Autism is more common in people with epilepsy, approximately 20%, and epilepsy is more common in people with autism with reported rates of approximately 20%. However, these figures are likely to be affected by the current broader criteria for autism spectrum disorder (ASD), which have contributed to an increased prevalence of autism, with the result that the rate for ASD in epilepsy is likely to be higher and the figure for epilepsy in ASD is likely to be lower. Some evidence suggests that there are two peaks of epilepsy onset in autism, in infancy and adolescence. The rate of autism in epilepsy is much higher in those with intellectual disability. In conditions such as the Landau-Kleffner syndrome and nonconvulsive status epilepticus, the epilepsy itself may present with autistic features. There is no plausible mechanism for autism causing epilepsy, however. The co-occurrence of autism and epilepsy is almost certainly the result of underlying factors predisposing to both conditions, including both genetic and environmental factors. Conditions such as attention deficit hyperactivity disorder, anxiety and sleep disorders are common in both epilepsy and autism. Epilepsy is generally not a contraindication to treating these conditions with suitable medication, but it is important to take account of relevant drug interactions. One of the greatest challenges in autism is to determine why early childhood regression occurs in perhaps 25%. Further research should focus on finding the cause for such regression. Whether epilepsy plays a role in the regression of a subgroup of children with autism who lose skills remains to be determined.

/pdf/epilepsy-in-patients-with-autism-links-risks-and-treatment-1kex87o14s.pdf

Epilepsy in patients with autism: links, risks and treatment challenges.

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

The mechanistic target of rapamycin (mTOR) integrates both intracellular and extracellular signals to regulate cell growth and metabolism. However, the role of mTOR signaling in osteoblast differentiation and bone formation is undefined, and the underlying mechanisms have not been elucidated. Here, we report that activation of mTOR complex 1 (mTORC1) is required for preosteoblast proliferation; however, inactivation of mTORC1 is essential for their differentiation and maturation. Inhibition of mTORC1 prevented preosteoblast proliferation, but enhanced their differentiation in vitro and in mice. Activation of mTORC1 by deletion of tuberous sclerosis 1 (Tsc1) in preosteoblasts produced immature woven bone in mice due to excess proliferation but impaired differentiation and maturation of the cells. The mTORC1-specific inhibitor, rapamycin, restored these in vitro and in vivo phenotypic changes. Mechanistically, mTORC1 prevented osteoblast maturation through activation of the STAT3/p63/Jagged/Notch pathway and downregulation of Runx2. Preosteoblasts with hyperactive mTORC1 reacquired the capacity to fully differentiate and maturate when subjected to inhibition of the Notch pathway. Together, these findings identified the role of mTORC1 in osteoblast formation and established that mTORC1 prevents preosteoblast differentiation and maturation through activation of the Notch pathway.

/pdf/mtorc1-prevents-preosteoblast-differentiation-through-the-qfeddjo24w.pdf

mTORC1 Prevents Preosteoblast Differentiation through the Notch Signaling Pathway

Focal cortical dysplasia (FCD), a local malformation of cortical development, is the most common cause of pharmacoresistant epilepsy associated with life-long neurocognitive impairments. It remains unclear whether neuronal misplacement is required for seizure activity. Here we show that dyslamination and white matter heterotopia are not necessary for seizure generation in a murine model of type II FCDs. These experimental FCDs generated by increasing mTOR activity in layer 2/3 neurons of the medial prefrontal cortex are associated with tonic-clonic seizures and a normal survival rate. Preventing all FCD-related defects, including neuronal misplacement and dysmorphogenesis, with rapamycin treatments from birth eliminates seizures, but seizures recur after rapamycin withdrawal. In addition, bypassing neuronal misplacement and heterotopia using inducible vectors do not prevent seizure occurrence. Collectively, data obtained using our new experimental FCD-associated epilepsy suggest that life-long treatment to reduce neuronal dysmorphogenesis is required to suppress seizures in individuals with FCD.

/pdf/convulsive-seizures-from-experimental-focal-cortical-3z5lbytmnq.pdf

Convulsive seizures from experimental focal cortical dysplasia occur independently of cell misplacement

Background
Previous studies have shown potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex. Although everolimus (a rapalog) is currently approved by the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency) for tuberous sclerosis complex-associated renal angiomyolipoma and subependymal giant cell astrocytoma, applications for other manifestations of tuberous sclerosis complex have not yet been established. A systematic review is necessary to establish the clinical value of rapamycin or rapalogs for various manifestations in tuberous sclerosis complex.

Objectives
To determine the effectiveness of rapamycin or rapalogs in people with tuberous sclerosis complex for decreasing tumour size and other manifestations and to assess the safety of rapamycin or rapalogs in relation to their adverse effects.

Search methods
Relevant studies were identified by authors from the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, and clinicaltrials.gov. Relevant resources were also searched by the authors, such as conference proceedings and abstract books of conferences, from e.g. the Tuberous Sclerosis Complex International Research Conferences, other tuberous sclerosis complex-related conferences and the Human Genome Meeting. We did not restrict the searches by language as long as English translations were available for non-English reports.

Date of the last searches: 14 March 2016.

Selection criteria
Randomized or quasi-randomized studies of rapamycin or rapalogs in people with tuberous sclerosis complex.

Data collection and analysis
Data were independently extracted by two authors using standard acquisition forms. The data collection was verified by one author. The risk of bias of each study was independently assessed by two authors and verified by one author.

