Stroke Flashcards Preview

These are due to posterior circulation. • One example of this kind of infarct is PICA infarct = posterior inferior cerebellar artery – medullar dorsolateral syndrome. It is the most common type of brainstem stroke. • When weakness/symptoms on same side of the face and opposite side of the body – whenever you have this crossed pattern of paralysis (opposite face and body), you know it is a brain stem infarct. • Can also affect swallowing because it affects nucleus ambiguous – CN IX and X • Infarction of pons bilaterally can lead to locked-in syndrome – due to blockage of basillar artery

These lacunar infarcts cause progressive, cumulative problems – leading to dementia and Parkinsonism (not Parkinson's disease itself, but parkinsonism). Vascular dementia is one of the main causes of age-related cognitive decline. • Acute Syndromes: ○ Pure motor ○ Pure sensory ○ Ataxia-hemiparesis ○ Dysarthria-Clumsy hand • Chronic Syndromes: ○ Executive cognitive impairment, bradyphrenia ○ Lower body parkinsonism, gait apraxia

Arterial: • Carotid Doppler – Looking for obvious stenosis/clot • MR Angiogram – Assessing the carotids/circle of Willis • Bubble Echocardiogram [of heart] – Look for Mural Thrombus, valve vegetations (aortic), inter-atrial shunt, endocarditis • 24 hour ECG - to look for AF, especially paroxysmal AF Venous: • CT-V – Contrast scan of cranial sinuses, especially Sagittal and Coronal views

This is caused by a ruptured vessel leads to bleed directly into the parenchyma. Caused by hypertension, amyloid angiopathy or AVM.

A bleed into the space between arachnoid and pia mater. Can cause a secondary vasospasm (leading to ischaemic stroke downstream). Caused by Aneurysm (e.g. Berry Aneurysm in PKD [polycystic kidney disease])/ Dissection/ Trauma

A bleed into space between arachnoid and Dura mater. - Subdural Haemorrhage

• Bleed into space between skull and Dura mater • Usually rupture of Meningeal artery (e.g. MMA damage in pterion injury) • Fast bleed, acute headache and rapid deterioration, convex bleed shape

20-30% die within 1 year. Most survive with considerable disability.

- Cerebral oedema - Aspiration Pneumonia due to weak swallowing muscles - Pulmonary embolism due to patients in bed for a long period of time

Rapid recognition and reaction to stroke symptoms. → Immediate call of emergency service → Priority transport with pre-announcement to target hospital (specifically trained and equipped to deal with acute stroke) → Rapid and targeted diagnostic work-up and therapy in hospital. The aim is to deliver thrombolysis within 30 minutes of entering the door. This involves taking vitals, performing examinations and a CT scan. Emergency room: In the emergency room four things are done: • Medical history - Stroke suspected? ○ Time since symptoms-onset/last seen well ○ Do symptoms correspond to a vascular territory (ischaemia)? • Vital signs ○ Vigilance → clinical ○ Respiration → clinical, plusoximetry ○ Circulation → BP,HR,ECG • Laboratory (CBC, coagulation) • Neuro exam: NIHSS stroke scale to grade severity Imaging is always necessary The modality of choice is CT, as it is fast and widely available. Imaging is important to tell the difference between ischaemic and haemorrhagic stroke.

After ICH has been ruled out with CT scan we can operate knowing it is ischaemic in nature. Important to rule out haemorrhage as treatments for ischaemic stroke would deteriorate the hemorrhaging patient. If the onset of the persisting deficit is <4.5h or CCT early infarct signs <1/3: • Intravenous thrombolysis (intravenous recannulisation) • Mechanical thrombectomy (a type of interventional recannulisation) Unfortunately for a significant proportion of patients, there is unknown symptom onset: • Multimodal MRI/CT based thrombolysis? • New therapies within trials?

rtPA is the only licensed medical therapy of acute ischaemic stroke - in 4.5 hour time window. • 0.9 mg/kg over 60 min (max. dose 90 mg) • With a bolus of 10% over 1 min Important to be aware of the eligibility criteria

