topiramate and Lennox-Gastaut-Syndrome

Lennox-Gastaut syndrome (LGS) is an age-specific epilepsy syndrome characterised by multiple seizure types, including drop seizures. LGS has a characteristic electroencephalogram, an onset before age eight years and an association with drug resistance. This is an updated version of the Cochrane Review published in 2013.. To assess the efficacy and tolerability of anti-seizure medications (ASMs) for LGS.. We searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 28 February 2020) on 2 March 2020. CRS Web includes randomised controlled trials (RCTs) or quasi-RCTs from the Cochrane Central Register of Controlled Trials (CENTRAL); the Specialised Registers of Cochrane Review Groups, including Cochrane Epilepsy; PubMed; Embase; ClinicalTrials.gov; and the World Health Organization's International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We contacted pharmaceutical companies and colleagues in the field to seek any unpublished or ongoing studies.. We considered RCTs, including cross-over trials, of ASMs for LGS in children and adults. We included studies of ASMs used as either monotherapy or as an add-on (adjunctive) therapy. We excluded studies comparing different doses of the same ASM.. We used standard Cochrane methodological procedures, including independent, dual assessment for risk of bias and application of the GRADE approach to rate the evidence certainty for outcomes.. We found no trials of ASM monotherapy. The review included 11 trials (1277 participants; approximately 11 weeks to 112 weeks follow-up after randomisation) using add-on ASMs for LGS in children, adolescents and adults. Two studies compared add-on cannabidiol (two doses) with add-on placebo in children and adolescents only. Neither study reported overall seizure cessation or reduction. We found high-certainty evidence that 72 more people per 1000 (confidence interval (CI) 4 more to 351 more) had adverse events (AE) leading to study discontinuation with add-on cannabidiol, compared to add-on placebo (two studies; 396 participants; risk ratio (RR) 4.90, 95% CI 1.21 to 19.87). One study compared add-on cinromide with add-on placebo in children and adolescents only. We found very low-certainty evidence that 35 more people per 1000 (CI 123 fewer to 434 more) had 50% or greater average reduction of overall seizures with add-on cinromide compared to add-on placebo (one study; 56 participants; RR 1.15, 95% CI 0.47 to 2.86). This study did not report participants with AE leading to study discontinuation. One study compared add-on clobazam (three doses) with add-on placebo. This study did not report overall seizure cessation or reduction. We found high-certainty evidence that 106 more people per 1000 (CI 0 more to 538 more) had AE leading to study discontinuation with add-on clobazam compared to add-on placebo (one study; 238 participants; RR 4.12, 95% CI 1.01 to 16.87). One study compared add-on felbamate with add-on placebo. No cases of seizure cessation occurred in either regimen during the treatment phase (one study; 73 participants; low-certainty evidence). There was low-certainty evidence that 53 more people per 1000 (CI 19 fewer to 716 more) with add-on felbamate were seizure-free during an EEG recording at the end of the treatment phase, compared to add-on placebo (RR 2.92, 95% CI 0.32 to 26.77). The study did not report overall seizure reduction. We found low-certainty evidence that one fewer person per 1000 (CI 26 fewer to 388 more) with add-on felbamate had AE leading to study discontinuation compared to add-on placebo (one study, 73 participants; RR 0.97, 95% CI 0.06 to 14.97). Two studies compared add-on lamotrigine with add-on placebo. Neither study reported overall seizure cessation. We found high-certainty evidence that 176 more people per 1000 (CI 30 more to 434 more) had ≥ 50% average seizure reduction with add-on lamotrigine compared to add-on pla. RCTs of monotherapy and head-to-head comparison of add-on ASMs are currently lacking. However, we found high-certainty evidence for overall seizure reduction with add-on lamotrigine and rufinamide, with low-certainty evidence for AE leading to study discontinuation compared with add-on placebo or another add-on ASM. The evidence for other add-on ASMs for overall seizure cessation or reduction was low to very low with high- to low-certainty evidence for AE leading to study discontinuation. Future research should consider outcome reporting of overall seizure reduction (applying automated seizure detection devices), impact on development, cognition and behaviour; future research should also investigate age-specific efficacy of ASMs and target underlying aetiologies.

Topics: Adolescent; Adult; Age of Onset; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Cinnamates; Clobazam; Electroencephalography; Felbamate; Humans; Lamotrigine; Lennox Gastaut Syndrome; Middle Aged; Placebos; Randomized Controlled Trials as Topic; Topiramate; Triazoles; Wakefulness; Young Adult

Although international guidelines exist, the clinical heterogeneity of Lennox-Gastaut syndrome (LGS) and the increasing availability of new and repurposed drugs (e.g., fenfluramine and cannabidiol) requires a practical guide to patient management in the clinical context. We report the results of a consensus survey among 42 Italian experts in the diagnosis and treatment of LGS.. The consensus procedure followed a modified Delphi approach. Statements were formulated, based on the most recent published evidence and the clinicians' personal experience, then discussed, and agreed upon by the experts through a two-round voting procedure. Approval of a statement was reached with an average score ≥7.. Thirteen statements dealing with three main topics (i.e., clinical diagnosis and prognosis, impact on the Quality of Life (QoL), and treatment strategies) were generated. Six statements achieved a level of agreement sufficient for approval on the first voting round. Following the discussion and a few consequent amendments, most of the statements increased their level of agreement and all 13 were approved.. Overall, the statements draw a slightly more benign picture of this rare and severe disease, highlighting the possibility of remission - albeit modest -, an apparent trend towards lower mortality, and the availability of several effective drugs, to which greater accessibility would be hoped for. Valproate remains a major therapeutic option in LGS patients although lamotrigine, rufinamide, topiramate, cannabidiol, and clobazam are popular therapeutic options in Italy, allowing for a tailor-made antiseizure therapy.

Topics: Anticonvulsants; Cannabidiol; Clobazam; Consensus; Fenfluramine; Humans; Lamotrigine; Lennox Gastaut Syndrome; Quality of Life; Topiramate; Valproic Acid

Lennox-Gastaut syndrome (LGS) is a well-defined epileptic encephalopathy highly drug resistant. The first-line treatment option is valproate (VPA), usually in combination with lamotrigine. VPA has been linked to serious hepatotoxicity. We report a 22-year-old liver transplanted patient with LGS successfully treated with VPA in combination with phenobarbital (100 mg/d; blood level: 36 mg/l), lamotrigine (125 mg/d; blood level: 4.81 mg/l) and topiramtate (175 mg/d), as well as immunosuppressive, antiviral, anti-anemic, hypo-phosphoric and alkaline medication. On VPA 1000 mg/d, the seizure frequency decreased significantly. Taking into consideration the patient's good tolerance and the normal liver function, VPA was increased to 1500 mg/d. At this dose the daily drop attacks and generalized tonic-clonic seizures totally ceased. The patient presented only some tonic seizures around awakening. During many years, VPA was avoided in this patient because of its potential hepatotoxicity. However the good functioning of the transplanted liver permitted its introduction. VPA can be used safely in liver transplanted patients under the strict control of the hepatic function.

Topics: Anticonvulsants; Chemical and Drug Induced Liver Injury; Electroencephalography; Female; Fructose; Humans; Immunosuppressive Agents; Intellectual Disability; Lamotrigine; Lennox Gastaut Syndrome; Liver Function Tests; Liver Transplantation; Phenobarbital; Seizures; Spasms, Infantile; Topiramate; Triazines; Valproic Acid; Young Adult