Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents

Francesco Brigo; Stanley C Igwe; Simona Lattanzi

doi:10.1002/14651858.CD003032.pub5

Etosuximida, valproato de sodio o lamotrigina para las crisis de ausencia en niños y adolescentes

Appendices

Appendix 1. Cochrane Register of Studies (CRS Web) search strategy

1. (Avugane OR Baceca OR Convulex OR Delepsine OR Depacon OR Depakene OR Depakine OR Depakote OR Deproic OR Epiject OR Epilex OR Epilim OR Episenta OR Epival OR Ergenyl OR Mylproin OR Orfiril OR Orlept OR Selenica OR Sprinkle OR Stavzor OR Valcote OR Valparin OR Valpro OR Valproate OR Valproic OR VPA):AB,KW,KY,MC,MH,TI

2. MeSH DESCRIPTOR Valproic Acid Explode All

3. (Aethosuximide OR Emeside OR Ethosucci* OR Ethosuxide OR Ethosuximide OR Etosuximida OR Zarontin):AB,KW,KY,MC,MH,TI

4. MeSH DESCRIPTOR Ethosuximide Explode All

5. (Epilepax OR Lamictal OR Lamotrigin* OR Lamotrine OR Lamitrin OR Lamictin OR Lamogine OR Lamitor):AB,KW,KY,MC,MH,TI

6. MESH DESCRIPTOR Lamotrigine EXPLODE ALL

7. #1 OR #2 OR #3 OR #4 OR #5 OR #6

8. MeSH DESCRIPTOR Epilepsy, Absence Explode All

9. absence adj1 (epilep* or seizure*)

10. "petit mal"

11. #8 OR #9 OR #10

12. #7 AND #11

13. >01/09/2016:CRSCREATED

14. #12 AND #13

Appendix 2. MEDLINE search strategy

This search strategy includes a modification of the Cochrane Highly Sensitive Search Strategy for identifying randomized trials (Lefebvre 2019).

1. exp controlled clinical trial/ or (randomi?ed or placebo or randomly).ab.

2. clinical trials as topic.sh.

3. trial.ti.

4. 1 or 2 or 3

5. exp animals/ not humans.sh.

6. 4 not 5

7. (Avugane or Baceca or Convulex or Delepsine or Depacon or Depakene or Depakine or Depakote or Deproic or Epiject or Epilex or Epilim or Episenta or Epival or Ergenyl or Mylproin or Orfiril or Orlept or Selenica or Sprinkle or Stavzor or Valcote or Valparin or Valpro or Valproate or Valproic or VPA).tw.

8. *Valproic Acid/

9. (Aethosuximide or Emeside or Ethosucci* or Ethosuxide or Ethosuximide or Etosuximida or Zarontin).tw.

10. *Ethosuximide/

11. (Epilepax or Lamictal or Lamotrigin* or Lamotrine or Lamitrin or Lamictin or Lamogine or Lamitor).tw.

12. exp Lamotrigine/

13. 7 or 8 or 9 or 10 or 11 or 12

14. exp Epilepsy, Absence/

15. (absence adj1 (epilep$ or seizure$)).tw.

16. petit mal.tw.

17. 14 or 15 or 16

18. 6 and 13 and 17

19. limit 18 to ed=20160901‐20200922

20. 18 not (1$ or 2$).ed.

21. 20 and (2016$ or 2017$ or 2018$ or 2019$ or 2020$).dt.

22. 19 or 21

23. remove duplicates from 22

Figure 1

Study flow diagram (results refer only to the updated version of the review). The previous versions of the review (Posner 2003; Posner 2005a; Posner 2005b; Brigo 2017; Brigo 2019) included eight studies.

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Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1: Ethosuximide versus valproate, Outcome 1: Seizure free

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Analysis 1.2

Comparison 1: Ethosuximide versus valproate, Outcome 2: 80% or greater reduction in seizure frequency

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Analysis 1.3

Comparison 1: Ethosuximide versus valproate, Outcome 3: 50% or greater reduction in seizure frequency

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Analysis 2.1

Comparison 2: Lamotrigine versus valproate, Outcome 1: Seizure free

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Analysis 2.2

Comparison 2: Lamotrigine versus valproate, Outcome 2: Normalisation of the EEG

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Analysis 3.1

Comparison 3: Ethosuximide versus lamotrigine, Outcome 1: Seizure free at 12 months

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Summary of findings 1. Ethosuximide compared to valproate for absence seizures in children and adolescents

