91529 PP1 lecture

8:30-10:00, 4 April

Stroke
Some images have been
removed in this note file due to
copy right issues. Professor Hui Chen
Information on vaccine-caused
conditions and traumatic brain Faculty of Science, UTS
injury is for your information,
and not examinable. hui.chen-1@uts.edu.au
Prof Hui Chen, Science. Copyright: UTS. 1
 Learning objectives

• Define a cerebrovascular accident, state the main types, identify key risk factors.
• Outline the pathophysiology of this condition.
• Describe the clinical manifestations, diagnosis and clinical management of cerebrovascular
accidents.
• Traumatic brain injury in this lecture is not examinable.

Reference book
Principles of Pathophysiology. eBook by Shane Bullock and Majella Hales
https://ebookcentral.proquest.com/lib/uts/reader.action?docID=5495513#ppg=562
Part 3 Nervous system Pathophysiology Chapter 9 to 15
Latest information citing peer reviewed clinical trials is provided where applies.

Prof Hui Chen, Science. Copyright: UTS. 2

 What is a stroke?
• A sudden disruption of the blood supply to a part of the brain
– Ischemic - a blockage develops (80-85%)
– Haemorrhagic - a blood vessel bursts

– cerebral ischemia = loss of blood supply = ↓ O2

– without treatment, cells in the brain quickly begin to die
– the result can be serious disability or death
• Classified as neurological disease (International Classification of Diseases 11 (ICD 11), effect
on 1/1/2022 )
Prof Hui Chen, Science. Copyright: UTS. 3
 Female

Global disability-adjusted life-years (DALYs;

the sum of years of life lost [YLLs] and
years lived with disability [YLDs]) Male

Global, regional, and national burden of neurological

disorders during 1990–2016: a systematic analysis for the
Global Burden of Disease Study 2016
Lancet Neurology 2019
DOI: https://doi.org/10.1016/S1474-4422(18)30499-X

Prof Hui Chen, Science. Copyright: UTS. Age (year) 4

 Disability-adjusted life-years Death

Global, regional, and national burden of neurological disorders during 1990–2015. Lancet Neurology 2017. DOI:https://doi.org/10.1016/S1474-
4422(17)30299-5 5
Prof Hui Chen, Science. Copyright: UTS.
 Statistics

• Stroke is the 10th leading cause of death, one of the biggest causes of adult disability
in Australia
• Over 38,000 strokes occur in Australia every year with a stroke - more than 100 / day
• More than 387,000 Australians had had a stroke at some time in their lives.
• In 2018, stroke caused 8,400 deaths, accounting for 5.3% of all deaths in Australia
• The total burden of disease due to stroke decreased by 41% between 2003 and 2015.
• Women are more likely to die after stroke than men.
• More women die each year from stroke than from breast cancer.
• Stroke costed $633 million each year in Australia

Prof Hui Chen, Science. Copyright: UTS. 6

Variation between selected populations

Prof Hui Chen, Science. Copyright: UTS. 7

 Risk Factors
Hypertension
Atrial fibrillation (irregular heartbeat)
Smoking
Diabetes
High cholesterol
Age
Gender
Diet
Excessive alcohol intake
In the week after a COVID-19
Obesity diagnosis, the risk of a first stroke
Lack of Exercise caused by a blood clot multiplied by
three to six times.
Birth control pills
Prof Hui Chen, Science. Copyright: UTS. 8
 Ischemic stroke

• A common cause of ischemic stroke is atherosclerosis

• Plaque leaves less space for blood to flow
• Easier for a clot to form
• Embolus or thrombus came from outside the brain
• Deep vein thrombosis
• Atrial Fibrillation (42% stroke cases)

Prof Hui Chen, Science. Copyright: UTS. 9

 Microvascular stroke
Example images of vascular density in the
two groups.
(A) A stroke patient's macular vessel
density in superficial capillary plexus

(B) A non-stroke subject's macular vessel

density in superficial capillary plexus

https://doi.org/10.3389/fnagi.2021.628336
Prof Hui Chen, Science. Copyright: UTS. 10
Haemorrhagic stroke
https://commons.wikimedia.org/
wiki/File:An_illustration_of_the_d
ifferent_types_of_brain_hemorrh
age.png

• If the blood vessel wall is weak, an aneurysm

may form at the weakened spot and rupture
• subarachnoid haemorrhage - in the area
between the arachnoid membrane and
the pia mater surrounding the brain
• Uncontrolled high blood pressure causes a
weakened artery to burst

Prof Hui Chen, Science. Copyright: UTS. 11

 Stroke Symptoms

• Sudden severe headache with unknown cause or unexplained change in the pattern of
headaches.
• Sudden vision changes in one or both eyes.
• Sudden dizziness.

