Sunday, June 28, 2020

Rapid sequence MRI protocol in the evaluation of pediatric brain attacks

De Jong G, Kannikeswaran N, DeLaroche A, Farooqi A, Sivaswamy L. Rapid Sequence MRI Protocol in the Evaluation of Pediatric Brain Attacks. Pediatr Neurol. 2020;107:77-83. doi:10.1016/j.pediatrneurol.2019.12.007


Background: The objective of our study was to evaluate the clinical utility of rapid sequence magnetic resonance imaging (MRI) utilizing diffusion-weighted imaging and fluid-attenuated inversion recovery sequences in children with acute ischemic strokes and nonstroke brain attacks.

Methods: We performed a retrospective chart review of patients aged one month to 25 years for whom a pediatric stroke clinical pathway was activated. Diffusion-weighted imaging and fluid-attenuated inversion recovery were obtained followed by a complete MRI. Imaging was interpreted by a pediatric radiologist and the study neurologist. We collected information regarding patient demographics, neuroimaging results, and final diagnosis.

Results: The Pediatric Stroke Clinical Pathway was activated for 59 patients of whom 52 were included for analysis. The majority of patients were female (n = 29, 55.8%) and African American (n = 32, 61.5%), with a median age of 12 years (interquartile range 9, 16). Six patients had an ischemic stroke. Seizures, migraines, and psychosomatic disorders (each with n = 7; 13.5%) were the most common nonstroke diagnoses. Diffusion-weighted imaging was more sensitive (100% [55.0% to 100%] versus 80 % [32% to 99%]) and specific (73.9% [68% to 74%] versus 37.2% [32% to 39%]) compared with fluid-attenuated inversion recovery in identification of an ischemic stroke. However, fluid-attenuated inversion recovery was useful in the identification of inflammatory and metabolic disorders.

Conclusion: Rapid sequence MRI can be utilized as a screening imaging modality in children with suspected brain attacks in cases where there may be delays in obtaining full sequence brain imaging.

Danon disease

Inspired by a colleague’s patient

Ntelios D, Parcharidou D, Zegkos T, et al. The multiple faces of Danon disease [published online ahead of print, 2020 Jun 15]. Hellenic J Cardiol. 2020;S1109-9666(20)30101-9. doi:10.1016/j.hjc.2020.06.004

No abstract.  From the article.

Danon disease is a rare genetic disorder characterized by cardiomyopathy accompanied by preexcitation, skeletal myopathy, retinopathy and intellectual disability. It results from mutations in the LAMP2 gene (mostly truncating mutations) and is inherited in an X-linked dominant pattern. LAMP2 encodes for lysosomal associated membrane protein-2, a type I transmembrane protein and among the most abundant proteins in lysosomes. Differential diagnosis of Danon disease can be difficult due to the non-specific or overlapping symptoms with other genetic syndromes causing cardiac hypertrophy and skeletal myopathy. Therefore, the wider implementation of genetic testing has enabled prompt recognition by the clinician of this previously underdiagnosed disease. Several studies have revealed sex-specific differences in the cardiovascular manifestations of the disease. Almost all male patients (88%) with Danon disease develop hypertrophic cardiomyopathy (HCM) (reported wall thickness up to 65mm), with progression to dilated cardiomyopathy observed in 12%. On the other hand, women present at an older age and have higher prevalence of dilated cardiomyopathy at presentation when compared to men. When Danon disease is identified, a multidisciplinary approach that includes cardiologists, neurologists and genetics professionals is key to the care of the family. However, the severity of the cardiac involvement that often requires advanced treatments such as catheter ablation, implantable devices and heart transplantation necessitates early referral to a specialized cardiomyopathy center and lifelong close monitoring.

Currently, there are no prospectively validated risk factors specific to Danon disease patients. However, a high frequency of ventricular arrhythmias has been reported in female patients. For primary prevention of sudden cardiac death (SCD) in Danon disease, HCM guidelines are followed for risk stratification. Interestingly, in one small study, ineffective ICD Shocks for ventricular tachyarrhythmias has been reported in five patients. There are no official recommendations for the use of electrophysiologic study (EPS) as a risk stratification tool for SCD in Danon disease. Additionally, EPS is currently not recommended for the identification of HCM patients who would benefit from primary prevention strategies in hypertrophic cardiomyopathy.  However, EPS can be used to rule out clinically important accessory atrioventricular pathways in Danon disease. The management of patients presenting with dilated cardiomyopathy relies upon guideline-directed therapy for heart failure. However, there are no prospective studies evaluating the efficacy of this approach.

