A scoping review of cerebral reperfusion therapies in childhood and adolescence with arterial ischemic stroke

Abstract

Background

Management of pediatric stroke is challenging because of the paucity of data supporting the efficacy of interventions. This scoping review details the treatments available for the acute phase of stroke in pediatric patients with arterial ischemic stroke.

Summary of Review

Overall, 68 relevant articles were published between 2001 and 2023. The primary study included 48 case reports (n = 48). Eleven articles reported the use of intravenous thrombolysis (IVT) with alteplase, eight used intra‐arterial (IA) alteplase, and 52 reported mechanical thrombectomy (MT). IVT was administered to 195 patients with a median of 5.5 h of stroke onset, and only four (2.0%) had intracranial hemorrhage after alteplase treatment. Of the 11 articles, nine used 0.9 mg/kg IVT administered as a 10% bolus, with the remaining 90% administered over one hour, and one study used 0.54 mg/kg. IA was performed in 17 patients with a median of 5.05 h of stroke onset, and three individuals (17.6%) had intracranial hemorrhage. Of the eight reports that document IA, two used 0.9 mg/kg; one each used 0.16 mg/kg, 0.1 mg/kg, 0.6 mg/kg, 100 mg/day, and 10 mg/day; and one article documented the use of urokinase 750 000 IU. MT was used in 434 and 215 individuals in a previous systematic review, with a median of 11.82 h of stroke onset, and only 2.9% had intracranial hemorrhage after the treatment. Stent retrievers were used in 33 reports (63.5%) and aspiration retrievers were mentioned in 15 articles (28.8%). Overall, the outcomes ranged from complete to moderate recovery for all modalities.

Conclusions

IVT and MT are safer than IA; however, despite the lack of clinical trials, all modalities seem effective in improving clinical recovery. To guide clinical practice and determine better intervention modalities, clinicians should note the key messages from this review, such as using magnetic resonance imaging in the acute phase and identifying key risk factors and presenting symptoms.

Introduction

Stroke can occur at any age or stage. Although it is generally considered a disease of the elderly, it also affects infants and children. ¹ The incidence of pediatric ischemic stroke ranges from 0.9 to 7.9 per 100 000 person‐years, with a particularly high incidence in neonates. ² In addition, most neonates with arterial ischemic stroke experience residual neurological deficits. ³ With the increasing incidence of pediatric thromboembolism, the use of hyperacute stroke therapies (thrombolytic agents or embolectomies) has increased as well. ⁴

The management of pediatric stroke is challenging due to a paucity of data supporting the efficacy of interventions, and management is based on adult society guidelines. ⁵ Advances in imaging and treatment modalities have improved pediatric arterial ischemic disease diagnosis and management. Accordingly, hyperacute treatments are becoming increasingly available to improve functional outcomes in children. ⁶ However, the main thrombolysis and mechanical thrombectomy (MT) guidelines for patients with stroke exclude patients under 18 years of age. ⁷ Nevertheless, the 2019 American Heart Association (AHA) guidelines acknowledge the paucity of age‐specific data but advise cautiously proceeding with these treatments without pediatric clinical trial data to guide treatment decisions. ⁶ , ⁷

According to a scientific statement from the AHA, stroke‐specific guidelines should be developed at the local, regional, and national levels. ³ Partnerships among emergency medical services, comprehensive stroke centers, and pediatric tertiary care hospitals should be encouraged to leverage regional stroke expertise. In view of the increasing number of children and adolescents with ischemic stroke, it is important to develop a protocol for the treatment of the acute phase, survey the available data on these treatments in the literature, and be aware of the results of each management strategy of the disease to produce a model protocol. This scoping review documents the treatments described for the acute phase of stroke in pediatric patients in the literature and summarizes the results of each management strategy.

Materials and Methods

Design and protocol registration

This scoping review identifies the main concepts, explain the research areas, and identifies the gaps in scientific knowledge regarding cerebral reperfusion therapy in individuals aged less than 18 years with stroke. Our review was based on the Joanna Briggs Institute methodology and the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses Extension for Scoping Reviews (PRISMA‐ScR) checklist ⁸ using the patient, concept, and context structure. The review was registered on the Open Science Framework platform.

