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

Table 4.

Full description of the sources: case reports

	Population	Etiology	Treatment	Add-on therapy	Outcome
Shoemaker et al. [65]	N = 3 term and preterm	N = 1 PAIS N = 2 PHVD	N = 2 PHB and PHE (dose: N/A) N = 1 PHE and OXC (dose: N/A)	N = 3 LEV as 3rd line (dose: N/A)	LEV’s administration resulted in seizure control in all three patients.
Tanriverdi et al. [66]	N = 1 term	SWS	PHB (20 mg/kg)	PHE as 2nd line (20 mg/kg) LEV as 3rd line (20 mg/kg)	Seizure control was achieved after LEV intravenous infusion.
Hmaimess et al. [67]	N = 1 Term	KCNT1 mutation	PHB (dose: N/A)	PHT, LTG, CLZ LEV (10–30 mg/kg)	LEV’s introduction resulted in dramatic decrease in seizure activity by the eighth day of treatment.
Ledet et al. [68]	N = 1 term	LLA	PHB (20 mg/kg)	LEV (40 mg/kg)	The patient was seizure-free on PHB and maintained seizure freedom on LEV that minimally interfered with her other ongoing treatments.
Li Jiang et al. [69]	N = 9 term	STXBP1mutations	PHB (dose: N/A)	5 patients did not respond and were tried on several AEDs (TPM, NZP, LEV, VPA, VIT B6, PDN, ACTH, KD)	44.4% of cases (4/9) in our study showed apparent responses to LEV.
Dilena et al. [70]	N = 1 term	SCN2A	PHB (dose: N/A)	LEV + PYR as 2nd line PHE as 3rd line (12–18 mg/kg/day)	Seizure freedom was reached on PHE, first, and maintained on oral CBZ.
Bonhorst et al. [71]	N = 1 term	KCNQ2	PHB (20 mg/kg) + VIT B6 (30 mg/kg/d)	MDZ c.i. as 2nd line (0.25 mg/kg/h) TPM as 3rd line (2 mg/kg/day) LID (6 mg/kg), then switched to PHE and, later CBZ (dose: N/A)	Seizure freedom was reached on LID; the patient developed methemoglobinemia as side-effect and seizure freedom was maintained with PHE, first, and oral CBZ, later.
Numis et al. [72]	N = 3 term and late preterm	KCNQ2 encephalopathy	PHB (dose: N/A)	LEV, TPM, VGB, CLZ, KD failed. CBZ was initiated at 3, 4 and 13 months (dose: N/A)	2/3 patients responded to CBZ and were seizure free at 30 months though developed severe psychomotor delay, quadriplegia, axial hypotonia with appendicular hypertonia, and a tendency to opisthotonos.
Spagnoli et al. [73]	N = 1 term	EIMFS due to KCNQ2 mutations	PHB (dose N/A)	PYR, LEV, PHE, MDZ, TPM, NTZ CBZ (dose: N/A)	After multiple AEDs failure, seizure ceased after 3 weeks from CBZ’s introduction. Patient was seizure free at nine months.
Blumkin et al. [74]	N = 1 Term	KNCQ2	PHB (dose: N/A)	TPM, LEV, VPA, LTG, PYR, folinic acid CBZ (50 mg/kg)	Seizure control was initially achieved with TPM. Seizures reoccurred after 3 weeks and did not respond to several AEDs until CBZ.
Buttle et al. [75]	N = 1 term	KCNQ2	PHB (dose: N/A)	LEV, LRZ, CLZ, PYR LID (2–4 mg/kg/h) CBZ (40 mg/kg)	After several AEDs failed, seizure freedom was reached on LID and maintained at a 13 months follow-up on oral CBZ.
Soldovieri et al. [76]	N = 1 term	KCNQ2 mutation (Kv7.2 subunit)	PHB (dose: N/A)	PYR, LEV, PHE, TPM, OXC	Partial response to an association of PHB, PHE, TPM. At 5 months he was switched to OXC and maintained seizure freedom until 14 months. The patient developed severe DD.