He J, Xu J, Chen L, et al. Clinical features and cardiovascular magnetic resonance characteristics in Danon disease [published online ahead of print, 2020 Jun 1]. Clin Radiol. 2020;S0009-9260(20)30168-9. doi:10.1016/j.crad.2020.04.012


Aims: To investigate the clinical spectrum, cardiovascular magnetic resonance imaging (cMRI) characteristics, including T1 and extracellular volume fraction, and outcomes of Danon disease to facilitate further understanding of the phenotype of patients with Danon disease.

Materials and methods: The study comprised six male patients 8-23 years old recruited to the study between 2014-2019. The clinical presentation, laboratory examinations, pathology/genetic analysis, electrocardiography (ECG), echocardiography, and cCMRI characteristics were summarised.

Results: Five out of six patients suffered from hypertrophic cardiomyopathy (HCM) phenotype of Danon disease, while one patient had dilated cardiomyopathy (DCM) phenotype. Left ventricular (LV) and left atrial (LA) function were impaired at strain measurement. Diffuse and focal late gadolinium enhancement (LGE) were observed separately in the LV walls of three patients and right ventricular (RV) insertion points of the remaining three patients. Furthermore, values for the native T1 (mean 1313.3 ms) and extracellular volume fraction (ECV; mean 39.17%) of three patients were increased.

Conclusions: Both dilated and hypertrophic cardiomyopathy may be the phenotypes of Danon disease. Comprehensive cCMRI played a unique role in the diagnosis and grading severity and risk factors of Danon disease in vivo, especially by using robust quantitative strain analysis, T1 mapping, and further ECV calculation.

Novelli V, Bisignani A, Pelargonio G, et al. Clinical utility of genetic testing in the early diagnosis of Danon disease mimicking hypertrophic cardiomyopathy: a case report. BMC Cardiovasc Disord. 2020;20(1):156. Published 2020 Apr 5. doi:10.1186/s12872-020-01421-4


Background: Danon disease (OMIM 300257) is an X-linked lysosomal storage disorder, characterized by hypertrophic cardiomyopathy (HCM), skeletal myopathy, variable intellectual disability, and other minor clinical features. This condition accounts for ~ 4% of HCM patients, with a more severe and early onset phenotype in males, causing sudden cardiac death (SCD) in the first three decades of life. Genetic alterations in the LAMP2 gene are the main cause of this inherited fatal condition. Up to date, more than 100 different pathogenic variants have been reported in the literature. However, the majority of cases are misdiagnosed as HCM or have a delay in the diagnosis.

Case presentation: Here, we describe a young boy with an early diagnosis of HCM. After 2 episodes of ventricular fibrillation within 2 years, genetic testing identified a novel LAMP2 pathogenic variant. Subsequently, further clinical evaluations showing muscle weakness and mild intellectual disability confirmed the diagnosis of Danon disease.

Conclusions: This report highlights the role of genetic testing in the rapid diagnosis of Danon disease, underscoring the need to routinely consider the inclusion of LAMP2 gene in the genetic screening for HCM, since an early diagnosis of Danon disease in patients with a phenotype mimicking HCM is essential to plan appropriate treatment, ie cardiac transplantation.

Friday, June 26, 2020

DLG4 neurodevelopmental disorder

Inspired by a colleague's patient

Xi XJ, Tang JH, Zhang BB, et al. Dlg4 and Vamp2 are involved in comorbid epilepsy and attention-deficit hyperactivity disorder: A microarray data study [published online ahead of print, 2020 Jun 21]. Epilepsy Behav. 2020;110:107192. doi:10.1016/j.yebeh.2020.107192

Objective: Children with epilepsy exhibit a significantly higher risk for attention-deficit hyperactivity disorder (ADHD), which is often associated with lower quality of life. In this study, we aimed to identify molecular mechanisms associated with both epilepsy and ADHD.

Materials and methods: Gene expression profiles of GSE12457 and GSE47752 were downloaded from the gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) were separately screened in epilepsy and ADHD samples and compared with controls. Weighted gene coexpression network analysis (WGCNA) was used to identify candidate modules associated with the two disorders. Functional annotation and analysis of hub genes and molecular complex detection (MCODE) was also performed.