Inclusion and exclusion criteria

The inclusion criteria for the selection of articles were defined by prioritizing those that contemplated cerebral reperfusion therapies in the acute stroke phase, individuals under 18 years of age, and primary and secondary studies without language limitations. Published conference abstracts were also included.

Information and research sources

The following information sources were used: Virtual Health Library (LILACS, BINACIS, CUMED, LIPECS, and BDENF), US National Library of Medicine National Institutes Database Search of Health (Medline/PubMed), Scopus, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, and Cochrane Library. The search was conducted until July 2022 and updated in June 2023, using the patient, concept, and context strategy, Boolean operators, and search codes specific to each database (Supporting Information S1: File 1).

The identified articles in each database were exported to the Rayyan Qatar Computing Research Institute to exclude duplicates, perform initial screening, and ensure high usability and effectiveness in the selection. After exporting the articles using this software, two pairs of reviewers independently screened all titles and abstracts identified in the literature search, obtained full‐text articles from all potentially eligible articles, and evaluated them for eligibility. The reviewers resolved any disagreements through discussion or, if necessary, third‐party adjudication. Subsequently, a full reading of the selected articles was performed, and the final study sample was defined. The reference lists of the included articles were searched to verify the possibility of new inclusions.

Data extraction process

The reviewers performed calibration exercises and worked in pairs to independently extract data from the included articles. Disagreements were resolved through discussion or, if necessary, third‐party adjudication. Information was extracted from studies that met the following criteria: author, year of publication, type of study, number of participants, sex, age, race, risk factors, stroke type, vascular imaging, neurological symptoms at admission, stroke onset, type of cerebral reperfusion (intravenous thrombolysis [IVT] with alteplace, de‐intra‐arterial alteplase, MT, aspiration, or stent retriever), and outcome. Safety was defined as the absence of symptomatic hemorrhage after treatment.

Data items and synthesis of results

The analysis and categorization of the articles were performed using thematic analysis in three steps: preanalysis (reading the evidence and organizing the information), exploration of the material (grouping similar information), and data processing (thematic categories). The results were interpreted and characterized using knowledge synthesis.

Results

Article selection

A flow diagram of the article selection is shown in Figure 1.

Figure 1.

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) 2020 flow diagram for new systematic reviews, which included searches of databases and registers only.

General study characteristics

The 68 included articles ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ , ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ , ⁷⁶ , ⁷⁷ were published between 2001 and 2023 (Supporting Information S2: File 2). The main articles included case reports (n = 48, 71 patients), prospective cohort studies (n = 7, 215 patients), literature reviews (n = 5), retrospective cohort studies (n = 6, 209 patients), case series (n = 1, nine patients), and systematic reviews (n = 1, 235 patients). The age of the included patients ranged from less than 28 days (neonates) to 18 years. The main risk factors were dissection (n = 9), cardiac disease (n = 9), infection (n = 5), sickle cell disease (n = 4), neck trauma (n = 4), moyamoya disease (n = 3), migraine (n = 3), coronavirus disease 2019 (n = 3), birth control pills (n = 2), genetic vasculopathy (n = 2), trisomy of chromosome 21 (n = 1), Crohn's disease (n = 1), suprasellar pilocytic astrocytoma (n = 1), polycystic ovary syndrome (n = 1), tobacco use in adolescents (n = 1), possible immune‐mediated (n = 1), and accidental fall (n = 1). The main cerebral imaging modalities included magnetic resonance imaging (MRI) (n = 43), computed tomography (n = 35), computed tomography angiography (CTA) (n = 29), magnetic resonance angiography (n = 23), computed tomography perfusion (n = 4), digital subtraction angiography (n = 2), arterial spin labeling (n = 1), and diffusion‐weighted imaging (n = 1).

