Ischemic Stroke Syndromes – Causes, Symptoms, Treatment

Ischemic stroke syndromes have a multitude of possible causes, characterized by a rule of quarters: 25% cardioembolic, 25% artery embolic (large-artery disease), 25% lacunar (small-vessel disease), and 25% due to other causes, with global variation in proportions by population.^[rx] In contrast, acute coronary syndromes are overwhelmingly due to rupture or erosion of an atherosclerotic plaque, with in situ formation of thrombus on the plaque, which in turn causes arterial obstruction.^[rx] We compare stroke syndromes and coronary syndromes in.

Stroke, a cerebrovascular accident, is prevalent across patient populations and can be a significant cause of morbidity and mortality. Stroke can be categorized as ischemic, hemorrhagic, or subarachnoid. Among ischemic strokes, the Trial Org 10172 in Acute Stroke Treatment (TOAST) classification is used to subdivide the categories that include cardioembolism, small-vessel occlusion, large-artery atherosclerosis, and stroke of undetermined etiology. [rx]

Types of Ischemic Stroke

Ischemic stroke can be divided into two main types: thrombotic and embolic. Deprived of oxygen and other nutrients, the brain suffers damage as a result of the stroke.

• A thrombotic stroke – occurs when diseased or damaged cerebral arteries become blocked by the formation of a blood clot within the brain. Clinically referred to as cerebral thrombosis or cerebral infarction, this type of event is responsible for almost 50 percent of all strokes. Cerebral thrombosis can also be divided into an additional two categories that correlate to the location of the blockage within the brain: large-vessel thrombosis and small-vessel thrombosis. Large-vessel thrombosis is the term used when the blockage is in one of the brain’s larger blood-supplying arteries such as the carotid or middle cerebral, while small-vessel thrombosis involves one (or more) of the brain’s smaller, yet deeper, penetrating arteries. This latter type of stroke is also called a lacunar stroke.
• An embolic stroke – is also caused by a clot within an artery, but in this case, the clot (or emboli) forms somewhere other than in the brain itself. Often from the heart, these emboli will travel in the bloodstream until they become lodged and cannot travel any farther. This naturally restricts the flow of blood to the brain and results in near-immediate physical and neurological deficits.

Pathophysiology

In thrombosis, there is an obstructive process that prevents blood flow to some regions of the brain. Risk factors include atherosclerotic disease, vasculitis, or arterial dissection.

Embolic events occur when there is a clot that originated from another location in the body. Most commonly, the source of the clot is the valve or chambers of the heart, for example, when a clot forms within the atria in atrial fibrillation and dislodges into the arterial vascular supply.

Other less frequent causes include venous, septic, air, or fat emboli. Lacunar infarcts are usually seen in the subcortical areas of the brain and occur due to small vessel disease. The proposed mechanism is a perforating artery in the subcortical region that causes the blood vessel occlusion.

Ischemic Stroke Syndromes

Ischemic strokes can present in pre-determined syndromes due to the effect of decreased blood flow to particular areas of the brain that correlate to exam findings. This allows clinicians to be able to predict the area of the brain vasculature that can be affected.

Middle Cerebral Artery (MCA) Infarction

The middle cerebral artery (MCA) is the most common artery involved in stroke. It supplies a large area of the lateral surface of the brain and part of the basal ganglia and the internal capsule via four segments (M1, M2, M3, and M4). The M1 (horizontal) segment supplies the basal ganglia, which is involved in motor control, motor learning, executive function, and emotions. The M2 (Sylvian) segment supplies the insula, superior temporal lobe, parietal lobe, and the inferolateral frontal lobe.

The MCA distribution involves the lateral cerebral cortex. MCA syndrome is best explained by the understanding of the somatosensory cortex, in which the lateral portion contains motor and sensory functions that involve the face and upper extremity. This correlates to the classical presentation of contralateral hemiparesis, facial paralysis, and sensory loss in the face and upper extremity. The lower extremity may be involved, but upper extremity symptoms usually predominate. Gaze preferences towards the side of the lesion may be seen. Additional symptoms include:

• Dysarthria characterized by difficulty phonating words due to the physical weakness of the muscles of the face used for phonation.
• Neglect in which the patient seems to “ignore” a hemisphere of their world due to an inability to see that area.
• Aphasia or the inability to produce or remember words due to injury to the verbal centers of the brain.

