Strokes
Composing 100 billion neurons and a trillion ganglia packed into a measly 1.4kg mass of tissue, our brain houses our consciousness and is a vital organ not to be messed with (Sibony et al., 2005). Every 40 seconds, someone has a stroke. Every 3.5 minutes, someone dies from a stroke. Especially in Malaysia, stroke is the 3rd leading cause of death, causing almost 20000 deaths in 2019 (Tan & Venketasubramanian, 2022). But what is a stroke? Broadly speaking, a stroke happens when there is inadequate blood flow to a part of the brain. This can cause that part of the brain to lose its oxygen supply and eventually undergo necrosis (cell death), leading to stroke symptoms (Pourasgari & Mohamadkhani, 2020).
Types of strokes
There are 3 main types of strokes, ischemic strokes, hemorrhagic strokes, and transient ischemic attacks (TIA). Among the 3 main types, there are multiple subtypes, differentiated by their exact cause. Ischemic strokes happen when a blood vessel supplying the brain is blocked or narrowed and blood cannot flow through causing decreased perfusion. A TIA is similar to an ischemic stroke in the way that it is caused by an ischemic source, but it differs in a way such that the blockage is brief and there is no permanent damage. Hemorrhagic strokes on the other hand are caused when a blood vessel supplying the brain ruptures and blood starts to leak out. This causes the part of the brain supplied by the blood vessels to get less blood flow. Most strokes are ischemic strokes, around 87%, whereas the remaining 13% consist of hemorrhagic strokes (Tsao et al., 2022). Hemorrhagic strokes however cause significantly higher morbidity and mortality than do ischemic strokes, ie: worse outcomes (Dupont et al., 2010).
Brain circulation
In order to make sense of the pathophysiology and symptoms of strokes, it may be useful to understand the blood vessels in our brains first. The brain receives blood flow from two main arteries, the internal carotid arteries and the vertebral arteries. The diagram below is an inferior view of the brain, where the left side of the image represents the right brain and vice versa.
Starting from the bottom, we have the vertebral arteries which give off branches called the posterior inferior cerebellar arteries (PICA) as it ascends the brain. It also gives off branches in the middle that converge to form the anterior spinal artery. As it continues to ascend, the vertebral arteries fuse into the basilar artery. At the point of fusion, the vertebral artery also branches into the anterior inferior cerebral arteries (AICA). The first branch after the AICA is called the labyrinthine arteries. The basilar artery also branches into the pontine branches after the labyrinthine arteries. The superior cerebellar arteries are also part of the branches of the basilar artery. At the level of the brain stem, the basilar artery branches terminally into the posterior cerebral arteries. Along the posterior cerebral artery branches out the posterior communicating artery. Along its journey, the internal carotid artery feeds into it, and they fuse to form the middle cerebral artery and the anterior cerebral artery. Before feeding into the posterior communicating artery, it gives off a branch called the ophthalmic artery. The middle cerebral artery then gives off many branches, collectively known as the lenticular-striate arteries. The artery that connects both sides of the anterior cerebral arteries is known as the anterior communicating artery. This whole circulation that connects to one another is known as the Circle of Willis and is the main source of blood supply to the brain (Alpers et al., 1959).
This variation of the Circle of Willis is known as the patent variation, which is the variation most common among populations. There are variations though which may confer risks of strokes.
Causes of strokes
Under each type of stroke, there are many different causes, but they share the uniform characteristic of whether it is caused by a block in the blood vessels (ischemic), or caused by a bleed (hemorrhagic).
An ischemic stroke is most commonly caused by an embolism, particularly of a cardiac origin (Feske, 2021). An embolism is a foreign material that breaks off from its origin and circulates in the blood to eventually occlude another blood vessel (Villines, 2021). Common diseases causing this embolism are atrial fibrillation, atrial flutter, systolic heart failure, recent myocardial infarction, valvular heart disease, infective endocarditis, rheumatic heart disease, etc. Atrial fibrillation is associated with a 3-5 fold relative risk increase of strokes (Wolf et al., 1991), and is characterised by an abnormal rhythm of the atrium causing it to quiver and not pump blood out (Nattel, 2002). Atrial flutter is a less severe form of atrial fibrillation in which the atrium is still contracting but at a much higher rate (Bun et al., 2015). In brief, these conditions cause blood to stagnate and form clots, which can cause embolism down the road (Kamel & Healey, 2017). A paradoxical embolism may also cause an ischemic stroke. This may happen when someone has patent foramen ovale (a flap opening between the right and left atria), or an atrial septal defect (a defect in the wall separating the two atria). In these situations, right-to-left shunting of blood may occur, although it is less likely due to higher left-sided pressure (Sommer et al., 2008). This shunting may allow a venous thrombus to enter the systemic circulation to eventually block a blood vessel in the brain (Parsi, 2012). An atherosclerotic plaque in a larger vessel may also break off and cause a block in smaller distal vessels (Feske, 2021).
Large vessel disease is also another common cause of ischemic strokes. This is most predominantly due to atherosclerotic plaque building up in the large blood vessels (internal carotid artery, proximal middle cerebral artery, vertebral artery, basilar artery). The fibrous cap of these plaques may rupture under acute hypertension, causing platelets to rapidly adhere to the damaged area causing a clot that occludes the vessel (Feske, 2021). If patients have stenosis of the carotid arteries, acute hypotension, perhaps due to medication use, may also cause ischemic strokes due to the low blood pressure being unable to allow blood flow past the stenotic area (Ruff et al., 1981). The plaque may also dislodge and cause an embolic ischemic stroke as discussed earlier. Small vessel diseases may also cause ischemic stroke although the pathophysiological mechanisms have not been fully understood. These vessels (lenticulostriate artery, pontine branches) are particularly sensitive to chronic hypertension and may develop defects leading to ischemia (Rincon & Wright, 2014).
Another rare cause of ischemic strokes is vasculitis, where blood vessels may get inflamed enough to occlude the lumen (Sharma et al., 2018, Zepper et al., 2012, Aljanabi et al., 2019). These can be caused by viral infections, autoimmune diseases, or primary CNS vasculitis. A dissection in an artery, whereby the lining between the tunica intima and tunica media breaks may also cause strokes by allowing blood to pool between the tunica intima and tunica media, eventually clotting and blocking the vessel lumen (Benninger et al., 2004). These can happen due to trauma, connective tissues, or an iatrogenic cause (ie caused by a medical procedure such as angioplasty). Lastly, a hypercoagulable state may also facilitate clot formation and potentially ischemic strokes (Maino et al., 2015). These can mainly be caused by genetic mutations such as a protein c/s deficiency, antithrombin 3 deficiency, prothrombin mutations, factor V Leiden mutation antiphospholipid syndrome, polycythemia vera, or an acquired cause such as heparin-induced thrombocytopenia (Thomas, 2001).
For hemorrhagic strokes, there are two main subtypes, namely subarachnoid haemorrhage (SAH) and intracerebral haemorrhage (ICH). Subarachnoid haemorrhage is characterised by a bleed into the subarachnoid space, the space between the arachnoid mater and pia mater (two membranes that cover and protect the spinal cord and brain). Intracerebral haemorrhage, on the other hand, is a bleed into the brain parenchyma, the functional tissues of the brain (Elliott & Smith, 2010).
For intracerebral haemorrhage, most of the cases are caused by hypertension, whether acute or chronic. High blood pressure causes blood vessels to rupture and bleed and has been shown to increase the risk of ICH by two to six-fold (Challa et al., 1992). High blood pressure may also induce lipohyalinotic changes in the blood vessels, a concentric hyaline thickening of the endothelium, occluding the lumen (Challa et al., 1992). That being said, hypertension is also usually a common symptom of ICH as a result of the body raising blood pressure to try and force blood up the brain (Qureshi et al., 2009).
Another potential cause of ICH is Cerebral Amyloid Angiopathy. This may sound familiar to those that know a little bit about Alzheimer’s disease as it involves one of the proteins associated with Alzheimer’s disease, beta amyloid proteins. These proteins are deposited in the arterial walls causing them to become stiff, brittle, and predisposed to ruptures (Mehndiratta et al., 2012). As you can expect, it is a more common cause in the elderly as their ability to clear beta-amyloid proteins is substantially reduced due to an imbalance in the amyloidogenic pathway of amyloid precursor protein (Sehar et al., 2022). These patients also often present with dementia, a symptom of Alzheimer’s disease.
An impaired ability to clot blood may also cause ICH such as from genetic causes of haemophilia A, or acquired causes such as liver failure, where the liver fails to make clotting factors, thrombocytopenia or disseminated intravascular coagulation (Del Zoppo & Mori, 1992). Ironically, those on antiplatelet agents such as aspirin for primary or secondary prevention of ischemic strokes may also have higher chances of developing ICH as a result of low coagulation abilities (Soo et al., 2008).
Abnormalities in the blood vessels of the brain such as the presence of aneurysms (an abnormal outpouching of a blood vessel), an arteriovenous malformation, dural arteriovenous fistulas (an abnormal connection between an artery and a vein), or cavernous angiomas (a blood vessel abnormality characterised by large, adjacent capillaries with little or no intervening brain) may also cause ICH as the blood vessels are more prone to ruptures. (Krings & Is, 2010).
A hemorrhagic conversion of an ischemic stroke is also a potential cause of hemorrhagic stroke and may be due to the administration of thrombolytic drugs. This happens more commonly in cardioembolic strokes as the obstructions are often larger (Molina et al., 2001). When a blood vessel becomes ischemic for long enough, the endothelium of the blood vessels dies and the vessel becomes very frail. Infarcted neurons also release proinflammatory cytokines that weaken the blood vessel’s integrity. Hence when blood flow is restored and blood pressure is not properly controlled, the sudden rise in hydrostatic pressure may cause ruptures which may lead to ICHs (Di Tullio & Homma, 2002).
A thrombosis in a cerebral vein may also cause blood to build up proximal to the vein, increasing hydrostatic pressure until too much water eventually seeps out of the capillary walls into the interstitium (Masuhr et al., 2004). This can cause edema, tissue dysfunction, neurological deficits, altered sensory inputs, and seizures. If this continues unabated, it could result in hemorrhagic necrosis and vasogenic edema in the affected area (Sagduyu et al., 2006).
Malignant cancers such as papillary thyroid cancers, lung cancers, small cell carcinoma, or melanoma can also cause ICH as these tumours may metastasize to the brain and disrupt the blood-brain-barrier (Rogers, 2003). Other causes include sympathomimetic drugs such as cocaine, often leading to hypertension, trauma to the head, cerebral angiopathy, vasculitis, or infective endocarditis (Burke et al., 2009).
Lastly are the causes for SAH which by far the most common are due to traumas to the head, while aneurysms make up 80% of the nontraumatic SAH (Cuvinciuc et al., 2010). Classical risk factors for strokes in general such as hypertension, sympathomimetic drug abuse, alcohol, smoking, oral contraceptives, and pregnancy also apply to SAH.
