Acute StrokeTreatment in Children: Are Adult Guidelines Applicable?

Abstract

Purpose of this Review:

This article provides an overview into acute treatments in stroke which are widely studied and available for adults and their applicability in the pediatric population.

Recent Findings:

Arterial ischemic stroke is an important cause of morbidity and mortality in the pediatric population. Neurological deficits and etiologies are age-dependent and more challenging to diagnose than in the adult population. Advancements in imaging and treatment modalities including increased treatment windows in acute stroke have led to improvement in the diagnosis and management of pediatric arterial ischemic disease. Accordingly, hyperacute treatments, such as endovascular therapy, are becoming increasingly available in an attempt to improve outcomes in children.

Summary:

Significant scientific and technological advances have transformed the hyperacute treatment of stroke in the recent years, allowing for improvement in the diagnosis and treatment of cerebrovascular pathologies in children. Optimization in the approach, and validation of existing stroke pathways/protocols is expected to further advance acute stroke therapy in pediatric patient care. Given that the lifelong individual, family, and societal burden of acute stroke is likely to be greater than in adults because infants and children surviving stroke live more years with disability, we must be knowledgeable about this pathology and the medical and therapeutic options available for this unique population as detailed in this review.

Introduction

Arterial ischemic stroke is a rare but a potentially devastating event in the pediatric population with a variety of etiologies that differ from adults. Pediatric stroke can affect survivors with lifelong disabilities in motor, cognitive, and behavioral function. Stroke is listed among the top 10 causes of death in the pediatric population, with a reported 7% to 28% mortality rate (1).

Based on the clinical presentation, etiology, and prognosis, pediatric stroke is predominantly separated into two age categories: stroke occurring from 28 weeks’ gestation to 28 postnatal days of life being defined as perinatal stroke and stroke occurring after 28 days to 18 years of age as childhood stroke (2). Updates on perinatal and childhood stroke, and considerations for clinical practice, attendant controversies, and knowledge gaps have been recently published by the American Heart Association Stroke Council’s Scientific Statement Oversight Committee and the American Heart Association’s Manuscript Oversight Committee(3).

Childhood arterial ischemic stroke (CAIS) affects approximately 1.6 per 100 000 children per year, while stroke recurs in up to 20% of patients at 5 years (4). Numerous conditions have been associated with AIS in children, and the etiologies of stroke in a child are more varied than in adults. We have summarized the most common etiologies of pediatric stroke in Table 1 and limit our discussion here to acute stroke treatments applicable in children. Unfortunately, despite its high toll on children it afflicts, study of treatments of pediatric strokes is hampered due to their low incidence. This lack of data becomes more pronounced when it comes to acute stroke treatments in children due to frequent delay in diagnosis, sometimes up to 24 hours or more. Thus, most of clinical practice in management of acute stroke in children is based on data translated from studies on adult populations.

Table 1.

Epidemiology of Stroke in Children

	References
Arteriopathies
Sickle Cell disease (SCD)	(41)
Moyamoya disease and Moyamoya syndrome	(42)
Transient cerebral arteriopathy	(43)
Postvaricella arteriopathy	(44)
Vasculitis	(45)
Takayasu arteritis	(46)
Kawaski disease	(47)
Thromboembolic disease related to cardiac, prothrombotic, and/or neoplastic processes
Cardiac
Congenital heart disease	(48, 49)
Rheumatic heart disease
Cardiomyopathy
Endocarditis/Myocarditis
Dysrhythmias
Iatrogenic
Prothrombotic
Sickle cell disease	(50, 51)
Polycythemia
Thrombocytosis
Leukemia/lymphoma
Protein C/S deficiency
Antithrombin III deficiency
Prothrombin gene G20210A mutation
Factor V Leiden mutation
Methyl tetrahydrofolate reductase (MTHFR)
Lipoprotein A
Antiphospholipid antibody syndrome
Lupus anticoagulant
Factor V Leiden mutation
Disseminated Intravascular coagulation
Oral contraceptives
Neoplastic Diseases	(52)
Extracranial arterial dissections with resulting intracranial occlusions
Head/neck trauma	(53)
Fibromuscular dysplasia	(54)
Hyperhomocystinemia	(55)
Connective tissue disorders
Ehlers-Danlos syndrome type IV	(56, 57)
Marfan’s syndrome
Autosomal dominant polycystic kidney disease
Osteogenesis imperfecta type I