McNally et al. [77]	N = 1 term	SCN8A	PHB (20 mg/kg) + LEV (20–60 mg/kg)	OXC (up to 80 mg/kg) + PHE (20 mg/kg) + LTG (2 mg/kg/day)	The association of three sodium channel blockers (OXC + PHE + LTG) reduced seizures’ frequency.
Okumura et al. [78]	N = 1 term	2q21-q31deletion (SCN1A cluster)	PHB (dose: 20 mg/kg)	LEV as 2nd line (40 mg/kg) VPA as 3rd line (50 mg/kg)	PHB and LEV failed to control seizures; VPA reduced seizures’ frequency.
Riesgo et al. [79]	N = 3 preterm and term	N = 1 NAS N = 1 fetal distress N = 1 PVL	PHB (dose: N/A)	TPM (0.5–8 mg/kg/d) after several other AEDs failed (PHB, PHE, CLZ, VPA, MDZ)	Seizure cessation in all three after TPM’s administration.
Sirsi et al. [80]	N = 3 term	N = 1 HIE N = 1 meningitis N = 1 EIEE	PHB (dose: N/A)	PHE as 2nd line (dose: N/A) MDZ as 3rd line (up to 0.2 mcg/kg/h)	Seizure control within 6–72 h after MDZ’s introduction. One patient developed hypotension, that responded to inotropic support.
Steinberg et al. [81]	N = 2 preterm	N = 1 IVHN = 1 PVL	PHB (20 mg/kg)	PHE as 2nd line (20 mg/kg) Rectal VPA as 3rd line (20–30 mg/kg)	Seizure control was achieved and maintained on a 12 months follow-up on VPA.
Tarocco et al. [82]	N = 1 late preterm	Pierre-Robin, polymicrogyria, lissencephaly	PHB (dose: N/A)	PHE, MDZ, LEV, PPF KTM (2 mg/kg + c.i. of 10 mcg/kg/min)	Immediate complete clinical and electrographic response was obtained after KTM introduction; after 15 days SE relapsed and the patient died.
Baxter et al. [83]	N = 3 term	N = 2 EIEE N = 1 Aicardi-Goutieres	PHB (dose: N/A)	PYR, CLZ, VPA VGB (40 mg/kg/d)	2/3 patients showed full response to VGB.
Wolf et al. [84]	N = 1 term	Incontinentia pigmenti	PHB (35 mg/kg)	LRZ as 2nd line (0.2 mg/kg) PHE as 3rd line (20 mg/kg) Dexamethasone (0.25 mg/kg/d)	Rapid improvement and clinical seizures termination followed the initiation of CCS therapy.
Shevell et al. [85]	N = 1 term	BFNE	PHB (10 mg/kg)	/	Patient presented no more seizures, was discharged home on oral PHB, suspended at five months of life
Lee et al. [86]	N = 1 term	KCNQ2	PHB (6 mg/kg/day)	PHE as 2nd line (8 mg/kg/day) VGB (50 mg/kg/day)	VGB reduced seizures; Once treatment with Vigabatrin was administered seizures reduced to one per day until day 24 of post-natal life, time at which the last seizure was recorded.
Sato et al. [87]	N = 2 late preterm and term	HIE	PHB (10 mg/kg)	/	Both patients temporarily controlled seizures on PHB. One relapsed and developed severe DD.
Sillanpää et al. [88]	N = 1 term	Feeding epilepsy	PHB (60 mg/day) + chlorpromazine (9 mg/day)	The patient was seizure-free since day 14 of PHB.	Only few cases of neonatal feeding seizures are described. In this case the patient was seizure-free on PHB, after a six days combination-therapy with chlorpromazine.
Tramonte et al. [89]	N = 1 term	Temporal lobe hemorrhage	PHB (dose: N/A)	/	After PHB’s administration no more autonomic seizures (apnea, desaturations) were noticed.

