Does time equal vision in the acute treatment of a cohort of AQP4 and MOG optic neuritis?

Objective To investigate whether visual disability which is known to accumulate by poor recovery from optic neuritis (ON) attacks can be lessened by early treatment, we investigated whether the time from symptom onset to high-dose IV methylprednisolone (IVMP) affected visual recovery. Methods: A retrospective study was performed in a consecutive cohort of patients following their first aquaporin-4 (AQP4)-IgG or myelin oligodendrocyte glycoprotein (MOG)-IgG-ON. Best-corrected visual acuity (BCVA) in ON eyes at 3 months (BCVA3mo) was correlated with time to IVMP (days). In cases of bilateral ON, 1 eye was randomly selected. Results: A total of 29 of 37 patients had ON (27 AQP4-seropositive neuromyelitis optica spectrum disorder [NMOSD] and 9 MOG-IgG-ON), 2 of whom refused treatment. Of the 27 patients included, 10 presented later than 7 days from onset. The median BCVA3mo of patients treated >7 days was 20/100 (interquartile range 20/100–20/200). Patients treated >7 days had an OR of 5.50 (95% CI 0.88–34.46, p = 0.051) of failure to regain 0.0 logMAR vision (20/20) and an OR of 10.0 (95% CI 1.39–71.9) of failure to regain 0.2 logMAR vision (20/30) (p = 0.01) compared with patients treated within 7 days. ROC analysis revealed that the optimal criterion of delay in IVMP initiation was ≤4 days, with a sensitivity and specificity of 71.4% and 76.9%, respectively. Conclusions: In this retrospective study of ON with AQP4 and MOG-IgG, even a 7-day delay in IVMP initiation was detrimental to vision. These results highlight the importance of early treatment for the long-term visual recovery in this group of patients. A prospective, multicenter study of the effects of timing of IVMP is currently underway. Classification of evidence: This study provides Class IV evidence that hyperacute treatment of AQP4 and MOG-ON with IVMP increases the chance for good visual recovery (20/20 vision) and that even a greater than 7-day delay in treatment is associated with a higher risk for poor visual recovery

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple cafe-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P \u3c 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients

Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

© 2019, The Author(s). The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article

Seizure detection and neuromodulation: A summary of data presented at the XIII conference on new antiepileptic drug and devices (EILAT XIII)

The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain from June 26th to 29th 2016. For the first time, the last day of the conference focused solely on new medical devices and neuromodulation. The current article summarises the presentations of that day, focusing first on EEG- and ECG based methods and devices for seizure detection. These methodologies form the basis for novel cardiac-based methods of vagal nerve and responsive deep brain stimulation that rely on the prediction or early detection of seizures and that are also included in this article

International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible

Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants

PurposeThe purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy.MethodsInvestigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure (GF). Kaplan-Meier survival analyses were conducted for the overall population and for treated and untreated patients.ResultsRecords for 35 patients, 26 with early GF, were analyzed. Prominent symptom manifestations included vomiting, diarrhea, and steatorrhea. Median age at death was 3.7 months; estimated probability of survival past age 12 months was 0.114 (95% confidence interval (CI): 0.009-0.220). Among patients with early GF, median age at death was 3.5 months; estimated probability of survival past age 12 months was 0.038 (95% CI: 0.000-0.112). Treated patients (hematopoietic stem cell transplant (HSCT), n = 9; HSCT and liver transplant, n = 1) in the overall population and the early GF subset survived longer than untreated patients, but survival was still poor (median age at death, 8.6 months).ConclusionsThese data confirm and expand earlier insights on the progression and course of LALD presenting in infancy. Despite variations in the nature, onset, and severity of clinical manifestations, and treatment attempts, clinical outcome was poor.Genet Med 18 5, 452-458

Overview of systematic reviews of therapeutic ranges : methodologies and recommendations for practice

BACKGROUND: Many medicines are dosed to achieve a particular therapeutic range, and monitored using therapeutic drug monitoring (TDM). The evidence base for a therapeutic range can be evaluated using systematic reviews, to ensure it continues to reflect current indications, doses, routes and formulations, as well as updated adverse effect data. There is no consensus on the optimal methodology for systematic reviews of therapeutic ranges. METHODS: An overview of systematic reviews of therapeutic ranges was undertaken. The following databases were used: Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts and Reviews of Effects (DARE) and MEDLINE. The published methodologies used when systematically reviewing the therapeutic range of a drug were analyzed. Step by step recommendations to optimize such systematic reviews are proposed. RESULTS: Ten systematic reviews that investigated the correlation between serum concentrations and clinical outcomes encompassing a variety of medicines and indications were assessed. There were significant variations in the methodologies used (including the search terms used, data extraction methods, assessment of bias, and statistical analyses undertaken). Therapeutic ranges should be population and indication specific and based on clinically relevant outcomes. Recommendations for future systematic reviews based on these findings have been developed. CONCLUSION: Evidence based therapeutic ranges have the potential to improve TDM practice. Current systematic reviews investigating therapeutic ranges have highly variable methodologies and there is no consensus of best practice when undertaking systematic reviews in this field. These recommendations meet a need not addressed by standard protocols

High incidence of Noonan Syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation

Article first published online: 21 AUG 2015Abstract not availableKitiwan Rojnueangnit ... Christopher P. Barnett ... et al

NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells

Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and resistance to glucocorticoids in leukemia cells confers poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia cells from 444 patients newly diagnosed with ALL and found significantly higher expression of CASP1 (encoding caspase 1) and its activator NLRP3 in glucocorticoid-resistant leukemia cells, resulting from significantly lower somatic methylation of the CASP1 and NLRP3 promoters. Overexpression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished the glucocorticoid-induced transcriptional response and increased glucocorticoid resistance. Knockdown or inhibition of CASP1 significantly increased glucocorticoid receptor levels and mitigated glucocorticoid resistance in CASP1-overexpressing ALL. Our findings establish a new mechanism by which the NLRP3-CASP1 inflammasome modulates cellular levels of the glucocorticoid receptor and diminishes cell sensitivity to glucocorticoids. The broad impact on the glucocorticoid transcriptional response suggests that this mechanism could also modify glucocorticoid effects in other diseases