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THROMBOLYSIS IN PEDIATRIC STROKE
Uluç Yiş, MDAssociate Professor of PediatricNeurologyDokuz Eylül University, School of MedicineIzmir-Turkey
No conflict of interest
No disclosures
Stroke is a focal cerebral injury with an underlying vascular basis.
Ischemic or hemorrhagic
ISCHEMIC STROKE
Arterial ischemic stroke Cerebral sinovenous thrombosis
Arterial ischemic stroke occurs with a frequency of 2 to 3/100,000 children per year.
Many cases occur during the perinatal or neonatal period, during which the incidence is 1 in 4000 live births.
PEDIATRIC STROKE VERSUS ADULT STROKE1. Rarer, subtler clinical presentation, wider differential diagnosis
2. The coagulation, vascular, and adaptive components of neurologic systemsdiffer
3. Risk factors are multiple, age-dependent-a complex set of investigations
4. Paucity of robust data of outcome
5. Evidence supporting specific treatments is lacking-variability in management
6. Burden of pediatric stroke is longer lasting
WHY IS PEDIATRIC STROKE SOIMPORTANT?
30% to 70% of patients with perinatal/neonatal arterial ischemicstroke will have cerebral palsy.
20% to 50% of patients with perinatal/neonatal arterial ischemicstroke may develop epilepsy.
Outcome in survivors of childhood arterial ischemic stroke rangesfrom 38% normal, 42% mild disability, 8% moderate disability, to12% severe handicap.
PEDIATRIC ARTERIAL ISCHEMIC STROKE(AIS)
50-80% children with AIS have at least one identifiable risk factorRisk factor variability is influenced by geography, age at presentation and availability of medicalresources
Arteriopathies50%
Congenital/acquiredheart disease
25%
InfectionsTurkey, China, India, Saudi Arabia
HemoglobinopathiesAfrican or Mediterranean population
Inherited metabolic disordersConsanguinityStroke like episodes
Neck traumaDehydrationProthrombotic dis.Systemic dis.
BARRIERS TO SUCCESS IN PEDIATRICSTROKE AND THROMBOLYTIC TREATMENT
Education/stroke awareness
-Relative rarity of pediatric stroke
Time to diagnosis
-Delays from onset of symptoms to medical care
-Delay from presentation for medical care to diagnosis
-Delay in obtaining diagnostic imaging
Age
-Need for anesthesia to obtain imaging
-Radiation risk (CT, CTA, cerebral angiography)
Etiology
-Etiology and risk factors are diverse with no one risk factorpredominating-hence each requires a different approach
Brick and mortar
-Free standing children’s hospital versus hospital within a hospital
(pediatric hospitals within an adult infrastructure)
Personnel
-Limited pediatric stroke/vascular neurologists
SUBACUTE STROKE TREATMENT ANDSECONDARY PREVENTION
There is still debate on subacute stroke treatment and secondaryprevention in pediatric AIS
A randomised clinical trial in childhood AIS that comparesantiplatelet and anticoagulant drugs for safety and efficacyoutcomes is needed to establish optimum antithrombotictreatment.
WHAT IS THE CURRENT KNOWLEDGE ABOUTANTIPLATELET AND ANTICOAGULANTDRUGS IN PEDIATRIC AIS?
Guidelines recommend antiplatelet treatment, specifying anticoagulation forcardiac disorders and arterial dissection.
Controversies about anticoagulation versus aspirin persist for other forms of childhood AIS.
Optimum duration of aspirin use is poorly defined, although 2 years as a minimum is suggested.
Low molecular weight heparin and clopidogrel are beingincreasingly used in children and are shown to be safe.
When either aspirin or anticoagulant therapy fails (failure definedas radiologic or clinical TIA/stroke recurrence), dual therapy withaspirin and anticoagulant therapy may be given in selectedcases.
HYPERACUTE THERAPY
Intravenous thrombolysis
Intra-arterial thrombolysis
Mechanical thrombectomy
IN ADULTS;
Intravenous (IV) tPA has been approved by the Food and Drug Administration for use within 3 hours of stroke onset, and a recent American Heart Association/American Stroke Association advisory recommends extending this time window to 4.5 hours.