Accuracy and timeliness of diagnosis are critical factors to provide successful therapeutic interventions in children presenting with acute arterial ischemic stroke. Unfortunately, onset recognition by parents and caregivers is often delayed, highlighting the need for increased awareness of and education regarding this condition (5). Initial diagnosis of a stroke is only accurate in ~60% of children (6). In fact, diagnosis of cerebral infarction is often made when imaging is obtained for other reasons, such as cardiac arrest or extracorporeal membrane oxygenation (ECMO) cannulation (7). Often, the outcome of CAIS is worsened by delayed diagnosis and lack of treatment protocols (8). Institutionally based guidelines of care for the emergency evaluation of children with suspected stroke should facilitate rapid evaluation and trigger an organized approach to defining the neurological deficit, initiating neuroprotective measures, and selecting appropriate neuroimaging (9).

Diagnostic evaluation in acute treatment of stroke in children

Even though symptoms and signs of stroke in children are similar to adults, initial evaluation is often counfounded by higher incidence of headaches (20-50%), altered metal status (17-38%) and seizures (15-25%) in children at onset of CAIS (10–12). These could be somewhat mitigated by institution of more pedaitric emergency rooms staffed by providers trained in pediatric emergency care and better education of frontline health care workers like emergency medical services for early identification of potential CAIS. Use of pediatric NIHSS has been shown to have high degree of concurrent validity and reliability (13, 14). Focal neurological deficits are more common in CAIS than stroke mimics. It is recommended that hospitals willing to provide care to CAIS should have established systems of care for pediatric population including buy-in from emergency providers, pediatric neurologists and radiologists. Even though CT based imaging is primary choice in adults with AIS, this modality is not readily considered in pediatrics due to radiation and contrast concerns. Although MRI based imaging is preferred in pediatric population, it has inherent delays including 24*7 availability of MRI machines/technologists, longer acquisition time and need for sedation and/or anesthesia. Rapid clinical and radiological evaluation is essential to providing appropariate care in CAIS.

Feasibility and safety of intravenous tissue-type plasminogen activator (tPA)

The role of tPA in treatment of AIS in adults was established in 1990s after the landmark clinical trial with expansion of the treatment window to 4.5 hours soon afterwards (15, 16). The wider application though was initially limited by rapid recognition of AIS in adults. This has significantly improved due to increased education of healthcare personnel including emergency medicine services and general population and advances in systems of care. These challenges are maginified in the pediatric population. Though tPA has been demonstrated to be safe in the pediatric population, efforts to study it in a prospective randomized trial in TIPS were unsuccessful due to poor enrolment (17, 18). The main barriers to administration of tPA to children in TIPS were delayed recognition of focal neurological deficits in the field, preponderance of stroke mimics (seizures, migraine, tumors, infections) and contraindications to administration of tPA. The study did identify that before performing a similar study in the future, it is important to develop systems of care for rapid identification and delivery of acute stroke treatments in the pediatric population. This may take the shape of regional pediatric stroke centers along with telemedicine, providing 24/7 access to pediatric stroke, intensivist, neurosurgeon and neurointervention trained physicians. Though the dose of tPA is not well established, the consensus is to use the adult dose of 0.9 mg/kg with 10% given as bolus over 1 minute and rest as an infusion over an hour (3). Considering children with AIS tend to have better prognosis than adults, tPA is usually limited to children with confirmed intracranial clot on imaging and high pediatric stroke scale. Since it might turn out that the dose of tPA in pediatric AIS may be different than adults, endovascular thrombectomy may have a bigger role in pediatric AIS, also due to its application in an expanded windown up to 24 hours.

Feasibility and safety of endovascular thrombectomy devices in pediatric AIS

Since the American Heart Association and the American Stroke Association guidelines reported level I evidence to support endovascular therapy in adults with acute arterial ischemic stroke, there has been growing body of evidence establishing the feasibility and safety of endovascular therapy in children. For instance, endovascular therapy using thrombectomy devices, such as stent retrievers are readily compatible with the vasculature of children over 5 years of age, at which diameters of the large cervical and cranial vessels reach adult size (Figure 1) (19). In addition, several case series have demonstrated that mechanical thrombectomy in children can be performed safely (Table 2). While randomized controlled trial would provide compelling evidence of the potential advantages to this technique, the lack of this should not prevent the use of this procedure by trained interventionists (20).