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Ethosuximide compared to valproate for absence seizures in children and adolescents
Patient or population: absence seizures in children and adolescents Setting: outpatients Intervention: ethosuximide Comparison: valproate
Outcomes	Risk with valproate	Risk with ethosuximide	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Seizure freedom at 12 months	Study population		‐	365 (4 RCTs)	⊕⊕⊕⊝ MODERATE ¹	None of the included trials found a difference for this outcome. Length of follow‐up in included studies: from 6 weeks to 4 years.
Seizure freedom at 12 months	see comment	see comment	‐	365 (4 RCTs)	⊕⊕⊕⊝ MODERATE ¹
80% or greater reduction in seizure frequency	Study population		RR 0.70 (0.19 to 2.59)	29 (1 RCT)^a	⊕⊝⊝⊝ VERY LOW ^2,3	No difference was found, but the confidence interval is wide and equivalence cannot be inferred. Length of follow‐up: 6 weeks.
80% or greater reduction in seizure frequency	286 per 1,000	200 per 1,000 (54 to 740)	RR 0.70 (0.19 to 2.59)	29 (1 RCT)^a	⊕⊝⊝⊝ VERY LOW ^2,3
50% or greater reduction in seizure frequency	Study population		‐	49 (2 RCTs)	⊕⊕⊝⊝ LOW ^4,5	No difference was found, but the confidence interval is wide and equivalence cannot be inferred. Length of follow‐up in included studies: from 1 to 4 years.
50% or greater reduction in seizure frequency	see comment	see comment	‐	49 (2 RCTs)	⊕⊕⊝⊝ LOW ^4,5
Normalisation of the EEG ‐ not reported	‐	‐	‐	‐	‐
Adverse effects (Table 1; Table 2) Ethosuximide treatment was mostly associated with nausea, vomiting, and behavioural/psychiatric changes. The most common adverse effects of treatment with valproate were fatigue, nausea, vomiting, increased appetite with weight gain, behavioural/psychiatric changes (decreased concentration, personality change, hyperactivity, attention problems, hostility), and thrombocytopenia
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹ Most information is from studies at low or unclear risk of bias; plausible bias is likely to seriously alter the results. ² Information is from a study with unclear and high risk of bias; plausible bias is likely to seriously alter the results. ³ Small number of patients included in this study (29) (see also footnote below). ⁴ Information is from two small studies with unclear or high risk of bias; plausible bias is likely to seriously alter the results. ⁵ Information is from two studies with small number of patients included. ^aIn this study, one patient in the ethosuximide group was subsequently treated with valproate, but failed to respond to either single drug and did not improve when both drugs were used in combination. The outcomes of this patient on combined treatment were therefore counted twice ("no remission"), since the patient received both drugs.

Summary of findings 1. Ethosuximide compared to valproate for absence seizures in children and adolescents

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Table 1. Adverse effects on valproate: number of participants experiencing each event

Event	Callaghan 1982	Sato 1982	Martinovic 1983	Coppola 2004	Huang 2009	Glauser 2013a
Acute pancreatitis	1
Obesity/Weight gain	1			1		14
Drowsiness		4
Nausea		5	3			12*
Vomiting		1	2			12*
Decreased platelet numbers		2	4
Increased appetite						15
Poor appetite		1				8
Diarrhoea				1		7
Dizziness		1				2
Hyperactivity						23
Attention problems						24
Hostility						22
Concentration decreased						18
Personality change						17
Sleep problem						17
Depression						11
Slow process speed						11
Memory problem						10
Apathy						9
Fatigue						27
Headache		1				18
Leukopenia		2
Elevated liver function tests		1			7
Elevated LDH		1
Rash						2
*Nausea, vomiting, or both LDH: lactate dehydrogenase Numbers of individuals within each study undertaking valproate: 14 (Callaghan 1982), 22 (Sato 1982), 10 (Martinovic 1983), 19 (Coppola 2004), 23 (Huang 2009), 146 (Glauser 2013a).

Table 1. Adverse effects on valproate: number of participants experiencing each event

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Table 2. Adverse effects on ethosuximide: number of participants experiencing each event

Event	Callaghan 1982	Sato 1982	Martinovic 1983	Glauser 2013a
Drowsiness	1	5
Tiredness			2
Nausea		3	2	29*
Vomiting		3		29*
Increased appetite				6
Poor appetite		1		10
Diarrhoea				9
Dizziness		1		10
Headache		2		23
Leukopenia		3
Hiccups		1
Moodiness		1
Hyperactivity				13
Attention problems				8
Hostility				4
Concentration decreased				6
Personality change				6
Sleep problem				11
Depression				4
Slow process speed				3
Memory problem				0
Apathy				4
Fatigue				26
Rash				6
* Nausea, vomiting, or both Numbers of individuals within each study undertaking ethosuximide: 14 (Callaghan 1982), 23 (Sato 1982), 10 (Martinovic 1983), 154 (Glauser 2013a).

