Long-term safety and influence on growth in patients receiving sirolimus: a pooled analysis.

BACKGROUND: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. METHODS: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. RESULTS: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). CONCLUSIONS: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. TRIAL REGISTRATION: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

Home Videos as a Cost-Effective Tool for the Diagnosis of Paroxysmal Events in Infants: Prospective Study.

BACKGROUND: The diagnosis of paroxysmal events in infants is often challenging. Reasons include the child's inability to express discomfort and the inability to record video electroencephalography at home. The prevalence of mobile phones, which can record videos, may be beneficial to these patients. In China, this advantage may be even more significant given the vast population and the uneven distribution of medical resources. OBJECTIVE: The aim of this study is to investigate the value of mobile phone videos in increasing the diagnostic accuracy and cost savings of paroxysmal events in infants. METHODS: Clinical data, including descriptions and home videos of episodes, from 12 patients with paroxysmal events were collected. The investigation was conducted in six centers during pediatric academic conferences. All 452 practitioners present were asked to make their diagnoses by just the descriptions of the events, and then remake their diagnoses after watching the corresponding home videos of the episodes. The doctor's information, including educational background, profession, working years, and working hospital level, was also recorded. The cost savings from accurate diagnoses were measured on the basis of using online consultation, which can also be done easily by mobile phone. All data were recorded in the form of questionnaires designed for this study. RESULTS: We collected 452 questionnaires, 301 of which met the criteria (66.6%) and were analyzed. The mean correct diagnoses with and without videos was 8.4 (SD 1.7) of 12 and 7.5 (SD 1.7) of 12, respectively. For epileptic seizures, mobile phone videos increased the mean accurate diagnoses by 3.9%; for nonepileptic events, it was 11.5% and both were statistically different (P=.006 for epileptic events; P<.001 for nonepileptic events). Pediatric neurologists with longer working years had higher diagnostic accuracy; whereas, their working hospital level and educational background made no difference. For patients with paroxysmal events, at least US $673.90 per capita and US $128 million nationwide could be saved annually, which is 12.02% of the total cost for correct diagnosis. CONCLUSIONS: Home videos made on mobile phones are a cost-effective tool for the diagnosis of paroxysmal events in infants. They can facilitate the diagnosis of paroxysmal events in infants and thereby save costs. The best choice for infants with paroxysmal events on their initial visit is to record their events first and then show the video to a neurologist with longer working years through online consultation.

Establishment and utility assessment of posterior reversible encephalopathy syndrome early warning scoring (PEWS) scale establishment and utility assessment of PEWS scale.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a complication that occurs during various diseases' treatment. Imaging examination is the gold standard for diagnosis. PRES frequently occurrence in patients with hematological malignancies results in poorer prognosis and higher mortality. We aim to establish a practical and operable scale for early prediction, assessment of the severity of the Posterior Reversible Encephalopathy Syndrome, and timely intervention for better prognosis. METHODS: The scale designed by reviewing the literature and by referring to clinical practice. We assessed the reliability and validity of the scale. Scale-based assessment of children undergoing chemotherapy for acute lymphoblastic leukemia conducted as early warning and intervention for those who may have PRES. RESULTS: Establishment of Posterior Reversible Encephalopathy Syndrome early warning scoring (PEWS) scale included three parts, as follows: (1) risk factors, including underlying disease, hypertension, Infection, and drug toxicity; (2) clinical features, including high cranial pressure, visual symptoms, seizure, and disturbance of consciousness; and (3) EEG features, including slow wave and epileptiform discharges. Utility assessment of PEWS scale showed that in 57 patients with acute lymphoblastic leukemia, 54 scored less than 10 and none of them detected as PRES. The other two had scores of 12 and 13 both diagnosed with PRES by brain MRI scan. CONCLUSIONS: PEWS scale can predict PRES early. PRES was highly suspected when the score was 10 points and more. Thus, prophylactic intervention can give to improve the prognosis of PRES.

Calcification in cerebral parenchyma affects pharmacoresistant epilepsy in tuberous sclerosis.

PURPOSE: Tuberous sclerosis (TSC) is an autosomal dominant inherited disease caused by mutations in the TSC1 or TSC2 gene and results in the over-activation of the mammalian target of the rapamycin (mTOR) signaling pathway. Rapamycin, an mTOR inhibitor, is clinically used to treat hamartomatous lesionsas in TSC and its effect on controlling epilepsy is also reported in many studies. This study aims to evaluate the risk factors of pharmacoresistant epilepsy in patients with TSC receiving long-term rapamycin treatment. METHOD: A total of 108 patients with TSC taking rapamycin for over 1 year were enrolled in this study. Factors that might influence seizure control were statistically analyzed by multiple factor analysis. A subgroup analysis was also conducted to access the relationship between calcified epileptic foci and pharmacoresistant epilepsy. (Clinical trial registration number: ChiCTR-OOB-15006535(2015-05-29)). RESULTS: Seizure was controlled in 53 patients but was not managed in 55 patients considered to be drug resistant. Logistic regression analysis showed that calcification in the cerebral parenchyma was a risk factor of pharmacoresistant epilepsy [P = 0.006, odds ratio (OR) = 4.831 (1.577, 14.795)]. Fifteen of 17 patients with calcified epileptic foci suffered from pharmacoresistant epilepsy (88.2%). Seizures in patients with calcified epileptic foci were probably pharmacoresistant (P = 0.010). CONCLUSION: Calcification in epileptic foci strongly indicates pharmacoresistant epilepsy in patients with TSC even when treated with appropriate anti-epilepsy drugs (AEDs) and rapamycin. Calcification can be used to evaluate pharmacoresistant epilepsy in patients with TSC.