Results: Three modules closely related to epilepsy and ADHD were screened using WGCNA; DEGs in this module were involved in the synaptic vesicle cycle, axon and neuron regeneration, and neurotransmission. The Dlg4 and Vamp2 genes were selected as common candidate factors in epilepsy and ADHD pathogenesis.

Conclusion: Dlg4 and Vamp2 could play essential roles in comorbidity between epilepsy and ADHD.

Chevarin M, Duffourd Y, A Barnard R, et al. Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability. J Med Genet. 2020;57(7):466-474. doi:10.1136/jmedgenet-2019-106425

Purpose: Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan-Fryns syndrome explain no more than 20% of subjects.

Methods: To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic.

Results: We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes.

Conclusion: We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10-4) and genes regulated by the fragile X mental retardation protein (p=3×10-8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.

Moutton S, Bruel AL, Assoum M, et al. Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features. Clin Genet. 2018;93(6):1172-1178. doi:10.1111/cge.13243

Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in known disease-causing genes and non-disease-causing genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients. Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes post-synaptic density protein 95 (PSD-95), a protein expressed in various tissues, including the brain. In neurons, PSD-95 is located at the post-synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one patient carried a a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients exhibited mild-to-moderate ID, similar marfanoid features, including a long face, high-arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus). Our study emphasizes the role of DLG4 as a novel post-synaptic-associated gene involved in syndromic ID associated with MH.

Thursday, June 25, 2020

Autoimmune encephalitis in children

Rutatangwa A, Mittal N, Francisco C, Nash K, Waubant E. Autoimmune Encephalitis in Children: A Case Series at a Tertiary Care Center [published online ahead of print, 2020 May 27]. J Child Neurol. 2020;883073820923834. doi:10.1177/0883073820923834

Autoimmune encephalitis is the third most common cause of encephalitis in children. We provide a detailed account of presenting symptoms, diagnosis, and response to treatment in pediatric autoimmune encephalitis patients evaluated at University of California San Francisco within a 2.5-year period. Eleven were identified: anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis (n = 4), antibody-negative autoimmune encephalitis (n = 4), steroid-responsive encephalopathy associated with thyroiditis (SREAT) (n = 2), and glial fibrillary acidic protein (GFAP)-associated encephalitis (n = 1). Most common presenting symptoms included seizures and behavior changes (54%). More than 90% of patients showed improvement following first-line immunotherapy (high-dose corticosteroids, intravenous immunoglobulin, and/or plasma exchange). A total of 64% received second-line treatment with rituximab, cyclophosphamide, or mycophenolate mofetil. One patient with NMDAR encephalitis died despite escalating immunotherapy. None of the patients showed complete recovery after median follow-up of 9 months (range 0.5-66). Children with autoimmune encephalitis have a diverse clinical presentation and may lack an identifiable autoantibody. Majority of patients show a good response to immunotherapy; however, recovery can be delayed.

Tuesday, June 23, 2020

Interventions to control children's screen use and their effect on sleep

Martin KB, Bednarz JM, Aromataris EC. Interventions to control children's screen use and their effect on sleep: A systematic review and meta-analysis [published online ahead of print, 2020 Jun 21]. J Sleep Res. 2020;e13130. doi:10.1111/jsr.13130

Prolonged viewing of screen-based media is associated with poor sleep in children. Previous systematic reviews have analysed the effectiveness of interventions that aim to limit children's screen use; however, none have evaluated its effect on sleep. The aim of this systematic review was to evaluate the effect of interventions that incorporate strategies to control children's screen use on screen use and sleep. The databases Pubmed, Embase, Eric, Scopus and PsycInfo were searched during October 2017 and updated in February 2019 for experimental studies with a control that assessed interventions to control screen use in children aged 2-14 years and reported both screen use and sleep outcomes. From 3,872 initial records, 11 studies (six randomized control [RCT], four cluster RCT and one cluster, quasi-experimental) were eligible for inclusion. A total of 4,656 children aged 2-13 years were included in the studies. The mean reduction in screen time was 0.56 hr (33 min)/day (95% confidence interval [CI], 0.92, 0.20) and the mean sleep duration increased by 0.19 hr (11 min)/day (95% CI, 0.05, 0.33). Bedtime was advanced by 0.16 hr (10 min) on weekdays and by 1.0 hr at the weekend. Subgroup analyses indicated stronger intervention effects for interventions of shorter duration (<3 months), which specifically targeted screen use or sleep, and those with direct participant contact. In conclusion, small improvements in screen time and sleep duration can be achieved in children. It is not possible to determine if a reduction in screen time directly improves sleep, due to the limited number of studies, the presence of co-interventions, issues with studies' methodological quality and heterogeneity.

