International validation of meaningfulness of postural sway and gait to assess myeloneuropathy in adults with adrenoleukodystrophy.

BACKGROUND: The most common manifestation of X-linked adrenoleukodystrophy (ALD) is a slowly progressive myeloneuropathy, which leads to imbalance and gait disturbances. The variable progression of the disease complicates evaluation of its progression rate. Wearable sensors allow for easy and frequent balance and gait collection. This study reports baseline data from a longitudinal study on the quantitative assessment of balance and gait with wearable sensors and their clinical relevance. METHODS: Data were collected from adult patients in two institutions. Postural body sway and gait parameters were measured using accelerometers. Disease severity was measured by the Expanded Disability Severity Scale (EDSS). Falling frequency and quality of life (QOL) were collected in men. The relationship between sway and gait variables and EDSS score, participants' use of a walking aid, and falling frequency was evaluated. RESULTS: One hundred twenty individuals with ALD were included. Sway variables significantly differentiate participants' assistive device use. Sway and gait variables were correlated to the EDSS in both sexes. Both gait speed and sway were correlated with falling frequency in men from one institution. Select QOL subscores were correlated with the EDSS in males from one institution. Accelerometry generated comparable results across sites. DISCUSSION: This study confirms the clinical correlation between spinal cord disease and imbalance and gait in ALD. For the first time, this study shows clinically meaningful relationships for sway and gait with use of an assistive device, falling frequency and QOL. Wearable accelerometers are a valid means to measure sway and gait in ALD. These measures are promising outcomes for clinical trial designs to assess myeloneuropathy in ALD and to monitor disease progression in individuals.

Presymptomatic Lesion in Childhood Cerebral Adrenoleukodystrophy: Timing and Treatment.

BACKGROUND AND OBJECTIVES: We sought to characterize the natural history and standard of care practices between the radiologic appearance of brain lesions, the appearance of lesional enhancement, and treatment with hematopoietic stem cell transplant or gene therapy among boys diagnosed with presymptomatic childhood-onset cerebral adrenoleukodystrophy (CCALD). METHODS: We analyzed a multi-center, mixed retrospective/prospective cohort of patients diagnosed with presymptomatic CCALD (Neurologic Function Score [NFS] = 0, Loes Score [LS] = 0.5 - 9.0, Age < 13 years old). Two time-to-event survival analyses were conducted: (1) Time from CCALD lesion-onset-to-lesional enhancement, (2) Time from enhancement-to-treatment. The analysis was repeated in the subset of patients with (1) the earliest evidence of CCALD, defined as an MRI LS < 1, and (2) patients diagnosed between 2016 - 2021. RESULTS: Seventy-one boys were diagnosed with presymptomatic cerebral lesions at a median age of 6.4yo [2.4 - 12.1] with a LS of 1.5 [0.5 - 9.0]. Fifty percent of patients had lesional enhancement at diagnosis. In the remaining 50%, the median KM-estimate of time from diagnosis-to-lesional enhancement was 6.0 months [95%CI 3.6 - 17.8]. The median KM-estimate of time from enhancement-to-treatment is 3.8 months [95%CI 2.8 - 5.9]; two patients (4.2%) developed symptoms prior to treatment. Patients with a diagnostic LS < 1 were younger (5.8yo [2.4 - 11.5]), had a time-to-enhancement of 4.7mo [95%CI 2.7 - 9.30], and were treated in 3.8mo [95%CI 3.1 - 7.1]; no patients developed symptoms prior to treatment. Time from CCALD diagnosis-to-treatment decreased over the course of the study (ρ = -0.401, p = 0.003). CONCLUSION: Our findings offer a more refined understanding of the timing of lesion formation, enhancement, and treatment among boys with presymptomatic CCALD. These data offer benchmarks for standardizing clinical care and designing future clinical trials.

Biochemical Studies in Fibroblasts to Interpret Variants of Unknown Significance in the ABCD1 Gene.

