Longitudinal study of MRI and functional outcome measures in facioscapulohumeral muscular dystrophy.

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. For MRI to be a useful biomarker in an FSHD clinical trial, it should reliably detect changes over relatively short time-intervals (~ 1 year). We hypothesized that fatty change over the study course would be most likely in muscles already demonstrating disease progression, and that the degree of MRI burden would be correlated with function. METHODS: We studied 36 patients with FSHD and lower-extremity weakness at baseline. Thirty-two patients returned in our 12-month longitudinal observational study. We analyzed DIXON MRI images of 16 lower-extremity muscles in each patient and compared them to quantitative strength measurement and ambulatory functional outcome measures. RESULTS: There was a small shift to higher fat fractions in the summed muscle data for each patient, however individual muscles demonstrated much larger magnitudes of change. The greatest increase in fat fraction was observed in muscles having an intermediate fat replacement at baseline, with minimally (baseline fat fraction < 0.10) or severely (> 0.70) affected muscles less likely to progress. Functional outcome measures did not demonstrate marked change over the interval; however, overall MRI disease burden was correlated with functional outcome measures. Direct comparison of the tibialis anterior (TA) fat fraction and quantitative strength measurement showed a sigmoidal relationship, with steepest drop being when the muscle gets more than ~ 20% fatty replaced. CONCLUSIONS: Assessing MRI changes in 16 lower-extremity muscles across 1 year demonstrated that those muscles having an intermediate baseline fat fraction were more likely to progress. Ambulatory functional outcome measures are generally related to overall muscle MRI burden but remain unchanged in the short term. Quantitative strength measurement of the TA showed a steep loss of strength when more fatty infiltration is present suggesting that MRI may be preferable for following incremental change or modulation with drug therapy.

Geometric morphometrics reveal altered corpus callosum shape in pyridoxine-dependent epilepsy.

OBJECTIVE: To evaluate the features and maturational changes in overall callosal shape in patients with pyridoxine-dependent epilepsy (PDE). METHODS: Measurements were conducted through landmark-based geometric morphometrics applied on cerebral MRIs of patients with PDE and age-matched control subjects. The outline of the corpus callosum was manually traced in the midsagittal plane. Three hundred semi-landmarks along the outline were collected and underwent statistical generalized Procrustes analysis. An allometric regression was applied to evaluate the callosal shape due to growth over time. RESULTS: Thirty-eight patients with PDE and 38 age- and sex-matched control subjects were included. Mean age at the time of the MRI in the patient group was 9.3 years (median 6.3 years, range 0.01-48 years). Significant differences (p < 0.01) in the mean callosal shape between patients and controls were found. The allometric regression model revealed significant shape variations (p < 0.01) between the 2 study groups across the developmental course after controlling for the effect of callosal size on shape. This latter effect turned out to be significant as well (p < 0.001). CONCLUSIONS: Patients with PDE show an altered callosal shape and variations in callosal ontogeny, which are likely secondary to the underlying genetic defect with abnormal function of antiquitin, the product of the ALDH7A1 gene.

MRI change metrics of facioscapulohumeral muscular dystrophy: Stir and T1.

INTRODUCTION: MRI evaluation in facioscapulohumeral muscular dystrophy (FSHD) demonstrates fatty replacement and inflammation/edema in muscle. Our previous work demonstrated short T1 inversion recovery (STIR)-hyperintense (STIR+) signal in muscle 2 years before fatty replacement. We evaluated leg muscle STIR changes and fatty replacement within 14 months. METHODS: FSHD subjects received 2 MRI scans of thigh and calf over a 6.9- to 13.8-month interval. Quality of life measures were collected. One Radiologist rated muscle changes on a semi-quantitative scale. RESULTS: Fifteen subjects completed longitudinal imaging. Four STIR + muscles and 3 STIR-normal (STIR-) muscles were rated as progressing to fatty tissue over the study period. DISCUSSION: STIR + muscles with confluent regions of fat at baseline increased more in fat, while STIR- muscles had increases in septal-fat over the study period. These changes may reflect two phases of FSHD, demonstrating MRI sensitivity is weighted toward gross pathological phases of the disease. Muscle Nerve 57: 905-912, 2018.