Hyaline arteriosclerosis of the vasa vasorum (tiny blood vessels that supply blood to the tunica media) may also reduce integrity of the blood vessel (McCORMICK & Rosenfield, 1973)..
Genetic diseases such as Marfan syndromes (fibrillin-1 deficiency), Ehler-Danlos Type IV (type III collagen deficiency), polycystic kidney disease, or neurofibromatosis type I may also cause the cranial blood vessels to become weak and more susceptible to aneurysms through their various etiologies. And again, infective endocarditis may also cause SAH (Pfohman & Criddle, 2001).
Stroke symptoms
In large, stroke symptoms depend on the location of the affected blood vessels and since there are numerous different blood vessels which may be affected, there are of course many different symptoms.
The most common artery affected in strokes is the middle cerebral artery (MCA). The MCA supplies blood to the lateral part of the brain, particularly the frontal lobe, temporal lobe, and parietal lobe. It also supplies some deeper structures such as the caudate nucleus, internal capsule, and thalamus (Nogles, 2023).
Strokes involving the MCA may cause contralateral (opposite side of the brain) weakness and sensation loss as the motor cortex in the frontal lobe and sensory cortex in the parietal lobe is affected. Besides, these symptoms tend to arise in the upper extremities as the motor and sensory homunculus of the lateral brain involves the upper extremities (Teasell & Hussein, ca. 2018). A homunculus is one of neuroscience's fundamental diagrams that shows the body parts controlled by corresponding brain regions. It is shown below.
The frontal eye field is also situated in the frontal lobe and if affected will cause ipsilateral (same side as the brain) gaze deviation (Singer et al., 2006). This is because the frontal eye field stimulates the contralateral abducens nerve and ipsilateral oculomotor nerve (Vernet et al., 2014). The abducens nerve innervates the ipsilateral lateral rectus muscle, while the oculomotor nerve innervates the ipsilateral medial rectus muscle, and a few other extraocular muscles (Vernet et al., 2014). It might be easier to visualise this with an example. If the right sided frontal eye field is affected, the left abducens and right oculomotor nerve is affected. This causes the left eye's lateral rectus muscle and the right eye's medial rectus muscle to lose its innervation. Hence, the left eye's medial rectus muscle becomes the dominant muscle, while the right eye's lateral rectus muscle becomes the dominant muscle. These two muscles act to pull the gaze towards the right side, hence the name ipsilateral gaze deviation.
There are two particular areas important for speech and comprehension that may be affected in an MCA stroke. These are the Broca's area, located in the frontal lobe, supplied by branches of the superior MCA, and the Wernicke's area, located in the upper temporal lobe, supplied by branches of the inferior MCA. Broca's area is primarily responsible for generating speech, while Wernicke's area is primarily responsible for comprehension of language (Dronkers & Ogar, 2004). Broca's area and Wernicke's area are both located in the dominant hemisphere of the brain which in 95% of people is the left side (Dehaene et al., 2003). If the left sided inferior MCA is occluded, the Wernicke’s area may be affected and patients may develop Wernicke’s aphasia, characterised by fluent speech but poor comprehension, whereas if the left sided superior MCA is occluded, the Broca’s area may be affected and patients may develop Broca’s aphasia where comprehension is unaffected but their ability to express reactions and speak fluently is severely affected. If the entire MCA is affected, global aphasia may develop where both comprehension and speaking skills are affected (Teasell & Hussein, ca. 2018).
Since the optic radiation is also supplied by the MCA, one may develop contralateral homonymous hemianopia, where they lose visual field on the opposite side of the affected artery in both eyes (Wolberg & Kapoor, 2022).
If the right sided MCA is occluded, right sided brain function will be compromised. The right hemisphere of the brain mediates learned behaviours that require voluntary initiation, planning and spatial perceptual judgement (Delaney & Ravdin, 1997). A right sided occlusion of the MCA may lead to contralateral hemineglect, that is patients tend to neglect what is on their left side and will need to turn their head around to notice what’s on their left side. It's important to contrast hemineglect, which is mainly an attention problem, and hemianopia, which is a physical loss of vision. This usually does not happen with left sided lesions as the right brain hemisphere can compensate for the left attention field too (Kwasnica, 2002). Right sided lesions may also cause emotional disorders, such as an indifference reaction, impulsivity, and emotional lability. Although aphasia is most commonly associated with left sided lesions, right sided lesions may also rarely produce aphasia. Patients may be able to speak fluently but are unable to utilise language skills properly, that is the pragmatics of conversations. Patients may not observe turn-taking rules of conversation, may have difficulty telling, or understanding, jokes (frequently missing the punchline), comprehending ironic comments and may be less likely to appropriately initiate conversation (Robert & Hussein, 2016).
MCA lesions that involve the premotor cortex, a part of the motor cortex in the frontal lobe responsible for the organisation of motor behaviours, may also produce ideomotor apraxia, where the patient can spontaneously do something but is unable to do something when being asked to do so specifically, eyelid apraxia, where the patient can't elevate their eyelids voluntarily, or ideational apraxia, where the patient has lost the concept of something such as using a toothbrush to comb hair (Miyai et al., 1999).
Moving on to the anterior cerebral artery (ACA), which supplies mostly the medial portion of the parietal lobe, frontal lobe and a little bit of the basal ganglia (Bogousslavsky & Regli, 1990). Similarly to MCA lesions, lesions in the ACA affect the parietal lobe and frontal lobe, producing contralateral sensation loss and weakness respectively. What differs is that these arise in the lower extremities as the ACA supplies the medial aspect of the cerebrum, corresponding to the lower extremities in both the sensory and motor homunculus. The paracentral lobule which innervates the lower extremities, particularly the gentalia area may be affected and cause urinary and faecal incontinence (Park et al., 2021). The prefrontal cortex, mainly responsible for controlling behaviour, decision making, emotions, and personality, along with the anterior cingulate cortex, responsible for the memory and limbic system may also be affected. These may cause abulia or akinetic mutism depending on whether one side or both sides of the ACA is affected, that is the patients may have a decrease in goal-oriented behaviour, ie: they'll have a lack of initiative in doing things (Teasell & Hussein, ca. 2018).
Since the ACA supplies the anterior superior frontal lobe that communicates with the Broca's area, it can indirectly cause a type of aphasia known as transcortical aphasia. Patients with transcortical aphasia have intact comprehension but nonfluent speech. However, they can repeat phrases after someone whereas if the Broca's area is affected, repetition of phrases is usually impaired (Teasell & Hussein, ca. 2018).
If the watershed zone of the MCA and ACA is affected, that is the zone where the ACA and MCA overlaps, patients may develop the man in a barrel syndrome (Rouanet et al., 2017). Patients will have sensory loss and weakness of the proximal upper extremities. This usually occurs when there is severe systemic hypotension causing the distal parts of the arteries to have extremely low perfusion.
Touching slightly on the internal carotid artery, which is seldom occluded due to its large size. If it is, however, a branch of it, the ophthalmic artery may be affected resulting in amaurosis fugax, or transient vision loss (Goodwin et al., 1987). This can cause permanent vision loss.
Next up is the posterior cerebral artery (PCA); this artery supplies blood to the temporal lobe, brain stem particularly the midbrain, the occipital lobe, and the thalamus (Javed et al., 2022). Since the occipital lobe is mainly responsible for vision, PCA lesions could cause contralateral homonymous hemianopia (Javed et al., 2022). Since the oculomotor nerve originates from the midbrain, if the midbrain is affected, so will the oculomotor nerve. The crus cerebri, a bundle of white matter fibre including the corticospinal tract in the anterior portion of the midbrain, will also be affected. Collectively, these can cause Weber's syndrome, which is an ipsilateral oculomotor nerve palsy and contralateral weakness. The oculomotor nerve palsy will cause drooping of the upper eyelids, double vision, and pupil mydriasis, an unusual dilation of the pupil (Munakomi, 2023). In another case, Claude syndrome, the red nucleus also in the midbrain is affected. The red nucleus communicates with the contralateral cerebellum, which helps coordinate movements and balance. Hence, patients can have contralateral ataxia along with the ipsilateral oculomotor nerve palsy, characterised by clumsy voluntary movements (DeBacker et al., 2018). Then, there is Benedict syndrome, which is a combination of Claude syndrome and Weber syndrome, where the oculomotor nerve, red nucleus, and crus cerebri are affected (Burr, 2022).
Similar to the ACA and MCA watershed infarct, an infarct could also happen to the intersection between the MCA and PCA, called an MCA PCA watershed zone. If the MCA PCA watershed zone is affected, near the occipitotemporal zone, one could develop prosopagnosia (Javed et al., 2022). In these patients, the primary visual cortex is intact, but the association areas may be dysfunctional, hence they can see but have trouble interpreting what they are seeing. If the affected area is near the occipitotemporal zone, patients could develop Balint syndrome characterised by optic ataxia, where they have trouble reaching somewhere without visual guidance, and oculomotor apraxia, an inability to volitionally direct gaze (Javed et al., 2022).
Before moving onto the other branches of the basilar artery, the PCA, superior cerebellar artery (SCA), anterior inferior cerebellar arteries (AICA), we should have a general idea of which area they innervate as there is quite some overlap. The basilar artery supplies the medial pons, the SCA supplies the superior cerebellum, the AICA supplies the lateral pons and anterior inferior cerebellum, while the PCA has been discussed earlier (Adigun, 2022).
If the medial pons is affected, the abducens nerve may be affected as it originates from the pons, which can result in abducens nerve palsy, where abduction of the ipsilateral eye is affected (Khazaal, 2022). Another structure in the medial pons, the medial longitudinal fasciculus (MLF) will also be affected. This structure is responsible for coordinating eye movements through the oculomotor nerve, trochlear nerve, and abducens nerve (Fiester et al., 2020). This could cause internuclear ophthalmoplegia, where the ipsilateral eye has trouble adducting, and nystagmus of the abducting eye. Classically however, the ability to cross over the eyes is preserved as it is controlled through a different pathway. To better understand this, assume a right MLF lesion. When the patient is asked to look to the right, everything will be fine, same with looking to the middle. However, when asked to look to the left, the left eye may have repetitive, uncontrolled movement, whereas the right eye cannot look to the left. The paramedian pontine reticular formation (PPRF) also exists in the medial pons and if affected will cause contralateral gaze deviation (One and a Half Syndrome - EyeWiki, 2023). This is because the PPRF stimulates the ipsilateral abducens nerve and contralateral oculomotor nerve. The medial lemniscus and corticospinal tract, as well as the descending sympathetic fibres in the medial pons may also be damaged resulting in contralateral sensation loss, particularly from fine touch, vibrations as well as proprioception, paralysis, and Horner’s syndrome respectively (Khazaal, 2022).
