Seizures In Tuberous Sclerosis Complex Research Articles

Long-term Effectiveness of Cannabidiol (CBD) Against Focal Seizures in Tuberous Sclerosis Complex (TSC): Results from the GWPCARE6 Open-label Extension (OLE) Trial (P8-1.001)

Long-term Effectiveness of Cannabidiol (CBD) Against Focal Seizures in Tuberous Sclerosis Complex (TSC): Results from the GWPCARE6 Open-label Extension (OLE) Trial (P8-1.001)

The use of cannabinoid compounds in therapy in children - future or threat?

Introduction and objective:
 Therapy with the use of "medical marijuana" is becoming more and more popular with patients, who often perceive it as a more natural and safe form of treatment. It is also more and more boldly considered by physicians in the pediatric population, especially when standard methods of pharmacotherapy prove insufficient. The following review focuses on the possibilities of using cannabis preparations in children with drug-resistant epilepsy, autism spectrum disorders and spasticity. It also draws attention to the possible side effects and risks of unjustified use of medical marijuana.
 State of knowledge:
 In the pediatric population, high efficacy and a favorable safety profile have been proven so far in the treatment of epileptic seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, and for the treatment of epileptic seizures in tuberous sclerosis complex, (TSC) . Although the therapy has been approved only for the above-mentioned indications, high hopes are also placed on the use of cannabinoids to treat the symptoms of other diseases and disorders, including spasticity and autism spectrum disorders.
 Conclusions:
 The research carried out so far gives hope for the possibility of using medical marijuana in other indications as well, as its use correlates with the reduction of i.a. symptoms of spasticity or autism spectrum disorders. At the same time, further studies are needed to assess the balance of benefits and potential risks of the therapy. Since recreational cannabis use in youth is known to be associated with serious adverse events, and medical cannabis use has a relatively strong placebo effect, decisions about its use should always be made carefully and based on scientific evidence.

Inhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a monogenic disorder characterized by hyperactivation of the mTOR signaling pathway and developmental brain malformations leading to intractable epilepsy. Although treatment with the recently approved mTOR inhibitor, everolimus, results in clinically relevant seizure suppression in up to 40% of TSC patients, seizures remain uncontrolled in a large number of cases, underscoring the need to identify novel treatment targets. The MEK-ERK signaling pathway has been found to be aberrantly activated in TSC and inhibition of MEK-ERK activity independently of mTOR rescued neuronal dendrite overgrowth in mice modeling TSC neuropathology. Here, we evaluated the efficacy of MEK-ERK inhibition on seizures in two mouse models of TSC. We found that treatment with the MEK inhibitor PD0325901 (mirdametinib) significantly reduced seizure activity in both TSC mouse models. These findings support inhibiting MEK-ERK activity as a potential alternative strategy to treat seizures in TSC.

Pharmacotherapy for Seizures in Tuberous Sclerosis Complex.

Epilepsy is one of the main symptoms affecting the lives of individuals with tuberous sclerosiscomplex (TSC), causing a high rate of morbidity. Individuals with TSC can present with various types of seizures, epilepsies, and epilepsy syndromes that can coexist or appear in relation to age. Focal epilepsy is the most frequent epilepsy typewith two developmental and epileptic encephalopathies: infantile spasms syndrome and Lennox-Gastaut syndrome. Active screening and early management of epilepsy is recommended in individuals with TSC to limit its consequences and its impact on quality of life,cognitive outcome and the economic burden of the disease. The progress in the knowledge of the mechanisms underlying epilepsy in TSC has paved the way for new concepts in the management of epilepsy related to TSC. In addition, we are moving from traditional "reactive" and therapeutic choices with current antiseizure medications used after the onset of seizures, to a proactive approach, aimed at predicting and preventing epileptogenesis and the onset of epilepsy with vigabatrin, and to personalized treatments with mechanistic therapies, namely mechanistic/mammalian target of rapamycin inhibitors. Indeed, epilepsy linked to TSC is one of the only epilepsies for which a predictive and preventive approach can delay seizure onset and improve seizure response. However, the efficacy of such interventions on long-term cognitive and psychiatric outcomes is still under investigation.

