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

Table 3.

Full description of the sources: retrospective studies

Retrospective studies	Population	Etiology	Treatment	Add-on therapy	Outcome
Abend et al. [38]	N = 23 late preterm and term	N = 8 HIE N = 4 genetic N = 3 malformative N = 3 infections N = 2 cryptogenic N = 2 stroke N = 1 tumor	N = 18 PHB (dose: N/A) N = 1 PHE (dose: N/A) N = 4 LEV (10–20 mg/kg)	N = 13 LEV as 2nd line (dose: N/A) N = 5 LEV as 3rd line	Seizure cessation in 7/23 (30%); seizure reduction (> 50%) in 1/23.
Khan et al. [39]	N = 22 term	N = 12 HIE N = 2 IVH N = 2 CNS infections N = 6 various	N = 16 PHB (dose: N/A) N = 3 LEV (dose: N/A)	N = 19 received LEV as 2nd (N = 16), 3rd (N = 2) or 4th (N = 1) line	7 of 22 patients (32%) achieved complete cessation of seizures after administration of the loading dose, 14 (64%) achieved cessation of seizures by 24 h, 19 (86%) by 48 h, and all 22 (100%) by 72 h
Khan et al. [40]	N = 12 preterm	N = 5 HIE N = 3 IVH N = 3 N/A N = 1 HSV encephalitis	N = 9 PHB (dose: N/A) N = 3 LID (dose: N/A)	N = 12 LEV (dose: N/A)	4 patients (36%) reached seizure cessation after the loading dose, 9 (82%) by 24 h, 10 (91%) by 48 h, and 10 subjects (91%) by 72 h.
Rakshabhuva- nkar et al. [41]	N = 8 term and preterm	N = 5 HIE N = 2 IVH N = 1 N/A	N = 8 PHB (dose: N/A) N = N/A PHE (dose: N/A)	N = 8 LEV (10 mg/kg)	LEV’s effectiveness in 6/8 patients.
Lo Yee Yau et al. [42]	N = 12 preterm and term	N = 6 HIE N = 3 CNS infections N = 1 hypoglicemia N = 2 metabolic	N = 12 PHB (dose: N/A)	N = 8 MDZ as 2nd line AED and LEV as 3rd line. N = 4 were given LEV as 2nd line AED.	LEV’s efficacy: 75% of patients treated. No side effects reported.
Maljevic et al. [43]	N = 10	KCNQ 3 mutations	N = 1 PYR N = 2 LEV N = 1 OXC	N = 1 LEV (65 mg/kg) N = 1 OXC (20 mg/kg)	1 was seizure free after one dose of LEV. 1 was seizure free after day 20 on LEV. 1 was seizure free on OXC.
Shin et al. [44]	N = 18 term and preterm	N = 12 HIE N = 1 CNS N = 1 IVH N = 4 malformative	N = 18 PHB or PHE (dose: N/A)	N = 18 LEV after PHB failure (N = 1 only LEV N = 11 LEV + PHB N = 6 PHE + LEV)	94% of patients had seizure cessation within the first week from LEV’s introduction, and 89% remained seizure-free under LEV monotherapy at 1 month.
Han et al. [45]	N = 37 preterm	N = 15 HIE N = 6 GMH N = 14 IVH N = 1 malformative N = 1 meningitis	LEV (40–60 mg/kg)	N = N/A PHB (20 mg/kg) N=N/A PHE, MDZ, TPM, VPA as 3rd line.	Seizure cessation in 21 patients (57%) with LEV alone. Seizure cessation in 9 infants (24%) after LEV + PHB. 7 required third-line AED.
Venkatesan et al. [46]	N = 32 term	HIE	N = 23 PHB N = 2 LEV N = 2 MDZ (doses: N/A)	N = 23 LEV as 2nd line N = 2 LEV as 3rd line after PHB and MDZ failure	84% of the patients treated with LEV achieved seizure cessation within 72 h.
Rao et al. [47]	N = 44 term	HIE	N = 23 PHB N = 2 LEV	N = 10 LEV as 2nd line	50% of patients treated with levetiracetam became seizure-free after 40 h, and 100% achieved seizure freedom between 100 and 120 h.
Van der Broek et al. [48]	N = 31 term	HIE	N = 31 PHB (20 mg/kg)	/	PHB’s efficacy: 66%.
Boylan et al. [49]	N = 14 term and preterm	N = 4 HIE N = 3 IVH N = 3 metabolic N = 1 meningitis N = 3 mild asphyxia	N = 14 PHB (20–40 mg/kg)	N = 4 CLZ N=N/A PHE (doses: N/A)	PHB was only effective in 29% of patients, those with normal background EEGs or mild to moderate background abnormalities and low seizure burden.
Spagnoli et al. [50]	N = 91 term and preterm	N = 45 HIE N = 21 IVH N = 4 malformative N = 12 metabolic disorders N = 4 CNS infection N = 1 genetic N = 4 N/A	N = 91 PHB (20 mg/kg)	N = N/A PHE 20 mg/kg as 2nd line N = N/A MDZ 0.15 mg/kg as 3rd line	PHB was effective alone in 62.6% of patients.
