Epigenome-wide association study of seizures in childhood and adolescence.

Caramaschi D, Hatcher C, Mulder RH, Felix JF, Cecil CAM, Relton CL, Walton E. Epigenome-wide association study of seizures in childhood and adolescence. Clin Epigenetics. 2020 Jan 8;12(1):8. doi: 10.1186/s13148-019-0793-z. PMID: 31915053; PMCID: PMC6950851.

Abstract

The occurrence of seizures in childhood is often associated with neurodevelopmental impairments and school underachievement. Common genetic variants associated with epilepsy have been identified and epigenetic mechanisms have also been suggested to play a role. In this study, we analyzed the association of genome-wide blood DNA methylation with the occurrence of seizures in ~ 800 children from the Avon Longitudinal Study of Parents and Children, UK, at birth (cord blood), during childhood, and adolescence (peripheral blood). We also analyzed the association between the lifetime occurrence of any seizures before age 13 with blood DNA methylation levels. We sought replication of the findings in the Generation R Study and explored causality using Mendelian randomization, i.e., using genetic variants as proxies. The results showed five CpG sites which were associated cross-sectionally with seizures either in childhood or adolescence (1-5% absolute methylation difference at p_FDR < 0.05), although the evidence of replication in an independent study was weak. One of these sites was located in the BDNF gene, which is highly expressed in the brain, and showed high correspondence with brain methylation levels. The Mendelian randomization analyses suggested that seizures might be causal for changes in methylation rather than vice-versa. In conclusion, we show a suggestive link between seizures and blood DNA methylation while at the same time exploring the limitations of conducting such study.

__________________________________________________________________________

Blood DNA methylation analyses revealed similar changes in blood and brain DNA methylation levels at the BDNF gene. Caramaschi and colleagues speculate that BDNF DNA methylation in blood samples might be linked to epigenetic changes in brain regions impacted by seizure/epilepsy episodes. The authors observed hypermethylation at the promoter and within introns of the BDNF gene, which correlated with seizures with the Mendelian randomization analysis. However, changes in BDNF mRNA levels in blood were not supported by their Mendelian randomization analysis of seizures method. Hence, the authors concluded that this unexpected finding was because BDNF mRNA levels in blood might be very low. Furthermore, when the authors analyzed DNA methylation in cross-tissue blood–brain concordance in 3 independent databases at 5 CpG sites that passed FDR correction in ALSPAC, the assumption that brain DNA methylation reflected changes in blood DNA methylation was not replicated, as this association was not observed in other human nor animal studies. Interestingly, the MACROD2 gene had promising associations with seizure-induced DNA methylation represented at a CpG site within the MACROD2 gene region, which had the strongest blood–brain correlation in the temporal cortex with low correlation in other brain regions. Analysis of MACROD2 DNA methylation was not explored in the blood–brain concordance studies from the ALSPAC database. 

There are several limitations to the study that may explain the more negative results and lack of replication. First, while it is appreciated that the authors used serum assays as a less invasive, more practical method for analysis of DNA methylation, whole blood preparations may not necessarily reflect all DNA methylation changes occurring in the brain. However, blood-derived exosome preparations may prove to be more reflective of these epigenetic changes. Exosomes are vesicle containing protein, DNA, and RNA that are secreted from cells and taken up by distant cells to affect cellular function and behavior.16 Another limitation of the study is that the authors did not consider the antiepileptic drugs (AEDs) regimen of epileptic patients which could have modified DNA methylation levels and influenced findings. Additionally, consideration of the medical history of the parents with genetic epilepsy and how their AEDs regimen could have impacted DNA methylation mechanisms in the offspring. Another major limitation of the study is that the DNA methylation detection strategy employed in the study does not distinguish between the 2 forms of DNA methylation, 5-mC and 5-hmC individually, but rather detects accumulative changes in both 5-mC and 5-hmC levels. Thus, future studies should consider analysis of 5-mC or 5-hmC DNA methylation markers individually in peripheral blood and in brain regions of epileptic patients across the different age groups. This could have greatly reduced variability and identified whether 5-mC, 5-hmC, or both DNA methylation forms were altered in blood samples. Finally, transcriptional states of the pathogenic variants in genes encoding for epigenetic enzymes that modify DNA and histones, control splicing, remodel chromatin, or modulate enhancers should be evaluated in epilepsy and/or seizures.

In conclusion, this study faced many challenges in conducting these epigenome-wide association studies, which no doubt, limited any definitive conclusions on whether seizures and blood DNA methylation changes correlated with childhood and adolescence epilepsy. Nonetheless, a major strength of the study that remains is the developmental assessment of DNA methylation changes in blood and brain across several ages, suggesting that the positive brain–blood correlations may have been developmentally influenced. Therefore, future studies should consider epigenetic factors that are developmentally regulated by seizures and in epilepsy.

https://journals.sagepub.com/doi/full/10.1177/1535759720960476 

Socioeconomic disparities in SUDEP. Declining rate of SUDEP.

Cihan E, Hesdorffer DC, Brandsoy M, Li L, Fowler DR, Graham JK, Karlovich M, Donner EJ, Devinsky O, Friedman D. Socioeconomic disparities in SUDEP in the US. Neurology. 2020 Jun 16;94(24):e2555-e2566. doi: 10.1212/WNL.0000000000009463. Epub 2020 Apr 23. PMID: 32327496; PMCID: PMC7455330.

Abstract

Objective: To determine the impact of socioeconomic status (SES) on sudden unexpected death in epilepsy (SUDEP) rates. 

Methods: We queried all decedents presented for medico-legal investigation at 3 medical examiner (ME) offices across the country (New York City, Maryland, San Diego County) in 2009 to 2010 and 2014 to 2015. We identified all decedents for whom epilepsy/seizure was listed as cause/contributor to death or comorbid condition on the death certificate. We then reviewed all available reports. Decedents determined to have SUDEP were included for analysis. We used median income in the ZIP code of residence as a surrogate for SES. For each region, zip code regions were ranked by median household income and divided into quartiles based on total population for 2 time periods. Region-, age-, and income-adjusted epilepsy prevalence was estimated in each zip code. SUDEP rates in the highest and lowest SES quartiles were evaluated to determine disparity. Examined SUDEP rates in 2 time periods were also compared. 

Results: There were 159 and 43 SUDEP cases in the lowest and highest SES quartiles. ME-investigated SUDEP rate ratio between the lowest and highest SES quartiles was 2.6 (95% confidence interval [CI] 1.7-4.1, p < 0.0001) in 2009 to 2010 and 3.3 (95% CI 1.9-6.0, p < 0.0001) in 2014 to 2015. There was a significant decline in overall SUDEP rate between the 2 study periods (36% decrease, 95% CI 22%-48%, p < 0.0001). 

Conclusion: ME-investigated SUDEP incidence was significantly higher in people with the lowest SES compared to the highest SES. The difference persisted over a 5-year period despite decreased overall SUDEP rates.