Synthesis of included studies

Tables 1, 2, and 3 present the main characteristics of the interventions and the evaluated outcomes. There were 11 reports describing the use of IVT ¹⁰ , ¹² , ¹⁷ , ¹⁸ , ²² , ²⁵ , ³² , ⁴⁴ , ⁴⁹ , ⁵¹ , ⁷⁷ ; eight reports of the use of the intra‐arterial modality; ⁹ , ¹² , ¹⁴ , ²⁰ , ²¹ , ²⁶ , ²⁷ , ⁵⁸ and 52 articles reporting interventions based on MT. ¹³ , ¹⁵ , ¹⁶ , ¹⁹ , ²³ , ²⁴ , ²⁶ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ , ⁵⁹ , ⁶¹ , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ , ⁷⁶ , ⁷⁷

Table 1.

Characterization and outcomes of studies with intervention based on the use of intravenous alteplase in individuals aged less than 18 years.

Reference	TTT	Number of participants	NIHSS at admission	Alteplase dose	Intracranial hemorrage after alteplase	Poor outcomea	Dead
[10]	Patient 1: 5 h Patient 2: 12 h	2	22	250 mg	0	0	0
[12]	3.3 h (2.0–52.0 h)	9	NR	4 patients: 0.9 mg/kg given as 10% bolus, with the remaining 90% over 1 h 5 patients: under adult dose	2b/9	3/9	1c/9
[17]	3.5 h	49	NR	0.9 mg/kg	0	NR	NR
[18]	Patient 1: 3 h Patient 2: 5 h 30 min	2	Patient 1: 12 Patient 2: 16	0.9 mg/kg	1	1	1d
[22]	1 h 43 min	1	7	0.9 mg/kg	0	NR	0
[25]	NR	67	NR	NR	2.9%	NR	10.4%e
[32]	4 h	1	21	0.9 mg/kg	0	0	0
[44]	4.5 h	93	4–24	0.9 mg/kg	0	NR	NR
[49]	3.5 h	1	14	0.9 mg/kg	0	0	0
[51]	2–4.5 h	26	14	24 patients: 0.9 mg/kg 1 patient: 0.99 mg/kg 1 patient: 0.54 mg/kg	1	NR	0
[77]	240 min (178–270 min)	11	9.7	0.9 mg/kg, given as 10% bolus, with the remaining 90% over 1 h	0	0	0

Abbreviations: CA, catheter angiogram; CT, computed tomography; ICA, internal carotid artery; MCA, terminus and proximal left M1 middle cerebral artery; MRA, magnetic resonance angiogram; NIHSS, National Institutes of Health Stroke Scale; NR, not reported; TTT, time to treatment (onset of stroke until initial reperfusion protocol).

^a Moderate to severe neurological deficits.

^b Asymptomatic.

^c Middle cerebral artery dissection and stroke with brain herniation.

^d Clinical signs of intracranial incarceration and died a few days later.

^e Not specified.

Table 2.

Characterization and outcomes of studies with intervention based on the use of intra‐arterial alteplase in individuals aged <18 years.

Reference	TTT	Number of participants	NIHSS at admission	Alteplase dose	Intracranial hemorrage after alteplase	Outcomes	Dead
[9]	2 h 48 min	1	NR	0.9 mg/kg	0	NR	0
[12]	4.5 h (3.8–24.0 h)	6	NR	NR	2/6	4a /6	1b /6
[14]	6 h	1	18	9 mg (0.16 mg/kg)	0	Mild right hemiparesis	0
[20]	3.36 h	1	NR	0.1 mg/kg	NR	Mild left hemiparesis	0
[21]	10 h	1	NR	10 mg/day	NR	NR	0
[26]	4 h	1	NR	0.6 mg/kg	NR	Slight dysarthria	0
[27]	NR	5	Patient 1: 13 Patient 2: 35 Patient 3: 1 Patient 4: 16 Patient 5: 36	NR	1	Patient 1: Speech deficit Patient 2: Less rhythmic alternating movements on the right Patient 3: Left sixth cranial nerve palsy	1c
[58]	NR	2	Patient 1: 13 Patient 2: 11	Patient 1: 0.9 mg/kg Patient 2: 100 mg/day	NR	NR	NR

Abbreviations: CA, catheter angiogram; CT, computed tomography; CTA, computed tomography angiography; ICA, internal carotid artery; MCA, proximal left M1 middle cerebral artery; MRA, magnetic resonance angiogram; NIHSS, National Institutes of Health Stroke Scale; NR, not reported; TTT, time to treatment (onset of stroke until initial reperfusion protocol).

