T2-Pseudonormalization and Microstructural Characterization in Advanced Stages of Late-infantile Metachromatic Leukodystrophy

Abstract

Purpose T2-weighted signal hyperintensities in white matter (WM) are a diagnostic finding in brain magnetic resonance imaging (MRI) of patients with metachromatic leukodystrophy (MLD). In our systematic investigation of the evolution of T2-hyperintensities in patients with the late-infantile form, we describe and characterize T2-pseudonormalization in the advanced stage of the natural disease course. Methods The volume of T2-hyperintensities was quantified in 34 MRIs of 27 children with late-infantile MLD (median age 2.25 years, range 0.5–5.2 years). In three children with the most advanced clinical course (age >4 years) and for whom the T2-pseudonormalization was the most pronounced, WM microstructure was investigated using a multimodal MRI protocol, including diffusion-weighted imaging, MR spectroscopy (MRS), myelin water fraction (MWF), magnetization transfer ratio (MTR), T1-mapping and quantitative susceptibility mapping. Results T2-hyperintensities in cerebral WM returned to normal in large areas of 3 patients in the advanced disease stage. Multimodal assessment of WM microstructure in areas with T2-pseudonormalization revealed highly decreased values for NAA, neurite density, isotropic water, mean and radial kurtosis, MWF and MTR, as well as increased radial diffusivity. Conclusion In late-infantile MLD patients, we found T2-pseudonormalization in WM tissue with highly abnormal microstructure characterizing the most advanced disease stage. Pathological hallmarks might be a loss of myelin, but also neuronal loss as well as increased tissue density due to gliosis and accumulated storage material. These results suggest that a multimodal MRI protocol using more specific microstructural parameters than T2-weighted sequences should be used when evaluating the effect of treatment trials in MLD.

Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy

“…We indeed found a significantly lower mean age at MRI, 1.9 versus 2.3, in symptomatic late-infantile patients with MLD MRI scores 0-6 than in late-infantile patients with MLD MRI scores >6 who were between 1.8 and 2.9 years old. This corroborates the previously reported breaking point of ~1.75 years of age to develop clear T2-hyperintensities 16 and our results confirm the hypothesis that T2-hyperintensities typically emerge after a certain minimum age, including splenial involvement as typical early MRI sign for late-infantile MLD, which also was only found in patients after that age. The possible influence of time after onset may, however, also play a role in this phenomenon.…”

“…13 Eventually, also the projection fibers and the cerebellum are involved, and signs of atrophy appear. [14][15][16][17] To quantify the severity of MRI abnormalities in MLD, a scoring system was developed, which has been widely used in the past decade. 18 Biffi et al (2008) adapted the MLD MRI score to increase its sensitivity, in particular for atrophy.…”

“…11,19 In MLD patients with a late-onset form, brain MRI often shows extensive WM abnormalities at the time of diagnosis, whereas those with an early-onset form can still have (almost) normal MRIs. 14,16,18,20 This implicates that around the time of diagnosis, just after clinical symptom onset, late-infantile MLD patients may present with nearnormal MRIs, which hampers early diagnosis required for timely therapy. Therefore, we aimed to investigate the previously reported observations 14 in a larger cohort and describe MRI changes for all four MLD subtypes in relation to clinical characteristics around the time of diagnosis.…”

Acute-onset paralytic strabismus in toddlers is important to consider as a potential early sign of late-infantile Metachromatic Leukodystrophy

“…It is suggested that white matter abnormalities only evolve after around 18 months of age (28,29) , but systematic studies on early MRI findings in late-infantile MLD are currently lacking and urgently needed, since these findings might cause important diagnostic pitfalls. The combination of cranial nerves dysfunction, demyelinating sensorimotor polyneuropathy and (yet) absence of brain whiter matter abnormalities may resemble chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome or Miller Fisher syndrome (30) .…”

Update on myelin imaging in neurological syndromes

“…MWI shows great promise for application to the study of hypomyelinating leukodystrophies, such as Pelizaeus–Merzbacher disease, caused by defects in the gene that encodes for PLP1. One application studied patients with metachromatic leukodystrophy and found that MWF values were highly decreased in advanced stages of the disease, despite hyperintensities on conventional T2-weighted images becoming less apparent [42 ▪▪ ]. Another study used MWI to assess the effect of hematopoietic stem cell transplantation in patients with late-onset Krabbe disease, another rare leukodystrophy, and found widespread reduction in MWF values compared with controls before treatment, which remained stable over 4 years following treatment.…”