Due to newborn screening for X-linked adrenoleukodystrophy (ALD), and the use of exome sequencing in clinical practice, the detection of variants of unknown significance (VUS) in the ABCD1 gene is increasing. In these cases, functional tests in fibroblasts may help to classify a variant as (likely) benign or pathogenic. We sought to establish reference ranges for these tests in ALD patients and control subjects with the aim of helping to determine the pathogenicity of VUS in ABCD1. Fibroblasts from 36 male patients with confirmed ALD, 26 healthy control subjects and 17 individuals without a family history of ALD, all with an uncertain clinical diagnosis and a VUS identified in ABCD1, were included. We performed a combination of tests: (i) a test for very-long-chain fatty acids (VLCFA) levels, (ii) a D3-C22:0 loading test to study the VLCFA metabolism and (iii) immunoblotting for ALD protein. All ALD patient fibroblasts had elevated VLCFA levels and a reduced peroxisomal ß-oxidation capacity (as measured by the D3-C16:0/D3-C22:0 ratio in the D3-C22:0 loading test) compared to the control subjects. Of the VUS cases, the VLCFA metabolism was not significantly impaired (most test results were within the reference range) in 6/17, the VLCFA metabolism was significantly impaired (most test results were within/near the ALD range) in 9/17 and a definite conclusion could not be drawn in 2/17 of the cases. Biochemical studies in fibroblasts provided clearly defined reference and disease ranges for the VLCFA metabolism. In 15/17 (88%) VUS we were able to classify the variant as being likely benign or pathogenic. This is of great clinical importance as new variants will be detected.

Magnetic resonance spectroscopy as marker for neurodegeneration in X-linked adrenoleukodystrophy.

X-linked adrenoleukodsytrophy (ALD) is a genetic neuro-metabolic disorder, causing a slowly progressive myelopathy in adult male and female patients. New disease modifying therapies for myelopathy are under development. This calls for new (imaging) markers able to measure disease severity and progression in clinical trials. In this prospective cohort study, we measured cerebral metabolite levels with Magnetic Resonance Spectroscopy (MRS), and evaluated their potential as biomarkers for disease severity and neurodegeneration in ALD. We used a comprehensive protocol of 3T Magnetic Resonance Spectroscopic Imaging (MRSI) and 7T Single Voxel Spectroscopy (SVS) in a large cohort of adult ALD males without cerebral demyelination. One hundred seven baseline scans - 59 obtained in ALD patients (42 3T MRSI and 17 7T SVS) and 48 obtained in healthy male controls (32 3T MRSI and 16 7T SVS) - and 82 one and two-year follow-up scans (66 3T MRSI and 16 7T SVS) of ALD patients were included. Both protocols showed significantly lower concentration ratios of N-acetylaspartate/creatine (tNAA/tCr) and Glx (glutamine + glutamate)/tCr in the grey and white matter of patients, compared to controls. A novel finding is the higher level of inositol (Ins)/tCr and choline containing compounds (tCho)/tCr in ALD patients without cerebral demyelination. Furthermore, tNAA/tCr correlated strongly with clinical measures of severity of myelopathy. There was no detectable change in metabolite ratios after one-year or two-year follow-up. Our results imply that cerebral metabolite levels - and more specifically the tNAA/tCr ratio - measured with MRS, have potential value as (imaging) biomarkers in ALD.

Imaging in X-Linked Adrenoleukodystrophy.

Magnetic resonance imaging (MRI) is the gold standard for the detection of cerebral lesions in X-linked adrenoleukodystrophy (ALD). ALD is one of the most common peroxisomal disorders and is characterized by a defect in degradation of very long chain fatty acids (VLCFA), resulting in accumulation of VLCFA in plasma and tissues. The clinical spectrum of ALD is wide and includes adrenocortical insufficiency, a slowly progressive myelopathy in adulthood, and cerebral demyelination in a subset of male patients. Cerebral demyelination (cerebral ALD) can be treated with hematopoietic cell transplantation (HCT) but only in an early (pre- or early symptomatic) stage and therefore active MRI surveillance is recommended for male patients, both pediatric and adult. Although structural MRI of the brain can detect the presence and extent of cerebral lesions, it does not predict if and when cerebral demyelination will occur. There is a great need for imaging techniques that predict onset of cerebral ALD before lesions appear. Also, imaging markers for severity of myelopathy as surrogate outcome measure in clinical trials would facilitate drug development. New quantitative MRI techniques are promising in that respect. This review focuses on structural and quantitative imaging techniques-including magnetic resonance spectroscopy, diffusion tensor imaging, MR perfusion imaging, magnetization transfer (MT) imaging, neurite orientation dispersion and density imaging (NODDI), and myelin water fraction imaging-used in ALD and their role in clinical practice and research opportunities for the future.

