Stroke Title of Guideline (must include the word “Guideline” (not protocol, policy, procedure etc) Contact Name and Job Title (author)

Directorate & Speciality

1a 2a 2b 3

4

5

Guideline for the management of stroke in children and young people Dr Keshavamurthy Kallambella, Paediatric Registrar, Dr William Whitehouse, Consultant Paediatric Neurologist. Directorate: Family Health – Children Speciality: Neuroscience March 2016 March 2019 1995 Children from 1 month to 18 years presenting with acute stroke or transient ischaemic attack.

Date of submission Date when guideline reviewed Guideline Number Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis) Abstract Key Words Dr William Whitehouse Statement of the evidence base of the guideline – has the guideline been peer reviewed by colleagues? meta analysis of randomised controlled Put a cross (X) in the highest level of evidence. trials at least one well-designed controlled study without randomisation at least one other type of well-designed quasi-experimental study well –designed non-experimental descriptive studies (ie comparative / correlation and case studies) expert committee reports or opinions and / or clinical experiences of respected authorities recommended best practise based on the clinical experience of the guideline developer

X

Staff at Nottingham Children’s Hospital via the Guidelines E-mail process. Target audience Staff at the Nottingham Children’s Hospital This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date. Consultation Process

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Document Control Document Amendment Record Version V1

Issue Date 01/2008

V2

12/06/2015

V3

22/06/2015

V4

01/03/2016

Author Dr Bhupendra Singh, Paediatric SpR Dr William Whitehouse, Consultant Paediatric Neurologist Dr Keshavamurthy Kallambella, ST Dr William Whitehouse Dr Keshavamurthy Kallambella, ST Dr William Whitehouse Dr Keshavamurthy Kallambella, ST Dr William Whitehouse

General Notes: This guideline has followed Child Health Guideline SOP. It has been circulated to all Paediatric Senior staff and comments incorporated before uploading to the Trust Guideline site. Martin Hewitt Clinical Guideline Lead 28 April 2016

_________________________________________________________

Summary of changes for new version: The definitions for stroke, TIA and stroke-like-episodes have been reviewed and modified where appropriate. The clinical presentation has been reviewed; commonest presenting features in different age groups have been given. The neuroimaging investigation has been simplified emphasising the need to liaise with the neuroradiologist/neurologist. The current recommendation on the suitability of thrombolytic treatment in children has been given and compared with the NUH adult stroke guideline. The thrombophilia screening for the arterial ischaemic stroke has been updated. Information about venous infarction and sinus thrombosis has been added.

______________________________________________________________

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Stroke in Children Introduction The incidence of stroke in children is 5/100,000 children/year [1]. The diagnosis can often be established with modern neuroimaging techniques. Identification of an underlying cause or contributing risk factor is essential and evaluation should proceed in an organised fashion to reduce the risk of recurrences [2].

Definitions • Stroke is a focal or global neurological deficit lasting more than 24 hours having a vascular basis [3, 4]. • Transient Ischaemic Attack (TIA) is a similar episode, but lasting for less than 24 hours; most resolve by 1 hour [5]. • Stroke-like-episode is a focal neurological deficit lasting more than 24 hours for which a vascular component is unproven but cannot be excluded [4]. Stroke should be suspected in all cases of acute onset focal neurological deficit unless there is another cause evident clinically. TIAs indicate increased risk of future strokes; up to 4.2% in the same hospitalisation (6).

Predisposing Conditions / Aetiology [7, 8] Risk factors associated with childhood strokes differ significantly from those in adults. The risk factors for different types of stroke are given below. Arterial Ischaemic Stroke [AIS] and cerebral venous and sinus thrombosis [CVST]

  

Heart diseaseCongenital heart diseases Acquired heart diseases e.g. infective endocarditis Arrhythmias

Haematological disorders Sickle cell disease  Hyperviscosity states  Hypercoagulable states- Protein C deficiency, Protein S deficiency, Antithrombin 3 deficiency, factor V Leiden, lupus anticoagulant, antiphospholipid antibody syndrome, THFR mutation, prothrombin mutation 2021A, oral contraceptive use Arteriopathy  Focal cerebral arteriopathy,  Moyamoya disease, Dr W Whitehouse

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  

Arterial dissection, Post-varicella arteriopathy, Vasculitis- HSP, PAN, Kawasaki disease

Metabolic disorders  Homocysteinuria/ homocysteinaemia,  Mitochondrial disorders [MELAS]  Organic acidurias Acute systemic disorders and CNS infections Infections- meningitis, encephalitis, sepsis, viral gastroenteritis, ENT infections  Acidosis  Dehydration 