Main results
Three placebo-controlled studies with a total of 263 participants (age range 0.8 to 61 years old, 122 males and 141 females, with variable lengths of study duration) were included in the review. We found high-quality evidence except for response to skin lesions which was judged to be low quality due to the risk of attrition bias. Overall, there are 175 participants in the treatment arm (rapamycin or everolimus) and 88 in the placebo arm. Participants all had tuberous sclerosis complex as proven by consensus diagnostic criteria as a minimum. The quality in the description of the study methods was mixed, although we assessed most domains as having a low risk of bias. Blinding of treatment arms was successfully carried out in all of the studies. However, two studies did not report allocation concealment. Two of the included studies were funded by Novartis Pharmaceuticals.

Two studies (235 participants) used oral (systemic) administration of everolimus (rapalog). These studies reported response to tumour size in terms of the number of individuals with a reduction in the total volume of tumours to 50% or more relative to baseline. Significantly more participants in the treatment arm (two studies, 162 participants, high quality evidence) achieved a 50% reduction in renal angiomyolipoma size, risk ratio 24.69 (95% confidence interval 3.51 to 173.41) (P = 0.001). For the sub-ependymal giant cell astrocytoma, our analysis of one study (117 participants, high quality evidence) showed significantly more participants in the treatment arm achieved a 50% reduction in tumour size, risk ratio 27.85 (95% confidence interval 1.74 to 444.82) (P = 0.02). The proportion of participants who showed a skin response from the two included studies analysed was significantly increased in the treatment arms, risk ratio 5.78 (95% confidence interval 2.30 to 14.52) (P = 0.0002) (two studies, 224 participants, high quality evidence). In one study (117 participants), the median change of seizure frequency was -2.9 in 24 hours (95% confidence interval -4.0 to -1.0) in the treatment group versus -4.1 in 24 hour (95% confidence interval -10.9 to 5.8) in the placebo group. In one study, one out of 79 participants in the treatment group versus three of 39 in placebo group had increased blood creatinine levels, while the median percentage change of forced expiratory volume at one second in the treatment arm was -1% compared to -4% in the placebo arm. In one study (117 participants, high quality evidence), we found that those participants who received treatment had a similar risk of experiencing adverse events compared to those who did not, risk ratio 1.07 (95% confidence interval 0.96 - 1.20) (P = 0.24). However, as seen from two studies (235 participants, high quality evidence), the treatment itself led to significantly more adverse events resulting in withdrawal, interruption of treatment, or reduction in dose level, risk ratio 3.14 (95% confidence interval 1.82 to 5.42) (P < 0.0001).

One study (28 participants) used topical (skin) administration of rapamycin. This study reported response to skin lesions in terms of participants' perception towards their skin appearance following the treatment. There was a tendency of an improvement in the participants' perception of their skin appearance, although not significant, risk ratio 1.81 (95% confidence interval 0.80 to 4.06, low quality evidence) (P = 0.15). This study reported that there were no serious adverse events related to the study product and there was no detectable systemic absorption of the rapamycin during the study period.

Authors' conclusions
We found evidence that oral everolimus significantly increased the proportion of people who achieved a 50% reduction in the size of sub-ependymal giant cell astrocytoma and renal angiomyolipoma. Although we were unable to ascertain the relationship between the reported adverse events and the treatment, participants who received treatment had a similar risk of experiencing adverse events as compared to those who did not receive treatment. Nevertheless, the treatment itself significantly increased the risk of having dose reduction, interruption or withdrawal. This supports ongoing clinical applications of oral everolimus for renal angiomyolipoma and subependymal giant cell astrocytoma. Although oral everolimus showed beneficial effect on skin lesions, topical rapamycin only showed a non-significant tendency of improvement. Efficacy on skin lesions should be further established in future research. The beneficial effects of rapamycin or rapalogs on tuberous sclerosis complex should be further studied on other manifestations of the condition.

/pdf/rapamycin-and-rapalogs-for-tuberous-sclerosis-complex-elfkbst5c2.pdf

Rapamycin and rapalogs for tuberous sclerosis complex

Purpose Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the formation of hamartomas in various organ systems. We would like share our experience from 86 patients and the results of rapamycin treatment in seven children with TSC. Methods Eighty-six children with TSC were enrolled into this retrospective study. The clinical features of seven children treated with oral rapamycin were presented in detail. Results The most common complaint of administration was convulsion in 77 children (89.5 %). Hypopigmented skin lesions, adenoma sebaceum, resistant epilepsy, intracardiac mass, renal angiomyolipomas, and West syndrome were detected (n = 83, 96.5 %; n = 47, 54.7 %; n = 36, 41.9 %; n = 27, 31.4 %; n = 18, 20.9 %; and n = 13, 15.1 %, respectively). Subependymal nodules were the most frequent finding in cranial imaging followed by cortical tubers and subependymal giant cell astrocytomas (n = 75, 87.2 %; n = 71, 82.6 %; and n =8 , 9.3 %, respectively). Of the seven patients treated with rapamycin, the lesions of six children with facial adenoma sebaceum showed regression in various degrees. The frequency of convulsions decreased in five patients with resistant epilepsy within the first 6 months of the treatment, and complete control of convulsion for all patients was achieved in the second 6 months. Conclusion This is the first study that showed that rapamycin is an effective agent for controlling epilepsy without any significant sideeffectinchildrenwithTSC. Rapamycin seems to be effective after 6 months of therapy, and we recommend tapering the dosage after successful management of epilepsy.

Levent Cinar

Papers

Rapamycin has a beneficial effect on controlling epilepsy in children with tuberous sclerosis complex: results of 7 children from a cohort of 86