Lesions of the lateral pons are the second commonest brain stem lesions due to strokes, and is called anterior inferior cerebellar artery syndrome (Lee et al., 2002). In the lateral pons, the middle cerebellar peduncles are affected. This structure communicates with the ipsilateral cerebellum to coordinate movements and balance, hence damage to it can cause ipsilateral ataxia (Morales & Tomsick, 2015). The vestibulocochlear nuclei, which is responsible for sensing equilibrium and hearing, may also be damaged. This can cause vertigo (dizziness), nausea, vomiting, hearing loss, and tinnitus (Fogwe, 2022). Within the lateral pons also reside the descending sympathetic fibres, and damage to these descending tracts may impair sympathetic function (Lee et al., 2009). This includes sympathetic functions of the face, eye, eyelids, and ciliary muscle. Patients may present with Horner syndrome, characterised by ptosis (drooping of the eyelids), anhidrosis (absence of sweating), and miosis (constriction of the pupil) (Reede et al., 2008). Two of the four trigeminal nerve's nuclei are also in the lateral pons, and if affected will cause ipsilateral weakness of the mastication muscles as well as loss of sensation (Lee et al., 2009). The facial nerve may also be affected causing ipsilateral facial weakness (Lee et al., 2009). The spinothalamic tract sending sensation signals from the periphery to the brain, if affected, will cause contralateral loss of sensation, particularly from nociceptors and thermoreceptors (Amarenco & Hauw, 1990).
If the cerebellum is affected, patients will develop ataxia, dysmetria and dysdiadochokinesia (Ioannides, 2022). Dysmetria is the inability to control the speed, distance, and range of motion of a movement, while dysdiadochokinesia is the inability to perform rapid alternating movements (Balami et al., 2013).
Next, we move onto branches of the vertebral arteries. The right and left vertebral arteries, as well as the anterior spinal artery supplies the medial medulla, whereas the posterior inferior cerebellar arteries (PICA), as its name suggests supplies the posterior inferior cerebellum and the lateral medulla (Piccinin, 2022).
As the medial medulla is affected, the hypoglossal nerve that originates from the medulla is also affected. This nerve innervates the genioglossus muscle on the ipsilateral side, which functions to protrude the tongue anteriorly and deviate the tongue to the opposite side (Siddik, 2022). Hence, if the hypoglossal nerve on one side is affected, the genioglossus muscle on the other side overpowers and an ipsilateral tongue deviation can be observed. Similar to that of the medial pons, the medial lemniscus and corticospinal tract may also be affected causing contralateral loss of sensation and paralysis (Kameda et al., 2004).
Damage to the lateral medulla is the commonest of brain stem lesions due to strokes, commonly known as posterior cerebellar artery syndrome (Kameda et al., 2004). Similar to the middle cerebellar peduncles in the lateral pons, the inferior cerebellar peduncles reside in the lateral medulla. Damage to the structure can similarly cause ipsilateral ataxia (Naga, 2021). Another nucleus of the trigeminal nerve, the spinal trigeminal nucleus is also in the lateral medulla. This nucleus is exclusively sensory and hence could cause ipsilateral loss of sensations, particularly pain and temperature from the face. The nucleus ambiguus is also located in the lateral medulla. This nucleus contributes to motor innervation of the larynx, pharynx, and soft palate through motor fibres of the glossopharyngeal nerve, vagus nerve, and accessory nerve. If damaged, this could cause ipsilateral bulbar palsy, characterised by dysphagia (trouble swallowing) , dysphonia (sound production impairment), an absence of a cough/gag reflex, as well as contralateral uvula deviation (Patel, 2022). The vestibular nucleus is also situated in the lateral medulla, and it controls the equilibrium of the body. Hence, damage to it can cause vertigo, nausea, and vomiting (Saleem, 2022). Lastly, the sympathetic tract and spinothalamic tract in the lateral medulla can also be damaged resulting in symptoms mentioned above (Balami et al., 2013). Hyponatremia as a result from inappropriate secretions of ADH has also been reported. The proposed pathophysiology includes the failure of propagation of non-osmotic stimuli from the carotid sinus through the vagal nerve due to the nucleus tractus solitarius lesion in the medulla. This results in the disinhibition of antidiuretic hormone (ADH) secretion by the pituitary gland causing SIADH (Saleem, 2022).
A patient with subarachnoid haemorrhage may present with the extra symptoms of severe headaches. The subarachnoid space is usually filled with a small amount of cerebrospinal fluid (CSF) that cushions the brain and plays a key role in autoregulation of cerebral blood flow at the arteriolar level (Pollay, 2012). When this area is infiltrated by blood, it irritates the meninges leading to headaches, and in fact sudden headaches accompanied by nausea, vomiting, or visual disturbances may be a warning sign of a SAH (Østergaard, 1991). Classical causes for strokes in general are also valid for SAH such as hypertension, sympathomimetics, smoking, alcohol, oral contraceptives, and pregnancy.
Talking about all the detailed symptoms that may arise, the most common symptoms to look out for is weakness in an arm or leg, as 70% of ischemic stroke patients present with this (Kimura et al., 2004).
With all that being said, women tend to have more non-traditional symptoms than men, which are in this study defined as face or hemibody pain, lightheadedness, mental status change, headaches, other neurologic symptoms, and non neurologic symptoms.. Nontraditional symptoms more frequently reported by women included pain and reduced level of consciousness. In contrast, “traditional” stroke symptoms of imbalance and hemiparesis were more frequently reported by men, especially those involving a change in mental status (Lisabeth et al., 2009). These nontraditional symptoms presentation may be the cause of a delayed patient arrival at hospital for women compared to men, and as a result can lead to the low usage of tissue plasminogen activator (tPA) (Mandelzweig et al., 2006; Reeves et al., 2009). This is because tPA should be administered within 4.5 hours after symptoms onset for optimum stroke care (Del Zoppo et al., 2009). Since tPA is the only approved therapy to reduce the functional limitations caused by ischemic stroke, and there is evidence that women derive greater benefit from tPA than men (Kent et al., 2005), this disparity may be the reason why the burden of strokes seems to fall disproportionately on women (Di Carlo et al., 2003). Slight gender differences may also be present in weakness and paralysis symptoms, with men having more frequent weakness symptoms while the opposite is true for paralysis, although the magnitude is likely small (Di Carlo et al., 2003). Some studies also find women have more frequent aphasia, and trouble seeing in one or both eyes, while having less gait disturbances (Beal, 2010). Hence, it may be useful for authorities to introduce stroke education messages to the public targeted at these non traditional symptoms, on top of the already existing “Give me 5”, that assesses the ability to talk, see, reach, feel, and walk as a means of detecting early strokes, and the FAST acronym, which stands for facial droop, arm weakness, speech problems, and time to call 999. This is because these 2 public health messages, although effective, only target the traditional symptoms and may miss some of the non-traditional symptoms some women present with.
Diagnosis of strokes
Diagnosis of strokes are highly reliant on imaging tools, but may vary between ischemic strokes and hemorrhagic strokes. Note that diagnostic testing may vary from doctor to doctor and are certainly not constant,
Many neurologic conditions can present with symptoms that are essentially indistinguishable from that of ischemic stroke, including brain mass lesions, meningitis, demyelination, migraine, seizures, metabolic encephalopathies, posterior reversible encephalopathy syndrome, and psychogenic symptoms. Cardiac syncope, vestibular dysfunction, epilepsy, and transient global amnesia may also be mistaken as ischemic strokes (Brown, 2001). In one study, strokes were diagnosed correctly in 81% of cases by stroke team physicians prior to imaging procedures, while the remaining 19% were determined to be stroke mimics. The most common stroke mimics in that study were seizures with postictal deficits, systemic infections, brain tumour, and toxic-metabolic disturbances (Hand et al., 2006). By using computed tomography (CT) and routine laboratory evaluation, the incidence of stroke mimics decreased to 4%, while with the additional use of magnetic resonance imaging (MRI) techniques, the incidence of mimics decreased to 1% to 2% (Huff, 2002).
When a patient presents to the hospital with stroke-like symptoms, typically evaluation of the patient’s blood glucose level is also done as hyperglycemia or hypoglycemia can act as a stroke mimic (N. N. Shah et al., 2014, Agrawal et al., 2014).
Usually, as a patient presents to the emergency room for a suspected stroke, it could be hard to differentiate between an acute stroke and a transient ischemic attack (TIA). The symptoms of a TIA are similar to those of stroke, yet they usually resolve 1 hour after onset (Albers et al., 2002). Despite that, a TIA should not be put aside as it indicates a high risk for secondary cerebrovascular events due to the presence of conditions that could lead to ischemic strokes. In one study, the estimated stroke risks following a TIA were 8.0% at 7 days, 11.5% at 30 days, and 17.3% at 90 days.
Referring back, the standard for diagnosing an ischemic stroke is a Cranial Computerised Tomography scan, or a cranial CT scan. This is because it is the only reliable way of differentiating between an ischemic stroke, or a hemorrhagic stroke (Jamieson, 2009). However, changes due to hyperacute ischemic strokes, or brainstem strokes may be harder to see on non-contrast CT (NCCT). Besides, a NCCT does not provide information on the severity of the perfusion deficit. Hence, newer techniques such as CT angiography (CTA) are used, and can aid the selection of appropriate treatments (Ezzeddine et al., 2002). A CTA however, may not always be present during an acute setting.
Multimodal MRI use for acute stroke evaluation has also started to grow despite its unfavourable cost and availability. Another limitation of MRI is its increased scanning time which may restrict its use in time-restrained patients. MRI use is also not recommended for those with pacemakers or metallic implants (Jamieson, 2009). A study comparing MRI to NCCT in patients with suspected strokes did show that MRI detected significantly more acute strokes (all types), acute ischemic strokes, and chronic haemorrhages. Hence, the use of MRI may be better than NCCT for identifying patients eligible for tPA use in early acute strokes, and also to identify patients eligible for tPA after the 3-4.5 hour window recommended (Chalela et al., 2007). Techniques used for MRI evaluation usually include perfusion weighted imaging (PWI), and diffusion weighted imaging (DWI). Things may get a little technical here as we should ideally know the general principles behind these techniques to understand their clinical significance.
The PWI works by injecting a contrast bolus into the patient’s circulation to measure hemodynamic parameters such as cerebral blood flow. The DWI is a little more complicated, but essentially it measures the rate of water diffusion in tissues, and the faster the water diffuses, the more out of phase it gets, and the less signal it has (Holdsworth & Bammer, 2008).
A decrease in the apparent diffusion coefficient of water (ADC), present as hyperintensity on DWI images indicates a restriction in the diffusional movement of water and is believed to result from energy failure and subsequent cytotoxic edema (Fisher & Garcia, 1996). This is because as cells get less oxygen, their ability to maintain fluid balance declines, and water starts to diffuse into the cells, which hinders water movement due to impeding organelles. On the other hand, PWI measures hemodynamic status of the tissues and can detect impaired perfusion, thus complementing the DWI images (Baird & Warach, 1998). In the clinical setting, the PWI lesion usually indicates the ischemic core and penumbra (a region of hypoperfused tissues that have not yet undergo necrosis), while the DWI lesion indicates the ischemic core (Neumann-Haefelin et al., 1999). Hence, the mismatch between the PWI and DWI lesions may represent an area that can still be saved, the main target of tPA (Fiehler et al., 2002). In fact, mismatch values may be used to determine patient eligibility for tPA after the 3-4.5 hour recommended window (Jamieson, 2009).
