Stroke Pathophysiology

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Learning objectives

  • How does stroke cause cell damage
  • What does it do and clinical effects of damage
  • What is blood supply and risk of stroke

Cell Death in Stroke

If a sufficient injury occurs then cell death proceeds through a variety of steps. Cell death in stroke is due to one of two causes, cytotoxic cell death and programmed cell death (apoptosis). The fundamental difference is that the first elicits an inflammatory response whereas the second doesn't. The stages of cytotoxic cell death are shown below. Haemorrhagic strokes are often a progressive event with ongoing initial damage. Brain perfusion can also be impaired due to damaged autoregulatory processes and then cerebral perfusion becomes very much dependent on systemic blood pressure - which can have consequences if this is too high or too low.

Stages of Hypoxic Injury and Death

A lack of perfusion soon leads to a failure of cellular metabolism generating insufficient ATP. This leads to a failure of membrane pump activity, failure to depolarise. Glutamate release increases cellular excitability and ATP demand and causes excitatoxicity [Castillo J et al. 1996] . Glutamate neurostimulation leads to the opening of calcium channels associated with N-methy1-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. Persistent membrane depolarisation causes influx of calcium, sodium, and chloride ions and efflux of potassium ions. A rise in intracellular calcium activates proteases, lipases and endonucleases with the release of cytokines and causes further cellular damage. Mitochondrial damage can lead to apoptosis and iNOS (inducible Nitric oxide synthase) release and the formation of free radicals. There is a breakdown of phospholipase and ultimately cytotoxic cell death. Blood-brain barrier integrity is reduced [Brown RC et al. 2002]. The additional paradox is that with the abundance of free radicals and other chemical species, reperfusion of these areas is preferable but is also not without its potential downside [Kuroda et al 1997].

Macroscopic changes post infarct

  • These develop with time and include
  • Cytotoxic and vasogenic oedema initially
  • Liquefactive necrosis with time
  • CT after several days shows radiodensity equal to CSF
  • CT will show loss of volume and 'ex vacuo dilatation'

Stroke Size and Shape

  • Territorial Infarcts: Wedge shaped infarction to the cortex following occlusion of a branch of Major cerebral artery
  • Subcortical infarction as vessel reperfuses or good anastomosis
  • Lacunar infarcts due to occluded deep penetrating vessel are small and circular
  • Border-zone: Infarcted area between 2 large vessels when blood pressure drops
  • Across arterial zones: Venous infarction, vasculitis

Haemorrhage

As mentioned above the rigid box principle applies very much to haemorrhage. The Monro-Kellie hypothesis states that the sum of volumes of brain, CSF, and intracranial blood is constant. The implication being that any added volume to any of these will be additional and lead to a rise in Intracranial pressure. This hypothesis has substantial theoretical implications in increased intracranial pressure and in decreased CSF volume which may help to balance any other volume. There are some mechanisms by which the brain can compensate. These include shunting away CSF from the brain to spinal subarachnoid space 'cisterns' and the dura can increase absorption. Changes in blood volume by vasodilation and vasoconstriction can control cerebral blood flow and maintain at a constant during variations in systemic BP. Cerebral veins are valveless and have little supporting tissue and are susceptible to compression. However at some point ICP will begin to rise inexorably and this will lead to pressure downwards onto the brainstem with coma and death. In terms of haemorrhage, the volume of 60 ml appears to be critical in terms of haematoma volume. However, there is much variability and older patients with reduced brain volume due to atrophy may well decompensate at a higher mass volume. Haemorrhage may also be surrounded by a degree of oedema which can exacerbate the situation.

Intracerebral Volume = Brain volume + CSF volume + Blood volume + Mass volume

  • CPP=MAP-ICP
  • CPP:70-100 mmHg
  • Normal ICP: 5 - 15 mmHg
  • Usual treatment goal ICP < 20 mmHg

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Cerebral oedema

Cerebral oedema increases brain volume. The most common form of oedema post-stroke is cytotoxic oedema and this is due to the breakdown of cell membrane function, an influx of ions and water into the cell. It may be seen in the brain post-stroke or global hypoperfusion e.g. cardiac arrest or with Reye's syndrome or some of the encephalopathies. Radiologically this shows as restricted diffusion on an MRI.

The other form of oedema is vasogenic oedema and is primarily due to a breakdown of the blood-brain barrier which allows normal plasma constituents to enter the CSF. It may be seen in later stages of cerebral ischaemia and stroke and PRES (will meet this later). This shows as enhancement with contrast on a CT/MRI. It is characteristic of certain tumours and inflammatory processes. It is often managed with steroids. A third cause is osmotic oedema which is due to reduced plasma osmolality as is seen with severe hyponatraemia. Water enters the more hypertonic cells with a resultant increase in cellular volume and oedema. Death can result from raised ICP. Management is to slowly increase plasma osmolality. Elderly patients with preexisting brain atrophy are often less vulnerable to pathological increases in brain volume as compared with young patients.

Rising ICP

ICP is only measured directly in patients who get to a neuro-critical ITU and this is a very small percentage, perhaps only really those who have required clot evacuation or aneurysmal surgery for SAH. Management is a balance between managing cerebral perfusion pressure and the intracranial pressure and ensuring there is adequate brain perfusion. There are five ways to decrease ICP.

  • Enhance venous drainage: Elevate head 30 degrees and ensure no neck constriction
  • Hyperosmolar therapy e.g. Mannitol
  • Hyperventilation - reduces carbon dioxide and causes vasoconstriction but is a short term strategy
  • CSF Drainage : Neurosurgical Procedure - External ventricular drainage
  • Decompression : Decompressive Hemicraniectomy which may be combined with haematoma evacuation. The bone flap can be saved for reimplantation later.

Avoid

  • Hypotension
  • Hypoxia
  • Hyponatraemia
  • Hypervolemia (avoid excess dextrose)
  • Hyperglycaemia (manage using sliding scale initially)
  • Hyperthermia (lower temp)
  • Hypermetabolism (treat seizures and agitation)

Herniation syndromes

  • Seen in the context of rising ICP in the comatose patient. These are all neurosurgical emergencies and demand rapid escalation.
  • Subfalcine: the brain is pushed under the falx separating right and left cortices. There may be compression and stroke involving the anterior cerebral artery with contralateral leg weakness. The lateral ventricles and brain midline will be distorted and shifted and can be seen on CT.
  • Transtentorial: A supratentorial mass or pressure gradient forces the uncus of the temporal lobe down beneath the tentorium 'tent' can result in an ipsilateral oculomotor paresis (dilated pupil, ptosis, down and out pupil) and compression of the posterior cerebral artery giving contralateral hemianopia. The shift forces the opposing cerebral peduncle against the edge of the tentorium causing contralateral hemiparesis to the peduncle. The indentation of the tentorium edge causes Kernohan's notch on the opposite cerebral peduncle. This is a false localising sign.
  • Transforaminal: the brainstem and cerebellar tonsils are forced down into the foramen magnum. Pressure on the medulla leads to apnoea and death