Cihan E, Devinsky O, Hesdorffer DC, Brandsoy M, Li L, Fowler DR, Graham JK, Karlovich MW, Yang JE, Keller AE, Donner EJ, Friedman D. Temporal trends and autopsy findings of SUDEP based on medico-legal investigations in the United States. Neurology. 2020 Aug 18;95(7):e867-e877. doi: 10.1212/WNL.0000000000009996. Epub 2020 Jul 7. PMID: 32636323.

Abstract

Objective: To determine time trends and distinguishing autopsy findings of sudden unexpected death in epilepsy (SUDEP) in the United States. 

Methods: We identified decedents where epilepsy/seizure was listed as cause/contributor to death or comorbid condition on the death certificate among all decedents who underwent medico-legal investigation at 3 medical examiner (ME) offices across the country: New York City (2009-2016), San Diego County (2008-2016), and Maryland (2000-2016). After reviewing all available reports, deaths classified as definite/probable/near SUDEP or SUDEP plus were included for analysis. Mann-Kendall trend test was used to analyze temporal trends in SUDEP rate for 2009-2016. Definite SUDEPs were compared to sex- and age ±2 years-matched non-SUDEP deaths with a history of epilepsy regarding autopsy findings, circumstances, and comorbidities. 

Results: A total of 1,086 SUDEP cases were identified. There was a decreasing trend in ME-investigated SUDEP incidence between 2009 and 2016 (z = -2.2, S = -42, p = 0.028) among 3 regions. There was a 28% reduction in ME-investigated SUDEP incidence from 2009 to 2012 to 2013-2016 (confidence interval, 17%-38%, p < 0.0001). We found no correlation between SUDEP rates and the month of year or day of week. There was no difference between SUDEP and non-SUDEP deaths regarding neurodevelopmental abnormalities, pulmonary congestion/edema, and myocardial fibrosis. 

Conclusions: There was a decreasing monotonic trend in ME-investigated SUDEP incidence over 8 years, with a 28% reduction in incidence from 2009-2012 to 2013-2016. Unlike SIDS and sudden cardiac death, we found no correlation between SUDEP and the season of year or day of week. No autopsy findings distinguished SUDEP from non-SUDEP deaths.

________________________________________________________________________

Wilner: SUDEP is hard to study because it's rare. What did you find in your paper? 

Friedman: Exactly. When you are looking at geographic, demographic, and temporal trends to identify risk factors for SUDEP, you really have to look at populations. We looked at three large medical examiner offices in San Diego county, Maryland, and New York City, which together encompass a population of over 20 million people. 

We found two major things. One is that, as in many other health outcomes, there are disparities in SUDEP rates between the lowest and highest socioeconomic bracket. We looked at the zip code of the person who died from SUDEP and estimated the community socioeconomic status. We found that patients who lived in a community that was in the lowest quartile of mean family income had a SUDEP rate two to three times higher than those in the top quartile. That disparity persisted over 5 years. We looked at the rates of SUDEP in 2009 and 2010 in these medical examiner offices and then again in 2014 and 2015.

What did change between those two time periods, which was the other interesting finding, is that the overall rate of SUDEP actually declined by about 30%. That's important because during that time period, we've had no specific intervention to address SUDEP, no introduction of new seizure medications that are any more efficacious than prior ones. The practice of epilepsy surgery has been well established in these communities for many years. Therefore, something is going on at a population level that is reducing the rates of SUDEP. I think the disparities exist and we need to identify their causes and perhaps create targeted interventions. 

There is good news in that we've been able to observe a decrease in the rate of SUDEP over time, at least in these communities. We have a companion paper that was just published in Neurology that looks at temporal trends in SUDEP over an 8-year period in more granular detail. It confirms our finding that SUDEP rates have been decreasing over the past decade. 

We can measure differences between communities over time and identify differences if we look on a population level with data that's already at hand, medical examiner reports. That's important if we want to create and test policy or public health interventions to improve epilepsy care, epilepsy treatment, and epilepsy-related mortality, as well as measure it. 

Wilner: To recap, there were two major findings of your paper. The first was that if you're in a low socioeconomic class vs high, your risk for SUDEP is two to three times increased. We don't know exactly why; it's just an objective finding. Second, over time, the overall incidence of SUDEP has decreased by about a third. 

The first finding isn't surprising. People who have trouble taking care of themselves because of low income often do worse in terms of healthcare, and we see that in many, many areas. But usually when we raise the level of awareness of an unusual disorder, the frequency increases because people are looking for it, they're educated about it, and you see a bump. But in fact, you've seen the opposite. I thought it was very interesting in your paper that you suggested that maybe this is because more people had health insurance and were able to take care of themselves. I think that that's really an important message. 

Friedman: I think so. All three jurisdictions that we looked at had expansion of Medicaid under Obamacare. So in those areas there probably was increased insurance and increased ability to get medications, specialist referrals, and all of those things. That's going to be hard to tease apart without finding control medical examiner offices that didn't participate in Medicaid expansion.

https://www.medscape.com/viewarticle/937275

Riboflavin prophylaxis in child and adolescent migraine

Das R and Qubty W.  Retrospective observational study on riboflavin prophylaxis in child and adolescent migraine.  Pediatric Neurology |September 28, 2020 

Abstract 

Objective 

To evaluate the efficacy of riboflavin in pediatric migraineurs. 

Study design 

A retrospective observational study was performed on 42 patients with migraine aged 6-18 years who were evaluated from January to December 2019 at Dell Children’s Medical Center in Austin Texas. Weight based dosing of riboflavin was recommended for migraine prevention. Descriptive statistics were used to study the population demographics. Nonparametric tests were used for inferential statistics to study the effect of riboflavin on headache frequency, intensity and duration. 

Results 

Patients treated with riboflavin had a significant reduction in headache days per month (frequency) at the first follow up visit at 2-4 months (T1) (11.07 d±10.52) compared to the baseline T0 (21.90 d±9.85); p<0.001 in regard to the primary outcome in 42 patients (mean age: 13.38±3.38). Mean headache intensity decreased from 8.85 (±6.41; T0) to 2.30 (±2.51; T1); p<0.001 on a 0-10 scale. The headache duration also reduced significantly from 18.23 h ±17.07 (T0) to 10.18 h ±10.49 (T1); p=0.001. There was a positive correlation between riboflavin efficacy and reduced utilization of acute medications (rs = 0.304; p=0.05). Riboflavin was useful in reducing the frequency and intensity in 2 patients with new daily persistent headache. 

Conclusions 

Patients treated with riboflavin had a reduction in headache frequency, utilization of acute medications and days of school missed. Riboflavin prophylaxis also reduced migraine intensity and duration. Riboflavin is recommended as a safe, inexpensive and effective nutraceutical in the treatment of pediatric migraine. 

From article:  100 mg and 200 mg of riboflavin twice a day was recommended for children weighing 20-40 kg and above 40 kg respectively.