Figure 1. Basilar Artery Mechanical Thrombectomy:

16-year-old boy was found down at 3 PM on his bathroom floor after his parents heard him fall. He was taken to the local ER where he was obtunded with dysconjugate gaze and minimal movement of any of his extremities. CT head (Panel A) was reported to be unremarkable (though on retrospective review, demonstrated hyperdense basilar artery. He was thought to be having seizures and treated with Ativan, Dilantin and Keppra with no improvement in clinical status and intubated for airway protection. MRI brain was obtained emergently which demonstrated absent flow void in basilar artery with no other evidence of acute ischemia. Then he underwent CTA head (Panel B) which demonstrated a long segment of occlusion of the basilar artery (red arrows). Due to the delayed diagnosis, he was outside the window for alteplase. He was transferred for higher level of care and taken emergently for mechanical thrombectomy. Initial DSA (Panel C) demonstrated occlusion of basilar artery (red arrow). Post mechanical thrombectomy, complete recanalization of basilar artery was visualized after one pass (Panel D). The boy made a complete recovery with no residual deficit and went on to complete college with good grades.

Table 2.

Summary of treatment details, recanalization rates, intracranial hemorrhagic complications, and clinical outcomes based on PubMed search of keywords child, pediatric, stroke, and endovascular. Studies of all pediatric AIS cases managed with endovascular treatment within the last 5 years ( >3 patients) were included.

Reference	Total patients	EVT	Recanalization (any EVT) (%)	Intracranial hemorrhage (any EVT) (%)	Clinical outcomes (any EVT)
van Es et al. 2021 (27)	9	9	100 mTICI grade ≥2b	10	8 out of the 9 patients showed neurological recovery within 24hrs
Ravindra et al. 2021 (58)	21	19	83% mTICI grade ≥ 2b	NR	14 (66%) patients had a mRS score of <2 at 30-d follow-up
Sporns et al. 2021 (59)	73	57	87.3 TICI 2b/3	1.4	NR
Fragata et al. 2021	7	7	6	14	4 (57%) patients had mRS score of<3 at 90-d follow-up
Bigi et al. 2018 (25)	16	10	81.8 complete/partial	6.3	Median PSOM 1.75 at 6 months

Pediatric stroke outcome measure (PSOM); not reported (NR); not applicable (NA); endovascular therapy (EVT); mRS (modified Rankin Scale); intravenous (IV)

Nevertheless, the 2019 American Heart Association (AHA)/American Stroke Association (ASA) guidelines state that in the absence of pediatric clinical trial data to guide treatment decisions, hyperacute therapies for childhood AIS remain controversial. AHA concludes that it would be reasonable to limit consideration of this intervention to cases meeting the below criteria: 1) persistent disabling neurological deficits (eg, Pediatric NIH Stroke Scale score ≥6 at the time of intervention or higher if DAWN trial criteria are being applied), 2) radiographically confirmed cerebral large artery occlusion, 3) larger children, 4) treatment decision made with neurologist with pediatric stroke expertise, and 5) intervention performed by endovascular surgeon with experience in pediatric stroke intervention. Several studies have begun to establish the foundation for the utilization of adult endovascular thrombectomy devices in pediatric AIS. In Table 2 we have summarized recent case series in regards to treatment details, recanalization rates, intracranial hemorrhagic complications, and clinical outcomes.

