A novel rapamycin cream formulation improves facial angiofibromas associated with tuberous sclerosis complex: a double-blind randomized placebo-controlled trial.

BACKGROUND: Facial angiofibromas (FAs) are a major feature of tuberous sclerosis complex (TSC). Topical rapamycin can successfully treat FAs. A new stabilized cream formulation that protects rapamycin from oxidation has been developed in 0.5% and 1% concentrations. OBJECTIVES: To assess the efficacy and safety of a novel, stabilized topical rapamycin cream formulation. METHODS: This multicentre double-blind randomized placebo-controlled dose-response phase II/III study with a parallel design included participants aged 6-65 years with FAs of mild or moderate severity according to the Investigator's Global Assessment (IGA) scale. Participants were randomized to one of three treatment arms: topical rapamycin 0.5%, topical rapamycin 1% or placebo. Treatment was applied once daily for 26 weeks. Safety and efficacy measures were assessed at days 14, 56, 98, 140 and 182. The primary endpoint was the percentage of participants achieving IGA scores of 'clear' or 'almost clear' after 26 weeks of treatment. Secondary measures included Facial Angiofibroma Severity Index (FASI) and participant- and clinician-reported percentage-based improvement. Safety measures included the incidence of treatment-emergent adverse events and blood rapamycin concentration changes over time. RESULTS: Participants (n = 107) were randomized to receive either rapamycin 1% (n = 33), rapamycin 0.5% (n = 36) or placebo (n = 38). All treated participants were included in the final analysis. The percentage of participants with a two-grade IGA improvement was greater in the rapamycin 0.5% treatment group (11%) and rapamycin 1% group (9%) than in the placebo group (5%). However, this was not statistically significant [rapamycin 0.5%: odds ratio (OR) 1.71, 95% confidence interval (CI) 0.36-8.18 (P = 0.50); rapamycin 1%: OR 1.68, 95% CI 0.33-8.40 (P = 0.53)]. There was a statistically significant difference in the proportion of participants treated with rapamycin cream that achieved at least a one-grade improvement in IGA [rapamycin 0.5%: 56% (OR 4.73, 95% CI 1.59-14.10; P = 0.005); rapamycin 1%: 61% (OR 5.14, 95% CI 1.70-15.57; P = 0.004); placebo: 24%]. Skin adverse reactions were more common in patients following rapamycin application (64%) vs. placebo (29%). CONCLUSIONS: Both rapamycin cream formulations (0.5% and 1%) were well tolerated, and either strength could lead to clinical benefit in the treatment of FA.

The genomic landscape of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare genetic disease causing multisystem growth of benign tumours and other hamartomatous lesions, which leads to diverse and debilitating clinical symptoms. Patients are born with TSC1 or TSC2 mutations, and somatic inactivation of wild-type alleles drives MTOR activation; however, second hits to TSC1/TSC2 are not always observed. Here, we present the genomic landscape of TSC hamartomas. We determine that TSC lesions contain a low somatic mutational burden relative to carcinomas, a subset feature large-scale chromosomal aberrations, and highly conserved molecular signatures for each type exist. Analysis of the molecular signatures coupled with computational approaches reveals unique aspects of cellular heterogeneity and cell origin. Using immune data sets, we identify significant neuroinflammation in TSC-associated brain tumours. Taken together, this molecular catalogue of TSC serves as a resource into the origin of these hamartomas and provides a framework that unifies genomic and transcriptomic dimensions for complex tumours.

Oxcarbazepine use in paroxysmal kinesigenic dyskinesia: report on four patients.

The paroxysmal dyskinesias are a heterogeneous group of movement disorders. They are distinguished from one another by the mechanism through which abnormal movements are induced. Paroxysmal kinesigenic dyskinesia is the most common subtype, consisting of involuntary dyskinesias induced by purposeful movements. It typically responds favorably to anticonvulsants. This retrospective review describes four unrelated children and adolescents with idiopathic paroxysmal kinesigenic dyskinesia who were treated with oxcarbazepine. Each patient achieved complete resolution of signs with low-dose oxcarbazepine monotherapy.

Effects of sleep deprivation on the pediatric electroencephalogram.

BACKGROUND: The routine electroencephalogram aids in epilepsy syndrome diagnosis. Unfortunately, routine outpatient electroencephalogram results are normal in roughly half of children with epilepsy. To increase the yield, practice guidelines recommend electroencephalograms with sleep and sleep deprivation. The purpose of this study was to rigorously evaluate this recommendation in children. METHODS: We conducted a randomized, blinded comparison of routine electroencephalograms versus sleep-deprived electroencephalograms in 206 children aged 0 to 18 years. Electroencephalograms were ordered for standard indications after a neurologist's clinical assessment indicated > or =1 seizure (83%) or unclear spell (17%). The primary outcome was the proportion of normal routine electroencephalogram results versus sleep-deprived electroencephalogram results. Logistic regression modeling was used to assess the influence of sleep, as well as other clinical factors. RESULTS: Although children with sleep-deprived electroencephalograms had less sleep the night before (4.9 vs 7.9 hours) and more sleep during electroencephalograms (73% vs 55%), the increase in electroencephalogram yield was borderline significant (56% normal sleep-deprived electroencephalogram versus 68% normal routine electroencephalogram). Moreover, sleep during the electroencephalogram did not increase its diagnostic yield. Sleep-deprived electroencephalogram yield tended to be higher in children with preelectroencephalogram clinical diagnosis of seizure(s) and at older ages (>3 years). CONCLUSIONS: Sleep deprivation, but not sleep during the electroencephalogram, modestly increases the yield of the electroencephalogram in children diagnosed with seizures by neurologists. Compared with a routine electroencephalogram, the number needed to test with sleep-deprived electroencephalogram to identify 1 additional child with epileptiform discharges is approximately 11.

Peripheral neuropathy in cardiofaciocutaneous syndrome.

A young adult male with cardiofaciocutaneous syndrome developed gait deterioration in childhood, with later evolution of distal wasting. His physical examination revealed intention tremor, distal weakness of the upper limbs with atrophy of the thenar, hypothenar, and interossei muscles, a wide-based gait, and large-fiber sensory loss in all limbs. Neuroimaging revealed stable mild chronic communicating hydrocephalus. Nerve conduction studies and electromyography demonstrated a moderately severe axonal neuropathy. The present case is, to our knowledge, the first reported case of peripheral neuropathy in association with cardiofaciocutaneous syndrome. The latter is a rare disorder, with significant comorbidities, in which a peripheral neuropathy may be under-recognized as a late cause of functional deterioration.