Childhood Cerebral Adrenoleukodystrophy: MR Perfusion Measurements and Their Use in Predicting Clinical Outcome after Hematopoietic Stem Cell Transplantation

Abstract

Background and Purpose To prospectively measure MR perfusion (MRP) parameters in patients with cerebral adrenoleukodystrophy (cALD) pre- and post-hematopoietic stem cell transplantation (HSCT), and to correlate those measurements with the clinical outcome. Materials and Methods Ten cALD patients prospectively underwent DSC-MRP at <45 days pre-(baseline), 30–60 days post-, and 1 year post-HSCT. MRP measurements in the 10 patients and 8 controls were obtained from the parietooccipital WM (POWM), callosal splenium (SCC), leading enhancing edge (LEE), and normal-appearing frontal white matter (NAFWM). MR severity (Loes) scores and clinical neurologic function (NFS) and neurocognitive scores were also obtained. MRP values were analyzed in the cALD patients at each time point, and compared to controls. Correlations were calculated between the pre-HSCT MRP values and 1-year clinical scores, with p-value adjustment for multiple comparisons. Results At baseline in cALD patients, both rCBV and rCBF within the SCC and POWM significantly differed from controls (p=0.005–0.031), and remained so 1 year post-HSCT (p=0.003–0.005). Meanwhile, no MRP parameter within the LEE differed significantly from controls at baseline or at 1 year (p=0.074–0.999), nor significantly changed by 1 year post-HSCT (p=0.142–0.887). Baseline Loes scores correlated with 1 year NFS (r=0.813, p<0.0001), while SCC rCBV also significantly correlated with 1 year NFS, as well as the neurocognitive FSIQ and PIQ scores (r=−0.730–0.815, p=0.007–0.038). Conclusion LEE measurements likely remain normal post-HSCT in cALD, suggesting local disease stabilization. Meanwhile, POWM and SCC rCBV and rCBF values worsen, signifying irreversible injury. Baseline SCC rCBV may predict clinical outcomes following HSCT.

The Spectrum of MR Imaging Patterns Suggestive of Pediatric Posterior Reversible Encephalopathy Syndrome in Children With Cerebral X‐Linked Adrenoleukodystrophy

“…As in prior studies, this study found that most children with pPRES have normal findings on the follow‐up neurologic examination, but this study's small number of patients precluded an adequate analysis for predictors of poor outcome 19,20 . Regarding DWI, reduced diffusion can be noted in 15‐20% of PRES, typically in the cortex‐subcortical WM, but did not occur in this study; reduced diffusion of the callosal splenium or PVWM did occur related to active demyelination or repair in the setting of cALD, as described previously 3,7,9,21 …”

“…Therefore, variations in the imaging appearance of these disorders could be multifactorial and related to the site of endothelial injury, severity, duration, or other exacerbating factors. Notably, regarding outcomes, preliminary studies of cALD have found that the initial sites of involvement on DTI/DWI and MR perfusion correlate with outcome, but involvement by pPRES was not accounted for, and thus this study's results are preliminary 18,21 …”

“…19,20 Regarding DWI, reduced diffusion can be noted in 15-20% of PRES, typically in the cortexsubcortical WM, but did not occur in this study; reduced diffusion of the callosal splenium or PVWM did occur related to active demyelination or repair in the setting of cALD, as described previously. 3,7,9,21 The overlap of these two entities seems rare, and thus their overlapping imaging findings from similar etiologies raise the question of a shared physiologic thread, perhaps one of injury to the endothelial architecture. 22 By injuring the cellcell junctions of the normally restrictive angioarchitecture, the paracellular diffusion of toxic materials could theoretically result in either vasogenic edema (pPRES) or cytotoxic intramyelinic edema (cALD), which could plausibly cause the myriad imaging appearances of PRES and cALD, with varying severity.…”

“…Notably, regarding outcomes, preliminary studies of cALD have found that the initial sites of involvement on DTI/DWI and MR perfusion correlate with outcome, but involvement by pPRES was not accounted for, and thus this study's results are preliminary. 18,21 Cyclosporine is a potent immunosuppressive agent utilized in HSCT. 23 The development of PRES presents an important clinical problem as continuous immunosuppression is needed for the prevention or treatment of graft versus host disease.…”

ABCD1 dysfunction alters white matter microvascular perfusion

“…( Schmid-Schönbein et al , 2001 ; Aubourg, 2015 ). Evidence of abnormal microvascular function in ALD patients includes: (i) ex vivo histopathology showing distorted microvascular permeability beyond the edge of the demyelinating lesions ( Musolino et al , 2015 ); (ii) in vitro experiments showing that lack of ABCD1 in human brain microvascular endothelial cell causes increased adhesion and permeability to leucocytes ( Musolino et al , 2015 ); and (iii) in vivo MRI demonstrating that contrast extravasation ( Loes et al , 2003 ) and white matter hypoperfusion predict lesion progression and clinical outcome after haematopoietic stem cell transplantation (HSCT) ( Musolino et al , 2012 ; McKinney et al , 2016 ). Magnetic resonance perfusion abnormalities have also been found to be associated with white matter lesion progression in other inflammatory demyelinating disorders, such as multiple sclerosis, optic neuritis, acute disseminated encephalomyelitis and progressive multifocal leukencephalopathy ( Khoury et al , 2013 ; Cramer et al , 2015 ; D'haeseleer et al , 2015 ; Hiremath et al , 2017 ).…”