Cerebral circulation
Two pairs of arteries feed the brain - the internal carotids in front, the vertebrals behind - and they join at the base of the brain in a ring, the circle of Willis, that can reroute flow between them; beyond that ring each branch waters its own patch of brain, with only thin surface anastomoses between territories and none at all for the deep perforators, so where the blockage sits tells you which part of the patient stops working.
What it normally does
The brain has two inflows. The internal carotids (anterior circulation) each give off the ophthalmic artery to the eye, then divide into the anterior cerebral artery (ACA) and the middle cerebral artery (MCA). The vertebral arteries run up through the transverse foramina of the cervical vertebrae, join to form the basilar artery (posterior circulation), and supply the brainstem and cerebellum through their own branches (pontine perforators, PICA, AICA and the superior cerebellar arteries) and the thalami and occipital lobes through the posterior cerebral arteries (PCA). The circle of Willis joins the two systems: the anterior communicating artery bridges the two ACAs, and a posterior communicating artery on each side runs from the internal carotid back to the PCA. A complete, well-formed ring is the exception rather than the rule - anatomical series put it at roughly a fifth to a half of people, with hypoplastic or absent communicating segments in the rest. Every one of those junctions is a branch point where the vessel wall is structurally weakest.
a complete ring lets one carotid feed the whole brain, so a carotid occlusion is silent in one person and devastating in the next; a clot from the heart or a carotid plaque can lodge in the ophthalmic artery or its central retinal branch and blind one eye for minutes (amaurosis fugax) as a warning shot before the brain infarct; and berry aneurysms grow at those junctions, which is why aneurysmal subarachnoid haemorrhage arises from the circle of Willis and its proximal branches rather than from cortical vessels.
Beyond the ring each artery waters a fixed map. The cortical branches are functional end arteries: they are linked only by thin leptomeningeal (pial) anastomoses over the surface, enough to keep tissue alive for a while but not enough to prevent infarction. The deep perforators have no anastomoses at all and are true end arteries. The ACA runs over the corpus callosum and supplies the medial surface of the hemisphere - the leg and foot part of the motor and sensory strip. The MCA fans out over the lateral convexity: face and arm on the strip, the language areas of the dominant hemisphere (usually left), the attention networks of the non-dominant hemisphere, and the optic radiation passing beneath. The PCA supplies the occipital cortex and the thalamus. The brainstem gets tiny perforators straight off the basilar, and there the long tracts (already crossed or about to cross) sit millimetres from cranial nerve nuclei that have not crossed.
a stroke is read backwards: face and arm weak with the leg spared points to the MCA, leg weak with the arm spared points to the ACA, a hemianopia with reasonable strength points to the PCA, and weakness on one side of the body with a cranial nerve palsy on the other side (crossed signs) can only be brainstem; and because the surface anastomoses are real but marginal, how good someone's leptomeningeal collaterals are decides how long their penumbra survives.
The brain is about 2 percent of body weight, takes about 15 percent of the cardiac output and consumes about 20 percent of the body's oxygen, at roughly 50 mL of blood per 100 g of brain each minute. It stores no oxygen and only a trivial amount of glucose as astrocytic glycogen. Small arteries constrict when pressure rises and dilate when it falls, holding flow steady across a mean arterial pressure of roughly 60 to 150 mmHg (autoregulation - the classic figures; the plateau is narrower and more variable between individuals than the textbook curve suggests); carbon dioxide is the most potent physiological cerebral vasodilator. Below about 20 mL/100 g/min neurons stop firing but stay alive - this is the penumbra, kept going by collateral trickle. Below about 10 mL/100 g/min they die. Chronic hypertension shifts the whole autoregulatory range upward.
symptoms appear the moment flow falls, minutes before tissue is lost, so the penumbra is what thrombolysis and thrombectomy are trying to save - an often-quoted estimate is around 2 million neurons a minute while the artery stays shut; blowing off carbon dioxide by hyperventilating constricts cerebral vessels and briefly drops intracranial pressure (a short-term rescue only, since the same vasoconstriction reduces perfusion); and in a chronically hypertensive brain a 'normal' blood pressure can already be below the autoregulatory floor.