Besides, imaging of the entire circulation by noninvasive techniques is important to identify a treatable lesion. Techniques such as Transcranial Doppler (TCD) imaging measures blood flow velocity and direction in segments of large intracranial arteries to assess intracranial artery disease (Machado et al., 2004). This can be used to routinely measure and identify patients with 70% and above angiography internal carotid artery stenosis (that is the internal carotid artery's lumen has been reduced by 70%) (Wilterdink et al., 1997), and right-to-left cardiac shunts (Machado et al., 2004), two risk factors for ischemic strokes. However, evaluation of the posterior cerebral arteries may be less reliable than investigations of the anterior portions by TCD (Jatuzis et al., 2000).
Carotid Duplex Sonography (CUS), is also a useful tool for screening for cervical carotid artery disease. This technique may be able to detect intimal thickening, atherosclerotic plaque, and proximal dissection in the area of the carotid artery bifurcation (Kupinski et al., 2004). In fact, one study showed that CUS has a >90% accuracy in diagnosing significant extracranial stenosis (T. Lee et al., 2002). That being said, CUS can only assess a limited portion of the extracranial circulation, and provide little information of the vertebral arteries (Jamieson, 2009).
In some cases, catheter angiography may be used to measure luminal diameter narrowing, to identify candidates for surgical carotid endarterectomy (Jamieson, 2009).
Techniques such as transthoracic echocardiography and transesophageal echocardiography are noninvasive and semi-invasive techniques that can be used to diagnose heart abnormalities leading to ischemic strokes. These abnormalities can include aortic arch atheromata, intracardiac thrombi, patent foramen ovale, atrial septal aneurysm, mitral or aortic valvular disease. They can also be used to detect right-to-left cardiac shunt (Strandberg et al., 2002).
An electrocardiogram may also be used to find cardiac abnormalities that may be the cause of the stroke, such as atrial fibrillation, atrial flutter, myocardial infarction etc (Bozluolcay et al., 2003)
Above discussed are imaging techniques to diagnose strokes, however in early strokes CT scans may appear normal directly after onset, and remain normal in patients with mild ischemic strokes. It’s important to achieve an accurate diagnosis in patients with suspected ischemic strokes, as they can be eligible for reperfusion therapies, or thrombolytic treatments, to reduce long term damage. A review article published in the American Heart Association journal reviewed 21 studies, testing 58 different blood biomarkers, and 7 blood panels consisting of different biomarkers. Of these biomarkers, 5 had sensitivities over 90% (NDKA, PARK7, UFD-1, NMDA receptor [NR] 2 fragment, NR2A/B antibodies), and 14 had a specificity more than 90% (PARK 7/ RNA-BP, UFDP, NDKA, GSTP, ischemia modified albumin [IMA], visin like protein [VLP-1], beta globin DNA, NR2 fragments, S100 beta, FABP, neuron specific enolase [NSE], NR2A/2B Ab, myelin basic protein [MBP], and thrombomodulin) (Whiteley et al., 2008). Two studies reported a positive test as a diagnosis (Brain Nr2 peptide, Apo-CI & Apo-CIII) of ischemic stroke in a mixed population of hemorrhagic and ischemic strokes, both with a high sensitivity and specificity (Dambinova et al., 2003, Allard et al., 2004) . However, all the blood biomarker studies had weaknesses in their methodology, which may explain the very high specificity and sensitivities reported (Whiteley et al., 2008). That being said, if these biomarkers are validated, they may be useful for early diagnosis of strokes when scanning techniques cannot be used, such as in the ambulance. They may also be useful for supporting a diagnosis of ischemic strokes in patients, when imaging alone is insufficient for diagnosis.
Besides differentiating between ischemic and hemorrhagic strokes, some plasma biomarkers may also be useful in identifying the underlying etiologies of the stroke. One study showed that levels of BNP, DD, and sRAGE were significantly higher in the group of patients with cardioembolic stroke. BNP was the biomarker that best differentiated cardioembolic stroke from any other aetiology (Montaner et al., 2008). The study primarily discussed the potential role of BNP and DD in identifying cardioembolic causes. High BNP levels may be caused due to heart failures, as BNP’s primary function is to reduce the heart’s workload by dilating blood vessels, and decreasing blood volume (Weber & Hamm, 2005), while DD levels are elevated as an embolus is broken down. DD levels may specifically be higher in cardioembolic cause compared to a large vessel disease as cardioembolism is mainly due to blood stasis, leading to a fibrin rich clot whereas clots in large arteries are due to platelet aggregation while fibrin mesh formation is secondary (Nagao et al., 1995). In fact, combining both biomarkers increases the probability of diagnosing a stroke as cardioembolic when it is actually cardioembolic; ie, if a patient has high levels of both (BNP >76 pg/mL and DD >0.96 μg/mL), the probability that that stroke is cardioembolic is 70% (positive predictive value).
After diagnosis is done, it may be useful to find the underlying cause, or accompanying features to aid with treatment. An INR test >1.7 is a contraindication for tPA treatment as it may cause an increased risk of bleeding. Besides, a complete blood count panel may also be useful in identifying anaemia, polycythemia, or thrombocytopenia, all contraindications to tPA (Hughes, 2022). Looking for troponin and Creatine kinase-myocardial bands may also help us identify heart problems as these biomarkers are commonly elevated after myocardial infarctions (Patibandla, 2022). Extremely low thyroid stimulating hormone, or T4 levels may indicate thyrotoxicosis that can lead to atrial fibrillation (Parmar, 2005). Checking for the risk factors of hypercoagulability may also aid in understanding what caused the ischemic stroke. These involve techniques way beyond the scope of this blog, but those interested can check out the cited article (Bushnell & Goldstein, 2000). Then, a check of the HbA1c level, lipid panel, erythrocyte sedimentation rate, and CRP levels may help identify risk factors.
That's about it for ischemic strokes. Let's move on to subarachnoid haemorrhages.
Still, the standard for diagnosis of subarachnoid haemorrhage is the CT scan. Physicians look for the subarachnoid haemorrhage pattern, where blood turns up white at sulci, cisterns, and the ventricles of the brain. Patients may also show hydrocephalus if the amount of blood in the ventricles is high enough to cause severe swelling (Marder et al., 2014). That being said, the sensitivity of a CT scan decreases over time and patients presenting with persistent headaches lasting a few days may receive less benefits from a CT scan (Edlow & Wyer, 2000). A CT angiogram may be used to identify which vessel that was affected. However, this technique may miss smaller lesions between 3 to 4mm in size (White et al., 2000). The CT angiogram may also be able to identify a differential diagnosis of reversible cerebral vasoconstriction, as patients with those typically present with stenosis (Burton & Bushnell, 2019). In both experimental and clinical studies, some have suggested that MRI—especially using fluid attenuated inversion recovery (FLAIR) sequences—can reliably diagnose acute SAH (Mitchell et al., 2001, Noguchi et al., 1995, Rumboldt et al., 2003, Wiesmann et al., 2002) . A lumbar puncture procedure used to study the cerebrospinal fluid (CSF) may also be used. This is because a SAH usually results in blood pooling in the ventricles where the CSF is. The red blood cells are then broken down by macrophages in vivo, converting the heme into bilirubin. When the fluid extracted from the lumbar puncture is centrifuged, the bilirubin may cause a yellowish hue to be present, called xanthochromia (Dugas, 2022). The visual evaluation can be done in two ways, visual detection, using the naked eye, and spectrometry, which measures the absorption of light of a substance to identify its identity. The former is less reliable (Petzold et al., 2005), as the presence of proteins or pigments such as carotenoids can obscure the colour change associated with the presence of xanthochromia. The presence of oxyhemoglobin with an acute bleed or traumatic lumbar puncture appears pink or orange and can hide the yellow discoloration of xanthochromia leading to a false-negative result. Furthermore, unlike spectrophotometry, a visual inspection cannot detect low concentrations of bilirubin and cannot distinguish bilirubin from oxyhemoglobin (Chu et al., 2015). The gold standard for diagnosing SAH, and in fact cerebrovascular diseases in general, is a digital subtraction angiogram, as it can be used to visualise blood vessels in 3D. However, this technique is very invasive and can puncture arteries or dissect a cerebral vessel (Edlow, 2005).
Up next, we will discuss the diagnosis of ICH.
Yet again, the standard for diagnosing is through a CT scan. Patients with ICH will usually present with a midline shift of the brain as blood builds up in the cerebrum, pushing one side to the other. Patients may also have hydrocephalus if the bleeding is extremely severe and blood enters the ventricles (McGurgan et al., 2021). CT scans of the lungs, pelvis, and abdomen may be warranted to find malignancy that may be the cause of the ICH. A CT angiogram or digital subtraction angiography may also be used to detect vascular abnormalities (Linn & Brückmann, 2009). A magnetic resonance venography (MRV) can also be used as it primarily visualises the veins, useful for finding cerebral venous sinus thrombosis (Saposnik et al., 2011). An MRI using susceptibility-weighted-imaging (SWI) can also be used to detect blood in the brain parenchyma. This is because SWI relies on the interaction of substances with the local magnetic field, and hence can be used to detect high iron levels, indicating a bleed (Hermier & Nighoghossian, 2004). If the SWI sequence shows tons of tiny little bleeds all over the brain, and the patient is over 60 years old, this may indicate a cerebral amyloid angiopathy (Chen et al., 2019). Based on MRI findings, the modified Boston criteria may also help in diagnosing a cerebral amyloid angiopathy CAA. Based on the modified Boston criteria, a probable CAA is defined as follows: age ≥55 years (an arbitrary cut-off); multiple ICH (including cerebral microbleeds), restricted to lobar, cortical or cortico-subcortical regions on CT or MRI; or a single lobar, cortical or cortico-subcortical ICH in addition to focal or disseminated superficial siderosis; and exclusion of other underlying cause of ICH (Linn et al., 2010). A transthoracic echocardiogram or transesophageal echocardiogram can be used to find a septic embolism, which can then warrant a search for the septic cause through blood cultures. A complete blood count to identify anaemia or low platelet count may be beneficial to identify the underlying coagulopathy. A complete metabolic panel may also identify liver failure if the liver function tests are high. Liver failure is a potential cause of low levels of procoagulants. A urine drug screen can also be used to look for toxic drugs such as cocaine or alcohol. Checking for procoagulants and anticoagulants levels such as factor V, antithrombin III, and protein C/S can also help identify any coagulopathy. ESR and CRP levels can also be used to identify any vasculitis cause (Freeman & Aguilar, 2012).
Treatment of strokes
The first line treatment for an ischemic stroke is the use of intravenous Alteplase, or commonly known as tPA with a dose of 0.9 mg/ kg, not to exceed 90 mg and with 10% of the dose given as a bolus and the rest as infusion over the following 60 minutes. This increases the chances by one-third of recovery to independent function at 3 months when administered within 3 hours of stroke onset (Fugate & Rabinstein, 2014).
