Save ChildS Pro Journal Presentation 2025

Save Childs Pro

1. Lancet Child Adolesc Health 2024; 8: 882–90 Published Online October 11, 2024 https://doi.org/10.1016/ S2352-4642(24)00233-5 Alyssa Cheah, Neuro Journal Read 5.2.25

2. Peter B. Sporns et al, JAMA Neurol . 2020;77(1):25-34.

3. Peter B. Sporns et al, Stroke . 2020;51:1182-1189

4. Peter B. Sporns et al, Neurology® 2021 ;96:e343-e351.

5. Presence of a mismatch between the severity of the clinical de fi cit and early infarct volume was evaluated according to criteria extrapolated from the DAWNtrial 2 and a recent study investigating the use of perfusion imaging in children. 12 Any of the following criteria de fi ned mismatch between clinical symptoms and infarct imaging: score of ≥ 10 on Pediatric NIH Stroke Scale ( PedNIHSS ) and an infarct volume of ≤ 50 mL or score of ≥ 20 on the Ped-NIHSS and an infarct volume of 51 to 70 mL. Infarct volume was assessed with the use of di ff usion-weighted MRI or perfusion CT. 2,3 Independently of PedNIHSS , a favorable imaging constellation for thrombectomy beyond 6 hours after onset was de fi ned by a very limited infarct core (Alberta Stroke Program Early CT Score [ASPECTS] ≥ 8 or an infarct volume of <25 mL) in patients with documented proximal LVO involving the internal carotid artery, basilar artery, or M1 segment of the middle cerebral artery.

6. JAMA Network Open. 2022;5(9):e2231343

7. Lancet Child Adolesc Health 2024; 8: 882–90 Published Online October 11, 2024 https://doi.org/10.1016/ S2352-4642(24)00233-5

8. Arterial ischaemic stroke affects 1·3–1·6 per 100 000 children/year 70% of paediatric strokes result in long-term neurological deficits, 20% in recurrent strokes, 10% in death E ndovascular thrombectomy revolutionised treatment of AIS caused by large-vessel occlusion in adult RCTs since 2015 Difficulties of conducting randomised trial in paediatric stroke patients (premature termination of prospective Thrombolysis in Pediatric Stroke trial due to recruitment difficulties)  P rospective multicentre registry considered the best option to generate evidence regarding hyperacute recanalisation treatments in children with arterial ischaemic stroke. Aetiology of paediatric stroke fundamentally different from adult stroke  Adult: atherosclerosis major risk factor VS paediatric : cardioembolic causes & arteriopathies  Paediatric brain might better compensate for ischaemic stroke due to greater neuronal plasticity  Leptomeningeal collaterals might be more efficient in children =/≠ ??Benefit of recanalisation reduced in children

9. Study design and participants I nternational prospective cohort study of children who presented with acute arterial ischaemic stroke across 53 centres in Europe, North America, South America, Asia, and Australia.  4 5 centres contributed eligible patient data included in this analysis. ‘Asia’ = National University Hospital, Singapore Inclusion criteria age 28 days to 18 years clinical diagnosis of arterial ischaemic stroke confirmed diagnosis of intracranial arterial occlusion consistent with symptoms including occlusion of terminal internal carotid artery, middle cerebral artery (M1, M2 segments), basilar artery, vertebral artery (V4 segment), anterior cerebral artery (A1, A2 segments), posterior cerebral artery (P1, P2 segments), and proximal superior cerebellar artery. Neonates with stroke were excluded All patients received best medical treatment , including systemic thrombolysis, platelet inhibition, and anticoagulation E ndovascular thrombectomy group  all patients in whom endovascular thrombectomy was attempted ( ie , patients with groin puncture initiated and all cases in which endovascular thrombectomy failed or was interrupted) B est medical treatment group  patients in whom endovascular thrombectomy was not attempted

10. Timepoint Admission • Patient data (age, year of birth, gender) • Patient logistics (symptom onset, admission weekday, date and time of admission, date and time of admission imaging, date and time of last known well, date, and time of symptom onset, referral from other hospital) • Pre-existing diseases • Medication • mRS at admission (deficits prior to stroke) • PedNIHSS • Imaging findings (type of admission imaging, occluded vessel, computed tomography or magnetic resonance imaging for Alberta stroke program early computed tomography (ASPECT) score, ASPECT score; in case of posterior circulation stroke, posterior circulation (pc)-ASPECTS) Treatment • Treatment with iv-tPA: date and time of iv-tPA, dose • EVT - timing (date and time of first angiography image, time of first pass, time of final recanalization result) - type of anesthesia - occluded vessel - stenosis or occlusion in a proximal vessel - number of passes - morphologic appearance (normal, arteriopathy, other) - type of treatment and devices used, - treatment complications [vasospasm, intracerebral hemorrhage (ICH), dissection, other] Data collected by l ocal study teams 24 h • PedNIHSS • Imaging findings (persistent or new occlusion, type of follow-up imaging, ASPECTS/pc-ASPECTS) • Adverse events (symptomatic ICH, non-symptomatic ICH, dissection, other) Discharge • Patient logistics (length of stay, transfer destination) • PedNIHSS • mRS • Pediatric Stroke Outcome Measure (PSOM) • Stroke etiology (according to childhood AIS standardized classification & diagnostic evaluation classification) • Adverse events (symptomatic ICH, non-symptomatic ICH, hemicraniectomy, external ventricular drainage, other) Day 90 ± 10 • mRS • PSOM • Adverse events (symptomatic ICH, non-symptomatic ICH, hemicraniectomy, external ventricular drainage, pneumonia, recurrent stroke, other) • Location (care facility, home)