Courtesy of:  https://www.mdlinx.com/journal-summary/retrospective-observational-study-on-riboflavin-prophylaxis-in-child-and-adolescent-migraine/2nwFvN5932HMFLZDSKX64B 

 

Duchenne muscular dystrophy. New treatments.

Smith EC, Conklin LS, Hoffman EP, Clemens PR, Mah JK, Finkel RS, Guglieri M, Tulinius M, Nevo Y, Ryan MM, Webster R, Castro D, Kuntz NL, Kerchner L, Morgenroth LP, Arrieta A, Shimony M, Jaros M, Shale P, Gordish-Dressman H, Hagerty L, Dang UJ, Damsker JM, Schwartz BD, Mengle-Gaw LJ, McDonald CM; CINRG VBP15 and DNHS Investigators. Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study. PLoS Med. 2020 Sep 21;17(9):e1003222. doi: 10.1371/journal.pmed.1003222. PMID: 32956407.

Abstract

Background: Treatment with corticosteroids is recommended for Duchenne muscular dystrophy (DMD) patients to slow the progression of weakness. However, chronic corticosteroid treatment causes significant morbidities. Vamorolone is a first-in-class anti-inflammatory investigational drug that has shown evidence of efficacy in DMD after 24 weeks of treatment at 2.0 or 6.0 mg/kg/day. Here, open-label efficacy and safety experience of vamorolone was evaluated over a period of 18 months in trial participants with DMD. 

Methods and findings: A multicenter, open-label, 24-week trial (VBP15-003) with a 24-month long-term extension (VBP15-LTE) was conducted by the Cooperative International Neuromuscular Research Group (CINRG) and evaluated drug-related effects of vamorolone on motor outcomes and corticosteroid-associated safety concerns. The study was carried out in Canada, US, UK, Australia, Sweden, and Israel, from 2016 to 2019. This report covers the initial 24-week trial and the first 12 months of the VBP15-LTE trial (total treatment period 18 months). DMD trial participants (males, 4 to <7 years at entry) treated with 2.0 or 6.0 mg/kg/day vamorolone for the full 18-month period (n = 23) showed clinical improvement of all motor outcomes from baseline to month 18 (time to stand velocity, p = 0.012 [95% CI 0.010, 0.068 event/second]; run/walk 10 meters velocity, p < 0.001 [95% CI 0.220, 0.491 meters/second]; climb 4 stairs velocity, p = 0.001 [95% CI 0.034, 0.105 event/second]; 6-minute walk test, p = 0.001 [95% CI 31.14, 93.38 meters]; North Star Ambulatory Assessment, p < 0.001 [95% CI 2.702, 6.662 points]). Outcomes in vamorolone-treated DMD patients (n = 46) were compared to group-matched participants in the CINRG Duchenne Natural History Study (corticosteroid-naïve, n = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to stand was not significantly different between vamorolone-treated and corticosteroid-naïve participants (p = 0.088; least squares [LS] mean 0.042 [95% CI -0.007, 0.091]), but vamorolone-treated participants showed significant improvement compared to group-matched corticosteroid-naïve participants for run/walk 10 meters velocity (p = 0.003; LS mean 0.286 [95% CI 0.104, 0.469]) and climb 4 stairs velocity (p = 0.027; LS mean 0.059 [95% CI 0.007, 0.111]). The vamorolone-related improvements were similar in magnitude to corticosteroid-related improvements. Corticosteroid-treated participants showed stunting of growth, whereas vamorolone-treated trial participants did not (p < 0.001; LS mean 15.86 [95% CI 8.51, 23.22]). Physician-reported incidences of adverse events (AEs) for Cushingoid appearance, hirsutism, weight gain, and behavior change were less for vamorolone than published incidences for prednisone and deflazacort. Key limitations to the study were the open-label design, and use of external comparators. 

Conclusions: We observed that vamorolone treatment was associated with improvements in some motor outcomes as compared with corticosteroid-naïve individuals over an 18-month treatment period. We found that fewer physician-reported AEs occurred with vamorolone than have been reported for treatment with prednisone and deflazacort, and that vamorolone treatment did not cause the stunting of growth seen with these corticosteroids. This Phase IIa study provides Class III evidence to support benefit of motor function in young boys with DMD treated with vamorolone 2.0 to 6.0 mg/kg/day, with a favorable safety profile. A Phase III RCT is underway to further investigate safety and efficacy. 

Trial registration: Clinical trials were registered at www.clinicaltrials.gov, and the links to each trial are as follows (as provided in manuscript text): VBP15-002 [NCT02760264] VBP15-003 [NCT02760277] VBP15-LTE [NCT03038399].

Courtesy of:  https://www.mdlinx.com/journal-summary/efficacy-and-safety-of-vamorolone-in-duchenne-muscular-dystrophy-an-18-month-interim-analysis-of-a/6E13KyBOgyQz92nvDXpMY0

Mendell JR, Sahenk Z, Lehman K, Nease C, Lowes LP, Miller NF, Iammarino MA, Alfano LN, Nicholl A, Al-Zaidy S, Lewis S, Church K, Shell R, Cripe LH, Potter RA, Griffin DA, Pozsgai E, Dugar A, Hogan M, Rodino-Klapac LR. Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. JAMA Neurol. 2020 Jun 15;77(9):1–10. doi: 10.1001/jamaneurol.2020.1484. Epub ahead of print. PMID: 32539076; PMCID: PMC7296461.

Abstract

Importance: Micro-dystrophin gene transfer shows promise for treating patients with Duchenne muscular dystrophy (DMD) using recombinant adeno-associated virus serotype rh74 (rAAVrh74) and codon-optimized human micro-dystrophin driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7). 

Objective: To identify the 1-year safety and tolerability of intravenous rAAVrh74.MHCK7.micro-dystrophin in patients with DMD. 

Design, setting, and participants: This open-label, phase 1/2a nonrandomized controlled trial was conducted at the Nationwide Children's Hospital in Columbus, Ohio. It began on November 2, 2017, with a planned duration of follow-up of 3 years, ending in March 2021. The first 4 patients who met eligibility criteria were enrolled, consisting of ambulatory male children with DMD without preexisting AAVrh74 antibodies and a stable corticosteroid dose (≥12 weeks). 

Interventions: A single dose of 2.0 × 1014 vg/kg rAAVrh74.MHCK7.micro-dystrophin was infused through a peripheral limb vein. Daily prednisolone, 1 mg/kg, started 1 day before gene delivery (30-day taper after infusion). 

Main outcomes and measures: Safety was the primary outcome. Secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. Functional outcomes measured by North Star Ambulatory Assessment (NSAA) and serum creatine kinase were exploratory outcomes. 

