19-22 The visual deficit of ON may worsen over 1 to 2 weeks and usually begins improving over the next month. Lack of improvement in visual function by 30 days is unusual.23 However, most patients have some residual visual function deficit, even if visual acuity improves to 20/20.1-18 Differential diagnosis includes compressive, ischemic, hereditary, toxic, or other inflammatory optic neuropathies (e.g., sarcoid). These conditions usually do not exhibit the same clinical pattern (table 1) or rate of recovery as monosymptomatic ON.1-13 View this table: Table 1. Features of acute demyelinating monosymptomatic optic neuritis Treatment of monosymptomatic ON has included oral, retrobulbar, and IV steroids, immunoglobulin, and acupuncture.23-77 Monosymptomatic acute ON is not rare and because the usefulness of oral prednisone in this disorder has recently been questioned,23,78-82 this practice parameter was developed to provide …

Clinical severity in CADASIL related to ultrastructural damage in white matter: in vivo study with diffusion tensor MRI.

CADASIL is a newly recognized cause of subcortical ischemic strokes that progressively leads to dementia associated with pseudobulbar palsy and severe motor disability. This deleterious progression and the severity of clinical presentation are widely variable among affected subjects. The exact role played by MRI white-matter abnormalities, a hallmark of the disease, in the severity of the clinical phenotype remains poorly understood. To address this issue, we used diffusion tensor imaging (DTI), a new MRI technique highly sensitive to white-matter microstructural changes, in 16 symptomatic patients and 10 age-matched controls. Mean diffusivity and anisotropy of diffusion were measured within hyperintensities identified on T2-weighted images (T2WI) and outside these lesions on 4 slices at the level of centrum semiovale. We found a 60% increase of water mean diffusivity and a parallel loss of diffusion anisotropy in hyperintensities identified on T2WI. The same pattern of diffusion changes, but of lesser intensity, was found in the normal-appearing white matter on T2WI. Mean diffusivity in regions with increased signal on T2WI was higher in patients with severe clinical disability compared with those with no or mild deficit (1.33+/-0.11 versus 1.13+/-0.11 10(-3) mm(2)/s, P<0.01). Furthermore, diffusion measured within T2 hyperintensities correlated with both the Mini-Mental State Examination and Rankin scale scores. In patients with a severe clinical status, the increase of water diffusion in these regions exceeded 70% in comparison with values obtained in the normal white matter in control subjects. These results indicate that DTI is able to detect important ultrastructural changes in regions with increased signal on T2WI and within the normal-appearing white matter in CADASIL. The diffusion changes might be related to both neuronal loss and demyelination. The degree of the underlying ultrastructural alterations is related to the severity of the clinical status with a possible threshold level of white-matter damage above which severe neurological impairment may occur in this disease. DTI appears to be a promising technique for monitoring disease progression in CADASIL.

Proximal myotonic myopathy with MRI white matter abnormalities of the brain.

Proximal myotonic myopathy (PROMM) is an autosomal dominantly inherited multisystemic disorder characterized by myotonia, proximal muscle weakness, and cataracts. This disorder is not linked to the gene locus of myotonic dystrophy (DM). We describe three new families with PROMM. In all patients, CTG repeats of the DM gene in DNA from blood leukocytes were normal. MRI of the brain revealed a consistent pattern of marked white matter hyperintensity on T2-weighted images in four patients; two additional patients had similar but mild to moderate MRI abnormalities. The morphology of these abnormalities is unknown. Clinical symptoms of brain disease were not consistent and included mental changes with hypersomnia, parkinsonian features, stroke-like episodes, and seizures. The causative relationship of these clinical features with the MRI white matter abnormalities remains to be established. Our observations suggest that PROMM may involve the brain.

Somatosensory and Visual Evoked Potentials in Congenital Muscular Dystrophy: Correlation with MRI Changes and Muscle Merosin Status

Congenital muscular dystrophy comprises a heterogeneous group of disorders, that have in common an early onset and a dystrophic picture on the muscle biopsy. The "pure" form of congenital muscular dystrophy is not associated with severe mental retardation or structural changes in the brain, though white matter changes on brain imaging have been detected in a significant proportion of cases. In this study we evaluated the incidence of sensory abnormalities (somatosensory and visual evoked responses) in a group of 17 patients with "pure" congenital muscular dystrophy and correlated the results of the evoked responses with the presence or absence of white matter changes on brain magnetic resonance imaging. Our results show close correlation between the presence of MRI white matter changes and abnormalities in the sensory evoked potentials. Conversely, all patients with normal brain MRI had normal somatosensory evoked potentials (SEP). Visual evoked potentials were less sensitive than somatosensory evoked potentials in detecting abnormalities in children with white matter changes on MRI. With the recent discovery of deficiency in merosin expression in the skeletal muscle of a subgroup of patients with CMD, we also correlated the presence or absence of white matter changes and the SEP responses with the merosin status. The results indicate that all merosin-negative patients had abnormal SEP as well as abnormal MRI, whilst no patient with normal merosin expression had an abnormal scan or abnormal SEP.(ABSTRACT TRUNCATED AT 250 WORDS)

White matter abnormalities in patients with treated hyperphenylalaninaemia: Magnetic resonance relaxometry and proton spectroscopy findings

In order to further clarify the pathogenesis and clinical significance of MRI white matter abnormalities in treated hyperphenylalaninaemia (HPA), ten patients (seven type I HPA, two type II and one type III) underwent T2 relaxometry (n = 8) and/or 1H spectroscopy (n = 7) in addition to conventional MR spin-echo imaging at 1.5 T. Two patients with severe MRI abnormalities had repeat examinations during and after a 6- to 8-month period of strict diet control. The clinical evaluation included a detailed neurological examination. In nine out of ten patients visual evoked potentials (VEP) were obtained parallel to the MR examination. MR imaging demonstrated typical symmetrical areas of prolonged T2 relaxation time predominantly in the posterior periventricular white matter in all but one of type I and II patients. There was no consistent relationship between MRI findings and time of diagnosis/initiation of therapy, IQ or visual evoked potential changes. MRI abnormalities tended to be more severe in patients with poor dietary control and high current plasma phenylalanine levels, whereas a normal MRI was found only in patients with plasma phenylalanine levels continuously below 0.36 mmol/l. There was marked regression of MRI abnormalities already after 3 months of strict diet control. T2 relaxometry showed a bi-exponential behaviour of T2 in the affected white matter, with a slow component of about 200-450 ms, indicating an increase in free (extracellular) water. 1H spectroscopy revealed no signs of severe neuronal damage. We conclude, that the observed white matter changes in treated HPA probably represent reversible structural myelin changes rather than permanent demyelination.