Table 2. Adverse effects on ethosuximide: number of participants experiencing each event

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Summary of findings 2. Lamotrigine compared to valproate for absence seizures in children and adolescents

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Lamotrigine compared to valproate for absence seizures in children and adolescents
Patient or population: absence seizures in children and adolescents Setting: outpatients Intervention: lamotrigine Comparison: valproate
Outcomes	Risk with valproate	Risk with lamotrigine	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Seizure freedom at 12 months	Study population		‐	405 (4 RCTs)	⊕⊕⊕⊝ MODERATE ¹	Higher proportion seizure free at 1 month in patients receiving valproate compared to those receiving lamotrigine (2 studies). No difference between valproate and lamotrigine for seizure freedom at 3 and 6 months (3 and 4 studies, respectively). Length of follow‐up in included studies: 12 months.
Seizure freedom at 12 months	see comment	see comment	‐	405 (4 RCTs)	⊕⊕⊕⊝ MODERATE ¹
80% or greater reduction in seizure frequency ‐ not reported	‐	‐	‐	‐	‐
50% or greater reduction in seizure frequency ‐ not reported	‐	‐	‐	‐	‐
Normalisation of the EEG	Study population		RR 2.39 (1.14 to 5.04)	45 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^2,3	Length of follow‐up: 12 months.
Normalisation of the EEG	273 per 1,000	652 per 1,000 (311 to 1,000)	RR 2.39 (1.14 to 5.04)	45 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^2,3	Length of follow‐up: 12 months.
Adverse effects (Table 1; Table 3) The most common adverse effects of treatment with lamotrigine were fatigue, and behavioural/psychiatric changes. The most common adverse effects of treatment with valproate were fatigue, nausea, vomiting, increased appetite with weight gain, behavioural/psychiatric changes (decreased concentration, personality change, hyperactivity, attention problems, hostility), and thrombocytopenia
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹ Most information comes from studies at low or unclear risk of bias; plausible bias is likely to seriously alter the results. ² Information comes from a small study at unclear and high risk of bias. ³ Information comes from a single study conducted in a small number of patients.

Summary of findings 2. Lamotrigine compared to valproate for absence seizures in children and adolescents

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Table 3. Adverse effects on lamotrigine: number of participants experiencing each event

Event	Frank 1999	Coppola 2004	Huang 2009	Glauser 2013a
Abdominal pain	5
Headache	2	2		14
Nausea	3			2*
Vomiting				2*
Poor appetite	2			9
Increased appetite		1		10
Diarrhoea				2
Dizziness	3		5	5
Hyperkinesia	2
Hyperactivity				12
Attention problems				11
Hostility				11
Concentration decreased				9
Personality change				10
Sleep problem				5
Depression				11
Slow process speed				7
Memory problem				8
Apathy				3
Fatigue			1	18
Rash	10	1	2	6
Nervousness		1
Diplopia		1
*Nausea, vomiting, or both Numbers of individuals within each study undertaking lamotrigine: 15 (Frank 1999), 19 (Coppola 2004), 24 (Huang 2009), 146 (Glauser 2013a).

Table 3. Adverse effects on lamotrigine: number of participants experiencing each event

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Summary of findings 3. Ethosuximide compared to lamotrigine for absence seizures in children and adolescents

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Ethosuximide compared to lamotrigine for absence seizures in children and adolescents
Patient or population: absence seizures in children and adolescents Setting: outpatients Intervention: ethosuximide Comparison: lamotrigine
Outcomes	Risk with lamotrigine	Risk with ethosuximide	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Seizure freedom at 12 months	Study population		RR 0.47 (0.33 to 0.67)	300 (1 RCT)	⊕⊕⊕⊕ HIGH	Length of follow‐up: 12 months.
Seizure freedom at 12 months	455 per 1,000	214 per 1,000 (150 to 305)	RR 0.47 (0.33 to 0.67)	300 (1 RCT)	⊕⊕⊕⊕ HIGH	Length of follow‐up: 12 months.
80% or greater reduction in seizure frequency ‐ not reported	‐	‐	‐	‐	‐
50% or greater reduction in seizure frequency ‐ not reported	‐	‐	‐	‐	‐
Normalisation of the EEG ‐ not reported	‐	‐	‐	‐	‐
Adverse effects (Table 2; Table 3) Ethosuximide treatment was mostly associated with nausea, vomiting, and behavioural/psychiatric changes. The most common adverse effects of treatment with lamotrigine were fatigue, and behavioural/psychiatric changes.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Summary of findings 3. Ethosuximide compared to lamotrigine for absence seizures in children and adolescents

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Comparison 1. Ethosuximide versus valproate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Seizure free Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1.1 Drug naive	4		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.2 80% or greater reduction in seizure frequency Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.2.1 Previously treated	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.3 50% or greater reduction in seizure frequency Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 1. Ethosuximide versus valproate

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Comparison 2. Lamotrigine versus valproate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Seizure free Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1.1 Seizure free at 1 month	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.1.2 Seizure free at 3 months	3		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.1.3 Seizure freedom at 6 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.1.4 Seizure free at 12 months	4		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.2 Normalisation of the EEG Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. Lamotrigine versus valproate

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Comparison 3. Ethosuximide versus lamotrigine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Seizure free at 12 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 3. Ethosuximide versus lamotrigine

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Etosuximida, valproato de sodio o lamotrigina para las crisis de ausencia en niños y adolescentes

Appendices