There are indications and contraindications to this therapy which varies from time of symptom onset. If symptoms started before 3 hours, tPA is indicated; if symptoms started between 3-4.5 hours, patients with either history of diabetes, previous strokes, are lesser than 18 years old, are greater than 80 years old, are taking oral anticoagulants, and those with a baseline National Institutes of Health Stroke Scale score >25 are excluded. If symptoms started more than 4.5 hours before, tPA is usually not given unless other imaging scans (such as the PWI/DWI mismatch) indicate otherwise (Del Zoppo et al., 2009).
Other contraindications of tPA are findings of intracranial haemorrhage, history of intracranial haemorrhage, although in some cases the benefits of tPA may be larger than the risks depending on a variety of factors. Besides, severe uncontrolled hypertension, history of strokes or brain trauma, thrombocytopenia, presence of coagulopathies, an international normalised ratio >1.7, severe hypoglycemia or hyperglycemia,although patients that do not improve after normalising blood glucose levels can be given tPA (Frank et al., 2013), and recent GI haemorrhages are all contraindications that have a decent consensus behind it (Fugate & Rabinstein, 2015).
The most serious complication from IV tPA is intracranial haemorrhage (ICH). It often occurs in the area of infarction and is caused by reperfusion injury. Although most of these reperfusion haemorrhages are asymptomatic, they can sometimes provoke neurologic decline and, when severe, can be fatal (Hasan et al., 2018).
After IV tPA, patients need to be monitored in a dedicated stroke unit for 24 hours. Strict blood pressure control below 180/105 mm Hg is necessary. This can be done by infusing nicardipine, a calcium channel blocker, IV labetalol, a beta-blocker, or hydralazine, a direct vasodilator. Oral antihypertensives may also be used after the patients have been stabilised such as angiotensin converting enzymes inhibitor, angiotensin receptor blockers, dihydropyridine calcium channel blockers, beta blockers, or alpha 2 antagonist. Antithrombotics should be avoided to reduce the risk of ICH. In case of neurologic worsening, CT should be repeated immediately (Hasan et al., 2018).
The presence of haemorrhage should prompt discontinuation of alteplase infusion if still ongoing. Cryoprecipitate or antifibrinolytics can be used to reverse the fibrinolytic effects of the drug (Frontera et al., 2016). Post-tPA, angioedema may be a side effect, especially in patients on angiotensin converting enzyme inhibitors, due to increased production of bradykinin, though rare. In these patients, antihistamines, IV steroids, or intubation should be given to prevent breathing difficulties (Hasan et al., 2018).
If the cause of the ischemic strokes was cardioembolic though, anticoagulants can be used after ruling out risks for ICH. These can include direct oral anticoagulants such as Apixaben or warfarin, more preferable for valvular disease. Caution should be warranted here as anticoagulants severely increase the risk of bleeding and risk of haemorrhages. If the patient has patent foramen ovale, what would be most helpful is to do a percutaneous closure to seal up the opening (Spence, 2018).
A carotid endarterectomy can also be done to remove the plaques present if the internal carotid artery is severely stenosed.
For treatment of ICH, blood pressure control should also be done, particularly keeping their systolic blood pressure between 130 to 140mmHg (McGurgan et al., 2021). This can be done in various ways as discussed above.
Since coagulopathies are part of ICH aetiology, if patients have any coagulopathies due to medication use, as in 20% of all cases, it would be ideal to reverse it (Flaherty, 2010). If the be given 15 units of PCC per kg of bodyweight, an INR of 2 to 4 can be given 25 units of patients are taking warfarin, 10mg of IV vitamin K can be given. Besides a prothrombin complex concentrate (PCC) can be given based on their INR (an INR between 1.5 to 1.9 can PCC per kg of bodyweight, an INR of 4 to 6 can be given 35 units of PCC per kg of bodyweight, and an INR of more than 6 can be given 50 units of PCC per kg of bodyweight). If patients are on heparin, give them protamine sulphate. If patients are on direct oral anticoagulants, they can be given 25 to 50 units of PCC per kg of bodyweight or a medication called andexanet alfa. If patients are taking dabigatran, a thrombin inhibitor, they can be given idarucizumab. If the patient is on antiplatelet agents such as aspirin or clopidogrel, a drug called DDAVP may be beneficial in reversing the coagulopathy (McGurgan et al., 2021).
Patients with ICH will also have their glucose be monitored to prevent hypoglycemia or hyperglycemia (Greenberg et al., 2022).
Patients with intracerebellar haemorrhage with clinical or imaging signs of hydrocephalus and/or a brainstem compression should undergo surgical intervention and hematoma evacuation as soon as possible (Greenberg et al., 2022).
Moving on to the treatment of SAH. Again, blood pressure control is crucial especially pre-coiling, a procedure to block the aneurysm, a common cause of SAH. The systolic blood pressure should be less than 160 mmHg, although there certainly are uncertainties in this area (Lawton & Vates, 2017). An external ventricular drain can also be done to remove the excess fluid in the ventricles. This should be done in patients with a high hunt/hess score, intraventricular haemorrhage, or obstructive hydrocephalus, a subtype of hydrocephalus where an intraventricular mass blocks the flow of cerebrospinal fluid in the ventricles (Suarez-Rivera, 1998). If the intraventricular mass is caused by a blood clot in the ventricles, intrathecal tPA can be given to break up the clots (Abdelmalik & Ziai, 2017). If the patient has communicating hydrocephalus, that is a hydrocephalus caused by a blockage of cerebrospinal fluid flow outside the ventricles such as at the subarachnoid villi where cerebrospinal fluid normally drains into the venous system, a longer term draining of the ventricular fluid would be needed. This is where a ventriculoperitoneal shunt comes in. This procedure as its name suggests shunts the fluid in the ventricles into the abdomen (Woernle et al., 2013).
Due to the nature of aneurysm being the most common non traumatic cause of SAH, a coiling or clipping procedure can be done. Coiling is where coils are inserted into the aneurysm to block off blood flow whereas clipping is when a metal surgical clip is used to close off an aneurysm in the brain. Coiling and clipping each have their own pros and cons with coiling being associated with higher rates of rebleeding but lower mortality and morbidity rates whe clipping is associated with higher rates of occlusion but a higher mortality and morbidity rates (Belavadi et al., 2021). Coiling is more suitable for older, hemodynamically unstable patients with small-necked aneurysms in the posterior circulation whereas clipping is more suitable for younger, hemodynamically stable patients with large-necked aneurysms in the anterior circulation (Rosenwasser et al., 2014). That being said, rebleeding of the aneurysm can occur especially in coiling. If rebleeding does occur, the fibrin mesh in the rupture can be stabilised by giving the patients tranexamic acid or aminocaproic acid (Raya & Diringer, 2014). They work by blocking lysine binding sites on plasminogen molecules, inhibiting the interaction of plasminogen with formed plasmin and fibrin, exerting an antifibrinolytic effect (Cai et al., 2020).
Complications such as vasospasm can develop if an aneurysm ruptures too. When a blood vessel ruptures, inflammatory molecules are released which causes vasoconstriction. If this vasoconstriction is prolonged, the brain receives less blood flow and eventually becomes infarcted if untreated. This is called delayed cerebral ischemia (DCI). This usually happens between day 3-14 of the stroke onset (De Rooij et al., 2013). Monitoring blood flow through use of a Transcranial Doppler Ultrasound can be useful in detecting an early vasospasm (Raya & Diringer, 2014). As vasoconstriction increases the velocity of blood flow, a mean systolic blood flow velocity of between 120cm/hour to over 200cm/hour typically indicates vasospasm. A Lindegaard ratio can also be used to support diagnosis. The Lindegaard ratio measures the ratio of the MCA blood flow velocity to the ICA blood flow velocity, and if this value is more than 3, it indicates a mild vasospasm, while a 4.5-6 ratio indicates moderate vasospasm, and a ratio of more than 6 indicates severe vasospasm. The mean systolic blood flow velocity indicating a vasospasm however may vary from artery to artery such as >85 for the posterior cerebral arteries and >80 for the anterior cerebral arteries (Kirsch et al., 2013). Treatment is well, pretty predictable, to relax their vessels, which can be done by giving nimodipine or other vasodilators, commonly used ones include verapamil orally or through an intra-arterial injection (Sehy et al., 2010). Although nimodipine specifically doesn’t seem to reduce the rate of vasospasm, it seems to improve outcome measures in patients with vasospasm with a recommended dose of 60 mg every 4 hours for 3 weeks (Mees et al., 2007). Although induced hypertension has been traditionally used to increase cerebral blood flow during vasospasm, a randomised clinical trial in 2018 was terminated early due to the group receiving induced hypertension having no benefits and higher risk of adverse events over the non induced hypertension group (Gathier et al., 2018). Guidelines have also recommended that blood transfusion be given so as to maintain haemoglobin concentration of greater than 8 to 10 g/dL and suggest that higher haemoglobin concentrations may be appropriate for patients with DCI (Raya & Diringer, 2014).
In patients with SAH, pyrexia or commonly known as a fever may be a complication as blood in the subarachnoid space can irritate the hypothalamus which is the main temperature control centre of the body. This can lead to an elevated intracranial pressure which is not ideal as it can cause vasospasms (Birg et al., 2021). Cooling measures should be done to reduce the patient's temperature. These includes a cold blanket, an Arctic Sun protocol, which is where adhesive gels with cool water circulating in them is sticked to a portion of the patient’s body, a Zoll catheter, where a catheter with cold water flowing in it is thread through the patient’s circulation, or a cold saline infusion (Diringer, 2004, Hoedemaekers et al., 2007). The physiological homeostatic mechanism to counteract cold however, is to shiver, which may increase the patient’s temperature. To reduce this negative feedback mechanism, medications such as buspirone, bromocriptine, propofol, opioids or even paralysis agents could be given (Jain et al., 2017).
Another complication is that of cerebral salt wasting (CSW). During a haemorrhage, the body releases a surge of epinephrine and norepinephrine to help induce vasoconstriction. The high levels of epinephrine and norepinephrine causes atrial natriuretic peptide to be released, and as its name suggests causes large amount of sodium and water to be lost in the urine leading to hyponatremia and hypovolemia (Tenny, 2022). This can be problematic as low blood sodium levels may cause water to diffuse into brain cells further increasing intracranial pressure, as well as reduce cerebral blood flow to the area of vasospasms due to reduced blood volume (Nathan, 2007). CSW can be treated by giving an aldosterone agonist known as fludrocortisone, as this can help the body reabsorb sodium (Mori et al., 1999). Besides, saline infusions or sodium chloride tablets can be given to restore sodium levels (Wijdicks et al., 1985).
The elevated levels of epinephrine and norepinephrine can increase the workload of the heart, which if sustained can lead to ischemia, a decreased ejection fraction, cardiac output, subsequent hypotension, and apex ballooning; this is called Takotsubo cardiomyopathy. Patient’s electrocardiogram reading may show ST elevations. In this case, vasopressors or inotropic agents should be given to increase the mean arterial pressure, so as to restore blood flow. A reduced heart function may also cause pulmonary edema, although it can also be caused by an increased capillary permeability due to high epinephrine and norepinephrine levels in this case. This pulmonary edema can cause hypoxia and/or dyspnea. Treatment includes increasing the positive end expiratory pressure (PEEP) to prevent alveolar collapse, and/or increasing the fraction of inspired oxygen (FiO2) to prevent hypoxia (Raya & Diringer, 2014).