Sunday, June 21, 2020

Risk factors for the recurrence of convulsions with mild gastroenteritis in children

Kaili Shi, Jiehui Yang, Yunhong Wu, Hong Han, Junxiu Guo, Wenxiong Chen.  Risk factors for the recurrence of convulsions with mild gastroenteritis in children. Seizure. Open Access Published: June 16, 2020 DOI:

Children with convulsions with mild gastroenteritis (CwG) have a risk of recurrence.
The risk of recurrence rate within 6 months of onset is high in children with CwG.
An age of onset of ≤18 months is a risk factors for CwG recurrence.
History of convulsions in first-degree relatives is a risk factor for CwG recurrence.


To identify risk factors for the recurrence of convulsions with mild gastroenteritis (CwG)1 in children.

Altogether, 613 children with CwG admitted to Children's Hospital of Shanxi Province from January 2010 to December 2015 were selected, their clinical data were retrospectively analyzed, and patients were followed up for 4-10 years. Risk factors for the recurrence of CwG were analyzed based on the clinical characteristics of the children.

Relapse occurred in 35 patients (6.3%). Recurrence occurred within 6 months after the first CwG in majority of the patients (80%), and recurrence occurred once in most patients (91.4%). Risk factors associated with CwG recurrence were age at first attack of ≤18 months (recurrence rates at ages ≤ and >18 months were 8.7%, and 3.1%, respectively; χ2 = 4.856, P = 0.028), and a history of convulsions in first-degree relatives (recurrence rates in first-degree relatives with and without a history of convulsion were 20% and 6.2%, respectively; χ2 = 5.501, P = 0.019).

Children with CwG have a possibility of recurrence. The risk of recurrence within 6 months of onset is high and such patients should be carefully observed. Furthermore, the age of onset of ≤18 months and history of convulsions in first-degree relatives are risks factors for CwG recurrence; therefore, these children should be closely followed up.

Coutesy of:

Wednesday, June 17, 2020

Gratification phenomena

Roshan Koul, Amna AlFutaisi, Renjith Mani, Rana Abdelrahim, Azza AlAdi.  Gratification Phenomena in Infancy: A Report of Twenty-Nine Children. Journal of Pediatric Neurology 2020; 18(03): 141-143 DOI: 10.1055/s-0039-1679902 

Twenty-nine children with gratification phenomena seen in last 10 years (January 2008 to December 2017) were analyzed retrospectively. A proper history, eyewitness account, and video recordings of the event helped in making the diagnosis. Twenty-seven out of 29 (93%) children with gratification phenomena were females. Four patterns of gratification phenomena were seen. Three of these patterns not described before are reported. A typical gratification phenomenon was seen in 16 of 29 (55%) children. At the time of referral, 24% of these children were labeled epileptic and were on antiepileptic medication. This benign condition has to be recognized and extensive investigations should be avoided.

Tuesday, June 16, 2020

Mitochondrial DNA mutation analysis from exome sequencing

Wagner M, Berutti R, Lorenz-Depiereux B, et al. Mitochondrial DNA mutation analysis from exome sequencing-A more holistic approach in diagnostics of suspected mitochondrial disease. J Inherit Metab Dis. 2019;42(5):909-917. doi:10.1002/jimd.12109

Diagnostics for suspected mitochondrial disease (MD) can be challenging and necessitate invasive procedures like muscle biopsy. This is due to the extremely broad genetic and phenotypic spectrum, disease genes on both nuclear and mitochondrial DNA (mtDNA), and the tissue specificity of mtDNA variants. Exome sequencing (ES) has revolutionized the diagnostics for MD. However, the nuclear and mtDNA are investigated with separate tests, increasing costs and duration of diagnostics. The full potential of ES is often not exploited as the additional analysis of "off-target reads" deriving from the mtDNA can be used to analyze both genomes. We performed mtDNA analysis by ES of 2111 cases in a clinical setting. We further assessed the recall rate and precision as well as the estimation of heteroplasmy by ES data by comparison with targeted mtDNA next generation sequencing in 49 cases. ES identified known pathogenic mtDNA point mutations in 38 individuals, increasing the diagnostic yield by nearly 2%. Analysis of mtDNA variants by ES had a high recall rate (96.2 ± 5.6%) and an excellent precision (99.5 ± 2.2%) when compared to the gold standard of targeted mtDNA next generation sequencing. ES estimated heteroplasmy levels with an average difference of 6.6 ± 3.8%, sufficient for clinical decision making. Taken together, the mtDNA analysis from ES is of sufficient quality for clinical diagnostics. We therefore propose ES, investigating both nuclear and mtDNA, as first line test in individuals with suspected MD. One should be aware, that a negative result does not exclude MD and necessitates further test (in additional tissues).