Results: Four patients were included (mean [SD] age at enrollment, 4.8 [1.0] years). All adverse events (n = 53) were considered mild (33 [62%]) or moderate (20 [38%]), and no serious adverse events occurred. Eighteen adverse events were considered treatment related, the most common of which was vomiting (9 of 18 events [50%]). Three patients had transiently elevated γ-glutamyltransferase, which resolved with corticosteroids. At 12 weeks, immunohistochemistry of gastrocnemius muscle biopsy specimens revealed robust transgene expression in all patients, with a mean of 81.2% of muscle fibers expressing micro-dystrophin with a mean intensity of 96% at the sarcolemma. Western blot showed a mean expression of 74.3% without fat or fibrosis adjustment and 95.8% with adjustment. All patients had confirmed vector transduction and showed functional improvement of NSAA scores and reduced creatine kinase levels (posttreatment vs baseline) that were maintained for 1 year. 

Conclusions and relevance: This trial showed rAAVrh74.MHCK7.micro-dystrophin to be well tolerated and have minimal adverse events; the safe delivery of micro-dystrophin transgene; the robust expression and correct localization of micro-dystrophin protein; and improvements in creatine kinase levels and NSAA scores. These findings suggest that rAAVrh74.MHCK7.micro-dystrophin can provide functional improvement that is greater than that observed under standard of care. 

Trial registration: ClinicalTrials.gov Identifier: NCT03375164.

Courtesy of:  https://www.mdlinx.com/journal-summary/assessment-of-systemic-delivery-of-raavrh74-mhck7-micro-dystrophin-in-children-with-duchenne/7cXLGh28OJ550umv6bPtvt

Locked in syndrome

 

Courtesy of :  https://www.medscape.com/slideshow/2019-wellcome-photography-prize-6011683?src=WNL_infoc_200923_MSCPEDIT_mnemonics_rm&uac=60196BR&impID=2580585&faf=1#15

Zika microcephaly

Courtesy of:  https://www.medscape.com/slideshow/2019-wellcome-photography-prize-6011683?src=WNL_infoc_200923_MSCPEDIT_mnemonics_rm&uac=60196BR&impID=2580585&faf=1#6

 

Gene therapy for spinal muscular atrophy: Safety and early outcomes

Waldrop MA, Karingada C, Storey MA, Powers B, Iammarino MA, Miller NF, Alfano LN, Noritz G, Rossman I, Ginsberg M, Mosher KA, Broomall E, Goldstein J, Bass N, Lowes LP, Tsao CY, Mendell JR, Connolly AM. Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes. Pediatrics. 2020 Sep;146(3):e20200729. doi: 10.1542/peds.2020-0729. PMID: 32843442.

Abstract

Background and objectives: Historically, autosomal recessive 5q-linked spinal muscular atrophy (SMA) has been the leading inherited cause of infant death. SMA is caused by the absence of the SMN1 gene, and SMN1 gene replacement therapy, onasemnogene abeparvovec-xioi, was Food and Drug Administration approved in May 2019. Approval included all children with SMA age <2 years without end-stage weakness. However, gene transfer with onasemnogene abeparvovec-xioi has been only studied in children age ≤8 months. 

Methods: In this article, we report key safety and early outcome data from the first 21 children (age 1-23 months) treated in the state of Ohio. 

Results: In children ≤6 months, gene transfer was well tolerated. In this young group, serum transaminase (aspartate aminotransferase and alanine aminotransferase) elevations were modest and not associated with γ glutamyl transpeptidase elevations. Initial prednisolone administration matched that given in the clinical trials. In older children, elevations in aspartate aminotransferase, alanine aminotransferase and γ glutamyl transpeptidase were more common and required a higher dose of prednisolone, but all were without clinical symptoms. Nineteen of 21 (90%) children experienced an asymptomatic drop in platelets in the first week after treatment that recovered without intervention. Of the 19 children with repeated outcome assessments, 11% (n = 2) experienced stabilization and 89% (n = 17) experienced improvement in motor function. 

Conclusions: In this population, with thorough screening and careful post-gene transfer management, replacement therapy with onasemnogene abeparvovec-xioi is safe and shows promise for early efficacy.

Association of miglustat with swallowing outcomes in Niemann-Pick Disease, Type C1

Solomon BI, Smith AC, Sinaii N, Farhat N, King MC, Machielse L, Porter FD. Association of Miglustat With Swallowing Outcomes in Niemann-Pick Disease, Type C1. JAMA Neurol. 2020 Sep 8. doi: 10.1001/jamaneurol.2020.3241. Epub ahead of print. PMID: 32897301.

Abstract

Importance: Niemann-Pick disease, type C1 (NPC1) is a progressive neurovisceral disease with no US Food and Drug Administration-approved therapy. Miglustat, a drug used off-label in the United States for the treatment of NPC1, appears to stabilize neurologic disease progression. Several prospective trials suggest that miglustat stabilizes oropharyngeal swallowing function; however, its effect on dysphagia and aspiration risk has not been demonstrated instrumentally. 

Objective: To determine if miglustat therapy is associated with stabilized swallowing dysfunction in individuals with NPC1. 

Design, setting, and participants: Patients with confirmed NPC1 diagnoses were evaluated in a single-center cohort study of NPC1 from April 1997 to November 2019. Longitudinal data from individuals with neurologic disease onset prior to age 15 years were analyzed. The study population was divided into those with neurologic disease onset in early childhood (age <6 years) and late childhood (age ≥6 years and <15 years). Analysis began September 2019. 

Exposures: Oral miglustat at baseline and at follow-up. 

Main outcomes and measures: Oropharyngeal swallowing function was assessed with videofluoroscopic swallowing studies. Overall swallowing ability and aspiration risk were evaluated using the American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain and an adapted Rosenbek aspiration-penetration scale, respectively. 

Results: Overall, 50 participants were evaluated at baseline (median [interquartile range] age, 9.4 [3.4-16.4] years; 26 [52%] female). The median (interquartile range) duration of follow-up was 3.0 (1.1-4.4) years. Miglustat use was associated with decreased odds of worse American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain outcomes in all 3 subsets (overall: odds ratio [OR], 0.09 [95% CI, 0.02-0.36); P < .001; early childhood: OR, 0.17 [95% CI, 0.04-0.67]; P = .01; late childhood: OR, 0.05 [95% CI, 0.01-0.29]; P = .001). Miglustat use was associated with decreased odds of worse Rosenbek aspiration-penetration scale outcomes in the overall cohort (OR, 0.28 [95% CI, 0.08-0.95]; P = .04) but not in each subgroup (early childhood: OR, 0.27 [95% CI, 0.06-1.22]; P = .09; late childhood: OR, 0.38 [95% CI, 0.06-2.33]; P = .29). 

Conclusions and relevance: These data suggest that miglustat use is associated with stabilized swallowing function and reduced aspiration risk in NPC1, thus supporting its use in this population. In addition, these data demonstrate that a quantification of swallowing dysfunction can be used as a clinically relevant, functional outcome measure in future therapeutic trials in NPC1.