Haemorrhagic Stroke   

Cerebrovascular structural anomalies, e.g. arterial aneurysms, arteriovenous malformations Coagulation Disorders- congenital or acquired Immune thrombocytopenic purpura (ITP)

Idiopathic Around 10% of the cases have no identifiable cause or predisposing factor, despite extensive investigations. Differential Diagnoses [‘Stroke mimics’] [9]          

Hemiplegic migraine Focal encephalitis including cerebellitis Tumour and other space occupying lesions such as brain abscess Traumatic extradural or subdural haemorrhage Demyelinating conditions e.g. acute disseminated encephalomyelitis (ADEM) Postictal paralysis (Todd’s paresis) Idiopathic Intracranial Hypertension Musculoskeletal disorders Functional / Medically Unexplained / Psychogenic symptoms Drug Toxicity

Clinical Presentation Stroke in children can present with specific symptoms and signs indicating involvement of a particular vascular territory (e.g. anterior circulation or posterior circulation). Generally the impairment is very acute (sudden), e.g. on waking from sleep, or with a collapse. But it can also present with a wide range of non-specific Dr W Whitehouse

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signs and symptoms e.g. headache, seizures with or without an associated focal neurological deficit, altered consciousness etc. The clinical presentation also depends on the age of the child. Focal features such as hemiparesis are the commonest presenting features of arterial ischaemic stroke; seen in 85%. Seizures are the most common feature in children less than 1 year; seen in 75% [8]. Diffuse features such as headache appears to be more common in children above 6 years. Decreased conscious level is seen in all age groups. Consider an alternative diagnosis by careful evaluation including brain imaging to rule out stroke ‘mimics’. These can be found in more than 20% of cases with similar presentations. [9] Neuroimaging 

Discuss urgently with the neuro-radiologist and paediatric neurologist on call.



Some paediatric patients with arterial ischaemic stroke, presenting within a certain time from the onset of the symptoms (currently up to 6 hours for adults in NUH) may require urgent intravenous (iv) or intra-arterial (ia) thrombolysis; hence time can be crucial in their management. This is still controversial in children with stroke meeting the adult criteria for thrombolysis; discuss with the on-call paediatric neurologist [10, 11]. Posterior circulation AIS may benefit from thrombolysis up to 12 hours after onset.



If contemplating thrombolysis, an urgent CT scan with angiography (CTA) is the imaging of choice to rule our haemorrhagic stroke and confirm vascular pathology. The current NUH adult guidelines suggest intravenous thrombolysis can be offered up to 6 hours after the onset although as soon as possible is ideal.



MRI is the imaging modality of choice even if CT has already been performed, irrespective of the CT findings. This is due to higher sensitivity and specificity both in the diagnosis of stroke and stroke mimics afforded by MRI.



Further imaging investigations will be done in liaison with neurologists and neuroradiologists.

Other investigations:  Thrombophilia screen [see below] should be performed on all children with ischaemic stroke arising from either arterial or venous thrombosis.  Thrombophilia screening should not be routinely requested in patients with TIAs.  MTHFR TT677 [see below] gene to be done only when Homocysteine is indicated.  See table below

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Investigations FBC, ESR, Haemoglobin Electrophoresis (if appropriate), Film examination, Coagulation profile

Type/colour of bottle 1 full paediatric EDTA (Purple top) 1 full citrate

Priority/urgency On admission

U&E

1 paediatric Li-heparin (Green top)

On admission

2 adult citrate (Blue top) + 1 paediatric clotted (Red top) to haematology

On admission/ before Commencing anticoagulation (otherwise will be delayed till 6 weeks after stopping)

Autoantibodies screen including anticardiolipin antibodies

1 paediatric clotted (Red top) to immunology

Can be done next day

Total homocysteine Fasting cholesterol Triglycerides Lp(a) lipoprotein

1 EDTA to be received by lab within 30 minutes 1 Paediatric Li-heparin (Green top) to clinical chemistry

Can be done next day

Antibody titres when infection is suspected: Herpes Mycoplasma Chlamydia pneumoniae, Helicobacter pylori Borrelia burgdorferi

1 full paediatric clotted (Red top) sample to microbiology

Can be done next day

Urine analysis (if clinical suspicion of nephrotic syndrome)

Bed side dip-stick

ECG, Echocardiography

Cardiology South

Thrombophilia screen Arterial Thrombosis: Lupus anticoagulant Anti-phospholipid antibodies Sino-Venous thrombosis: Protein C & S Antithrombin-3 Factor V Leiden mutation Lupus anticoagulant Antiphospholipid antibodies Prothrombin gene mutation [only if elevated homocysteine]