• Swallowing difficulties
• Sudden confusion, difficulty speaking or understanding the others.
• Sudden numbness or weakness of the body, especially on one side, problems with walking,
or balancing.
• Changes in consciousness

Prof Hui Chen, Science. Copyright: UTS. 12

Stroke captured by a patient

Prof Hui Chen, Science. Copyright: UTS. 13

 Left or right?

Motor cortex damage

leads to paralysis on the
opposite side.

Sensory cortex damage

leads to partial loss of
sensation on arm and leg
on the opposite side.

Prof Hui Chen, Science. Copyright: UTS. 14

 Transient ischemic attack
(TIA)

• Similar signs to stroke, which only last a few seconds or up to 24 hours and then disappear.
• All called ‘mini strokes’.
• They indicate a hidden problem with blood flow and could trigger a stroke - should not be
ignored
• Early identification of the symptoms and treatments can greatly reduce the chances of a
major stroke.

Prof Hui Chen, Science. Copyright: UTS. 15

 Changes in white matter

Signs of cerebral small vessel disease. (doi: 10.1136/bmj.b2477)

White matter hyperintensities are associated with a more than 2-fold increase in the risk of stroke.
(doi: 10.1136/bmj.c3666) Prof Hui Chen, Science. Copyright: UTS. 16
 Stroke Test
• The F.A.S.T. test helps spot symptoms:
Smile, Wave, Talk
 Face. Ask for a smile. Does one side droop?
 Arms. When raised, does one side drift down?
 Speech. Can the person repeat a simple sentence? Does he or she have trouble or
slur words?
 Time. critical = brain damage

one hour of ischemic brain damage can be

compared to 3.6 years of normal brain aging

Prof Hui Chen, Science. Copyright: UTS. 17

 Diagnosis
• When someone with stroke symptoms arrives in the ER
• determine which type: CT scan
• 24-48h MRI for extent of damage

Emergency treatment
• Aspirin: within 48h of onset - antiplatelet
Clopidogrel (duel therapy significantly reduces ischemic stroke risk)
• rt-PA thrombolytic therapy (if < 3-4.5 hrs) or endovascular treatment
• > 3h ↑ risk of haemorrhage, best functional outcomes within 60 minutes
• Thrombectomy: surgery to remove a blood clot from inside an artery
• Heparin iv: neutralise activated clotting factors
• Warfarin may be needed for a short period

Prof Hui Chen, Science. Copyright: UTS. 18

 Against rt-PA guidelines

• Current guidelines recommend against use of intravenous alteplase in patients with acute
ischemic stroke who are taking non–vitamin K antagonist oral anticoagulants (NOACs) in the
previous 48 hours
• US retrospective cohort study included 163 038 patients with acute ischemic stroke
treated with alteplase
• patients with acute ischemic stroke either taking NOACs or not taking anticoagulants
prior to stroke and treated with intravenous alteplase within 4.5 hours of symptom
• primary outcome - symptomatic intracranial haemorrhage occurring within 36 hours
• 4 secondary safety outcomes, including inpatient mortality, and 7 secondary functional
outcomes assessed at hospital discharge, including the proportion of patients
discharged home
• use of NOACs within the preceding 7 days was not associated with a significantly
increased risk of intracranial haemorrhage

Kam et al. JAMA. 2022;327(8):760-771.

doi:10.1001/jama.2022.0948
Prof Hui Chen, Science. Copyright: UTS. 19
 After several hours After 30 days
At baseline

perfusion

Dead
zoon

penumbra No perfusion
Area at risk
(penumbra)

Intermediate lesions Final brain lesion

A recent Cochrane meta-analysis (10.1002/14651858.CD000024.pub5. ) showed that No evidence suggests

that early anticoagulation reduced the odds of death or dependence at the end of follow-up.

Prof Hui Chen, Science. Copyright: UTS. 20

 Progression of stroke damage

MRI
red = 4 hours
blue = 28 hours
green = 56 hours

Acute stroke therapeutics aim to contain the tissue damage happening at the
'penumbra' level and restore the penumbra's functionality.