Two sets of vessels have no rescue supply. The deep perforators - lenticulostriate branches off the MCA stem, thalamoperforators off the PCA and basilar tip, pontine branches off the basilar - come off large high-pressure arteries at right angles, are only a few hundred micrometres wide (well under a millimetre), and end in the internal capsule, basal ganglia, thalamus and pons with no collaterals at all. Years of hypertension and diabetes thicken and hyalinise their walls (lipohyalinosis) and weaken them (Charcot-Bouchard microaneurysms). Separately, the far ends of the ACA, MCA and PCA trees meet in border (watershed) zones - the parasagittal strip between ACA and MCA, the parieto-occipital region between MCA and PCA, and the deep white matter internal border zone - which sit at the end of the plumbing at the lowest perfusion pressure in the brain.
the same hypertensive small vessels produce two opposite lesions - occlude and you get a lacunar infarct, rupture and you get a deep intracerebral haemorrhage in the putamen, thalamus, pons or cerebellum; and because border zones are watered last, a fall in perfusion pressure kills them first, giving a pattern of damage that fits no named artery.
What goes wrong
- Middle cerebral artery territory infarct (embolic or thrombotic)← from “Beyond the ring each artery waters a fixed map…”
A clot from the left atrium in atrial fibrillation, from a carotid plaque, or from the aortic arch travels up the internal carotid and wedges in the MCA - the largest branch and the direct continuation of the internal carotid, so it catches most emboli. Flow stops in one hemisphere's lateral convexity. The core dies within minutes; the surrounding penumbra survives on leptomeningeal collateral flow over the surface from the ACA and PCA and dies over hours unless the artery reopens. If the whole MCA territory infarcts, dead tissue swells, and oedema peaks at day 2 to 5 and can push the brain sideways.
Face plus arm worse than leg, plus a cortical sign (aphasia, neglect, hemianopia) equals MCA. Eyes look towards a hemispheric lesion, away from a pontine one. Non-contrast CT is done first to exclude blood, not to see the infarct - early ischaemia is often invisible. Malignant MCA oedema peaks day 2 to 5 and decompressive hemicraniectomy is considered, mainly in patients under about 60. Stroke is one of Australia's leading causes of death and of adult disability; it strikes Aboriginal and Torres Strait Islander Australians at roughly twice the rate and one to two decades earlier.
You would find: Sudden weakness and sensory loss of the face and arm more than the leg on the opposite side, the eyes deviated towards the side of the lesion, and a homonymous hemianopia. Add loss of speech (dominant, usually left hemisphere) or dense neglect of the left side with denial of any deficit (non-dominant). Onset is instantaneous - the patient can often name the minute. A drop in conscious level after the second day means malignant oedema, not a second stroke.
- Posterior circulation stroke (vertebrobasilar)← from “The brain has two inflows. The internal caroti…”
Atherothrombosis of the vertebral or basilar artery, embolus to the basilar tip, or a vertebral artery dissection after neck trauma or manipulation in a younger patient. PCA occlusion infarcts occipital cortex and thalamus. Occlusion of a basilar perforator infarcts a slice of brainstem: the long motor tract on one side (signs on the opposite side of the body) plus a cranial nerve nucleus on the same side (signs on that side of the face). Occlusion of the basilar trunk itself infarcts the ventral pons.
Posterior circulation strokes are the ones missed - filed as vertigo, migraine or intoxication. Any acute vertigo with a truncal ataxia too severe to walk, or with any other brainstem sign, is a stroke until proven otherwise, and CT is nearly blind in the posterior fossa (MRI with diffusion imaging is the test). Lateral medullary (Wallenberg) syndrome from the vertebral artery or PICA: same-side Horner and facial pain and temperature loss, opposite-side body pain and temperature loss, hoarseness and severe dysphagia.
You would find: Homonymous hemianopia with the central vision preserved (macular sparing, attributed to collateral supply to the occipital pole from distal MCA branches). Or vertigo, diplopia, dysarthria, dysphagia, ataxia and crossed sensory loss - and, unlike a peripheral vertigo, a normal head impulse test, direction-changing nystagmus, or skew deviation (the HINTS pattern, valid only in continuous vertigo with nystagmus and only in trained hands). Basilar occlusion gives fluctuating consciousness then quadriparesis with preserved awareness and vertical eye movements only (locked-in). Sudden neck or occipital pain in a young person with brainstem signs suggests dissection.
