Post‐transplant adaptive function in childhood cerebral adrenoleukodystrophy

Abstract

ObjectiveHematopoietic stem cell transplantation (HSCT) is the only treatment known to slow or halt inflammatory demyelination among boys with the cerebral form of X‐linked adrenoleukodystrophy (cALD), a devastating childhood condition affecting the central nervous system. HSCT can lead to a range of adverse outcomes including fatality. Previous studies have examined the potential predictors of post‐HSCT survival and neurologic functioning. However, little is known about patients' daily‐life adaptive functional outcomes (i.e., ability to communicate, maintain social relationships, and independently execute tasks of daily living). The purpose of this retrospective cohort study was to identify which patient characteristics and treatment‐related variables predict long‐term adaptive function among the survivors of HSCT for cALD.MethodsWe obtained caregiver ratings of adaptive functioning of 65 transplant survivors at an average of 4.6 years (range: 1.0–24.1 years) post‐HSCT. Using linear regression with penalized maximum likelihood estimation, we modeled the relative contribution of pre‐transplant neurocognitive test performance, MRI severity, transplant regimen, and length of time since transplant on patient adaptive functioning outcomes.ResultsHigher radiographic disease severity and poorer performance on baseline neurocognitive tests requiring fine motor skills and visual perception were associated with inferior adaptive functioning after HSCT. Use of radiation during the transplant preparative regimen also predicted poorer adaptive outcomes.InterpretationIn addition to radiological disease severity, baseline neurocognitive test performance is associated with post‐transplant adaptive functional outcomes. Neurocognitive measures may play an important role in prognostic counseling and post‐transplant treatment planning for patients considering HSCT for cALD.

Differential outcomes for frontal versus posterior demyelination in childhood cerebral adrenoleukodystrophy

“…MRI severity, the neurocognitive status of a patient at the time of HCT, treatment-related variables, and the location of the lesion may all impact the likelihood of neurological and neuropsychological morbidities in the years following treatment. 4,5,12 This retrospective study spanned over three decades with different conditioning regimens, GVH prophylaxis and potential neurotoxicity, which could have adversely affected neurocognitive function. Since moderate reduction in memory is a potential neurocognitive side effect of total body irradiation (TBI), 13,14 use of fractionated TBI conditioning could have contributed to neurocognitive deficits in two of the four patients with FWM lesions who experienced severe working memory impairment.…”

“…Taken together with recent studies, our findings suggest that over‐reliance on MRI severity “cutoff” scores to aid in prediction of favorable vs unfavorable outcomes may oversimplify the factors contributing to treatment response in this complex demyelinating disease. MRI severity, the neurocognitive status of a patient at the time of HCT, treatment‐related variables, and the location of the lesion may all impact the likelihood of neurological and neuropsychological morbidities in the years following treatment 4,5,12 …”

Neurocognitive benchmarks following transplant for emerging cerebral adrenoleukodystrophy

“… 4 Early intervention is critical, as long-term neurocognitive capabilities and other functional outcomes are associated with the severity of the MRI lesion and neurocognitive status at the time of HSCT. 2 , 5 – 7 Current understanding of outcomes is based largely on boys whose cALD was identified due to clinical signs, which may not emerge until the lesion has spread substantially. The NBS era requires that this understanding be updated.…”

Gene Therapy for Childhood Cerebral Adrenoleukodystrophy

“…A total score of 0 indicates the absence of clinical signs of cerebral disease and a higher total score indicates more severe deficits. Multiple studies have shown that lower Loes and NFS scores, indicating lower stage disease, are associated with superior survival and disease control following allogeneic HCT compared to those with higher scores [16,[28][29][30].…”