One‐third of boys with X‐linked adrenoleukodystrophy (ALD) develop inflammatory demyelinating lesions, typically at the splenium. These lesions share similarities with multiple sclerosis, including ...cerebral hypoperfusion and links to vitamin D insufficiency. We hypothesized that increasing vitamin D levels would increase cerebral blood flow (CBF) in ALD boys. We conducted an exploratory analysis of vitamin D supplementation and CBF using all available data from participants enrolled in a recent single‐arm interventional study of vitamin D supplementation in boys with ALD. We measured whole brain and splenium CBF using arterial spin labeling (ASL) from three study time points (baseline, 6 months, and 12 months). We used linear generalized estimating equations to evaluate CBF changes between time points and to test for an association between CBF and vitamin D. ASL data were available for 16 participants, aged 2–22 years. Mean vitamin D levels increased by 72.7% (p < .001) after 6 months and 88.6% (p < .01) after 12 months. Relative to baseline measures, mean CBF of the whole brain (6 months: +2.5%, p = .57; 12 months: +6.1%, p = .18) and splenium (6 months: +1.2%, p = .80; 12 months: +7.4%, p = .058) were not significantly changed. Vitamin D levels were positively correlated with CBF in the splenium (slope = .59, p < .001). In this exploratory analysis, we observed a correlation between vitamin D levels and splenial CBF in ALD boys. We confirm the feasibility of measuring CBF in this brain region and population, but further work is needed to establish a causal role for vitamin D in modulating CBF.
Splenial CBF correated positively with vitamin D levels in male patients with X‐linked adrenoleukodystrophy.
IMPORTANCE: There has been limited surveillance for acute flaccid paralysis in North America since the regional eradication of poliovirus. In 2012, the California Department of Public Health received ...several reports of acute flaccid paralysis cases of unknown etiology. OBJECTIVE: To quantify disease incidence and identify potential etiologies of acute flaccid paralysis cases with evidence of spinal motor neuron injury. DESIGN, SETTING, AND PARTICIPANTS: Case series of acute flaccid paralysis in patients with radiological or neurophysiological findings suggestive of spinal motor neuron involvement reported to the California Department of Public Health with symptom onset between June 2012 and July 2015. Patients meeting diagnostic criteria for other acute flaccid paralysis etiologies were excluded. Cerebrospinal fluid, serum samples, nasopharyngeal swab specimens, and stool specimens were submitted to the state laboratory for infectious agent testing. MAIN OUTCOMES AND MEASURES: Case incidence and infectious agent association. RESULTS: Fifty-nine cases were identified. Median age was 9 years (interquartile range IQR, 4-14 years; 50 of the cases were younger than 21 years). Symptoms that preceded or were concurrent included respiratory or gastrointestinal illness (n = 54), fever (n = 47), and limb myalgia (n = 41). Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging and 43 patients had cerebrospinal fluid pleocytosis. During the course of the initial hospitalization, 42 patients received intravenous steroids; 43, intravenous immunoglobulin; and 13, plasma exchange; or a combination of these treatments. Among 45 patients with follow-up data, 38 had persistent weakness at a median follow-up of 9 months (IQR, 3-12 months). Two patients, both immunocompromised adults, died within 60 days of symptom onset. Enteroviruses were the most frequently detected pathogen in either nasopharynx swab specimens, stool specimens, serum samples (15 of 45 patients tested). No pathogens were isolated from the cerebrospinal fluid. The incidence of reported cases was significantly higher during a national enterovirus D68 outbreak occurring from August 2014 through January 2015 (0.16 cases per 100 000 person-years) compared with other monitoring periods (0.028 cases per 100 000 person-years; P <.001). CONCLUSIONS AND RELEVANCE: In this series of patients identified in California from June 2012 through July 2015, clinical manifestations indicated a rare but distinct syndrome of acute flaccid paralysis with evidence of spinal motor neuron involvement. The etiology remains undetermined, most patients were children and young adults, and motor weakness was prolonged.
