Improving diagnosis and treatment of pediatric AIS

Reviewed by Christine Fox, MD

Pediatric arterial ischemic stroke (AIS) is an important cause of long-term morbidity and is among 1 of the top 10 reasons for death in children.^1,2 Although it occurs in 2 to 3 children per 100,000 children per year, with an increased incidence of about 1 in 4000 during the perinatal or neonatal period, accurate diagnosis is commonly delayed or missed.² As such, increasing recognition of the signs and symptoms of this significant cause of morbidity and mortality in children is critical to improving diagnosis and providing optimal treatment.

This article provides guidance on improving rapid recognition and diagnosis of pediatric AIS to facilitate better acute management necessary to limit or reduce the effects of stroke. Also discussed are current guidelines on acute management, and the variation among the guidelines on the use of antithrombotic therapy in the acute setting. Emphasized is the need for pediatricians to work with other specialists, and the additional help now available from the newly established pediatric acute stroke centers, to ensure the best possible care for these children. Issues regarding secondary stroke prevention are also discussed.

More: The long-term effects of pediatric stroke

Important for pediatricians and other healthcare providers who care for children with AIS is the recognition that high-quality good evidence on treatment is largely lacking, and suggested recommendations by current guidelines are largely based on consensus only. The need to better treat childhood AIS is highlighted by data showing that many children will have lifelong neurological residual symptoms, including hemiparesis and/or dysphasia, as well as neurocognitive and behavioral problems attributed to AIS.³

Diagnosis of AIS in children

Making the differential diagnosis of AIS in children is challenging and contributes to its often delayed or missed diagnosis. Among the diseases that AIS can mimic include focal seizures, demyelination, tumor with hemorrhage, hemiplegic migraine, hypoglycemia, and conversion disorder.² Some data show a mean of 7 days between initial assessment and final accurate diagnosis, with a change in diagnoses often leading to changes in therapy.³

Because AIS may present differently in children than adults (Table 1),^1,2,4the first step in diagnosis is recognizing the particular clinical signs and symptoms of pediatric AIS, as well as risk factors. The most important differences of AIS in children compared with adults is that about 30% of children will present with headache or seizure, and symptoms of AIS may wax and wane (unlike in adults who usually have a sudden onset).^5,6 Table 1 lists other things to look for that differentiate AIS in children from adults,^1,2,5,6 and Table 2 provides guidance on clinical evaluation of AIS in neonates and children.^2,3,7

About 50% of children with AIS will have a preexisting medical condition relevant to AIS, including congenital heart disease, sickle cell disease, trisomy 21, iron deficiency, prothrombotic states, and infection.¹

An immediate workup to identify or rule out AIS is critical. Once AIS is suspected, neuroimaging with magnetic resonance imaging (MRI) of the brain and magnetic resonance angiography (MRA) of the intracranial arteries is indicated to confirm a diagnosis.² Other imaging studies that may be useful include computed tomography (CT) or CT angiography (CTA) when MRI is difficult to undergo for a child, and invasive catheter cerebral angiography if CTA and MRA findings are unremarkable or detect vascular abnormality of unclear etiology.

Treatment of AIS

Treatment for pediatric AIS is aimed at acute treatment and secondary prevention. Because of the lack of good evidence-based studies in pediatric AIS, treatment has been variable with available guidelines offering only consensus-based recommendations.^2,7-9 In addition, because of the dearth of high-quality evidence on pediatric AIS, historic treatment has been based on extrapolating treatments from those used in adult AIS despite significant differences in the underlying etiology of disease.¹

Read More: The risk factor and diagnostic challenges for pediatric stroke

Because of the complexity of AIS in children, acute management in most cases of stroke should involve a multidisciplinary approach that includes pediatric subspecialties (ie, intensive care, neurology, neuroradiology, thrombosis/hematology, and rehabilitation) as well as other specialties as needed per individual patient (ie, cardiology, neurosurgery, infectious diseases, and rheumatology).² The new emergence of pediatric acute stroke centers also can provide a useful resource for pediatricians to help in accurately diagnosing and acutely treating AIS in children.¹⁰

ACUTE TREATMENT

The goal of acute treatment of AIS in children is to limit or reverse the effects of stroke on brain injury,¹ as well as to look for etiology and risk factors that also may need treatment.²

The cornerstone of acute treatment is supportive neuroprotective measures based on an assessment of airway, breathing, circulation, and disability (Table 3).^1,11

Although data is scarce on whether controlling hyperthermia or hypertension/hypotension is beneficial to children with AIS, as it is in adults, the American Heart Association (AHA) guidelines suggest avoiding these conditions as well as hypovolemia/hypervolemia.² Overall, blood pressure management in children should be aimed at avoiding sudden acute changes in blood pressure by maintaining stable and adequate cerebral perfusion.¹

Prompt treatment of seizures is important to help maintain systemic homeostasis and prevent infarct expansion,^1,2 and aggressive management of raised intracranial pressure can be lifesaving.¹ For children with sickle cell disease, exchange transfusion to reduce levels of sickle cell hemoglobin to less than 30% is suggested for acute treatment of AIS, although this has not been tested in a clinical trial.