Abstract 293: Second-generation tricyclic pyrimido-pyrrolo-oxazine mTOR inhibitors suitable for the treatment of CNS disorders

Abstract Mechanistic target of rapamycin (mTOR) is activated downstream of phosphoinositide 3-kinase (PI3K), and is dysregulated in cancer and neurological disorders.[1,2] Tuberous Sclerosis Complex (TSC) is a genetic disease caused by TSC gene inactivation, where TSC loss of function leads to the hyperactivation of mTOR signaling. TSC is characterized by hyperplastic lesions in multiple organs, and in ~90% of patients it affects the brain causing epilepsy. Rapalogs have recently been explored to alleviate epileptic seizures in TSC[3], however a limited clinical success has been reported. Crossing the blood-brain barrier (BBB) opens up a new challenge in the development of highly selective mTOR inhibitors (TORKi) that could be applied in the treatment of CNS disorders.[4-7] Very recently, we have disclosed a conformational restriction strategy to explore a novel chemical space for TORKi. A first-generation highly selective tricyclic compounds had been developed, but they displayed a limited brain penetration.[8] Herein, we discovered the first pyrimido-pyrrolo-oxazine derivative with predicted BBB permeability using an CRISPR-Cas9 engineered MDCK in vitro assay containing only the human homolog of the P-gp protein[9]. An extensive exploration of the heteroaromatic ring engaging the binding affinity region in mTOR kinase was performed, and chemical moieties, including 3-CF3-substituted pyridine, thiazole and 1,3,4-thiadiazole, have been identified as building blocks providing exquisite mTOR selectivity. Computational modelling studies revealed that the 3-trifluoromethyl group is well accommodated in mTOR, while it induces a steric clash with Lys802 and Asp933 in PI3Kα, highlighting the possibility to further exploit this heteroaromatic ring in the development of highly selective mTOR inhibitors. In MDCK assays, compound 11 showed an excellent passive permeability and was not a human P-gp substrate. Our results pave the way for the application of second-generation tricyclic derivatives in the treatment of neurological disorders and epilepsy. [1] Rageot D. et al. J Med Chem. 2018, 61 (22), 10084-10105 [2] Tarantelli C. et al. Cancers (Basel) 2019, 11 (6), 775. [3] Krueger DA. et al. Neurology 2016, 87, 2408-2415. [4] Singer E. et al. Neuropharmacology 2020, 162, 107812. [5] Brandt C. et al. Neuropharmacology 2018, 140, 107-120. [6] Theilmann W. et al. Neuropharmacology 2020, 180, 108297 [7] Borsari C. et al. J Med Chem. 2020 [ahead of print] doi: 10.1021/acs.jmedchem.0c00620. [8] Borsari C. et al. J Med Chem. 2019, 62 (18), 8609-8630. [9] Karlgren M et al. Drug Metab Dispos. 2018, 46 (11), 1776-1786. Citation Format: Chiara Borsari, Erhan Keles, Andrea Treyer, Martina De Pascale, Paul Hebeisen, Matthias Hamburger, Matthias P. Wymann. Second-generation tricyclic pyrimido-pyrrolo-oxazine mTOR inhibitors suitable for the treatment of CNS disorders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 293.

The Effect of Everolimus on Subependymal Giant Cell Astrocytoma (SEGA) in Children with Tuberous Sclerosis Complex.

