Stroke, TIA, and ICH

INTRACRANIAL HEMORRHAGE – ICH

Etiology:

• Commonest causes are: (a) hypertensive basal ganglion and cerebellar hemorrhages and (b) lobar hemorrhages (usually in the elderly) due to amyloid angiopathy • Secondary causes include: vascular malformations, hemorrhages into tumors or ischemic , cerebral venous sinus or cerebral vein thrombosis, and sympathomimetic drugs

Investigations:

• Blood sugar • CT head +- CT angiography • Spot sign: on CTA, the extravasation of contrast into the hemorrhage indicates ongoing and high risk for deterioration • Routine blood work to include INR and drug screen

Mortality Scores:

• ↑ Risk of mortality with: GCS <13, ICH volume > 30 cc, IVH (intraventricular hemorrhage), infratentorial bleeding, age > 80

Treatment:

• Airway management especially if GCS < 9 or patient deteriorating – do not allow BP to drop precipitously during intubation – particularly risky if significant ↓ LOC (due to probability of increased ICP and chance that cerebral perfusion pressure will drop) • Pre-treatment with fentanyl to minimize jump in BP • After intubation: sedate with fentanyl and sedatives to minimize jump in BP • Do not let SBP drop < 100 at any point • Reversal of anti-coagulants (do not give platelets to reverse asa/clopidogrel (unhelpful and likely harmful) • Give platelets if absolute count is <50,000 (many neurosurgeons prefer if < 100,000) • Ideal BP is SBP of 140 or minimally less • Minimize risk for ↑ ICP and manage ↑ ICP • No compression to neck • Head of bed elevated to 30 degrees • If ICP↑: mannitol at 1 gm/kg over 30 minutes (must insert foley and replace lost fluids to prevent dehydration, hypotension, and renal failure) and may repeat ever 4- 6 hours • if serum osmolality is monitored – serum osmolality should be followed q 4 hours – mannitol plays little role if osmolality is > 320

• Other options: hypertonic saline – 150 ml boluses 3% or 30 ml or 23.4% saline (23.4% needs central line) – monitor serum Na q 4 hours – serum Na should not be > 160 • Blood sugar: maintain at 5 – 10 mmol/l • Temperature: treat if > 37.5 C

Seizures:

• Prophylaxis not indicated for ICH • If : IV benozodiazepines, then IV dilantin (20 mg/kg) or keppra - levitiracetam- (50 mg/kg)

Surgery:

• Prophylactic (hematoma evacuation) in the absence of clear indications shown to be unhelpful (STITCH trial I and II) • Clear indication for surgery is cerebellar hematoma if > 3 cm in diameter or if clinical/imaging signs of hydrocephalus or compression • Indications for ICP monitoring +/- external ventricular drainage: Hydrocephalus Significant intraventricular blood

TIA

• The distinction between a TIA and a minor has become somewhat less important because the approaches are similar and both are urgent • TIA: traditional definition is a neurological event which is focal, due to focal ischemia of a single vessel, and has symptoms that fully resolve in 24 hours – modern imaging shows that ~1/3 of these patients demonstrates a stroke (infarcted brain tissue) at 24 hrs • New definition: transient neurological dysfunction due to focal ischemia of brain, or retina, or cord AND without evidence of infarction (on imaging) • If imaging is not available: symptoms > 24 hours will define a stroke

Etiology:

The etiology of TIA is the same as stroke

• About ¼ : large vessel • About ¼ : lacunar (small vessel disease) • About ¼ : cardioembolic • About ¼: thrombogenic states (including dehydration), dissections, cryptogenic

The ABCD2 Rule:

• Age (A) = 1 point for age > 60 • Blood pressure (B) 1 point if BP > 140/90 • Clinical (C) 1 or 2 points – 1 point for for speech disturbance without , 2 points for weakness; • Duration (D) zero points if < 10 min, 1 point if 10-60 minutes, 2 points if > 60 min • Diabetes (D) – this is the second D, 1 point if history of diabetes • Low risk 0-3 • Moderate risk: 4-5 • High risk: 6-7 • Historically, the risk of a TIA leading to a stroke was about 2-17% in the first 3 months and half of this risk was in the first 2 days (up to 5-7%)

The ABCD2 rule has been used to predict the specific risk and, traditionally, all patients with a high score (4-7) were felt to need a more urgent assessment

Prospective studies have shown that the score is neither sensitive nor specific and is inaccurate, at any cut-point, as a predictor of imminent stroke - so, what to do?

