MRI characteristics and scoring in HDLS due to CSF1R gene mutations

Abstract

Objective: To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5.

Methods: We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0-57) for each MRI scan.

Results: Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10-33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology.

Conclusion: Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion.

Figure 1. MRI scans of patients 4, 6, 12, and 14

(A) Patient 4 (axial fluid-attenuated inversion recovery [FLAIR]-weighted). Localized confluent white matter lesion (WML) with interspersed multifocal bifrontal WML (arrow). WML signal intensity is marked (MRI performed 2.5 years after the onset of the symptoms). (B) Patient 4 (axial T2-weighted). Involvement of the corticospinal tracts bilaterally (arrows) at the level of mesencephalon (MRI performed 2.5 years after the onset of the symptoms). (C) Patient 6 (axial FLAIR-weighted). Bilateral confluent WML frontoparietally (arrows), most pronounced on the right where it also affects the U-fibers (lower arrow). WML extending into the corpus callosum (MRI performed 1.9 years after the onset of the symptoms). (D) Patient 6 (axial FLAIR-weighted). Generalized confluent WML, most pronounced on the right (arrow) (MRI performed 1.9 years after the onset of the symptoms). (E) Patient 12 (axial FLAIR-weighted). Localized confluent bifrontoparietal WMLs with frontal predominance involving the periventricular, deep and subcortical regions but sparing of the U-fibers (arrow) (MRI performed 3.9 years after the onset of the symptoms). (F) Patient 14 (axial FLAIR-weighted). Localized confluent bifrontal WML (thin upper arrow) with involvement of the anterior corpus callosum (thick arrow) and localized focal WML in the biparietal periventricular and deep regions (lower thin arrow) (MRI performed 3.5 years after the onset of the symptoms). For additional images of patients 1, 2, 5, 7−11, and 15, see figure e-1.

Figure 2. Longitudinal MRI scans of patients 2 and 13

(A) Patient 2 (axial fluid-attenuated inversion recovery [FLAIR]-weighted). Minimal localized multifocal periventricular white matter lesion (WML) frontoparietally (arrows) (MRI performed 1.8 years after the onset of the symptoms). (B) Patient 2 (axial FLAIR-weighted). Increase in WML frontoparietally (arrows) with involvement of deep regions (MRI performed 2.8 years after the onset of the symptoms). (C) Patient 2 (axial FLAIR-weighted). Progression of WML frontoparietally, becoming more confluent (arrows) with involvement of the corpus callosum (thick arrowhead) (MRI performed 3.5 years after the onset of the symptoms). (D−G) Patient 2 (coronal FLAIR-weighted). Increase in periventricular, deep, and subcortical involvement of WML (arrows) with progressive involvement of the corpus callosum (arrowheads). (MRI performed 1.8 [D], 2.8 [E], 3.3 [F] ,and 3.5 [G] years after the onset of the symptoms). (H, I) Patient 13 (axial FLAIR-weighted). Progression of generalized cortical atrophy with slight progression of bifrontal WML (arrows) (MRI performed 4.0 [H] and 5.0 [I] years after the onset of the symptoms).