As mentioned a significant proportion of patients have an unknown time of symptom onset for various reasons, meaning they will miss out on thrombolysis treatment. To overcome this, we are trying to substitute the clock with pathophysiology, using imaging modalities. There’s a mismatch between the small area of infarct and the large area of generalised reduced perfusion. The difference is the penumbra, which is at risk and should be salvaged. We can use diffusion weighted imaging (DWI) to image the ischaemic core, and perfusion weighted imaging (PWI) to image the area of reduced perfusion (core + penumbra). By subtracting the two, you can image the penumbra to see how much tissue can be salvaged, informing whether to use thrombolysis. There are new trials to select suitable patients according to various imaging techniques. ECASS-4/EXTEND trial was a phase III RCT showing rtPA with selection via MRI-mismatch had a 4.5-9h time window. Similar phase III EU funded trial called Wake-up trial currently ongoing.

Interventional recanalisation is carried out by different devices: • Ultrasound (EKOS) • Shockwave/vacuum • Angiojet • Retrieval devices (MERCI, penumbra) • Laser devices (EPAR) • Stent retrievers

These endovascular treatments have been shown to be more effective than rtPA alone by randomised control trials. With mechanical thrombectomy, again faster is better in producing patients with a good clinical outcome. A 30% delay translates to 12% less chance of good clinical outcome. Unlike rtPA, you need a specialised team to carry out endovascular treatment, so this presents a challenge for the chronically underfunded NHS.

- Basilar Artery Thrombosis - Space-Occupying Middle Cerebral Artery

A hemicraniectomy is vital in reducing brainstem death. In the DESIRE trial, patients showed much better outcomes with surgery compared to conservative treatment.

Only a minority of patients are able to benefit from revascularisation by thombolysis or endovascular therapy. There are hundred of studies suggesting potential molecular targets for neuroprotective drugs. However, none so far have made it into clinics :( An essential part of stroke treatment is provided by the infrastructure of stroke units.

The stroke unit is not just a ward, it is an interdisciplinary team formed of ICU, A&amp;E, neurovascular surgery, neuroradiology, discharge to home, neurology ward, inpatient rehabilitation, physiotherapy, SALT, long-term care and home care.

They are used to: • Monitor patients with acute stroke (>24g, unstable phase) • Immediate diagnostic work-up for cause of stroke • Immediate specific therapy and secondary prevention (very important also) • Continuous monitoring of vital signs and aims for homeostasis • Prevention of secondary complications • Stay therefore rarely exceeds 5 days.

? Stroke units are the most effective ?treatment. Level 1 evidence shows: • Reduced morbidity and mortality independent of sex, age, severity • Shorten inpatient treatment • Lower number of patients surviving with severe disability and needing long-term care • Increase proportion of patients with complete recovery.

• Causes 8-15% of all strokes • 1 year mortality is 37-47% - 2/3 X higher than ischaemic stroke • 1/3 of survivors remain severely disabled (dependent on nursing)

• Hypertensive arteriolopathy (70%) [Hypertension is number 1 risk factor] • Cerebral amyloid angiopathy (5-20%) related to Alzheimer's disease Other causes: • Anticoagulants (15%) • Tumour (5%) • Vascular malformations (1-2%)

Early haematoma enlargement is frequent and is associated with clinical deterioration. In fact, size of the haematoma is one of the best indicators of prognosis. The dynamic nature of ICH during the first several hours represents an opportunity and a challenge to physicians. If one could stop the bleeding during the first few hours and remove the accumulated blood without significant additional brain trauma from the operation, neurological deterioration and poor outcome could be prevented in some patients but this is extremely rare at present.

• Haemostatic therapy for ICH • Anticoagulation reversal for OAC-ICH • Antihypertensive therapy in acute ICH • Surgery

Recombinant factor VIIa can help push the clotting process so that bleeding does not occur. In the FAST trial, you could see that there was a volume reduction of the bleeding, but no improvement of death and disability, and also there was increased risk of thromboembolic events. Maybe we need to improve patient selection by finding out who is likely to continue bleeding and who is not. Generally, administration of haemostatic drugs is not recommended in spontaneous ICH

