Authors: Kingswood J.C., Belousova E., Benedik M.P., Carter T., Cottin V., Curatolo P., Dahlin M., D'Amato L., d'Augères G.B., de Vries P.J., Ferreira J.C., Feucht M., Fladrowski C., Hertzberg C., Jozwiak S., Lawson J.A., Macaya A., Marques R., Nabbout R., O'Callaghan F., Qin J., Sander V., Sauter M., Shah S., Takahashi Y., Touraine R., Youroukos S., Zonnenberg B., Jansen A.C., TOSCA Consortium and TOSCA Investigators.
Nephrol Dial Transplant. 2018 Apr 25. doi: 10.1093/ndt/gfy063.
Renal angiomyolipoma occurs at a high frequency in patients with tuberous sclerosis complex (TSC) and is associated with potentially life-threatening complications. Despite this frequency and severity, there are no large population-based cohort studies. Here we present baseline and follow-up data of the international TuberOus SClerosis registry to increase disease Awareness (TOSCA) with an aim to provide detailed clinical characteristics of renal angiomyolipoma among patients with TSC.
Patients of any age with a documented clinic visit for TSC within 12 months or who were newly diagnosed with TSC before participation in the registry were eligible. Data specific to renal angiomyolipoma included physical tumour characteristics (multiple, bilateral, lesion size and growing lesions), clinical signs and symptoms, and management. The effects of age, gender and genotype on the prevalence of renal angiomyolipoma were also evaluated.
Renal angiomyolipoma was reported in 51.8% of patients at baseline, with higher frequency in female patients (57.8% versus 42.2%). The median age at diagnosis was 12 years. Prevalence of angiomyolipoma was higher in patients with TSC2 compared with TSC1 mutations (59.2% versus 33.3%, P < 0.01). Of the 1031 patients with angiomyolipoma at baseline, multiple lesions were reported in 88.4% and bilateral in 83.9% of patients, while the size of angiomyolipoma was >3 cm in 34.3% of patients. Most patients were asymptomatic (82%). Frequently reported angiomyolipoma-related symptoms included bleeding, pain, elevated blood pressure and impaired renal function. Embolization and mammalian target of rapamycin inhibitors were the two most common treatment modalities.
The TOSCA registry highlights the burden of renal angiomyolipoma in patients with TSC and shows that renalmanifestations are initially asymptomatic and are influenced by gender and genotype. Furthermore, the occurrence of significant problems from angiomyolipoma in a minority of younger patients suggests that surveillance should begin in infancy or at initial diagnosis.
Authors: Drion C.M., van Scheppingen J., Arena A., Geijtenbeek K.W., Kooijman L., van Vliet E.A., Aronica E., Gorter J.A.
J neuroinflammation. 2018 Jul 23;15(1):212. doi: 10.1186/s12974-018-1247-9.
Previous studies in various rodent epilepsy models have suggested that mammalian target of rapamycin (mTOR) inhibition with rapamycin has anti-epileptogenic potential. Since treatment with rapamycin produces unwanted side effects, there is growing interest to study alternatives to rapamycin as anti-epileptogenic drugs. Therefore, we investigated curcumin, the main component of the natural spice turmeric. Curcumin is known to have anti-inflammatory and anti-oxidant effects and has been reported to inhibit the mTOR pathway. These properties make it a potential anti-epileptogenic compound and an alternative for rapamycin.
To study the anti-epileptogenic potential of curcumin compared to rapamycin, we first studied the effects of both compounds on mTOR activation, inflammation, and oxidative stress in vitro, using cell cultures of human fetal astrocytes and the neuronal cell line SH-SY5Y. Next, we investigated the effects of rapamycin and intracerebrally applied curcumin on status epilepticus (SE)-induced inflammation and oxidative stress in hippocampal tissue, during early stages of epileptogenesis in the post-electrical SE rat model for temporal lobe epilepsy (TLE).
Rapamycin, but not curcumin, suppressed mTOR activation in cultured astrocytes. Instead, curcumin suppressed the mitogen-activated protein kinase (MAPK) pathway. Quantitative real-time PCR analysis revealed that curcumin, but not rapamycin, reduced the levels of inflammatory markers IL-6 and COX-2 in cultured astrocytes that were challenged with IL-1β. In SH-SY5Y cells, curcumin reduced reactive oxygen species (ROS) levels, suggesting anti-oxidant effects. In the post-SE rat model, however, treatment with rapamycin or curcumin did not suppress the expression of inflammatory and oxidative stress markers 1 week after SE.