Intermittent oral levetiracetam reduced recurrence of febrile seizure accompanied with epileptiform discharge: a pilot study.

BACKGROUND: In previous study, we have found intermittent oral levetiracetam (LEV) can effectively prevent recurrence of febrile seizure (FS). This study aimed to analyze the effects of the preventive on the patients with frequent FS accompanied with epileptiform discharge. METHODS: Patients with frequent FS were assigned to undergo Electroencephalogram (EEG). At the onset of fever, the patients who presented epileptiform discharge were orally administered with LEV with a dose of 15-30 mg/kg per day twice daily for 1 week, thereafter, the dosage was gradually reduced until totally discontinued in the second week. The seizure frequency associated with febrile events and FS recurrence rate during a 48-week follow-up were analyzed. RESULTS: among the 19 patients presented epileptiform discharge on EEG, 31.58% (6 of 19) had complex FS, 68.42% (13 of 19) had simple FS. Up to 57.89% (11 of 19) had a family history of seizure disorder and 36.84% (7 of 19) had a family history of FS in first-degree relatives. 42.11% (8 of 19) happened the first FS episode at the age < 18 months. 36.84% (7/19) presented generalized spikes, 63.16% (12/19) showed focal spikes. During the 48-week follow-up period, the patients experienced 26 febrile episodes, none of them presented seizure recurrence. CONCLUSION: Intermittent oral LEV can prevent the seizure recurrence of FS accompanied with epileptiform discharge in 48-week. However, further randomized controlled trials should be conducted. TRIAL REGISTRATION: ChiCTR-IPR-15007241 ; Registered 1 January 2014 - Retrospectively registered.

Sirolimus alternative to blood transfusion as a life saver in blue rubber bleb nevus syndrome: A case report.

RATIONALE: Blue rubber bleb nevus syndrome (BRBNS) is a rare disease characterized by multiple venous malformations. The gastrointestinal bleeding and secondary iron deficiency anemia are the most common complications. There are currently no effective treatments for BRBNS. Here, we report a case of successful treatment with a small dose of sirolimus of a BRBN patient with a de novo gene mutation. PATIENT CONCERNS: A 12-year-old female was admitted to our hospital with multiple hemangiomas for 12 years. The patient often displayed melena; she recently received transfusion of 2 units of red blood cells once every 2 weeks. Multiple fist-sized hemangiomas were piled up on both sides and back of the neck, and were also noted on the arms, legs, chest, back, and on the tip of the tongue. The laboratory findings demonstrated severe anemia. Blood sample sequencing detected a heterozygous de novo mutation c.2545C > Tin the TEK gene. DIAGNOSES: Based on these findings, final diagnosis of Blue rubber bleb nevus syndrome (BRBNS) was made. INTERVENTIONS: After the diagnosis, low-dose sirolimus was orally administered. OUTCOMES: The patient's hemoglobin was increased after treatment with sirolimus for 1 month. Since the initial treatment with sirolimus, she had not received any blood transfusions. The skin and mucosal hemangioma decreased significantly, and new digestive tract hemorrhage, muscle hematoma, or adverse drug reactions were not observed. LESSONS: we report a case of a mutation in exon 15 of the TEK gene leading to BRBN. It was successfully treated with a small dose of sirolimus as an alternative to blood transfusion in order to save the of BRBN patient's life.

Epilepsy may be the major risk factor of mental retardation in children with tuberous sclerosis: A retrospective cohort study.

Mental retardation (MR) is one of the most common cognitive comorbidities in children with tuberous sclerosis, and there are enormous studies about its risk factors. The genetic difference and the severity of epilepsy are the two main factors, but their weight in the occurrence of MR is still unclear. Two hundred twenty-three patients with tuberous sclerosis who received intelligence assessment, genetic mutation analysis, and the epilepsy severity assessment were included in our study. Genotype-neurocognitive phenotype correlations and epilepsy-neurocognitive phenotype correlations were analyzed by binary logistic regression analysis. No statistical significant result was found on genotype-neurocognitive phenotype correlations, which contrasted the previous report. The prevalence of MR was 50.0% for the patients with tuberous sclerosis complex-1 (TSC1) mutation, 54.5% for TSC2 (p=0.561), 54.7% for patients with protein-truncating (PT) and 50.0% for patients with nontruncating (NT) (p=0.791), and 54.3% for patients with family history and 53.7% for patients without family history (p=0.748). Statistical significant results were found on epilepsy-neurocognitive phenotype correlations, both on E-chess score (p=0.01) and the occurrence of infantile spasms (p=0.014), which was consistent to the previous study. For children with tuberous sclerosis, instead of genetic factors, epilepsy may play the main role for the presence of mental retardation. Patients with mental retardation tend to have earlier seizure attack, take more AEDs, have more seizure types, and have higher seizure frequency. Among the four cognitive functions in Denver II, social ability and language ability are more vulnerable to be influenced than fine and gross motor ability.