Recommendations are to stop Vit K antagonists and give vitamin K/prothrombin concentrate. Evidence for positive effect of fast anticoagulation reversal on haematoma growth in VKA-ICH (Vit K Antagonist). For NOAC: Idarucizumab is a humanised Fab fragment. Highly specific antagonisation of dabigatran activity (binding affinity for dabigatran ~300x higher than dabigatran to thrombin) • i.v. administration, immediate onset of action • Short half-life (terminal HL about 10h) • Small distribution volume (about 8-9l) • No intrinsic pro-anticoagulatory effect expected Idarucizumab also prevents excess haematoma expansion and Idarucizumab reduces mortality. Andexanet-alpha - recombinant modified human factor Xa • Designed to reverse anticoagulant effects of factor Xa inhibitors • Acts as factor Xa decoy to bind molecules that inhibit factor Xa

• In the INTERACT-2 trial, researchers used intensive BP lowering drugs <140mmHg in 1 hour versus standard care • Made sure to have exclusion criteria, excluding people with a structural cause of haematoma, coma, massive haematoma with bad prognosis or planned early surgery • They found that there was no effect on early haematoma volume but: ○ Lowering BP below 140mmHg in acute phase of ICH is safe ○ It reduces the likelihood of unfavourable outcome ○ The time to reaching BP target could be shorter ○ But it’s still unclear why the risk of bad outcomes was reduced • In the ATACH-2 trial, they went even further and lowered BP to <120mmHg. They found no effect of very intensive therapy on outcome .

• In a meta analysis for mortality in prospective studies of haematoma evacuation, there was a favourable outcome • In the STICH trial, researchers compared surgery vs. conservative treatment and looked after favourable outcomes .They found that there was no difference regarding survival but in a subgroup of patients who had haematomas less than 1 cm from the cortical surface, there was a favourable outcome of surgery • So in the STICH II trial, they focused on lobar ICH less than 1cm from the brain surface, and found that there was increased survival and better outcomes for that specific group of patients • Decompressive surgery might be useful if there is oedema • In general, we do not recommend surgery for patients with haematoma

• Insight into pathophysiology: Selective neuronal loss, cortical spreading depression, neuroinflammation, "ischaemic penumbra", etc. • Validation of clinical observations and concepts: Brain imaging (e.g. DWI, PWI), tPA-toxicity, immunodepression, hypothermia, etc. • Drug development

80% of animal models in stroke are rodents. There are a variety of techniques used to cause ischaemic stroke in the animal models (in order of most popular): 1. Intraluminal filament - a filament is advanced via the carotid artery into the skull to occlude the MCA. 2. Coaugulation/cauterisation/transection 3. Clip/ligation 4. Emboli: autologous clot/microsphere/macrosphere 5. Photochemical 6. Endothelin 7. Compression/balloon/torniquet - often used in big animals

Filament placed into MCA to cause occlusion. Can vary length of time before removal (and hence reperfusion) - so you can get different levels of ischaemia. Most commonly used method - 45-90 min occlusion time Pros: ○ Relatively easy operation ○ No craniectomy ○ Can simulate reperfusion • Cons: ○ Hypothermia ○ Weight loss ○ High mortality ○ Short observation period

• Transient occlusion can be modeled using Clip or Ligation • Permanent occlusion can be modeled using Coagulation or Ligation Pros of using these surgical methods: • Suitable also for large animal models • High proportion of successful procedures • High reproducibility • No hypothermia, low mortality • Long-term observation possible Cons: • Skull opened (dura incision, CSF leakage, surgical trauma) • Usually permanent MCAo • Does not model recanalisation • Surgical skill required

One method is to inject an externally produced emboli, similar to using the filament model. Another method is to inject thrombin. Both can by lysed by rt-PA Pros: • Models most common cause of human stroke • Allows analysis of thrombolysis • No craniectomy (except thrombin injection) • No hypothermia • Lower mortality compared to filament MCAo Cons: • Low rate of successful MCAo • Little control over site of clot lodgement • Certainty of occlusion versus effective reperfusion • Excellent surgical skills needed (clot emboli; thrombin injection)

This is done by inject agent called rose bengal, then apply laser at certain wavelength, which via reactive oxygen species causes very small strokes within the brain. This produces very small, precisely defined lesions. Lesions can be induced stereotactically in predefined anatomical regions. Pros: • Precise localisation of infarction • Targeting functionally defined regions • High reproducibility • Dura not opened • Minimal mortality Cons: • Additional direct effects on brain function o Endothelial lesion • Expensive material / difficult method • Useful only for specific study aims

