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Meta-Analysis
. 2021 Apr 7;4(4):CD003277.
doi: 10.1002/14651858.CD003277.pub4.

Anti-seizure medications for Lennox-Gastaut syndrome

Francesco Brigo  1 , Katherine Jones  2   3 , Christin Eltze  4   5 , Sara Matricardi  6
Affiliations
Meta-Analysis

Anti-seizure medications for Lennox-Gastaut syndrome

Francesco Brigo et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: To assess the efficacy and tolerability of anti-seizure medications (ASMs) for LGS.

Search methods: 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 We contacted pharmaceutical companies and colleagues in the field to seek any unpublished or ongoing studies.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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 placebo (one study; 167 participants; RR 2.12, 95% CI 1.19 to 3.76). We found low-certainty evidence that 40 fewer people per 1000 (CI 68 fewer to 64 more) had AE leading to study-discontinuation with add-on lamotrigine compared to add-on placebo (one study; 169 participants; RR 0.49, 95% CI 0.13 to 1.82). Two studies compared add-on rufinamide with add-on placebo. Neither study reported seizure cessation. We found high-certainty evidence that 202 more people per 1000 (CI 34 to 567 more) had ≥ 50% average seizure reduction (one study; 138 participants; RR 2.84, 95% CI 1.31 to 6.18). We found low-certainty evidence that 105 more people per 1000 (CI 17 fewer to 967 more) had AE leading to study discontinuation with add-on rufinamide compared to add-on placebo (one study; 59 participants; RR 4.14, 95% CI 0.49 to 34.86). One study compared add-on rufinamide with another add-on ASM. This study did not report overall seizure cessation or reduction. We found low-certainty evidence that three fewer people per 1000 (CI 75 fewer to 715 more) had AE leading to study discontinuation with add-on rufinamide compared to another add-on ASM (one study; 37 participants; RR 0.96, 95% CI 0.10 to 9.57). One study compared add-on topiramate with add-on placebo. This study did not report overall seizure cessation. We found low-certainty evidence for ≥ 75% average seizure reduction with add-on topiramate (one study; 98 participants; Peto odds ratio (Peto OR) 8.22, 99% CI 0.60 to 112.62) and little or no difference to AE leading to study discontinuation compared to add-on placebo; no participants experienced AE leading to study discontinuation (one study; 98 participants; low-certainty evidence).

Authors' conclusions: 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.

Trial registration: ClinicalTrials.gov NCT01405053 NCT02224560 NCT00518713 NCT01146951 NCT00236756 NCT02224690 NCT02834793.

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Conflict of interest statement

FB: Francesco Brigo received travel support and accommodation by Lusofarmaco to attend the annual Congress of the Italian Chapter of ILAE; he received fees for speaking from Lusofarmaco.

KJ: is employed as a NIHR Network Support Fellow for the Cochrane Mental Health and Neuroscience Network and Cochrane Acute and Emergency Care Network.

CE: none known.