Corpus Callosum Diffusion and Connectivity Features in High Functioning Subjects With Pyridoxine-Dependent Epilepsy.

BACKGROUND: In this observational study, white matter structure, functional magnetic resonance imaging (fMRI) task-based responses, and functional connectivity were assessed in four subjects with high functioning pyridoxine-dependent epilepsy and age-matched control subjects. METHODS: Four male subjects with pyridoxine-dependent epilepsy (mean age 31 years 8 months, standard deviation 12 years 3 months) and age-matched control subjects (32 years 4 months, standard deviation 13 years) were recruited to participate in the study. Diffusion tensor data were collected and postprocessed in Functional Magnetic Resonance Imaging of the Brain Software Library to quantify corpus callosum tracts as a means to assess white matter structure. Task-based fMRI data were collected and Functional Magnetic Resonance Imaging of the Brain Software Library used to assess task response. The fMRI resting-state data were analyzed with the functional connectivity toolbox Conn to determine functional connectivity. RESULTS: Subjects with high functioning pyridoxine-dependent epilepsy retained structural white matter connectivity compared with control subjects, despite morphologic differences in the posterior corpus callosum. fMRI task-based results did not differ between subjects with pyridoxine-dependent epilepsy and control subjects; functional connectivity as measured with resting-state fMRI was lower in subjects with pyridoxine-dependent epilepsy for several systems (memory, somatosensory, auditory). CONCLUSION: Although corpus callosum morphology is diminished in the posterior portions, structural connectivity was retained in subjects with pyridoxine-dependent epilepsy, while functional connectivity was diminished for memory, somatosensory, and auditory systems.

Longitudinal features of STIR bright signal in FSHD.

INTRODUCTION: Magnetic resonance imaging of muscle shows short tau-inversion recovery (STIR) brightness in autosomal dominant facioscapulohumeral muscular dystrophy (FSHD1) suggestive of active inflammation/injury. We measured the longitudinal stability/progression of this potential disease biomarker. METHODS: Nine subjects underwent calf MRI imaging over 2 years. Two radiologists evaluated qualitative muscle changes. RESULTS: In 3/9 subjects, calf muscles demonstrated moderate/severe STIR hyperintensity at Time 1 that had progressed to fatty replacement 2 years later (Time 2). In the remaining subjects, moderate/severe muscle STIR abnormalities, when present, were consistent between exams. Mild STIR+ elevations had roughly similar patterns between exams. CONCLUSIONS: Moderate/severe STIR hyperintensities often foreshadow fatty replacement over a 2-year interval. Whether longer time courses are required to observe muscle degeneration and fatty replacement in some subjects remains to be explored.

The magnetic resonance imaging spectrum of facioscapulohumeral muscular dystrophy.

INTRODUCTION: Facioscapulohumeral muscular dystrophy (FSHD) is associated with a repeat contraction in the D4Z4 gene locus on chromosome 4q35. We used a one-step quantitative magnetic resonance imaging (MRI) method to evaluate muscle, edema, and fat in patients spanning the range of severity. METHODS: Fifteen patients with FSHD were compared with 10 healthy subjects using non-negative linear least-squares fitting of 32-echo relaxation data (T2). The results were compared with a biexponential approach for characterizing muscle/fat ratio and T2 relaxation measurements from fat-suppressed inversion recovery. RESULTS: Increased T2 signal consistent with edema was common in FSHD subjects, a pattern not present in healthy controls. A varied pattern of edema and fatty replacement in muscles was shown. CONCLUSIONS: As a discrete biomarker, edema may be useful for following the clinical course of FSHD. Future work toward optimizing measurement is discussed.