These results indicate anti-inflammatory and anti-oxidant properties of curcumin, but not rapamycin, in vitro. Intracerebrally applied curcumin modified the MAPK pathway in vivo at 1 week after SE but failed to produce anti-inflammatory or anti-oxidant effects. Future studies should be directed to increasing the bioavailability of curcumin (or related compounds) in the brain to assess its anti-epileptogenic potential in vivo.
Authors: de Vries P.J., Belousova E., Benedik M.P., Carter T., Cottin V., Curatolo P., Dahlin M., D'Amato L., d'Augères G.B., Ferreira J.C., Feucht M., Fladrowski C., Hertzberg C., Jozwiak S., Kingswood J.C., Lawson J.A., Macaya A., Marques R., Nabbout R., O'Callaghan F., Qin J., Sander V., Sauter M., Shah S., Takahashi Y., Touraine R., Youroukos S., Zonnenberg B., Jansen A.C., TOSCA Consortium and TOSCA Investigators.
Orphanet J Rare Dis. 2018 Sep 10;13(1):157. doi: 10.1186/s13023-018-0901-8.
Most evidence for TSC-associated neuropsychiatric disorders (TAND) to date have come from small studies and case reports, and very little is known about TAND in adults. We explored baseline TAND data from the large-scale international TOSCAnatural history study to compare childhood and adult patterns, describe age-based patterns, and explore genotype-TAND correlations.
The study enrolled 2216 eligible participants with TSC from 170 sites across 31 countries at the data cut-off for the third interim analysis (data cut-off date: September 30, 2015). The most common behavioural problems (reported in > 10% of participants) were overactivity, sleep difficulties, impulsivity, anxiety, mood swings, severe aggression, depressed mood, self-injury, and obsessions. Psychiatric disorders included autism spectrum disorder (ASD, 21.1%), attention deficit hyperactivity disorder (ADHD, 19.1%), anxiety disorder (9.7%), and depressive disorder (6.1%). Intelligence quotient (IQ) scores were available for 885 participants. Of these, 44.4% had normal IQ, while mild, moderate, severe, and profound degrees of intellectual disability (ID) were observed in 28.1, 15.1, 9.3, and 3.1%, respectively. Academic difficulties were identified in 58.6% of participants, and neuropsychological deficits (performance <5th percentile) in 55.7%. Significantly higher rates of overactivity and impulsivity were observed in children and higher rates of anxiety, depressed mood, mood swings, obsessions, psychosis and hallucinations were observed in adults. Genotype-TAND correlations showed a higher frequency of self-injury, ASD, academic difficulties and neuropsychological deficits in TSC2. Those with no mutations identified (NMI) showed a mixed pattern of TAND manifestations. Children and those with TSC2 had significantly higher rates of intellectual disability, suggesting that age and genotype comparisons should be interpreted with caution.
These results emphasize the magnitude of TAND in TSC and the importance of evaluating for neuropsychiatriccomorbidity in all children and adults with TSC, across TSC1 and TSC2 genotypes, as well as in those with no mutations identified. However, the high rates of unreported or missing TAND data in this study underline the fact that, even in expert centres, TAND remains underdiagnosed and potentially undertreated.
Authors: Curatolo P., Nabbout R., Lagae L., Aronica E., Ferreira J.C., Feucht M., Hertzberg C., Jansen A.C., Jansen F., Kotulska K., Moavero R., O'Callaghan F., Papavasiliou A., Tzadok M., Józwiak S.
Eur J Paediatr Neurol. 2018 Sep;22(5):738-748. doi: 10.1016/j.ejpn.2018.05.006
Patients with tuberous sclerosis complex (TSC) are at very high risk for developing epilepsy, and the majority experience seizure onset during the first year of life. Early targeted interventions increase the probability of seizure-freedom and may protect neurodevelopment. In 2012, clinicalrecommendations for the management of epilepsy in patients with TSC were published by a panel of European experts. Since that time novel studies, reports, and expert opinions in preclinical and clinical TSC-related sciences prompted the need for updatedrecommendations, including epileptogenesis in TSC, the potential role of predictive biomarkers, the possible benefits of presymptomatic diagnosis and preventive treatment, and new treatment options including mTOR inhibitors. A reconvened panel reviewed the current literature to answer specific questions and five panelists discussed the findings, followed by a general discussion during which all issues were debated to achieve consensus regarding recommendations. A draft manuscript based on these discussions and recommendations was then circulated several times among the panelists, who added their own comments. All the panelists/authors agreed with the final manuscript, which was then submitted for publication. The panel concluded that the need for early diagnosis of TSC-associated seizures is now established, electroencephalographic monitoring has good predictive value for epilepsy before seizure onset in TSC, and, until conclusive data from the EPISTOP trial are available, administration of vigabatrin may be considered in children with subclinical epileptiform EEG discharges. The panel also supported the role of adjunctive everolimus for TSC-associated drug-refractory seizures and emphasized the necessity of early surgical evaluation.
