Neurocognitive trajectory of boys who received a hematopoietic stem cell transplant at an early stage of childhood cerebral adrenoleukodystrophy

Elizabeth I. Pierpont, Julie B. Eisengart, Ryan Shanley, David Nascene, Gerald Raymond, Elsa G. Shapiro, Rich S. Ziegler, Paul J. Orchard, Weston P. Miller

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)710-717
Number of pages8
JournalJAMA neurology
Volume74
Issue number6
DOIs
StatePublished - Jun 1 2017

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Adrenoleukodystrophy
Hematopoietic Stem Cells
Transplants
Magnetic Resonance Imaging
Nervous System
Outcome Assessment (Health Care)
Benchmarking
Demyelinating Diseases
Standard of Care
Short-Term Memory
Newborn Infant
Survival

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Pierpont, Elizabeth I. ; Eisengart, Julie B. ; Shanley, Ryan ; Nascene, David ; Raymond, Gerald ; Shapiro, Elsa G. ; Ziegler, Rich S. ; Orchard, Paul J. ; Miller, Weston P. / Neurocognitive trajectory of boys who received a hematopoietic stem cell transplant at an early stage of childhood cerebral adrenoleukodystrophy. In: JAMA neurology. 2017 ; Vol. 74, No. 6. pp. 710-717.
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title = "Neurocognitive trajectory of boys who received a hematopoietic stem cell transplant at an early stage of childhood cerebral adrenoleukodystrophy",
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.",
author = "Pierpont, {Elizabeth I.} and Eisengart, {Julie B.} and Ryan Shanley and David Nascene and Gerald Raymond and Shapiro, {Elsa G.} and Ziegler, {Rich S.} and Orchard, {Paul J.} and Miller, {Weston P.}",
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Pierpont, EI, Eisengart, JB, Shanley, R, Nascene, D, Raymond, G, Shapiro, EG, Ziegler, RS, Orchard, PJ & Miller, WP 2017, 'Neurocognitive trajectory of boys who received a hematopoietic stem cell transplant at an early stage of childhood cerebral adrenoleukodystrophy', JAMA neurology, vol. 74, no. 6, pp. 710-717. https://doi.org/10.1001/jamaneurol.2017.0013

Neurocognitive trajectory of boys who received a hematopoietic stem cell transplant at an early stage of childhood cerebral adrenoleukodystrophy. / Pierpont, Elizabeth I.; Eisengart, Julie B.; Shanley, Ryan; Nascene, David; Raymond, Gerald; Shapiro, Elsa G.; Ziegler, Rich S.; Orchard, Paul J.; Miller, Weston P.

In: JAMA neurology, Vol. 74, No. 6, 01.06.2017, p. 710-717.

Research output: Contribution to journalArticle

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T1 - Neurocognitive trajectory of boys who received a hematopoietic stem cell transplant at an early stage of childhood cerebral adrenoleukodystrophy

AU - Pierpont, Elizabeth I.

AU - Eisengart, Julie B.

AU - Shanley, Ryan

AU - Nascene, David

AU - Raymond, Gerald

AU - Shapiro, Elsa G.

AU - Ziegler, Rich S.

AU - Orchard, Paul J.

AU - Miller, Weston P.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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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