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Review Articles

Reperfusion Therapies for Children With Arterial Ischemic Stroke

Heit, Jeremy J. MD∗,†; Muthusami, Prakash MD; Chandra, Ronil V. MD§; Hui, Ferdinand MD; Negrotto, Matias MD||; Lee, Sarah MD#; Wasserman, Bruce A. MD; Abruzzo, Todd A. MD∗∗,††,‡‡

Author Information
Topics in Magnetic Resonance Imaging: October 2021 - Volume 30 - Issue 5 - p 231-243
doi: 10.1097/RMR.0000000000000273
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Abstract

REPERFUSION THERAPIES

Reperfusion therapies commonly used to treat adult ischemic stroke patients with thrombotic or embolic arterial occlusions include intravenous thrombolysis and mechanical clot removal procedures. The safety and efficacy of these reperfusion therapies have been well demonstrated in randomized clinical trials (RCTs), and there is widespread consensus concerning eligibility and indications.1,2 In adult patients with symptomatic cerebral ischemia due to cerebral vasoconstriction, intra-arterial vasodilators and transluminal balloon angioplasty have been used to achieve cerebral reperfusion through spasmolysis.3–5 Spasmolytic reperfusion therapies are not supported by clinical trial data and are outside the scope of this review.

Although the median door-to-needle time for modern stroke centers in North America is in the range of 59 to 75 minutes, it is estimated that 50% of pediatric strokes are diagnosed more than 24 hours after hospital arrival.6,7 Numerous factors contribute to delayed diagnosis, including a higher number of stroke mimics in the pediatric population, inexperience with stroke amongst pediatric care providers, challenges related to examination, imaging and safe management of the small or agitated child, and pediatric systems of care that are not designed for rapid arterial ischemic stroke (AIS) diagnosis and treatment. Discounting other issues that determine eligibility, a substantial majority of children with AIS will therefore not qualify for IV fibrinolytic therapy, and as many as half of them will not qualify for endovascular therapy (EVT) under current guidelines for adult AIS.

Medical Therapies

IV fibrinolytic therapy with tissue-type plasminogen activator (tPA) has been shown to improve clinical outcomes for adults with acute AIS when administered within 3 to 4.5 hours of stroke onset.1,2,8 Recent studies suggest that properly selected adult stroke patients identified by advanced imaging techniques may benefit from IV fibrinolytic therapy administered within 9 hours of stroke onset. Whether and how to administer IV fibrinolytic therapy to children with AIS remains controversial.2,9–11 The National Institutes of Health–funded Thrombolysis in Pediatric Stroke Study (TIPS) was a phase 1, prospective study that aimed to establish the dose, safety, and efficacy of IV tPA for AIS in children 2 to 17 years of age. Children younger than 2 years of age were excluded from TIPS because clinical neurological assessment of this age group was not considered sufficiently reliable to confirm timing of stroke onset or determine stroke severity, according to the pediatric National Institutes of Health stroke scale (NIHSS) score. In practice, however, it is reasonable to administer IV tPA to otherwise eligible children younger than 2 years of age with known time of stroke onset and unequivocal neurological deficit.

Unfortunately, the TIPS trial was closed after 3 years due to lack of accrual12,13; thus, there is currently no prospective data confirming efficacy of IV tPA in children. Although the study was terminated early due to low patient enrollment, the TIPS investigators succeeded in establishing systems of care for children with AIS, and provided initial safety data for IV tPA in the setting of childhood AIS.13,14 TIPSTERS, a follow-up study to TIPS, retrospectively collected information on 29 children who received IV tPA at the standard adult dose (0.9 mg/kg) within 4.5 hours of stroke onset at 16 TIPS sites. In that study, none of the patients suffered symptomatic intracranial hemorrhage (sICH), as compared with 6.4% of adult patients in the original National Institute of Neurological Disorders and Stroke (NINDS) trial.14,15 Using a statistical model, the investigators estimated an sICH rate of 2.1% based on the rate of sICH in young adults.14 Even though there continues to be a lack of prospective evidence for efficacy, many pediatric neuroscience centers offer IV tPA to eligible children who satisfy TIPS-enrollment criteria, using the standard adult dosing, with 10% administered as a bolus over 1 minute, and the remainder infused over 60 minutes to a maximum of 90 mg (Fig. 1). This may be a conservative dose estimate, because developmental differences in plasminogen levels suggest that the effective dose of IV tPA may be higher for young children.13

FIGURE 1
FIGURE 1:
Intravenous thrombolysis in pediatric population. A 17-year-old boy with Duschenne muscular dystrophy and dilated cardiomyopathy presents with acute onset aphasia and right hemiplegia within 3 hours of last known well. A, Initial brain MRI showed small punctate foci of diffusion restriction in left insular cortex and posterior left temporal lobe. B, Time of flight MRA revealed occlusion of the M1 segment of the left middle cerebral artery. Recombinant tissue plasminogen activator was administered intravenously as the interventional team was mobilized. Within a few minutes the patient began to demonstrate rapid clinical improvement with minimal residual weakness and word finding difficulty. C, A rapid CT angiogram confirmed interval recanalization of the left middle cerebral artery. D, Brain MRI obtained 3 days later showed no significant infarct growth on diffusion-weighted imaging. E, No arterial occlusions on time of flight MRA. MRA, magnetic resonance angiography.

