An Italian consensus on the management of Lennox-Gastaut syndrome

Riva, Antonella; Coppola, Giangennaro; Bonaventura, Carlo Di; Elia, Maurizio; Ferlazzo, Edoardo; Gobbi, Giuseppe; Marini, Carla; Meletti, Stefano; Romeo, Antonino; Santoro, Katia; Verrotti, Alberto; Capovilla, Giuseppe; Striano, Pasquale; Aguglia, Umberto; Bagnasco, Irene; Bartolini, Emanuele; Battaglia, Domenica; Beccaria, Francesca; Belcastro, Vincenzo; Bernardo, Pia; Bonanni, Paolo; Boniver, Clementina; Bonuccelli, Alice; Briatore, Eleonora; Brigo, Francesco; Cesaroni, Elisabetta; Coa, Roberta; Costa, Cinzia; D’Aniello, Alfredo; Giorgis, Valentina De; Gennaro, Giancarlo Di; Ferrari, Anna Rita; Marchese, Francesca; Matricardi, Sara; Messana, Tullio; Morano, Alessandra; Operto, Francesca Felicia; Orsini, Alessandro; Parmeggiani, Lucio; Peruzzi, Cinzia; Pruna, Dario; Puligheddu, Monica; Pulitano, Patrizia; Ragona, Francesca; Romigi, Andrea; Rosati, Anna; Rosati, Eleonora; Russo, Angelo; Sartori, Stefano; Spagnoli, Carlotta; Spanò, Maria; Trabacca, Antonio; Troisi, Serena; Viri, Maurizio; Zucca, Claudio

doi:10.1016/j.seizure.2022.07.004

Cited by 9 publications

(5 citation statements)

References 51 publications

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“…Considering the limited therapeutic effect of these ASMs, some relevant clinical trials are ongoing, which have led to the preliminary verification of newly discovered antiseizure drugs, such as stiripentol (STP) and cannabidiol (CBD) for DS, and rufinamide, CBD, and felbamate for LGS, followed by their approval in several countries and regions (8)(9)(10)(11)(12). More recently, fenfluramine (FFA) has gained prominence as a possible alternative to treat both DS and LGS, as well as other DREs (13)(14)(15)(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Optimal dose of fenfluramine in adjuvant treatment of drug-resistant epilepsy: evidence from randomized controlled trials

Xu,

Chen,

Liu

2024

Front. Neurol.

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ObjectiveSeveral clinical trials have suggested that fenfluramine (FFA) is effective for the treatment of epilepsy in Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS). However, the exploration of its optimal target dose is ongoing. This study aimed to summarize the best evidence to inform this clinical issue.Materials and methodsWe searched PubMed, Embase (via Ovid), and Web of Science for relevant literature published before December 1st, 2023. Randomized, double-blind, placebo-controlled studies that evaluated the efficacy, safety, and tolerability of FFA in DS and LGS were identified and meta-analysis was performed according to doses. The study was registered with PROSPERO (CRD42023392454).ResultsSix hundred and twelve patients from four randomized controlled trials were enrolled. The results demonstrated that FFA at 0.2, 0.4, or 0.7 mg/kg/d showed significantly greater efficacy compared to placebo in terms of at least 50% reduction (p < 0.001, p < 0.001, p < 0.001) and at least 75% reduction (p < 0.001, p = 0.007, p < 0.001) in monthly seizure frequency from baseline. Moreover, significantly more patients receiving FFA than placebo were rated as much improved or very much improved in CGI-I by both caregivers/parents and investigators (p < 0.001). The most common treatment-emergent adverse events were decreased appetite, diarrhea, fatigue, and weight loss, with no valvular heart disease or pulmonary hypertension observed in any participant. For dose comparison, 0.7 mg/kg/d group presented higher efficacy on at least 75% reduction in seizure (p = 0.006) but not on at least 50% reduction. Weight loss (p = 0.002), decreased appetite (p = 0.04), and all-cause withdrawal (p = 0.036) were more common in 0.7 mg/kg/d group than 0.2 mg/kg/d. There was no statistical difference in other safety parameters between these two groups.ConclusionThe higher range of the licensed dose achieves the optimal balance between efficacy, safety, and tolerability in patients with DS and LGS.Clinical trial registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023392454.

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Section: Introductionmentioning

confidence: 99%

Optimal dose of fenfluramine in adjuvant treatment of drug-resistant epilepsy: evidence from randomized controlled trials

Xu,

Chen,

Liu

2024

Front. Neurol.

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“…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. 4 Perampanel (PER) is a first-in-class, selective, noncompetitive αamino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor antagonist and acts as a potentially broad-spectrum ASM. [5][6][7] This study aimed to assess the long-term effectiveness of PER as an adjunctive treatment of seizures in a cohort of children and adults with LGS.…”

Section: Introductionmentioning

confidence: 99%

“…Despite the increasing number of approved drugs and new, repurposed compounds, there are still unmet needs for the management of this epileptic condition in clinical practice. 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 4 …”