SM: received travel support and accommodation by Eisai to attend the 2018 American Epilepsy Society Annual Meeting.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 1: Number of participants free from drop seizures during the treatment phase
1.2
1.2. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 2: Number of participants with ≥ 75% reduction in drop seizures during the treatment phase
1.3
1.3. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 3: Number of participants with ≥ 50% reduction in drop seizures during the treatment phase
1.4
1.4. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 4: Number of participants with ≥ 25 % reduction in drop seizures during the treatment phase
1.5
1.5. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 5: Number of participants with > 0% to < 25% reduction in drop seizures during the treatment phase
1.6
1.6. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 6: Number of participants with > 0% to < 25% increase in drop seizures during the treatment phase
1.7
1.7. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 7: Number of participants with > 25 % increase in drop seizures during the treatment phase
1.8
1.8. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 8: Number of participants with improvement in the patient and caregiver Global Impression of Care scale
1.9
1.9. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 9: Number of participants free from drop seizures during the maintenance phase
1.10
1.10. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 10: Number of participants with ≥ 75% reduction in drop seizures during the maintenance phase
1.11
1.11. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 11: Number of participants with ≥ 50% reduction in drop seizures during the maintenance phase
1.12
1.12. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 12: Number of participants with ≥ 25 % reduction in drop seizures during the maintenance phase
1.13
1.13. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 13: Number of participants with adverse events
1.14
1.14. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 14: Number of participants with treatment‐related adverse events
1.15
1.15. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 15: Number of participants with serious adverse events
1.16
1.16. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 16: Number of participants with adverse events leading to dose reduction
1.17
1.17. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 17: Number of participants with adverse events leading to study discontinuation
1.18
1.18. Analysis
Comparison 1: Cannabidiol (10 mg/kg and 20 mg/kg) + ASMs versus placebo + ASMs, Outcome 18: Death
2.1
2.1. Analysis
Comparison 2: Cinromide + ASMs versus placebo + ASMs, Outcome 1: Number of participants free from all seizures
2.2
2.2. Analysis
Comparison 2: Cinromide + ASMs versus placebo + ASMs, Outcome 2: Number of participants with ≥ 75% reduction in mean weekly seizures
2.3
2.3. Analysis
Comparison 2: Cinromide + ASMs versus placebo + ASMs, Outcome 3: Number of participants with ≥ 50% reduction in mean weekly seizures
2.4
2.4. Analysis
Comparison 2: Cinromide + ASMs versus placebo + ASMs, Outcome 4: Number of participants with ≥ 25% reduction in mean weekly seizures
2.5
2.5. Analysis
Comparison 2: Cinromide + ASMs versus placebo + ASMs, Outcome 5: Number of participants with ≥ 0% to < 25% reduction in mean weekly seizures
2.6
2.6. Analysis
Comparison 2: Cinromide + ASMs versus placebo + ASMs, Outcome 6: Number of participants with ≥ 0% to < 25% increase in mean weekly seizures
2.7
2.7. Analysis
Comparison 2: Cinromide + ASMs versus placebo + ASMs, Outcome 7: Number of participants with > 25% increase in mean weekly seizures
2.8
2.8. Analysis
Comparison 2: Cinromide + ASMs versus placebo + ASMs, Outcome 8: Number of participants with improvement in global evaluation
2.9
2.9. Analysis
Comparison 2: Cinromide + ASMs versus placebo + ASMs, Outcome 9: Number of participants with no change in global evaluation
2.10
2.10. Analysis
Comparison 2: Cinromide + ASMs versus placebo + ASMs, Outcome 10: Number of participants with worsening in global evaluation
2.11
2.11. Analysis
Comparison 2: Cinromide + ASMs versus placebo + ASMs, Outcome 11: Number of participants with worsening in global evaluation ‐ Week 24
3.1
3.1. Analysis
Comparison 3: Clobazam (low, medium and high doses) + ASMs versus placebo + ASMs, Outcome 1: Number of participants free from drop seizures