Hyperacute and acute medical management of AIS in children with sickle cell disease (SCD) is highly differentiated, and surprisingly efficacious (Fig. 2). When a child with SCD presents acutely with suspected cerebral ischemia, simple transfusion should be emergently performed before imaging if the hemoglobin is <10 g/dL. If hemoglobin concentration is >11 g/dL, exchange transfusion should be performed before imaging. Exchange transfusion is preferred in this group to mitigate the risk of hyperviscosity syndrome. When brain imaging confirms infarction, or if transient ischemic attack is strongly suspected, exchange transfusion should be performed to achieve a hemoglobin S concentration <30% as soon as possible. Additional critical supportive measures include supplemental oxygen to maintain saturation >95%, hydration, and maintenance of normothermia, with consideration of antibiotics if infection is suspected.16 It is not known whether IV fibrinolytic therapy is beneficial for acute AIS in children with SCD; however, it is typically deferred given the risk of intracranial hemorrhage in this population.

FIGURE 2
FIGURE 2:
Thrombotic microangiopathy in SCS. An 11-year-old boy with SCD presenting with acute onset left hemiplegia. A, Axial T2-weighted fluid attenuated inversion recovery image shows extensive gyral pattern of abnormal hyperintense signal throughout the right hemisphere, and in the subcortical white matter bilaterally. B, There is associated gyral swelling and sulcal effacement. B, Axial diffusion-weighted b1000 image shows diffusion restriction in affected cortical gray matter on the right and reveals extensive diffusion restriction in more acutely affected cortical gray matter in the left cerebral hemisphere. C, Time of flight MR angiography does not demonstrate occlusion of medium or large arteries supplying affected brain tissue. D, Axial susceptibility-weighted image shows extensive multifocal blooming artifact corresponding to slow flow and sludging as a result of sickling of erythrocytes in cerebral microvasculature. E, Repeat axial susceptibility-weighted imaging after hydration, transfusion, and right-sided decompressive hemicraniectomy shows resolution of slow flow and sludging in cerebral microvasculature. SCD, sickle cell disease.

Transcatheter Mechanical Revascularization Therapies

Mechanical thrombectomy for adults with AIS is supported by multiple well-designed RCTs (class I, level A).1 All of these trials excluded patients younger than 18 years of age. Despite this, endovascular intervention for pediatric AIS has achieved class IIb recommendation status, supported by level C evidence.2,9–11,17,18 Moreover, a growing body of observational clinical data suggest that endovascular thrombectomy is feasible, safe, and improves neurological outcomes in properly selected children with AIS due to large vessel occlusion (LVO).17–21 Proponents of EVT point out that neurological outcomes for severe AIS due to intracranial LVO are historically poor for the majority of pediatric patients managed with supportive care.22–24 In contrast, neurological outcomes for comparable cases of pediatric AIS due to LVO are usually very good when appropriately selected children are treated with EVT.17,18,20,21

We believe that current selection of pediatric patients for mechanical thrombectomy should be primarily guided by LVO subtype (types 1 and 2), site of occlusion, timing of stroke onset, clinical stroke severity, and size of core infarction in relation to the arterial territory at risk. The role of imaging in patient selection will be covered in another section of this review. Although the age of the patient influences selection of treatment approach and devices, specific age-oriented contraindications do not clearly exist.25

An increasing majority of neuropediatric specialists agree that endovascular interventions should be considered for well selected pediatric patients with AIS with LVO on a case-by-case basis.25 Despite this, neuropediatric specialists remain concerned that endovascular interventions may cause harm in children with intracranial arteriopathies. There is specific concern that mechanical therapy with a stent retriever or large-bore thromboaspiration catheter, in the setting of intracranial arteriopathy, could aggravate the occlusive process or destroy the structural integrity of the vessel wall resulting in hemorrhage. Forceful attempts to retract an expanded stent retriever across noncompliant, subocclusive stenoses with geometric (spiral or angulated luminal path) or topographical (banding) irregularities could also lead to vessel perforation. Some arteriopathies have been associated with catastrophic complications of endovascular procedures due to excessive arterial frailty.26,27

In the largest published case series of pediatric patients with AIS treated with mechanical thrombectomy, 9% of patients had intracranial arteriopathy (type 3 pediatric intracranial LVO), which was not known at the time treatment was initiated.17 Although none of the intracranial arteriopathy patients in the aforementioned series suffered serious procedure related harm, the attempted stent retriever revascularization was unsuccessful in a third, and 43% experienced a less than satisfactory clinical outcome. The results contrast with those reported in a comparable pediatric EVT series reporting technically successful revascularization in 88% to 90%, with good clinical outcome in 91% to 95%.18,20,21 Although a surprising number of arteriopathic patients in the index series were successfully revascularized and did experience good clinical outcome, it remains unclear if good clinical outcome was because of EVT or in spite of EVT in those cases. Initial angiographic improvement in these cases may have been transient and related to “stent retriever angioplasty” rather than thrombus removal. Our experience shows that intracranial arteriopathy complicated by in situ thrombosis and LVO is prone to early reocclusion after EVT, likely due to underlying prothrombotic conditions and the aggravating effects of mechanical instrumentation (Fig. 3A–H). Further study is needed to establish whether there may be specific limited indications for endovascular treatment of type 3 pediatric intracranial LVO. A recent study of short-term outcomes in children undergoing mechanical thrombectomy found that patients prospectively enrolled in a clinical trial did not achieve the same degree of neurological improvement as reported in published case series.28 The findings raise concern that publication bias may lead to overly optimistic estimates of mechanical thrombectomy treatment effects in the pediatric population.