^a Moderate to severe neurological deficits.

^b Brainstem infarction from thrombotic occlusion of the basilar artery with atypical vasculitis and brainstem necrosis.

^c Diffuse brain edema and basilar cistern subarachnoid hemorrhage due to right vertebral artery dissection with basilar artery occlusion.

Table 3.

Characterization and outcomes of studies with intervention based on the use of mechanical thrombectomy in individuals aged less than 18 years.

Reference	TTT	Number of participants	NIHSS at admission	Type of device	Intracranial hemorrage after procedure	mTICIa	Attempts	Outcomes after discharge
[13]	NR	38	NR	NR	3	NR	NR	Poor outcome (45%)
[15]	9	1	NR	Merci	NR	0	NR	NR
[16]	Patient 1: 8 h Patient 2: 3 h Patient 3: 3.5 h	3	Patient 1: 36 Patient 2: 26 Patient 3: 26	Penumbra (Phenox)	0	Patient 1: 3 Patient 2: 3 Patient 3: 3	NR	10‐ to 26‐point NIHSS improvement
[19]	24 h	1	NR	SR	NR	3	NR	Complete recovery
[23]	>72 h	1	11	A + stent	NR	2A	NR	mRS 1
[24]	316 min (270–460 min)	4	14	NR	None	Total recanalization (50%)	NR	All children had returned to school at 1 year
[26]	4 h	1	NR	Solitaire stent	0	NR	1	Slight dysarthria
[28]	9 h	1	PedNIHSS: 22	SR	NR	2B	NR	PSOM 0
[29]	8 h	1	NR	Solitaire	NR	NR	2	Functionally independent
[30]	7 h	1	PedNIHSS: 3	SR	NR	3	NR	NIHSS 3
[31]	7 h	1	NR	SR	None	2b	NR	mRS 1
[32]	NR	1	21	Solitaire	0	2b	1	Mild right hemiparesis
[33]	26 h	1	15	SR	NR	3	NR	PedNIHSS 0; mRS 0
[34]	8 h	1	22	Retriever (Solitaire)	0	0	1	Complete recovery
[35]	16 h	1	NR	SR	NR	3	NR	NR
[36]	36 h	1	35	SR	NR	3	NR	NIHSS 3; PSOM 0
[37]	8 h	1	9	SR	NR	2b	NR	NIHSS 0
[38]	5 h and 5 h 15 m	1	7	Trevo (Stryker)	NR	NR	1	Right hemiparesis
[39]	13.7 h	44	NR	Penumbra, Solitaire, and Trevo	0	3 (34 patients)	NR	Complete recovery in 35 patients
[40]	>17 h	1	NR	A	NR	2b	NR	mRS 1
[41]	18 h	1	NR	SR	None	3	NR	NR
[42]	50 h	1	NR	SR	NR	2b	NR	NR
[43]	NR	5	Patient 1: 9 Patient 2: 2 Patient 3: 15 Patient 4: 7 Patient 5: 23	Patient 1: Stent retriever pREset and pREset Lite Patient 2: Prowler Select and Solitaire Patient 3: Solitaire Patient 4: Alligator (Medtronic) Patient 5: NR	NR	NR	Patient 1: 1 Patient 2: 2 Patient 3: 1 Patient 4: 2 Patient 5: 1	Patient 1: Mild right hemiparesis Patient 2: NR Patient 3: Mild aphasia and right hemiparesis Patient 4: Mild ataxia and facial nerve paralysis Patient 5: NR
[45]	5 h 35 min	1	NR	Retriever	1	NR	1	NR
[46]	NR	1	NR	SR	0	NR	NR	NR
[47]	NR	12	11.5 (10–14)	Solitaire Trevot, Penumbra, and Mercit	1	87.5% had successful reperfusion (TICI 2b, 2c, or 3)	NR	Favorable outcomes in 78% of treated patients
[48]	NR	19	13.9 (±5.7)	Solitaire, Merci, Penumbra, Trevo, ACE060, and 5MAX	0	Successful revascularization was achieved in 89.5%	2.2 (±1.5)	Good neurological outcome was achieved in 89.5% of the patients