Objective:Subependymal Giant Cell Astrocytomas (SEGAs) are slow-growing glioneuronal tumors typically found around the ventricles of the brain, particularly near the foramen of Monro in 15%-20% of patients with tuberous sclerosis complex (TSC). Surgical resection is the standard treatment for these symptomatic tumors. The mTOR inhibitor everolimus can be regarded as an alternative treatment for SEGAs due to the complications of surgery. The present study primarily aimed to specify the effect of everolimus on SEGA volume change before and after treatment. The secondary objective was to determine the effect of this drug on renal angiomyolipoma (AML), skin lesions, and seizures in TSC patients. Materials & Methods:This pre- and post-treatment clinical trial was performed on 14 children (eight females and six males with a mean age of 10 years) previously diagnosed with TSC based on the diagnostic criteria. The subjects received oral everolimus at a dose of 3 mg/m2 for at least six months. Results:Half of the patients had more than 30% of volume loss in SEGA, and in 28.5% of them, a ≥ 50% reduction in SEGA volume was observed (P=0.01). Moreover, 92.9% of the patients had a ≥ 50% decrease in the frequency of seizures (P=0.000). The response rate in AML and skin lesions was 14.2% and 50%, respectively. Conclusion:Everolimus significantly reduced the seizure frequency and SEGA volume in the subjects; hence, it can be used as a potential alternative treatment for symptomatic SEGA in TSC patients.

Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial.

ObjectiveEpilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants.MethodsIn this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open‐label trial (OLT). Subjects were followed until 2 years of age. The primary endpoint was the time to first clinical seizure.ResultsIn 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty‐seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364 days (95% confidence interval [CI] = 223–535) vs 124 days (95% CI = 33–149); OLT: 426 days (95% CI = 258–628) vs 106 days (95% CI = 11–149)]. At 24 months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug‐resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p < 0.001). No adverse events related to preventive treatment were noted.InterpretationPreventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 2021;89:304–314

4-(Difluoromethyl)-5-(4-((3R,5S)-3,5-dimethylmorpholino)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)pyridin-2-amine (PQR626), a Potent, Orally Available, and Brain-Penetrant mTOR Inhibitor for the Treatment of Neurological Disorders.

The mechanistic target of rapamycin (mTOR) pathway is hyperactivated in cancer and neurological disorders. Rapalogs and mTOR kinase inhibitors (TORKi) have recently been applied to alleviate epileptic seizures in tuberous sclerosis complex (TSC). Herein, we describe a pharmacophore exploration to identify a highly potent, selective, brain penetrant TORKi. An extensive investigation of the morpholine ring engaging the mTOR solvent exposed region led to the discovery of PQR626 (8). 8 displayed excellent brain penetration and was well-tolerated in mice. In mice with a conditionally inactivated Tsc1 gene in glia, 8 significantly reduced the loss of Tsc1-induced mortality at 50 mg/kg p.o. twice a day. 8 overcomes the metabolic liabilities of PQR620 (52), the first-in-class brain penetrant TORKi showing efficacy in a TSC mouse model. The improved stability in human hepatocytes, excellent brain penetration, and efficacy in Tsc1GFAPCKO mice qualify 8 as a potential therapeutic candidate for the treatment of neurological disorders.

Abstract 665: Discovery and preclinical characterization of PQR626: A potent, orally available, and brain-penetrant mTOR inhibitor for the treatment of tuberous sclerosis complex