The Best Approach Is An Aggressive One

The most important risk factor is the “C” – speech deficit or weakness is very significant

Best approach is to get imaging of the brain and vessels fast – the move is in the direction of getting immediate CT and CTA of vessels from aortic arch to the vertex (i.e., both extracranial and intracranial vessels)

Identifying A. Fib (with ongoing monitoring if necessary up to 30 days in cryptogenic cases) and then treatment with anti-coagulants if found

Get to a TIA / Stroke clinic in < 2 days

Begin ASA in the department

Begin anti-coagulants in the department if cardio-embolic TIA and no acute stroke present

Investigations:

1. CT head always indicated - If not available, will have to be delayed - CT is primarily to rule out mimics (tumors, bleeds, other masses) – evidence of previous large vessel stroke or lacunar infarcts (which may have been subclinical) increase the risk of the TIA

- CTA of vessels from arch to circle is Willis is an excellent, if not preferred, investigation to Doppler of neck vessels 2. Heart tests: - EKG: always indicated to look for a. fib, flutter - 2D-ECHO HEART: may be indicated if suspect clot or PFO 3. Doppler of neck arteries – primarily to look for of the ICA – sensitivity for cervical artery dissection is good (if high suspicion for dissection – might be better to get an immediate CT/CTA 4. Basic blood work

Anti-platelet Therapy:

• ASA: dose is asa 81 mg per day (most will give a loading dose of 160-325mg)

- Lower dose effectiveness = higher dose. Therefore, giving more than 81 mg of no value and only increases the side effects

- Bleeding risk /year of ASA 81 mg: 0.4%/yr (this is 2.5 times the risk of non-users)

• Clopidogrel: dose is 75 mg per day (probably wise to give a loading does of 300 mg) - PPI’s: if one is going to use a PPI – best to use pantoprazole (tecta, pantoloc) – the other PPI’s affect the CYP system (cytochrome P450 system) and may impair the activation of clopidogrel

• Aggrenox: another option: aggrenox is a combination drug (asa 25 mg + dipyridamole 200 mg) BID - Some studies suggested it may be more effective than ASA (ESPSII – European Stroke Prevention Study II) –IF it is, the benefit is minimal

• Long term use of ASA + Clopidogrel: NO

- The MATCH trial clearly showed that long term ASA and clopidogrel together is bad – no benefit and increased risk of ICH

• Which is better? Clopidogrel or Aggrenox - Neither - THE PRoFESS trial showed they were equally effective

• Is There a Role for Short Term ASA + Clopidogrel after a TIA or Minor Stroke

- In high risk TIA: may consider a 21 day combination of asa 81 and clopidogrel 75 – not long term - Three trials have looked at this so far: FASTER, EXPRESS, and CHANCE - Currently, the POINT trial is being conducted in an attempt to determine if ASA 81 + clopidogrel 75 together for a brief period (21 days) is the best option – no definitive answer yet

TIA and Internal Carotid Artery (ICA) stenosis and Surgery – Does Time Matter – YES:

• For TIA caused by stenosis of the ICA > 70%: - surgery (endarterectomy) is indicated • Time is essential – the highest risk time is the first two days and then the first two weeks: therefore, surgery should be done with 2-14 days after the TIA – the sooner the better • Will reduce risk of a major stroke for 26% over 2 years to 9 % - 17% absolute risk reduction • The absolute risk reduction is 30% if done within 2 weeks • If ICA (internal carotid artery) stenosis 50% - 70%: - surgery still beneficial (22% to 15%) but surgery must be done early ( < 2 weeks) or the benefit is quickly lost • For Intracranial artery stenosis: the best treatment is ASA – surgery (stenting) has shown to be harmful and anti-coagulants to not benefit intracranial artery stenosis causing TIA’s or strokes