[49]	9 h	1	14	Retriever (Trevo)	0	2b	1	Completely recovered
[50]	12 h	11	7–21	Merci, Penumbra, Trevo, Solitaire, and Preset	NR	Total recanalization (grade 3) in five patients	NR	Good clinical recovery in nine patients
[52]	7 h 6 min (2 h 58 min–21 h 38 min)	7	PedNIHSS 15 (3–24)	Patient 1: SR Patient 2: SR Patient 3: SR Patient 4: Combined Patient 5: Aspiration Patient 6: Aspiration Patient 7: Aspiration	1	Patient 1: 3 Patient 2: 2c Patient 3: 2b Patient 4: 0 Patient 5: 3 Patient 6: 2b Patient 7: 2c	NR	NR
[53]	Patient 1: 17 h Patient 2: 16 h Patient 3: 8 h	3	Patient 1: 0 Patient 2: 6 Patient 3: NR	Patient 1: SOFIA Patient 2: Solitaire FR Patient 3: SOFIA	None	Patient 1: 2b Patient 2: 2b Patient 3: NR	Patient 1: NR Patient 2: 4 Patient 3: NR	Patient 1: Right hand and foot dystonia Patient 2: Right‐sided hemiplegia Patient 3: Reduced school performance
[54]	NR	1	12	NR	NR	NR	NR	Functional improvement
[55]	6.05 h	21	13 (4–13)	SR (Solitaire)	NR	mTICI grade ≥2b (83%)	NR	14 (66%) patients had an mRS score of 0–2 at 30 days follow‐up; 18/21 (86%) achieved that by 90 days
[56]	Patient 1: 5 h Patient 2: 10 h	2	Patient 1: 10 Patient 2: 14	NR	NR	Patient 1: 2b Patient 2: 2b	Patient 1: 1 Patient 2: 1	Patient 1: Left hemiparesis Patient 2: Left hemiparesis
[57]	4 h 25 min	9	17 (9.5–19.5)	Trevo, Solitaire, Embotrap, and Aspiration	1	2a (1 patient); 2b (5 patients); 3 (3 patients)	2 (1–4)	3 died, mild paresis to complete recovery
[58]	11 h	1	4	SR	None	2b	NR	NIHSS 1
[59]	8–>72 h	15 studies	4–35	SR; A; RD	NR	0–3	NR	NIHSS: 0–3 mRS: 1 PSOM: 0
[60, 61, 62, 63]	1	1	16	Solitaire	0	NR	NR	NR
[64]	6 h	1	NR	Retriever (Phenox)	0	NR	1	Abduction deficit of the right partially fixed head malposition with left rotation
[65]	4 h	73	14	NR	NR	Proportion of successful recanalization (87%)	NR	1
[66]	2 h	1	17	SR + A	No	3	6	PSOM: 1
[67]	NR	1	16	A	NR	3	NR	PedNIHSS: 2
[68]	8 h	1	NR	A (pRESET LITE)	Yes	3	NR	Full recovery
[69]	5.4 h	41	NR	NR	NR	Total recanalization (61%)	2.2 ± 1.2	mRS score at 90 days: 2 (range 0–6)
[70]	3.15 h	40	16 (10–20)	NR	4/40	Proportion of successful recanalization 2b (80%)	NR	mRS score at 90 days: 2 (IQR: 0–3) and 1 (IQR: 0–2) at 1 year
[71]	14:30 h	1	NR	A	No	3	NR	PSOM and PedmRS: 0 at 3 and 12 months treatment
[72]	29.5 h	1	12	NR	No	3	1	PSOM: 1
[73]	4–25 h	4	NR	NR	Malignant brain edema and brain hernia (1 patient)	≥2b (100%)	NR	mRS score range 1 and 2 (3 patients)
[74]	13.5 h	1	NR	A	No	2b	2	Left hemiparesis
[75]	Patient 1: 10 h	1	Patient 1: 15	Patient 1: A	Patient 1: No	Patient 1: NR	Patient 1: NR	Patient 1: mRS score 4
[76]	3.5 h	6	PedNIHSS: 16 (5–22)	NR	1b	Complete: 3 Partial: 3		PSOM at discharge: 1.8 (0.5–2.5)
[77]	NR	215	NR	NR	0.59%	Total recanalization (90.3%)	NR	Favorable (mRS  0–2) and excellent (mRS 0–1) outcome rates: 83.3% and 59.5%, respectively