Courtesy of:  https://www.mdlinx.com/journal-summary/association-of-miglustat-with-swallowing-outcomes-in-niemann-pick-disease-type-c1/77M89yYQUvGMFwUtePNZHI

Melatonin for acute treatment of migraine in children and adolescents

Amy A. Gelfand, Alexandra C. Ross,  Samantha L. Irwin,  Kaitlin A. Greene, William F. Qubty , I. Elaine Allen.  Melatonin for Acute Treatment of Migraine in Children and Adolescents: A Pilot Randomized Trial.  Headache.  First published: 02 September 2020 https://doi.org/10.1111/head.13934

Abstract

Objective

To determine what dose of melatonin is most effective for treating migraine acutely in children and adolescents. 

Background

Acute migraine medications may not work for all patients and may cause side effects. Melatonin is effective for migraine prevention in adults and has been used acutely for procedural pain in children. Our goal was to determine whether a “high” or “low” dose of melatonin is more effective for treating migraine acutely in youth. 

Methods

In this pilot, randomized, open‐label, single‐center, dose‐finding trial, children and adolescents aged 4‐17 years with episodic migraine were randomized to “high‐dose” or “low‐dose” dose melatonin (<40 kg: 4 mg vs. 1 mg; ≥40 kg: 8 mg vs. 2 mg). The primary outcome measure was change in mean pain score between time 0 and 2 hours. Secondary outcomes included 2‐hour pain‐relief and pain‐freedom rates. 

Results

Eighty‐four participants (n = 42 per group) were enrolled in this study. Mean (SD) participant age was 11.8 (3.5) years and 55% (46/84) were female. Mean (SD) headache days/month was 5.6 (3.8). Sixty‐six (79%) participants provided outcome data and were included in the analyses, n = 24 in the high‐dose group and n = 22 in the low‐dose group. The drop‐out rate was 43% (18/42) in the high‐dose group vs. 48% (20/42) in the low‐dose group. Mean (SD) change in pain intensity at 2 hours was −2.7 (2.1) cm in the high‐dose group vs. −2.3 (2.1) cm in the low‐dose group (p = .581), a difference of 0.4 cm (95% CI: −1.17 to 1.92). Two‐hour pain‐freedom rate was 41% (7/17) vs. 27% (4/15) in the high‐dose vs. low‐dose groups (p = .415), and 2‐hour pain‐relief rate was 94% (16/17) vs. 80% (12/15), (p = .482). There were no serious adverse events. Napping occurred in the majority (67% (14/21) high dose vs. 47% (9/19) low dose). Higher mg/kg dose of melatonin and napping were each independently associated with greater headache benefit. 

Conclusions

As an acute treatment for pediatric migraine, both low and high doses of melatonin were associated with pain reduction; however, study drop‐out was high. Higher dose and napping after treatment predicted greater benefit. _________________________________________________________________

From the article:

Pain was also graded on a continuous scale that participants could “X” at any point along a 10-cm line, representing 0-10 pain, which was positioned above the Wong-Baker FACES Pain Rating Scale. The Wong-Baker FACES Pain Rating Scale is a validated visual analog scale for  assessing physical pain in individuals ages 3 and up; the 10-cm line placed above it is a modification…

Neither dose tested hit the primary outcome measure of decreasing mean pain intensity by at least 3 cm at 2 hours, and there was a high drop-out rate in both groups.

Melatonin treatment was safe and well tolerated in this study. Many parents and participants preferred using melatonin to treat their child’s/their migraine compared to other acute treatments tried previously. Napping was predictive of headache benefit, suggesting that facilitating sleep is one of the mechanisms by which melatonin might help migraine acutely.

Courtesy of:  https://www.mdlinx.com/journal-summary/melatonin-for-acute-treatment-of-migraine-in-children-and-adolescents-a-pilot-randomized-trial/3x1QgzvcrTsy4Gvwj81q14

Thanatophoric dysplasia. Perfectly human.

She knew they would only have a few fleeting months together, but in that time Sarah’s unborn daughter would transform her understanding of beauty, worth, and the gift of life. 

Happily married and teaching history at the University of Oxford, Sarah Williams had credentials, success, and knowledge. It took someone who would never have any of these things to teach her what it means to be human. 

This extraordinary true story begins with the welcome news of a new member of the Williams family. Sarah’s husband, Paul, and their two young daughters share her excitement. But the happiness is short-lived, as a hospital scan reveals a lethal skeletal dysplasia. Birth will be fatal. 

Sarah and Paul decide to carry the baby to term, a decision that shocks medical staff and Sarah’s professional colleagues. Sarah and Paul find themselves having to defend their child’s dignity and worth against incomprehension and at times open hostility. They name their daughter, Cerian, Welsh for “loved one.” Sarah writes, “Cerian is not a strong religious principle or a rule that compels me to make hard and fast ethical decisions. She is a beautiful person who is teaching me to love the vulnerable, treasure the unlovely, and face fear with dignity and hope.” 

In this candid and vulnerable account, Sarah brings the reader along with her on the journey towards Cerian's birthday and her deathday. It’s rare enough to find a writer who can share such a heart-stretching personal experience without sounding sappy, but here is one who at the same time has the ability to articulate the broader cultural issues raised by Cerian’s story. In a society striving for perfection, where worth is earned, identity is constructed, children are a choice, normal is beautiful, and deformity is repulsive, Cerian’s short life raises vital questions about what we value and where we are headed as a culture.

https://www.amazon.com/Perfectly-Human-Nine-Months-Cerian/dp/0874866693#customerReviews

Sara Williams and her husband, Paul, have learned how to trust God by walking through the fires of suffering.

A routine 20-week pregnancy scan revealed a problem. Sarah’s baby had a lethal skeletal issue called thanatophoric dysplasia, a malformity of the skeletal structure where the bones don’t develop sufficiently to allow the proper development of the lungs. The baby was safe inside the womb but would die at birth or shortly thereafter.

Sarah remembers the shock of hearing that the best medical recommendation for her situation was to terminate the life of her baby. Her first instinct was to view this as solely a medical situation that demanded solely a medical response. Why go through the suffering of giving birth to a child that has no chance for survival? 

She now considers that response a defense mechanism against her own fear and uncertainty.

Then an extraordinary thing happened to Sarah and Paul later that night, after their terrible diagnosis.

Sarah says:

“As we prayed together, God spoke to us. We had no idea until that night what people experienced when they say that. I can only describe it as a deep sense that God was sitting on that sofa with us in our despair. He was saying, ‘Here is a sick and dying child. Will you love her for me and take care of her until she dies?’ That changed everything for us because suddenly our circumstances weren’t so much about our capacity to deal with this terrible situation, but about God’s love for this tiny, vulnerable baby that the hospital didn’t even think of as a human being.”

It’s a hard truth: God doesn’t always rescue us from our grief and pain. But He does always meet us in it.

Sarah and Paul faced great opposition from colleagues, friends, and doctors. Yet, during labor, Sarah felt God’s presence as never before, and knew He had come to take their baby (named Cerian, Welsh for loved one) home.

https://jimdaly.focusonthefamily.com/honoring-the-preborn-cerians-story/

Thanatophoric dysplasia (TD) is the most common form of skeletal dysplasia known to be lethal in the neonatal period. The term thanatophoric derives from the Greek word thanatophorus, which means "death bringing" or "death bearing." Salient phenotypic features of TD include macrocephaly, narrow bell-shaped thorax with shortened ribs, normal trunk length, and severe shortening of the limbs. See the image below.