- Lacunar infarct (small vessel disease)← from “Two sets of vessels have no rescue supply. The…”
Long-standing hypertension and diabetes thicken and hyalinise the wall of a single deep perforator until it occludes. Because that vessel is a true end artery with no collateral, the small volume of tissue it feeds dies completely - a cavity a few millimetres up to about 15 mm across in the internal capsule, corona radiata, thalamus, basal ganglia or pons. The tracts are packed so tightly there that a tiny infarct causes a large deficit, but the cortex is untouched.
Equal face, arm and leg weakness with no cortical sign means a deep perforator, not a cortex-sized artery. Same vessels, opposite failure mode: rupture instead of occlusion gives hypertensive intracerebral haemorrhage in putamen, thalamus, pons or cerebellum - and a cerebellar haematoma over about 3 cm, or any cerebellar bleed with brainstem compression, deteriorating consciousness or hydrocephalus, needs urgent neurosurgical referral rather than observation. Accumulated lacunes and white matter disease produce vascular cognitive impairment and a shuffling, unsteady gait. This is the stroke of untreated hypertension, and it falls hardest on communities with the least access to primary care.
You would find: A full-strength deficit with no cortical signs at all: no aphasia, no neglect, no visual field loss, no change in consciousness. Pure motor hemiparesis affecting face, arm and leg equally (internal capsule or pons); or pure sensory loss of the whole side (thalamus); or ataxic hemiparesis; or dysarthria with a clumsy hand. Blood pressure is usually high and has been for years.
- Watershed (border zone) infarction← from “The brain is about 2 percent of body weight, t…”
Perfusion pressure falls below the autoregulatory floor - cardiac arrest, major haemorrhage, septic or cardiogenic shock, cardiac surgery, or a tight carotid stenosis that already leaves the far fields running on empty. The last-perfused tissue at the ends of the arterial trees dies first. The ACA/MCA cortical border zone runs down the parasagittal strip that serves shoulder and hip; the MCA/PCA border zone covers the parieto-occipital cortex; the internal border zone lies in deep white matter and infarcts as a string of beads.
A deficit that fits no single artery, after a documented drop in blood pressure, is watershed. It is part of why blood pressure is generally left alone rather than lowered in the first days after an ischaemic stroke (permissive hypertension) - the main concern is collapsing the penumbra, and border zones fail for the same reason. Look for carotid disease and image the carotids: for a symptomatic tight stenosis, carotid endarterectomy done early (best within two weeks of the event) adds substantially to outcome, but it is done in addition to best medical therapy - antiplatelet, statin, blood pressure and smoking cessation - never instead of it.
You would find: Weakness of both shoulders and hips with the face and hands working - the patient can grip and smile but cannot lift the arms (man in a barrel). Bilateral posterior border zone infarction gives cortical blindness with pupils that still react, and sometimes denial of the blindness (Anton syndrome) or an inability to reach for or attend to more than one object at a time (Balint syndrome). The history is a blood pressure event, not a sudden focal onset. In severe carotid disease, transient jerking of the opposite arm on standing (limb-shaking TIA) says the same thing.
- Aneurysmal subarachnoid haemorrhage← from “The brain has two inflows. The internal caroti…”
A saccular (berry) aneurysm forms at a branch point of the circle of Willis where the tunica media is thin or defective and the internal elastic lamina degenerates under haemodynamic stress - anterior communicating artery, posterior communicating artery, MCA bifurcation, basilar tip. Hypertension, smoking, polycystic kidney disease and connective tissue disorders accelerate it. When it ruptures, arterial blood floods the subarachnoid space at systemic pressure. Intracranial pressure spikes, cerebral perfusion pressure collapses for seconds to minutes, and blood breakdown products then irritate the arteries of the ring, which constrict days later.
Sudden severe headache peaking in seconds is subarachnoid haemorrhage until CT (and if needed LP) says otherwise - a normal neurological examination does not exclude it. Definitive treatment is occluding the aneurysm early by endovascular coiling or surgical clipping. Nimodipine is the only drug shown to improve outcome. Roughly a third die and a third are left dependent, and it hits at a younger age than ischaemic stroke.