Abbreviations: A, aspiration (Penumbra Stry@Penumbra Inc.); CA, catheter angiography; CT, computed tomography; CTA, computed tomography angiography; ICA, internal carotid artery; MCA, proximal left M1 middle cerebral artery; MRA, magnetic resonance angiography; mRS, modified Rankin scale; mTICI, thrombolysis in cerebral ischemia; NIHSS, National Institutes of Health Stroke Scale; NR, not reported; PedmRS, pediatric modified Rankin scale; PedNIHSS, pediatric NIHSS; poor outcome, defined as need for tracheostomy, gastrostomy, discharge to a rehabilitation facility, or death; PSOM, pediatric stroke outcome measure; RD: Revive, Revive SE clot retrieval device (Codman & Shurtleff Inc.); SR, stent retriever (Solitaire: Solitaire FR revascularization device by Medtronic or Trevo: Trevo Provue Retriever by Stryker); TTT, time to treatment (onset of stroke until initial reperfusion protocol).

^a Grade 0: no perfusion; grade 1: antegrade reperfusion past the initial occlusion but limited distal branch filling with little or slow distal reperfusion; grade 2a: antegrade reperfusion of less than half of the previously occluded target artery ischemic territory; grade 2b: antegrade reperfusion of more than half of the previously occluded target artery ischemic territory; grade 3: complete antegrade reperfusion of the previously occluded target artery ischemic territory, with an absence of visualized occlusion in all distal branches.

^b Stroke‐related mortality.

IVT was administered to 195 individuals with stroke onset between 1.4 and 52 h (median 5.5 h). The National Institutes of Health Stroke Scale (NIHSS) at admission was 14.4 (range, 4–24). Nine of the 11 documented the use of 0.9 mg/kg IVT, administered as a 10% bolus, with the remaining 90% administered over one hour, ¹² , ¹⁷ , ¹⁸ , ²² , ³² , ⁴⁴ , ⁴⁹ , ⁵¹ , ⁷⁷ and one study documented a dose of 0.54 mg/kg. ⁵¹ Of the 195 individuals, only four (2.0%) had intracranial hemorrhage after alteplase treatment, four (2.0%) had poor outcomes, and two (1.0%) died. However, five articles did not report outcomes and two did not report mortality (Table 1).

IA was used in 17 individuals, and the time since stroke onset was between 2.4 and 24 h (median 5.1 h). The NIHSS score at admission was 17.8 (range, 1–36). Of eight reports, two ⁹ , ⁵⁸ used 0.9 mg/kg; one study each used 0.16 mg/kg, ¹⁴ 0.1 mg/kg, ²⁰ 0.6 mg/kg, ²⁶ 100 mg/day, ⁵⁸ and 10 mg/day; ²¹ and one used urokinase 750 000 IU. ¹⁰ Of the 17 individuals, three (17.6%) had intracranial hemorrhage after alteplase treatment, four (23.5%) had poor outcomes, and two (11.7%) died (Table 2).

In a review, MT was used in 434 individuals and 215 individuals with stroke onset between 2.2 and >72 h (median, 11.82 h). NIHSS scores at admission were 14.7 (range, 2–36). Stent retrievers were used in 33 studies (63.5%), and aspiration was used in 15 studies (28.8%). The modified treatment for cerebral infarction ≥2b was found in 37 articles, and 13 reports did not describe this variable. The number of retrieval attempts was 1.6 (range, 1–4). Of the 434 patients, only 13 (2.9%) had intracranial hemorrhage after MT, and one died of malignant brain edema and brain hernia. In another systematic review, only 0.59% had symptomatic intracranial hemorrhage. Outcomes ranged from complete to moderate recovery after MT (Table 3).

