Large artery-to-artery embolism causes about 40% of ischaemic strokes.

The most common identified cause of ischaemic stroke is large artery-to-artery embolism. Focal brain infarction results from interruption of blood flow, most commonly from emboli from thrombi on the surface of atheromatous plaques in large arteries, the aorta or its major branches and particularly the internal carotid vertebral and basilar arteries. Rarely emboli may break off from thrombi formed on dissected flaps of the arterial wall.

Large-artery (carotid or vertebral) occlusion by thrombosis developing on atheroma is considerably less common causing less than 10% of infarcts [29].

Cardiac embolism causes between 20% and 30% of ischaemic strokes.

The most important cardiac cause is non-valvular atrial fibrillation. Known paroxysmal AF is thought to as likely as permanent atrial fibrillation to cause stroke. Occult paroxysmal AF is believed to be a significant cause of large cortical strokes when there is no other apparent cause and particularly when there have been typical wedge-shaped cortical lesions in two different vascular territories. The frequency and duration of attacks of AF necessarily being a significant risk factor for stroke are under active investigation with implantable and wearable prolonged recording devices and indirectly by assessing the value of anticoagulation compared with antiplatelet therapy after likely embolic stroke of unknown cause. Since AF is a marker for more severe cardiovascular and arterial disease, some patients in AF, estimated to be about 25%, will have another cause for stroke [30]. The rate of recurrent stroke in non-valvular AF patients is about 4% in a month. After stroke or TIA when the patient is in sinus rhythm, particularly when the stroke syndrome is a PACI with normal carotids, or large POCI, and particularly if there are multiple lesions in two vascular territories, the possibility of cardiac embolism and intermittent AF needs to be considered. Different strategies have been proposed to detect intermittent AF after stroke from repeated ECGs to Holter monitor to 48 h of continuous cardiac monitoring with different detection rates [28]. It is likely that in the future detection may require several months monitoring with an implantable device. The CRYSTAL AF study in 441 patients found that long-term monitoring with an insertable cardiac monitor (ICM) detected atrial fibrillation (lasting >30 s) by 6 months after stroke in 8.9% of patients in the ICM group versus 1.4% of patients in the control group (hazard ratio, 6.4; 95% CI, 1.9–21.7) [28].

Other causes of cardiac embolism:

Small deep infarcts result from occlusion of single small perforating arteries. The most common sites are in the internal capsule from occlusion of perforating striate branches of the M1 segment of the middle cerebral artery deep in the Sylvian fissure, posterior cerebral perforators to the thalamus and paramedian basilar perforators to the pons. The occlusion is usually local thrombosis of arterial wall damaged and narrowed by lipohyalinosis associated with age, hypertension and diabetes. Less commonly occlusion may be embolic from a proximal source (heart, aorta, carotid).

The state of the brain arterial collateral circulation often determines the size and location of infarction after arterial occlusion.

The anterior, middle and posterior cerebral arteries are not end arteries. Collaterals exist between the arteries across the distal boundaries of their territories. After occlusion of one intracerebral artery, significant perfusion from the surrounding arteries often limits infarct size. For example, after occlusion of the proximal middle cerebral artery by embolism, the size of the resulting infarct is determined by collateral flow from the anterior and posterior cerebrals. Infarct after MCA proximal occlusion may be restricted to the deep grey and white matter supplied by the occluded striate vessels, sparing the overlying subcortical white matter and cortex, or larger infarcts up to the entire MCA territory.

In internal carotid occlusion, collateral flow through the anterior communicating artery and posterior cerebral branches may prevent any infarction (see below).

When the internal carotid is occluded, ischaemia may be confined to small patchy infarcts in watershed areas in a parasagittal arc at the boundaries between territories of the anterior, middle and posterior cerebral arteries or lead to large infarcts in part of or the entire middle and anterior cerebral arterial territories. The resulting stroke syndrome may stutter over hours or days and fluctuate, possibly worsening with erect posture. The clinical defects may be subtle because the functional areas affected are relatively silent affecting shoulder and trunk rather than limb motor function, higher cortical visual function and the anterior frontal lobe.