Pros: • Closer to human brain anatomy and function • Imaging techniques (PET, MRI) easier • Better monitoring of physiology Cons: • Intensive in cost and labour • Large variability • High mortality • Limitations by animal welfare • Public and ethical concerns

• Rodents have greater capillary density • Lesser inter-capillary diffusion distance • Greater CSF turnover • Gyral complexity much more defined in man • Grey:White matter ratio: Rodent brains are 90% grey matter, whereas for humans it is the white matter tracts that are especially important for function

Animal studies • Used only young, healthy animals • Statistical problems: Randomization, blinded analysis, power, sample size • No clinically relevant time point of treatment • Physiological parameters not controlled Clinical studies • Adequate drug levels were not reached • Time window was not used based on preclinical data • Inclusion of patients to study not adjusted for mode of drug action

Either inject something that makes the blood vessel wall break down (collagenase), or inject blood directly. Collagenase-injection model: Bacterial collagenase destroys the basal lamina of cerebral blood vessels dose-dependently. This causes bleeding in the surrounding tissue. Blood injection model Direct injection of blood into the striatum. Here there is no vessel damage.

There are two sides to the immune system's involvement: • Evidence for increased susceptibility to infections due to suppression of peripheral immune system. • Ischaemic CNS damage leads to secondary neuroinflammation, which can cause infarct growth Two effects that are opposite to each other

30 % of all stroke patients develop infections (Pneumonia: 10%, UTI: 10%) with pneumonia being the most important cause of death (subacute phase). Some people are calling this Stroke-Induced Immunodeficiency Syndrome. This is characterised by: • Spontaneous bacteraemia and pneumonia in murine stroke model • Lymphocytopenia (blood, lymphatic organs: apoptosis) • Reduced responsiveness of innate and adaptive immune cells to in vitro stimulation

Mainly mediated by stress hormones (e.g. NA, glucocorticoids, ACh) • Immune cells have receptors for these hormones, leading to immunodepression • Breakdown on immunological barriers This makes them more susceptible to infection

Following ischaemia, there is activation of microglia, which secrete pro-inflammatory cytokines, which makes the BBB more permeable and leads to infiltration of systemic immune cells (also with increased adhesion molecules). As a result, you get systemic immune cells in the brain which release cytokines and chemokines themselves, which are also cytotoxic. Inflammatory cascades in acute phase of ischemia predominantly deleterious and lead to infarct enlargement. Pro-inflammatory T-cells are increasingly recognized as an important deleterious systemic immune cell populations.

Are T-cells a suitable target for protective therapeutic approaches? Anti-inflammatory therapy by blocking leukocyte adhesion - Anti-CD49d therapy is used in MS. Natalizumab is humanised, monoclonal antibody against α4-Integrin (=CD49d) which blocks CNS-migration, but does not destroy lymphocytes. • Phase III Studies: > 70% Reduction of episodes in MS Natalizumab was shown to minimise immune cell infiltration around the lesion site. While this had no effect on the acute inflammatory phase, it did prevent infarct growth.

Experimental Design: • Permanent occlusion of middle cerebral artery (MCAO) by electro-coagulation after trepanation • Infarct volumetry [imaging] by silver staining of coronary sections • Blockade of integrin alpha4 (CD49d) on leukocytes by monoclonal antibody Experiment results: • Substantial reduction of infiltrating cells around infarct • No change in infarct size at 1 day • But significant decrease in infarct size by 7 days

Protection in several experimental stroke models → Proof-of-concept by complementary methodology approach → Confirmation in multicentre preclinical RCT → Phase 2 RCT with proof-of-concept approach → (Currently in planning:) Phase 2b/3 efficacy and safety Study design of the Phase 2 - Randomised, double blind, placebo-controlled trial of natalizumab in acute ischemic stroke: Primary Endpoint - change in infarct volume: • Natalizumab did not affect infarct volume growth compared to placebo! • I.e. it wasn't like it was in the animal models Clinical outcomes in Natalizumab- and placebo- treated patients: • At days 30 and 90, natalizumab showed a meaningful benefit over placebo treatment on global clinical and cognitive function, but not NIHSS [National Institutes of Health Stroke Scale] score • The likelihood of an excellent outcome on the mRS [modified ranking score] (score ≤1) was analysed in patient subgroups stratified by baseline infarct size, treatment time window, and tPA use