FIGURE 3
FIGURE 3:
COVID arteritis. An 8-year-old girl with postinfectious systemic arteritis following COVID-19 infection presents with abrupt onset of right hemiplegia and language impairment (NIHSS score 15). A, Initial brain MRI obtained within 10 hours of last know well shows small area of diffusion restriction limited to left striatocapsular region on axial B1000 diffusion-weighted image. A small focus of diffusion restriction was revealed in the contralateral middle cerebral artery territory (image not shown). B, Time of flight (TOF) MRA shows absence of flow-related signal in terminal left internal carotid artery (LICA), proximal left A1, and left M1. C, Initial catheter angiogram of LICA in frontal projection shows complete occlusion of left M1 with intrusion of thrombus into LICA terminus and left A1. A Neuron MAX (Penumbra Incorporated, Alameda, CA) guide sheath is stationed in LICA. D, Follow-up LICA angiogram after stent retriever–assisted contact aspiration thrombectomy using 4 × 20 mm Solitaire X (Medtronic Neurovascular, Irvine, CA) and JET 7 (Penumbra Incorporated) thromboaspiration catheter shows reperfusion of left M1 with sluggish progression of anterograde flow into cortical tributaries of both M2 divisions. E, Axial T2-weighted fluid attenuated inversion recovery image through the level of the foramen of Monro on day 5 shows extension of infarction to putamen, insular cortex, and portions of the left frontal lobe and temporal lobe. Day 5 NIHSS score remains 15. F, TOF MRA obtained 5 hours after thrombectomy showed reocclusion of the distal left M1. G, Gadolinium-enhanced black blood vessel wall imaging shows concentric mural enhancement of the intradural LICA (arrows) consistent with arteritis. H, LICA catheter angiogram following completion of thrombectomy and 15 minutes after direct infusion of 10 mg verapamil into LICA shows persistent arteriopathic changes manifested as luminal banding of inferior M2 division and daughter branches (arrows), consistent with arteritis. MRA, magnetic resonance angiography.

Regardless, the preponderance of published observational data supports utilization of EVT in properly selected pediatric patients with AIS. A majority of neuropediatric specialists favor implementation of a late treatment window that extends to 24 hours from the time of AIS onset.25 Advances in cerebral perfusion imaging and neuroprotection may further extend the late treatment window in the future.29 Selection of patients based on neuroimaging criteria will be covered in a subsequent section of this review.

The anatomical location of LVO is an important deterministic factor in the decision to perform EVT. The intracranial internal carotid artery, middle cerebral artery (M1), and basilar artery are suitable targets, although additional occlusion sites may be considered based on clinical and neuroimaging criteria. Some authors have argued that endovascular treatment of M2 occlusions should only be considered in children who are at least 12 years of age.18

Although the majority of neuropediatricians advocate for EVT in children with severe neurological deficits, there is less consensus on children and adults presenting with minor neurological deficits, generally defined as an NIHSS <6.25 Some argue that children may display minor symptoms early in the course of their stroke due to robust collaterals temporarily maintaining the penumbra, but that hemodynamic shifts and other factors may lead to collateral failure and disabling infarction in the subacute setting.30–32 Children with LVO and cardiac comorbidities are particularly at risk for delayed neurological deterioration.

TECHNICAL ASPECTS OF ENDOVASCULAR THERAPY IN PEDIATRIC ARTERIAL ISCHEMIC STROKE

Most early clinical reports of EVT for acute pediatric AIS focused on intra-arterial thrombolysis and suboptimal first-generation thrombectomy devices.33 These treatments were associated with low rates of technically successful vessel recanalization, and less than satisfactory improvement in clinical outcomes. More recent reports using modern revascularization technologies have shown high rates of technically successful reperfusion (∼90%) without major procedure-related complications, or significant rates of sICH.17,20,21,34 Moreover, the majority of treated patients experience major neurological improvement and good long-term clinical outcome.17,20,21 These results are achieved using revascularization devices developed and indicated for adult EVT.17,20,21 The data further suggest that treatment of pediatric LVO with stent retrievers, versus thromboaspiration catheters achieves technical success with equal frequency.35 One caveat associated with the use of large bore thromboaspiration catheters in young children, younger than 5 years of age, is that blood transfusion may be required to replace blood losses associated with thromboaspiration.

