•Imaging biomarkers with high effect sizes are needed for clinical trials in AMN.•Spine imaging studies are scarce.•Multiparametric brain and spine imaging better characterizes the disease.
...Progressive myelopathy causes severe handicap in men with adrenomyeloneuropathy (AMN), an X-linked disorder due to ABCD1 pathogenic variants. At present, treatments are symptomatic but disease-modifying therapies are under evaluation. Given the small effect size of clinical scales in AMN, biomarkers with higher effect size are needed. Here we used high-resolution magnetic resonance techniques to identify non-invasive in vivo biomarkers of the brain and spine with high effect sizes.
We performed a multiparametric imaging and spectroscopy study in 23 male patients with AMN (age: 44 ± 11) and 23 male controls (age: 43 ± 11) of similar age and body-mass index. We combined (i) macrostructural analyses of the spine, using cross-sectional area (CSA) and magnetization transfer ratio (MTR), (ii) microstructural analyses of the spine and the brain, using diffusion tensor and the newly developed fixel-based analysis, and (iii) advanced metabolic analyses of the spine using metabolite cycling coupled to a semi-LASER sequences.
Macrostructural alterations (decrease in CSA and MTR) were observed in patients at all spinal cord levels studied (C1-T2 for CSA and C1-C5 for MTR) (p < 0.001). Microstructural alterations were observed in the spine and brain on diffusion tensor and fixel-based metrics though the latter showed higher effect sizes. Metabolic alterations were observed in patients as a decreased total N-acetylaspartate/myo-inositol ratio (p < 0.001). Overall, MTR showed the highest effect size.
This cross-sectional study supports the use of multiparametric techniques that elucidate the structural, microstructural and metabolic alterations in AMN. These outcome measures should be tested longitudinally and in clinical trials.
Le diagnostic d’épilepsie est fondé essentiellement sur les informations cliniques obtenues par l’interrogatoire : description précise des épisodes, antécédents personnels et familiaux. L’EEG est le ...seul examen complémentaire indispensable, mais ne peut à lui seul ni éliminer, ni affirmer le diagnostic. Il est généralement considéré que l’EEG doit être réalisé de façon précoce, si possible dans les 24 heures qui suivent l’épisode suspect 1 . Mais malgré une large utilisation en routine, peu d’études sont disponibles pour estimer l’apport de l’EEG dans le diagnostic d’une épilepsie débutante, en particulier chez l’enfant 2 . Dans le cadre de la clinique de l’épilepsie du service de neuropédiatrie, nous recevons des enfants pour le diagnostic positif de crise de nature épileptique. La plupart bénéficient d’un EEG. Nous avons répertorié de façon rétrospective les résultats de ces examens pour les 354 enfants reçus en 2016 afin d’évaluer l’apport de cet examen pour le diagnostic positif et syndromique. Nous souhaitons mieux cerner les indications et les conditions de réalisation les plus favorables au diagnostic dans cette population.
Abstract Cerebral adrenoleukodystrophy (CALD) is an X-linked rapidly progressive demyelinating disease leading to death usually within a few years. The standard of care is hematopoietic stem cell ...transplantation (HSCT), but many men are not eligible due to age, absence of a matched donor, or lesions of the corticospinal tracts (CST). Based on the ADVANCE study showing that leriglitazone decreases the occurrence of CALD, we treated 13 adult CALD patients (19-67 years of age) either not eligible to HSCT (n= 8) or awaiting HSCT (n= 5). Patients were monitored every 3 months with standardized neurological scores, plasma biomarkers and brain MRI comprising lesion volumetrics and diffusion tensor imaging. The disease stabilized clinically and radiologically in 10 patients with up to 2 years of follow-up. Five patients presented with gadolinium enhancing CST lesions that all turned gadolinium negative and, remarkably, regressed in four patients. Plasma neurofilament light chain levels stabilized in all 10 patients and correlated with lesion load. The two patients who continued to deteriorate were over 60 years of age with prominent cognitive impairment. One patient rapidly died from Covid19. These results suggest that leriglitazone can arrest disease progression in adults with early-stage CALD and may be an alternative treatment to HSCT.