11. OutcomeS P rimary outcome - difference between mRS scores recorded pre-stroke and at 90 days after stroke Secondary outcomes - differences between Pediatric National Institutes of Health Stroke Scale ( PedNIHSS ) scores recorded at hospital admission and at discharge , the 90-day PSOM , and safety outcomes (symptomatic or non-symptomatic intracranial haemorrhage , peri-interventional vasospasm, and arterial dissection during treatment and 90-day mortality). Primary and secondary outcomes were analysed separately for patients with focal cerebral arteriopathy (CASCADE subtype 2).

12. Baseline characteristics M edian age in EVT higher Y oungest EVT patient aged 3 months Median PedNIHSS score higher in EVT Intravenous thrombolysis was used in both treatment groups.

13. Cascade Childhood AIS Standardized Classification and Diagnostic Evaluation.

14. 3.8 hr 2.2 hr 6.5 hr 5.6 hr

15. Efficacy outcomes †PSOM (Pediatric Stroke Outcome Measure) range 0 to 10 in 0·5 steps, higher scores greater disability. mITCI (modified thrombectomy in cerebral infarction) range 0-3 (Data are median (IQR) or n (%)) 100% reperfusion of occluded cerebral artery territory ≥50% reperfusion of occluded cerebral artery territory **Primary outcome

16. at 90 days after the stroke Ordinal regression analyses revealed significant effect of age (p=0·0029), PedNIHSS score at hospital admission (p=0·0017), and treatment group (p=0·020), whereas no other parameter showed an effect on the primary and secondary outcomes (data not shown).

17. Safety outcomes Further CASCADE classification of patients with persistent occlusion revealed suspected focal cerebral arteriopathy aetiology in 8/18 ( 44% ) in endovascular thrombectomy group & 19/49 ( 39% ) in best medical treatment group. ‡Recorded within 24 h of hospital admission.  resolved in all cases, either spontaneously or after intra-arterial nimodipine. non-flow-limiting *Death was determined at 90 (±10) days after stroke. †defined as an increase in PedNIHSS score of at least 4 points with presence of parenchymal haemorrhage .

18. Comparison Outcome of Patients with Focal Cerebral Arteriopathy (CASCADE 2) vs. all other patients no difference

19. Propensity Score matched analysis 79 EVT patients propensity score matched 1:1 based on age, sex, PedNIHSS score at admission Median age matched patients 10 years (IQR 7 to 13) in EVT & 7 years (4 to 11) in BMT M edian PedNIHSS score 12 (IQR 8 to 15) in EVT & 9 (7 to 12) in BMT No sex-specific differences were observed with respect to clinical outcome measures (data not shown).

20. Discussion endovascular thrombectomy successful recanalisation in 89% of patients (Similar to previous studies) D ecision for thrombectomy should not be based on one single parameter ( eg , PedNIHSS ), but always as a combination of multiple parameters ( eg , PedNIHSS , occlusion location, the Alberta Stroke Program Early CT Score [ASPECTS], pre-existing neurological deficits, potentially salvageable tissue) due to limitations of PedNIHSS /ASPECTS  potentially fluctuating symptoms, less posterior circulation symptoms, or high inter-rater variability. Save ChildS Pro registry study shows superior outcomes in children with large-vessel and medium-vessel occlusion treated with endovascular thrombectomy compared with best medical treatment alone. Primary outcome (change in median mRS score from pre-stroke baseline to day 90) & secondary outcomes (change in PedNIHSS score from hospital admission to discharge & 90-day PSOM score) significantly better in EVT Findings consistent even after propensity score matching for age, sex, and initial stroke severity matched case–control study  similarly, outcomes better with endovascular thrombectomy than best medical treatment alone

21. Factors affecting outcome Age & PedNIHSS score at baseline showed significant effect on patient outcome  might present important selection criteria for or against endovascular thrombectomy in children  more severely affected children might benefit more from endovascular thrombectomy However, current existing data do not justify dedicated cutoff values in selection for endovascular thrombectomy Current analysis cohort size too small to allow formation of subgroups of younger and less severely affected children  observed positive treatment effect for EVT possibly confined to older & more severely affected children Larger studies needed to determine whether potential benefit for EVT similarly exists in younger & less severely affected children superior outcomes of endovascular thrombectomy in large-vessel occlusion stroke Adequate training of all physicians involved in acute stroke care Development of clear selection criteria for endovascular thrombectomy Standardisation of interventional procedures Require dedicated training & continuous practice of Neurointerventionists  ? case load of respective centre gaining more experience in smaller vessels, tailored approaches for children & development of softer devices C rucial to maintain these positive treatment effects