Skeptics of EVT for children with AIS emphasize that smaller children are more vulnerable to vascular injury at the arterial access site and the intracranial treatment site because vessels are smaller, more fragile, and more prone to spasm. Although many neurointerventionists have appreciated a tendency toward spasm of cervical and intracranial arteries during EVT in young children, experience shows that this phenomenon is usually self-limiting, and can be safely managed by proper technique and intra-arterial administration of calcium channel blockers.17 Although administration of parenteral verapamil to neonates in the first 6 weeks of life has been associated with severe cardiac toxicity, there is no evidence that parenteral administration to older children is unsafe.36

Most experience with endovascular AIS treatment in the pediatric population has developed around the transfemoral arterial access route.17–21,34,37 In experienced stroke centers, transradial embolectomy has shown clinical outcomes and puncture to reperfusion times comparable to transfemoral embolectomy in adults with anterior circulation AIS, with the theoretical benefit of reduced access site complications and faster recovery.38 Increasing experience with transradial pediatric neurointerventions may eventually confirm the superiority of the transradial approach in children with adequately large radial arteries.39 Femoral artery and radial artery diameter correlates closely with age and height.40 The incidence of procedure-related access artery thrombosis and its outcome correlates with the size of the indwelling arterial introducer sheath in relation to the size of the sheath bearing artery, and the duration of the procedure. Since EVT procedures are usually very short by most standards, access strategies can usually be safely adjusted and personalized to facilitate success even in very young patients (Table 1).17,20

TABLE 1 - Cervical Artery Access and Compatible Revascularization Options for Pediatric Arterial Ischemic Stroke
Transfemoral-Cervical Artery Access Compatible Stent-Retriever and Microcatheter Delivery Options Compatible Thromboaspiration Catheter Options
5 F sheath extended from transfemoral arterial access site into cervical artery • 80 cm Medtronic Asahi Fubuki sheath; 2.4 mm OD; 0.081” ID • 90 cm 5 F Shuttle guide sheath; 2.3 mm OD; 0.074” ID Trevo XP ProVue stent-retriever (3 × 20 mm, 4 × 20 mm, 6 × 25 mm) • Stryker Trevo Pro 14 microcatheter (157 cm, 2.0 F distal, 2.4 F proximal, 0.014” lumen) • Trevo 3 × 20 mm and 4 × 20 mm are generally compatible with most 0.021” or larger in microcatheters • Trevo 6 × 25 mm is generally compatible with other 0.027” microcathetersMedtronic Solitaire X stent retriever (4 × 20/40 mm, 6 × 20/40 mm) • Medtronic Phenom 21 microcatheter (160 cm, 2.3 F distal, 2.6 F proximal, 0.021” lumen) • Penumbra velocity microcatheter§ (160 cm, 2.6 F distal, 2.95 F proximal, 0.025” lumen) • All Solitaire stent retrievers are generally compatible with 0.021” or larger microcatheters  • Penumbra 3 MAX tapered thromboaspiration catheter§ (ID 0.043” → 0.035”)- 3.8 F/1.4 mm distal OD • Penumbra 4 MAX straight thromboaspiration catheter§ (ID 0.041”)- 4.1 F/1.4 mm distal OD • Microvention SOFIA 5 F thromboaspiration catheter (ID 0.055”)- distal OD 1.7 mm
6 F sheath extended from transfemoral arterial access site into cervical artery • 80–90 cm Penumbra Neuron MAX sheath§; 2.7 mm OD; ID 0.088” • 90 cm 6 F Shuttle guide sheath; 2.5 mm OD; 0.087” ID Trevo XP ProVue stent retriever (3 × 20 mm, 4 × 20 mm, 6 × 25 mm) • Stryker Trevo Pro 14 microcatheter (157 cm, 2.0 F distal, 2.4 F proximal, 0.014” lumen) • Trevo 3 × 20 mm and 4 × 20 mm are generally compatible with most 0.021” or larger in microcatheters • Trevo 6 × 25 mm is generally compatible with other 0.027” microcathetersMedtronic Solitaire X stent-retriever (4 × 20/40 mm, 6 × 20/40 mm] • Medtronic Phenom 21 microcatheter (160 cm, 2.3 F distal, 2.6 F proximal, 0.021” lumen) • Penumbra velocity microcatheter§ (160 cm, 2.6 F distal, 2.95 F proximal, 0.025” lumen) • All solitaire stent-retrievers are generally compatible with other 0.021” or larger microcatheters  • Penumbra 3 MAX tapered thromboaspiration catheter§ (ID 0.043” → 0.035”)- 3.8 F distal tip • Penumbra 4 MAX straight thromboaspiration catheter§ (ID 0.041”)- 4.1 F distal tip • Penumbra 4 MAX tapered thromboaspiration catheter§ (ID 0.064” → 0.041”)- 4.3 F (1.43 mm) distal 20 cm • Penumbra JET D thromboaspiration catheter§ (ID 0.054” → 0.064”)- 4.9 F (1.65 mm) distal 20 cm • Microvention SOFIA 5F thromboaspiration catheter (ID 0.055”)-Distal OD 1.7 mm • Penumbra ACE 60, ACE 64, ACE 68, JET7 thromboaspiration catheters§ Distal OD 1.8–2.16 mm • Microvention SOFIA 6F thromboaspiration catheters Distal OD 2.1 mm
These devices are subject to regional availability, and new devices are becoming available with similar ID, OD, and material characteristics which may represent valid alternative device choices.
Medtronic Neurovascular, Irvine, CA.
Cook Medical, Bloomington, IN.
Stryker Neurovascular, Fremont, CA.
§Penumbra Incorporated, Alameda, CA.
Microvention Inc, a subsidiary of Terumo Medical, Alisa Viejo, CA.ID indicates inner diameter; OD, outer diameter.

