. 2021 Apr 7;47:85. doi: 10.1186/s13052-021-01027-2

Table 2.

Full description of the sources: prospective studies

Prospective studies	Population	Etiology	Treatment	Add-on therapy	Outcome
Ramantani et al. [27]	N = 38; term and preterm.	N = 9 HIE N = 16 IVH N = 13 sepsis	N = 38 LEV (10–30 mg/kg)	N = 11 PHB as 2nd line	LEV’s efficacy: 79%; 27/30 (90%) remained seizure free at 4 weeks.
Sharpe et al. [28]	N = 18; term.	N = 8 HIE N = 2 IVH N = 1 birth trauma N = 2 stroke N = 1 brain malformation N = 4 N/A	PHB (20 mg/kg)	LEV (20-40 mg/kg)	LEV’s efficacy: 42%. 5 of the responders were among the 12 subjects who received the higher dose of LEV.
Furwentsches et al. [29]	N = 6; term and preterm	N = 1 HIE N = 1 IVH N = 3 brain malformation N = 1 N/A	N = 4 oral LEV (10–50 mg/kg) N = 2 PHB (10 mg/kg)	N = 2 LEV	All 6 patients treated with oral LEV became seizure free within 6 days. After 3 months, five out of six patients were seizure free under monotherapy with LEV.
Falsaperla et al. [30]	N = 16; late preterm and term.	N = 5 MAS N = 8 RDS N = 3 APD	LEV (10–40 mg/kg)	/	LEV’s efficacy: 100%.Seizure freedom reached from 24 h to 15 days. EEGs at three months resulted normal.
Boylan et al. [31]	N = 17	N = 7 HIE N = 1 RDS N = 1 IUGR N = 3 sepsis N = 3 prematurity N = 1 NAS N = 1 kernicterus	N = 15 PHB (20–30 mg/kg)	N = 2 PHE (20 mg/kg)	Full response to PHB in 6/17 (35%). Partial response to PHB in 6/17 (35%). No response in 2/17 (12%).
Low et al. [32]	N = 19 term or near term	N = 10 HIE N = 6 stroke N = 1 CNS infection N = 1 BFNE N = 1 N/A	PHB 10–40 mg/kg i.v.	PHE or MDZ as 2nd line (dose: N/A)	PHB abolished seizurs in 13/19 patients within 1 h. Only 3 patients showed permanent reduction. Loading dose of 20 mg/kg was more effective than 10 mg/kg.
Van der Broek et al. [33]	N = 53 term newborns	HIE	PHB 20–40 mg/kg	MDZ c.i. 0.05–0.1 mg/kg/h	The observed responsiveness of MDZ add-on therapy after PHB monotherapy was low (23%) compared to PHB monotherapy’s effectiveness (66%).
Hellstrom- Westas et al. [34]	N = 24 both term and preterm	N = 15 HIE N = 6 IVH N = 2 HIE N = 1 hypoglicemia	N = 24 PHB (10–15 mg/kg)	N = 21 DZP as 2nd line (0.5–2 mg/kg) N = 24 LID as 3rd line (1.6–2.2 mg/kg)	LID’s introduction conducted to seizure cessation in 15/24 patients. 2 of them developed bradycardia and acidosis.
Maytal et al. [35]	N = 7	N = 4 HIE N = 2 IVH N = 1 CNS infections	N = 7 PHB (20–40 mg/kg)	N = 7 LRZ (0.05 mg/kg i.v.)	After PHB’s failure, 6/7 patients had complete cessation of seizures within 3 min. 4/6 remained seizure-free on follow-up. No side-effects were reported.
Glass et al. [36]	N = 92	N = 30 HIE N = 25 IVH	N = N/A PHB (20 mg/kg) N = N/A LEV (dose: N/A) N = N/A PHE (dose: N/A)	N/A	64% had seizures that persisted after loading doses of PHB, 58% after LEV and 100% after PHE. .
Glass et al. [37]	N = 543 term and preterm	N = 284 HIE N = 142 stroke N = 108 IVH	N = 508 PHB N = 21 LEV N = 5 PHE (doses: N/A)	N/A	354/543 (66%) neonates had incomplete response to the initial loading dose of AED. Incomplete response was similar for PHB (66%), LEV (67%), PHE (80%).

Prospective studies

Population

Etiology

Treatment

Add-on therapy

Outcome

Ramantani et al.

[27]

N = 38;

term and preterm.

N = 9 HIE

N = 16 IVH

N = 13 sepsis

N = 38 LEV

(10–30 mg/kg)

N = 11 PHB as 2nd line

LEV’s efficacy: 79%;

27/30 (90%) remained seizure free at 4 weeks.