Thursday, June 11, 2020

Accuracy of MR imaging for detection of sensorineural hearing loss in infants with bacterial meningitis

G. Orman, M.K. Kukreja, J.G. Vallejo, N. Desai, T.A.G.M. Huisman and S.F. Kralik. Accuracy of MR Imaging for Detection of Sensorineural Hearing Loss in Infants with Bacterial Meningitis
American Journal of Neuroradiology June 2020, 41 (6) 1081-1086; DOI:


BACKGROUND AND PURPOSE: Bacterial meningitis most commonly affects young children and can result in critical adverse outcomes, including sensorineural hearing loss (SNHL). The purpose of this study is to determine the diagnostic accuracy of MR imaging for predicting the development of SNHL among infants with bacterial meningitis.

MATERIALS AND METHODS: A retrospective review was performed among infants (age <365?days) with bacterial meningitis (n?=?115). Independent and consensus blinded review of brain MRIs (n?=?239) performed less than 90?days from presentation were conducted. Abnormal appearance of the inner ear was defined as enhancement on postcontrast T1-weighted (T1-weighted+C) sequence and FLAIR hyperintensity. The consensus MR imaging appearance of the inner ear on FLAIR, T1-weighted+C, and combined evaluation was compared with criterion standard audiometric testing to determine the sensitivity and specificity of MR imaging for detecting SNHL.

RESULTS: The mean age at diagnosis of bacterial meningitis was 50.6?days (range, 0–338?days) and 24.3% had SNHL. Sensitivity and specificity was 0.61/0.96, 0.50/0.94, and 0.61/0.94 for T1-weighted+C, FLAIR hyperintensity, and combined evaluation, respectively, for prediction of SNHL. There was excellent interobserver agreement for both the T1-weighted+C and FLAIR sequences and combined evaluation for presence of abnormal enhancement and hyperintense signal, respectively. Factors associated with abnormal MR imaging findings on T1-weighted+C and/or FLAIR in patients with SNHL included low CSF glucose (P?=?.04, .02) and high CSF protein (P?=?.04, .03).

CONCLUSIONS: Abnormal enhancement and/or FLAIR hyperintensity of the inner ear demonstrate high specificity and average sensitivity for prediction of SNHL among infants with bacterial meningitis.

Courtesy of:

Use of ketogenic diet therapy in infants with epilepsy

Lyons L, Schoeler NE, Langan D, Cross JH. Use of ketogenic diet therapy in infants with epilepsy: A systematic review and meta-analysis [published online ahead of print, 2020 May 26]. Epilepsia. 2020;10.1111/epi.16543. doi:10.1111/epi.16543


Objective: Ketogenic diet therapy (KDT) is a group of high-fat, low-carbohydrate diets used as an effective treatment option for children and adults with drug-resistant epilepsy. There is limited research on the efficacy of KDT in infants, where there is the highest incidence of onset of the epilepsy. We aimed to systematically review studies that have reported on response to KDT in infants with epilepsy.

Methods: An online comprehensive literature search was performed, including studies that provided seizure frequency data for at least one infant younger than 2 years of age who was treated with KDT for =1 month. The proportions of infants achieving =50% seizure reduction, seizure-freedom rates, retention rates, and reported side effects were extracted from studies. Meta-analyses were performed using a random-effects model, and subgroup analyses were performed to investigate possible between-study heterogeneity.

Results: Thirty-three studies met inclusion criteria and were included in the final analysis, with a total of 534 infants with efficacy data. Two studies were randomized-controlled trials, and the remainder were uncontrolled cohort studies. All studies were categorized as low quality. Meta-analyses of uncontrolled studies estimate 59% (95% confidence interval [CI] 53-65) of infants achieved =50% seizure reduction and 33% (95% CI 26-43) of infants achieved seizure freedom. Retention rates ranged from 84% at 3 months to 27% at 24 months. The most commonly reported side effects were dyslipidemia (20/171, 12%), vomiting (11/171, 6%), constipation (7/171, 4%), gastroesophageal reflux (6/171, 4%), and diarrhea (6/171, 4%).