Hakeem et al. [51]	N = 11 term and preterm	N = 6 HIE N = 3 IVH N = 1 CNS N = 1 N/A	N = 2 oral cloral hydrate (30 mg/kg) N = 7 PHB (20 mg/kg) N = 2 DZP (1 to 2 mg iv bolus)	N = 1 CLZ c.i. (10 mcg/kg/hr)	6/7 responded to PHB but 4/7 later relapsed.
Weeke et al. [52]	N = 413 (N = 319 term, N = 94 preterm)	N = 228 HIE N = 45 HIE N = 32 PAIS N = 40 CNS infections N = 100 others	N = 413 PHB (dose: 20 mg/kg)	N = 186 LID as 2nd line N = 172 LID as 3rd line	In term infants, a response to LID was seen in 72.5–80%, with cessation of seizures and no need for rescue AED in 21.4–67.6%. Lower response rate in preterm (55.5–58.2% with cessation of seizures and no other AED in only 16.4–40.7%).
Lundqvist et al. [53]	N = 30 term	N = 18 HIE N = 4 meningitis N = 6 PAIS N = 1 hypoglicemia N = 1 uncertain	N = 17 DZP (dose: N/A) N = 8 MDZ (dose: N/A) N = 5 DZP + MDZ (dose: N/A)	N = 30 LID	LID’s efficacy: 65%.
Van der Broek et al. [54]	N = 22 term	HIE	N = 22 PHB (dose: N/A)	N = 22 MDZ (dose: N/A) N = 22 LID (dose: 2 mg/kg, followed by 4 mg/kg/h c.i.)	20/22 (90%) newborns responded to LID. No cardiac arrythmias were reported (91%)
Jennekens et al. [55]	N = 11 term	N = 11 stroke	N = 11 PHB (20 mg/kg)	N = 8 MDZ as 2nd line N = 9 LID as 3rd line	In term newborns with PAIS, MDZ and LID induce a shift from lower to higher frequency electrocortical activity. Compared to LID, MDZ reduced more pronouncedly the total EEG power.
Shany et al. [56]	N = 30 term	N = 30 HIE	N = 30 DZP or PHB	N = 22 LID as 2nd line N = 8 MDZ as 2nd line	77% response rate to LID.
McDermott et al. [57]	N = 10 term	HIE	N = 5 LRZ N = 4 PHB or PHE (20 mg/kg) N = 1 PHB (20 mg/kg)	N = 5 LRZ as 2nd line	Administration of a single dose of LRZ stopped seizures in all neonates. 4 neonates receiving simultaneously PHB and/or PHE had no further seizures. 6 had seizure recurrence.
Castro Conde et al. [58]	N = 13 term and preterm	N = 7 HIEN = 3 stroke N = 2 IVH N = 1 N/A	N = 32 PHB (20 mg/kg tritated up to 40 mg/kg) followed by PHE as 2nd line AED (20 mg/kg)	N = 13 MDZ as 2nd (9/13) or 3rd (4/13) line AED in non-responders.	Ten of 13 neonates with SE treated with midazolam were electrically controlled in the first hour of treatment.
Vilan et al. [59]	N = 9 term	KCNQ2 mutations	N = 9 PHB	N = 8 PYR, N = 6 LID, N = 6 MDZ, N = 3 CZP, N = 3 LEV, N = 2 PHE, N = 2 VPA, N = 2 CBZ, N = 1 TPM	PH and PYR (used in 8/9 patients) were ineffective. 2 patients were SF during LID infusion and were later switched to oral PHT or oral CBZ.
Montesclaros Hortigüela et al. [60]	N = 13 G.A. = N/A	KCNQ2 mutations	N = 10 PHB N = 2 LEV N = 1 MDZ (doses: N/A)	Several AED were administered as 2nd line: CBZ, LEV, MDZ, VPA, PHE, TPM, VGB, LID, OXC, PYR	5/9 were seizure free but with severe impairment in psychomotor development in treatment with CBZ (n = 2), VPA + CBZ + LCM (n = 1), PHB + VPA + OXC (n = 1), OXC + TPM (n = 1).
Pisano et al. [61]	N = 15 term	KCNQ2 mutations	Multiple AEDs (including PHB as first-line AED, VPA, steroids) were tried unsuccessfully	N = N/A CBZ (20 mg/kg/day) N = N/A PHE (dose widely ranging)	53% of the patients were seizure-free on CBZ; 33% responded to PHE; the remaining 47% of the patients responded to TPM and LEV.
Sands et al. [62]	N = 19 term	SLC13A5 mutations (KCNQ2 gene)	N = 13 PHB (dose: N/A) N = 4 CBZ (10 mg/kg)	N = 15 CBZ (10 mg/kg)	CBZ’s efficacy: 89%.
Singh et al. [63]	N = 10 term	N = 8 HIE N = 2 unknown	N = 10 CBZ (dose: 10 mg/kg)	N = 2 DZP	Seizure control in 80% of patients on CBZ; 2 patients needed DZP as 2nd line.
Glass et al. [64]	N = 6 term	HIE	N = 5 PHB (30–60 mg/kg)	N = 5 TPM (10 mg/kg)	3/5 patients treated with TPM had seizure reduction or cessation. One adjunctive patient achieved seizure freedom on TPM at 6 months.