Discussion

Generally, more case reports than efficacy and safety studies are available to guide clinical practice. IVT therapy is safe in children and adolescents; however, intracranial hemorrhage, poor outcomes, and mortality have been observed in a small number of patients. IA was used in 17 individuals aged less than 18 years, and the negative outcome rates were higher than those with IVT. Furthermore, MT was performed in 269 patients; only 0.38% had an intracranial hemorrhage. However, some individuals with arterial infarction experience hemorrhagic transformation of the lesion, even in the absence of therapy. The patients generally had better outcomes (complete to moderate recovery).

In this review, we have highlighted treatments with positive results to help clinicians choose appropriate investigations. The most common causes of stroke were arteriopathies (vasculitis and dissection) and nonarteriopathies (cardiac). Vascular disorders are the most common causes of pediatric ischemic stroke, particularly moyamoya disease. ⁷⁸ Renal disease and systemic vasculitis were also major risk factors for pediatric ischemic stroke. The main neuroimaging modality used in most studies was MRI, which differs from the international thrombolysis protocol used for adults. MRI can facilitate clinical investigations, mainly in arteriopathies (head and neck vascular imaging), with a lower radiation dose than CTA ⁷⁹ and can also reduce the chance of cerebral reperfusion in stroke mimics. Because children's neurological presentations vary, a condition that simulates a stroke (mimic) can sometimes confuse clinicians, leading them to apply cerebral reperfusion therapies with a considerable risk of brain hemorrhage.

In many articles, the NIHSS, which has been validated for adults, was only used on admission to verify stroke severity in pediatric patients. Since 2011, the Pediatric NIHSS has been validated in a multicenter cohort study with excellent interrater reliability. ⁸⁰ However, most studies have used adult NIHSS scores after this period to quantify acute neurological deficits for outcome. ⁸¹ Other tools used in our review were the Pediatric Stroke Outcome Measure (PSOM) and PedmRS. The PSOM is an examination based on the adult mRS to classify the overall neurological severity of pediatric stroke. There are two published pediatric modifications of the mRS. ⁸² , ⁸³ A comparison of the PSOM and pediatric mRS showed concordance of the two instruments in 88% of patients when dichotomized into “good” versus “poor” outcomes. ⁸⁴ Future clinical trials should further assess the use of validated pediatric scales to measure the overall neurological status of this population.

Regarding the heterogeneity of the intervention protocols, all articles describing IV thrombolysis used the standard adult dose except for one article that used 0.54 mg/kg. ⁵¹ However, for intra‐arterial interventions, the dose is highly variable. The main studies on these interventions were case reports, perhaps due to the rare occurrence of stroke and the national shortage of pediatric neurologists. ⁸⁵ In general, our review shows that the time to onset of IVT is extended in some cases but is safe in pediatric stroke according to symptomatic hemorrhagic rates. Filatov et al. ⁸⁶ observed that alteplase administration in children is associated with risks similar to those observed in adults, and can restore cerebral blood and reduce brain damage in pediatric strokes.

MT appears to be safe and effective in this population, with a low bleeding rate and a high functional recovery rate. Malik et al. ⁸⁷ showed that using intravenous recombinant tissue plasminogen activator and endovascular thrombectomy increased the risk of mortality and hemorrhagic conversion but suggested more clinical studies to evaluate the risk–benefit ratio. However, our review shows that MT is safe, has a high recanalization rate, and is an excellent clinical prognosis, even with an extended window. Bhatia et al. ⁸⁸ showed that MT may be considered for acute ischemic stroke (AIS) due to large‐vessel occlusion in patients aged 1–18 years. The Save ChildS Study, a retrospective multicenter cohort study, is currently the best evidence supporting extended time‐window MT in pediatric patients with AIS of up to 24 h. ⁶⁵ However, extended time‐window MT in pediatric AIS continues to be discussed and is not supported by evidence‐based medicine. ⁸⁹