Optical coherence tomography to measure the progression of myelopathy in adrenoleukodystrophy.

OBJECTIVE: To prospectively determine the value of optical coherence tomography (OCT) as a surrogate outcome measure for the progression of myelopathy in males with adrenoleukodystrophy. METHODS: Retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness were measured at baseline, 1- and 2-year follow-up in patients and age-matched controls. We assessed the severity of myelopathy with clinical parameters: Expanded Disability Status Scale (EDSS), Severity Scoring system for Progressive Myelopathy (SSPROM), and timed up-and-go. Linear mixed model analysis was used to compare changes in retinal layer thickness of patients to controls. In addition, we correlated changes in retinal layer thickness with changes in clinical parameters. RESULTS: Longitudinal data were available for 28 patients and 29 controls. Peripapillary RNFL (pRNFL) thickness decreased significantly in patients compared to controls (-1.75µm, p = 0.001), whereas change in macular GCL and RNFL was not different between groups. Analysis of the symptomatic subgroup showed that, apart from a similar decrease in pRNFL thickness, GCL thickness decreased significantly (-0.55 µm, p = 0.014). There were moderately strong correlations between changes in retinal layer thickness and changes in clinical parameters of severity of myelopathy. INTERPRETATION: This prospective study demonstrates the potential of OCT-measured retinal neurodegeneration as a surrogate outcome measure for the progression of myelopathy in adrenoleukodystrophy. As differences were small, our findings need to be confirmed with longer follow-up and/or in a larger patient sample.

Plasma NfL and GFAP as biomarkers of spinal cord degeneration in adrenoleukodystrophy.

OBJECTIVE: To explore the potential of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) as biomarkers of spinal cord degeneration in adrenoleukodystrophy, as objective treatment-outcome parameters are needed. METHODS: Plasma NfL and GFAP levels were measured in 45 male and 47 female ALD patients and compared to a reference cohort of 73 healthy controls. For male patients, cerebrospinal fluid (CSF) samples (n = 33) and 1-year (n = 39) and 2-year (n = 18) follow-up data were also collected. Severity of myelopathy was assessed with clinical parameters: Expanded Disability Status Scale (EDSS), Severity Scoring system for Progressive Myelopathy (SSPROM), and timed up-and-go. RESULTS: NfL and GFAP levels were higher in male (P < 0.001, effect size (partial ƞ2 ) NfL = 0.49, GFAP = 0.13) and female (P < 0.001, effect size NfL = 0.19, GFAP = 0.23) patients compared to controls; levels were higher in both symptomatic and asymptomatic patients. In male patients, NfL levels were associated with all three clinical parameters of severity of myelopathy (EDSS, SSPROM, and timed up-and go), while GFAP in male and NfL and GFAP in female patients were not. Changes in clinical parameters during follow-up did not correlate with (changes in) NfL or GFAP levels. Plasma and CSF NfL were strongly correlated (r = 0.60, P < 0.001), but plasma and CSF GFAP were not (r = 0.005, P = 0.98). INTERPRETATION: Our study illustrates the potential of plasma NfL as biomarker of spinal cord degeneration in adrenoleukodystrophy, which was superior to plasma GFAP in our cohort.

Postural Body Sway as Surrogate Outcome for Myelopathy in Adrenoleukodystrophy.