Abstract Mechanistic target of rapamycin (mTOR), a key player in cell proliferation, growth and survival, is overactivated in tumors and neurological disorders.[1] Rapalogs have recently been explored to alleviate epileptic seizures in Tuberous Sclerosis Complex (TSC).[2] Herein, we combined pharmacophore features of PQR620[3], the first-in-class brain penetrant ATP-competitive mTOR kinase inhibitor showing efficacy in a TSC mouse model, and PQR617[4], a potent, highly selective mTOR inhibitor. An extensive chemical exploration of the morpholine ring led to the discovery of PQR626, a highly potent, selective, brain penetrant inhibitor of mTORC1/2 kinase. In male Sprague Dawley rats and female C57BL/6J mice, PQR626 displayed an excellent brain penetration compared to everolimus, which possessed a limited ability to cross the blood-brain-barrier (brain/plasma levels ~ 1.4:1 vs 1:92). An additional pharmacokinetic comparative study with everolimus and AZD2014 confirmed the superiority of PQR626 [brain/plasma levels: ~ 1:25 (AZD2014), ~ 1:61 (everolimus), ~ 1.8:1 (PQR626)]. PQR626 showed very good tolerability in mice (MTD 100-150 mg/kg). Efficacy studies, using mice with conditional inactivation of the Tsc1 gene primarily in glia (Tsc1GFAPCKO mice), were performed in a dose-range finding study. PQR626 (50 mg/kg, BID - twice a day) showed a significant effect on survival and significantly prevented/decreased mortality as compared to the vehicle. On the basis of its favorable pharmacological parameters, excellent brain penetration, safety profile and efficacy in Tsc1GFAPCKO mice, PQR626 qualifies as a novel mTOR inhibitor with potential application in the treatment of epilepsy and neurological disorders. [1] Wymann M. P. and Schneiter R. Nat. Rev. Mol. Cell Biol. 2008, 9, 162-176. [2] Krueger D. A. et. al. Neurology 2016, 87, 2408-2415. [3] Rageot D. et. al. J Med Chem. 2018, 61 (22), 10084-10105. [4] Borsari C. et. al. J Med Chem. 2019, 62 (18), 8609-8630. Citation Format: Chiara Borsari, Erhan Keles, Denise Rageot, Anna Melone, Thomas Bohnacker, Lucinda Kate Batchelor, Martina De Pascale, Paul Hebeisen, Petra Hillmann, Doriano Fabbro, Matthias Wymann. Discovery and preclinical characterization of PQR626: A potent, orally available, and brain-penetrant mTOR inhibitor for the treatment of tuberous sclerosis complex [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 665.

Early developmental electroencephalography abnormalities, neonatal seizures, and induced spasms in a mouse model of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is one of the most common genetic causes of epilepsy. Seizures in TSC typically first present in infancy or early childhood, including focal seizures and infantile spasms. Infantile spasms in TSC are particularly characteristic in its strong responsiveness to vigabatrin. Although a number of mouse models of epilepsy in TSC have been described, there are very limited electroencephalographic (EEG) or seizure data during the preweanling neonatal and infantile-equivalent mouse periods. Tsc1GFAP CKO mice are a well-characterized mouse model of epilepsy in TSC, but whether these mice have seizures during early development has not been documented. The objective of this study was to determine whether preweanling Tsc1GFAP CKO mice have developmental EEG abnormalities or seizures, including spasms. Longitudinal video-EEG and electromyographic recordings were performed serially on Tsc1GFAP CKO and control mice from postnatal days 9-21 and analyzed for EEG background abnormalities, sleep-wake vigilance states, and spontaneous seizures. Spasms were also induced with varying doses of N-methyl-D-aspartate (NMDA). The interictal EEG of Tsc1GFAP CKO mice had excessive discontinuity and slowing, suggesting a delayed developmental progression compared with control mice. Tsc1GFAP CKO mice also had increased vigilance state transitions and fragmentation. Tsc1GFAP CKO mice had spontaneous focal seizures in the early neonatal period and a reduced threshold for NMDA-induced spasms, but no spontaneous spasms were observed. Neonatal Tsc1GFAP CKO mice recapitulate early developmental aspects of EEG abnormalities, focal seizures, and an increased propensity for spasms. This mouse model may be useful for early mechanistic and therapeutic studies of epileptogenesis in TSC.

Update on Drug Management of Refractory Epilepsy in Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a genetic neurocutaneous disorder with epilepsy as a common and early presenting symptom. The neurological phenotype, however, is variable and unpredictable. Early and refractory seizures, infantile spasms in particular, are associated with a poor neurological outcome. Preliminary data suggests early and aggressive seizure control may mitigate the detrimental neurodevelopmental effects of epilepsy. For infantile spasms, vigabatrin is the first line of treatment, and steroids and classic antiepileptic drugs (AEDs) are suitable for second line. Based on retrospective data, vigabatrin should be considered for other indications, especially in infants with focal seizures, as this may prevent infantile spasms, but also in children and adults with epileptic spasms and tonic seizures. Otherwise, for most seizure types, treatment is similar to that for patients without TSC, including the use of novel AEDs, although limited data are available. Three major developments are changing the field of epilepsy management in TSC. First, final recommendations on preventive treatment with vigabatrin will result from two multicenter trials in the US (PREVeNT, clinicaltrials.gov #NCT02849457) and Europe (EPISTOP, clinicaltrials.gov #NCT02098759). Second, treatment with everolimus, an inhibitor of the mechanistic target of rapamycin (mTOR), reduced seizures when compared to placebo. Further, mTOR inhibitors may have an overall disease-modifying effect. Third, the role of cannabidiol in the treatment of refractory seizures in TSC is yet to be established. With treatment recommendations in TSC, we keep an eye on the prize for the broader field of pediatric epilepsy: the lessons learned from TSC are likely applicable to other epileptic encephalopathies.