In the vertebrobasilar circulation, basilar artery occlusion may cause paramedian pontine perforator occlusion or more extensive often catastrophic midbrain and pontine infarction, producing coma if the midbrain is involved and locked-in syndrome if confined to the pons.

In about 10% of people the posterior cerebral artery originates from the internal carotid via the posterior communicating artery so that occipital lobe infarction may result from carotid territory disease. For this reason isolated PCA territory occipital infarcts should have cervical carotid and Circle of Willis arterial imaging. Conversely a large posterior communicating artery may preserve the occipital and inferior temporal lobes after basilar occlusion.

Venous infarction after venous sinus thrombosis is uncommon and occurs in prothrombotic states from oestrogen-containing oral contraceptives and in inflammatory bowel disease. It usually presents as a parasagittal haemorrhagic infarction, often with headache, occasionally thunderclap, and seizures.

The essence of the diagnosis of ischaemic stroke is deciding whether or not there has been sudden or very rapid onset of a focal brain defect, while excluding mimics, particularly persistent deficits after focal seizures, or migraines particularly with aphasia or hemiparesis, and from functional illness—see mimics section. Primary confusion or depressed consciousness without focal signs is unlikely to be due to stroke and more likely due to encephalopathy, sepsis, meningitis, encephalitis or sometimes persistent seizure.

The evaluation of suspected acute stroke is urgent, since if thrombolysis is possible within 4.5 h of stroke, a worthwhile improvement in outcome is likely. If there is ICA or proximal MCA occlusion, recanalization with IV thrombolysis is unlikely, but provided that intraarterial clot extraction commences before 6 h from the onset of symptoms, the chance of recovery disability-free will be improved. The earlier these measures are undertaken, the better the outcome so that no time can be wasted.

History, medications particularly anticoagulants or antiplatelets, matters relevant to safety of thrombolysis and previous functional status must all be covered quickly.

The diagnostic process begins with the recognition usually from the patient’s, sometimes a witness’s, account of their illness, of the abrupt or rapid onset of symptoms most likely to arise from a focal CNS defect (and not from a cranial nerve, such as Bell’s palsy, or from a peripheral nerve or spinal root causing wrist and finger or foot drop). The sudden or rapid evolution suggests ischaemic stroke, particularly combined with the focal impairment of CNS function. The clinical defects in most ischaemic strokes develop over seconds to a few minutes, but defects may fluctuate and in rare cases continue to worsen over several days.

Use the NIH stroke score as the skeleton of your examination approach supplemented with attention to pupils, eye movements and, if practical, ability to walk. The NIHSS is a very useful guide to important aspects of the examination, especially for language, and can be performed very quickly. Most of the necessary NIHSS observations are covered in the quick screening examination also designed to identify and localize any relevant brain lesion outlined below (http://​www.​ninds.​nih.​gov/​doctors/​NIH_​Stroke_​ Scale.​pdf). There is more than one app available—I use 10-Second NIHSS for iPhone.

Stroke mimics need to be excluded. Migraine, seizure and functional syndromes are the most common, and the inability to speak is one of the more common stroke mimic presentations (and challenging to distinguish from global aphasia).

Recognition of post-ictal states after unobvious seizures can be challenging. Past known epilepsy is helpful, as is initial obtundation clearing during the acute assessment. Prolonged post-ictal aphasia, hemianopia and hemiplegia all may occur without there having been a preceding recognized partial or generalized seizure.

Sudden global aphasia without weakness can be due to TIA, stroke, seizure or migraine and is quite commonly functional. If available, urgent MRI DWI scan is ideal.