Significance: This review indicates that KDT is safe and tolerable and that it can be an effective treatment option for infants with drug-resistant epilepsy. However, there are few studies focusing on infants treated with KDT, and high-quality evidence is lacking. High-quality randomized-controlled trials are needed to confirm the effectiveness, safety, and tolerability of dietary treatment in this vulnerable age group.

Courtesy of:

Monday, June 8, 2020

Ataxia telangiectasia treated with intra-erythrocyte dexamethasone

Menotta M, Biagiotti S, Spapperi C, et al. ATM splicing variants as biomarkers for low dose dexamethasone treatment of A-T. Orphanet J Rare Dis. 2017;12(1):126. Published 2017 Jul 5. doi:10.1186/s13023-017-0669-2

Background: Ataxia Telangiectasia (AT) is a rare incurable genetic disease, caused by biallelic mutations in the Ataxia Telangiectasia-Mutated (ATM) gene. Treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this syndrome. Nevertheless, the molecular mechanism underlying the glucocorticoid action in AT patients is not yet understood. Recently, we have demonstrated that Dexamethasone treatment may partly restore ATM activity in AT lymphoblastoid cells by a new ATM transcript, namely ATMdexa1.

Results: In the present study, the new ATMdexa1 transcript was also identified in vivo, specifically in the PMBCs of AT patients treated with intra-erythrocyte Dexamethasone (EryDex). In these patients it was also possible to isolate new "ATMdexa1 variants" originating from canonical and non-canonical splicing, each containing the coding sequence for the ATM kinase domain. The expression of the ATMdexa1 transcript family was directly related to treatment and higher expression levels of the transcript in patients' blood correlated with a positive response to Dexamethasone therapy. Neither untreated AT patients nor untreated healthy volunteers possessed detectable levels of the transcripts. ATMdexa1 transcript expression was found to be elevated 8 days after the drug infusion, while it decreased 21 days after treatment.

Conclusions: For the first time, the expression of ATM splicing variants, similar to those previously observed in vitro, has been found in the PBMCs of patients treated with EryDex. These findings show a correlation between the expression of ATMdexa1 transcripts and the clinical response to low dose dexamethasone administration.

Leuzzi V, Micheli R, D'Agnano D, et al. Positive effect of erythrocyte-delivered dexamethasone in ataxia-telangiectasia. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e98. Published 2015 Apr 9. doi:10.1212/NXI.0000000000000098

Objective: Ataxia-telangiectasia (AT) is a rare, devastating neurodegenerative disease presenting with early-onset ataxia, oculocutaneous telangiectasia, immunodeficiency, radiosensitivity, and proneness to cancer. In a previous phase 2 study, we showed that 6 monthly infusions of autologous erythrocytes loaded with dexamethasone (EryDex; EryDel, Urbino, Italy) were effective in improving neurologic impairment in young patients with AT. The present article reports the results of the extension of this study for an additional 24-month period.

Methods: After the end of the first trial, 4 patients continued to be treated with monthly EryDex infusions for an additional 24 months, and their clinical outcome was compared with that of 7 age-matched patients who stopped the treatment after the first 6 infusions. The protocol included serial assessment of ataxia (by International Cooperative Ataxia Rating Scale) and adaptive behavior (by Vineland Adaptive Behavior Scales) and clinical and laboratory tests revealing treatment- and steroid-dependent adverse effects, if present.

Results: Patients in the extended study experienced a continuous neurologic improvement with respect to their pretreatment status, whereas controls showed a progressive neurologic deterioration (according to the natural history of the disease) after the discontinuation of the treatment. The delivery system we adopted proved to be safe and well-tolerated, and none of the side effects usually associated with the chronic administration of corticosteroids were observed during the entire trial.

Conclusions: These promising preliminary results call for a large-scale controlled study on protracted treatment of patients with AT with dexamethasone-loaded erythrocytes.

Saturday, June 6, 2020

Hydroxychloroquine and azithromycin as a treatment of COVID-19 3

The Lancet, one of the world’s top medical journals, on Thursday retracted an influential study that raised alarms about the safety of the experimental Covid-19 treatments chloroquine and hydroxychloroquine amid scrutiny of the data underlying the paper.