Limitations and future implications

Despite the large number of included studies, no randomized controlled trials were conducted in the pediatric population. There was also substantial heterogeneity in the reporting patterns of case reports and case series, including scales, imaging methods, dose selection, and length of follow‐up. In addition, the rates of poor outcomes and complications are underestimated because cases with poor outcomes may not have been reported in the literature, leading to publication bias. However, cerebral reperfusion therapy is a promising treatment modality for pediatric patients with AIS, and the overall recommendations are displayed in Table 4. Future multicenter clinical trials should establish guidelines for the application of these therapies, including the optimal dose, number of treatments needed, risks and benefits, and long‐term functional impact.

Table 4.

Summary of all results.

	IV (n = 10 studies)	IA (n = 8 studies)	MT (n = 50 studies)
Time to treatment (h)	1.4–52	2.4–24	2.2–>72
NIHSS at admission	4–24	1–36	2–36
Alteplase dose	0.9 mg/kga	0.1–0.9 mg/kg	‐
Type of device (%)	‐	‐	Stent retrievers: 78.6 Aspiration: 30.6
mTICI (grade)b	‐	‐	0–3
Attempts (numbers)	‐	‐	1–4
Intracranial hemorrhage (%)	2.17	17.6	0.38
Good clinical outcomesc	97.83	82.4	>99%

Abbreviations: IA, intra‐arterial alteplase; IV, intravenous; mRS, modified Rankin scale; MT, mechanical thrombectomy; mTICI, thrombolysis in cerebral ischemia; NIHSS, National Institutes of Health Stroke Scale.

^a Administered as a 10% bolus, with the remaining 90% administered over one hour.

^b Grade 0: no perfusion; grade 1, antegrade reperfusion past the initial occlusion, but limited distal branch filling with little or slow distal reperfusion; grade 2a, antegrade reperfusion of less than half of the previously occluded target artery ischemic territory; grade 2b, antegrade reperfusion of more than half of the previously occluded target artery ischemic territory; grade 3, complete antegrade reperfusion of the previously occluded target artery ischemic territory, with an absence of visualized occlusion in all distal branches.

^c NIHSS 0–4, mRS 0–2, or being asymptomatic.

Conclusion

Our study examined the use of cerebral reperfusion therapy in individuals aged <18 years. In general, IVT and MT are safer than IA; despite the paucity of multicenter clinical trials, all modalities seem effective in improving clinical recovery. To guide clinical practice and determine better intervention modalities, clinicians should note the key messages from this review, such as the use of MRI, computed tomography, and CTA in the acute phase (including head and neck vascular investigations), key risk factors, and presenting symptoms. In addition, our review highlights the importance of using validated scales in the pediatric population and demonstrates the main modalities of cerebral reperfusion, including dose, window, adverse effects, and outcomes.

Author Contributions

Ana Lúcia de Paula Garcia: Investigation; methodology; validation; writing—original draft; writing—review and editing. Flávia Guirro Zuliani: Investigation; methodology; project administration; validation; writing—original draft. Cristiane Lara Mendes‐Chillof: Project administration; validation; visualization; writing—review and editing. Silméia Garcia Zanati Bazan: Conceptualization; project administration; writing—review and editing. Carlos Clayton Macedo Freitas: Formal analysis; project administration; supervision; writing—review and editing. Gabriel Pinheiro Modolo: Conceptualization; methodology; writing—review and editing. Vitor Mendes Pereira: Conceptualization; data curation; validation; writing—review and editing. Gustavo José Luvizutto: Conceptualization; formal analysis; investigation; methodology; supervision; writing—original draft; writing—review and editing. Rodrigo Bazan: Conceptualization; funding acquisition; methodology; supervision; writing—original draft; writing—review and editing.

Conflict of Interest

The authors declare no conflict of interest.

Supporting information

Additional supporting information can be found online in the Supporting Information section at the end of this article.

Supporting information.

Supporting information.

Data Availability Statement

Any additional information may be obtained from the corresponding author by email.