Anterior Cerebral Artery (ACA) Infarction

The anterior cerebral artery (ACA) provides blood supply to the frontal, prefrontal, primary motor, primary sensory, and supplemental motor cortices. Pure ACA infarcts are uncommon because of significant collateral blood supply provided by the anterior circulating artery.  The sensory and motor cortices receive sensory information and control movement of the contralateral lower extremity. The supplemental motor area contains the Broca area, which is involved in the initiation of speech. The prefrontal cortex is used to organize and plan complex behavior and is thought to influence the personality.

The ACA distribution involves the medial cerebral cortex. The somatosensory cortex in that area comprises a motor and sensory functions of the leg and foot. The clinical presentation of an ACA infarction includes contralateral sensory and motor deficits in the lower extremity. The upper extremity and face are spared. Kumral et al. examined clinical spectrums of ACA with correlation to MRI/MRA and demonstrated that left-sided lesions presented with more transcortical motor aphasia, in which patients have difficulty responding spontaneously with speech, but repetition is preserved. Right-sided lesions presented with more acute confusional state and motor hemineglect (unilateral motor function is lost) [7].

Posterior Cerebral Artery (PCA) Infarction

The superficial posterior cerebral artery (PCA) supplies the occipital lobe and the inferior portion of the temporal lobe, while the deep PCA supplies the thalamus and the posterior limb of the internal capsule, as well as other deep structures of the brain. The occipital lobe is the location of the primary and secondary visual areas, where sensory input from the eyes is interpreted. The thalamus relays information between the ascending and descending neurons, while the internal capsule contains the descending fibers of the lateral and ventral corticospinal tracts.

PCA infarctions can be divided into deep and superficial categories, based on the PCA supply. If the deep segments of the PCA are involved, symptoms may include hypersomnolence, cognitive deficits, ocular findings, hypoesthesia, and ataxia. Ocular findings may include homonymous hemianopsia, in which patients experience visual field deficits in one half of their visual field. Larger infarcts that involve the deep structures can lead to hemisensory loss and hemiparesis due to the involvement of the thalamus and the internal capsule. Superficial infarcts present with visual and somatosensory deficits, which can include impairment of stereognosis, tactile sensation, and proprioception. Rarely, bilateral PCA infarcts present with amnesia and cortical blindness. Cortical blindness is due to lesions in the optic radiation that causes vision loss. A unilateral headache is a common finding, which can be confused with a complicated migraine. [rx][rx]

Vertebrobasilar Infarction

The vertebrobasilar region of the brain is supplied by the vertebral arteries and the basilar arteries that originate within the spinal column and terminate at the Circle of Willis. These areas supply the cerebellum and brainstem.

The clinical presentation includes ataxia, vertigo, headache, vomiting, oropharyngeal dysfunction, visual-field deficits, and abnormal oculomotor findings. Patterns of clinical presentation vary depending on the location and the infarction pattern of embolism or atherosclerosis. [rx][rx]

Cerebellar Infarction

Patients may present with ataxia, nausea, vomiting, headache, dysarthria, and vertigo symptoms. Edema and rapid clinical deterioration can complicate cerebellar infarction.

Lacunar Infarction

Lacunar infarcts result from occlusion of a small perforating artery. The exact mechanism is under debate, as the nature of the infarct can result from intrinsic vessel occlusion or an embolism. Infarction in this territory can present with pure motor or sensory loss, sensorimotor deficit, or ataxia with hemiparesis. [rx][rx]

In addition to the neurological exam, the neck is examined to rule out signs of meningitis via palpation of the paraspinal musculature and testing the range of motion. The presence of a carotid bruit indicates underlying atherosclerosis. Besides testing extraocular muscle function and the visual field for visual defects, a fundus examination is performed to check for hypertensive changes, retinal hemorrhage, and emboli. A peripheral vasculature exam includes palpation of the carotid, radial, femoral, and posterior tibial pulses. A cardiac exam is also performed to detect murmurs, rubs, gallops, or arrhythmias.[rx]

Causes of Ischemic stroke syndromes

The etiology of ischemic stroke is due to either a thrombotic or embolic event that causes a decrease in blood flow to the brain. In a thrombotic event, the blood flow to the brain is obstructed within the blood vessel due to dysfunction within the vessel itself, usually secondary to atherosclerotic disease, arterial dissection, fibromuscular dysplasia, or inflammatory condition.