Regardless of stroke types, if severe cytotoxic edema causes a midline shift or severely elevated intracranial pressure, surgery such as hemicraniectomy can be done. This involves opening part of the skull to provide pressure relief for the swollen brain. Medications such as 3% hypertonic saline, 23.4% hypertonic saline, or mannitol may also be used to draw water out from the brain and reduce pressure. These are used mainly for the lack of other options, rather than a therapeutic superiority (Walcott et al., 2012). There are many more effective therapeutics, however their complexity may be too much for this discussion. In general, these work by inhibiting the flow of ions, or water into the brain parenchyma by blocking channels such as aquaporins, ion channels, or antagonising the effects of antidiuretic hormone (Yao et al., 2021). Physicians would also monitor the patient's intracranial pressure, which if elevated over 20mmHg over a sustained period of time may warrant extra caution (Pinto, 2022). These patients will usually already be bedridden, hereafter their head position will be elevated by about 30 degrees and be in a midline position. Sedation medications such as propofol or midazolam can also be given (Oddo et al., 2016). Mechanical hypoventilation can also be used, although there may be risks for other strokes (Balami & Buchan, 2012). Permissive hypercapnia from the hypoventilation may be beneficial in reducing intracranial pressure as CO2 can act as a vasodilator (Mas et al., 2000), inhibit Caspase-3 (Xu et al., 2017), a protease that stimulates apoptosis, and reduces glutamate expression after brain injury; glutamate levels often accumulate after brain injury, causing massive calcium ion influx into the neurons, causing damage (Van Leuven et al., 1977).
Similarly, if patients develop seizures from the infarct, which can happen after any type of stroke, anti epileptic drugs can be used to reduce symptoms. If patients still have dysphagia after treatment, this may cause oral secretions to get stuck in the oral cavity and enter the respiratory tract, causing pneumonia. Treating this can be done by using antibiotics in case of an infection or a feeding tube to prevent malnourishment (Silverman et al., 2002).
If patients have decreased consciousness, measured by the Glasgow Coma Scale of <8, they should be intubated, although this approach has been severely questioned recently as observational data seem to indicate no mortality benefits and perhaps a risk of intubation (Hatchimonji et al., 2021),
Mannitol or hypertonic saline can also be given to reduce fluid in the brain and reduce intracranial pressure (Balami & Buchan, 2012).
Can strokes cause permanent damage?
In brief, the brain requires a constant influx of blood at around 54-56 ml per 100g of brain tissue a minute. During a stroke, the blood supply of the brain is reduced. At around 15-20ml/100g/min of cerebral blood flow, brain cells start to suffer damage, their membrane pumps begin to fail, intracellular processes can’t proceed, and the brain tissues become swollen. At this point, if perfusion is restored, the damage can be reversed. However, when cerebral blood flow drops to <8-10 ml/100g/min, irreversible cell death may occur within 4-8 minutes (Hossmann, 1994).
So yes, strokes can and will cause permanent damage, while the degree of damage depends on the severity of the stroke and the time taken before treatment.
Risk factors of strokes
Unlike diseases such as myocardial infarction, risk factors for strokes are more complicated as there are many varieties of strokes. Even after the distinction between ischemic and hemorrhagic strokes, there may be many different aetiology behind the disease.
The risk factors for ischemic strokes and hemorrhagic strokes may overlap, but there are some notable differences. For example, hypertension is a risk factor for hemorrhagic stroke due to causing blood vessels to rupture, but is also a risk factor for ischemic stroke due to the acceleration of atherosclerosis (Boehme et al., 2017).
Atrial fibrillation is a risk factor for cardioembolic strokes,due to perhaps blood stasis causing thrombus formation and subsequently embolism (Boehme et al., 2017).
Risk factors can be divided into non modifiable and modifiable risk factors. Arguably the most important non modifiable stroke risk factor is age, with the incidence of stroke doubling for each decade after 55 years of age (Roger et al., 2012).
The relationship of sex to stroke risk depends on age where younger women have as high or higher risk of stroke as men, although at older ages, the relative risk is higher for men (Kapral et al., 2005). This may be due to risks associated with pregnancy and postpartum state at a younger age in women. Overall though, the absolute number of strokes is higher in women than men as they live longer (Roger et al., 2012).
Race is also a well-documented risk factor. Blacks are at twice the risk of stroke when compared to their white counterparts and have higher mortality associated with strokes (Cruz-Flores et al., 2011). Furthermore, American Indians have an increased incidence of stroke compared with non-Hispanic whites (Zhang et al., 2008). Asians also seem to be at a higher risk for stroke and are associated with worse outcomes (Turana et al., 2021). These racial disparities may be explained partially by the higher prevalence of stroke risk factors, such as hypertension, obesity, and diabetes mellitus. The racial disparities can also be attributed to rurality, and access to healthcare (Cruz-Flores et al., 2011).
Moving on to modifiable risk factors. These are particularly important as they as the name suggests can be modified and interventions aimed at reducing these factors can reduce stroke risk.
Hypertension is by far the most important modifiable risk factor, having a strong, direct, linear, and continuous relationship with stroke risk (Chobanian, 2003). Even among those who are not deemed hypertensive, the higher the blood pressure, the higher the risk of strokes (Stansbury et al., 2005).
Besides, diabetes mellitus seems to also be an independent risk factor, with a 2-fold increased risk of stroke in diabetic patients. Prediabetes is also a risk factor for stroke. The duration of diabetes is also associated with an increased risk of stroke. In a Northern Manhattan study, diabetes was associated with a 3% relative risk increase of ischemic stroke per year. Compared with nondiabetic participants, those with diabetes mellitus for 0 to 5 years (relative risk increase of 70%) and 5 to 10 years (relative risk increase of 80%) were at increased risk, and the risk for those with diabetes mellitus for ≥10 years increased markedly (relative risk increase of 220%) (Banerjee et al., 2012).
Dyslipidemia is also a major risk factor for stroke, especially for ischemic stroke, due to atherosclerotic plaque formation (Lindenstrøm et al., 1994). The role of dyslipidemia in hemorrhagic stroke however is less consistent, with some observational studies finding no increased risk of intracerebral haemorrhage with statin therapy, whereas some treatment trials have (Hackam, 2012). It is also difficult to infer causality from these observational studies, due to confounding factors. In patients with a history of hemorrhagic stroke then, PCSK9 inhibitors may be of better utility for lowering cholesterol levels due to them not increasing hemorrhagic stroke risk (Qin et al., 2021). However, the relatively large reduction in risk of ischemic stroke and other ischemic events with statins, moreover, outweighs any small increased risk of haemorrhage in most patients.
Physical inactivity has many deleterious effects and an increased risk of strokes is one of them (Zhou et al., 2007) . The relationship between physical activity and stroke may be because of the associated decrease in blood pressure, reduction in diabetes mellitus, and reduction in excess body weight (Manson et al., 1991) .
Diet also influences the risk of stroke, primarily due to its effect on the other risk factors such as hypertension, diabetes mellitus, dyslipidemia etc (Appel et al., 2006). . Although there are limitations to diet studies including recall bias and measurement error, there are some components of a diet that are established risk factors such as excessive sodium, and/or saturated fat intake (Li et al., 2012). Fibre intake on the other hand is inversely associated with stroke risk (Threapleton et al., 2013).
Excessive body weight is also associated with an increased risk of stroke, although there is room for discussion regarding the specific way in which weight affects stroke risk (Suk et al., 2003). Furthermore, the distinction between abdominal obesity, as measured by waist-to-hip ratio, and general increase in weight, as measured by BMI, is being increasingly recognized. This may be because visceral adipose tissue is more strongly linked to metabolic syndrome than subcutaneous adipose tissue (Lu et al., 2014).
Commonly, alcohol has been purported as protective at low amounts (≤2 drinks per day in men and ≤1 drink per day in women), due to most observational studies finding a J-shaped curve for alcohol consumption and disease risk (Gill et al., 1986). This view however has been scrutinised as meta-analyses that adjusted for potential confounders not accounted for in older studies showed no protective effects of low alcohol consumption (Zhao et al., 2023). Furthermore, Mendelian randomization trials have also shown that no amount of alcohol consumption is beneficial, and may potentially be detrimental to health (Millwood et al., 2019).
Abuse of illicit substances, including cocaine, heroin, amphetamines, and ecstasy, is also associated with an increased risk of ischemic and hemorrhagic subtypes of strokes (Esse et al., 2011) .
Cigarette smoking remains a major risk factor for stroke, nearly doubling the risk with a dose–response relationship between pack-years and stroke risk (Bhat et al., 2008). Smoking cessation rapidly reduces the risk of stroke, with excess risk nearly disappearing 2 to 4 years after smoking cessation (K. Kim & Cho, 2008). Secondhand smoke has been identified as an independent risk factor for stroke in the REGARDS cohort, with the risk of stroke increasing 30% after accounting for other stroke risk factors, for those who have been exposed to secondhand smoke versus those who have not been exposed (Malek et al., 2015).
Just as in most causes of mortality. High levels of chronic inflammation leads to an increased risk of stroke. C-reactive protein, measured with a high sensitivity assay (hsCRP) has been widely recognized as a good inflammatory marker in the clinical setting, due to its consistent association with cardiovascular events, long half-life, and stability when stored frozen for prolonged periods of time (Boehme et al., 2017). 2 meta-analyses have shown that high hsCRP level is associated with increased risk of ischemic stroke and overall stroke although causality cannot be inferred (Kaptoge et al., 2010, Y. Zhou et al., 2016). This may be due to in part that inflammatory markers are simply a marker for inflammatory burden from atherosclerotic plaque (Boehme et al., 2017). In fact, genetic studies evaluating the effects of CRP gene mutations have failed to show increased risk of stroke (Zacho et al., 2008). Acute measures of inflammation however, such as CRP may directly contribute to stroke risk. This could be due to interaction with platelets and complement proteins (Eisenhardt et al., 2009). Evidence in this area is lacking, however.
Chronic exposures to common infections may also be a risk factor for strokes. In the Northern Manhattan Study mentioned previously, a composite measure of chronic infection assessed by serologies against several common bacterial and viral infections was associated with an increased risk of all strokes, although each individual infection was not (Elkind et al., 2010). Some studies have also shown that HIV could increase risk of strokes, although the mechanisms are unclear (Ovbiagele & Nath, 2011, Chow et al., 2014). It could involve damage to the artery wall by HIV, adverse metabolic effects of antiretroviral drugs, or other explanations (Gutierrez et al., 2013).
