Cerebral adrenoleukodystrophy (cALD) remains a devastating neurodegenerative disease; only allogeneic hematopoietic cell transplantation (HCT) has been shown to provide long-term disease stabilization and survival. Sixty boys undergoing HCT for cALD from 2000 to 2009 were analyzed. The median age at HCT was 8.7 years; conditioning regimens and allograft sources varied. At HCT, 50% demonstrated a Loes radiographic severity score > 10, and 62% showed clinical evidence of neurologic dysfunction. A total of 78% (n ‫؍‬ 47) are alive at a median 3.7 years after HCT. The estimate of 5-year survival for boys with Loes score < 10 at HCT was 89%, whereas that for boys with Loes score > 10 was 60% (P ‫؍‬ .03). The 5-year survival estimate for boys absent of clinical cerebral disease at HCT was 91%, whereas that for boys with neurologic dysfunction was 66% (P ‫؍‬ .08). The cumulative incidence of transplantationrelated mortality at day 100 was 8%. Posttransplantation progression of neurologic dysfunction depended significantly on the pre-HCT Loes score and clinical neurologic status. We describe the largest single-institution analysis of survival and neurologic function outcomes after HCT in cALD. These trials were registered at www.clinicaltrials.gov as #NCT00176904, #NCT00668564, and #NCT00383448. (Blood. 2011;118(7): [1971][1972][1973][1974][1975][1976][1977][1978]

A B S T R A C T Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients' abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P = .01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE + ) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE + at baseline, with an NFS 1 and Loes score of 0.5 to 9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100 days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE + status is a strong predictor of disease progression in untreated patients. This study confirms journal homepage: www.bbmt.org HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.

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). (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. MAIN OUTCOMES AND MEASURES Longitudinal neurocognitive test performance in 4 domains RESULTSAmong 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. 38. Miller WP, Mantovani LF, Muzic J, et al. Intensity of MRI gadolinium enhancement in cerebral adrenoleukodystrophy: a biomarker for inflammation and predictor of outcome following transplantation in higher risk patients. AJNR Am J Neuroradiol. 2016;37(2):367-372. 39. Orchard PJ, Lund T, Miller W, et al. Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy. J Neuroinflammation. 2011; 8:144. 40. Rocken...

Interlaminar lumbar puncture and cervical puncture may not be ideal in all circumstances. Recently, we have used a transforaminal approach in selected situations. Between May 2016 and December 2017, twenty-six transforaminal lumbar punctures were performed in 9 patients (25 CT-guided, 1 fluoroscopy-guided). Seven had spinal muscular atrophy and were referred for intrathecal nusinersen administration. In 2, CT myelography was performed via transforaminal lumbar puncture. The lumbar posterior elements were completely fused in 8, and there was an overlying abscess in 1. The L1-2 level was used in 2; the L2-3 level, in 10; the L3-4 level, in 12; and the L4-5 level, in 2 procedures. Post-lumbar puncture headache was observed on 4 occasions, which resolved without blood patching. One patient felt heat and pain at the injection site that resolved spontaneously within hours. One patient had radicular pain that resolved with conservative treatment. Transforaminal lumbar puncture may become an effective alternative to classic interlaminar lumbar puncture or cervical puncture.

BACKGROUND AND PURPOSE Outcomes following hematopoietic stem cell transplantation for higher-risk childhood-onset cerebral adrenoleukodystrophy are variable. We explored whether a brain MRI gadolinium intensity scoring system improves prediction of neurologic outcome. METHODS A four-point scale of gadolinium intensity relative to the choroid plexus was developed: 0 = no enhancement; 1 = hypo-intense; 2 = iso-intense; 3 = hyper-intense. The scale’s inter-observer concordance was assessed on 30 randomly chosen studies. Scores were generated for 64 evaluable patients and compared with cerebrospinal fluid chitotriosidase levels, a known inflammatory marker correlating with outcomes following transplant. For 25 evaluable higher-risk patients (Loes ≥ 10), the gadolinium intensity score was compared with longer-term post-transplant clinical change. RESULTS The gadolinium intensity scoring system showed good inter-observer reproducibility (kappa = 0.72). Of 64 evaluable boys, the score positively correlated with average concomitant cerebrospinal fluid chitotriosidase activity in ng/mL/hr: (0), 2,717, n=5; (1), 3,218, n=13; (2), 6,497, n=23; and (3), 12,030, n=23 (p < 0.01). For 25 evaluable higher-risk patients, more intense pre-transplant brain MRI gadolinium enhancement predicted greater average loss on the adrenoleukodystrophy neurologic function scale following transplant: (0/1), ΔNFS = 4.3, n = 7; (2/3), ΔNFS = 10.4, n = 18 (p = 0.05). CONCLUSION Gadolinium enhancement intensity on brain MRI can be scored simply and reproducibly for cerebral adrenoleukodystrophy. Enhancement score significantly correlates with chitotriosidase. In boys with higher-risk cerebral disease (Loes ≥ 10), enhancement score itself predicts neurologic outcome following treatment. Such data may help to guide treatment decisions for clinicians and families.