Recent randomized controlled trials in adults have demonstratedthe superiority of endovascular intra-arterial thrombolysis (IAT) over IV tPA when performed within 6-12 hours of stroke onset.
Recanalization is more often achieved by intra-arterial thrombolysis than intravenous thrombolysis.
Bridging intravenous thrombolysis, followed by angiography and additional intra-arterial thrombolysis, is becoming the treatment of choice in adults.
The recently published study MR CLEAN has shown that mechanical thrombectomy is superior to lyses by tpA or urokinase.
IN CHILDREN;
There are no controlled data to support thrombolysis or thrombectomy inchildren (case reports, small case series, hospital databases).
The American College of Chest Physicians guidelines currently recommendagainst the use of tPA in childhood AIS outside of clinical trials.
The AHA guidelines take the same stance, although consensus is lacking regarding the use of tPA in older adolescents who otherwise meet the adult tPA eligibility criteria.
The paucity of data with which to make any recommendations regardingmechanical thrombectomy is even greater.
CHILDREN ARE NOT ADULTS
Given the fact that outcome from AIS in children is more favorable in general than in adults, the drive to initiate IV or intra-arterial tPA even in a child presenting within the appropriate time window should be carefully scrutinized.
During childhood, fibrinolytic system is not mature.
Baseline-free tPA is decreased and plasminogen activator inhibitor-1 concentration is increased in children.
Children have an increased volume distribution and more rapidhepatic clearance, suggesting they will clear tPA more quickly.
Higher dose of tPA may be needed to promote thrombolysis in children.
The median time from presentation to diagnosis of stroke in children is almost 24 hours, with in-hospital delays accounting for the largest proportion of this time.
WHY ARE WE LATE REGARDING THROMBOLYTIC TREATMENT IN CHILDREN AND WHAT SHOULD BE DONE TO IMPROVE?
PUBLIC EDUCATION CAMPAINGS FORCHILDREN
Knowledge of pediatric stroke symptoms in the community, amongst paramedics, primary care and emergency physicians, is essential to decreasing diagnostic delays.
Current stroke awareness campaigns such as «FASTR-face drooping, arm weakness, speech difficulty, time to call 911 and REMEMBER CHILDREN HAVE STROKE TOO»
More importantly, ongoing education of physicians about the importance of recognizing and considering stroke in a focal neurologic deficit in any child with, or without, altered mental function is critical.
BEDSIDE STROKE RECOGNITION TOOLS
Instruments in the emergency department to improve strokerecognition:
FAST: Face Arm Speech Test
CPSS: Cincinnatti Pre-Hospital Stroke Scale
LAPSS: Los Angeles Pre-Hospital Stroke Scale
ROSIER: Recognition of Stroke in the Emergency Department
SYMPTOMS AND SIGNS OF STROKE
Similar frequencies of headache, hemiparesis and facialweakness
Increased frequency of speech disturbance and seizures.
The frequent occurence of seizures in childhood stroke is a notable difference to adults (50% of pediatric cases).
PEDIATRIC STROKE MIMICS
Stroke is the cause of focal neurologic symptoms in three quarters of adults.
A wide variety of conditions mimic stroke.
Migraine
Seizures
Posterior reversable leukoencephalopathy
Intracranial infections
Demyelinating disorders
Syncope
ADULT EMERGENCY STROKE MANAGEMENT: RADIOLOGICALCONFIRMATION OF DIAGNOSİS (45 MIN); DECISION TOTHROMBOLYSE (60 MIN); ADMISSION TO STROKE UNIT (3 H)
Suggested multidisciplinary team composition
NEUROLOGY
RADIOLOGY
ANESTHESIA
CRITICAL CARE
NEUROSURGERY
HEMATOLOGY
ESTABLIHED IMAGING PROTOCOL
Need for sedation, the most important barrier
Two or three sequences to obviate the need for sedation
Diffusion weighted imaging: restricted diffusion
Gradient echo: hemorrhage
MRA: large or medium vessel cerebral arterial abnormalities
In 10 minutes no need for contrast
TAILORING LABORATORYEXAMINATIONS
Basic examinations as an emergency (BC, CRP, glucose, liver andrenal function, coagulation, lactate)
To do at appropriate time (lipid profile, homocystein, prothrombotic studies)
THROMBOLYSIS IN PEDIATRIC STROKE
Stroke 2015;46:880-885.