TD is divided into 2 clinically defined subtypes: TD type I (TD-I or TD-1) and TD type II (TD-II or TD-2). The clinical subtypes of TD are defined by either a curved or straight appearance of the long bones. TD-I, the more common subtype, is characterized by a normal-shaped skull and curved long bones (shaped like old-fashioned telephone receivers); the femurs are most affected in TD-I. TD-II is associated with a cloverleaf-shaped skull and straight femurs. However, reported cases have cited clinical overlap between these subtypes.

Both TD-I and TD-II are part of a group of skeletal disorders associated with mutations within the Fibroblast Growth Factor Receptor 3 gene (FGFR3). TD-I and TD-II are due to an autosomal dominant point mutation, with the gene responsible, FGFR3, being mapped to the short arm of chromosome 4 (4p16.3). Penetrance of this mutation is 100%. Currently, all cases of TD are due to de novo mutations in FGFR3. Germline mosaicism has not been clearly documented but remains a theoretical possibility...

Epidemiology

Frequency

United States

Thanatophoric dysplasia (TD) has an incidence of 1 per 20,000 to 1 per 50,000 births.

International

Incidence in Spain is reported as 1 per 37,000 births. 

Mortality/Morbidity

Newborns with TD are stillborn or die shortly after birth. Death occurs usually within 48 hours and is due to severe respiratory insufficiency from a reduced thoracic capacity and hypoplastic lungs and/or respiratory failure due to brainstem compression. Survival into early childhood has been rarely reported.

Sex

Males and females are equally affected.

Age

TD is lethal in neonates. Although extremely rare, survival beyond the neonatal period has been described in the medical literature.

https://emedicine.medscape.com/article/949591-overview

Accelerated regression of cardiac rhabdomyoma by mTOR inhibitors in a neonate with heart failure

Krishna Prasad, Parag Barwad, Pruthvi,C.R, Krishna Santosh, JyothiVijay, SanjeevNaganur.  Accelerated regression of cardiac rhabdomyoma by mTOR inhibitors in a neonate with heart failure: A case report.  Indian Heart Journal, in press.  https://doi.org/10.1016/j.ihjccr.2020.08.008

Abstract

Cardiac Rhabdomyomas (CR) are a rare occurrence with an incidence of 0.1% and are the most common primary cardiac tumors in the fetus and pediatric age groups. Although largely known as “spontaneously regressing tumor” very rarely they cause symptoms of heart failure due to ventricular dysfunction or outflow tract obstruction, or arrhythmias. When associated with tuberous sclerosis complex (TSC) they are usually multiple in number. mTOR inhibitors were recently approved by FDA for the treatment of TSC. We report a case of fetal and neonatal rhabdomyoma presenting as heart failure refractory to medical management and was treated with mTOR inhibitors (Everolimus) with which the patient had improvement in symptoms and accelerated regression of tumor. We conclude that rhabdomyomas though asymptomatic in most, can present with refractory heart failure and mTOR inhibitors can be helpful in such cases.

Altered spontaneous brain activity in patients with childhood absence epilepsy

Yan Y, Xie G, Zhou H, Liu H, Wan M. Altered spontaneous brain activity in patients with childhood absence epilepsy: associations with treatment effects. Neuroreport. 2020;31(8):613-618. doi:10.1097/WNR.0000000000001447

Abstract

The study aims to detect resting-state functional MRI (RS-fMRI) changes and their relationships with the clinical treatment effects of anti-epileptic drugs (AEDs) for patients with childhood absence epilepsy (CAE) using the fractional amplitude of low-frequency fluctuation (fALFF). RS-fMRI data from 30 CAE patients were collected and compared with findings from 30 healthy controls (HCs) with matched sex and age. Patients were treated with first-line AEDs for 46.2 months before undergoing a second RS-fMRI scan. fALFF data were processed using DPABI and SPM12 software. Compared with the HCs, CAE patients at baseline showed increased fALFF in anterior cingulate cortex, inferior parietal lobule, inferior frontal lobule, supplementary motor area and reduced fALFF in putamen and thalamus. At follow-up, the fALFF showed a clear rebound which indicated a normalization of spontaneous brain activities in these regions. In addition, the fALFF changes within thalamus showed significant positive correlation with the seizure frequency improvements. Our results suggest that specific cortical and subcortical regions are involved in seizure generation and the neurological impairments found in CAE children and might shed new light about the AEDs effects on CAE patients.

Eating epilepsy

 Introduction

To begin with, my name is Tarushi Tyagi. I belong to city name Alwar, India. By profession I am a Chartered Accountant, member of Institute of Chartered Accountant of India and have been working for a bank for the past 6 years.

I have wonderful family of 4 including my mother, father and brother who have been a great support throughout my life. They brought me up with lots of love, affection and most importantly never made me feel that I was different from other kids because I had epilepsy. They didn’t ever make me feel that I wouldn’t be able to do some things in life. I still remember my doctor telling me that I couldn’t do 2 things in life: fly an aeroplane and drive a bus.

Diagnosis

I have had epilepsy for the past 24 years. For as long as I can remember it has been a part of me and I am part of it. I don’t think of it like a disease though, rather it’s simply a part of me. The sooner we accept ourselves the way we are, the sooner we are set free - trust me, it’s the best thing in world and I love the feeling.

I was 7 years old when I first had a seizure in school. My doctors told me that this didn’t always mean that a person had epilepsy, but, after having a cluster of 3 seizures just after lunch one day, I went on to have an EEG and MRI, the results of which led to my doctors diagnosing me with epilepsy. They diagnosed me with a rare form of Reflex epilepsy known as Eating Epilepsy. My uncle is a doctor hence I was lucky to be in the right hands regarding the diagnosis.

Multiple doctors were consulted all over in North India but were not able to reach or decide upon the drug or dosage that could suit my body and stop my seizures. I was referred to another doctor in Delhi8 who was able give me partial control over my seizures however.

All my life my seizures have occurred between 3 and 4pm, just after lunch! I used to tell my ma (mother) that I was seeing lots of flashing lights around my eyes and that I wasn’t feeling well, and I would then go and lie down.

Both my parents have personally focused and enabled me to focus on both my studies, and the things that I excel in. Families, relatives, friends, and schools have the responsibility to support people with epilepsy just like they would everyone else. They must be treated with equality so that people don’t feel that they are less than anyone else.

Through the support of loved ones I have been able to overcome hard times and look forward. Many times that I’ve had seizures it has been due to stress from my studies. After the seizures I would have a cry, put the seizure out of my mind and focus on plans for the next day.

It’s very important to be able to find things to look forward to. What has helped me is to decide upon and lay out my goals in front of me.

Reduced medications!

After being seizure-free for 7 years (during which I completed one of the toughest national courses in finance), my doctor told me that we were going to slowly reduce my epilepsy medication dosage and have me come off of them over 2 years.