Aim
To describe cognitive abilities through the evaluation of academic difficulties in children with acute demyelinating syndromes (ADS) and myelin oligodendrocyte glycoprotein (MOG) antibodies.
...Method
This was an observational, retrospective study of a French paediatric cohort that included children aged 18 years and younger. Clinical, biological, and imaging data were collected and academic outcome was measured.
Results
Seventy‐six children were included in the study with a mean (SD) follow‐up of 4 years 7 months (6y 4mo). Median age at disease onset was 9 years 1 months (interquartile range=4y 7mo–13y 11mo; 36 females, 40 males). Thirty‐six children relapsed and 20 had academic difficulties at the last follow‐up. Academic difficulties, as well as deep grey matter and putaminal lesions (p=0.047 and p=0.006 respectively), were significantly more prevalent in children aged 10 years and younger (p=0.02). Using univariate binary regression analysis, we found that age at disease onset of 10 years and younger (odds ratio OR 3.72 95% confidence interval {CI} 1.19–11.64; p=0.024), acute disseminated encephalomyelitis at disease onset (OR 52.5 95% CI 5.97–461.4; p<0.001), and deep grey matter lesions (OR 17.33 95% CI 3.87–77.72; p<0.001) were associated with academic difficulties.
Interpretation
MOG antibody‐associated ADS have distinct clinical and radiological patterns that are age‐dependent. Indirect cognitive evaluation through academic difficulties was prevalent in younger children and is associated with specific clinical and magnetic resonance imaging factors that need to be considered earlier on when assessing this patient population.
Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop ...life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy.
ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2–3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18–65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL SD 20%) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing.
Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 81% of 77 patients receiving leriglitazone and 34 87% of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean SD change from baseline leriglitazone: –27·7 41·4 m; placebo: –30·3 60·5 m; least-squares mean difference –1·2 m; 95% CI –22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 70% of 77 vs nine 23% of 39 patients, respectively) and peripheral oedema (49 64% of 77 vs seven 18% of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six 5% of 116 patients, all of whom were in the placebo group.
The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy.
Minoryx Therapeutics.
ATP2B2 encodes the variant-constrained plasma-membrane calcium-transporting ATPase-2, expressed in sensory ear cells and specialized neurons. ATP2B2/Atp2b2 variants were previously linked to isolated ...hearing loss in patients and neurodevelopmental deficits with ataxia in mice. We aimed to establish the association between ATP2B2 and human neurological disorders.
Multinational case recruitment, scrutiny of trio-based genomics data, in silico analyses, and functional variant characterization were performed.
We assembled 7 individuals harboring rare, predicted deleterious heterozygous ATP2B2 variants. The alleles comprised 5 missense substitutions that affected evolutionarily conserved sites and 2 frameshift variants in the penultimate exon. For 6 variants, a de novo status was confirmed. Unlike described patients with hearing loss, the individuals displayed a spectrum of neurological abnormalities, ranging from ataxia with dystonic features to complex neurodevelopmental manifestations with intellectual disability, autism, and seizures. Two cases with recurrent amino-acid variation showed distinctive overlap with cerebellar atrophy-associated ataxia and epilepsy. In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects.
Presentations in our series recapitulate key phenotypic aspects of Atp2b2-mouse models and underline the importance of precise calcium regulation for neurodevelopment and cerebellar function. Our study documents a role for ATP2B2 variants in causing heterogeneous neurodevelopmental and movement-disorder syndromes.
Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a rare recently defined antibody-mediated encephalitis. Meningo-encephalomyelitis presentation is frequent with lymphocytic ...pleiocytosis in the cerebro-spinal fluid and brain MRI classically demonstrates in 50% of cases, a linear perivascular enhancement extending radially from the ventricles. Here, we describe 2 cases of pediatric autoimmune GFAP astrocytopathy with limbic encephalitis presentation and peculiar MRI characteristics: one with normal MRI and the second suggestive of Mild Encephalitis/Encephalopathy with reversible splenial lesion syndrome (MERS). These two cases illustrate that anti-GFAP antibodies should be sought in children presenting limbic encephalitis with a normal and/or MERS suggestive MRI, as treatment strategies may differ.