Functional weakness is common, especially in the setting of acute severe headache. Particularly useful guides to definite functional weakness in the setting of emergency assessment are the dropped shoulder sign on testing shoulder abduction and a give-way pattern of jerky weakness. Normal motor power can be demonstrated in suspected functional leg weakness by having the patient stand, using the examiner for balance, and while holding one leg off the ground 1. Rise to tip toe, lifting their body weight off the ground showing ankle plantar flexion is normal; and 2. perform a partial knee bend followed by straightening the leg – showing hip and knee extension are normal. It can be helpful to the patient’s recovery to point out that power can be normal with some activities but not others – see www.​neurosymptoms.​org for an in depth discussion of functional symptoms by Dr. Jon Stone intended to help patients get better.

Global cognitive impairment from metabolic encephalopathy (ME) is sometimes mistaken for stroke—attention to onset and progression of symptoms and awareness of this entity should avoid this problem. Depressed consciousness alone is a highly unusual presentation for stroke, since upper brainstem infarction affecting the reticular activating system is required and is invariably accompanied by either or both of pupil inequality and ocular misalignment. In ME/delirium, there is usually impaired arousal either sleepiness or, particularly in postoperative delirium, hypervigilance with agitation. Language if affected at all shows mild nominal aphasia not sufficiently severe to impair communication. The striking and definitive abnormalities are with attention and concentration tested rapidly and effectively by orientation in place and time and the ability to register three objects and then recall them after a working memory task such as subtraction of serial sevens or days of the week backwards. In the usual case, even registration of the three objects is unsuccessful. There may be lack of cooperation with formal neurological examination in the presence of observable bilateral limb use. Other typical features (when present) include multifocal myoclonic jerks and asterixis.

Occasionally, the apparently acute onset of Bell’s palsy, peroneal nerve palsy and particularly radial nerve palsy, the latter usually acquired from compression while intoxicated or sedated, is mistaken for stroke.

Bell’s palsy symptoms often begin in mild form on the preceding day and are much worse on the day of presentation. The constellation of face LMN weakness, “numbness”, unilateral loss of taste, pain behind the ear and hyperacusis in the same ear are common in Bell’s palsy and do not occur in stroke. There is no other cranial nerve (horizontal diplopia from the sixth nerve as it curves around the seventh nerve nucleus in the brainstem) or long tract signs such as arm or leg weakness. Speech, language and swallowing are not affected.

Radial nerve palsy from compression against the humerus while intoxicated produces weakness of wrist, finger and thumb extensors, and the flexed wrist and finger posture causes finger abduction to be weak, unless tested with the forearm, hand and fingers on a flat surface. Peroneal nerve palsy causes characteristic weakness of ankle dorsiflexion and eversion with normal inversion (performed by tibial nerve innervated tibialis posterior) never seen in acute stroke. Knee and ankle jerks and ankle plantar flexion are normal. The lower motor neuron weakness causes a typical flaccid flopping down of the foot when walking. Symptoms of nerve compression may be first noticed on waking and are often the result of peripheral nerve compression during deeper than usual sleep from intoxication. Partial anaesthesia with alcohol, sedatives and/or analgesia for chronic pain is the common cause and often either not mentioned or flatly denied.

Vertigo may be due to stroke but is most often due to idiopathic episodic vertigo, commonly due to migraine.

The Oxford stroke study categorization of stroke cases is both a guide to the examination findings most useful to determine lesion location and severity and a guide to likely outcome. Lesions were divided on clinical grounds into:

Total anterior circulation infarct—TACI

Patients with large acute lesions of the MCA territory are easily recognized. In the dominant hemisphere, aphasia is a distinctive feature. In the non-dominant hemisphere, speech is often dysarthric, and there will be sensory and visual neglect or hemianopia. If there is a large premotor lesion, the head and eyes will be deviated away from the lesion, with apathy and reduced responsiveness.

Small cortical infarcts in the posterior cerebral, MCA or anterior cerebral territory will cause one or more components of the TACI syndrome, hemianopia with or without sensory loss, sensory and/or visual neglect in the nondominant hemisphere, receptive or expressive aphasia in the dominant hemisphere and paralysis largely confined to the mid-face and upper limb in the MCA territory or the leg only in the anterior CA territory.