3.2
3.2. Analysis
Comparison 3: Clobazam (low, medium and high doses) + ASMs versus placebo + ASMs, Outcome 2: Number of participants with ≥ 75 % reduction in drop seizures (from baseline to maintenance phase in average weekly rate)
3.3
3.3. Analysis
Comparison 3: Clobazam (low, medium and high doses) + ASMs versus placebo + ASMs, Outcome 3: Number of participants with ≥ 50 % reduction in drop seizures (from baseline to maintenance phase in average weekly rate)
3.4
3.4. Analysis
Comparison 3: Clobazam (low, medium and high doses) + ASMs versus placebo + ASMs, Outcome 4: Number of participants with ≥ 25 % reduction in drop seizures (from baseline to maintenance phase in average weekly rate)
3.5
3.5. Analysis
Comparison 3: Clobazam (low, medium and high doses) + ASMs versus placebo + ASMs, Outcome 5: Number of participants with adverse events
3.6
3.6. Analysis
Comparison 3: Clobazam (low, medium and high doses) + ASMs versus placebo + ASMs, Outcome 6: Number of participants with adverse events leading to dose reduction
3.7
3.7. Analysis
Comparison 3: Clobazam (low, medium and high doses) + ASMs versus placebo + ASMs, Outcome 7: Number of participants with aggression‐related adverse events
3.8
3.8. Analysis
Comparison 3: Clobazam (low, medium and high doses) + ASMs versus placebo + ASMs, Outcome 8: Number of participants with serious adverse events
3.9
3.9. Analysis
Comparison 3: Clobazam (low, medium and high doses) + ASMs versus placebo + ASMs, Outcome 9: Number of participants with adverse events leading to study discontinuation
3.10
3.10. Analysis
Comparison 3: Clobazam (low, medium and high doses) + ASMs versus placebo + ASMs, Outcome 10: Death
4.1
4.1. Analysis
Comparison 4: Felbamate + ASMs versus placebo + ASMs, Outcome 1: Number of participants free from all seizures (recorded by closed‐circuit television and electroencephalography)
4.2
4.2. Analysis
Comparison 4: Felbamate + ASMs versus placebo + ASMs, Outcome 2: Number of participants free from all seizures ‐ Treatment phase
4.3
4.3. Analysis
Comparison 4: Felbamate + ASMs versus placebo + ASMs, Outcome 3: Number of participants free from all seizures ‐ Maintenance phase
4.4
4.4. Analysis
Comparison 4: Felbamate + ASMs versus placebo + ASMs, Outcome 4: Number of participants free from atonic seizures
4.5
4.5. Analysis
Comparison 4: Felbamate + ASMs versus placebo + ASMs, Outcome 5: Number of participants free from tonic‐clonic seizures
4.6
4.6. Analysis
Comparison 4: Felbamate + ASMs versus placebo + ASMs, Outcome 6: Number of participants with severe side effects
4.7
4.7. Analysis
Comparison 4: Felbamate + ASMs versus placebo + ASMs, Outcome 7: Number of participants with adverse events leading to study discontinuation
5.1
5.1. Analysis
Comparison 5: Lamotrigine + ASMs versus placebo + ASMs, Outcome 1: Number of participants with ≥ 50% median reduction in all seizures
5.2
5.2. Analysis
Comparison 5: Lamotrigine + ASMs versus placebo + ASMs, Outcome 2: Number of participants with > 25% to < 50% median reduction in all seizures
5.3
5.3. Analysis
Comparison 5: Lamotrigine + ASMs versus placebo + ASMs, Outcome 3: Number of participants with either 0 to ≤ 25% median reduction or an increase in all seizures
5.4
5.4. Analysis
Comparison 5: Lamotrigine + ASMs versus placebo + ASMs, Outcome 4: Number of participants with ≥ 50% median reduction in drop attacks
5.5
5.5. Analysis
Comparison 5: Lamotrigine + ASMs versus placebo + ASMs, Outcome 5: Number of participants with > 25% to < 50% median reduction in drop attacks
5.6
5.6. Analysis
Comparison 5: Lamotrigine + ASMs versus placebo + ASMs, Outcome 6: Number of participants with either ≤ 25% median reduction or an increase in the number of drop attacks
5.7
5.7. Analysis
Comparison 5: Lamotrigine + ASMs versus placebo + ASMs, Outcome 7: Number of participants with ≥ 50% median reduction in tonic‐clonic seizures
5.8
5.8. Analysis
Comparison 5: Lamotrigine + ASMs versus placebo + ASMs, Outcome 8: Number of participants with > 25% to < 50% median reduction in tonic‐clonic seizures
5.9
5.9. Analysis
Comparison 5: Lamotrigine + ASMs versus placebo + ASMs, Outcome 9: Number of participants with 0 to ≤ 25% median reduction or an increase in the number of tonic‐clonic seizures
5.10
5.10. Analysis
Comparison 5: Lamotrigine + ASMs versus placebo + ASMs, Outcome 10: Number of participants with adverse events leading to study discontinuation
6.1
6.1. Analysis
