Proposed anti-seizure medication combinations with rufinamide in the treatment of Lennox-Gastaut syndrome: Narrative review and expert opinion.

Lennox-Gastaut syndrome (LGS) is a severe, chronic, complex form of early childhood-onset epilepsy characterized by multiple seizure types, generalized slow (≤2.5 Hz) spike-and-wave activity and other electroencephalography abnormalities, and cognitive impairment. A key treatment goal is early seizure control, and several anti-seizure medications (ASMs) are available. Due to the low success rate in achieving seizure control with monotherapy and an absence of efficacy data supporting any particular combination of ASMs for treating LGS, a rational approach to selection of appropriate polytherapy should be applied to maximize benefit to patients. Such "rational polytherapy" involves consideration of factors including safety (including boxed warnings), potential drug-drug interactions, and complementary mechanisms of action. Based on the authors' clinical experience, rufinamide offers a well-considered first adjunctive therapy for LGS, particularly in combination with clobazam and other newer agents for LGS, and may be particularly useful for reducing the frequency of tonic-atonic seizures associated with LGS.

Long-term efficacy and safety of cannabidiol (CBD) in children with treatment-resistant epilepsy: Results from a state-based expanded access program.

INTRODUCTION: An intermediate-sized, multicenter, expanded-access study was opened in 2015 through the support of the State of Georgia. This study provided children with treatment-resistant epilepsy (TRE) access to plant-derived highly purified cannabidiol (CBD; Epidiolex® in the US; Epidyolex® in the EU; 100 mg/mL oral solution). These children had failed to achieve seizure freedom with available treatment options and were ineligible to participate in randomized controlled trials that only included patients with Lennox-Gastaut and Dravet syndromes. METHODS: Cannabidiol safety, changes in seizure type, frequency, and seizure-free days were evaluated for children aged 1-18 years (at time of consent) as an adjunctive treatment for 36 months. The study consisted of a two-month baseline period, a titration period, treatment period, and optional titration period, which occurred after ≥26 weeks of treatment. Cannabidiol treatment was administered up to a targeted dose of 25 mg/kg/day, with an optional secondary treatment up to 50 mg/kg/day. Daily seizure type, seizure frequency, and seizure-free days were recorded in a Web-based diary, and changes in these outcomes were recorded and analyzed for the duration of the study. The occurrence of adverse events (AEs) was also recorded. RESULTS: The median percentage change in seizures for 45 patients in Months 3, 6, 12, 18, 24, and 36 showed a statistically significant (p < 0.001) reduction in major seizures (ranging from 54 to 72% at various time points) and all seizures (61-70%) compared with baseline. A mean increase in seizure-free days per 28 days was >5 in all treatment periods after Month 2, and an average increase of 7.52 (p < 0.001) seizure-free days per 28 days was observed at the end of follow-up compared with baseline. All patients experienced ≥1 AE. Children who transitioned to the optional secondary treatment (high-dose group) reported more AEs before increasing their dose to >25.0 mg/kg/day compared with the low-dose group. However, the average rate of AEs was significantly lower after moving to a high-dose regimen (p = 0.004). Twelve children reported 20 serious AEs, none of which were considered related to CBD. CONCLUSIONS: This study supports CBD as an adjunctive treatment for children with TRE. Treatment was well tolerated in doses up to 50 mg/kg/day. Patients who did not achieve desired results at a dose of ≤25.0 mg/kg/day reported more AEs when CBD dose increased to >25.0 mg/kg/day. Decreases in major seizure frequency and an increase in seizure-free days compared with baseline were reported during treatment. This supports the efficacy and tolerability of CBD for mixed seizure etiologies.

Efficacy and tolerability of adjunctive lacosamide in pediatric patients with focal seizures.

OBJECTIVE: To evaluate efficacy and tolerability of adjunctive lacosamide in children and adolescents with uncontrolled focal (partial-onset) seizures. METHODS: In this double-blind trial (SP0969; NCT01921205), patients (age ≥4-<17 years) with uncontrolled focal seizures were randomized (1:1) to adjunctive lacosamide/placebo. After a 6-week titration, patients who reached the target dose range for their weight (<30 kg: 8-12 mg/kg/d oral solution; ≥30-<50 kg: 6-8 mg/kg/d oral solution; ≥50 kg: 300-400 mg/d tablets) entered a 10-week maintenance period. The primary outcome was change in focal seizure frequency per 28 days from baseline to maintenance. RESULTS: Three hundred forty-three patients were randomized; 306 (lacosamide 152 of 171 [88.9%]; placebo 154 of 172 [89.5%]) completed treatment (titration and maintenance). Adverse events (AEs) were the most common reasons for discontinuation during treatment (lacosamide 4.1%; placebo 5.8%). From baseline to maintenance, percent reduction in focal seizure frequency per 28 days for lacosamide (n = 170) vs placebo (n = 168) was 31.7% (p = 0.0003). During maintenance, median percent reduction in focal seizure frequency per 28 days was 51.7% for lacosamide and 21.7% for placebo. Fifty percent responder rates (≥50% reduction) were 52.9% and 33.3% (odds ratio 2.17, p = 0.0006). During treatment, treatment-emergent AEs were reported by 67.8% lacosamide-treated patients (placebo 58.1%), most commonly (≥10%) somnolence (14.0%, placebo 5.2%) and dizziness (10.5%, placebo 3.5%). CONCLUSIONS: Adjunctive lacosamide was efficacious in reducing seizure frequency and generally well tolerated in patients (age ≥4-<17 years) with focal seizures. CLINICALTRIALSGOV IDENTIFIER: NCT01921205. CLASSIFICATION OF EVIDENCE: This trial provides Class I evidence that for children and adolescents with uncontrolled focal seizures, adjunctive lacosamide reduces seizure frequency.