2010 TIPS (Thrombolysis in Pediatric Stroke Trial) (NIH Grant R01NS065848)
A multi-institutional, multidisiplinary design to determine safety, bestdose, and feasibility of IV tPA in children who present with AIS.
Pharmacokinetics of tPA in children
Assessment of 90-day clinical outcome among treated children
Three dosing tiers were planned:
0.75, 0.9 and 1.0 mg/kg of IV tPA, with a maximum dose reachedat 90 kg body weight.
The IV tPA was to be given for 1 hour, 10% of total dose as a bolusover 5 minutes with the remaining 90% over the subsequent 55 minutes.
Stroke 2014;45:2018-2023
Data collected from 17 TIPS sites
Prior to 2004, <25% of TIPS sites had 24 hour availability of acutestroke teams. Following TIPS preperation, >80% of sites now haveacute stroke teams and treat the children with acute AIS usingthe standardized protocol in TIPS study.
Stroke 2009;40:801-807
17 patients
IV: 6 cases
IA: 10 cases
MT: 1 case
No symptomatic intracranial hemorrhage, but 2 asymptomaticintracranial hemorrhage
16 (94%) survived, 12 (71%) good outcome (modified Rankin scale 0 or 1)
IVT 6 CHILDREN
5 girls, median age 14 (8-16 years)
NIHSS 10 (7-22)
Delay 150 minutes (105-168 minutes)
tPA: 0.9 mg/kg body weight
Clinical outcome good (4 patients), near baseline (1 patient), mRS 3 in one patient
IAT FOR MCA 3 CHILDREN
3 boys, median age 12 years (7-15 years)
NIHSS 22 (9-28)
MCA, ICA (C1), ICA (T occlusion)
Delay 300 minutes (120-345 minutes)
Urokinase (560.000-750.000 IU), tPA (0.11 mg/kg)
Good (1 patient), mRS 3 (1 patient), death (1 patient-malignantedema)
Asymptomatic ICH in one
IAT FOR BASILAR ARTERY OCCLUSION7 PATIENTS
5 boys, median age 9 years (6-18 years)
Delay 20 hours (4-72 hours)
Urokinase (750.000 IU [200.000-1.000.000]), tPA (2 cases)
Balloon angioplasty 3 patients
Good (4 patients), mRS 1-2 (2 patients), mRS 4 (1 patient)
Asymptomatic ICH in one
MT 1 PATIENT
16 year old boy
20 hours after symptom onset
Clot retrieval followed by balloon angioplasty
No complication-neurologic deficit
Lancet Neurology 2009;8:530-536
687 patients from IPSS
2% (n:15) received alteplase: 9 IV, 6 IA
Median time for IV 3.3 hours (2-52 h), for IA 4.5 hours (3.8-24 h)
4 intracranial hemorrhages, all of them asymptomatic
2 patients died
At discharge, only one patient was healthy and 12 had neurological deficits.
When the results were compared with 10 children reported in published articles who were given IV alteplase, 9 patients in the IPSS cohort
were mostly younger
waited longer for treatment
had worse outcomes
Older age, short treatment intervals from onset, favorable outcome?