Although a large area of uncertainty and persistent lack of clear data is the role of antithrombotic therapy for neuroprotection in acute treatment,¹ most stoke experts agree that some level of either antiplatelet or anticoagulation therapy is beneficial to prevent acute progression of thrombus.² Important for the effective use of antithrombotic therapy for acute management of AIS is to use it within a window of time from symptom onset (within 6 hours), which further reinforces the need for prompt recognition and diagnosis.¹² Table 4 summarizes current guidance on antithrombotic therapy for acute treatment of pediatric AIS from current clinical guidelines.^1,2

Some pediatric stroke centers may consider other types of antithrombotic treatment as well, such as intravenous thrombolytic treatment for older adolescents or children with basilar artery thrombosis or endovascular hyperacute treatment in some cases.^13-16

Caution is needed in using antithrombotic therapy in children, however, given the paucity of data on the safety and efficacy in this population. “When considering antithrombotic therapy in any child with arterial ischemic stroke, it is critical to continually balance the risk (hemorrhagic complication) of antithrombotic therapy with the risk of nontreatment (extension of preexisting infarction and recurrence of stroke),” according to Mahendra Moharir, MD, Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada, in a review article of pediatric arterial ischemic stroke.²

More: Using an electronic stethoscope for auscultation

Further understanding of the role of anticoagulant and antiplatelet therapy for acute treatment of pediatric AIS may come from the ongoing International Pediatric Stroke Study, the largest nonrandomized, multicenter, observational cohort to assess the safety and efficacy of these therapies in pediatric AIS. Current data show that subtypes of AIS treated with initial anticoagulant therapy were children with dissection and congenital heart disease, whereas children with sickle cell disease were associated with not using anticoagulation. For antiplatelet therapy, use was frequent in children with moyamoya disease but less frequent in children with dissection, altered consciousness, and bilateral ischemia.^2,17

SECONDARY PREVENTION

Secondary prevention of AIS is aimed at identifying the underlying risk factors of AIS in individual children to help tailor treatment to prevent recurrence and estimate prognosis.^1,2 Table 5 lists the most frequent etiologies associated with childhood AIS.^1-3,11,18

Secondary prevention of AIS remains challenging, with little evidence-based recommendations available to help guide physicians. The only clear guidance is for children with sickle cell disease for whom chronic transfusion is clearly established and for children with moyamoya disease for whom surgical revascularization is well accepted. Anticoagulation or antiplatelets are both commonly used, and additional research is needed to determine best strategies for acute treatment and secondary stroke prevention.^17,18

Table 6 provides an example of general recommendations on the role of antithrombotic therapy for secondary prevention based on expert consensus in the AHA guideline.⁷ For more specific recommendations by the AHA and by the other 2 guidelines on the use of antithrombotic therapy for secondary prevention, see the specific guidelines.^7-9

Of note, secondary prevention of perinatal/neonatal AIS focuses on rehabilitation recommended for secondary prevention that includes physiotherapy, occupational therapy, and speech therapy.

Observation is needed over time to watch for deficits that may emerge with maturation. Currently, there is no role for antithrombotic therapy in perinatal/neonatal AIS unless prothrombotic abnormalities or congenital heart disease are identified.²

What lies ahead?

The need to improve early diagnosis and optimal treatment of childhood AIS is highlighted by growing recognition of the long-term deficits that many children may have after a stroke (Table 7).^2,19-21

Future research that can provide a deeper understanding of the multiple mechanisms underlying pediatric AIS is needed to better tailor treatment specifically to children rather than base it largely on treatments for adults as current guidelines suggest.¹ Among the multiple mechanisms that need to be examined are genetic predisposition; inflammation; thrombosis and dysregulation of smooth muscle proliferation; and an aberrant response by the host to common environmental insults.^1,22 With more insight into these mechanisms, future therapies that include more aggressive anti-inflammatory strategies as well as a better understanding of the role of antithrombotic therapy will hopefully emerge to provide these children with the best care they need.