•Anti-GFAP astrocytopathy is a rare condition in adults and children and specific MRI lesions have been suggested.•Clinical outcome is good in most of the cases after immunotherapies.•The pathogenicity of anti-GFAP antibodies is far from being demonstrated.•Anti-GFAP antibodies should be tested for meningo-encephalitis with normal or MERS suggestive MRI, as treatment may differ.
GLUT1 deficiency syndrome (Glut1DS) is a treatable neurometabolic disease that causes a wide range of neurologic symptoms in children and adults. However, its diagnosis relies on an invasive test, ...that is, a lumbar puncture (LP) to measure glycorrhachia, and sometimes complex molecular analyses of the
gene. This procedure limits the number of patients able to receive the standard of care. We wished to validate the diagnostic performance of METAglut1, a simple blood test that quantifies GLUT1 on the erythrocyte surface.
We performed a multicenter validation study in France, involving 33 centers. We studied 2 patient cohorts: a prospective cohort consisting of patients with a clinical suspicion of Glut1DS explored through the reference strategy, that is, LP and analyses of the
gene, and a retrospective cohort that included patients previously diagnosed with Glut1DS. All patients were blind-tested with METAglut1.
We analyzed 428 patients in the prospective cohort, including 15 patients newly diagnosed with Glut1DS, and 67 patients in the retrospective cohort. METAglut1 was 80% sensitive and >99% specific for the diagnosis of Glut1DS. Concordance analyses showed a substantial agreement between METAglut1 and glycorrhachia. In the prospective cohort, the positive predictive value of METAglut1 was slightly higher than that of glycorrhachia. METAglut1 succeeded to identify patients with Glut1DS with
mosaicism and variants of unknown significance.
METAglut1 is an easily performed, robust, and noninvasive diagnostic test for the diagnosis of Glut1DS, which allows wide screening of children and adults, including those with atypical forms of this treatable condition.
This study provides Class I evidence that a positive METAglut1 test accurately distinguishes patients with suspected GLUT1 deficiency syndrome from other neurologic syndromes as compared with invasive and genetic testing.
OBJECTIVETo describe the clinical phenotypes, treatment response, and outcome of children with antibodies against aquaporin-4 (AQP4-Ab) neuromyelitis optica spectrum disorder (NMOSD).
...METHODSRetrospective, multicenter, and multinational study of patients with AQP4-Ab NMOSD aged <18 years at disease onset from a center in Brazil and 13 European centers. Data on demographics, clinical findings, and laboratory results were analyzed; calculation of annualized relapse rates (ARRs) pre- and on-treatment with disease-modifying therapies (DMTs) and of ORs for predictors of poor outcome was performed.
RESULTSA total of 67 children were identified. At last follow-up (median 4 years, interquartile range 2–10 years), 37/67(57.8%) were found to have permanent disability. A more severe disease course was seen in the non-White ethnicity with both a shorter time to first relapse (p = 0.049) and a worse Expanded Disability Status Scale score at last follow-up (p = 0.008). The median ARR on treatment was 0.18 on azathioprine (n = 39, range 0–4), 0 on mycophenolate mofetil (n = 18, range 0–3), and 0 on rituximab (n = 29, range 0–2). No patient treated with rituximab as first-line therapy relapsed. Optic neuritis at onset was associated with a poor visual outcome below 20/200 (OR 8.669, 95% CI 1.764–42.616, p = 0.008), and a younger age at onset was associated with cognitive impairment (OR 0.786, 95% CI 0.644–0.959, p = 0.018).
CONCLUSIONSAQP4-Ab NMOSD in children is an aggressive disease with permanent disabilities observed in over half the cohort. All DMTs were associated with a reduction of ARR. First-line rituximab prevented further clinical relapses. International consensus on treatment protocols for children is required to reduce heterogeneity of treatment regimens used worldwide.
CLASSIFICATION OF EVIDENCEThis study provides Class IV evidence that for children with AQP4-Ab NMOSD, all DMTs, particularly first-line rituximab, reduced the ARR and prevented further clinical relapses.
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