TIA subtypes, classified according to the pathophysiological mechanisms are similar to ischemic stroke subtypes. They include large artery atherothrombosis, cardiac embolism, small vessel (lacunar), cryptogenic, and uncommon subtypes such as vascular dissection, vasculitis, etc. The common risk factors for all TIA include diabetes, hypertension, age, smoking, obesity, alcoholism, unhealthy diet, psychosocial stress, and lack of regular physical activity. A previous history of stroke or TIA will increase substantially the subsequent risk of recurrent stroke or TIA.[rx][rx] Among all risk factors, hypertension is the most important one for an individual as well as in a population.

The pathophysiology of TIA depends on the subtype as follows. The common issue is the transient interruption of arterial blood flow to an area of the brain supplied by that particular artery.

• Large artery atherothrombosis – This may be intracranial or extracranial atherothrombosis. The mechanism may be a lack of blood flow distal to the site of arterial stenosis or an artery to artery embolism which is actually the more common mechanism.
• Small vessel ischemic diseases – The underlying pathology is either lipohyalinosis or small vessel arteriolosclerosis. The commonest risk factor is hypertension followed by diabetes and age.
• Cardiac embolism – A clot in the cardiac chamber most commonly in the left atrium secondary to atrial fibrillation.
• Cryptogenic – This is usually a cortical pattern of ischemia without any identifiable large artery atherothrombosis or cardiac source of emboli. More recently it is often referred to as ESUS (embolic stroke of unknown source).
• Other uncommon – causes such as arterial dissection or hypercoagulable states.

In an embolic event, debris from elsewhere in the body blocks blood flow through the affected vessel. The etiology of stroke affects both prognosis and outcomes. [rx][rx]

Symptoms of Ischemic stroke syndromes

Symptoms of stroke are

• Sudden numbness or weakness of the face, arm or leg (especially on one side of the body)
• Sudden confusion, trouble speaking or understanding speech
• Sudden trouble seeing in one or both eyes
• Sudden trouble walking, dizziness, loss of balance or coordination
• Sudden severe headache with no known cause
• Sudden trouble speaking
• Sudden trouble seeing in one or both eyes
• Sudden trouble walking
• Sudden dizziness, loss of balance or coordination
• Sudden, severe headache with no known cause

The effects of an acute ischemic stroke may cause additional symptoms in women including:

• Face, arm or leg pain
• Hiccups or nausea
• Chest pain or palpitations
• Shortness of breath

Features of middle cerebral artery stroke

• Contralateral hemiparesis and hypesthesia (Weakness of arm& face is worse than in the lower limb)
• Gaze towards to side of lesion
• Ipsilateral hemianopsia
• Receptive or expressive aphasia is dominant hemisphere is affected
• Agnosia
• Inattention, neglect

Features of anterior cerebral artery stroke

• Speech is preserved but there is disinhibition
• Mental status is altered
• Judgment is impaired
• Contralateral cortical sensory deficits
• Contralateral weakness greater in legs than arms
• Urinary incontinence
• Gait apraxia

Posterior cerebral artery stroke

• Cortical blindness
• Contraletarl homonynous heminopsia
• Altered mental status
• Visual agnosia
• Memory impairment

Vertebral/basilar artery stroke

• Nystagmus
• Vertigo
• Diploma and visual field deficits
• Dysarthria
• Dysphagia
• Syncope
• Facial hyperesthesia
• Ataxia

Diagnosis of Ischemic stroke syndromes

• Check ABCs (airway, breathing, and circulation) first. In some patients with stroke, the level of consciousness is reduced, and intubation may be required. Rarely, there is circulatory instability due to arrhythmia or another concurrent cardiac disease.

Perform a quick assessment of the degree of disability

• Speech and spatial perception: Aphasia or hemispatial neglect?
• Vision: Hemianopia or quadrantanopia?
• Hemiparesis: Facial droop? Antigravity arm strength? Antigravity leg strength?
• Hemianesthesia: Check gross light touch on the face, arm, and leg.
• Coordination and walking: If possible, have the patient get out of bed and try to walk.