Nationwide Inpatient Sample from 2001 to 2010 (30 day-18 years) AIS
7044 patients with AIS
The rate of tPA use 1.4% (99 patients)
The average age was 12.4±9.4 years
The most common comorbidities were hypercoagulable state andcongenital heart disease
2001-2005 tPA use 0.9% increased to 2006-2010 2%
Low risk of fatal hemorrhage
There was an increased discharge to long term facilities rate
Children with AIS in Kids’ Database for the years 1998-2009
9257 children
0.7% (n:67) received thrombolysis
Thrombolysis treated children were older (13 years vs 8 years) and had a longer hospital stay(11 days vs 6 days)
Vascular comorbidities (diabetes, heart disease, hypercoagulation and cervical arterydissection)
Secondary outcomes of percutaneous gastrostomy and tracheostomy tube placement werealso higher in the thrombolysis group.
Higher hospital mortality and intracerebral hemorrhage
The overall rate of thrombolysis per 3 years intervals had increased from 5.2 to 9.7 per 1000 children with AIS
This increase was seen mainly in non-children hospital
Nationwide Inpatient Sample between 2000 and 2003
2904 children with AIS
1.6% (n:46) received thrombolytic treatment
Children who received thrombolytic treatment were older (11 years vs 9 years)
Higher rates of death and dependecy
Higher hospital costs ($81.000 vs $38.000)
SUMMARY
Only about 2% of pediatric AIS are treated with thrombolytictreatment
The age of treated children is generally above 10 years
Higher vascular comorbidities
Low risk of cerebral hemorrhage
Higher hospital stays and costs
Higher rates of dependency due to neurologic deficits
the overall rate of thrombolysis increases very year
THROMBOLYTIC TREATMENT IN POSTERIOR STROKE AND SINOVENOUS THROMBOSIS
CHILDHOOD BASILAR ARTERYOCCLUSION
68 published cases
Have better outcomes than adults
There is a strong correlation between NIHSS and mRS.
50 were treated with anticoagulation, antiplatelet agents, intravenous thrombolysis or no treatment (FIRST GROUP)
18 were treated with intra-arterial treatments (SECOND GROUP)
First group (50 patients): 28 (56%) good outcomes, 15 pooroutcomes and 7 died.
Second group (18 patients): 13 (72%) good outcomes, 4 pooroutcomes, none died.
The proportion of good outcomes is higher in intra-arterialtreatment group.
CAUTION: NIHSS are higher in conservatively treated group.
Patients may be selected, intra-arterial treatments need not be performed in all cases.
Low initial NIHSS might be conservatively managed withanticoagulation and observed for clinical deterioration.
***arterial recanalization can cause reperfusion injury includingincreased cerebral hemorrhage, arterial recanalization does not itself equate to a good relevant outcome.
CEREBRAL SINOVENOUS THROMBOSIS
Medical management with systemic anticoagulation is themainstay treatment strategy.
Some patients may not respond to this teatment or may presentwith very severe symptoms indicating more aggressivemanagement strategies.
Increasing reports of endovascular treatment accompanied bythe administration of urokinase or tPA.
There are only a few cases of direct thrombolysis for cerebralsinovenous thrombosis in children.
Urokinase or tPA
Favorable outcomes with excellent recovery, no intracerebralhemorrhages.
MECHANICAL THROMBECTOMY
About 20 cases reported in the literature
Locations: MCA, ICA, BA
Mechanism: mostly cardioembolic, vertebral artery dissection
Time to arterial puncture: 16.18 hr (3.4-48 hr)
Devices: Penumbra, Solitaire, CAPTURE, Revive, Merci, Balloonangioplasty
35% (n:7) of the patients received IA or IV tPA or urokinase
40% (n:8) of the patients received ASA and/or heparin after post-mechanical thrombectomy
35% (n:7) of the patients were asymptomatic at 3-6 months
CONCLUSION
The results of studies are inconclusive.
Acute onset of neurologic deficit in childhood must be recognizedand treated as an emergency.
Early and rapid management and treatment of childhood strokerequires the development of 24/7 stroke team with a singleactivation.
Planning a study regarding thrombolysis in children has manyobstacles.
After establishing pediatric stroke centers, TIPS protocol may be used, because it is a very well designed protocol.
The data of treated patients in different centers with TIPS protocolshould be collected in a database.
This database should tell us the role of thrombolysis in childhoodstroke.