Once a decision is made to proceed with EVT, we recommend utilizing ultrasound to screen the size of the access artery. The outer diameter of the arterial introducer sheath should be kept below the luminal size of the access artery. This approach should adjust for vasospasm, which may occur during placement of the introducer sheath. As general advice, for children who are 3 years of age or younger, extension of a long 5 French transfemoral arterial introducer sheath into the cervical carotid or vertebral artery will enable treatment of intracranial LVO with a wide variety of commercially available stent retrievers and thromboaspiration catheters (Table 1). In children who are 4 years of age or older, a long 6-French transfemoral arterial introducer sheath extended into the cervical access artery will expand the range of intracranial treatment options and allow en bloc extraction of larger thrombi (Fig. 4A–F). These strategies will pose a minimal threat to the femoral access site artery. In smaller children, younger than 5 years of age, particularly those who are anticoagulated for mechanical circulatory support, a short operative procedure to surgically close the arteriotomy could be considered if manual compression is inadequate. In older children with adequately sized arteries, a closure device may be a satisfactory alternative.

FIGURE 4
FIGURE 4:
Thrombectomy in children. A 15-year-old girl with congenital heart disease and acute heart failure presents with acute intracranial right internal carotid artery (ICA) occlusion. ICA access was obtained with a 6 F sheath Neuron MAX (Penumbra Incorporated, Alameda, CA) advanced through a 9 F transfemoral hemostasis sheath. A, Initial selective angiogram of right ICA shows pseudo-occlusion of distal cervical right ICA. B, Follow-up angiography shows modified Thrombolysis In Cerebral Infarction (mTICI) 3 reperfusion after initial direct contact aspiration with ACE 68 (Penumbra Incorporated) and second pass “solumbra” approach with 4 × 40 mm Solitaire Platinum (Medtronic Neurovascular, Irvine, CA) + ACE 68 (Penumbra Incorporated). Six-year-old girl with Fontan circulation awaiting heart transplant presents with acute left M1 occlusion. ICA access was obtained with a transfemoral 6 F sheath Neuron MAX (Penumbra Incorporated). C, Initial selective angiogram of left ICA shows proximal left M1 occlusion. D, Follow-up angiography shows mTICI 3 reperfusion after first pass direct contact aspiration with 5 Max ACE (Penumbra Incorporated). Four-year-old girl with Berlin heart awaiting second heart transplant found to have intracranial left ICA occlusion on CT imaging studies performed to evaluate seizures. Carotid access was obtained with a transfemoral 6 F sheath Neuron MAX (Penumbra Incorporated). E, Initial selective angiogram of left common carotid artery shows occlusion of communicating segment of left ICA. F, Follow-up angiography shows mTICI 2b reperfusion after a total of 4 passes direct contact aspiration and “SOLUMBRA” using ACE 68 (Penumbra Incorporated) + 4 × 40 mm Solitaire Platinum (Medtronic Neurovascular).

The use of balloon guide catheters during mechanical embolectomy has been shown to reduce distal embolization, improve first pass revascularization success, and improve functional outcomes in adults undergoing mechanical thrombectomy.41,42 In the pediatric population, 6 French balloon guide catheters stationed in the extracranial vertebral artery have been used to support mechanical thrombectomy in children with basilar artery occlusion as young as 17 months of age, although most reported cases of pediatric thrombectomy have been performed without balloon guide catheters.18,43,44 Eight or nine French balloon guide catheters are preferred for mechanical thrombectomy in adults because the large lumen enables en bloc removal of arterial occlusive thrombi without fragmentation, clot stripping, or stent retriever collapse.45 It is possible that the technical advantage of flow arrest/reversal offered by balloon guide catheters is offset by the disadvantage of a smaller working lumen in smaller children for whom a 8 or 9 French balloon guide catheter may be too large.

Our experience shows that preschool children, from 5 years of age can be safely treated using the full range of conventional adult embolectomy devices and techniques (Fig. 4A–F). Mechanical thrombectomy in children younger than 4 years of age has been reported and appears to be technically feasible in children as young as 6 months of age, although higher rates of complications have been reported in this group and special considerations are warranted.18–20,37,46 Although EVT with stent retrievers may be feasible in infants, optimizing endovascular technique for safety in the infant population may require alternative approaches (Fig. 5A–G). In infants younger than 9 months of age, the diameter of the proximal intracranial ICA is frequently <3 mm (Fig. 6).47 Published reports of stent retriever thrombectomy in the infant population have not been associated with good clinical outcomes and raise concerns that early reocclusion and delayed rupture may not be infrequent.19,46 A recent individual patient meta-analysis of pediatric thrombectomy concluded that there is insufficient evidence to make any recommendation regarding mechanical thrombectomy in infants.18 The anatomical basis for technical success of EVT in children derives from rapid growth of the brain and cerebral arteries in early childhood. Imaging data obtained from more than 300 developmentally normal pediatric patients without cardiac or cerebrovascular disease show that by 5 years of age, cerebral arterial growth is 90% complete, and that the average diameter of the cavernous segment of the internal carotid artery is approximately 4 mm (Fig. 6).47 Notably, the diameter of the M1 segment of the middle cerebral artery may be <2 mm in infants younger than 6 months of age, whereas current commercially available stent retrievers are not recommended for vessels <2 or 2.5 mm in diameter depending on the manufacturer. A range of commercially available thromboaspiration catheters may be used to treat cerebral vessels as small as 1.9 mm, if one safely aspires to limit the size of the distal catheter tip to less than two thirds of the target vessel lumen.