Use the National Institutes of Health Stroke Scale (NIHSS) to guide the assessment of disability

• NIHSS = 0–5: transient ischemic attack (NIHSS = 0 and no signs on examination) or minor stroke (NIHSS 1–5)
• NIHSS = 6–10: moderate disabling stroke
• NIHSS = 11–20: moderate to a severe disabling stroke
• NIHSS ≥ 20: severe, life-threatening stroke

History and Physical

Ischemic strokes present acutely, and establishing the time of symptom onset is critical. If the time of symptom onset is unknown, the time the patient was last known to be normal without new neurological symptoms is used. The time that is established is then utilized to decide whether giving intravenous thrombolytics is indicated or not.

• A neurological exam should be performed for all patients suspected of stroke. The National Institutes of Health Stroke Scale (NIHSS) is most commonly used to measure the severity of the stroke and has 11 categories and a score that ranges from 0 to 42. The 11 categories include the level of consciousness (LOC), which incorporates LOC questions evaluating best gaze, visual, facial palsy, motor arm, motor leg, limb ataxia, sensory, best language, dysarthria, and extinction and inattention. The stroke scale should be performed in the order listed. Each score is based on the patient’s action on the exam, and it is not a prediction of what the patient can do.
• The vertebrobasilar arterial (VBA) system supplies blood to the brainstem, cerebellum, and peripheral labyrinths. Occlusion of the system, therefore, can result in either central or peripheral vertigo, depending on the specific artery affected. Occlusion can occur as a result of an embolism (e.g., cardioembolism or plaque from the vertebral arteries) and may result in an ischemic infarct. Central vertigo is more commonly associated with vertical nystagmus (rather than rotational) and is typically worse with attempted gaze fixation. Peripheral vertigo often improves with gaze fixation.  Additionally, dizziness associated with central vertigo is multidirectional and may change with altered gaze direction, while peripheral vertigo-associated nystagmus is unidirectional. [rx]

Evaluation

An organized stroke protocol is highly recommended to expedite evaluation. The door-to-needle time of 60 minutes is recommended for acute ischemic strokes for patients who qualify for thrombolytics.

• The initial evaluation of any patient is airway, breathing, circulation, and vital signs. Patients may present with respiratory abnormalities from elevated intracranial pressure and are at risk of aspiration and asphyxiation. Endotracheal intubation may be necessary to ensure adequate oxygenation and ventilation.
• A fingerstick glucose check should be performed, as it is an easy way of ruling out hypoglycemia as a cause of neurological abnormalities.
• plain CT head or brain MRI is recommended for patients within 20 minutes of presentation to rule out hemorrhage. In hospitals that are stroke centers or can provide emergency care, vascular imaging should be considered for possible endovascular intervention; however, this should not delay the administration of thrombolytics.
• Other diagnostic tests include an electrocardiogram (ECG), troponin, complete blood count, electrolytes, blood urea nitrogen (BUN), creatinine (Cr), and coagulation factors. An ECG and troponin are suggested because stroke is often associated with coronary artery disease.
• A complete blood count can look for anemia or suggest infection. Electrolyte abnormalities should be corrected. BUN and Cr should be monitored as contrast studies may worsen kidney function. Coagulation factors, including PTT, PT, and INR, should also be done as the elevated levels can suggest a cause of hemorrhagic stroke.
• For institutions without expert imaging interpretation, the US Food and Drug Administration highly recommends the teleradiology system for image interpretation for suspected stroke patients. This helps with the decision to administer IV alteplase. A discussion and agreement between telestroke neurologists and radiologists are highly recommended.

In areas that do not have an in-house stroke team or telestroke protocol, a telephone consultation may be considered for the administration of thrombolytics. The level of evidence is limited for this recommendation. [rx][rx][rx]

Treatment of Ischemic stroke syndromes

The goal of therapy in acute ischemic stroke is to preserve tissue in areas where perfusion is decreased but sufficient to avoid infarction. The tissue in this area of oligemia is preserved by restoring blood flow to the compromised regions and improving collateral flow. Recanalization strategies include recombinant tissue-type plasminogen activator. Restoring blood flow can minimize the effects of ischemia only if performed quickly.