The Efficacy of Everolimus for Refractory Seizures in Childhood Onset Epilepsy with Tuberous Sclerosis Complex

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor that has cytoreductive effects on subependymal giant cell astrocytoma and renal angiomyolipoma in tuberous sclerosis complex (TSC). Recent studies have also shown its efficacy against refractory seizures in TSC. We investigated the efficacy of everolimus in nine patients with TSC, who were admitted to the TSC clinic in Seirei Hamamatsu General Hospital and who suffered from refractory seizures. At the start of treatment, patients ranged from 1 month to 23 years of age, and were refractory to a mean of 5.4 antiepileptic agents. Main seizures were focal in six patients and generalized in three patients. After 0.5 to 4.0 years (mean=2.4 years), three patients (33%) were seizure-free and two patients (22%) experienced >90% reduction in seizures. Everolimus may therefore be effective in the treatment of refractory seizures in TSC. (Received February 20, 2019; Accepted April 2, 2019; Published June 1, 2019).

Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complex

Astrocytes serve many functions in the human brain, many of which focus on maintenance of homeostasis. Astrocyte dysfunction in Tuberous Sclerosis Complex (TSC) has long been appreciated with activation of the mTORC1 signaling pathway resulting in gliosis and possibly contributing to the very frequent phenotype of epilepsy. We hypothesized that aberrant expression of the astrocyte protein aquaporin-4 (AQP4) may be present in TSC and contribute to disease pathology. Characterization of AQP4 expression in epileptic cortex from TSC patients demonstrated a diffuse increase in AQP4. To determine if this was due to exposure to seizures, we examined Aqp4 expression in mouse models of TSC in which Tsc1 or Tsc2 inactivation was targeted to astrocytes or glial progenitors, respectively. Loss of either Tsc1 or Tsc2 from astrocytes resulted in a marked increase in Aqp4 expression which was sensitive to mTORC1 inhibition with rapamycin. Our findings in both TSC epileptogenic cortex and in a variety of astrocyte culture models demonstrate for the first time that AQP4 expression is dysregulated in TSC. The extent to which AQP4 contributes to epilepsy in TSC is not known, though the similarities in AQP4 expression between TSC and temporal lobe epilepsy supports further studies targeting AQP4 in TSC.

The specificity and role of microglia in epileptogenesis in mouse models of tuberous sclerosis complex

Microglial abnormalities have been reported in pathologic specimens from patients with tuberous sclerosis complex (TSC), a genetic disorder characterized by epilepsy, intellectual disability, and autism. However, the pathogenic role of microglia in epilepsy in TSC is poorly understood, particularly whether microglia defects may be a primary contributor to epileptogenesis or are secondary to seizures or simply epiphenomena. In this study, we tested the hypothesis that Tsc1 gene inactivation in microglia is sufficient to cause epilepsy in mouse models of TSC. Using a chemokine receptor, Cx3cr1, to target microglia, conventional Tsc1Cx3cr1-Cre CKO (conditional knockout) mice and postnatal-inducible Tsc1Cx3cr1-CreER CKO mice were generated and assessed for molecular and histopathologic evidence of microglial abnormalities, mechanistic target of rapamycin 1 (mTORC1) pathway activation, and epilepsy. Tsc1Cx3cr1-Cre CKO mice exhibited a high efficiency of microglia Tsc1 inactivation, mTORC1 activation, increased microglial size and number, and robust epilepsy, which were rapamycin-dependent. However, Cre reporter studies demonstrated that constitutive Cx3cr1 expression affected not only microglia, but also a large percentage of cortical neurons, confounding the role of microglia in epileptogenesis in Tsc1 Cx3cr1-Cre CKO mice. In contrast, postnatal inactivation of Tsc1 utilizing a tamoxifen-inducible Cx3cr1-CreER resulted in a more-selective microglia Tsc1 inactivation with high efficiency, mTORC1 activation, and increased microglial size and number, but no documented epilepsy. Microglia abnormalities may contribute to epileptogenesis in the context of neuronal involvement in TSC mouse models, but selective Tsc1 gene inactivation in microglia alone may not be sufficient to cause epilepsy, suggesting that microglia have more supportive roles in the pathogenesis of seizures in TSC.