Retrospective studies

Population

Etiology

Treatment

Add-on therapy

Outcome

Abend et al.

[38]

N = 23

late preterm and term

N = 8 HIE

N = 4 genetic

N = 3 malformative

N = 3 infections

N = 2 cryptogenic

N = 2 stroke

N = 1 tumor

N = 18 PHB

(dose: N/A)

N = 1 PHE

(dose: N/A)

N = 4 LEV

(10–20 mg/kg)

N = 13 LEV as 2nd line

(dose: N/A)

N = 5 LEV as 3rd line

Seizure cessation in 7/23 (30%); seizure reduction (> 50%) in 1/23.

Khan et al.

[39]

N = 22 term

N = 12 HIE

N = 2 IVH

N = 2 CNS infections

N = 6 various

N = 16 PHB

(dose: N/A)

N = 3 LEV

(dose: N/A)

N = 19 received LEV as 2nd (N = 16), 3rd (N = 2) or 4th (N = 1) line

7 of 22 patients (32%) achieved complete cessation

of seizures after administration of the loading dose, 14 (64%) achieved cessation of seizures by 24 h, 19 (86%) by 48 h, and all 22 (100%) by 72 h

Khan et al.

[40]

N = 12 preterm

N = 5 HIE

N = 3 IVH

N = 3 N/A

N = 1 HSV encephalitis

N = 9 PHB

(dose: N/A)

N = 3 LID

(dose: N/A)

N = 12 LEV

(dose: N/A)

4 patients (36%) reached seizure cessation after the loading dose, 9 (82%) by 24 h, 10 (91%) by 48 h, and 10 subjects (91%) by 72 h.

Rakshabhuva-

nkar et al.

[41]

N = 8

term and preterm

N = 5 HIE

N = 2 IVH

N = 1 N/A

N = 8 PHB

(dose: N/A)

N = N/A PHE

(dose: N/A)

N = 8 LEV

(10 mg/kg)

LEV’s effectiveness in 6/8 patients.

Lo Yee Yau et al.

[42]

N = 12 preterm and term

N = 6 HIE

N = 3 CNS infections

N = 1 hypoglicemia

N = 2 metabolic

N = 12 PHB

(dose: N/A)

N = 8 MDZ as 2nd line AED and LEV as 3rd line.

N = 4 were given LEV as 2nd line AED.

LEV’s efficacy: 75% of patients treated.

No side effects reported.

Maljevic et al.