Long-Term Use of Everolimus in Patients with Tuberous Sclerosis Complex: Final Results from the EXIST-1 Study.

BACKGROUND: Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has demonstrated efficacy in treating subependymal giant cell astrocytomas (SEGAs) and other manifestations of tuberous sclerosis complex (TSC). However, long-term use of mTOR inhibitors might be necessary. This analysis explored long-term efficacy and safety of everolimus from the conclusion of the EXIST-1 study (NCT00789828). METHODS AND FINDINGS: EXIST-1 was an international, prospective, double-blind, placebo-controlled phase 3 trial examining everolimus in patients with new or growing TSC-related SEGA. After a double-blind core phase, all remaining patients could receive everolimus in a long-term, open-label extension. Everolimus was initiated at a dose (4.5 mg/m2/day) titrated to a target blood trough of 5-15 ng/mL. SEGA response rate (primary end point) was defined as the proportion of patients achieving confirmed ≥50% reduction in the sum volume of target SEGA lesions from baseline in the absence of worsening nontarget SEGA lesions, new target SEGA lesions, and new or worsening hydrocephalus. Of 111 patients (median age, 9.5 years) who received ≥1 dose of everolimus (median duration, 47.1 months), 57.7% (95% confidence interval [CI], 47.9-67.0) achieved SEGA response. Of 41 patients with target renal angiomyolipomas at baseline, 30 (73.2%) achieved renal angiomyolipoma response. In 105 patients with ≥1 skin lesion at baseline, skin lesion response rate was 58.1%. Incidence of adverse events (AEs) was comparable with that of previous reports, and occurrence of emergent AEs generally decreased over time. The most common AEs (≥30% incidence) suspected to be treatment-related were stomatitis (43.2%) and mouth ulceration (32.4%). CONCLUSIONS: Everolimus use led to sustained reduction in tumor volume, and new responses were observed for SEGA and renal angiomyolipoma from the blinded core phase of the study. These findings support the hypothesis that everolimus can safely reverse multisystem manifestations of TSC in a significant proportion of patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00789828.

Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study.

BACKGROUND: In the EXIST-1 trial, initiated on Aug 10, 2009, more than 35% of patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex had at least 50% reduction in SEGA volume after 9·6 months of treatment with everolimus. In this Article, we report interim data (up to Jan 11, 2013) to support longer-term tolerability and efficacy of everolimus from the continuing 4-year extension phase of EXIST-1. METHODS: We assessed data from a prospective, open-label extension of a multicentre, phase 3, randomised, double-blind, placebo-controlled study in patients with tuberous sclerosis complex who had SEGA that was growing and needed treatment. In this extension study, we included all patients who had been assigned everolimus during the double-blind, randomised phase of the trial and those patients who crossed over from the placebo group to receive everolimus during the randomised phase or at the start of the extension phase. All patients received oral everolimus at a starting dose of 4·5 mg/m(2) per day. Everolimus dose was subsequently adjusted subject to tolerability to attain blood trough concentrations of 5-15 ng/mL. An independent central radiology review team assessed SEGA response (at least a 50% reduction from baseline in total volume of all target SEGAs; the primary endpoint) by MRI at 12, 24, and 48 weeks, then every year thereafter in all patients who received at least one dose of everolimus. This study was registered with ClinicalTrials.gov, number NCT00789828. FINDINGS: Of the original 117 randomly assigned patients, 111 were given everolimus between Aug 20, 2009, and Jan 11, 2013 (date of data cutoff); we included these patients in our longer-term analysis. Median duration of everolimus exposure was 29·3 months (IQR 19·4-33·8). Median follow-up was 28·3 months (IQR 19·3-33·0). 54 (49%) patients had a response of 50% or greater reduction in SEGA volume (95% CI 39·0-58·3), and duration of response was between 2·1 and 31·1 months (median not reached). SEGA volume was reduced by 50% or more in 39 (37%) of 105 patients at 24 weeks, 48 (46%) of 104 patients at 48 weeks, 36 (47%) of 76 patients at 96 weeks, and 11 (38%) of 29 patients at 144 weeks. Stomatitis (48 [43%] patients) and mouth ulceration (33 [30%] patients) were the most frequent treatment-related adverse events; infections were the most commonly reported treatment-related serious adverse event, occurring in 15 (14%) patients. 35 (32%) patients reported treatment-related grade 3 or 4 adverse events, the most common of which were stomatitis (nine [8%]) and pneumonia (nine [8%]). 18 (16%) patients had treatment-related serious adverse events. Six (5%) patients withdrew because of adverse events. INTERPRETATION: These results support the longer-term use of everolimus in patients who have few treatment options and who need continued treatment for tuberous sclerosis complex and its varied manifestations. Reduction or stabilisation of tumour volume with everolimus will hopefully provide long-term clinical benefit in patients with SEGA. FUNDING: Novartis Pharmaceuticals.