Endovascular techniques have been used in the treatment of acute ischemic stroke. Carotid endarterectomy has been but there is no evidence that supports its use in acute ischemic stroke. Another consideration is neuroprotective agents but none so far have been shown to improve clinical outcomes.

The following may be considered

• IV labetalol 10 to 20 mg
• IV nicardipine 5 mg per hour. Increase 2.5 mg per hour every 5 to 15 minutes. The maximum dose is 15 mg per hour
• Clevidipine 1 to 2 mg per hour IV. Double dose every 15 minutes. Maximum 21 mg per hour
• Hydralazine, enalaprilat may be considered

Hypotension and hypovolemia should be avoided because the cerebral perfusion pressure is dependent on the maintenance of elevated MAP as ICP increases due to an ischemic event.

• Acetaminophen – Hyperthermia of greater than 38 C should be avoided and treated appropriately. Antipyretics such as acetaminophen may be used. Common sources of infection should be ruled out, such as pneumonia and urinary tract infections. There is insufficient data to support therapeutic hypothermia in acute ischemic strokes currently. A retrospective study recently demonstrated an association between a peak temperature in the first 24 hours of greater than 39 C (100.4 F) and an increased risk of in-hospital mortality.
• Antiplatelet Treatment – Aspirin is recommended within 24 to 48 hours of symptom onset. A Cochrane review concluded that aspirin given within 48 hours of symptom onset for ischemic strokes prevented the recurrence of ischemic strokes and improved long-term outcomes. There was no major risk of early intracranial hemorrhage with aspirin [rx].
• Antithrombotic Treatment – The use of warfarin in secondary stroke prevention is not recommended. In patients with atrial fibrillation, the guidelines state it is reasonable to initiate oral anticoagulation within 4 to 14 days after neurological symptoms onset.
• Statins – High-intensity statins (atorvastatin 80 mg daily or rosuvastatin 20 mg daily) are recommended for patients who are 75 years old or younger and who have clinical atherosclerotic cardiovascular disease. In addition, patients may be continued on statins if they were on them prior to the ischemic stroke. When to start anticoagulation in patients with atrial fibrillation after acute stroke is always a dilemma. Usually, it depends on various factors like the size of the stroke and other comorbidities. Usually, if the size of the stroke is smaller to moderate, we start anticoagulation in 7-14 days. [rx]
• Alteplase – The AHA/ASA recommends intravenous (IV) alteplase for patients who satisfy inclusion criteria and have symptom onset or last known baseline within 3 hours. IV alteplase is 0.9 mg/kg, with a maximum dose of 90 mg. The first 10% of the dose is given over the first minute as a bolus, and the remainder of the dose is given over the next 60 minutes. The time has been extended to 4.5 hours for selected candidates. Inclusion criteria include diagnosis of ischemic stroke with “measurable neurological deficit,” symptom onset within 3 hours before treatment, and age 18 years or older.
• ACE inhibitors – Orolingual angioedema is a potential side effect of IV alteplase. If angioedema should occur, the management of the airway is a priority. Endotracheal intubation or awake fiberoptic intubation may be necessary to secure the airway. If there is suspected angioedema, hold IV alteplase and ACE inhibitors.
• Methylprednisolone – Administer methylprednisolone, diphenhydramine, and ranitidine or famotidine.
• Epinephrine – may be considered if the previous therapies do not alleviate signs and symptoms. Icatibant or C1 esterase inhibitor may be considered for the treatment of hereditary angioedema and ACE inhibitor angioedema.
• Tenecteplase – other fibrinolytic agents, such as tenecteplase, may be considered as an alternative to alteplase. In one study, tenecteplase appeared to have similar efficacy and safety profiles in a mild stroke but did not demonstrate superiority when compared to alteplase [rx][rx].
• Anti-epileptic drugs – If patients experience recurrent seizures,  are recommended. However, the routine prophylactic use of anti-epileptic drugs is not recommended.