Comparison 6: Rufinamide + ASMs versus placebo + ASMs, Outcome 1: Number of participants with ≥ 50% reduction in all seizures
6.2
6.2. Analysis
Comparison 6: Rufinamide + ASMs versus placebo + ASMs, Outcome 2: Number of participants with ≥ 75 % reduction in tonic‐atonic seizures
6.3
6.3. Analysis
Comparison 6: Rufinamide + ASMs versus placebo + ASMs, Outcome 3: Number of participants with ≥ 50% reduction in tonic‐atonic seizures
6.4
6.4. Analysis
Comparison 6: Rufinamide + ASMs versus placebo + ASMs, Outcome 4: Number of participants with ≥ 25% reduction in tonic‐atonic seizures
6.5
6.5. Analysis
Comparison 6: Rufinamide + ASMs versus placebo + ASMs, Outcome 5: Number of participants 'unchanged' (< 25% reduction in tonic‐atonic seizures)
6.6
6.6. Analysis
Comparison 6: Rufinamide + ASMs versus placebo + ASMs, Outcome 6: Number of participants with increased tonic‐atonic seizures
6.7
6.7. Analysis
Comparison 6: Rufinamide + ASMs versus placebo + ASMs, Outcome 7: Number of participants with improvement in seizure severity rating
6.8
6.8. Analysis
Comparison 6: Rufinamide + ASMs versus placebo + ASMs, Outcome 8: Number of participants with adverse events
6.9
6.9. Analysis
Comparison 6: Rufinamide + ASMs versus placebo + ASMs, Outcome 9: Number of participants with adverse events suspected to be treatment‐related
6.10
6.10. Analysis
Comparison 6: Rufinamide + ASMs versus placebo + ASMs, Outcome 10: Number of participants with serious adverse events
6.11
6.11. Analysis
Comparison 6: Rufinamide + ASMs versus placebo + ASMs, Outcome 11: Number of participants with adverse events leading to study discontinuation
7.1
7.1. Analysis
Comparison 7: Rufinamide + ASMs versus other ASM + ASMs, Outcome 1: Number of participants with treatment‐emergent adverse events
7.2
7.2. Analysis
Comparison 7: Rufinamide + ASMs versus other ASM + ASMs, Outcome 2: Number of participants with severe treatment‐emergent adverse events
7.3
7.3. Analysis
Comparison 7: Rufinamide + ASMs versus other ASM + ASMs, Outcome 3: Number of participants with serious treatment‐emergent adverse events
7.4
7.4. Analysis
Comparison 7: Rufinamide + ASMs versus other ASM + ASMs, Outcome 4: Number of participants with treatment‐emergent adverse events leading to study‐drug dose adjustment
7.5
7.5. Analysis
Comparison 7: Rufinamide + ASMs versus other ASM + ASMs, Outcome 5: Number of participants with treatment‐emergent adverse events leading to study discontinuation
7.6
7.6. Analysis
Comparison 7: Rufinamide + ASMs versus other ASM + ASMs, Outcome 6: Death
7.7
7.7. Analysis
Comparison 7: Rufinamide + ASMs versus other ASM + ASMs, Outcome 7: Child Behaviour Checklist Questionnaire
8.1
8.1. Analysis
Comparison 8: Topiramate + ASMs versus placebo + ASMs, Outcome 1: Number of participants with ≥75% reduction in all seizures
8.2
8.2. Analysis
Comparison 8: Topiramate + ASMs versus placebo + ASMs, Outcome 2: Number of participants free from major seizures (drop attacks and tonic‐clonic seizures)
8.3
8.3. Analysis
Comparison 8: Topiramate + ASMs versus placebo + ASMs, Outcome 3: Number of participants with ≥ 75% reduction in major seizures (drop attacks and tonic‐clonic seizures)
8.4
8.4. Analysis
Comparison 8: Topiramate + ASMs versus placebo + ASMs, Outcome 4: Number of participants with ≥ 50% reduction in major seizures (drop attacks and tonic‐clonic seizures)
8.5
8.5. Analysis
Comparison 8: Topiramate + ASMs versus placebo + ASMs, Outcome 5: Number of participants free from drop attacks
8.6
8.6. Analysis
Comparison 8: Topiramate + ASMs versus placebo + ASMs, Outcome 6: Number of participants with ≥ 75% reduction in drop attacks
8.7
8.7. Analysis
Comparison 8: Topiramate + ASMs versus placebo + ASMs, Outcome 7: Number of participants with ≥ 50% reduction in drop attacks
8.8
8.8. Analysis
Comparison 8: Topiramate + ASMs versus placebo + ASMs, Outcome 8: Number of participants free from drop attacks during the maintenance phase
8.9
8.9. Analysis
Comparison 8: Topiramate + ASMs versus placebo + ASMs, Outcome 9: Number of participants with severe adverse events
8.10
8.10. Analysis
Comparison 8: Topiramate + ASMs versus placebo + ASMs, Outcome 10: Number of participants with adverse events leading to dose reduction or temporary discontinuation
8.11
8.11. Analysis
Comparison 8: Topiramate + ASMs versus placebo + ASMs, Outcome 11: Number of participants with adverse events leading to study discontinuation
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References