Summary Background Enterovirus D68 was implicated in a widespread outbreak of severe respiratory illness across the USA in 2014 and has also been reported sporadically in patients with acute flaccid ...myelitis. We aimed to investigate the association between enterovirus D68 infection and acute flaccid myelitis during the 2014 enterovirus D68 respiratory outbreak in the USA. Methods Patients with acute flaccid myelitis who presented to two hospitals in Colorado and California, USA, between Nov 24, 2013, and Oct 11, 2014, were included in the study. Additional cases identified from Jan 1, 2012, to Oct 4, 2014, via statewide surveillance were provided by the California Department of Public Health. We investigated the cause of these cases by metagenomic next-generation sequencing, viral genome recovery, and enterovirus D68 phylogenetic analysis. We compared patients with acute flaccid myelitis who were positive for enterovirus D68 with those with acute flaccid myelitis but negative for enterovirus D68 using the two-tailed Fisher's exact test, two-sample unpaired t test, and Mann-Whitney U test. Findings 48 patients were included: 25 with acute flaccid myelitis, two with enterovirus-associated encephalitis, five with enterovirus-D68-associated upper respiratory illness, and 16 with aseptic meningitis or encephalitis who tested positive for enterovirus. Enterovirus D68 was detected in respiratory secretions from seven (64%) of 11 patients comprising two temporally and geographically linked acute flaccid myelitis clusters at the height of the 2014 outbreak, and from 12 (48%) of 25 patients with acute flaccid myelitis overall. Phylogenetic analysis revealed that all enterovirus D68 sequences associated with acute flaccid myelitis grouped into a clade B1 strain that emerged in 2010. Of six coding polymorphisms in the clade B1 enterovirus D68 polyprotein, five were present in neuropathogenic poliovirus or enterovirus D70, or both. One child with acute flaccid myelitis and a sibling with only upper respiratory illness were both infected by identical enterovirus D68 strains. Enterovirus D68 viraemia was identified in a child experiencing acute neurological progression of his paralytic illness. Deep metagenomic sequencing of cerebrospinal fluid from 14 patients with acute flaccid myelitis did not reveal evidence of an alternative infectious cause to enterovirus D68. Interpretation These findings strengthen the putative association between enterovirus D68 and acute flaccid myelitis and the contention that acute flaccid myelitis is a rare yet severe clinical manifestation of enterovirus D68 infection in susceptible hosts. Funding National Institutes of Health, University of California, Abbott Laboratories, and the Centers for Disease Control and Prevention.
Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this ...group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records.
Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into “original” and “imputed” encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics.
The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.
Objective
Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied.
Methods
A prospective time‐delayed crossover design trial of GS to ...assess the efficacy of GS as a first‐line diagnostic tool for genetic white matter disorders took place between December 1, 2015 and September 27, 2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for 4 months followed by GS.
Results
Thirty‐four individuals were assessed at interim review. The genetic origin of 2 patient's leukoencephalopathy was resolved before randomization. Nine patients were stratified to the immediate intervention group and 23 patients to the delayed‐GS arm. The efficacy of GS was significant relative to SoC in the immediate (5/9 56% vs 0/9 0%; Wild–Seber, p < 0.005) and delayed (control) arms (14/23 61% vs 5/23 22%; Wild–Seber, p < 0.005). The time to diagnosis was significantly shorter in the immediate‐GS group (log‐rank test, p = 0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5%, 95% confidence interval = 58.8–89.3%) in <4 months, greater than historical norms of <50% over 5 years. Owing to loss of clinical equipoise, the trial design was altered to a single‐arm observational study.
Interpretation
In this study, first‐line GS provided earlier and greater diagnostic efficacy in white matter disorders. We provide an evidence‐based diagnostic testing algorithm to enable appropriate clinical GS utilization in this population. ANN NEUROL 2020;88:264–273.
Pathogenic variants in the
gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly ...progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.
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).
We analyzed a multicenter, mixed retrospective/prospective cohort of patients diagnosed with presymptomatic CCALD (Neurologic Function Score = 0, Loes Score LS = 0.5-9.0, and age <13 years). Two time-to-event survival analyses were conducted: (1) time from CCALD lesion onset-to-lesional enhancement and (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 and 2021.
Seventy-one boys were diagnosed with presymptomatic cerebral lesions at a median age of 6.4 years 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 Kaplan-Meier (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); 2 patients (4.2%) developed symptoms before treatment. Patients with a diagnostic LS ≤ 1 were younger (5.8 years 2.4-11.5), had a time-to-enhancement of 4.7 months (95% CI 2.7-9.30), and were treated in 3.8 months (95% CI 3.1-7.1); no patients developed symptoms before treatment. Time from CCALD diagnosis-to-treatment decreased over the course of the study (ρ = -0.401,
= 0.003).
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.
Objective
To characterize the phenotype of pediatric Bickerstaff’s brainstem encephalitis (BBE) and evaluate prognostic features in the clinical course, diagnostic studies, and treatment exposures.
...Methods
We systematically reviewed
PubMed
,
Web of Science
, and
SCOPUS
databases as well as medical records at the Lucile Packard Children’s Hospital to identify cases of pediatric BBE. Inclusion required all of the following criteria: age ≤ 20 years, presence of somnolence or alterations in mental status at the time of presentation or developed within 7 days of presentation, ataxia, and ophthalmoplegia.
Results
We reviewed 682 manuscripts, identifying a total of 47 pediatric BBE cases. We also describe five previously unreported cases. The phenotype of these pediatric patients was similar to previously published literature. Sixty-eight percent of patients demonstrated positive anti-GQ1b antibody titers, yet the presence of these antibodies was not associated with longer times to recovery. Patients with neuroimaging abnormalities featured a longer median time to recovery, but this was not statistically significant (
p
= 0.124). Overall, patients treated with any form of immunotherapy (intravenous immunoglobulin, steroids, or plasmapheresis) demonstrated shorter median time to resolution of symptoms compared to supportive therapy, although this trend was not statistically significant (
p
= 0.277). Post-hoc
t
tests revealed a trend towards use of immunotherapy against supportive care alone (
p
= 0.174).
Conclusion
Our study identified clinical, radiologic, and treatment features that may hold prognostic value for children with BBE. The role of immunotherapy remains under investigation but may prove of utility with further, randomized controlled studies in this rare disease.
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