Prof Hui Chen, Science. Copyright: UTS. 21

Reperfusion Injury

• Occurred in 6-7% r-tPA treated patients

• Beyond a critical time, instead of preserving brain tissues, restoration of oxygen
amplifies the destruction of an already deranged neurovascular environment.
• Prolonged ischemia and hypoxia result in a change to anaerobic metabolism
• Re-introducing oxygen causes enhanced oxidative stress, which directly damages the cells
• activation of platelets and neutrophils aggregate and may clog the brain's
microvasculature, called 'no-reflow'
• damage blood brain barrier integrity: bleeding
• Complications: penumbral damage, ischemia expansion, haemorrhagic transformation,
seizures, malignant cerebral oedema, and herniation.

Prof Hui Chen, Science. Copyright: UTS. 22

 Increased intracranial pressure

• Cerebral hypoperfusion
• Herniation

• Intubation if unresponsive
• Osmotic diuretic, eg. mannitol iv.
• Neurosurgery: common 48h after onset of stroke

Prof Hui Chen, Science. Copyright: UTS. 23

 Endovascular therapy in large infarction

• Endovascular therapy for acute ischemic stroke is generally avoided when the
infarction is large
• a multicenter, open-label, randomised clinical trial in Japan involving patients with
occlusion of large cerebral vessels and sizable strokes on imaging
• 101 patients in endovascular-therapy, 102 in the medical-care group
• 27% of patients in each group received alteplase (rt-PA)
functional improvement at 48h intracranial haemorrhage
endovascular-therapy 31% 58%
medical-care 8.8% 31.4%

• improve function recovery, however also increase intracranial haemorrhage risk

Yoshimura et al. N Engl J Med 2022 Feb 9. doi: 10.1056/NEJMoa2118191

Prof Hui Chen, Science. Copyright: UTS. 24

 Acute ischemic stroke patients presenting with early consciousness disorder had
greater mortality and worse discharge outcomes.
• longer hospitalisation
• less likely to be discharged home or to rehab
• less likely to ambulate independently

Mortality was largely influenced by the decision to withdraw life-sustaining

treatment.
https://doi.org/10.1212/WNL.0000000000200018
Prof Hui Chen, Science. Copyright: UTS. 25
 Haemorrhage Stroke
Hemorrhagic Stroke

Prof Hui Chen, Science. Copyright: UTS. 26

 Brain Herniation

• Increased intracranial pressure pushes the brain out of position (projectile vomiting)
• Brain tissue is compressed, against bone or against rigid folds of the dura mater
• Compression of the oculomotor nerve is an early sign
 disabled eye movement
 drop of eyelid and pupil dilationBrain stem hernia can cause sudden death
• Brain stem hernia can cause sudden death

Prof Hui Chen, Science. Copyright: UTS. 27

 Management of haemorrhage
stroke

• General medical management plays an

important role in minimising secondary injury
• airway management
• avoid constipation
• Early intervention: the best chance for
improving outcome
• correction of coagulopathies: performed
ASAP
• blood pressure management: without
excessive reduction
• surgery: not universal, some may benefit.

Prof Hui Chen, Science. Copyright: UTS. 28

 Life After a Stroke

STROKE
48 000

DEATH DEPENDENCY RECOVERY

One third One third One third

Chance of
death or a more RECURRENT
severe stroke
STROKE
approx. 10%

Prof Hui Chen, Science. Copyright: UTS. 29

Life After a Stroke

Wang et al. Stroke 2022 doi: 10.1161/STROKEAHA.121.037121.

9,038 patients with acute ischemic stroke between 2015 - 2018

• females older than males

Unfavourable functional outcomes

• at 3 months, female patients were more likely to have unfavourable functional outcomes, especially
among patients aged 65 years or older
• no sex difference in patients aged < 65 years
• at 6 or 12 months, no sex differences

stroke recurrence and mortality

• no sex differences at 3, 6, or 12 months

Prof Hui Chen, Science. Copyright: UTS. 30

 • helps patients regain lost skills and learn to compensate for
Stroke Rehab damage that can't be undone.
• the goal is to help restore as much independence as possible
• Speech therapy
• Physical therapy
• Talk therapy

Stroke Prevention Medications

 Control High Blood Pressure: Angiotensin Converting Enzyme
(ACE) Inhibitors
 Lower blood cholesterol levels: Statins - very promising
 Prevent further clots: aspirin as ‘blood thinners’, warfarin for
atrial fibrillation

Surgery
• Carotid endarterectomy
• Angioplasty - stent
• Aneurysm: clipping, coiling
Lifestyle
• Quit smoking
• Exercise and maintain a healthy weight
• Limit alcohol and salt intake
• Eat a healthier diet with more veggies, fish, and whole grains