Just over an hour later, the New England Journal of Medicine retracted a separate study, focused on blood pressure medications in Covid-19, that relied on data from the same company.

The retractions came at the request of the authors of the studies, published last month, who were not directly involved with the data collection and sources, the journals said.

“We can no longer vouch for the veracity of the primary data sources,” Mandeep Mehra of Brigham and Women’s Hospital, Frank Ruschitzka of University Hospital Zurich, and Amit Patel of University of Utah said in a statement issued by the Lancet. “Due to this unfortunate development, the authors request that the paper be retracted.”

Meanwhile, on Wednesday, researchers reported the results of the first gold-standard clinical trial of hydroxycholoroquine in Covid-19, concluding that it did not prevent infections any better than placebo. Other clinical trials, including some looking at the drugs as treatments, are ongoing.

The Lancet study gained so much attention because it went further than other observational studies that had similarly found the drugs were not associated with improved outcomes for patients. The study, which was purportedly based on patient data from 671 hospitals on six continents, reported the drugs also corresponded to higher mortality.

The findings led to the pause of some global clinical trials studying hydroxychloroquine so researchers could check for any safety concerns. Outside experts, however, quickly raised concerns after noticing inconsistencies in the data. They asked the company that compiled and analyzed the data, Surgisphere, to explain how it sourced its data.

As scrutiny grew, the authors on the paper not affiliated with Surgisphere called for an independent audit. In their Lancet statement Thursday, they said that Surgisphere was not cooperating with the independent reviewers and would not provide the data.

“As such, our reviewers were not able to conduct an independent and private peer review and therefore notified us of their withdrawal from the peer-review process,” the researchers wrote.

The retraction of the Lancet paper is sure to add fuel to contentious arguments about the potential of chloroquine and hydroxychloroquine, two old malaria drugs, in Covid-19, the disease caused by the novel coronavirus. President Trump has touted them as valuable treatments, despite a lack of rigorous data showing they have a benefit.

RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis
Prof Mandeep R Mehra, MD
Sapan S Desai, MD
Prof Frank Ruschitzka, MD
Amit N Patel, MD
Published:May 22, 2020DOI:


Thursday, June 4, 2020

Aprepitant in the treatment of subacute sclerosing panencephalitis

Ibrahim Oncel, Mesut Sancar, Bahadir Konuskan, Safak Parlak, Ekim Gumeler, Banu Anlar.  Aprepitant in the treatment of subacute sclerosing panencephalitis: a randomized, double-blind, placebo-controlled study.  Pediatric Neurology.  Published:June 01, 2020 DOI:


Aprepitant is a neurokinin-1 receptor antagonist (NK1R) approved for the treatment of chemotherapy-induced nausea. We aimed to investigate the safety and efficacy of aprepitant in patients with subacute sclerosing panencephalitis (SSPE).

A randomized, double-blind, placebo-controlled study was conducted in patients with SSPE assigned to receive two courses of aprepitant 250 mg/day p.o. or placebo for 15 days with an interval of 2 months between courses. Primary endpoints were safety and tolerability and secondary endpoint, clinical improvement/stabilization assessed by SSPE Scoring System. Electroencephalography (EEG), brain magnetic resonance imaging (MRI) and cerebrospinal fluid measles-specific IgG index were evaluated before and after treatment.

Sixty-two SSPE patients were allocated to aprepitant (n=31, median age 18 years) or placebo (n=31, median age 22 years) groups. Fifteen patients left the study within the first 6 months and 12 patients left between 6-12 months. Aprepitant was well tolerated and treatment–associated adverse events were similar to those described in the treatment of nausea. Clinical status at 6 and 12 months follow-up did not differ between aprepitant and placebo groups. Post-treatment EEG scores at 12 months were better in the aprepitant group (p=0.015). Cerebral atrophy on MRI increased in both groups while measles-specific IgG index decreased in the placebo group.

In this first clinical trial of aprepitant treatment in SSPE patients, the drug was safe and well tolerated. No clinical effect was observed. A modest improvement in EEG findings might justify trials for longer periods because EEG changes can precede clinical findings in SSPE.