I’d previously had my body tell me to sleep 13-14 hours a day but my mind conflicted and told me I should be active – they conflicted. Anyway, after 2 years I was taking only 1 medication and the way I felt was like nothing I’d ever felt before – I felt so fresh and with so much more energy that it was like I’d just sobered up from drinking! 😊 This made me realise the psychological and physical impacts that my medication had been having on me.

Feeling energised was new to me as at age 25. Being on this one medicine didn’t make me feel sleepy and I’m told that I didn’t look sleepy to other people anymore either!

Mental health - depression & negative feelings/thoughts

Negative emotions hit you back even after having greatest support of loved ones.

Whilst I was enjoying an energised life, I had another seizure. I’d completed my studies but was jobless and I went into very bad zone of self-doubt. Some jobs I had to turn down because they’d have stopped me from getting the sleep I needed (sleep is like a form of medicine!). After a while though I got some great news: I’d won a job with an amazing organisation!

After 3 months with the new company I had another seizure, in the office. I’d told my colleagues about my epilepsy though, so they took good care of me. I was back to the office after 4 days although was feeling drowsy because I’d had to have my medicine dosage increased.  

Increasing the dosage caused a new negative psychological issue for me as well; I feared that I might have another seizure and was really doubting myself. I did find some ways of relaxing, but I started distancing myself from people: I felt that I had no choice but to do so.

It took me few months to get back to “normal” – and life was really challenging, but I did it and had another wonderful 4.5 years of seizure freedom!

In October 2018, my seizure freedom ended again when I had 4 seizures over the period of a few months. The dosages of my medicines were increased again (!), but this time with different side effects. It’s crazy stuff: you don’t know how your body will react to the medicines. Again, I had an issue with coordination between my mind and body, which was so frustrating. I tried everything to get back to my normal life through routine, but it was quite a struggle. One day I read a quote:

“There are only two ways to live your life. One is as though nothing is a miracle. The other is as though everything is miracle.”

Albert Einstein

It felt like a miracle that I was still alive. Every time I had a seizure my first thought was: “My parents will be worried, and I am troubling them again”. Slowly and gradually though, I removed my feelings of guilt from within and started taking 1 day at a time.

Due to the latest dosage increase I was sleeping 12 hours a night, but as I got used to it, I felt less tired, and now I’m back to 9.5 hours – it’s a happy moment for me.

My next target is to get back to 9 hours and start yoga/meditation which is crucial and just like medicine and sleep for me.

Conclusion

What I have learned from my journey to date is that the most control I have over my epilepsy is to take my medicine on time, keep to my sleep schedule and try and manage my thoughts (which can play a crucial role in overall health).

For families who care for anyone with epilepsy, providing them with emotional support and confidence can encourage them to lead their lives with confidence. They might still face negative thoughts and self-doubt but having a strong family foundation can help them towards overcoming this.

Accepting the diagnosis of epilepsy has helped me to live with it and how it has influenced much of my life. Acceptance is key. There is not a specific path; each day brings new beginnings and new struggles.

During these unfortunate times of COVID-19 we need to take care of ourselves as it is deeply impacting many people mentally. Take care of yourself and those you care for both mentally and physically.

https://www.epilepsysparks.com/blog/tarushi-tyagi

Wang X, Chen B, Jin L, Zhang W, Liu Y. Eight years follow-up of a generalized epilepsy patient with eating-induced late-onset epileptic spasms and atypical absence with myoclonic jerks [published online ahead of print, 2020 Aug 10]. Brain Dev. 2020;S0387-7604(20)30201-1. doi:10.1016/j.braindev.2020.07.018

Abstract

Purpose: Eating epilepsy was previously known as a kind of focal reflex epilepsy. However, the development of eating-induced multiple generalized seizures and the associated EEG changes were rarely reported. Herein, we present a 13-year-old generalized epilepsy patient with eating-induced generalized seizures since the age of 5.

 Case presentation: The 13-year-old male patient had suffered from late-onset eating-induced epileptic spasms during the meal since the age of 5. Meanwhile, he also experienced spontaneous epileptic spasms during the period of sleep. The seizure frequency and type gradually increased from 7 years of age. In addition to epileptic spasms, he started experiencing atypical absence with myoclonic jerks during the meal. Ictal EEG presented as the appearance of an irregular slow-wave mixed with generalized polyspike wave with the intake of food, and gradually evolved to bursts of generalized polyspike wave complexes. At the end of the meal, the EEG returned to normal. Nevertheless, at the age of 13, his seizure frequency increased and appeared new seizure type, and besides epileptic spasm and atypical absence, he began to experience myoclonic seizure during sleep and awaking-generalized tonic-clonic seizure in the morning. In this period he started taking valproic acid, topiramate and clonazepam, and his seizure frequency was reduced. 

Conclusion: In conclusion, this case demonstrated the variability of eating induced multiple generalized seizure types, and eight years follow-up also indicates that generalized epilepsy progressed with age. The EEG and clinical changes of our patient contribute to a better understanding of the electro-clinical features of eating-induced multiple generalized seizures and the course of generalized epilepsy with such seizures.

Clinical, ethical and legal considerations in the treatment of newborns with non-ketotic hyperglycinaemia

Boneh A, Allan S, Mendelson D, Spriggs M, Gillam LH, Korman SH. Clinical, ethical and legal considerations in the treatment of newborns with non-ketotic hyperglycinaemia. Mol Genet Metab. 2008;94(2):143-147. doi:10.1016/j.ymgme.2008.02.010

Abstract

Non-ketotic hyperglycinaemia (NKH) is a devastating neurometabolic disorder leading, in its classical form, to early death or severe disability and poor quality of life in survivors. Affected neonates may need ventilatory support during a short period of respiratory depression. The transient dependence on ventilation dictates urgency in decision-making regarding withdrawal of therapy. The occurrence of patients with apparent transient forms of the disease, albeit rare, adds uncertainty to the prediction of clinical outcome and dictates that the current practice of withholding or withdrawing therapy in these neonates be reviewed. Both bioethics and law take the view that treatment decisions should be based on the best interests of the patient. The medical-ethics approach is based on the principles of non-maleficence, beneficence, autonomy and justice. The law relating to withholding or withdrawing life-sustaining treatment is complex and varies between jurisdictions. Physicians treating newborns with NKH need to provide families with accurate and complete information regarding the disease and the relative probability of possible outcomes of the neonatal presentation and to explore the extent to which family members are willing to take part in the decision making process. Cultural and religious attitudes, which may potentially clash with bioethical and juridical principles, need to be considered.

Trimetinib for progressive pediatric low-grade gliomas 2

15 year old adolescent asymptomatic female with neurofibromatosis and Beckwith-Weidemann treated with trimetinib for a progressively enlarging right cerebellar peduncular lesion.  Serial images postcontrast T1.