BACKGROUND: Myelopathy is the core clinical manifestation of adrenoleukodystrophy (ALD), which is the most common peroxisomal disorder. Development of therapies requires sensitive and clinically relevant outcome measures. Together with spastic paraparesis, balance disturbance is the main cause of disability from myelopathy in ALD. In this cross-sectional study, we evaluated whether postural body sway - a measure of balance - could serve as a surrogate outcome in clinical trials. METHODS: Forty-eight male ALD patients and 49 age-matched healthy male controls were included in this study. We compared sway amplitude and sway path of ALD patients to controls. We then correlated the body sway parameters showing the largest between-group differences with clinical measures of severity of myelopathy. To correct for age, we performed multiple linear regression analysis with age and severity of myelopathy as independent variables. RESULTS: All body sway parameters were significantly higher in patients than in controls, with medium to large effect sizes (r = 0.43-0.66, p < 0.001). In the subgroup of asymptomatic patients, body sway amplitude was also higher, but the difference with controls was smaller than for symptomatic patients (effect size r = 0.38-0.46). We found moderate to strong correlations between body sway amplitude and clinical severity of myelopathy (r = 0.40-0.79, p < 0.005). After correction for age, severity of myelopathy was a significant predictor of body sway amplitude in all regression models. CONCLUSIONS: These results indicate that postural body sway may serve as a surrogate outcome for myelopathy in ALD. Such outcomes are important to evaluate new therapies in clinical trials. Further longitudinal studies are needed and ongoing in this cohort.

Clinical and radiographic course of arrested cerebral adrenoleukodystrophy.

OBJECTIVE: To gain insight into the natural history of arrested cerebral adrenoleukodystrophy (CALD) by quantifying the change in Neurologic Function Score (NFS) and Loes Score (LS) over time in patients whose cerebral lesions spontaneously stopped progressing. METHODS: We retrospectively reviewed a series of 22 patients with arrested CALD followed longitudinally over a median time of 2.4 years (0.7-17.0 years). Primary outcomes were change in radiographic disease burden (measured by LS) and clinical symptoms (measured by NFS) between patients who never developed a contrast-enhancing lesion (gadolinium enhancement (GdE)- subgroup) and those who did (GdE+ subgroup). Secondary analyses comparing patterns of neuroanatomic involvement and lesion number, and prevalence estimates, were performed. RESULTS: Cerebral lesions were first detected at a median age of 23.3 years (8.0-67.6 years) with an initial LS of 4 (0.5-9). NFS was 0.5 (0-6). Overall change in NFS or LS per year did not differ between subgroups. No patients who remained GdE- converted to a progressive CALD phenotype. The presence of contrast enhancement was associated with disease progression (r s = 0.559, p < 0.001). Four patients (18.2%) underwent step-wise progression, followed by spontaneous resolution of contrast enhancement and rearrest of disease. Three patients (13.6%) converted to progressive CALD. Nineteen patients (86.4%) had arrested CALD at the most recent follow-up. The prevalence of arrested CALD is 12.4%. CONCLUSION: Arrested CALD lesions can begin in childhood, and patients are often asymptomatic early in disease. The majority of patients remain stable. However, clinical and MRI surveillance is recommended because a minority of patients undergo step-wise progression or conversion to progressive CALD.

Spinal cord atrophy as a measure of severity of myelopathy in adrenoleukodystrophy.

All men and most women with X-linked adrenoleukodystrophy (ALD) develop myelopathy in adulthood. As clinical trials with new potential disease-modifying therapies are emerging, sensitive outcome measures for quantifying myelopathy are needed. This prospective cohort study evaluated spinal cord size (cross-sectional area - CSA) and shape (eccentricity) as potential new quantitative outcome measures for myelopathy in ALD. Seventy-four baseline magnetic resonance imaging (MRI) scans, acquired in 42 male ALD patients and 32 age-matched healthy controls, and 26 follow-up scans of ALD patients were included in the study. We used routine T1 -weighted MRI sequences to measure mean CSA, eccentricity, right-left and anteroposterior diameters in the cervical spinal cord. We compared MRI measurements between groups and correlated CSA with clinical outcome measures of disease severity. Longitudinally, we compared MRI measurements between baseline and 1-year follow-up. CSA was significantly smaller in patients compared to controls on all measured spinal cord levels (P < .001). The difference was completely explained by the effect of the symptomatic subgroup. Furthermore, the spinal cord showed flattening (higher eccentricity and smaller anteroposterior diameters) in patients. CSA correlated strongly with all clinical measures of severity of myelopathy. There was no detectable change in CSA after 1-year follow-up. The cervical spinal cord in symptomatic ALD patients is smaller and flattened compared to controls, possibly due to atrophy of the dorsal columns. CSA is a reliable marker of disease severity and can be a valuable outcome measure in long-term follow-up studies in ALD. SYNOPSIS: A prospective cohort study in 42 adrenoleukodystrophy (ALD) patients and 32 controls demonstrated that the spinal cord cross-sectional area of patients is smaller compared to healthy controls and correlates with severity of myelopathy in patients, hence it could be valuable as a much needed surrogate outcome measure.