You would find: Thunderclap headache - worst ever, maximal within seconds, often occipital, with vomiting, neck stiffness and photophobia, sometimes brief collapse or a seizure. A posterior communicating aneurysm can announce itself first by pressing on the third nerve: ptosis, the eye down and out, and a wide unreactive pupil. Non-contrast CT within 6 hours of onset, on a modern scanner and expertly read, picks up almost all of them; after that, lumbar puncture for xanthochromia (or CT angiography, depending on local pathway). Rebleeding is most likely in the first 24 to 48 hours; delayed cerebral ischaemia arrives around day 4 to 14.
What we give, and how it works
Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.
- Binds
- Plasminogen bound to fibrin within the thrombus; tenecteplase is engineered to be more fibrin-selective, resist plasminogen activator inhibitor-1 and be given as a single bolus rather than an infusion.
- Which does
- It converts plasminogen to plasmin on the clot surface. Plasmin digests the fibrin strands holding the thrombus together and the clot breaks up.
- So you see
- The artery reopens, the penumbra is reperfused, and the deficit can improve within minutes to hours - the earlier it is given, the more brain survives.
- And the same mechanism causes
- Plasmin cannot tell your target clot from the haemostatic plugs holding every other vessel shut, so it lyses those too: symptomatic intracranial haemorrhage in a few percent, and bleeding from any recent puncture, ulcer or surgical site. Plasmin also cleaves kininogen and activates the contact system, generating bradykinin, which is why orolingual angioedema occurs - and why it is much more likely in a patient already on an ACE inhibitor, since that drug blocks bradykinin breakdown.
- Handling
- Plasma half-life is only a few minutes for alteplase and around 20 minutes for tenecteplase, so the fibrinolytic state is short - but the bleeding risk it creates outlasts it.
Catches people out: The clock starts when the patient was last seen well, not when they woke up - though selected wake-up and unknown-onset strokes can still be treated when advanced imaging (diffusion-FLAIR mismatch or perfusion mismatch) shows salvageable tissue. Blood pressure must be brought under about 185/110 mmHg first, and there is no thrombolysis for a haemorrhage - so the CT comes before the drug, always. In large vessel occlusion the definitive treatment is not a drug at all: it is mechanical thrombectomy, pulling the clot out with a catheter, effective up to 24 hours in patients selected by perfusion imaging. That service exists in comprehensive stroke centres, which is why remote and regional Australians - and Aboriginal and Torres Strait Islander people disproportionately - depend on telestroke and retrieval to get it. Doses and eligibility criteria come from the local stroke protocol, not from memory.
- Binds
- Aspirin irreversibly acetylates cyclo-oxygenase-1 inside the platelet; clopidogrel (an irreversible thienopyridine prodrug) and ticagrelor (a directly acting, reversible agent) block the P2Y12 ADP receptor on the platelet surface.
- Which does
- Aspirin permanently disables COX-1, so that platelet can make no more thromboxane A2; P2Y12 blockade stops ADP released by activated platelets recruiting more of them. Either way glycoprotein IIb/IIIa activation falls and platelets aggregate poorly.
- So you see
- Platelet aggregation on damaged endothelium falls, and with it the rate of recurrent ischaemic stroke and myocardial infarction.
- And the same mechanism causes
- Aspirin's COX-1 blockade is not confined to platelets: the same block in the gastric mucosa removes the prostaglandins that maintain mucus, bicarbonate and mucosal blood flow, so ulceration and gastrointestinal bleeding follow, and because the block is irreversible the bleeding tendency persists for days after the last dose. The P2Y12 agents do not cause ulcers this way, but by blocking platelet aggregation they make any existing lesion bleed and heal poorly. All of them raise the risk of intracranial haemorrhage for the same reason they prevent thrombosis.
- Handling
- The platelet has no nucleus and cannot make new COX-1, so a single aspirin exposure lasts that platelet's whole 7 to 10 day life and the effect wears off only as new platelets are made; clopidogrel behaves the same way, while ticagrelor binds reversibly and its effect fades over a few days as the drug is cleared.
Catches people out: Antiplatelets are the smaller half of the answer in small vessel disease. What actually stops the next lacune is treating the blood pressure, the diabetes and the smoking, and clopidogrel is a prodrug needing CYP2C19 activation - loss-of-function variants are common in East Asian populations and leave some patients effectively untreated. Never start an antiplatelet before imaging has excluded haemorrhage.
- Binds
- Apixaban and rivaroxaban bind the active site of factor Xa directly; dabigatran binds thrombin; warfarin inhibits vitamin K epoxide reductase in the hepatocyte.