FIGURE 5
FIGURE 5:
Thrombectomy in infants. Fourteen-month-old boy with acute intraoperative distal right M1 occlusion during preoperative embolization of choroid plexus carcinoma. ICA access was obtained with a 5 F Envoy catheter (Cordis Endovascular, Miami Lakes, FL) advanced from a transfemoral 5 F hemostasis sheath. A, Initial selective angiogram of right ICA shows occlusion of distal right M1. B, Follow-up angiography shows mTICI 2b reperfusion after initial direct contact aspiration of M1 clot with a syringe and 0.027” microcatheter followed by sequential revascularization of each M2 division with a Penumbra 0.026” thromboaspiration catheter and vacuum pump (Penumbra Incorporated, Alameda, CA). C, 8-Month-old patient with cystic lung disease on extracorporeal membrane oxygenation (ECMO). Axial CTA maximum intensity projection image demonstrates left internal carotid artery (LICA) occlusion (white arrow). D, The patient underwent mechanical thrombectomy with a stent retriever (white arrow) and aspiration catheter (white arrowhead). E, Completion angiography shows compete revascularization of LICA occlusion (white arrow). F, Following thrombectomy, a small amount of subarachnoid hemorrhage was present within the Sylvian fissure immediately after treatment (white arrow). G, After restarting anticoagulation for ECMO the patient suffered a fatal cerebral hemorrhage (white arrow).
FIGURE 6
FIGURE 6:
Vascular growth chart. Diameter of the cavernous segment of the internal carotid artery (ICA) as a function of age for 318 pediatric subjects without stroke, cerebrovascular disease, or vascular risk factors. ICA diameters were measured on axial and coronal T2-weighted images of the brain obtained for evaluation of trauma, headaches, or hearing loss. The mean ICA diameter for all patients within a given age range is indicated as a circle, and error bars show + and – 1 standard deviation. The growth curve is divided into 3 growth regions by 3 red lines. The subject age, and the percentage of fully mature ICA diameter in the plateau of the curve corresponding to each of the red lines is annotated above each red line. The measured ICA diameter corresponding to each of the red lines is indicated in red text to the left of each read line. SD indicates standard deviation.

Some skeptics of EVT for the treatment of pediatric AIS have expressed concerns about excessive administration of iodine contrast media and associated risks of renal injury. Experience in the multiple expanding fields of pediatric interventional therapy has shown that contrast nephropathy is not a clinically significant problem in the pediatric population when patients receive adequate intraoperative and postoperative hydration. This holds true over a wide range of contrast loads in excess of 10 mL/kg.48 Furthermore, only small amounts of contrast are necessary in the relatively short EVT procedures performed for pediatric AIS. Nonetheless, conservative use of contrast media and flush solutions is necessary to avoid fluid overload, particularly in children with significant cardiac pathology.

Some have expressed concern that the procedure-related radiation exposure associated to EVT is dangerous for small children. The authors assert that EVT procedures are very short and exposure rates are very low using modern equipment and technique with pediatric-specific protocols.49 Moreover, these concerns are outweighed by the potential rewards of reperfusion therapy in well-selected pediatric patients, who are likely to benefit from neurological recovery and prevention of long-term disability.

After EVT procedures, pediatric patients should receive supportive care with particular attention to optimization of normoglycemia, euvolemia, oxygenation, blood pressure, and prevention of hyperthermia and infection. Although there are no data to demonstrate the benefit of pediatric stroke units, care of pediatric patients with AIS often occurs in pediatric intensive care settings. A minority of patients may develop raised intracranial pressure, which should prompt early supportive care and early neurosurgical referral for consideration of decompressive craniectomy, particularly for patients with AIS with malignant middle cerebral arterial territory infarction.50 Given the plasticity of the young brain, rehabilitation for children following stroke can likely lead to vast improvements in long-term outcomes, with a favorable impact on long-term morbidity, quality of life, and emotional health for the child and the family.6

IMAGING SELECTION OF CHILDREN FOR ENDOVASCULAR STROKE THERAPY

One of the greatest challenges involved with EVT in the pediatric population concerns the implementation and interpretation of neuroimaging-based patient selection. In the hyperacute phase of adult AIS, which extends 6 hours from the time of stroke onset, American Heart Association (AHA) guidelines recommend that imaging selection of patients for endovascular treatment is limited to noncontrast computed tomography (CT) or magnetic resonance imaging (MRI) Alberta Stroke Program Early CT (ASPECT) score, and vascular imaging for confirmation and localization of intracranial LVO.2 This recommendation is based on the results of multiple RCTs, which show that anterior circulation LVO patients with severe neurological deficits and ASPECT scores ≥6 will benefit from EVT initiated within 6 hours of stroke onset.51–53 In contrast, multiple RCTs in adult stroke support the use of perfusion imaging techniques to select patients for thrombolysis and thrombectomy in extended time windows (6–24 hours from stroke onset).54–56