Prof Hui Chen, Science. Copyright: UTS. 31

Stroke Prevention Slomski. JAMA 2022 doi: 10.1001/jama.2022.0148

Efficacy
Japan Stroke Data Bank

all stroke types have become less severe over the past 2 decades

strokes are occurring later in life

better preventive approaches, such as stronger anti-hypertensives and an

emphasis on low-salt diets, may have driven these changes

development of acute reperfusion therapy appears to have gradually improved

functional outcomes at discharge for patients with ischemic strokes

Prof Hui Chen, Science. Copyright: UTS. 32

33
 Thrombosis with thrombocytopenia syndrome (TTS)
• TTS is a potentially life-threatening condition associated with adenoviral-vectored COVID-19
vaccination.
• Vaxzevria (AstraZeneca)
• Janssen/Johnson & Johnson
• TTS causes blood clotting (thrombosis) and low blood platelet counts (thrombocytopenia)
• mechanism not fully understand: antibodies mediated to complexes formed between the
adenovirus and platelet factor 4 (PF4)
• Occurs between 4 - 42 days after vaccination
• 1 in 100K after the first dose of AZ
• 1 in 500K after the second dose (no confirmed case in Oz)
• Risk factor: previous history of Science https://doi.org/10.1126/sciadv.abl8213 (2021)
 heparin induced thrombocytopenia (HIT) Blood https://doi.org/10.1182/blood.2021013231 (2021)

 central venous sinus thrombosis (CVST)

 idiopathic splanchnic (mesenteric, portal, splenic) vein thrombosis
 antiphospholipid syndrome with thrombosis.

Prof Hui Chen, Science. Copyright: UTS. 34

 Thrombosis with thrombocytopenia syndrome (TTS)
• Symptoms
Cerebral venous sinus • Headache is a common adverse event following AstraZeneca, and usually subsides
thrombosis (CVST) blood 48
• Diagnosis: within hours.
tests and CT scans.
• Headaches related to a CVST diagnosis have been described as starting any time
following AstraZeneca, and may initially respond to simple analgesia (e.g. paracetamol
or ibuprofen). What makes them different to the common, expected headache is that
they are persistent beyond 48 hours or appear later than 48 hours after vaccination,
and they may progress to have some unusual features, such as:
o Signs or symptoms of raised intracranial pressure (e.g. headache worse when
supine or associated with nausea and vomiting)
o Neurological deficit (e.g. blurred vision, dysarthria, altered mental status, seizures).
Abdominal • Variable presentation and can be asymptomatic.
(splanchnic) circulation • Abdominal pain is the most common symptom. Accompanying symptoms may include
thrombosis gastrointestinal bleeding, nausea, vomiting, anorexia, diarrhoea or constipation, fever.
DVT • Lower limb pain, redness or swelling
Pulmonary embolism • Sudden onset chest pain, shortness of breath
Arterial ischaemia • Limb coldness or pallor, signs/symptoms of myocardial ischemia or stroke
Thrombocytopenia • Petechiae, purpura, acute onset bleeding (e.g. nose, gums).
35
Prof Hui Chen, Science. Copyright: UTS.
Thrombosis with thrombocytopenia syndrome (TTS)

Clinical case

Mr Bradly is a 56 year old man who presents to his GP with a headache for 24 hours.
He has a past history of bilateral tension headaches, but this headache is left-sided.
It is not alleviated by paracetamol. He has no other associated symptoms. His
neurological examination and blood pressure are normal.
Mr B had his first dose of AstraZeneca 5 days ago.

Prof Hui Chen, Science. Copyright: UTS. 36

Thrombosis with thrombocytopenia syndrome (TTS)

Symptoms: change of headache pattern

Diagnosis: blood tests and imaging scans.

• Full blood count – looking for thrombocytopenia (platelets < 150x109/L, noting that the platelet count can
initially be normal or fall from a higher baseline
• D-dimer – usually raised ≥5 X the upper limit of normal (ULN).
• urgent non-contrast CT brain with contrast enhanced cerebral venography or MRI/MRI venography
• Further haematology investigations should be arranged in consultation with a haematologist and include ELISA
testing for anti-PF4 antibodies. If ELISA is positive, further functional antibody tests should be arranged.

Management

• If TTS is confirmed, management is with a non-heparin anticoagulant and/or intravenous immunoglobulin.