REFERENCES

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2. Moharir M, Deveber G. Pediatric arterial ischemic stroke. Continuum (Minneap Minn). 2014;20(2 Cerebrovascular Disease)):370-386.

3. Steinlin M. A clinical approach to arterial ischemic childhood stroke: increasing knowledge over the last decade. Neuropediatrics. 2012;43(1):1-9.

4. Numis AL, Fox CK. Arterial ischemic stroke in children: risk factors and etiologies. Curr Neurol Neurosci Rep. 2014;14(1):422.

5. Mackay MT, Wiznitzer M, Benedict SL, et al; International Pediatric Stroke Study Group. Arterial ischemic stroke risk factors: the International Pediatric Stroke Study. Ann Neurol. 2011;69(1):130-40.

6. Braun KP, Rafay MF, Uiterwaal CS, Pontigon AM, DeVeber G. Mode of onset predicts etiological diagnosis of arterial ischemic stroke in children. Stroke. 2007;38(2):298-302.

7. Roach ES, Golomb MR, Adams R, et al; American Heart Association Stroke Council; Council on Cardiovascular Disease in the Young. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke. 2008;39(9):2644-2691. Erratum in: Stroke. 2009;40(1):e8-e10.

8. Monagle P, Chan AK, Goldenberg NA, et al; American College of Chest Physicians. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e737S-e801S.

9. Royal College of Physicians. Paediatric Stroke Working Group. Stroke in childhood: clinical guidelines for diagnosis, management and rehabilitation. Suffolk, Great Britain: Lavenham Press; 2004. Available at:

. Published November 2004. Accessed January 26, 2015.

10. Bernard TJ, Rivkin MJ, Scholz K, et al; Thrombolysis in Pediatric Stroke Study. Emergence of the primary pediatric stroke center: impact of the Thrombolysis in Pediatric Stroke Trial. Stroke. 2014;45(7):2018-2023.

11. Freundlich CL, Cervantes-Arslanian AM, Dorfman DH. Pediatric stroke. Emerg Med Clin North Am. 2012;30(30:805-828.

12. Rafay MF, Pontigon AM, Chiang J, et al. Delay to diagnosis in acute pediatric arterial ischemic stroke. Stroke. 2009;40(1):58-64.

13. Nasr DM, Biller J, Rabinstein AA. Use and in-hospital outcomes of recombinant tissue plasminogen activator in pediatric arterial ischemic stroke patients. Pediatr Neurol. 2014;51(5):624-631.

14. Amlie-Lefond C, deVeber G, Chan AK, et al; International Pediatric Stroke Study. Use of alteplase in childhood arterial ischaemic stroke: a multicentre, observational, cohort study. Lancet Neurol. 2009;8(6):530-536.

15. Tatum J, Farid H, Cooke D, et al. Mechanical embolectomy for treatment of large vessel acute ischemic stroke in children. J Neurointerv Surg. 2013;5(2):128-134.

16. Hu YC, Chugh C, Jeevan D, Gillick JL, Marks S, Stiefel MF. Modern endovascular treatments of occlusive pediatric acute ischemic strokes: case series and review of the literature. Childs Nerv Syst. 2014;30(5):937-943.

17. Goldenberg NA, Bernard TJ, Fullerton HJ, et al; International Pediatric Stroke Study. Antithrombotic treatments, outcomes, and prognostic factors in acute childhood-onset arterial ischaemic stroke: a multicentre, observational, cohort study. Lancet Neurol. 2009;8(12):1120-1127.

18. Sinclair AJ, Fox CK, Ichord RN, et al. Stroke in children with cardiac disease: report from the International Pediatric Stroke Study Group Symposium. Pediatr Neurol. 2015;52(1):5-15.

19. Golomb MR. Outcomes of perinatal arterial ischemic stroke and cerebral sinovenous thrombosis. Semin Fetal Neonatal Med. 2009;14(5):318-322.

20. Westmacott R, MacGregor D, Askalan R, deVeber G. Late emergence of cognitive deficits after unilateral neonatal stroke. Stroke. 2009;40(6):2012-2019.

21. Fox CK, Glass HC, Sidney S, Lowenstein DH, Fullerton HJ. Acute seizures predict epilepsy after childhood stroke. Ann Neurol. 2013;74(2):249-256.

22. Guo DC, Papke CL, Tran-Fadulu V, et al. Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and moyamoya disease, along with thoracic aortic disease. Am J Hum Genet. 2009;84(5):617-627. 

Ms Nierengarten, a medical writer in St Paul, Minnesota, has over 25 years of medical writing experience, coauthoring articles for Lancet Oncology, Lancet Neurology, Lancet Infectious Diseases, and Medscape. She has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.