In meta-analysis by Bhatia et al (21), the authors found in 113 cases of mechanical thrombectomy 90.6% of pediatric patients had good long term neurological outcomes (mRS score 0-2). Of note, sixteen patients were < 5 years of age. Another recent meta-analysis from Pacheco et al reviewed a total of 16,987 pediatric stroke patients’ records, of whom 181 received IV thrombolysis. Despite the extensive research work, efficacy of revascularization therapies could not be conclusive due to lack of outcome data (22). Satti et al. performed a comprehensive review of available literature on pediatric stroke intervention, with a focus on modern mechanical devices (23). In a patient cohort with an average age of 10.3 years, the authors found that mechanical thrombectomy was associated with high recanalization rates and excellent clinical outcome. Wilson et al reviewed 3184 pediatric discharges with a diagnosis code for arterial ischemic stroke and found that endovascular therapy was infrequently utilized (~1%). Outcomes in patients undergoing endovascular therapy were similar to those in children who did not receive endovascular therapy (24). Bigi et al assessed feasibility, safety, and outcome of EVT in children with AIS in a retrospective cohort of 150 patients (age 7.1 ± 4.9 years). Complete or partial recanalization was achieved in 63% of patients and complications of recanalization therapy occurred in two patients (12.5%): one patient experienced an asymptomatic ICH and one mucosal bleeding (25). Shoirah et al assessed pediatric acute ischemic stroke with underlying large vessel occlusion in nineteen patients with a mean age of 10.9(6) years. Good neurological outcome was achieved in 89.5% of the patients. One patient had post-revascularization seizure, but no other procedural complications or mortality occurred (26). A very recent study by van Es et al. describes the safety and efficacy of EVT in children with anterior circulation acute ischemic stroke in nine children (median age 14) who were included in the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) (27). In all but one patient, EVT was technically successful and no major periprocedural complications occurred (27).

Complications during invasive neurovascular imaging techniques during the diagnosis and treatment of a child with suspected arterial ischemic stroke

Despite the extensive evidence of benefit and safety profile in adults (< 1% complication rates), our understanding on the role of catheter-based angiography (CA) in pediatric arterial ischemic stroke is limited. The assumption remains that CA is more challenging and dangerous in children. This hesitation is based on the assumption that the rate of complications resulting from femoral access and intracranial catheter navigation is increased for children because of the smaller vessel-to-catheter ratio and resultant higher risk for vasospasm, dissection, and peripheral vascular injury. Nevertheless, there is clearly a growing interest in diagnosing and treating cerebrovascular disorders in children using cerebral angiography (28) and there is an urgent need to understand complications associated with CA in children. Recently curated guidelines for evidence-based decision making were published (29).

Recent data indicates that the rate of immediate complications occurring during diagnostic cerebral angiography in children is very low. Hoffman et al. reviewed data for over 300 consecutive cerebral angiograms obtained in 87 children younger than 36 months (range 1–36 months) of age from 2004 to 2010 at a single institution (28). The authors found that rate of complications for CA in young children is comparable to rates reported for older children and lower than rates reported for adults. They concluded that CA should not be omitted from the therapeutic strategy of children younger than 36 months of age (28). Complications related to vascular access for catheter based digital subtraction angiography are also minimal and include (30) hematoma, pseudoaneurysm, retroperitoneal hemorrhage, and limb ischemia. In neonates and infants, a small amount of bleeding might have important hemodynamic repercussion to the cardiovascular system and can easily lead to hypovolemic shock. Loss of pulse pedal pulses usually secondary to vasospasm or thrombosis is observed in 6% of pediatric patients and typically occurs within the first 2 years of life (31). Duplex ultrasonography may allow a rapid determination of vasospasm versus thrombosis. When venous access is needed, there is a risk of developing an arteriovenous fistula when both the artery and vein are simultaneously punctured. Most often this occurs with low groin punctures but is typically asymptomatic and 80% resolve spontaneously over a few months. Another chronic complication that may occur is ipsilateral limb ischemia with concomitant leg length asymmetry. This can be related to multiple groin punctures at different time points when staging treatments are needed, thus leading to scarring and progressive reduction in caliber of the vessel. It can also be caused by multiple attempts at puncture in the same session leading to mural hematoma and vessel injury. Burger et al found in a patient cohort including 115 boys and 90 girls, with age ranging from 1 week to 18 years (mean±SD, 12±5 years) and data from 241 consecutive pediatric cerebral angiograms), that DSA rates of intraprocedural and postprocedural complications were essentially zero (32).

While these single-institution retrospective studies are not conclusive, the above highlighted examples support the idea that CA performed by experienced pediatric trained angiographers is a safe procedure and can provide critical diagnostic information.