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Acute care This consists of: 1. General measures, 2. Hyperacute thrombolysis [only if suitable] 3. Acute anti-coagulation treatment 1. General measures • Maintain ABC • Use Glasgow Coma Scale (GCS) or child’s GCS [12] to assess the level of consciousness (see appendix 1) • Admit to PICU if consciousness is deteriorating or in coma (GCS 8 or less) • Control seizures • Maintain temperature between 36.5 – 37.0 °C • Monitor BP and optimise it • Minimal handling • Fluid therapy- Restrict to 60% of normal fluid requirements if there are concerns about cerebral oedema or SIADH; otherwise normal maintenance, and avoid dehydration. For sickle cell disease patients discuss with Paediatric Haematologist and Paediatric Neurologist as fluid management may vary from case to case. 2. Hyperacute thrombolysis: The use of thrombolytic agents in childhood AIS continues to be an area of debate; to date no clinical trials has been successfully completed to offer good quality evidence. Given the diverse risk factors, a universal approach of hyperacute thrombolysis in childhood stroke is not recommended. There have been many case reports of their successful use in childhood stroke. The current recommendation especially for older children meeting the adult criteria for thrombolysis is for an experienced clinician in childhood stroke to decide on a case-by-case basis [10, 11, and 13]. The criteria used for a retrospective audit by Great Ormond Street Children’s Hospital, based on the TIPS [Thrombolysis in Paediatric Stroke] study are given below for reference only. The plan will need to be agreed by the consultant paediatrician and the paediatric neurologist oncall; note the contraindications. Criteria to consider for Thrombolysis in AIS with IV Alteplase [ rt-PA] Discuss with the on-call paediatric consultant before initiation:   

Age ≥8y Upper limit of time after onset of symptoms: 6 hours Imaging confirmation of acute AIS o Diagnostic or normal CT, with occluded major artery on CTA OR o Confirmation of arterial ischaemic stroke on MRI

Contraindications for thrombolysis  CNS surgery, trauma, or haemorrhage in the previous 30 days Dr W Whitehouse

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       

Bleeding within the previous few weeks Surgery in the past 7–10 days Cardiopulmonary resuscitation or lumbar puncture within the past 7 days Diagnosis of a CNS tumour Uncorrectable thrombocytopenia or coagulopathy Pregnancy Severe liver disease Significantly preterm birth

3. Acute systemic anticoagulation: We suggest initiation of anticoagulation therapy in both arterial and venous infarctions using low molecular weight heparin (Enoxaparin) with Anti-factor Xa monitoring [aim for 0.5 - 1.0 U/mL][13]. Continuation of the anticoagulation depends on the aetiology of the stroke [see below].

Secondary Prevention of Arterial Ischaemic Stroke Strokes recur in one fifth of cases of later childhood AIS [14] and up to 60% in children with Sickle Cell Disease [SCD]. Secondary prevention in non- SCD children is by either antiplatelet therapy or anticoagulation therapy. Children found to have a pro- thrombotic condition should be referred to the haematologist.

1. Antiplatelet therapy: This is recommended as a secondary prophylaxis for all arterial strokes other than those secondary to sickle cell disease, cardiac emboli and extra-cranial dissection. Duration of treatment needs to be discussed on case-to-case basis; this is usually given for 1-2 years [13]. Available agents and doses:  



Aspirin: 1- 5 mg/kg/day (maximum 75 mg); usually start between 3-5 mg/kg/day; consider reducing if side effects occur [13]. Dipyridamole: in addition or as an alternative as a second line after discussion with neurologist 2.5 mg /kg BD for 1 month – 12 years; and 100-200 mg 3 times a day for 12 –18 years old (also available as modified release 200 mg capsules, to be used as twice a day). Clopidogrel- being used in combination with Aspirin in adults. It can be considered in older children in discussion with the neurologist/haematologist. Documented dose in the literature is 1 mg/kg per day up to the maximum of 75 mg [15].

2. Anticoagulation therapy:

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Secondary prevention by anticoagulation with LMWH or warfarin is recommended for strokes secondary to extra-cranial dissection, or cardiac emboli [13]. The recommended duration of anticoagulation in extra-cranial dissection is 3-6 months [16]. In children with a risk of cardiac embolism, it is reasonable to continue either LMWH or warfarin for at least 1 year or until the lesion responsible for the risk has been corrected [16]. If the risk of recurrent embolism is judged to be high, it is reasonable to continue anticoagulation indefinitely as long as it is well tolerated; liaising closely with the cardiologist responsible for the child is advised.

Stroke in Sickle Cell Disease 

Any child with sickle cell disease and a suspected stroke must be discussed with a consultant paediatric haematologist (or out of hours the consultant on call for paediatric haematology/oncology). See Sickle cell protocol for more detailed information.