See   https://childnervoussystem.blogspot.com/2019/05/trametinib-for-progressive-pediatric.html            https://childnervoussystem.blogspot.com/2015/05/venriculomegaly-in-nf1.html

8/17/2020  Right brachium pontis lesion enhances over an area of 17 x 15 mmwith local mass effect without distortion of fourth ventricle. 

12/4/19  Slight decrease in the size of the enhancing focus in the right cerebellar hemisphere.

8/15/19  Significant improvement in the size and enhancement of lesions in the right basal ganglia, left cerebral peduncle, and right cerebellar peduncle compared to 05/06/2019  

5/06/19  In addition, overall enhancement within the right middle cerebellar peduncle lesion has also increased from the prior study, with increased adjacent T2/FLAIR hyperintense signal in the right middle cerebellar peduncle and the right cerebellum.

 

Primary amoebic meningoencephalitis 4

 A brain-eating amoeba claimed the life of a 13-year-old boy in Florida, according to multiple reports. The parents of Tanner Lake Wall told Florida news outlet News4Jax that their son contracted the amoeba, Naegleria fowleri, when he was swimming at a campground in North Florida near Tallahassee just a few days before his death.

“He swam in a lake there Friday and Saturday with 50-plus kids and our daughters were there, my husband was there, no one else got it, and he’s the only one," Alicia Whitehill, Tanner’s mother, said in an interview with the TV news outlet.

Tanner’s parents said the boy was a healthy and active teenager. But he began to complain of bad headaches two days after swimming, which was followed by nausea and vomiting. His parents took him to Putnam Community Medical Center, where he was diagnosed with strep throat, according to the news outlet. When he did not get better, they drove him to UF Health in Gainesville, where he was put on a ventilator, the report said.

Tanner’s father, Travis Wall, said in the interview with the media outlet that doctors told them: “We’re sorry to tell you this but your son doesn’t have bacterial meningitis, he has the parasitic amoeba and there is no cure.”

Tanner didn't show signs of brain activity on Aug. 2, ultimately leading his parents to decide to take him off life support. He then succumbed to the infection, according to the report.

The family told the news outlet that they hope health care professionals will be more aware of this rare illness and that signs need to be placed on warm water lakes to warn swimmers of the potential invisible killer.

According to the Florida Department of Health in Hillsborough County, Naegleria fowleri is a single-celled amoeba that can cause a rare fatal infection that destroys brain tissue. The amoeba is commonly found in warm freshwaters such as lakes, ponds, canals and rivers.

The site stated a person can get infected when water enters through the nose. The state health site said contamination occurs during periods of prolonged high temperatures when water temps are higher and water levels are lower. As of July, the county health department stated 37 cases have been documented in the state since 1962.

“Unfortunately, there are always such rare reports of this very serious infection caused by a free-living amoeba being acquired from swimming in outdoor freshwater bodies of water," infectious disease specialist Dr. Aaron Glatt, the chief of infectious disease at Mount Sinai South Nassau, in New York, told Fox News. Glatt was not affiliated with this case.

 “Infected water containing this organism, Naegleria fowleri, enters the nose and the amoeba migrates to the brain and causes serious infection. While very rare, it can be a fatal infection that does not always respond to therapy. The disease progresses rapidly and the diagnosis is usually made after death," added Glatt, who is also a clinical professor of medicine at the Icahn School of Medicine at Mount Sinai.

"To make the diagnosis you would need a sample of cerebral spinal fluid (CSF) commonly obtained through a lumbar puncture. While it is a rare infection, with the CDC noting only 145 cases in the U.S., the mortality is upwards of 97% once someone becomes infected. There is a non-commonly used drug called miltefosine that has been used to treat amoeba infections and can be tried in such infections," Dr. Fred Davis, associate chair of the Emergency Medicine Department at Northwell Health Long Island Jewish Medical Center in New York, told Fox News.

Symptoms to look for include frontal headache, nausea, vomiting and fever. As the disease progresses, a stiff neck, altered mental status, and possible seizure, hallucinations and coma can occur, according to Florida health officials. The health site also recommends contacting your health care provider immediately if you experience any of the aforementioned symptoms after swimming in a warm body of water.

https://www.foxnews.com/health/brain-eating-amoeba-kills-florida-boy

 

Analysis of risk factors associated with poor outcome in posterior reversible encephalopathy syndrome after treatment in children

Marady Hun, Jidong Tian, Min Xie, Zhou She, Amin Sheikh Abdirahman, Phanna Han, Wuqing Wan and Chuan Wen.  Analysis of Risk Factors Associated With Poor Outcome in Posterior Reversible Encephalopathy Syndrome After Treatment in Children: Systematic Review and Meta-Analysis.  Front. Neurol., 26 August 2020 | https://doi.org/10.3389/fneur.2020.00938 

Objective: Chemotherapy and hematopoietic stem cell transplantation (HSCT) play important roles in clinical etiology, symptoms, signs, imaging findings, and biochemical parameters for inducing posterior reversible encephalopathy syndrome (PRES) in pediatric oncologic diseases. We aimed to evaluate various risk factors of pediatric oncologic diseases after conducting chemotherapy and HSCT to induce PRES for predicting the clinical prognosis frequency. 

Methods: The literature was performed on PubMed, Web of Science, and Embase databases to recognize the qualified studies. The odds ratios (ORs) of related risk factors and their corresponding 95% confidence intervals (CIs) were used to compute the pooled assessments of the outcomes. 

Results: Six studies were included in the meta-analysis, involving 828 records. The risk of female children has a significantly higher incidence than male children in oncologic age groups of PRES. Children over the age of 10 years old in oncologic age groups develop a significantly increased risk of PRES. Acute graft-versus-host disease (GVHD) has a significant promotion effect on the occurrence of PRES. Hypertension can promote the occurrence of PRES in children. The risk of PRES in immunodeficient children increases significantly. Children with sickle cell disease (SCD) have a significantly increased risk of PRES. The risk of PRES in children with T-cell leukemia rises considerably. The central nervous system (CNS) leukemia/involvement has a significant role in promoting the occurrence of PRES in children. The pooled OR for the factors male, ≥ 10 years old of age, acute GVHD, hypertension, immunodeficiency, SCD, T-cell leukemia, CNS leukemia/involvement was 0.66 (95% CI: 0.58, 0.76; P < 0.00001), 2.06 (95% CI: 1.23, 3.43; P < 0.006), 1.32 (95% CI: 1.14, 1.53; P < 0.0003), 8.84 (95% CI: 7.57, 10.32; P < 0.00001), 2.72 (95% CI: 1.81, 4.08; P < 0.00001), 2.87 (95% CI: 2.15, 3.83; P < 0.00001), 2.84 (95% CI: 1.65, 4.88; P < 0.0002), and 3.13 (95% CI: 1.43, 6.84; P < 0.004), respectively. 

Conclusions: The result of this meta-analysis suggests that female children, age over 10 years old, acute GVHD, hypertension, immunodeficiency, SCD, T-cell leukemia, and CNS leukemia/involvement are likely to have the poor outcome in pediatric oncologic/hematologic diseases in PRES.