Our report describes the MRI pattern of HDLS in patients with CSF1R
gene mutations. MRI findings in patients with HDLS have been described previously in 20 reports,5,12–30
however, without knowledge of the CSF1R
gene mutation carrier status.4
We developed an HDLS MRI severity scoring system, modified from those devised for X-ALD, Krabbe disease, and MLD.9–11
Our scoring system provides quantitative markers to track HDLS progression and characterize the natural history of HDLS MRI lesions.
WMLs were localized bifrontally and asymmetrically in 93% of the patients. Patient 6 (highest total MRI severity score) showed generalized confluent WMLs, possibly reflecting disease severity. Current evidence suggests that HDLS initially manifests focally in the WM and becomes confluent.5,16,26
Our study demonstrates that in some patients, lesions develop deep in the WM, spreading to periventricular and subcortical regions, and finally becoming confluent and generalized. Focal lesions may occur in the early stages of HDLS. In the advanced stages, WM abnormalities are all confluent. This is also true for other leukoencephalopathies including leukodystrophies and the advanced stages of multiple sclerosis (MS), which may mimic HDLS radiologically. Some vasculopathies might also reveal confluent WMLs in advanced stages but usually have additional signal changes and microhemorrhages in the basal ganglia, thalamus, and brainstem.31
The punctate WMLs in patient 1 could be mistaken for ischemia and the multifocal lesions in patient 8 for small-vessel disease. Both patients may have been imaged at an early stage of the disease burden, because each lived 2 years or more after the initial MRI examination, and their mean total MRI severity score was 8.5 points.
Fourteen patients had corpus callosum involvement (). This finding may suggest MS or Susac syndrome. However, in MS, the ependymal corpus callosal undersurface is involved and characteristic right angle lesions are seen in the sagittal sections, reflecting the perivenular inflammation.32
In Susac syndrome, the corpus callosal lesions are centrally located without atrophy.33
They are of variable shapes and sizes, and they will eventually evolve into pathognomic central callosal holes. There is a characteristic “string of pearls” in the internal capsule and leptomeningeal enhancement in Susac syndrome, which is not expected in MS or HDLS.33
Some vasculopathies can involve the corpus callosum but usually include neighboring structures.31
Brain atrophy on MRI has shown to correlate with clinical parameters in MS. Cortical atrophy present in patients with MS is partially independent of WML load, and the pattern of atrophy differs from normal aging.34
The cortical atrophy in MS may have regional variation, more prominent within the regions of most corticocortical connections. Atrophy is limited in primary motor, sensory, and visual cortices, even though these areas often have prominent WMLs.34
This does not completely fit with findings in HDLS; although cortical atrophy was present in 93% of our patients, the WMLs in the specific distributions were more prominent than the atrophy. Twelve of the patients had localized atrophy in the same region as the WMLs, and of those, patient 6 trended toward more generalized atrophy. Interestingly, when the whole group was compared for cortical atrophy, the parietal lobe had the greatest atrophy (mean atrophy score 22 points) compared with the frontal lobe (17 points). We hypothesize that the cortical atrophy on MRI may reflect irreversible tissue loss demonstrated neuropathologically in all deceased patients, reflecting the extent of axonal damage and loss. The loss of axonal density has been proposed as the cause of transition into progressive MS and of the continuous and irreversible neurologic decline seen in MS.34,35
It is not known whether this phenomenon is true for HDLS.
Atrophy of the anterior and posterior aspects of the corpus callosum has recently shown significant correlation to the increasing load of age-related WM changes in elderly neurologically normal subjects with leukoaraiosis.36
In our study, 8 patients had atrophy of the corpus callosum, which is also reported in MS and dementia, a finding only partially explained by Wallerian degeneration.37,38
There was U-fiber preservation in 93% of the patients with HDLS. The diagnostic utility of this finding is limited, because it is found in other WM disorders.1,2
Importantly, none of our patients had gray matter pathology on MRI. Many of the disorders that can demonstrate WMLs also have abnormalities in the gray matter, including MS, Alzheimer disease, certain leukodystrophies, Parkinson disease, atypical Parkinson disease and vasculopathies,1,31,39
and other non-neurodegenerative disorders, distinguishing them from HDLS.
Age at onset and disease course varied among patients with different mutations. This may be related to specific mutations; however, even onset ages varied significantly within the same family, potentially reflecting the influence of currently unknown genetic modifiers or environmental factors. Individuals from the same families can show unique MRI findings, including corpus callosal WMLs, atrophy, or both (). These features may be useful markers to follow the disease course in different family members and to evaluate response to future clinical research trials.
In our study, indicators of rapid progressive disease were disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, and a total MRI severity score greater than 15 points. There was significant evidence that the total WML score decreases as disease duration at the time of MRI increases. The individual with the highest total MRI severity score also had one of the shortest durations, the highest total WML score, and a mutation of deletion type. Overall, a total MRI severity score less than 15 was suggestive of longer disease duration.
Our study demonstrates that the MRI abnormalities in patients with HDLS have a characteristic pattern, most recognizable in the middle stages. Minor WMLs in early stages lack diagnostic specificity. End-stage HDLS is characterized by confluent involvement of the cerebral WM, which may also be nonspecific. The MRI abnormalities are generally similar among patients with the same mutation and slightly different in patients with different mutations. There are limitations in interpreting these results, because this study did not use the same imaging technique protocols for all patients, and the MRI studies were performed at different time points in disease progression. The number of patients included in this study is small and MRI examinations were limited. Prospective longitudinal studies with a more uniform imaging protocol are warranted.
Typical MRI findings for patients with HDLS with CSF1R gene mutations include T2 hyperintense foci in the periventricular, deep, and subcortical bifrontal or bifrontoparietal cerebral WM, as well as involvement of the corpus callosum and corticospinal tracts; central atrophy; and no significant gray matter pathology, no brainstem atrophy, and no enhancement. Cerebellar pathology is minimal. Knowledge of the MRI appearance may assist in correctly diagnosing HDLS with CSF1R gene mutations.