Authors: Curatolo P., Franz D.N., Lawson J.A., Yapici Z., Ikeda H., Polster T., Nabbout R., de Vries P.J., Dlugos D.J., Fan J., Ridolfi A., Pelov D., Voi M., French J.A.
Lancet Child Adolesc Health 2018 Jul;2(7):495-504. doi: 10.1016/S2352-4642(18)30099-3.
Epilepsy occurs in 70-90% of patients with tuberous sclerosis complex. We aimed to assess the efficacy and safety of adjunctive everolimus for treatment-refractory seizures associated with tuberous sclerosis complex in paediatric patients enrolled in the EXIST-3 trial, a double-blind, placebo-controlled, randomised, phase 3 study.
This post-hoc analysis focused on paediatric patients (age <18 years) in the EXIST-3 trial, which consisted of baseline (8 weeks), core (18 weeks), and extension phases (≥48 weeks) and was done at 99 centres in 25 countries worldwide. Briefly, patients with tuberous sclerosis complex-associated treatment-refractory seizures, who were receiving a stable dose of one to three antiepileptic drugs, were randomly assigned (1:1:1) to receive placebo, low-exposure everolimus (3-7 ng/mL), or high-exposure everolimus (9-15 ng/mL). Following the core phase, patients could enter the extension phase to receive everolimus at a targeted exposure range of 3-15 ng/mL up to 48 weeks after the last patient had completed the core phase. Efficacy endpoints were response rate (≥50% of reduction from baseline in average weekly seizure frequency) and median percentage reduction in seizure frequency during the 12-week maintenance period of the core phase, and at 12-week intervals throughout the extension phase. This study is registered with ClinicalTrials.gov, number NCT01713946.
Between July 3, 2013, and May 29, 2015, 299 paediatric patients enrolled in the trial. In the younger subgroup (<6 years; n=104), 34 received placebo, 33 low-exposure everolimus, and 37 high-exposure everolimus; in the older subgroup (≥6 years to <18 years; n=195), 62 received placebo, 63 low-exposure everolimus, and 70 high-exposure everolimus. At the end of the core phase, response rate was higher in the treatment groups than placebo in both the younger subgroup (17·6% [6·8-34·5] for placebo vs 30·3% [95% CI 15·6-48·7; p=0·2245] for low-exposure everolimus vs 59·5% [42·1-75·2; p=0·0003] for high-exposure everolimus) and the older subgroup (12·9% [5·7-23·9] vs 27·0% [16·6-39·7; p=0·0491] vs 30·0% [19·6-42·1; p=0·0179]), as were median reduction in seizure frequency (12·3% [95% CI -10·1 to 24·8] vs 29·3% [95% CI 13·4 to 46·3; p=0·0474] vs 54·7% [43·5 to 73·1; p<0·0001] in younger patients; 13·5% [-3·0 to 26·8] vs 31·0% [16·1 to 42·9; p=0·0128] vs 34·8% [26·7 to 41·3; p=0·0006] in older patients). The efficacy persisted, with sustained seizure reduction after 1 year of treatment across both paediatric subgroups (response rate 48·9% [95% CI 38·1-59·8] for the younger subgroup vs 47·2% [39·3-55·2] for the older subgroup; median percentage reduction in seizure frequency 48·4% [95% CI 34·3-73·6] vs 48·0% [38·2-57·5]). At the cutoff date for the extension phase, grade 3 or 4 adverse events were reported in 45 (45%) younger patients (commonly pneumonia [n=16]) and 74 (38%) older patients (commonly pneumonia [n=8] and stomatitis [n=6]). Two deaths (pneumonia, which was suspected to be treatment-related, and sudden unexplained death due to epilepsy) were reported.
Adjunctive everolimus resulted in sustained reductions in seizure frequency after 1 year and was well tolerated in paediatric patients with treatment-refractory seizures associated with tuberous sclerosis complex.
Novartis Pharmaceuticals Corporation.