The general approach to imaging-based patient selection begins with quantitative determination of core infarction (irreversibly damaged, nonviable brain tissue), and ischemic penumbra (reversibly injured, viable brain tissue). These quantitative values are implemented in a “mismatch” centered, core infarction–bounded decision-making algorithm designed to select patients who will benefit from revascularization and exclude patients in whom revascularization would be futile or potentially harmful. The “mismatch” metric quantifies how much larger the volume of ischemic penumbra is relative to the volume of core infarction. The decision-making algorithm is driven by quantitative parameters empirically determined by RCT. In clinical studies of adults presenting within 16 hours of stroke onset, endovascular treatment improves the likelihood of a good clinical outcome when the volume of ischemic penumbra is at least 15 mL and 1.8 times greater than the core infarct volume (class I, Level of Evidence A).10,55 Endovascular treatment in the 16- to 24-hour window improves the probability of a good clinical outcome in adult anterior circulation LVO patients younger than 80 years of age, if they have a moderate clinical stroke (NIHSS score 10–19) and a core infarction <31 mL or a severe clinical stroke (NIHSS score >19) and a core infarction <51 mL (class IIa, Level of Evidence B).56 Note the differential application of an imaging-derived mismatch metric and a clinically derived mismatch metric to the 6- to 16-hour and 16- to 24-hour windows, respectively. The origin of this difference lies in the varied inclusion criteria used for clinical trials addressing the different time windows.55,56

Automated quantitation of brain imaging data has improved the speed, accuracy, reproducibility, and generalizability of imaging-based patient selection for adult AIS treatment. RAPID software is one such automated image processing program that has been validated in adult clinical stroke trials.53,55–57 Recent reports suggest that MR perfusion imaging of the brain, and analysis with RAPID software is feasible in children and can be completed for individual patients within 10 minutes.19

Common approaches to quantitative assessment of core infarction in patients with AIS are based on noncontrast CT, perfusion CT, and brain MRI. Noncontrast CT ASPECT score may be used to quantitatively estimate ischemic core, although it may underestimate core infarction size in the hyperacute and acute phases of AIS. On the contrary, hypodensity on noncontrast CT is a more reliable indicator of irreversible infarction than cerebral blood flow on perfusion CT imaging, particularly when there is partial reperfusion of nonviable tissue.58 In adults, CT perfusion provides a reasonably accurate estimate of irreversibly infarcted tissue when cerebral blood flow is <30% (relative to contralateral normal brain) is used a threshold, although there is a tendency toward clinically significant overestimation of ischemic core in the hyperacute period.59–61 The ability of this threshold to consistently select patients who benefit from revascularization was proven in multiple thrombectomy trials, including DAWN and DEFUSE 3.53,55–57 CT perfusion has been previously studied for a number of indications in children and has been shown to be feasible; however, as with MRI, established adult CT perfusion thresholds may be different in the pediatric brain (Fig. 7A–D). Consequently, for all cases, it is prudent to weight clinical neurological assessment, the individual patient's vascular anatomy, the site of arterial occlusion, and relative perfusion measures to estimate the arterial territory-at-risk.

FIGURE 7
FIGURE 7:
Pediatric CT perfusion imaging. CT perfusion imaging (A, B) in same patient shown in Figure 4E and F. Predicted core infarction in red (cerebral blood flow ≤30% of contralateral normal) and penumbra in green (TTP ≥6 seconds). It is notable that unaffected left posterior cerebral artery territory shows quantitative perfusion levels in the penumbral range, likely due to chronically reduced tissue perfusion in this child with severely depressed cardiac function. CT imaging obtained 48 hours after revascularization (C, D) demonstrates that CT perfusion imaging overestimated the patient's core infarction.

In general, MRI is preferred over CT for neuroimaging of suspected stroke in children for its superior sensitivity to acute ischemia, superior differentiation of stroke mimics, and lack of exposure to ionizing radiation. In adults, MRI-based ischemic core quantification paradigms delineate ischemic core as tissue with an apparent diffusion coefficient (ADC) <620 × 10–6 mm2/s.62 It is notable that the visibly hyperintense lesion on diffusion-weighted imaging (DWI) is above this ADC threshold in up to one third of children with AIS.63 Another caveat is that diffusion restricted brain tissue demonstrated by early imaging may be salvageable if prompt revascularization is performed, particularly in the hyperacute phase of AIS. Counter to these points, clinical studies in adults with AIS have shown that the final infarct volume is smaller than the initial DWI lesion volume in only 3% of patients undergoing EVT within 12 hours of stroke onset, and the median volume of DWI reversal was only 11% of the initial DWI lesion volume. Furthermore, there was no correlation between early reperfusion and DWI reversal.64 Reversibility of diffusion restriction has been reported in pediatric patients with AIS, although this phenomenon has not been well characterized.65 In a cohort of 29 children with ischemic stroke, the established adult ADC threshold of <620 × 10–6 mm2/s strongly correlated with the DWI lesion in early time windows.63 Another report of 4 children with acute stroke and MR RAPID perfusion imaging also found that ADC volume <620 × 10–6 mm2/s correlated with final DWI volume on follow-up imaging.19