Fluid management: normal or hyper-hydration may be required; seek advice from haematology.



Urgent exchange transfusion to reduce HbS 5 years

Child < 5 years

spontaneous to verbal stimulus to pain no response to pain

As older child As older child As older child As older child

V5

orientated

V4

confused

Alert babbles, coos, words or sentences to usual ability Less than usual ability or spontaneous irritable cry

V3 V2 V1 VT

inappropriate words incomprehensible sounds no response to pain Intubated

Cries to pain Moans to pain no response to pain Intubated

spontaneous normal facial/oromotor activity, for example sucks tube, coughs less than usual spontaneous ability or only responds to touch

As older child

vigorous grimace to pain mild grimace or some change in facial expression to pain no response to pain

As older child As older child

M6

obeys commands

Normal spontaneous movements

M5

localises to pain stimulus

M4 M3 M2 M1

withdraws from pain abnormal flexion to pain abnormal extension to pain no response to pain

As older child or withdraws to touch As older child As older child As older child As older child

Eye opening E4 E3 E2 E1 Verbal

Grimace (in place of Verbal if intubated or mute) G5

G4

G3 G2

G1

As older child

As older child

Motor

Arch. Dis. Child. 1997; 77; P 519

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References 1. De Veber G. In pursuit of evidence-based treatments for paediatric stroke: the UK and chest guidelines. Lancet Neurology 2005; 4: 432-6. 2. Riela AR, Roach ES. Aetiology of Stroke in Children, Journal of Child Neurology, 1993; 201-220 3. Intercollegiate working party for paediatric stroke. Clinical guidelines for diagnosis and management of acute stroke in childhood. 2004, Royal College of Physician, London. 4. Kirkham FJ. Stroke in Childhood, Archives of Diseases in Childhood, 1999; 8189 5. https://www.rcplondon.ac.uk/sites/default/files/national-clinical-guidelines-forstroke-fourth-edition.pdf 6. Adil MM, Qureshi AI, Beslow LA et al. Transient ischemic attack requiring hospitalization of children in the United States: kids' inpatient database 2003 to 2009. Stroke 2014 Mar; 45(3):887-8. 7. Gemmete JJ, Davagnanam I, Toma AK et al. Arterial Ischaemic Stroke in Children. Neuroimag Clin N Am 23[2013] 781-798 8. Mallick AA, Gamesan V, Kirkham FJ et al. Childhood arterial ischaemic stroke incidence, presenting features, and risk factors. Lancet Neurol 2014;13:35-43 9. Shellhaas RA Smith SE, O’Tool E et al. Mimics of Childhood Stroke: Characteristics of a Prospective Cohort. Pediatrics 2006;118:70. 10. Ganesan V. Neuroimaging of childhood arterial ischaemic stroke. Developmental Medicine and Child Neurology; Nov 2010; 52, 11; 983. 11. Marecos C, Gunny R, Robinson R et al. Are children with acute arterial ischaemic stroke eligible for hyperacute thrombolysis? A retrospective audit from a tertiary UK centre. Developmental Medicine and Child Neurology 2015, 57: 181-186. 12. A Tatman, A Warren, A Williams, JE Powell, W P Whitehouse. Development of a modified paediatric coma scale in intensive care clinical practice. Archives of Diseases in Childhood 1997; 77; 519-521.

13. Lyle CA Bernard TJ, Goldenberg NA et al. Childhood Arterial Ischemic Stroke: A Review of Etiologies, Antithrombotic Treatments, Prognostic Factors, and Priorities for Future Research. Semin Thromb Hemost. 2011 October; 37(7): 786–793.

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14. Fullerton HJ, Wu YW, Sidney S, et al. Risk of recurrent childhood arterial ischemic stroke in a population-based cohort: the importance of cerebrovascular imaging. Pediatrics. 2007 Mar; 119(3):495–501 15. Soman T, Rafay MF, Hune S,et al. The risks and safety of clopidogrel in pediatric arterial ischemic stroke. Stroke 2006 Apr; 37(4):1120-2

16. Roach ES, Golomb MR, Adams R, et al. 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. ; American Heart Association Stroke Council; Council on Cardiovascular Disease in the Young. Stroke 2008 Sep; 39(9):2644-9

17. Se´bire G, Tabarki B, Saunders DE et al. Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome. Brain (2005), 128, 477– 489. DeVeber G, Andrew M, Adams C et al. Cerebral Sinovenous Thrmbosis in Children. N Engl J Med 2001; 345:417-23. 18.

19. Tait

C, Baglin T, Watson H et al. Guidelines on the investigation and management of venous thrombosis at unusual sites. British Journal of Haematology, 2012, 159, 28–38

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