Stroke slides Flashcards
Epidemiology
- Stroke is a leading cause of death and disability worldwide.
- Affects 13.7 million people globally per year and is the second
leading cause of death, with 5.5 million deaths per year - Elevated incidences in the southern USA (‘Stroke belt’)
Types
There are two main causes of stroke: a blocked artery (ischemic
stroke) or leaking/bursting of a blood vessel (hemorrhagic stroke).
Ischaemic stroke is defined as infarction of the brain, spinal cord or
retina and represents ~71% of all strokes globally
Ischemic Stroke
In the 1970s, pioneering experiments
identified that much of the initial
clinical deficit in patients with stroke is
due to a hibernating, hypoperfused,
electrically non-functional part of the
brain termed the ischemic penumbra.
* This region progressively converts to
irreversibly injured tissue over time
(known as the ischemic core), but at a
rate that varies considerably between
individuals.
* However, with rapid reperfusion, this
penumbral brain can be salvaged, and
it can recover normal function.
* This rationale for the reperfusion
therapies that have transformed
outcomes for patients with ischemic
stroke since the first positive trial of
stroke thrombolysis (1995)
Transient
Ischemic Attack
- Transient ischemic attack (TIA; mini stroke)
occurs when blood flow is temporarily
interrupted and resolves before causing
permanent injury. - Approximately 20 to 25% of ischemic
strokes are heralded by transient ischemic
symptoms. - The pathogenesis is the same as
ischaemic stroke, and the investigations
for the underlying cause and the
secondary prevention strategies are
identical. - Acute MRI is advantageous over CT to
confirm the probable ischemic nature and
to identify the etiology in TIA patients
(Förster et. al. 2012). - Immediate diffusion-weighted imaging
assessed with magnetic resonance
imaging (MRI) is the current preferred test
for patients with a suspected TIA
Cerebral
Vasculature
- Two common carotid arteries on each side of
the neck, which branch into ICA and ECA
(face and neck). - ICA carries 75% of blood to the brain.
- ICA splits to ACA and MCA.
- PCA branches off from the basilar artery and
irrigates the occipital lobe.
Signs of Stroke
Numbness/weakness in face, arm or leg
Confusion or trouble speaking or understanding speech
Trouble seeing in one or both eyes
Trouble walking, dizziness, or problems balancing
severe headache
Risk Factors
- Stress
- Trauma
- Infections
- Drugs
- Sleep apnea
Cellular Effects of Ischemic Stroke
(A) Excitotoxicity in ischemic stroke, in which
excessive glutamate are released and both
synaptic and extra-synaptic NMDARs are
involved.
(B) Cell death signaling pathways, which mainly
involves autophagy, apoptosis and necroptosis
in ischemic stroke.
(C) Neuroinflammation and BBB breakdown in
ischemic stroke. Here we’ve presented the
participation of various immune cells and
chemokines and cytokines released, which thus
contribute to blood-brain barrier breakdown.
(D) Oxidative stress, which is mainly characterized
by reactive oxygen species (ROS) production
and mitochondrial dysfunction that involves
Ca 2+ influx into mitochondria and mitochondrial
permeability transition pore (MPTP) opening
and cytochrome c release, thereby impairing
cellular respiration.
Excitotoxicity
influx of Ca2+ through NMDA receptors
NMDA promotes neuronal death or survival depending on downstream
neuronal death: interactions with FluN2B subunit of NMDAR forms signaling death unit with PSD95 and nNOS -> Ca2+ dependent production of superoxide anion (O2-) which combines with NO to form ONOO- this an interrupt protein S-S interactions.
can be disrupted with NR2B9c
Anoxic
Depolarization
Definition: An acute neuronal event involving the
loss of cell membrane potentials caused by
energy failure secondary to oxygen deprivation.
* A disproportionate amount of energy in the brain
is required to maintain Na + gradient, which is
largely governed by the Na + / K + -ATPase pump.
When energy failure occurs, neuronal ischemic
injury begins with cessation of Na + / K + -ATPase
activity and consequent dysregulation of ionic
balance. This leads to dramatic influx of Na + , Cl –
and Ca 2+ , as well as an efflux of K + , ultimately
leading to widespread anoxic depolarizatio
Role of
inflammation
- Physiological signaling between neurons and
microglia is essential for maintaining neuronal
health and function. - In health, microglia maintain a quiescent
immunophenotype, which facilitates neuronal
homeostasis and survival by releasing trophic
factors. Homeostatic microglia. - During ischemia, microglia are activated
(ameboid and pro-inflammatory). - The release of various damage-associated
molecular patterns (DAMPs) from neighboring
neurons activates microglial Toll-like receptors
(TLRs), driving a proinflammatory
immunophenotype. In turn, microglia
upregulate production of reactive oxygen and
nitrogen species (ROS and RNS). - Furthermore, breakdown of blood brain barrier
(BBB) in the penumbra brings in additional
peripheral immune cells leading to an over-the-
board immune response (cytokine storm).
Therapeutic strategies
(A) Therapeutic hypothermia: inhibits the depletion of ATP, thus
delays Na + /K + pump failure. This prevents downstream anoxic
depolarization and excitotoxicity. That in turn mitigates
supraphysiological accumulation of calcium, and therefore
reduces mitochondrial dysfunction, apoptosis and the production
of reactive oxygen species (ROS) and reactive nitrogen species
(RNS). Also prevents necrotic death. Most potent pre-clinically.
(B) Perfusates: Whole-blood reperfusion can form microthrombi,
impeding vascular flow. Instead, acellular and non-coagulative
perfusates could exert their beneficial effects by ensuring robust
delivery of oxygen and therapeutics.
(C) Rational polytherapy: Use of independent pharmacological
agents that can simultaneously target multiple deleterious
mechanisms known to cause ischemia-induced cellular injury and
death. For e.g., antioxidants, antiapoptotic agents and
mitochondrial permeability transition pore (mPTP) blockers could
act synergistically to promote mitochondrial health and function.
These, together with anti-excitotoxicity agents, sodium channel
blockers, inhibitors of postsynaptic death signaling complex, and
calcium chelators could limit the extent of excitotoxicity during
ischaemia injury.
DOI: 10.1038/s41583-021-00488-y