Sharpe et al. [28]

N = 18;

term.

N = 8 HIE

N = 2 IVH

N = 1 birth trauma

N = 2 stroke

N = 1 brain malformation

N = 4 N/A

PHB

(20 mg/kg)

LEV

(20-40 mg/kg)

LEV’s efficacy: 42%.

5 of the responders were among the 12 subjects who received the higher dose of LEV.

Furwentsches et al.

[29]

N = 6;

term and preterm

N = 1 HIE

N = 1 IVH

N = 3 brain malformation

N = 1 N/A

N = 4 oral LEV

(10–50 mg/kg)

N = 2 PHB

(10 mg/kg)

N = 2 LEV

All 6 patients treated with oral LEV became seizure free within 6 days.

After 3 months, five out of six patients were seizure free under monotherapy with LEV.

Falsaperla et al.

[30]

N = 16;

late preterm and term.

N = 5 MAS

N = 8 RDS

N = 3 APD

LEV

(10–40 mg/kg)

LEV’s efficacy: 100%.Seizure freedom reached from 24 h to 15 days. EEGs at three months resulted normal.

Boylan et al. [31]

N = 17

N = 7 HIE

N = 1 RDS

N = 1 IUGR

N = 3 sepsis

N = 3 prematurity

N = 1 NAS

N = 1 kernicterus

N = 15 PHB

(20–30 mg/kg)

N = 2 PHE

(20 mg/kg)

Full response to PHB in 6/17 (35%).

Partial response to PHB in 6/17 (35%).

No response in 2/17 (12%).

Low et al.

[32]

N = 19 term or near term

N = 10 HIE

N = 6 stroke

N = 1 CNS infection

N = 1 BFNE

N = 1 N/A

PHB 10–40 mg/kg i.v.

PHE or MDZ as 2nd line (dose: N/A)

PHB abolished seizurs in 13/19 patients within 1 h.

Only 3 patients showed permanent reduction.

Loading dose of 20 mg/kg was more effective than 10 mg/kg.

Van der Broek et al.

[33]

N = 53 term newborns

HIE

PHB 20–40 mg/kg

MDZ c.i. 0.05–0.1 mg/kg/h

The observed responsiveness of MDZ add-on therapy after PHB monotherapy was low (23%) compared to PHB monotherapy’s effectiveness (66%).

Hellstrom- Westas et al. [34]

N = 24 both term and preterm

N = 15 HIE

N = 6 IVH

N = 2 HIE

N = 1 hypoglicemia

N = 24 PHB

(10–15 mg/kg)

N = 21 DZP as 2nd line

(0.5–2 mg/kg)

N = 24 LID as 3rd line

(1.6–2.2 mg/kg)

LID’s introduction conducted to seizure cessation in 15/24 patients.

2 of them developed bradycardia and acidosis.

Maytal et al. [35]

N = 7

N = 4 HIE

N = 2 IVH

N = 1 CNS infections

N = 7 PHB

(20–40 mg/kg)

N = 7 LRZ

(0.05 mg/kg i.v.)

After PHB’s failure, 6/7 patients had complete cessation of seizures within 3 min. 4/6 remained seizure-free on follow-up.

No side-effects were reported.

Glass et al. [36]

N = 92

N = 30 HIE

N = 25 IVH

N = N/A PHB

(20 mg/kg)

N = N/A LEV

(dose: N/A)

N = N/A PHE

(dose: N/A)

N/A

64% had seizures that persisted after loading doses of PHB, 58% after LEV and 100% after PHE. .

Glass et al.

[37]

N = 543 term and preterm

N = 284 HIE

N = 142 stroke

N = 108 IVH

N = 508 PHB

N = 21 LEV

N = 5 PHE

(doses: N/A)

N/A

354/543 (66%) neonates had incomplete response to the initial loading dose of AED.

Incomplete response was similar for PHB (66%), LEV (67%), PHE (80%).

N number of patients; PHB phenobarbital; PHE phenytoin; CNS central nervous system; AED anti-epileptic drug; N/A not available; HIE hypoxic ischemic encephalopathy; IVH intra-ventricular hemorrhage; BFNE benign familial neonatal epilepsy; IUGR intra-uterine growth restriction; MDZ midazolam; LID lidocaine; BMT bumetanide; MAS meconium aspiration syndrome; RDS respiratory distress syndrome; LEV levetiracetam. EEG electroencephalography; LRZ lorazepam; DZP diazepam; CFM cerebral function monitoring; NAS neonatal abstinence syndrome; APD acute placental detachment