In adults presenting with acute AIS, penumbral quantification is performed with dynamic contrast enhanced perfusion brain imaging. Penumbra is identified as brain tissue with a time-to-maximum tissue residue (Tmax) >6 seconds. Adult stroke studies have shown that brain tissue with Tmax >6 seconds is critically hypoperfused but salvageable. Early experience with penumbral imaging in children with AIS suggests that the same threshold may not apply. Lee et al reported 5 cases of pediatric LVO who underwent brain perfusion imaging. In 2 cases, the volume of tissue with Tmax >6 seconds was insignificantly small, whereas the volume of tissue with Tmax >4 seconds was very large and correlated much more closely with cortical deficits on clinical examination that were not explained by the DWI lesion.19 One explanation supported by the literature is that cerebral collaterals in children are more robust than in adults.66 Consequently, the well supported pediatric penumbra has a lower Tmax than the more poorly supported adult penumbra. Because there is no data correlating Tmax with tissue fate in children, it is uncertain whether or how brain tissue perfusion metrics of the pediatric penumbra differ from those of the adult penumbra.

It is possible that imaging biomarkers of ischemia may be altered by patient age and chronically impaired cardiopulmonary function. The level of perfusion needed to meet the metabolic demand of brain tissue may be different for adults and young children. Cerebral perfusion and mean diffusivity are known to undergo significant changes over infancy and toddlerhood.67 In addition, children with longstanding congenital heart disease may have profoundly altered cerebral perfusion and oxygen extraction, particularly those with single ventricle physiology, chronic hypoxia, or children requiring prolonged support from extracorporeal circulatory assist devices.68,69 Direct translation of adult Tmax threshold values may thus be misleading for estimation of penumbra in childhood AIS (Fig. 7A–D) and requires further study.

One report of 5 children with LVO strokes suggested a possible correlation between DSC cerebral perfusion imaging and cardiac status.19 In 1 child with heart failure, symptomatic cerebral ischemia correlated with Tmax >6 seconds, but in 2 children without cardiac insufficiency, symptomatic cerebral ischemia correlated with Tmax >4 seconds. One straight forward explanation for these findings is that the penumbra of children with impaired cardiac function has a relatively longer Tmax compared to children with normal cardiac function because brain tissue perfusion strongly depends on cardiac output. It is unknown if neuronal metabolic activity is adapted to compensate for chronically low perfusion levels in children with chronic cardiopulmonary insufficiency. It is possible that the depth and duration of ischemia required for irreversible infarction is altered in such children independent of collateral support. Consequently, simple metrics of tissue perfusion may need additional context in the pediatric population with chronically depressed cardiopulmonary function. Imaging-based patient selection for EVT will improve with advances in imaging biomarker research and new trials such as the proposed Pediatric Endovascular Therapy after Imaging in acute stroke.

One important goal of imaging-based patient selection for EVT is to avoid futile or harmful revascularization procedures. Although there is a lack of guidance concerning imaging biomarkers predictive of patient harm, imaging biomarkers of neurological prognosis such as the ischemic core have been used as a surrogate. Critics of this approach point out that a small but significant number of patients presenting with large ischemic cores achieve functional independence.70 In clinical studies of endovascular stroke therapy, the absolute size of the ischemic core on brain imaging correlates well with clinical outcome. Two recent large adult cohorts showed that good clinical outcome was significantly less likely in patients with ischemic core volumes >100 mL.71 This corresponds to 40% of the adult MCA territory, or a CT ASPECT score <6.72 Imaging-based estimates in children suggest that brain volumes do not change significantly between 4 and 18 years of age.73 In younger children, Wintermark et al estimated that 70 mL represents approximately 40% of the MCA territory (personal communication, Max Wintermark, MD). Extrapolation of adult ischemic core principles to the pediatric population should be made with caution. Beyond core infarct volume, eloquence of affected tissue is an important determinant of clinical outcome in patients with AIS.74 There are reasons to believe that the same fractional loss of tissue, and function within the MCA territory may translate into significantly different long-term clinical outcomes for children relative to adults. Young children have a uniquely remarkable capacity to adapt to neurological deficits and recover function through synaptic reorganization.

CONCLUSIONS

Clinical studies have shown that administration of IV tPA to pediatric patients with AIS 2 to 17 years of age is safe within 4.5 hours of stroke onset, when the adult dose of 0.9 mg/kg is used. Mounting observational data supports mechanical thrombectomy in properly selected children with type 1 or type 2 pediatric intracranial LVO, but additional caution and use of modified techniques is warranted in the infant population. Familiarity with common forms of pediatric cerebral arteriopathy is necessary for safe surgical decision making. Cerebral perfusion imaging metrics have not yet been characterized in the pediatric population, particularly in those with severe cardiopulmonary pathology. Further research is needed before penumbral imaging can be used for clinical decision making in pediatric AIS.

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Keywords:

pediatric neuroimaging; pediatric stroke; stroke imaging; stroke intervention

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