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.