• Mechanical Thrombectomy – The use of mechanical thrombectomy should be considered in all patients, even in those who received fibrinolytic therapy. The AHA/ASA guidelines do not recommend observation for a response after IV alteplase in patients who are being considered for mechanical thrombectomy.[rx][rx]The current recommendation in selected patients with large vessel occlusion with acute ischemic stroke in the anterior circulation and who also meet other DAWN and DEFUSE 3 criteria, mechanical thrombectomy is recommended within the time frame of 6 to 16 hours of last known normal. In selected patients who meet the DAWN criteria, mechanical thrombectomy is reasonable within 24 hours of last known normal [rx][rx].
• Blood Pressure – The guidelines suggest blood pressure management of less than 180/105 mm Hg for the first 24 hours after IV alteplase. A new recommendation is lowering BP initially by 15% in patients with comorbid conditions such as acute heart failure or aortic dissection. There is no benefit of antihypertensive management to prevent death or dependency in patients with BP less than 220/120 mm Hg, who did not receive IV alteplase and have no comorbid conditions requiring blood pressure reduction. This applies to the first 48 to 72 hours after an acute ischemic stroke. For patients with greater than or equal to 220/120 mm Hg who did not receive IV alteplase, the guideline suggests it may be reasonable to reduce BP by 15% in the first 24 hours, although the benefit is uncertain.
• Glucose – Maintain glucose in the range of 140 to 180 in the first 24 hours. Hypoglycemic patients less than 60 mg/dL should be treated to achieve normoglycemia. The brain is dependent on oxidative pathways that require glucose for metabolism, and the metabolic demand of the brain is high; therefore, episodes of hypoglycemia can decrease the repair of the brain. However, hyperglycemia is hypothesized to decrease reperfusion due to oxidation of nitric oxide-dependent mechanisms and subsequent loss of vascular tone. Moreover, increased acidosis also plays a part, possibly due to injury to lactic acid-sensing channels. Capes et al. showed that hyperglycemia in ischemic stroke patients increases 30-day mortality and is an independent risk factor for hemorrhagic stroke conversion [rx].
• Nutrition – Early enteric feeding should be encouraged. For patients with dysphagia, use a nasogastric tube to promote enteric feeding. If there is concern that the patient may have swallowing difficulties for a prolonged period (more than 2 to 3 weeks), placing a percutaneous gastrostomy tube is recommended. Early feeding has been demonstrated to have an absolute reduction in the risk of death [rx].
• DVT Prophylaxis – Intermittent pneumatic compression is recommended for all immobile patients unless there are contraindications. Although prophylactic heparin is often used for immobile patients, the benefit is not clear in stroke patients [rx].
• Depression Screening – Screening for depression should be considered; however, the optimal timing is unclear.
• Cerebellar/Cerebral edema  – Cerebellar edema complicates cerebellar infarctions, and clinicians must be aware that these patients can rapidly decompensate. Cerebellar swelling is thought to be due to cytotoxic and vasogenic edema. The increased intracranial pressure can cause obstructing hydrocephalus on the fourth ventricle, or cause transtentorial herniation of the superior vermis and downward cerebellar tonsillar herniation. Signs include change or worsening mental status, decreased level of consciousness, respiratory abnormalities, change in pupillary size, posturing, and death. Obtain neurosurgical consult early. A ventriculostomy is indicated in the setting of obstructive hydrocephalus after cerebellar infarct. In cases of cerebral edema with mass effect, a decompressive suboccipital craniectomy is highly recommended. [rx][rx]
• Troponin – Cardiac monitoring for atrial fibrillation or other arrhythmias is recommended in the first 24 hours. The benefit of further monitoring is unclear. An initial troponin is recommended because there is an association between stroke and coronary artery disease.

Sometimes there are patients with small hemorrhagic transformation after acute stroke, and in this scenario, it is better to wait for anticoagulation for a couple of weeks. This delay is not associated with excessive stroke recurrence. [30]

Differential Diagnosis

Differentials include:

• Complicated migraines
• Drug toxicity
• Intracranial hemorrhage
• Intracranial tumor
• Intracranial abscess
• Hypoglycemia
• Hyperglycemia
• Hypertensive encephalopathy
• Multiple sclerosis
• Seizure, sepsis
• Syncope
• Wernicke encephalopathy
• Metabolic abnormalities

References