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    1. Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Short-term and long-term efficacy and safety of rufinamide as adjunctive therapy in patients with inadequately controlled Lennox-Gastaut syndrome. Annals of Neurology 2005;58(Suppl 9):S92, abstract no: M15.
    1. Glauser T, Kluger G, Sachedo R, Krauss G, Perdomo C, Arroyo S. Efficacy and safety of rufinamide adjunctive therapy in patients with Lennox-Gastaut syndrome (LGS): a multicenter, randomized, double-blind, placebo-controlled, parallel trial. Neurology 2005;64(10):1826, abstract no: LBS.001.
Group for the Evaluation of Cinromide 1989 {published data only}
    1. Group for the Evaluation of Cinromide in the Lennox-Gastaut syndrome. Double-blind, placebo-controlled evaluation of cinromide in patients with the Lennox-Gastaut syndrome. Epilepsia 1989;30(4):422-9. [PMID: ] - PubMed
Motte 1997 {published data only}
    1. Billard C, Motte J, Arvidsson D, Trevathan E, Talladai M, Campos J, et al. Double-blind, placebo-controlled evaluation of the safety and efficacy of lamotrigine (Lamictal) for the treatment of patients with a clinical diagnosis of Lennox-Gastaut syndrome. Epilepsia 1996;37(Suppl 4):92.
    1. Gallagher J, Mullens L, Rigdon G, Donahue R. Clinician and caregiver assessments of global response to therapy strongly agree in a double-blind, placebo-controlled trial of lamotrigine in the Lennox-Gastaut syndrome. Neurology 1997;48(3):A109.
    1. Motte J, Trevathan E, Arvidsson JF, Barrera MN, Mullens EL, Manasco P. Lamotrigine for generalised seizures associated with the Lennox-Gastaut syndrome. Lamictal Lennox-Gastaut Study Group. New England Journal of Medicine 1997;337(25):1807-12. [PMID: ] - PubMed
    1. Mullens L, Gallagher J, Manasco P, for the Lamictal Lennox-Gastaut Study Group. Improved neurological function accompanies effective control of the Lennox-Gastaut syndrome with Lamictal: results of a multinational, placebo-controlled trial. Epilepsia 1996;37(Suppl 5):163, abstract no: 6.47.
    1. Trevathan E, Motte J, Arvidsson J, Manasco P, Mullens L. Safety and tolerability of adjunctive Lamictal® for the treatment of the Lennox-Gastaut syndrome: results of a multinational, double-blind, placebo-controlled trial. Epilepsia 1996;37(Suppl 5):202, abstract no: I.3.
Ng 2011 {published data only}
    1. Chung SS, Gidal BE, Lemming OM, Karnik-Henry M, Hackler E, Tolbert D et al. Combination AED treatment with clobazam in patients with Lennox–Gastaut syndrome: post hoc analyses of the CONTAIN study. Neurology 2018;90(15 Suppl):Abstract no: P4.264.
    1. Conry J, Ng Y, Collins S, Bradt J, Stolle J, Tracy K, et al. Safety and efficacy of clobazam, a novel 1,5-benzodiazepine, in the treatment of Lennox-Gastaut syndrome. Epilepsia 2007;48(Suppl 6):360-1, Abstract no: 3.305.
    1. Conry J, Ng Y, Drummond R, Stolle J, Sagar S. Efficacy and safety of clobazam in the treatment of seizures associated with Lennox Gastaut syndrome: results of a phase III trial. In: 64th Annual Meeting of the American Epilepsy Society; 2010 December 3-7; San Antonio, TX. www.aesnet.org/go/publications/aes-abstracts/abstract-search/mode/displa..., (accessed 28 April 2012):Abstract no: 1.283.
    1. Conry J, Ng YT, Peng G, Lee D, Isojarvi J. Efficacy and safety of clobazam for LGS patients who completed all 15 weeks of the phase III CONTAIN trial. Epilepsy Currents 2014;14(Suppl 1):391-2, Abstract no: 3.204.
    1. Conry JA, Ng YT, Drummond R, Stolle J, Owen JR, Weinberg MA. Efficacy and safety of clobazam for seizures associated with Lennox-Gastaut syndrome (LGS): results of a phase III study. Annals of Neurology 2011;70(S15):S113, Abstract no: 14. [DOI: 10.1002/ana.22572] - DOI
Ohtsuka 2014 {published data only}
    1. Ohtsuka Y, Yoshinaga H, Shirasaka Y, Takayama R, Takano H, Iyoda K. Rufinamide as an adjunctive therapy for Lennox-Gastaut syndrome: a randomized double-blind placebo-controlled trial in Japan. Epilepsy Research 2014;108(9):1627-36. [PMID: ] - PubMed
Sachdeo 1999 {published data only}
    1. Glauser TA, Levisohn PM, Ritter F, Sachdeo RC. Topiramate in Lennox-Gastaut syndrome: open-label treatment of patients completing a randomized controlled trial. Topiramate YL Study Group. Epilepsia 2000;41(Suppl 1):S86-90. [PMID: ] - PubMed
    1. Glauser TA, Sachdeo RC, Ritter FJ, Reife R, Lim P, Topiramate YL Study Group. A double-blind trial of topiramate in Lennox-Gastaut syndrome (LGS). Epilepsia 1997;38(Suppl 3):131.
    1. Ritter FJ, Glauser TA, Sachdeo RC, Shu-Chen W. Long-term experience with topiramate in Lennox-Gastaut syndrome. Epilepsia 1998;39(Suppl 2):2-3.
    1. Ritter FJ, Sachdeo RC, Glauser TA, Topiramate YL Study Group. Topiramate as open-label adjunctive therapy in Lennox-Gastaut syndrome. Epilepsia 1997;38(Suppl 3):94.
    1. Ritter FJ, Topiramate YL Study Group. Open-label treatment of Lennox-Gastaut syndrome with topiramate. Epilepsia 1997;38(Suppl 3):37. - PubMed
Thiele 2018 {published data only}
    1. French J, Thiele E, Mazurkiewicz-Beldzinska M, Benbadis S, Marsh E, Joshi C, et al. Cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox-Gastaut syndrome (LGS): results of a multi-center, randomized, double-blind, placebo controlled trial (GWPCARE4). Neurology 2017;88(16 Suppl):Abstract no: S21.001.
    1. Joshi C, Thiele E, Marsh E, French J. Treatment with cannabidiol (CBD) significantly reduces drop and total seizure frequency in Lennox-Gastaut Syndrome (LGS): results of a multicenter, randomized, double-blind, placebo controlled trial (GWPCARE4). Annals of Neurology 2017;82(S21):S293, Abstract no: 42.
    1. Mazurkiewicz-Beldzinska M, Thiele EA, Benbadis S, Marsh ED, Joshi C, French JA, et al. Treatment with cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox-Gastaut syndrome (LGS): results of a multi-centre, randomised, double-blind, placebo-controlled trial (GWPCARE4). Epilepsia 2017;58(Suppl 5):S55, Abstract no: p0238. [DOI: 10.1111/epi.13944] - DOI
    1. Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2018;391(10125):1085-96. [PMID: ] - PubMed
    1. Thiele EA, Mazurkiewicz-Beldzinska M, Benbadis S, Marsh ED, Joshi C, French JA et al. Treatment with cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox Gastaut Syndrome (LGS): results of a multi-center, randomized, double-blind, placebo-controlled trial (GWPCARE4). Neurotherapeutics 2017;14(3):824-5. [DOI: 10.1007/s13311-017-0543-x] - DOI