Recent Updates in Stroke: r-tPA (recombinant tissue plasminogen activator)

The American Heart Association/American Stroke Association Guidelines (2018 update)

• The AHA/ASA recommends the use of r-pTA for acute stroke up to 4.5 hours in those patients without contraindications • Cannot be used if patient has had LMWN in the previous 24 hrs • Absolute contraindications: BP > 180/110, ischemic stroke within past 3 months, severe head trauma within 3 months, intracranial or intraspinal surgery within 3 months, platelet count < 100,000, INR > 1.7, infective endocarditis • Major changes have occurred in that some of the previous contra-indications are no longer considered contra-indications • Three of the previous contraindications have been removed – for patients > 80 years age: MAY now receive r-tPA even if: (i) they are in the 3 hr – 4 ½ window, or (ii) are on warfarin and have INR <1.7, or (iii) have had a previous stroke and have diabetes.

• For the 3 hr – 4 ½ window and very severe stroke (NIHSS > 25): - r-tPA may have no value or be harmful • Mild early improvement is now not a contra-indication to r-tPA – therefore, even with spontaneous improvement, should still give r-tPA if meaningful impairment is still present • Seizure at the onset is not a contra-indication

Canadian Association of Emergency Physicians Position Statement on Acute Ischemic Stroke 2015

• Patients with acute ischemic stroke and no contraindications and within the three hour window, should be offered r-tPA with the goal of improving functional outcome – STRONG RECOMMENDATION, HIGH QUALITY EVIDENCE • Recommend door to needle time < 60 minutes • Suggest that in rural hospitals this decision should fall to the discretion of the local dicision- making team • Thrombolytic therapy should not be routinely offered for the treatment of acute ischemic stroke beyond 3 hours – WEAK RECOMMENDATION, MODERATE QUALITY EVIDENCE • However, may be offered in the 3 – 4 ½ window IF the patient is thought to be low hemorrhage risk and advanced neuro-imaging suggests that there is salvageable brain. • This guideline opens the door for physicians to administer thrombolysis in a subgroup (in the 3 – 4 ½ window) that may benefit as deemed by the treating team [these words used in the CAEP guidelines]

American College of Emergency Physicians – reviewed and re-released 2015

In the 3 hr window: r-tPA should be offered and may be given to selected patients within 3 hours where systems are in place to safely administer the medication

In the 3 hr to 4 ½ hr window: may (as opposed to “should” in the < 3 hr window) be offered and may be given to carefully selected patients

North American Guidelines DO NOT support the use of r-tPA after 4 /2 hours

Massive New Developments As Of 2015 – endovascular thrombectomy in acute ischemic stroke:

This is a major development

Every patient with a significant stroke is considered for thrombectomy up to six hours (stroke to groin puncture time < 6 hours)

What this means:

Does every patient with a stroke require a CT/CTA and discussion with a thrombectomy center or possibly, just a stat transfer to the stroke center based on clinical assessments (i.e., just transfer the patient and let the stroke centre do all the imaging? Maybe. This is my practice because the stroke center is a 10 minute trip and getting an immediate CTA is not always easily done at my hospital. If uncertain, I put in a stat call to the on-call stroke neurologist at the stoke center. [This is only possible because a well-worked out relationship has been established. Each hospital must develop a strategy that is workable. ]

Every patient with a significant stroke needs to be assessed if there is a possibility of stroke onset to puncture time of 6 hours – many referral centers will take direct transfer from non-stroke centre if the patient was seen at < 4.5 hours. This means there are 90 minutes for transfer, assessment, and commencement of treatment. If this patient arrives in your ED, you should consider direct transfer to a stroke centre without a CT [it will be done at the stroke center] if, in your opinion, there is a high probability of a stroke. This pathway must be worked out by each institution that sees or may see a patient with a stroke.