Section: Introductionmentioning

confidence: 99%

Long‐term effectiveness of add‐on perampanel in patients with Lennox–Gastaut syndrome: A multicenter retrospective study

et al. 2023

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This retrospective study assessed long‐term effectiveness of add‐on perampanel (PER) in patients with Lennox–Gastaut syndrome (LGS). Outcomes included time to PER failure and time to seizure relapse in responders. PER failure was defined as either discontinuation of PER or initiation of another treatment. Seizure relapse in responders was defined as occurrence of a seizure in seizure‐free patients and increase of at least 50% in average monthly seizure frequency for those who were responders. Eighty‐seven patients were included. Treatment failure occurred in 52 (59.8%) subjects at a median time of 12 months. Treatment failure was due to lack of efficacy in 27 (52.0%) patients, lack of tolerability in 14 (27.0%), and both reasons in 11 (21.0%). A slower titration was associated with a lower risk of PER failure compared to faster titration schedules, and the occurrence of adverse events increased the risk of treatment failure. Thirty‐six patients (41.4%) were responders during a median follow‐up of 11 months. Seizure relapse occurred in 13 of 36 (36.1%) patients after a median time of 21 months. The overall rate of seizure responders was 23 of 87 (26.4%) at the end of follow‐up. This study provides real‐world evidence on the effectiveness of PER as adjunctive treatment in LGS patients.

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“…We have conducted a narrative review of the effects of ASMs on PBAEs, cognition, sedation and sleep, with a focus on ASMs used to treat DEEs/drug-resistant epilepsy (DRE), particularly DS, LGS and TSC, either as approved therapies (bold text in Table 1) or off-label (unbold text in Table 1), as specified in recent treatment guidance/reviews for DS [3,[15][16][17], LGS [18][19][20][21] and TSC [2,[22][23][24][25][26]. Studies of particular interest were those that included patients with DEE/DREs, especially studies whose main objective was to assess these specific outcomes, pooled safety analyses and meta-analyses (as rarer events may only become evident with such analyses), and data from real-world studies (as regulatory clinical trials can often exclude people with suicidal ideation and psychosis) [27,28].…”

Section: Introductionmentioning

confidence: 99%

“…However, because of differences in study designs and populations, it is not possible to make comparisons between the ASMs. In addition, most ASMs have a precautionary warning for an increased risk of suicidal behaviour and ideation; however, suicidal outcomes are not a specific focus of this As specified in recent treatment guidance/reviews for DS [3,5,[15][16][17], LGS [18][19][20][21] and TSC [2,[22][23][24][25][26] c…”

Section: Introductionmentioning

confidence: 99%

Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies

Strzelczyk

Schubert‐Bast

2022

CNS Drugs

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The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood and significant neurodevelopmental comorbidities. The latter include intellectual disability, developmental delay, behavioural problems including attention-deficit hyperactivity disorder and autism spectrum disorder, psychiatric problems including anxiety and depression, speech impairment and sleep problems. Classical examples of developmental and epileptic encephalopathies include Dravet syndrome, Lennox–Gastaut syndrome and tuberous sclerosis complex. The mainstay of treatment is with multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated with psychobehavioural adverse events, and effects (negative or positive) on cognition and sleep. We have performed a targeted literature review of ASMs commonly used in the treatment of developmental and epileptic encephalopathies to discuss the latest evidence on their effects on behaviour, mood, cognition, sedation and sleep. The ASMs include valproate (VPA), clobazam, topiramate (TPM), cannabidiol (CBD), fenfluramine (FFA), levetiracetam (LEV), brivaracetam (BRV), zonisamide (ZNS), perampanel (PER), ethosuximide, stiripentol, lamotrigine (LTG), rufinamide, vigabatrin, lacosamide (LCM) and everolimus. Bromide, felbamate and other sodium channel ASMs are discussed briefly. Overall, the current evidence suggest that LEV, PER and to a lesser extent BRV are associated with psychobehavioural adverse events including aggressiveness and irritability; TPM and to a lesser extent ZNS are associated with language impairment and cognitive dulling/memory problems. Patients with a history of behavioural and psychiatric comorbidities may be more at risk of developing psychobehavioural adverse events. Topiramate and ZNS may be associated with negative effects in some aspects of cognition; CBD, FFA, LEV, BRV and LTG may have some positive effects, while the remaining ASMs do not appear to have a detrimental effect. All the ASMs are associated with sedation to a certain extent, which is pronounced during uptitration. Cannabidiol, PER and pregabalin may be associated with improvements in sleep, LTG is associated with insomnia, while VPA, TPM, LEV, ZNS and LCM do not appear to have detrimental effects. There was variability in the extent of evidence for each ASM: for many first-generation and some second-generation ASMs, there is scant documented evidence; however, their extensive use suggests favourable tolerability and safety (e.g. VPA); second-generation and some third-generation ASMs tend to have the most robust evidence documented over several years of use (TPM, LEV, PER, ZNS, BRV), while evidence is still being generated for newer ASMs such as CBD and FFA. Finally, we discuss how a variety of factors can affect mood, behaviour and cognition, and untangling the associations between the effects of the underlying syndrome and those of the ASMs can be challenging. In particular, there is enormous h...

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An Italian consensus on the management of Lennox-Gastaut syndrome

Cited by 9 publications

References 51 publications

Optimal dose of fenfluramine in adjuvant treatment of drug-resistant epilepsy: evidence from randomized controlled trials

Optimal dose of fenfluramine in adjuvant treatment of drug-resistant epilepsy: evidence from randomized controlled trials

Long‐term effectiveness of add‐on perampanel in patients with Lennox–Gastaut syndrome: A multicenter retrospective study

Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies

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