Quantitative MRI in leukodystrophies

Leukodystrophies constitute a large and heterogeneous group of genetic diseases primarily affecting the white matter of the central nervous system. Different disorders target different white matter structural components. Leukodystrophies are most often progressive and fatal. In recent years, novel therapies are emerging and for an increasing number of leukodystrophies trials are being developed. Objective and quantitative metrics are needed to serve as outcome measures in trials. Quantitative MRI yields information on microstructural properties, such as myelin or axonal content and condition, and on the chemical composition of white matter, in a noninvasive fashion. By providing information on white matter microstructural involvement, quantitative MRI may contribute to the evaluation and monitoring of leukodystrophies. Many distinct MR techniques are available at different stages of development. While some are already clinically applicable, others are less far developed and have only or mainly been applied in healthy subjects. In this review, we explore the background, current status, potential and challenges of available quantitative MR techniques in the context of leukodystrophies

Different Scoring Methods of FDG PET/CT in Giant Cell Arteritis:Need for Standardization

Giant cell arteritis (GCA) is the most frequent form of vasculitis in persons older than 50 years. Cranial and systemic large vessels can be involved. [F-18] fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is increasingly used to diagnose inflammation of the large arteries in GCA. Unfortunately, no consensus exists on the preferred scoring method. In the present study, we aim to define the optimal FDG PET/CT scoring method for GCA diagnosis using temporal artery biopsy and clinical diagnosis as the reference method. FDG PET/CT scans of GCA patients (12 glucocorticoid-naive, 6 on glucocorticoid treatment) and 3 control groups (inflammatory, atherosclerotic, and normal controls) were evaluated. We compared 2 qualitative visual methods (i.e. (1a) first impression and (1b) vascular uptake versus liver uptake) and 4 semiquantitative methods ((2a) SUVmax aorta, (2b) SUVmax aorta-to-liver ratio, (2c) SUVmax aorta-to-superior-caval-vein ratio, and (2d) SUVmax aorta-to-inferior-caval-vein ratio). FDG uptake pattern (diffuse or focal) and presence of arterial calcifications were also scored. Diagnostic accuracy of the visual method vascular versus liver uptake (1b) was highest when the cut-off point vascular uptake higher than liver uptake (sensitivity 83%, specificity 91%) was used. Sensitivity increased to 92% when patients on glucocorticoids were excluded from the analysis. Regarding the semiquantitative methods, the aorta-to-liver ratio (2b) with a cutoff of 1.03 had the highest diagnostic accuracy, with a sensitivity and specificity of 69% and 92%, respectively. Sensitivity increased to 90% when patients on glucocorticoids were excluded. The number of vascular segments with diffuse FDG uptake pattern was significantly higher in GCA patients without glucocorticoid use compared with all control patient groups. CRP was not significantly different between positive and negative FDG PET scans in the GCA group. Visual vascular uptake higher than liver uptake resulted in the highest diagnostic accuracy for the detection of GCA, especially in combination with a diffuse FDG uptake pattern. Of the semiquantitative methods, the aorta-to-liver SUVmax ratio (cutoff point=1.03) had the highest diagnostic accuracy. The diagnostic accuracy increased when patients using glucocorticoids were excluded from the analyses

Nerve ultrasound: A useful screening tool for peripheral nerve sheath tumors in NF1?

Objective: To determine ultrasonographic peripheral nerve involvement in patients with asymptomatic neurofibromatosis type 1 (NF1). Methods: Thirteen asymptomatic and 4 minimally symptomatic patients with NF1 were included in this cross-sectional pilot study to detect asymptomatic abnormalities of the brachial plexus and upper and lower extremity nerves. Patients underwent clinical examination, nerve conduction studies (NCS), and high-resolution ultrasonography (HRUS). Results: HRUS showed abnormalities in 16 patients (94.1%). Neurofibromas were identified in 10 patients (58.8%): localized neurofibromas were found in 3 patients (17.6%), plexiform neurofibromas in 3 (17.6%), and both in 4 (23.5%). In 6 patients (35.3%), only nerve enlargement without an abnormal fascicular pattern was observed. Severe involvement of the peripheral nervous system with multiple plexiform neurofibromas was observed in 7 patients (41.2%), while 4 patients (23.5%) had no or only minor involvement. Both NCS and HRUS were performed on 73 individual nerve segments. In 5.5%, abnormalities were found with both tests; in 50.7%, only with HRUS; and in 1.4%, only with NCS. Conclusions: HRUS frequently showed subclinical involvement of the peripheral nerves in NF1, also when NCS were normal. HRUS findings ranged from normal to widespread peripheral nerve involvement. Because the presence of plexiform neurofibromas and the benign tumor load are risk factors for the development of a malignant peripheral nerve sheath tumor, HRUS may be a useful tool to identify a subgroup of patients who could benefit from regular follow-up

Radiological correlates of episodes of acute decline in the leukodystrophy vanishing white matter