Functional neural substrates of football fanaticism

n.b. football is soccer 

Bilgiç B, Kurt E, Makar ÇC, et al. Functional Neural Substrates of Football Fanaticism: Different Pattern of Brain Responses and Connectivity in Fanatics [published online ahead of print, 2020 May 31]. Psychiatry Clin Neurosci. 2020;10.1111/pcn.13076. doi:10.1111/pcn.13076 


Aim: Sports activities provide social interaction for humans. Commitment to a given team is a salient feature of being a sports fan and becomes a prominent part of self-identification for fanatics. Emotion, subjective hedonic experience, and non-romantic love are related to fan behaviors. Few studies have evaluated the neural basis of sports fanaticism. 

Methods: Thirty men, including 16 football fanatics and 14 non-fanatics, with a mean age of 27.4 ± 6.4 years (range, 20-48) were enrolled. Subjects underwent fMRI while watching a set of goals scored by favorite, rival, and neutral teams. 

Results: The analysis of variance in GLM revealed a significant Group-by-Condition interaction effect in the bilateral dorsal anterior cingulate cortex (dACC), more prominent in the left hemisphere. In the post-hoc comparisons, fanatics showed increased activation in bilateral dACC, supplementary motor cortex (SMA), superior frontal cortex, right dorsolateral prefrontal cortex and right insula for favorite>neutral contrast and an increased activation in bilateral dACC and SMA for rival>neutral contrast. Seed-based connectivity analyses using the areas with significant activation differences revealed increased connectivity between dACC and several regions, including left posterior lateral temporal area, insula, and bilateral medial temporal, medial superior frontal areas as well as basal ganglia in fanatics compared to non-fanatics. 

Conclusion: Our results suggest that football fanatics exhibit different brain activation and connectivity pattern, both under favorable and unfavorable conditions. This brain activity and connectivity pattern under emotionally-laden conditions may represent higher responses to rewards, higher emotional valence attribution, and stronger motivational state of the football fanatics that might underlie their unusual behavioral responses. This article is protected by copyright. All rights reserved.

From the article

There are several classification systems for sports fans based on the  level of their devotion. Hunt and coworkers grouped sports fans as “temporary fan”, “local fan”, “devoted fan”, “fanatical fan” and “dysfunctional fan”.  In the case of fanatic and dysfunctional fans, commitment to a favorite team becomes a prominent part of their social identity. Another important determinant factor for fanatics is having an opponent, a “rival team,” which introduces an in-group/out-group bias in their social life. On the other hand, it was proposed that feeling of belongingness and passion for a football team could be considered as a form of non-romantic love called “tribal love”.

Wednesday, June 3, 2020

Diagnostic approach to the congenital muscular dystrophies

Bönnemann CG, Wang CH, Quijano-Roy S, et al. Diagnostic approach to the congenital muscular dystrophies. Neuromuscul Disord. 2014;24(4):289‐311. doi:10.1016/j.nmd.2013.12.011

Congenital muscular dystrophies (CMDs) are early onset disorders of muscle with histological features suggesting a dystrophic process. The congenital muscular dystrophies as a group encompass great clinical and genetic heterogeneity so that achieving an accurate genetic diagnosis has become increasingly challenging, even in the age of next generation sequencing. In this document we review the diagnostic features, differential diagnostic considerations and available diagnostic tools for the various CMD subtypes and provide a systematic guide to the use of these resources for achieving an accurate molecular diagnosis. An International Committee on the Standard of Care for Congenital Muscular Dystrophies composed of experts on various aspects relevant to the CMDs performed a review of the available literature as well as of the unpublished expertise represented by the members of the committee and their contacts. This process was refined by two rounds of online surveys and followed by a three-day meeting at which the conclusions were presented and further refined. The combined consensus summarized in this document allows the physician to recognize the presence of a CMD in a child with weakness based on history, clinical examination, muscle biopsy results, and imaging. It will be helpful in suspecting a specific CMD subtype in order to prioritize testing to arrive at a final genetic diagnosis.

A–D: Differential diagnostic considerations for various clinical findings in infancy (A) and beyond infancy (B and C), as well as for various laboratory findings that may be available at the outset of the diagnostic encounter (D). Note: The most important tools in the clinical differential diagnosis are: EMG/NCV to diagnose neurogenic involvement, muscle biopsy, and selective biochemical and genetic testing. The differential diagnostic considerations are not exhaustive but highlight a few of the more relevant conditions to consider with a given clinical picture. To save space we are only using the gene/protein symbols to indicate specific diagnosis.