Traumatic brain injuries (TBI), such as a concussion, can also increase the risk of strokes, especially in the first 4 months post TBI, according to a recent meta-analysis that included six cohort studies comparing stroke risks post-TBI versus non-TBI controls. All six of said studies pointed in the same direction that TBI increases risk of strokes, with the pooled hazard ratio being 1.86. This means post-TBI patients are 86% more likely to experience a stroke compared to non-TBI controls (Turner et al., 2021).
Recently, a new area of investigation has arised known as stroke triggers. These include acute events that severely increase the risk of strokes. In a case-crossover analysis from the CHS (n=5888), for example, a recent hospitalisation for infection was associated with an increased risk of stroke. Among 669 participants who experienced a stroke, the risk of stroke was increased after hospitalisation for infection within the previous 90 days. The risk increased as the time interval after hospitalisation decreased: odds ratio 7.3 for a time window of 30 days and odds ratio 8.0 for a window of 14 days. The finding that risk from infection decreases as time from hospitalisation increases indicates that the triggering effects of the hospitalisation with infection diminish over time (Elkind et al., 2011). Other evidence suggests that more minor respiratory and urinary tract infections are associated with increased stroke risk and that vaccinations may help prevent stroke. A Cochrane review of 8 randomised controlled trials with a total of 12 029 participants provides evidence that influenza vaccination decreased cardiovascular outcomes (Clar et al., 2015). An analysis of 20 studies identified that exposure to a 5-µg/m3 increase in particulate matter (i.e. air pollution) smaller than 2.5µm in diameter increases the risk of a stroke by 6% and stroke mortality by 12.5% (Scheers et al., 2015).
Continuing onto genetic factors. Genetic factors may be a bit debated whether they are modifiable or not as it has been shown that the gene-environment interaction may modify how a gene affects the risk of stroke. Nevertheless, these genetic factors are some things to look out for to better understand stroke risk.
There are a few ways by which genes can affect our risk of strokes: gene mutations where strokes are the primary manifestation, gene mutations where strokes are one of the many manifestations, genetic polymorphism associated with a modest increase in risk of strokes, and gene mutations that affect the conventional risk factors of strokes such as hypertension leading to increased stroke risk.
An example of single gene mutations where strokes are the primary manifestations is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. The pathology involves degeneration of the media of small vessels and a prominent progression of leukoencephalopathy (disease of the white matter). It is commonly associated with missense mutations in the gene Notch3, on chromosome 19q2 (Tournier-Lasserve et al., 1991), altering the number of cysteine residues expressed in an extracellular receptor domain (Joutel et al., 2000). Notch3 is a gene that encodes the Notch3 transmembrane receptor responsible for vascular smooth muscle cell differentiation and survival (Coupland et al., 2018).
Other rare single gene disorders that cause stroke include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (Cordeiro et al., 2015), caused by mutations in the HtrA serine peptidase-1 gene (Hara et al., 2009), arterial tortuosity syndrome, caused by mutations in the SLC2A10 gene encoding a glucose transporter, GLUT10 (Coucke et al., 2006); and familial cerebral amyloid angiopathy, caused by mutations affecting cystatin C (Levy et al., 2006).
Among the genetic disorders that have stroke as one of the manifestations, sickle cell anaemia is by far the most well recognized. It is caused by a single point mutation of the haemoglobin beta gene on chromosome 11p15. This defect in the haemoglobin protein causes its shape to distort and form long polymers when deoxygenated, causing occlusion of small vessels (Talahma et al., 2014) . Sickle cell anaemia is seen in approximately 6% of children with stroke, but 25% of individuals with sickle cell anaemia will experience a stroke by 45 years of age (Ohene-Frempong et al., 1998).
Other than that, Fabry disease is an X-linked deficiency in α-galactosidase A, a lysosomal enzyme, caused by mutations in the GLA gene (Boehme et al., 2017). This enzyme normally cleaves terminal alpha-galactose groups from substrates such as glycoproteins and glycolipids, and when dysfunctional causes a buildup of substrates, primarily globotriaosylceramide, in the tissues (Garman, 2007). Mechanisms of the disease have not yet been fully understood but may involve the proliferation of smooth muscle cells, subsequent inflammatory cascade, and endothelial dysfunction (Mishra et al., 2020). In the Fabry Outcome Survey, the frequency of stroke among males aged 25 to 44 years was ≈12 times the expected frequency in the general population (Mehta & Ginsberg, 2005).
Mutations in mitochondrial DNA can also cause mitochondrial encephalopathy. The failure of energy production leads to dysfunction and injury of brain tissues from a metabolic cause rather than from an occlusive vascular process (Boehme et al., 2017).
Genetic disorders affecting connective tissues such as Ehler-Danlos syndrome can also result in impaired vessel-wall integrity through mutations in gene(s) producing collagen, subsequently increasing the risks of stroke (Boehme et al., 2017). Other connective tissue diseases such as Marfan syndrome and ACTA2-associated vasculopathy, are similarly associated with vascular fragility and can lead to arterial dissections. Marfan syndrome is caused by a mutation in the FBN1 gene encoding a protein known as fibrillin-1. This defect increases inflammation, increases smooth muscle cell proliferation, and fibrosis, causing weakened blood vessels (Salik, 2023). Mutations in the ACTA2 gene, encoding actin α2, an isoform of actin found in vascular smooth muscle, leads to actin polymerization and smooth muscle cell proliferation (Guo et al., 2009).
Some genetic variants are also associated with a higher risk of strokes, especially those related to coagulation. In a European cohort, MetaStroke, gene variants in the blood type gene ABO (rs505922) are associated with levels of the coagulation proteins von Willebrand factor and factor 8. Stroke was also associated with the gene although the associations were present for large vessel and cardioembolic stroke subtypes but not for small vessel disease (Williams et al., 2013). In a subsequent collaborative analysis among MetaStroke and several other cohorts, the PITX2 and ZFHX3 genes were also associated with cardioembolic stroke, and the HDAC9 gene and 9p21 locus were associated with large vessel stroke 10.1002/ana.21480. . In a genome-wide association study, a locus near the TSPAN2 gene on chromosome 1 was also associated with large artery strokes. PITX2 encodes a transcriptional activator that is involved in the development of the sinoatrial node and in regulation of ion channels that modulate cardiac conduction, hence variants may cause defective sinus rhythms, predisposing someone to atrial fibrillation. ZFHX3 also encodes a transcription factor. The HDAC9 gene encodes histone deacetylase, although its mechanism for causing atherosclerotic stroke remains uncertain. TSPAN2 encodes tetraspanin-2, a transmembrane protein that regulates signal transduction and plays a role in cell development and growth (Pulit et al., 2016). TSPAN2 is expressed in arterial tissue and blood cells, and TSPAN2 knockout mice have activation of microglia and astrocytes (Boehme et al., 2017).
It also seems that the ApoE allele polymorphism could be associated with a higher risk of stroke, especially ischemic stroke, with ApoE4 being the worst risk factor out of the 3 alleles: ApoE2, ApoE3, and ApoE4 (Sudlow et al., 2006). Lp(a) levels, primarily determined by genetics, seem to also be correlated with a higher risk of stroke (Kumar et al., 2021).
A separate meta-analysis of genome-wide association studies identified a novel locus on chromosome 6p25 (rs12204590), near the forkhead transcription factor FOXF2 gene, that was associated with stroke risk (Chauhan et al., 2016). Deletion of FOXF2 in young patients was associated with extensive white matter disease (French et al., 2014). Functional experiments in mice confirmed that deletion of Foxf2 is associated with cerebral infarction, reactive gliosis, and microhemorrhages (Boehme et al., 2017).
Other less frequent genetic variations such as variants in GUCY1A3, a gene that has been associated with early myocardial infarction, was associated with large vessel stroke and had an allele frequency of 1.5%. This gene encodes the α1 subunit of soluble guanylyl cyclase, which plays a role both in nitric oxide-induced vasodilation and platelet inhibition (Erdmann et al., 2013). Another gene, GCH1, also with an allele frequency of only 1.5%, was associated with small vessel stroke; GCH1 encodes GTP cyclohydrolase 1, which plays a role in endothelial nitric oxide synthase (Malik et al., 2016).
Heritability of strokes also vary across stroke etiologies, where there is similar heritability for cardioembolic (32.6%), and large vessel disease (40.3%), but less so for small vessel disease (16.1%) (Bevan et al., 2012). Family history of stroke increases stroke risk by 30%. Monozygotic twins are at 1.65-fold higher risk of stroke than dizygotic twins (Flossmann et al., 2003).
Avoiding strokes
Although it may be impossible to totally prevent strokes, it is definitely possible for anyone to minimise their risk. Prevention can be divided into primary prevention, before the first event, or secondary prevention, after the first event. Ways to do this incorporate mainly lifestyle changes, and the use of pharmacotherapies, especially in secondary prevention to further target modifiable risk factors.
Arguably the lowest hanging fruit for risk reduction is behavioural modification. Healthy lifestyle behaviours such as abstaining from tobacco, a healthy diet, and regular exercise should start in childhood and continue throughout one's life.
Classically, the lack of standard definitions of exercise intensity and variability in exercise routines, along with difficulty measuring the exposure and long time frame needed to see an effect, have all made studying the effects of exercise on the outcome of stroke difficult. It is now standard to report energy expenditure as metabolic equivalents (METs). One MET is equivalent to the amount of energy expended by an individual at rest in one hour. Using this model, physical activity is classified as sedentary between 1 and 1.5 METs, light between 1.6 and 2.9 METs (eg, playing an activity-promoting video game), moderate between 3 and 5.9 METs (eg, ballet dancing), and vigorous when >6 MET (eg, outdoor bicycling) (Ainsworth et al., 2011). There is an abundance of evidence that suggests an inverse relationship with exercise. Physically inactive individuals (less than 10 MET hours a week) are at a 25%-30% higher risk of stroke compared to physically active individuals (more than 8000 MET minutes a week) (Kyu et al., 2016). However, there are also some studies showing a reverse-J shaped curve for exercise and cardiovascular outcomes, where benefits start to reverse at excessive amounts of exercise (>10 hours a week) (O’Keefe, 2020). This however could be confounded by the fact that those in the upper extremes of exercise quantity may be those elite athletes that tend to use illegal compounds for the performance enhancing effect. The jury is still out on this topic as some have touted the importance of maintaining a high VO2max as a marker of longevity, while others have recommended against excessive exercise (Harber et al., 2017). Case in point, elite athletes training >10 hours a week still have lower mortality risks compared to sedentary individuals, but whether they have lower mortality risks compared to individuals exercising a moderate amount is debatable. Currently, an accepted general guideline from the WHO is to get 150 minutes of moderate intensity exercise a week as a bare minimum (World Health Organization: WHO, 2022).