Purpose: Patients with vanishing white matter (VWM) experience unremitting chronic neurological decline and stress-provoked episodes of rapid, partially reversible decline. Cerebral white matter abnormalities are progressive, without improvement, and are therefore unlikely to be related to the episodes. We determined which radiological findings are related to episodic decline. Methods: MRI scans of VWM patients were retrospectively analyzed. Patients were grouped into A (never episodes) and B (episodes). Signal abnormalities outside the cerebral white matter were rated as absent, mild, or severe. A sum score was developed with abnormalities only seen in group B. The temporal relationship between signal abnormalities and episodes was determined by subdividing scans into those made before, less than 3 months after, and more than 3 months after onset of an episode. Results: Five hundred forty-three examinations of 298 patients were analyzed. Mild and severe signal abnormalities in the caudate nucleus, putamen, globus pallidus, thalamus, midbrain, medulla oblongata, and severe signal abnormalities in the pons were only seen in group B. The sum score, constructed with these abnormalities, depended on the timing of the scan (χ2(2, 400) = 22.8; p <.001): it was least often abnormal before, most often abnormal with the highest value shortly after, and lower longer than 3 months after an episode. Conclusion: In VWM, signal abnormalities in brainstem, thalamus, and basal ganglia are related to episodic decline and can improve. Knowledge of the natural MRI history in VWM is important for clinical interpretation of MRI findings and crucial in therapy trials

Quantitative MRI in leukodystrophies

Leukodystrophies constitute a large and heterogeneous group of genetic diseases primarily affecting the white matter of the central nervous system. Different disorders target different white matter structural components. Leukodystrophies are most often progressive and fatal. In recent years, novel therapies are emerging and for an increasing number of leukodystrophies trials are being developed. Objective and quantitative metrics are needed to serve as outcome measures in trials. Quantitative MRI yields information on microstructural properties, such as myelin or axonal content and condition, and on the chemical composition of white matter, in a noninvasive fashion. By providing information on white matter microstructural involvement, quantitative MRI may contribute to the evaluation and monitoring of leukodystrophies. Many distinct MR techniques are available at different stages of development. While some are already clinically applicable, others are less far developed and have only or mainly been applied in healthy subjects. In this review, we explore the background, current status, potential and challenges of available quantitative MR techniques in the context of leukodystrophies

Mri natural history of the leukodystrophy vanishing white matter

Background: In vanishing white matter (VWM), a form of leukodystrophy, earlier onset is associated with faster clinical progression. MRI typically shows rarefaction and cystic destruction of the cerebral white matter. Information on the evolution of VWM according to age at onset is lacking. Purpose: To determine whether nature and progression of cerebral white matter abnormalities in VWM differ according to age at onset. Materials and Methods: Patients with genetically confirmed VWM were stratified into six groups according to age at onset: Younger than 1 year, 1 year to younger than 2 years, 2 years to younger than 4 years, 4 years to younger than 8 years, 8 years to younger than 18 years, and 18 years or older. With institutional review board approval, all available MRI scans obtained between 1985 and 2019 were retrospectively analyzed with three methods: (a) ratio of the width of the lateral ventricles over the skull (ventricle-to-skull ratio [VSR]) was measured to estimate brain atrophy; (b) cerebral white matter was visually scored as percentage normal, hyperintense, rarefied, or cystic on fluid-attenuated inversion recovery (FLAIR) images and converted into a white matter decay score; and (c) the intracranial volume was segmented into normal-appearing white and gray matter, abnormal but structurally present (FLAIRhyperintense) and rarefied or cystic (FLAIR-hypointense) white matter, and ventricular and extracerebral cerebrospinal fluid (CSF). Multilevel regression analyses with patient as a clustering variable were performed to account for the nested data structure. Results: A total of 461 examinations in 270 patients (median age, 7 years [interquartile range, 3-18 years]; 144 female patients) were evaluated; 112 patients had undergone serial imaging. Patients with later onset had higher VSR [F(5) = 8.42; P <.001] and CSF volume [F(5) = 21.7; P <.001] and lower white matter decay score [F(5) = 4.68; P <001] and rarefied or cystic white matter volume [F(5) = 13.3; P <001]. Rate of progression of white matter decay scores [b = -1.6, t(109) = -3.9; P , .001] and VSRs [b = -0.05, t (109) = -3.7; P<.001] were lower with later onset. Conclusion: A radiologic spectrum based on age at onset exists in vanishing white matter. The earlier the onset, the faster and more cystic the white matter decay, whereas with later onset, white matter atrophy and gliosis predominate

Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants

Objective Heterozygous NOTCH3 variants are known to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with patients typically presenting in adulthood. We describe three patients presenting at an early age with a vascular leukoencephalopathy. Genome sequencing revealed bi-allelic variants in the NOTCH3 gene. Methods Clinical records and available MRI and CT scans of three patients from two unrelated families were retrospectively reviewed. Results The patients presented at 9 to 14 months of age with developmental delay, seizures, or both. The disease course was characterized by cognitive impairment and variably recurrent strokes, migraine attacks, and seizures. MRI findings pointed at a small vessel disease, with extensive cerebral white matter abnormalities, atrophy, lacunes in the basal ganglia, microbleeds, and microcalcifications. The anterior temporal lobes were spared. Bi-allelic cysteine-sparing NOTCH3 variants in exons 1, 32, and 33 were found. Interpretation This study indicates that bi-allelic loss-of-function NOTCH3 variants may cause a vascular leukoencephalopathy, distinct from CADASIL