Sirolimus Can Increase the Disappearance Rate of Cardiac Rhabdomyomas Associated with Tuberous Sclerosis: A Prospective Cohort and Self-Controlled Case Series Study.

OBJECTIVES: To investigate the efficacy and safety of sirolimus in the treatment of cardiac rhabdomyomas associated with tuberous sclerosis complex and the specific benefits in different subgroups. STUDY DESIGN: The study was a prospective cohort and self-controlled case series study. Based on the prevalence of cardiac rhabdomyoma at different ages, we estimated the natural tumor disappearance rate. The subgroup analysis was done by Cox regression. Self-controlled case series method was used to assess the magnitude and duration of the drug effect. Adverse events were described. RESULTS: A total of 217 patients were included in the cohort study. Tumor disappearance rate was higher in younger age groups (hazard ratio = 0.99, P = .027) and female patients (hazard ratio = 2.08, P = .015). The age-adjusted incidence ratio showed that the disappearance of rhabdomyomas between 3 and 6 months was more related to sirolimus. Adverse events were observed 60 times in 42 of 217 children, mainly stomatitis. CONCLUSIONS: Sirolimus can increase the disappearance rate of cardiac rhabdomyoma in the tuberous sclerosis complex population. Efficacy varies by sex and age: female and younger patients have higher tumor disappearance rate. Sirolimus is well-tolerated.

Acute autonomic neuropathy with severe gastrointestinal symptoms in children: a case series.

BACKGROUND: Acute autonomic neuropathy (AAN) is rare disorder with anecdotal report, especially for childhood onset patients. Misdiagnosis or delays in treatment can always be found in clinical practice. We conducted this study to give a description of the manifestations and treatment of AAN in children and therefore help clinicians to make the accurate diagnosis early so that the prognosis of the patients can be improved. METHODS: A systematic record from 3 clinical centers was used to identify 11 subject, 3 males and 8 females, with clinical diagnosed AAN. RESULT: The age ranged from 2 years and 4 months to 14 years and 6 months (mean, 9 ± 3.6 years old) and the course from onset to diagnosis ranged from 7 days to 8 months. All children shared prominent initial symptoms, 7 with frequent vomiting and 4 with motor dysfunctions. The condition of 9 patients improved after treatment of IVIg and intravenous glucocorticoid. CONCLUSION: The clinical manifestations of AAN are diverse, generalized, and non-specific. Gastrointestinal disorders were the most common initial symptoms. Symptoms of gastrointestinal system and abnormal secretion of glands were severe and more common than other symptoms. The mechanism of AAN remains unknown. Although IVIg and intravenous glucocorticoid can be used in clinical practice, there is still no treatment recommendation and further study is needed.

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.

Levetiracetam: Probably Associated Diurnal Frequent Urination.

Diurnal frequent urination is a common condition in elementary school children who are especially at risk for associated somatic and behavioral problems. Levetiracetam (LEV) is a broad-spectrum antiepileptic drug that has been used in both partial and generalized seizures and less commonly adverse effects including psychiatric and behavioral problems. Diurnal frequent urination is not a well-known adverse effect of LEV. Here, we reported 2 pediatric cases with epilepsy that developed diurnal frequent urination after LEV administration. Case 1 was a 6-year-old male patient who presented urinary frequency and urgency in the daytime since the third day after LEV was given as adjunctive therapy. Symptoms increased accompanied by the raised dosage of LEV. Laboratory tests and auxiliary examinations did not found evidence of organic disease. Diurnal frequent urination due to LEV was suspected, and then the drug was discontinued. As expected, his frequency of urination returned to normal levels. Another 13-year-old female patient got similar clinical manifestations after oral LEV monotherapy and the symptoms became aggravated while in stress state. Since the most common causes of frequent micturition had been ruled out, the patient was considered to be diagnosed with LEV-associated psychogenic frequent urination. The dosage of LEV was reduced to one-third, and the frequency of urination was reduced by 60%. Both patients got the Naranjo score of 6, which indicated that LEV was a "probable" cause of diurnal frequent urination. Although a definite causal link between LEV and diurnal urinary frequency in the 2 cases remains to be established, we argue that diurnal frequent urination associated with LEV deserves clinician's attention.

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.

A Retrospective Study of Recurrent Bacterial Meningitis in Children: Etiology, Clinical Course, and Treatment.

Objectives: Recurrent bacterial meningitis (RBM) is a rare but life-threatening disease. This study aims to analyze the clinical features, potential causes, and therapeutic outcomes of RBM in children. Methods: This article retrospectively reviews the clinical characteristics, etiologies, and treatments in children with RBM hospitalized in Hebei children's hospital from 2012 to 2020. Results: A total of 10 children with RBM, five males and five females, were included in this study. The age of RBM in children spans from the neonatal stage to the childhood stage. The underlying illnesses were identified and classified as cerebrospinal fluid rhinorrhea (1 case), humoral immunodeficiency with Mondini dysplasia (1 case), common cavity deformity with cerebrospinal fluid ear leakage (1 case), Mondini malformations (2 cases), incomplete cochlear separation type I with a vestibular enlargement (2 cases), local inflammation of the sphenoid bone caused by cellulitis (1 case), congenital skull base defects (1 case), and congenital dermal sinus with intraspinal abscess (1 case). 6 patients chose targeted therapy for potential reasons. Conclusions: Congenital abnormalities or acquired injuries lead to intracranial communication with the outside world, which can quickly become a portal for bacterial invasion of the central nervous system, resulting in repeated infections.

Sirolimus treatment for tuberous sclerosis complex prior to epilepsy: Evidence from a registry-based real-world study.

OBJECTIVE: To evaluate whether sirolimus treatment could relieve the later burden of new-onset seizures in patients with tuberous sclerosis complex (TSC) prior to epilepsy. METHODS: A real-world matched case-control study was nested in another registry cohort study. Infants with TSC (<12 months old) without seizures whose parents agreed on sirolimus treatment for other symptoms were eligible for inclusion to the early sirolimus (ES) group. These patients were enrolled from 2015 to 2018. Controls in the late sirolimus (LS) group were matched from the registry cohort database for 2015-2018. Age and genotype were used as the initial stratifying criteria and other symptoms as the greedy matching criteria at a matching ratio of 1:4. None of the preventive drugs were introduced before seizure onset or before 2 years of age in the LS group. Both groups were followed up until June 2020. The primary objective was a comparison of the characteristics of the first seizure between the two groups. The secondary objective was the assessment of the final seizure status at the endpoint. RESULTS: There were 42 and 168 patients with TSC in the ES and LS groups, respectively. Early sirolimus treatment significantly reduced the seizure onset, especially in the patients aged <6 months. The mean onset-age was significantly delayed by sirolimus treatment (11.34±7.93 months vs. 6.94±6.03 months, P<0.001). The subtype of seizures that benefited the most was spastic (onset) seizures (all were infantile spasms) [5/42 (11.90%) vs. 73/168 (43.45%), P<0.001]; these seizures were either eliminated or alleviated. The sirolimus treatment addition prior to seizures was more effective than its addition after seizures in reducing drug-resistant epilepsy [10/42 (23.81%) vs. 70/147 (47.62%), P=0.004]. CONCLUSION: Early sirolimus treatment for TSC effectively modified the disease by preventing infantile spasms, delaying seizure onset, and relieving its severity. The anti-epileptogenic effect of sirolimus may be time- and dose-dependent.

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.

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.