On the side of diet, a Cochrane review in 2013 suggested that adherence to a healthy diet can decrease lifetime risk of stroke by ≈20% (Rees et al., 2013). We won’t dive into the nuances of nutrition as that is a topic for another day. The strongest evidence in favour of a nutritional intervention is perhaps the Mediterranean diet, characterised by high intake of vegetable, fruits, legumes; olive oil as the principal source of fat; preferential consumption of fish and poultry over red meat; low dairy intake; and an option of low intake of red wine (Willett et al., 1995). The PREDIMED study (Primary Prevention of Cardiovascular Disease with a Mediterranean Diet), a multicenter randomised trial that compared the effects of the Mediterranean diet on cardiovascular outcomes found an approximate 30% reduction of stroke incidence for a Mediterranean diet high in olive oil, and a 50% reduction for a Mediterranean diet high in mixed nuts, compared to a standard low fat diet (Estruch et al., 2013). Similarly, a meta-analysis showed that the Dietary Approaches to Stop Hypertension diet was associated with a nearly 20% lowered risk of stroke (Kwon et al., 2013). The benefits of polyphenols from plant sources may also be worth mentioning. Polyphenols can come in many various forms, and have been shown consistently in epidemiological study and intervention studies to reduce the risk of strokes and established markers of stroke risk (Noad et al., 2016). Polyphenols exert their effects in many ways, potentially involving decreasing inflammation (Denny et al., 2014), reducing LDL particle numbers (Hernáez et al., 2015), improving HDL function (Hernáez et al., 2014), maintaining endothelium-dependent vasodilation (Lamuela-Raventós & Quifer-Rada, 2016), and nitric oxide induced vasodilation (Botden et al., 2011). In general, any diet that revolves around the high intake of plant-based nutrients, low salt, and curbing of saturated fats and simple sugars, such as the Mediterranean, Dietary Approaches to Stop Hypertension, US Department of Agriculture food patterns or AHA diets, are recommended for the purpose of good cardiovascular health and primary stroke prevention.
Surprisingly, coffee intake seems to be inversely correlated with risk of strokes despite the acute rise in blood pressure post consumption of coffee. However, this effect seems to be also present in decaffeinated coffee, suggesting the potential role of other compounds in coffee besides caffeine (Chan et al., 2021). That being said, emerging research suggests an individualised plan of coffee consumption for people with different genetics. There exists polymorphism in the main enzyme that metabolises caffeine, coded by the gene CYP1A2, which can affect the effects of caffeine on those individuals (Palatini et al., 2009, Hou et al., 2021). It seems that individuals with CYP1A2 C alleles are associated with a higher risk of stroke (Mao et al., 2020). This could be due to the different rates of metabolism of caffeine, predisposing to hypertension, or it could be not related to caffeine, as of now research is still lacking.
Among smokers, cessation leads to a decrease in stroke risk to levels similar to nonsmokers by 5 years (Wolf et al., 1988). Hence, smoking cessation should be a primary focus of a smoker if he/she wants to minimise the risk of strokes.
In postmenopausal women taking hormone replacement therapies, data seems to be conflicting. In one observational study, it appears that early onset of initiation (0-5 years) is associated with a decrease in risk of strokes. Late initiation is associated with a higher risk of strokes when conjugated equine oestrogen was used as single therapy whereas combined hormonal therapy was associated with hemorrhagic stroke risk (Carrasquilla et al., 2017). In another study however, hormone replacement therapy was associated with an increased risk of stroke regardless of initiation time (Johansson et al., 2022). Overall however, the data seems to point in the direction that hormonal use can increase the risk of strokes (Santen et al., 2010). It is also likely that different hormonal therapies carry different risks and should be evaluated properly before administration.
Up next are targeted risk factors modification, which includes treating underlying risk factors such as hypertension, diabetes, obesity etc.
A meta-analysis of 147 trials, including 464 000 participants without a history of vascular disease or stroke, found that blood pressure reductions of 10 mm Hg systolic or 5 mm Hg diastolic were associated with a 40% reduction in stroke risk. The effect is present even at levels below those thought to be normotensive and down to 110 mm Hg systolic and 60 mm Hg diastolic. In the meta analysis, it was shown that β-Blockers, thiazide diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers, being the most widely studied agents, exert most of their benefits through blood pressure control, although there are some class difference.There also seems to be an additional minor protective effect of calcium channel blocker on stroke risk beyond the other medications used to reduce blood pressure. In patients aged 60-69, it appears a multidrug approach, with 3 antihypertensives at half standard dose was more effective at lowering stroke risk (62%), compared with standard dose monotherapy, where the benefits were halved (Law et al., 2009). In hypertensive patients, lifestyle modification and pharmacological therapy should be combined to achieve strict blood pressure goals <140/90 mm Hg. Although the effects on stroke prevention are still unproven, it may be reasonable to target systolic blood pressure goals <120 mm Hg in individuals who are at low risk for complications from antihypertensive therapy (Boehme et al., 2017).
In terms of diabetes mellitus, there seems to be a bit more of a complex interplay. Intensive glucose therapy seems to lower risk of other cardiovascular diseases such as myocardial infarctions but has no overall effect on stroke risk (Hemmingsen et al., 2013). This suggests that it may be that the greatest effects of hyperglycemia on stroke risk accumulate early in the course of the disease and in the prediabetes stage, rather than late in the course when comorbid cardiovascular risk factors are more likely to be present. This hypothesis is supported by a randomised controlled trial of pioglitazone used after stroke or TIA in those with prediabetes. The combined outcome of recurrent stroke and myocardial infarction was seen in 9.0% of the pioglitazone group and 11.8% of the placebo group during a ≈5-year follow-up (Kernan et al., 2016). The takeaway is that more effort should be put into diagnosing prediabetes and diabetes as early as possible before the damage is done, and should be managed with intensive lifestyle intervention, or with medication, as indicated by a qualified physician.
The role of dyslipidemia in stroke has been discussed earlier, and should be targeted if present in a patient. Large epidemiological studies, such as the MRFIT, have shown a positive association between increased cholesterol levels and stroke mortality. Primary stroke prevention trials evaluating the effects of statins have shown risk reduction from 11% to 40% depending on the type of statin. However, these results are mainly driven by a decrease in risk of ischemic strokes, not hemorrhagic strokes (Féasson, 2002). The SPARCL trial (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), provides the most direct evidence about the role of statins in secondary prevention patients. Patients (n=4731) with stroke or TIA and baseline LDL 100 to 190 mg/dL were randomised to atorvastatin 80 mg versus placebo beginning 1 to 6 months after their event. Atorvastatin was associated with an ≈2% absolute reduction in recurrent stroke risk (13.1% versus 11.2%) during a median follow-up of 5 years, with a relative risk reduction of 16%. These benefits were consistent across all ischemic stroke subtypes, which means all ischemic stroke patients, regardless of underlying aetiology should receive statin therapy (Amarenco et al., 2006). Furthermore, the addition of ezetimibe on top of simvastatin seemed to lower risk of strokes especially in those who had a prior stroke before randomization in the IMPROVE-IT trial (Bohula et al., 2017). Also as discussed above, if a patient is especially worried about the increase in risk of hemorrhagic stroke, though minor, may opt for PCSK9 inhibitors.
In terms of primary stroke prevention, antiplatelet therapies have little evidence to back them up. A meta-analysis of vascular events in 6 primary prevention trials, showed no overall effect of aspirin on stroke incidence (Baigent et al., 2009). Dual antiplatelet therapies such as the combination of aspirin and clopidogrel are recommended against for primary prevention as they do not lower risk of strokes, and increases risk of bleeding (Bhatt et al., 2006).
In terms of secondary stroke prevention however, antiplatelet therapies have been shown to be beneficial. Aspirin at 30-1500 mg daily can reduce vascular events by 25% in patients with ischemic strokes, or transient ischemic attacks (Baigent et al., 2002). However, high doses of aspirin are associated with higher risk of extracranial bleeding and overall side effects, hence the minimum effective dose is recommended. In terms of secondary prevention, clopidogrel (75mg) is slightly but not statistically significantly more effective as medium-dose aspirin (325mg) at lowering the composite measure of vascular events (Creager, 1998). Furthermore, clopidogrel’s higher cost also limits its usage. In The Second European Stroke Prevention Study (ESPS-2), dipyridamole was as effective as aspirin at preventing recurrent strokes (Forbes, 1997).
Combination therapies such as aspirin-clopidogrel dual therapy has not been shown to be more effective than aspirin or clopidogrel alone at preventing vascular events (Diener et al., 2004). However, dual therapy may have a role in specific subtypes of stroke. Aspirin-clopidogrel dual therapy has been shown to reduce the rate of embolism compared to aspirin alone in patients with recent symptomatic carotid artery stenosis >50% (Markus et al., 2005). That being said, aspirin-clopidogrel dual therapy seems to cause more bleeding complications. In the previously mentioned ESPS-2 study, aspirin-dipyridamole dual therapy was superior to both aspirin and dipyridamole monotherapy (Forbes, 1997).
In patients who have atrial fibrillation, it is well recognized that warfarin is extremely effective in lowering the risk of strokes. Multiple randomised controlled trials have shown a positive effect of warfarin compared to placebo or aspirin for patients with atrial fibrillation (Petersen et al., 1989, Wilkins, 1991). Aggregate analysis of these studies showed that the intensity of anticoagulation should be to produce INR of between 2.0-2.9. Since then, novel anticoagulants such as dabigatran, edoxaban, rivaroxaban, and apixaban, were shown to be as efficacious as warfarin in reducing strokes in patients with atrial fibrillation, while reducing the rates of major haemorrhages (Connolly et al., 2009).
A device known as the Watchman device, has been approved by the FDA for use in patients who: (1) have nonvalvular AF, (2) carry an increased risk of stroke, (3) are indicated for and may take warfarin, and (4) have a reason to seek a non drug alternative to anticoagulation (Waksman & Pendyala, 2015). This device is a quarter-sized, parachute-shaped device that closes off the left atrial appendage, as it is estimated 90% of thromboembolic material originates from there in patients with nonrheumatic atrial fibrillation. Similar to the appendix, the left atrial appendage's function seemed to have become obsolete over the years. The implantation of the Watchman device is complex but involves the insertion of a catheter through the left femoral vein all the way up to the left atrium where the Watchman device is implanted to seal off the left atrial appendage. Patients are generally expected to be on therapeutic doses of warfarin for at least 45 days after a closure procedure, followed by 6 months of dual antiplatelet therapy and indefinite aspirin use (Boehme et al., 2017). In the two trials that compared the Watchman device to warfarin, it has been shown that the Watchman device is as efficacious as warfarin in preventing ischemic strokes (Reddy et al., 2013, Holmes et al., 2014).
In patients with congestive heart failure, evidence is lacking in favour of the use of anticoagulants courtesy of a meta-analysis including 3663 patients (M. Lee et al., 2013).
In patients with patent foramen ovale, closure of the foramen ovale is weakly recommended, along with antiplatelet therapy (Kuijpers et al., 2018).
For those with symptomatic carotid stenosis, carotid endarterectomy on top of best medical management might be of some benefit for participants with 50% to 69% symptomatic stenosis and highly beneficial for those with 70% to 99% stenosis. Overall, stenting and carotid endarterectomy seems to be equally effective at preventing strokes in asymptomatic and symptomatic carotid stenosis patients, although stenting had a higher risk of stroke in the periprocedural period (Rerkasem et al., 2020).
Comments
Post a Comment