The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1.

BACKGROUND: Tuberous sclerosis complex (TSC) is characterized by benign tumours in multiple organs, including the brain, kidneys, skin, lungs and heart. Our objective was to evaluate everolimus, an mTOR inhibitor, in the treatment of angiomyolipoma in patients with subependymal giant cell astrocytoma (SEGA) associated with TSC. METHODS: EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 (NCT00789828), a prospective, double-blind, randomized, placebo-controlled, Phase 3 study, examined everolimus in treating SEGA associated with TSC. Patients with serial SEGA growth from pre-baseline to baseline scans were randomly assigned (2:1) to receive 4.5 mg/m(2)/day everolimus (target blood trough: 5-15 ng/mL; n = 78) or placebo (n = 39). Angiomyolipoma response rates were analysed in patients (n = 44) with target baseline angiomyolipoma lesions (≥1 angiomyolipoma; longest diameter ≥1.0 cm). An angiomyolipoma response rate, defined as the proportion of patients with confirmed angiomyolipoma response, was assessed by kidney CT or MRI screening at baseline, at 12, 24 and 48 weeks and annually. RESULTS: Angiomyolipoma response rates were 53.3% (16/30) and 0% (0/14) for everolimus- and placebo-treated patients, respectively. Angiomyolipoma reductions ≥50% in the sum of volumes of all target lesions were seen only in everolimus-treated patients (56.5, 78.3 and 80.0%) compared with placebo-treated patients (0% at each time point) at Weeks 12, 24 and 48, respectively. Greater percentages of everolimus-treated patients had angiomyolipoma reductions ≥30% at these same time points (82.6, 100 and 100% versus 8.3, 18.2 and 16.7% for everolimus versus placebo, respectively). CONCLUSIONS: Everolimus showed efficacy in reducing angiomyolipoma lesion volume in patients with SEGA associated with TSC.The trial is registered with ClinicalTrials.gov, number NCT00789828; http://clinicaltrials.gov/ct2/show/NCT00789828?term=EXIST-1&rank=1.

Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex. METHODS: In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response--ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828. FINDINGS: 117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]). INTERPRETATION: These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis. FUNDING: Novartis Pharmaceuticals.

Carbonic anhydrase-inhibiting medications and the intracarotid amobarbital procedure in children.

The intracarotid amobarbital procedure (IAP) is routinely conducted as part of the presurgical evaluation of pediatric patients with epilepsy. The aim of the present study was to investigate the possibility that anesthetization failures are the result of interactions of carbonic anhydrase-inhibiting (CAI) medications with sodium amobarbital. An archival review of 81 cases conducted between 1999 and 2008 was performed across two pediatric epilepsy centers. chi(2) analysis was used to assess whether CAI medications interfered with the outcome of these procedures. Of 81 patients, 85.2% had conclusive findings. All of the remaining 14.8% with anesthetization failures were taking CAI medications at the time of the procedure. However, 53.8% of patients taking CAI medications had conclusive results. This suggests that these medications may interact with sodium amobarbital, raising the possibility of anesthetization failures in children prescribed CAI medications.

Surgical treatment of epilepsy in children caused by focal cortical dysplasia.

Focal cortical dysplasia (FCD) is a congenital disorder of neuronal migration that is increasingly recognized as a common cause of seizures in children, occurring in 20-30% of all surgically treated cases of epilepsy in the pediatric population. Advances in neuroimaging have contributed to recognition of FCD. We report 15 children (9 female, 6 male) with FCD and surgically treated intractable epilepsy. In 9 cases, a surgical strategy of anatomic (frameless stereotactic) grid placement and physiologic (electrocorticography) resection was employed. Postoperative MRI scans were obtained, the pathologic specimen was graded according to the Brannstrom system, and seizure outcome was defined using the Engel classification. There were no deaths and no permanent morbidity. After, on average, 4 years since treatment, 10 children are seizure free, 2 are 2A, 2 are 2B and 1 is 3A. Predictors of good outcome are an MRI-defined lesion and increased cortical disorganization (higher Brannstrom grade). Subtotal resection did not preclude a seizure-free outcome.