Vigabatrin for Epileptic Spasms and Tonic Seizures in Tuberous Sclerosis Complex.

Vigabatrin is recommended as first-line treatment for infantile spasms in tuberous sclerosis complex (TSC), but other indications in children with tuberous sclerosis complex are less known. We retrospectively reviewed 201 children with tuberous sclerosis complex, and identified 21 children older than 1 year started on vigabatrin for any indication and with sufficient follow-up data. The indication for vigabatrin was epileptic spasms (n = 13), tonic seizures (n = 5), both (n = 2), and status epilepticus (n = 1). Mean age of treatment onset was 4.0 years (range 1.1-18.3). All but 1 patient had a reduction in seizures. Ten patients became seizure free and 4 had an improvement of >90%. In 9 patients, vigabatrin was tapered successfully after 8 to 33 months. Side effects reported included rash (n = 1) and behavioral decline (n = 1). No retinal toxicity was detected in 14 of 21 patients with adequate ophthalmologic surveillance data. In conclusion, vigabatrin may be an effective treatment for epileptic spasms and tonic seizures beyond the infantile age.

Secular changes in severity of intellectual disability in tuberous sclerosis complex: A reflection of improved identification and treatment of epileptic spasms?

SummaryTuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in TSC1 or TSC2. Epilepsy occurs in 80%‐90% of affected individuals during their lifetime, and up to one‐third of children with TSC will develop epileptic (infantile) spasms, for which vigabatrin has been shown to be particularly effective. Epilepsy severity and epileptic spasms are consistent markers of risk for the development of intellectual impairment in TSC. Although previous studies demonstrate a bimodal distribution of intellectual ability in TSC, recent findings suggest a unimodal distribution, which may reflect a change in IQ distribution over time. We compared 3 large historical UK cohorts of TSC (n = 331) that show varied distributions of intellectual ability, first ruling out differences in study methodology. Later‐born individuals had a higher frequency of reported spasms and higher likelihood of vigabatrin administration, but were less likely to have profound intellectual impairment, compared to the earlier‐born individuals. Our findings suggest that epileptic spasms went undetected in the older patients and therefore were not treated, leading to a higher occurrence of profound impairment, whereas the later born cohort had better access to treatment. These findings support the importance of early identification and treatment of seizures in TSC.

P.039 mTOR inhibitors as a new therapeutic strategy in treatment resistant epilepsy in hemimegalencephaly: a case report

Background: Hemimegalencephaly (HME) is a hamartomatous malformation of one cerebral hemisphere, resulting in refractory epilepsy, intellectual disability, and autistic features. Hemispherectomy is the definitive treatment, but there is risk of high morbidity and mortality, especially when done in early infancy. Various preclinical studies have shown that dysregulation of the mTOR pathway has an integral role in the development of various epilepsy syndromes, including tuberous sclerosis complex (TSC), focal cortical dysplasia and HME. Recently, mTOR inhibitors were proven to be effective in treating seizures in TSC. Methods: We present a case of a 6 day old female with refractory epilepsy despite the trial of 9 anti-seizure medications and the ketogenic diet. As the patient was awaiting epilepsy surgery, an mTOR inhibitor, rapamycin was initiated. Results: After 1 week of the initiation, she had over a 50% reduction in seizures. At two weeks, the parents felt that for the first time, she was making developmental gains. She also appeared brighter and more interactive. Due to her response to treatment, her hemispherectomy was deferred to when she is older, so there will be a decreased risk of complications from the surgery. Conclusions: This case exemplifies how mTOR inhibitors should be considered as a treatment option for patients with HME and refractory epilepsy.

Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder with highly variable expression. The most common neurologic manifestation of TSC is epilepsy, which affects approximately 85% of patients, 63% of whom develop treatment-resistant epilepsy. Herein, we evaluate the efficacy, safety, and tolerability of cannabidiol (CBD), a nonpsychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seizures in the setting of TSC. Eighteen of the 56 patients who have enrolled in our current expanded-access study of cannabidiol for patients with treatment-resistant epilepsy carry a diagnosis of TSC. After an initial baseline period of 1month, patients began treatment with CBD. The initial dose of 5mg/kg/day was increased by 5mg/kg/day every week up to a maximum dose of 50mg/kg/day, if tolerated. Weekly seizure frequencies, percent change in seizure frequencies, and responder rates were calculated during the 2nd, 3rd, 6th, 9th, and 12th month of treatment with CBD. The median weekly seizure frequency during the baseline period was 22.0 (interquartile range [IQR] 14.8-57.4), which decreased to 13.3 (IQR 5.1-22.1) after 3months of treatment with cannabidiol. The median percent change in total weekly seizure frequency was -48.8% (IQR -69.1% to -11.1%) after 3months of treatment. The 50% responder rates over the course of the study were 50%, 50%, 38.9%, 50%, and 50% after 2, 3, 6, 9, and 12months of treatment with CBD, respectively. In patients taking clobazam concurrently with CBD (n=12), the responder rate after 3months of treatment was 58.3%, compared to 33.3% in patients not taking clobazam (n=6). Twelve (66.7%) of 18 patients in this study experienced at least one adverse event thought possibly related to CBD; the most common adverse events were drowsiness (n=8, 44.4%), ataxia (n=5, 27.8%), and diarrhea (n=4, 22.2%). Although double-blind, placebo-controlled trials are still necessary, these findings suggest that cannabidiol may be an effective and well-tolerated treatment option for patients with refractory seizures in TSC.

Targeting tubers in paediatric epilepsy surgery candidates.

This scientific commentary refers to ‘Centre of epileptogenic tubers generate and propagate seizures in tuberous sclerosis’, by Kannan et al. (doi:10.1093/brain/aww192) . First described clinically at the end of the 19th century, tuberous sclerosis complex is a multi-organ system disorder displaying characteristic skin involvement, benign tumours, and hamartomatous and cystic lesions. Affected children often experience debilitating focal epilepsy that typically begins in very early life and remains medically resistant. For this reason, surgical therapy was advocated as far back as 1966 (Perot et al. , 1966) based on the hypothesis that a single tuber might well be responsible for the epileptogenesis. This conceptual approach has been well validated, and yet the precise anatomical and physiological substrates of focal epilepsy in affected individuals remain a matter of debate. Do the seizures in tuberous sclerosis complex begin directly within the cortical tuber itself or does onset occur in surrounding tissue? And do seizures propagate from the seizure onset zone to distant non-tuberal sites? In this issue of Brain , Kannan and co-workers provide elegant support for a central role of the tuberal core in seizure initiation and propagation (Kannan et al. , 2016). Building on previous analyses (Mohamed et al. , 2012), Kannan et al. investigated the spatio-temporal patterns of seizure onset and propagation in children with tuberous sclerosis complex by analysing intracranial EEG recordings in 10 patients with focal epilepsy. Multiple depth and surface electrodes sampled tubers and perituberal cortex both during seizures and interictally. In many cases, depth electrodes were positioned directly into the centre of the tuber. Analyses of 10 electro-clinically distinct seizure types revealed that nine originated in the centre of the tuber; one began in the tuberal rim, and most importantly, none originated in perituberal tissue alone. In all cases, electrical seizure activity preceded …

Seizures in tuberous sclerosis complex: hitting the target

Seizures in tuberous sclerosis complex: hitting the target