- Which does
- Blocking factor Xa stops prothrombin being converted to thrombin. Less thrombin means less fibrin and less platelet activation, so a stagnant-blood clot cannot organise. Warfarin instead starves the liver of the reduced vitamin K needed to carboxylate factors II, VII, IX and X (and proteins C and S), so it makes non-functional factors over days.
- So you see
- Clot formation in the fibrillating, poorly emptying left atrium is prevented, cutting stroke risk by roughly two thirds compared with no treatment - far more than any antiplatelet achieves in atrial fibrillation.
- And the same mechanism causes
- The same impaired clot formation causes bleeding wherever a vessel is breached - gastrointestinal bleeding most often, intracranial haemorrhage most dangerously. Every anticoagulation decision is that trade: the stroke you prevent against the bleed you cause. Reversal follows the mechanism too - idarucizumab for dabigatran; vitamin K plus prothrombin complex concentrate (Prothrombinex-VF) for warfarin; and for the factor Xa inhibitors, andexanet alfa where it is available, with prothrombin complex concentrate the usual option in most Australian hospitals.
- Handling
- Direct agents work within hours and wear off within a day or two in normal renal function, which is what makes them manageable around procedures; warfarin takes days in both directions and interacts with diet and dozens of drugs, needing INR monitoring.
Catches people out: Direct oral anticoagulants are wrong for two groups who still need warfarin: mechanical heart valves, and moderate to severe rheumatic mitral stenosis. That second exception matters in Australia, where acute rheumatic fever and rheumatic heart disease remain far more common in Aboriginal and Torres Strait Islander communities and in remote northern Australia, and produce atrial fibrillation and stroke in young adults. Dabigatran is largely cleared by the kidney, so falling renal function silently raises the level; all the direct agents need dose checking against renal function, age and weight.
- Binds
- The dihydropyridine binding site on L-type voltage-gated calcium channels in vascular smooth muscle.
- Which does
- Blocking the channel reduces calcium entry, so less calcium binds calmodulin, myosin light chain kinase is less active, and the muscle cell cannot maintain contraction.
- So you see
- Cerebral arterioles relax and distal perfusion is better preserved through the delayed ischaemia window from about day 4 to day 14, lowering the rate of delayed ischaemic deficits and improving the chance of survival free of disability.
- And the same mechanism causes
- The same smooth muscle relaxation in systemic arteries drops blood pressure - and in a brain that has just lost its autoregulation, hypotension is precisely what you were trying to avoid, so blood pressure is monitored closely and, if it falls, the usual response is to reduce the individual dose and give it more frequently rather than stop the drug. Flushing, headache and ankle oedema come from the same arteriolar dilatation.
- Handling
- Heavy first-pass metabolism by CYP3A4, so grapefruit juice and azole antifungals raise the level, while strong inducers such as carbamazepine, phenytoin and rifampicin drop it enough that co-administration is avoided.
Catches people out: It is given by mouth or nasogastric tube. The oral preparation must never be injected: intravenous or intra-arterial administration of it has caused profound hypotension, cardiac arrest and death. And be honest about what it does: it improves neurological outcome and reduces delayed cerebral ischaemia, but angiographic vasospasm itself barely changes - some of the benefit is probably protection of the microcirculation and of neurons rather than opening large vessels. It does not treat the aneurysm; only clipping or coiling does that.
A third nerve palsy is read by the pupil, and the anatomy tells you why. The parasympathetic fibres run superficially in the nerve, the motor fibres deeper. A posterior communicating artery aneurysm compresses the nerve from outside, so the pupil goes early: ptosis, the eye down and out, and a wide unreactive pupil - that is a surgical emergency, image the vessels now. Diabetic or hypertensive microvascular disease infarcts the core and tends to spare the surface, so the eye is down and out with a normal reactive pupil (still worth imaging if there is pain, incomplete recovery or any doubt). Same nerve, opposite urgency. The other rule worth carrying: sudden headache that peaks within seconds gets an immediate non-contrast CT, and if that is normal and the CT was done more than 6 hours after onset, the pathway continues - lumbar puncture for xanthochromia, timed at least 12 hours from headache onset so the pigment has had time to form, or CT angiography depending on local practice - before you can call it a migraine.
Now test whether it stuck
Reading this through is not the same as being able to reconstruct it. Every question in the bank is free, with a full debrief on each option.