37
Prof Hui Chen, Science. Copyright: UTS.
 Thrombosis with thrombocytopenia syndrome (TTS)
What about Pfizer/BNT162b2 mRNA vaccine?
Myocardial Infarction, Stroke, and Pulmonary Embolism in people aged 75 years or older in a
French population Jabagi et al. JAMA. 2022;327(1):80-82. doi:10.1001/jama.2021.21699

• admitted between 15 December, 2020 – 30 April, 2021

• relative incidence: no increase after 14 days after vaccine
• myocardial infarction first dose 0.97, second dose 1.04
• ischemic stroke first dose 0.90, second dose 0.92
• hemorrhagic stroke first dose 0.90, second dose 0.97
• pulmonary embolism first dose 0.85, second dose 1.10
Israeli and US studies reported that persons receiving the BNT162b2 vaccine were not at
increased risk of myocardial infarction, pulmonary embolism, or cerebrovascular events in the 42
days and 21 days following vaccination.
Prof Hui Chen, Science. Copyright: UTS. 38
 Neurological complications
• neurologic complications developing within 28 days after
• receiving the first dose of the AstraZeneca vaccine (n = 20,417,752) or the Pfizer/BNT (n =
12,134,782)
• tested positive for SARS-CoV-2 (n = 2,005,280; 91% unvaccinated at the time of a positive
test).

• increased risk of
• Guillain–Barre syndrome (incidence rate ratio [IRR], 2.90) and Bell’s palsy (IRR, 1.29) at 15 to
21 days after ChAdOx1nCoV-19 vaccination,
• haemorrhagic stroke (IRR, 1.38) at 15 to 21 days after BNT162b2 vaccination.
• all neurologic outcomes in the 28 days after a positive SARS-CoV-2 test (IRR, 5.25): acute
CNS demyelinating events, encephalitis, meningitis and myelitis, Guillain–Barre syndrome,
Bell’s palsy, Myasthenic disorder, hemorrhagic stroke, subarachnoid haemorrhage

Nat Med. 2021;27(12):2144-2153 Prof Hui Chen, Science. Copyright: UTS. 39

Traumatic Brain Injury

Prof Hui Chen, Science. Copyright: UTS. 40

Prof Hui Chen, Science. Copyright: UTS. 41
 Traumatic Brain Injury

• Primary injuries: due to impact

– Focal (contusion or laceration)
– Diffuse (concussion or diffuse axonal injury)
– Hematoma
• Secondary injuries resulting from complicating processes:
 increased intracranial pressure
 ischemia
 edema
 infection

Prof Hui Chen, Science. Copyright: UTS. 42

 Primary Injury
• Concussion – momentary loss of brain function with or without loss of consciousness.
Recovery 24 hours. Symptoms (headaches, insomnia, poor concentration and memory) may
last for months.
• Contusion – bruise to cortical surface of the brain. Can cause permanent damage to brain
as bruised necrotic tissue is phagocytized by macrophages leading to scarring
• Diffuse Axonal injury – diffuse microscopic damage to axons in the cerebral
hemispheres, corpus callosum and brain stem. Lesions results from stretch or tear of
nerve cell within white matter. Responsible for most cases of post traumatic dementia

• The hematoma may be tiny, with just a dot of blood or it can be large and cause significant
swelling and compression of the brain
• Unconsciousness brief lucid period of consciousness  rapid progression to unconsciousness
• Prognosis is excellent if removed before loss of consciousness occurs otherwise death may
result
Prof Hui Chen, Science. Copyright: UTS. 43
 Chronic traumatic encephalopathy (CTE)

• Substantial exposure to repetitive head injury

• Core clinical features
• Cognitive impairment – episodic memory and executive dysfunction
• Behavorial impairment- explosiveness, impulsivity, rage, violent outbursts, emotional
lability
• Post-mortem diagnosis
• A tau-pathology characterised by the deposition of hyper-phosphorylated tau (p-tau) as
neurofibrillary tangles, astrocytic tangles, and neurites in striking clusters around small
blood vessels of the cortex. Severely affected cases show p-tau pathology throughout
the brain.
• May have features of other neurodegenerative disease
• No disease modifying treatment

Prof Hui Chen, Science. Copyright: UTS. 44

 Treatment
• Clinical management options are not adequate to deal with the range of consequences
• Mild brain injury cases are generally not treated other than rest and over-the-counter
pain relievers to treat a headache
• Severe TBI cases are managed in the intensive care unit, focusing on oxygen supply,
managing blood pressure to maintain blood supply, coagulopathy and haemorrhagic
progression, and preventing any further injury to the head or neck
• surgery: removing clotted blood, repairing skull
fractures, stop bleeding in the brain, opening a
window in the skull to provide more room for
swollen tissues
• rehabilitation

The Lancet Neurology Commission 2017 Volume 16, ISSUE 12

Prof Hui Chen, Science. Copyright: UTS. 45