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Original Investigation
April 17, 2017

Neurocognitive Trajectory of Boys Who Received a Hematopoietic Stem Cell Transplant at an Early Stage of Childhood Cerebral Adrenoleukodystrophy

Author Affiliations
  • 1Division of Clinical Behavioral Neuroscience, Department of Pediatrics, University of Minnesota, Minneapolis
  • 2Biostatistics and Bioinformatics Core, University of Minnesota Masonic Cancer Center, Minneapolis
  • 3Department of Radiology, University of Minnesota, Minneapolis
  • 4Department of Neurology, University of Minnesota, Minneapolis
  • 5Shapiro & Delaney LLC, University of Minnesota, Minneapolis
  • 6Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis
JAMA Neurol. Published online April 17, 2017. doi:10.1001/jamaneurol.2017.0013
Key Points

Question  What factors are associated with the neurocognitive trajectory of patients with childhood cerebral adrenoleukodystrophy (cALD) undergoing a hematopoietic stem cell transplant in early-stage cerebral disease?

Findings  In this cohort study of neurocognitive assessments from 62 boys with cALD, higher baseline magnetic resonance imaging (MRI) severity scores were associated with greater neurocognitive decline after a transplant. Despite expedient intervention after detection of early cerebral disease on MRI scans, most boys with cALD exhibited clinically significant neurocognitive deficits at long-term follow-up.

Meaning  Patients with cALD who have greater than minimal evidence of cerebral disease on MRI scans at the time of a hematopoietic stem cell transplant are at risk for severe, persistent neurocognitive impairment.

Abstract

Importance  Untreated childhood cerebral adrenoleukodystrophy (cALD) is a fatal disease associated with progressive cerebral demyelination and rapid, devastating neurologic decline. The standard of care to enhance long-term survival and stabilize cerebral disease is a hematopoietic stem cell transplant (HSCT). Neurologic outcomes are better when HSCT occurs at an earlier stage of cALD, yet there is limited understanding of the neurocognitive trajectory of patients who undergo HSCT.

Objectives  To characterize neurocognitive outcomes of boys with cALD and early-stage cerebral disease who were treated with an allogeneic HSCT and to identify disease- and treatment-related factors associated with long-term functioning.

Design, Setting, and Participants  Baseline and follow-up neurocognitive test performance was analyzed for all boys with cALD who received an HSCT at the University of Minnesota between January 1, 1991, and October 20, 2014, and who had a pretransplant magnetic resonance imaging (MRI) severity score of less than 10 (scale range, 0-34; higher scores indicate greater severity).

Main Outcomes and Measures  Longitudinal neurocognitive test performance in 4 domains (verbal comprehension, perceptual [visual] reasoning, working memory, and processing speed) were the primary outcome measures. Secondary analysis at the most recent evaluation also included measures of sustained attention, verbal memory, visual-motor integration, and fine motor function.

Results  Among the 62 boys in this study (mean [SD] age at transplant, 8.37 [2.80] years; range, 4-16 years), there was a significant association of pretransplant MRI severity and baseline verbal comprehension (r = –0.340; P = .008), perceptual reasoning (r = –0.419; P = .001), and processing speed (r = –0.285; P = .03) scores. Higher pretransplant MRI severity scores were also associated with a steeper decline in neurocognitive functioning during the 5-year follow-up period. Twenty-two of 33 patients (67%) with available long-term follow-up neurocognitive testing had severe impairment in at least 1 neurocognitive domain at the most recent evaluation.

Conclusions and Relevance  Boys with cALD who have greater than minimal cerebral disease detected on MRI scans at the time of an HSCT are at risk for severe, persistent neurocognitive deficits. These findings motivate further exploration of methods of detecting cerebral disease prior to development of lesions observable on MRI scans, an endeavor that may be facilitated by newborn screening for adrenoleukodystrophy. These findings may serve a benchmark role in evaluating the efficacy of novel interventions for cALD.

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