22. Safety outcomes: Similar in both groups similar rates in both treatment groups for mortality & non-symptomatic intracranial haemorrhage Only 1 patient had symptomatic intracerebral haemorrhage in endovascular thrombectomy group Small number of procedure-related adverse events : arterial dissections (2%) & radiographic vasospasm (15%)  dissections not flow limiting , and vasospasm resolved in all cases after intra-arterial administration of nimodipine & without any radiographic or clinical signs of ischaemia . Persistent or recurrent vessel occlusion rate at 24 h follow-up imaging  54% best medical treatment group vs 15% in endovascular thrombectomy group  44% (8/18) in EVT & 39% (19/49) in BMT had a suspected focal cerebral arteriopathy aetiology Recent adult studies shown intravenous thrombolysis works synergistically with endovascular thrombectomy  s hould be administered if no contraindications Observational data that intravenous thrombolysis will fragment thrombi , causing thrombus migration and fragmentation which will be more difficult to remove mechanically and could potentially result in lower rates of complete recanalisation .

23. Concerns in arteriopathies (Focal) for patients with focal cerebral arteriopathy, primary outcome measure not significantly different between groups, but secondary outcomes significantly improved in endovascular thrombectomy group  m ight reflect smaller sample size & heterogeneity of focal cerebral arteriopathy subgroup , or potentially a more subtle yet still clinically relevant effect of endovascular thrombectomy  show that more severely affected patients will potentially benefit from endovascular thrombectomy , whereas patients with milder stroke might not benefit in same way. Important Note: mRS does not capture cognitive & academic deficits, which are more likely to be captured by PSOM. Major concern is safety & efficacy of endovascular thrombectomy procedures in patients with arteriopathies In Save ChildS Pro registry  patients with arteriopathies had similar outcomes to those with other aetiologies when treated with endovascular thrombectomy. Furthermore, patients had greater improvement in PedNIHSS & PSOM sco re at day 90 regardless of underlying aetiology .

24. Reassuring that even children with suspected focal cerebral arteriopathies who presented with large-vessel occlusion stroke appeared to benefit from the endovascular restoration of blood flow. However, in patients presenting with classic imaging features of focal cerebral arteriopathy, such as arterial banding and narrowing of the terminal segment of the internal carotid artery, even greater caution must be applied . Concerns in arteriopathies (Focal) Diagnosis of inflammatory subtype of focal cerebral arteriopathy is difficult if initial presentation is with complete arterial occlusion; most commonly focal cerebral arteriopathy presents subacutely with stenosis rather than complete acute occlusion.  some cases diagnosis is made retrospectively on basis of the presence of residual or progressive stenosis in affected vessel after clot retrieval of a superimposed acute thrombus.  can be confounded by iatrogenic stenosis caused by intimal injury that can occur after use of a stent retriever for endovascular thrombectomy. Therefore, the CASCADE 2 stroke subtype (focal cerebral arteriopathy) is a group of patients in whom a definitive diagnosis is difficult to establish.

25. Limitations Not a randomised trial  potential selection bias Patients nested under centres  possible centre -specific effects bias Most centres included average of ˂5 patients (only 5 centres reported >10 patients)  cannot conclude whether high-volume centres create different outcomes compared with lower-volume centres . In general, sites appeared to select EVT preferentially in greater PedNIHSS scores & older children  h owever propensity score matched analysis showed treatment effect was still maintained across all outcome variables C hildren in BMT more often had arteriopathies vs EVT more often presented with cardioembolic aetiologies  probably reflecting reluctance of treating physicians to refer children with arteriopathic changes for endovascular thrombectomy. - However, outcome of children with suspected arteriopathies who did EVT better than that of those treated with BMT alone No restrictive selection criteria regarding time from symptom onset and infarct size on admission imaging for this study.  This aligns with recent trials in adults, which have all shown that absolute and relative infarct size & time from onset are less important as long as there is salvageable tissue on advanced imaging and a mismatch between clinical deficit and infarct. Time from symptom onset to admission comparably short in the Save ChildS Pro cohort and even though comparable to similar studies  might be longer in less specialised centres , which might affect patient outcomes. Clinicians performing outcomes measurements not masked  might also have introduced bias Cohort size was too small for more detailed subanalyses , such as investigating different outcomes with respect to age and sex.  Larger patient cohorts will provide more detailed insights in outcomes after endovascular thrombectomy with respect to different aetiologies and in children with different age, sex, and demographics.

26. In conclusion Endovascular thrombectomy plus best medical treatment was associated with improved functional outcomes in paediatric patients with large and medium intracranial occlusions compared with best medical treatment alone Future studies are needed to investigate whether the positive treatment effect of endovascular thrombectomy is confined to older and more severely affected children