1. Endovascular thrombectomy with retrievable stents is the current treatment for acute ischemic stroke patients due to a large vessel occlusion. These patients require a CT/CTA to determine whether there is an occlusion of the ICA or proximal middle cerebral. This is best done at the stroke centre. The patient needs to have substantial deficits but a small core of infarct with a significant penumbra of viable brain. These conditions can be determined clinically (eg, ASPECT score > 6 and NIHSS > 6) or with a CT/CTA/Perfusion CT scan or with an MRI diffusion-perfusion scan. Increasingly, due to time, availability, and reliability, the CT path is being used. 2. Endovascular thrombectomy with retrievable stents is safe. 3. r-tPA should be given if < 4.5 hours and may be given after an acceptable after an acceptable non-contrast CT even if the CTA is not done yet done. Some referring centers may give the r-tPA as the patient is being transferred IF the patient had an acceptable CT scan. 4. Endovascular thrombectomy was effective. An excellent outcome was defined as the ability to live independently and a modified Rankin Scale 0 – 2. The absolute difference in the five studies published in 2015 showed this clinically and statistically significant benefit. The absolute improvement that occurred was 14% to 31% of the patients (absolute not relative) depending on the study. This is a NNT of about 3.5 to 7 depending on the study. Of course, many patients have to be evaluated to find the appropriate patients who will derive this amazing benefit. Some have argued that the burden on the system will be overwhelming. 5. R-tPA was given in the majority of the patients but not in the group after 4.5 hours after stroke onset.

American Heart Association/American Stroke Association Focussed Update 2015

Patient should receive endovascular therapy with a stent retriever if they meet all the following criteria:

(a) Prestroke mRS 0 to 1 (b) r-tPA within 4.5 hours of stroke onset (c) occlusion in the ICA or proximal middle cerebral artery (d) age >= 18 (e) NIHSS of >= 6 (f) ASPECTS score A>= 6 (g) Stroke onset time to groin puncture time of < = 6 hours.

New Developments as of January 2018 – thrombectomy up to 16 to 24 hours after stroke onset

DAWN Trial – NEJM Jan 2018

• Stroke patients with a groin puncture time of 6 – 24 hours after the stroke onset and with a NIHSS of > 10 • All patients required a CT/CTA/CT perfusion scan or MRI diffusion/perfusion scan • Had to have a demonstrable and significant penumbra and a small infarct core on scanning • Amazing benefits in these highly selected patients • Independent Functional Status ( mRS 0-2 = functional independence): thrombectomy 49% vs 13% in control group

DEFUSE 3 Trial

• Thrombectomy at 6 - 16 hours after stroke onset • Similar patients to the DAWN trial. Patients required similar sophisticated imaging. • Independent Functional status (mRS 0-2 = functional independence): thrombectomy 45% vs 17% control

What does this mean?

Hard to say. Should every patient with a NIHSS > 10 and 6 – 24 hours after stroke onset be transferred to a stroke centre stat? Maybe.

I am only going to include the most relevant papers to review. (Otherwise, I will end up with an intolerable number of references.)

Edlow J. et al. Neurologic Emergencies. Emergency Medicine Clinics of North America 2016;34(4):811- 900

Koyfman A. et al. Vascular Disasters. Emergency Medicine Clinics of North America 2017;35(4):825-846.

Airton L. et al. The critical care management of spontaneous intracranial hemorrhage: a contemporary review. Critical Care 2016;20:272.

Perry J. et al. Prospective validation of the ABCD2 score for patients in the emergency department with transient ischemic attack. CMAJ 2011;183(10):1137-1145.

Powers et al. 2018 Guideliens for the early management of patients with acute ischemic stroke. Stroke 2018;49:Exxx-xxx.DOI (only on web until print edition in March)

Demaerschalk B. et al. Scientific tationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke. Stroke2016;47:581-621.