Challenges in the diagnoses and treatment of arterial ischemic stroke in children using catheter angiography

Pre-procedure evaluation

Initial knowledge of the clinical history of the referred patient will allow the neuro-interventionist to develop a plan of attack focused on what initially needs to be done and to assess the need for the procedure. A detailed review of patient anatomy from non-invasive diagnostic imaging prior to catheterization might also help with appropriate catheter and wire selection. The child’s height and weight should also be reviewed as these guide contrast and anesthetics dosages. Vascular access (intravenous) must be determined prior to starting the angiogram depending on the anesthesia of choice. Because children less than 2 years old are susceptible to ambient temperature and temperature changes, thermal monitoring is recommended. Warming mattress, overhead lamps and radiant heat warmers can be utilized to maintain body temperature. Furthermore, urinary catheters are used to ensure comfort during a lengthy procedure. Pressure padding can prevent compressive nerve palsies and ensure patient immobilization (33).

Sedation

Sedation is often needed for angiography in children (34). Patients over 10 years of age can often tolerate diagnostic angiography with conscious sedation whereas those less than 10 years of age almost always require deep sedation or general anesthesia to achieve cooperation and adequate immobility.

Contrast

Weight-based contrast limitations are rare in adults, but they should be taken into consideration since they might limit the amount of number of vessels studied in a young infant. Typically, low osmolarity contrast media (CM) 300-350 mg iodine/mL are preferred in children as they reduce the chances of nephrotoxicity as well as lessen the risk for an allergic reaction (35). Reactions to CM fall into idiosyncratic or non-idiosyncratic. Issues like contrast and osmotic related volume load which can result in congestive heart failure and nephrotoxicity fall into the non-idiosyncratic category (35). These reactions are dose-dependent, therefore there is a consensus to limit the total contrast dose to 5-7 ml/kg (36). CIN is usually transient and clinically insignificant and the chances of it occurring are reduced with adequate hydration. Idiosyncratic reactions are different than typical allergic reactions as they can occur on the first exposure to CM and may have variable reactivity on future exposures.

Vascular Access and microcatheter decisions

Vascular anatomy in pediatric patients can pose a significant challenge to performing diagnostic cerebral angiography. Secure vascular access is most commonly gained in the right common femoral artery using ultrasound guidance (37). Typically for neonates, infants, and younger children up to 10 years of age, a linear thin, high frequency ultrasound probe is utilized to determine the bifurcation site of superficial femoral and arteria profunda femoris and a micro-puncture needle is utilized to access the right common femoral artery with a 3.3 or 4 Fr arterial sheath. To maintain preservation of the femoral artery, alternate access sites (right/left) are recommended in children needing multiple procedures. Sheaths sizes of 5 Fr for children weighing more than 20 kg can be usually used safely but are usually reserved for therapeutic interventions. In premature neonates, umbilical arterial/venous access is an alternative in the neonate or premature infant. The umbilical artery is patent up to 5 days after birth and can accommodate larger sheaths and catheters. Once the procedure is completed, hemostasis is achieved by manual compression held for 15 – 20 minutes. Microcatheters can be used to obtain a diagnostic cerebral angiogram in patients with anatomic challenges limiting catheterization by standard techniques (38).

Radiation Considerations

Pediatric patients have been shown to be more sensitive to radiation dose effects, due to their rapid and continuing growth (39). Thus, awareness of methods for dose reduction and radiation dose tracking should be a mandatory first step for all neuro-interventionalists participating in the care of pediatric patients. ALARA, “as low as reasonably achievable”, is the guiding principle that the Centers of Disease Control has created to guide physicians who must use radiation for diagnostic or therapeutic purposes (40).

Conclusion

Though children with acute ischemic stroke tend to have better outcomes when compared to adults, there has been an increasing recognition that acute interventions by use of thrombolytics and endovascular therapy, may improve the outcomes of more children. Unfortunately, due to the multitude of reasons listed above, randomized control data on management of acute stroke in children is lacking. Thus the need to extrapolate data gathered and analysed in prospective manner in adults and apply it for management of acute stroke in children. These knowledge gaps can be improved with at least reporting of children with acute stroke and their management in ongoing regsitries like the International Pediatric Stroke Study, which is an ongoing database for stroke in infants and children. As was demonstrated by Wilson et al(24) through their analysis of 2012 Kids’ Inpatient Database, management of children with acute stroke happens majority of the time in hospitals not dedicated to taking care of children with limited application of current treatment modalities. Hopefully with improvement in systems of care at children’s hospitals and wider availability through telemedicine, better care to children with acute stroke can be provided.

DATA SHARING

All data relevant to the study are included in the article.