Population

Etiology

Treatment

Add-on therapy

Outcome

Shoemaker et al.

[65]

N = 3

term and preterm

N = 1 PAIS

N = 2 PHVD

N = 2 PHB and PHE

(dose: N/A)

N = 1 PHE and OXC

(dose: N/A)

N = 3 LEV as 3rd line

(dose: N/A)

LEV’s administration resulted in seizure control in all three patients.

Tanriverdi et al.

[66]

N = 1

term

SWS

PHB

(20 mg/kg)

PHE as 2nd line

(20 mg/kg)

LEV as 3rd line

(20 mg/kg)

Seizure control was achieved after LEV intravenous infusion.

Hmaimess et al.

[67]

N = 1

Term

KCNT1 mutation

PHB

(dose: N/A)

PHT, LTG, CLZ

LEV

(10–30 mg/kg)

LEV’s introduction resulted in dramatic

decrease in seizure activity by the eighth day of treatment.

Ledet et al.

[68]

N = 1

term

LLA

PHB

(20 mg/kg)

LEV

(40 mg/kg)

The patient was seizure-free on PHB and maintained seizure freedom on LEV that minimally interfered with her other ongoing treatments.

Li Jiang et al.

[69]

N = 9

term

STXBP1mutations

PHB

(dose: N/A)

5 patients did not respond and were tried on several AEDs (TPM, NZP, LEV, VPA, VIT B6, PDN, ACTH, KD)

44.4% of cases (4/9) in our study showed apparent responses to LEV.

Dilena et al.

[70]

N = 1

term

SCN2A

PHB

(dose: N/A)

LEV + PYR as 2nd line

PHE as 3rd line

(12–18 mg/kg/day)

Seizure freedom was reached on PHE, first, and maintained on oral CBZ.

Bonhorst et al.

[71]

N = 1

term

KCNQ2

PHB

(20 mg/kg)

VIT B6

(30 mg/kg/d)

MDZ c.i. as 2nd line

(0.25 mg/kg/h)

TPM as 3rd line

(2 mg/kg/day)

LID (6 mg/kg), then switched to PHE and, later CBZ (dose: N/A)

Seizure freedom was reached on LID; the patient developed methemoglobinemia as side-effect and seizure freedom was maintained with PHE, first, and oral CBZ, later.

Numis et al.

[72]

N = 3

term and late preterm

KCNQ2 encephalopathy

PHB

(dose: N/A)

LEV, TPM, VGB, CLZ, KD failed.

CBZ was initiated at 3, 4 and 13 months

(dose: N/A)

2/3 patients responded to CBZ and were seizure free at 30 months though developed severe psychomotor delay, quadriplegia, axial hypotonia with appendicular hypertonia, and a tendency to opisthotonos.

Spagnoli et al.

[73]

N = 1

term

EIMFS due to KCNQ2 mutations

PHB

(dose N/A)

PYR, LEV, PHE, MDZ, TPM, NTZ

CBZ

(dose: N/A)

After multiple AEDs failure, seizure ceased after 3 weeks from CBZ’s introduction. Patient was seizure free at nine months.

Blumkin et al.

[74]

N = 1

Term

KNCQ2

PHB (dose: N/A)

TPM, LEV, VPA, LTG, PYR, folinic acid

CBZ

(50 mg/kg)

Seizure control was initially achieved with TPM. Seizures reoccurred after 3 weeks and did not respond to several AEDs until CBZ.

Buttle et al.

[75]

N = 1

term

KCNQ2

PHB

(dose: N/A)

LEV, LRZ, CLZ, PYR

LID

(2–4 mg/kg/h)

CBZ

(40 mg/kg)

After several AEDs failed, seizure freedom was reached on LID and maintained at a 13 months follow-up on oral CBZ.

Soldovieri et al.

[76]

N = 1

term

KCNQ2 mutation

(Kv7.2 subunit)

PHB

(dose: N/A)

PYR, LEV, PHE, TPM, OXC

Partial response to an association of PHB, PHE, TPM. At 5 months he was switched to OXC and maintained seizure freedom until 14 months. The patient developed severe DD.

McNally et al.

[77]

N = 1

term

SCN8A

PHB

(20 mg/kg)

LEV

(20–60 mg/kg)

OXC

(up to 80 mg/kg)

PHE

(20 mg/kg)

LTG

(2 mg/kg/day)

The association of three sodium channel blockers (OXC + PHE + LTG) reduced seizures’ frequency.

Okumura et al.

[78]

N = 1

term

2q21-q31deletion (SCN1A cluster)

PHB

(dose: 20 mg/kg)

LEV as 2nd line

(40 mg/kg)

VPA as 3rd line

(50 mg/kg)

PHB and LEV failed to control seizures;

VPA reduced seizures’ frequency.