[43]

N = 10

KCNQ 3 mutations

N = 1 PYR

N = 2 LEV

N = 1 OXC

N = 1 LEV

(65 mg/kg)

N = 1 OXC

(20 mg/kg)

1 was seizure free after one dose of LEV.

1 was seizure free after day 20 on LEV.

1 was seizure free on OXC.

Shin et al.

[44]

N = 18

term and preterm

N = 12 HIE

N = 1 CNS

N = 1 IVH

N = 4 malformative

N = 18 PHB or PHE

(dose: N/A)

N = 18 LEV after PHB failure

(N = 1 only LEV

N = 11 LEV + PHB

N = 6 PHE + LEV)

94% of patients had seizure cessation within the first week from LEV’s introduction, and 89% remained seizure-free under LEV monotherapy at 1 month.

Han et al.

[45]

N = 37 preterm

N = 15 HIE

N = 6 GMH

N = 14 IVH

N = 1 malformative

N = 1 meningitis

LEV

(40–60 mg/kg)

N = N/A PHB

(20 mg/kg)

N=N/A PHE, MDZ, TPM, VPA as 3rd line.

Seizure cessation in 21 patients (57%) with LEV alone.

Seizure cessation in 9 infants (24%) after LEV + PHB.

7 required third-line AED.

Venkatesan et al.

[46]

N = 32 term

HIE

N = 23 PHB

N = 2 LEV

N = 2 MDZ

(doses: N/A)

N = 23 LEV as 2nd line

N = 2 LEV as 3rd line after PHB and MDZ failure

84% of the patients treated with LEV achieved seizure cessation within 72 h.

Rao et al.

[47]

N = 44 term

HIE

N = 23 PHB

N = 2 LEV

N = 10 LEV as 2nd line

50% of patients treated with levetiracetam became seizure-free after 40 h, and 100% achieved seizure freedom between 100 and 120 h.

Van der Broek et al.

[48]

N = 31 term

HIE

N = 31 PHB

(20 mg/kg)

PHB’s efficacy: 66%.

Boylan et al.

[49]

N = 14

term and preterm

N = 4 HIE

N = 3 IVH

N = 3 metabolic

N = 1 meningitis

N = 3 mild asphyxia

N = 14 PHB

(20–40 mg/kg)

N = 4 CLZ

N=N/A PHE

(doses: N/A)

PHB was only effective in 29% of patients, those with normal background EEGs or mild to moderate

background abnormalities and low seizure burden.

Spagnoli et al.

[50]

N = 91

term and preterm

N = 45 HIE

N = 21 IVH

N = 4 malformative

N = 12 metabolic disorders

N = 4 CNS infection

N = 1 genetic

N = 4 N/A

N = 91 PHB

(20 mg/kg)

N = N/A PHE 20 mg/kg as 2nd line

N = N/A MDZ 0.15 mg/kg as 3rd line

PHB was effective alone in 62.6% of patients.

Hakeem et al.

[51]

N = 11

term and preterm

N = 6 HIE

N = 3 IVH

N = 1 CNS

N = 1 N/A

N = 2 oral cloral hydrate (30 mg/kg)

N = 7 PHB

(20 mg/kg)

N = 2 DZP

(1 to 2 mg iv bolus)

N = 1 CLZ c.i. (10 mcg/kg/hr)

6/7 responded to PHB but 4/7 later relapsed.

Weeke et al.

[52]

N = 413

(N = 319 term, N = 94 preterm)

N = 228 HIE

N = 45 HIE

N = 32 PAIS

N = 40 CNS infections

N = 100 others

N = 413 PHB

(dose: 20 mg/kg)

N = 186 LID as 2nd line

N = 172 LID as 3rd line

In term infants, a response to LID was seen in 72.5–80%, with cessation of seizures and no need for rescue AED in 21.4–67.6%. Lower response rate in preterm (55.5–58.2% with cessation of seizures and no other AED in only 16.4–40.7%).

Lundqvist et al.

[53]

N = 30 term

N = 18 HIE

N = 4 meningitis

N = 6 PAIS

N = 1 hypoglicemia

N = 1 uncertain

N = 17 DZP

(dose: N/A)

N = 8 MDZ

(dose: N/A)

N = 5 DZP + MDZ

(dose: N/A)

N = 30 LID

LID’s efficacy: 65%.

Van der Broek et al.