References to studies excluded from this review

Battaglia 1991 {published data only}
    1. Battaglia A, Ferrari AR, Guerrini R. Double-blind placebo-controlled trial of flunarizine as add-on therapy in refractory childhood epilepsy. Brain and Development 1991;13(4):217-22. [PMID: ] - PubMed
Conry 2009 {published data only}
    1. Conry JA, Ng YT, Paolicchi JM, Kernitsky L, Mitchell WG, Ritter FJ, et al. Clobazam in the treatment of Lennox-Gastaut syndrome. Epilepsia 2009;50(5):1158-66. [PMID: ] - PubMed
Inanaga 1989 {published data only}
    1. Inanaga K, Kumashiro H, Fukyama Y, Ohtahara S, Shirouzu M. Clinical study of oral administration of DN-1417, a TRH analog, in patients with intractable epilepsy. Epilepsia 1989;30(4):438-45. [PMID: ] - PubMed
Oletsky 1996 {published data only}
    1. Oletsky H, Kelley K, Stertz B, Reeves-Tyer P, Flamini R, Malow B, et al. The efficacy of felbamate as add-on therapy to valproic acid in the Lennox-Gastaut syndrome. Epilepsia 1996;37(Suppl 5):155, Abstract no: 6.13. - PubMed
Perry 2019 {published data only}
    1. Perry MS. Don't fear the reefer - evidence mounts for plant-based cannabidiol as treatment for epilepsy. Epilepsy Currents 2019;19(2):93-5. [DOI: 10.1177/1535759719835671] [PMID: ] - DOI - PMC - PubMed
Vajda 1985 {published data only}
    1. Vajda FJ, Bladin PF, Parsons BJ. Clinical experience with clobazam: a new 1,5 benzodiazepine in the treatment of refractory epilepsy. Clinical and Experimental Neurology 1985;21:177-82. [PMID: ] - PubMed
Vassella 1978 {published data only}
    1. Vassella F, Rudeberg A, Da Silva V, Pavlincova E. Double-blind study on the anticonvulsive effect of phenobarbital and valproate in the Lennox syndrome [Doppletblind-Untersuchung uber die antikonvulsive Wirkung von Phenobarbital und Valproat beim Lennox-Syndrom]. Schweizerische Medizinische Wochenschrift 1978;108(19):713-6. [PMID: ] - PubMed
Vigevano 1994 {published data only}
    1. Vigevano F, Cilio MR, Antonini L. Clinical experience with Felbamate in paediatric age. In: Bollettino - Lega Italiana Contro L'Epilessia. Vol. 86-87. 1994:63-6. [DOI: 10.1016/s0920-1211(01)00290-x] - DOI