Riesgo et al.

[79]

N = 3

preterm and term

N = 1 NAS

N = 1 fetal distress

N = 1 PVL

PHB

(dose: N/A)

TPM

(0.5–8 mg/kg/d)

after several other AEDs failed (PHB, PHE, CLZ, VPA, MDZ)

Seizure cessation in all three after TPM’s administration.

Sirsi et al.

[80]

N = 3

term

N = 1 HIE

N = 1 meningitis

N = 1 EIEE

PHB

(dose: N/A)

PHE as 2nd line

(dose: N/A)

MDZ as 3rd line

(up to 0.2 mcg/kg/h)

Seizure control within 6–72 h after MDZ’s introduction.

One patient developed hypotension, that responded to inotropic support.

Steinberg et al.

[81]

N = 2

preterm

N = 1 IVHN = 1 PVL

PHB

(20 mg/kg)

PHE as 2nd line

(20 mg/kg)

Rectal VPA as 3rd line

(20–30 mg/kg)

Seizure control was achieved and maintained on a 12 months follow-up on VPA.

Tarocco et al.

[82]

N = 1

late preterm

Pierre-Robin, polymicrogyria, lissencephaly

PHB

(dose: N/A)

PHE, MDZ, LEV, PPF

KTM (2 mg/kg + c.i. of 10 mcg/kg/min)

Immediate complete clinical and electrographic response was obtained after KTM introduction; after 15 days SE relapsed and the patient died.

Baxter et al.

[83]

N = 3

term

N = 2 EIEE

N = 1 Aicardi-Goutieres

PHB

(dose: N/A)

PYR, CLZ, VPA

VGB

(40 mg/kg/d)

2/3 patients showed full response to VGB.

Wolf et al.

[84]

N = 1

term

Incontinentia pigmenti

PHB

(35 mg/kg)

LRZ as 2nd line

(0.2 mg/kg)

PHE as 3rd line

(20 mg/kg)

Dexamethasone

(0.25 mg/kg/d)

Rapid improvement and clinical seizures termination followed the

initiation of CCS therapy.

Shevell et al.

[85]

N = 1

term

BFNE

PHB

(10 mg/kg)

Patient presented no more seizures, was discharged home on oral PHB, suspended at five months of life

Lee et al.

[86]

N = 1

term

KCNQ2

PHB

(6 mg/kg/day)

PHE as 2nd line

(8 mg/kg/day)

VGB

(50 mg/kg/day)

VGB reduced seizures; Once treatment with Vigabatrin was administered seizures reduced to one per day until day 24 of post-natal life, time at which the last seizure was recorded.

Sato et al.

[87]

N = 2

late preterm and term

HIE

PHB

(10 mg/kg)

Both patients temporarily controlled seizures on PHB. One relapsed and developed severe DD.

Sillanpää et al.

[88]

N = 1

term

Feeding epilepsy

PHB

(60 mg/day)

chlorpromazine

(9 mg/day)

The patient was seizure-free since day 14 of PHB.

Only few cases of neonatal feeding seizures are described. In this case the patient was seizure-free on PHB, after a six days combination-therapy with chlorpromazine.

Tramonte et al.

[89]

N = 1

term

Temporal lobe hemorrhage

PHB

(dose: N/A)

After PHB’s administration no more autonomic seizures (apnea, desaturations) were noticed.

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; LEV levetiracetam. EEG electroencephalography; LRZ lorazepam; VPA valproic acid; CBZ carbamazepine; TPM topiramate; PYR pyridoxine; OXC oxcarbazepine; TPM topiramate; CLZ clonazepam; DZP diazepam; LRZ lorazepam; PAIS perinatal arterial ischemic stroke; VGB vigabatrin; LLA acute lymphoblastic leukemia; PHVD post-hemorrhagic ventricular dilatation; SWS Sturge Weber syndrome; NZP nitrazepam; ACTH adrenocorticotropic hormone; PDN prednisone; LTG lamotrigine; PVL periventricular leukomalacia; EIEE early infantile epileptic encephalopathy; PPF propofol; KTM ketamine; EIMFS early infantile migrating focal seizures; DD developmental delay