Thrombolysis related symptomatic intracranial hemorrhage in estimated versus measured body weight.

BACKGROUND AND AIM: In acute ischemic stroke, under- or overestimation of body weight can lead to dosing errors of recombinant tissue plasminogen activator with consequent reduced efficacy or increased risk of hemorrhagic complications. Measurement of body weight is more accurate than estimation of body weight but potentially leads to longer door-to-needle times. Our aim was to assess if weight modality (estimation of body weight versus measurement of body weight) is associated with (i) symptomatic intracranial hemorrhage rate, (ii) clinical outcome, and (iii) door-to-needle times. METHODS: Consecutive patients treated with intravenous thrombolysis between 2009 and 2016 from 14 hospitals were included. Baseline characteristics and outcome parameters were retrieved from medical records. We defined symptomatic intracranial hemorrhage according to the European Cooperative Acute Stroke Study (ECASS)-III definition and clinical outcome was assessed with the modified Rankin Scale. The association of weight modality and outcome parameters was estimated with regression analyses. RESULTS: A total of 4801 patients were included. Five hospitals used measurement of body weight (n = 1753), six hospitals used estimation of body weight (n = 2325), and three hospitals (n = 723) changed from estimation of body weight to measurement of body weight during the study period. In 2048 of the patients (43%), measurement of body weight was used and in 2753 (57%), estimation of body weight. In the measurement of body weight group, an inbuilt weighing bed was used in 1094 patients (53%) and a patient lift scale in 954 patients (47%). In the estimation of body weight group, policy regarding estimation was similar. Estimation of body weight was not associated with increased symptomatic intracranial hemorrhage risk (adjusted odds ratio = 1.16; 95% confidence interval 0.83-1.62) or favorable outcome (adjusted odds ratio = 0.99; 95% confidence interval 0.82-1.21), but it was significantly associated with longer door-to-needle times compared to measurement of body weight using an inbuilt weighing bed (adjusted B = 3.57; 95% confidence interval 1.33-5.80) and shorter door-to-needle times compared to measurement of body weight using a patient lift scale (-3.96; 95% confidence interval -6.38 to -1.53). CONCLUSION: We did not find evidence that weight modality (estimation of body weight versus measurement of body weight) to determine recombinant tissue plasminogen activator dose in intravenous thrombolysis eligible patients is associated with symptomatic intracranial hemorrhage or clinical outcome. We did find that estimation of body weight leads to longer door-to-needle times compared to measurement of body weight using an inbuilt weighing bed and to shorter door-to-needle times compared to measurement of body weight using a patient lift scale.

[Estimating weight accurately for safe treatment: body weight estimation in patients with acute ischaemic stroke is frequently inaccurate]. / Accurate gewichtschatting voor een veilige dosering. Gewicht van patiënten met een herseninfarct vaak niet goed geschat.

Patients with acute ischaemic stroke should receive intravenous thrombolysis with 0.9 mg/kg of recombinant tissue plasminogen activator as quickly as possible. In order to reduce the door-to-needle time, many physicians estimate the patient's body weight. However, these estimates are frequently inaccurate and inaccuracy can lead to dosage errors. According to a meta-analysis in a Cochrane study, the risk of developing intracranial haemorrhage is almost tripled for patients treated with higher thrombolytic doses, compared with patients receiving a dosage based on accurate weight measurements (odds ratio: 2.71). Only 28% of physicians estimate to within 5 kilograms of actual body weight. In order to reduce the risk of complications, patients arriving at the emergency room should be weighted with a scale. Alternatively, the body weight can be estimated using a validated nomogram.