References to studies awaiting assessment

Ohtahara 2008 {published data only}
    1. Ohtahara S, Linuma K, Fujiwara T, Yamatogi Y. Single-blind and controlled comparative study of lamotrigine with zonisamide for refractory pediatric epilepsy. Journal of the Japan Epilepsy Society 2008;25(4):425-40. [DOI: 10.3805/jjes.25.425] - DOI

References to ongoing studies

CTRI/2010/091/001449 {published data only}
    1. CTRI/2010/091/001449. A comparative, randomized, open label, multicentric, prospective clinical study to evaluate the efficacy, safety and tolerability of rufinamide tablet vs. lamotrigine (adjunctive therapy) in the treatment of seizures associated with Lennox-Gastaut syndrome. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=2237 2011.
NCT00004776 {published data only}
    1. NCT00004776. Phase III randomized, double-blind, placebo-controlled study of oral topiramate for Lennox-Gastaut syndrome. http://ClinicalTrials.gov/show/NCT00004776 1993.
NCT01370486 {published data only}
    1. NCT01370486. Melatonin versus placebo in the Lennox-Gastaut syndrome: neurophysiological and neuropsychological effects. http://ClinicalTrials.gov/show/NCT01370486 2011.
NCT02318537 {published data only}
    1. NCT02318537. Cannabidiol oral solution as an adjunctive therapy for treatment of subjects with inadequately controlled Lennox-Gastaut syndrome. https://ClinicalTrials.gov/show/NCT02318537 2016.
NCT03355209 {unpublished data only}
    1. NCT03355209. A study to investigate the efficacy and safety of ZX008 (fenfluramine hydrochloride) as an adjunctive therapy in children and adults with Lennox-Gastaut syndrome. https://clinicaltrials.gov/show/NCT03355209 (first received November 28, 2017).
NCT03650452 {published data only}
    1. NCT03650452. A phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of TAK-935 (OV935) as an adjunctive therapy in pediatric patients with developmental and/or epileptic encephalopathies. https://ClinicalTrials.gov/show/NCT03650452 2018.
NCT03808935 {unpublished data only}
    1. NCT03808935. Cannabis extract in refractory epilepsy study. https://clinicaltrials.gov/show/NCT03808935 2019.
Wechsler 2017 {unpublished data only}
    1. Wechsler RT, Popli G, Dimos J, Ferreira J, Bibbiani F, Laurenza A, et al. Design and methods of study 338: a multicenter, double-blind, randomized, placebo-controlled trial of perampanel as adjunctive treatment in subjects >=2 years of age with inadequately controlled seizures associated with Lennox-Gastaut syndrome. Epilepsia 2017;58(Suppl 5):S157-8, Abstract no: p0891. [DOI: 10.1111/epi.13944] - DOI
    1. Wechsler RT, Popli G, Dimos J, Ferreira J, Bibbiani F, Laurenza A, et al. Design and methods of study 338: a multicentre, double-blind, randomised, placebo-controlled trial of perampanel as adjunctive treatment in patients >=2 years of age with inadequately controlled seizures associated with Lennox-Gastaut syndrome. Developmental Medicine and Child Neurology 2017;59(Suppl 4):121-2, Abstract no: 207. [DOI: 10.1111/dmcn.13623] - DOI

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References to other published versions of this review

Hancock 2003
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