Determining that there is a unilateral hemisphere cortical lesion and its extent means systematically checking for these easily recognized signs of focal brain dysfunction.

Lacunar syndromes tend to affect face, arm and leg with equal severity, usually with no defect of language or of sensory neglect (with occasional exceptions) or visual field defect, headache, drowsiness or vomiting. Pure motor stroke and sensorimotor stroke tend to occur in the genu or front part of the posterior limb of the internal capsule or ventral pons dysarthric clumsy hand; ataxic hemiparesis tend to occur in the more posterior part of the internal capsule, most likely in the territory of perforators from the posterior cerebral artery or in the pons. Pure sensory stroke occurs in the thalamic classical lacunar syndromes:

Vertigo may be the sole obvious clinical feature of stroke, particularly if the HINTS criteria are met. HINTS (horizontal VOR, multidirectional nystagmus and test of skew, a cover test to demonstrate vertical ocular misalignment when fixing on a Snellen chart letter or similar improvised fixation target) [31]. The brainstem or inferior cerebellar lesions are small, and early MRI DWI is only about 80% sensitive. A delayed scan after 48 hours is more likely to identify the lesion. Vertigo is more commonly due to peripheral vestibular lesions; most of these are episodic idiopathic acute vertigo—the classic cause, inflammatory vestibular neuritis, is fairly rare with an incidence of ~3/100,000/year. A few are typical Meniere’s with unilateral deafness, roaring tinnitus and acute vertigo lasting 30–75 min with reversing horizontal nystagmus. Some are clearly migrainous in migraine sufferers with typical headaches at the time of the dizziness; many others are a similar idiopathic syndrome usually suspected to be a migraine aura with or without headache. Vertigo can last weeks in the absence of abnormal signs. Occasionally with migrainous vertigo, there may be positioning nystagmus with head down to right, to left and in the midline.

In this patient group, the examination features of particular importance are:

Patients whose only obvious clinical problems are vomiting and inability to walk should be suspected of large-volume cerebellar infarction or haemorrhage—the fatal gastroenteritis described by CM Fisher. Sudden deterioration from brainstem compression by the swollen cerebellum can cause death in a matter of minutes [32].

The key point is that the outcome from large MCA strokes is very poor. 4/10 will be dead inside a month and more than half within 6 months. All other strokes do fairly well, with low immediate death rate and two-thirds independent at 3 months.

Life-threatening brain swelling occurs in up to 10% of patients with middle cerebral artery (MCA) infarct. Prognosis is poor, death rate nearly 80%. No medical treatment is effective. Deterioration from raised intracranial pressure causes increasing drowsiness with Cheyne–Stokes respiration within 24 h in up to a third, but more commonly begins between the second and fifth day after stroke.

If an MCA infarct has occurred larger than 50% of the MCA territory on CT scan, irrespective of thrombolysis and clot retrieval, and the patient is otherwise healthy and under age 60, the outlook for reduced disability and improved survival is significantly better after decompressive hemicraniectomy. The outcome is better still if this is done early before significant deterioration and in all cases must be done within 48 h of the stroke.

Pooled analysis of 93 patients from three trials with decompressive surgery undertaken within 48 h of stroke onset showed that substantially more patients in the decompressive-surgery group had an mRS ≤4 with 51% absolute risk difference, an mRS ≤3 with 23% absolute risk difference and survived with 50% absolute risk difference for numbers needed to treat two for survival with mRS ≤4, four for survival with mRS ≤3 and two for survival regardless of functional outcome.

The infarct volume criteria used in the three pooled RCTs were as follows: more than 145 cm³ on diffusion-weighted MRI in DECIMAL, brain CT ischaemic changes affecting more than two-thirds of the MCA territory including the basal ganglia in DESTINY and brain CT ischaemic changes affecting at least two-thirds of the MCA territory with space-occupying oedema in HAMLET [35].