[54]

N = 22

term

HIE

N = 22 PHB

(dose: N/A)

N = 22 MDZ

(dose: N/A)

N = 22 LID

(dose: 2 mg/kg, followed

by 4 mg/kg/h c.i.)

20/22 (90%) newborns responded to LID.

No cardiac arrythmias were reported

(91%)

Jennekens et al.

[55]

N = 11

term

N = 11 stroke

N = 11 PHB

(20 mg/kg)

N = 8 MDZ as 2nd line

N = 9 LID as 3rd line

In term newborns with PAIS, MDZ and LID induce a shift from lower to higher frequency electrocortical activity. Compared to LID, MDZ reduced more pronouncedly the total EEG power.

Shany et al.

[56]

N = 30

term

N = 30 HIE

N = 30 DZP or PHB

N = 22 LID as 2nd line

N = 8 MDZ as 2nd line

77% response rate to LID.

McDermott et al.

[57]

N = 10

term

HIE

N = 5 LRZ

N = 4 PHB or PHE (20 mg/kg)

N = 1 PHB

(20 mg/kg)

N = 5 LRZ as 2nd line

Administration of a single dose of

LRZ stopped seizures in all neonates. 4 neonates receiving simultaneously PHB and/or PHE

had no further seizures. 6 had seizure recurrence.

Castro Conde et al.

[58]

N = 13

term and preterm

N = 7 HIEN = 3 stroke

N = 2 IVH

N = 1 N/A

N = 32 PHB (20 mg/kg tritated up to 40 mg/kg) followed by PHE as 2nd line AED (20 mg/kg)

N = 13 MDZ as 2nd (9/13) or 3rd (4/13) line AED in non-responders.

Ten of 13 neonates with SE treated with midazolam

were electrically controlled in the first hour of treatment.

Vilan et al.

[59]

N = 9

term

KCNQ2 mutations

N = 9 PHB

N = 8 PYR, N = 6 LID,

N = 6 MDZ, N = 3 CZP, N = 3 LEV,

N = 2 PHE, N = 2 VPA, N = 2 CBZ, N = 1 TPM

PH and PYR (used in 8/9 patients) were ineffective.

2 patients were SF during LID infusion and were later switched to oral PHT or oral CBZ.

Montesclaros Hortigüela et al.

[60]

N = 13

G.A. = N/A

KCNQ2 mutations

N = 10 PHB

N = 2 LEV

N = 1 MDZ

(doses: N/A)

Several AED were administered as 2nd line: CBZ, LEV, MDZ, VPA, PHE, TPM, VGB, LID, OXC, PYR

5/9 were seizure free but with severe impairment in psychomotor development in treatment with CBZ (n = 2), VPA + CBZ + LCM (n = 1), PHB + VPA + OXC (n = 1), OXC + TPM (n = 1).

Pisano et al.

[61]

N = 15

term

KCNQ2 mutations

Multiple AEDs (including PHB as first-line AED, VPA, steroids) were tried unsuccessfully

N = N/A CBZ

(20 mg/kg/day)

N = N/A PHE

(dose widely ranging)

53% of the patients were seizure-free on CBZ;

33% responded to PHE;

the remaining 47% of the patients responded to TPM and LEV.

Sands et al.

[62]

N = 19

term

SLC13A5 mutations

(KCNQ2 gene)

N = 13 PHB

(dose: N/A)

N = 4 CBZ

(10 mg/kg)

N = 15 CBZ

(10 mg/kg)

CBZ’s efficacy: 89%.

Singh et al.

[63]

N = 10

term

N = 8 HIE

N = 2 unknown

N = 10 CBZ

(dose: 10 mg/kg)

N = 2 DZP

Seizure control in 80% of patients on CBZ;

2 patients needed DZP as 2nd line.

Glass et al.

[64]

N = 6

term

HIE

N = 5 PHB

(30–60 mg/kg)

N = 5 TPM

(10 mg/kg)

3/5 patients treated with TPM had seizure reduction or cessation. One adjunctive patient achieved seizure freedom on TPM at 6 months.

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; VPA valproic acid; CBZ carbamazepine; TPM topiramate; G.A. gestational age; SE status epilepticus; HSV herpes simplex virus; PYR pyridoxine; OXC oxcarbazepine; GMH germinal matrix hemorrhage; TPM topiramate; CLZ clonazepam; DZP diazepam; LRZ lorazepam; PAIS perinatal arterial ischemic stroke; SF seizure- free