Ischemic Stroke

Article topic: Ischemic Stroke
Author: Zain Sarhan Alsaddi
Keywords: Ischemic Stroke, Neurology, Neuromedicine, Cerebrovascular Diseases

OVERVIEW

A stroke results from a sudden cessation of sufficient blood supply to the brain. The disruption of blood supply is either due to a blockage of a main cerebral artery or a rupture in one causing it to bleed. This subsequently deprives the brain tissue of oxygen and nutrients and eventually leads to cell death within few minutes. ¹

There are three main types of stroke. The most common type is the Ischemic stroke, which accounts for 87% of all strokes. It is the consequence of an occluded cerebral artery that clogged up by either a thrombus or an embolism. The second, less common yet more severe type is the hemorrhagic stroke, and this happens as a leaking or burst of a blood vessel. It is further subdivided into types which are intracerebral hemorrhage as well as subarachnoid hemorrhage. ⁷

The third type, sometimes called a “mini stroke”, or what is more commonly known as the transient ischemic attack (TIA), the definition of a TIA has changed from time-based to tissue-based. It is defined as a transient episode of neurologic dysfunction due to the focal brain, spinal cord or retinal ischemia without acute infarction. A TIA is a temporary disruption of blood flow that typically lasts a few minutes and does not cause lasting symptoms. It is important to know that a TIA is a warning sign of a future stroke and just like the other two major types of stroke, it requires emergency care. ⁸

Stroke is considered the third leading cause of death in the world and tends to lead to a long-term disability and cognitive impairment. Immediate or delayed vascular cognitive impairment (VCI) or vascular dementia (VaD) was detected in about 25–30% of ischemic stroke survivors. ^{1, 9}

PATHOGENESIS AND ETIOLOGY

The exact mechanism for stroke injury is not fully understood despite considerable research efforts. However, it is established that cerebral ischemia induces a cascade of inflammatory and immune reactions that encircle molecular, cellular as well as genomic events. Furthermore, the body’s Immune response has been shown to play a major role in ischemic stroke progression. Neuronal damage’s extent seems to correlate with the degree of innate immune activity.

After the ischemic stroke event occurrence, Pathophysiological changes take place like ionic imbalance, neuro-inflammation, excitotoxicity, and activation of microglia which contribute to neuronal death. Moreover, Ischemia induces a significant increase in microvascular density, a sign of angiogenesis and its degree is positively correlated with the survival rate of stroke patients. In addition to that, an improvement in functional outcome after ischemic stroke was found to be associated with increased angiogenesis. However, in a clinical setting, neither neuroprotection nor angiogenesis strategies showed any therapeutic benefit.

Marcet et al. discussed the impacts of inflammation in ischemic stroke and traumatic brain injury indicating that although the initial trauma that led to brain damage is most likely unsalvageable, the secondary immunologic deterioration of neural tissue gives many opportunities for therapeutic strategists. ^{9, 10}

RISK FACTORS

The risk factors for ischemic stroke greatly mirror the risk factors of atherosclerosis and primary prevention of stroke focuses on the identification and modification of risk factors. They are divided into non-modifiable and modifiable risk factors. ^{2, 11,}¹²

Non-modifiable risk factors

Age: In general, stroke is known to be a disease of aging. Its incidence increases as the person grows older, with the incidence doubling after age 55 for each decade. ³⁴
Gender: The relationship of sex to stroke risk mainly depends on age. Previously the risk of stroke was thought to be higher in men, however recent studies and research suggest otherwise indicating that, at younger ages, women have a higher risk of stroke and this is related to pregnancy and the postpartum state that follows it as well as hormonal factors like the use of contraception. Furthermore, it is believed to be higher in women due to their longer lifespan when compared to men. ³⁴A study that was performed in 8 different European countries discovered that the risk of stroke increased in men and women yearly by 9% and 10% respectively. ³⁵
Race: when compared to their white counterparts, African Americans showed that they are at twice the risk of stroke incidence, and also have a higher mortality associated with stroke.³⁶
Family history
Genetic risk factors³³:

1. Single gene disorders that primarily cause stroke
2. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
3. Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL)
4. Familial amyloid angiopathy
5. Collagen 4 (COL4A1) mutations
6. Ehlers-Danlos Type 4
7. Fabry Disease
8. Marfan syndrome
9. Mitochondrial encephalopathy with lactic acid and stroke- like episodes (MELAS)
10. Sickle cell disease
11. Smooth Muscle Alpha-Actin (ACTA2) mutation associated disorders

Modifiable risk factors

Hypertension: It is considered to be the most important modifiable risk factor for stroke. With the increasing age, the risk of developing hypertension also increases regardless of the hypertension status. Alongside medical hypertension control, the hypertensive patients are also encouraged to engage in lifestyle behavioral modifications, such as dieting and increase physical activity. These two methods of hypertension remain the most effective strategies in reducing stroke risk. ³⁷
Diabetes mellitus is an independent risk factor that increases the risk for stroke by 2 folds. ³⁸
Dyslipidemia: Stroke incidence also increases with an increase in total cholesterol level and low LDL. It causes thick and hard plaque to build up in your arteries and thus clog them. Subsequently reducing the flow of blood and leading to an infarct.
Cardiovascular issues like Atrial fibrillation (AF) for the longest, the relation between AF and stroke has been initially assumed to be due to blood stasis in the fibrillating left atrium that causes a thrombus to form and embolize to the brain. however recent data challenged this assumption stating that, First, around one-third of patients do not show evidence of AF until after a stroke despite being preceded by months of continuous monitoring of the heart-rhythm.39 Second, other types of arrhythmias like PSVT have also been linked to stroke risk. Finally, those with a genetic mutation that is associated with AF like the gene for Natriuretic Peptide Precursor A, can have a stroke even before the onset of AF.⁴⁰
Kidney Disease : The risk of stroke is high in patients with chronic kidney disease, especially in patients on dialysis
Diet and Exercise: low Physical inactivity is linked with many health issues, stroke included. In those who are physically active, their risk of stroke is lesser than those who are not active. The relationship is explained with the fact that exercising decreases blood pressure, reduces excess body fat and subsequently diabetes. ⁴¹
Smoking is also considered a major risk factor for stroke, which nearly doubles the stroke risk. ⁴²
Alcohol. heavy drinking associated with an increased risk of ischemic stroke. ⁴³
Substance abuse like cocaine, heroin, amphetamines, and ecstasy have shown to increase risk of both the ischemic and hemorrhagic stroke. ⁴⁴

a continuously updated well known and widely used score that is used to estimate a 10-year stroke risk stratified by the gender is the The Framingham Stroke Risk Profile (FSRP). It combines the various predictors of stroke like age, systolic blood pressure, anti-hypertensive therapy, diabetes, cigarette smoking, left ventricular hypertrophy by electrocardiogram, and the presence of cardiovascular disease (coronary heart disease, peripheral vascular disease, congestive heart failure).⁴⁵ There are other scores, which were developed from different population samples, that determine the risk of stroke and include additional metrics like physical disabilities, depression, and marital status. ⁴⁶

CLINICAL PRESENTATION AND COMPLICATIONS

Stroke typically presents with a sudden rapid onset of neurological deficits. The signs and symptoms that the patient presents vary depending on the area of the brain is involved and whether a main artery or its branches are affected. Thus, the clinical presentation is influenced by the size of the infarct.

Figure 1. Case courtesy of Assoc Prof Frank Gaillard.

Mainly, focal weakness and speech disturbance are the two most common physical findings of ischemic stroke. Other signs and symptoms of ischemic stroke that are also considered as most common are listed below: ^{13, 14, 15}

Symptoms

Subjective arm weakness
Subjective leg weakness
Self-reported speech disturbance
Subjective facial weakness
Arm paresthesia
Leg paresthesia
Headache
Non-orthostatic dizziness
Seizure

Signs

Arm and/or leg paresis
Aphasia
Dysphasia or dysarthria
Hemiparetic or ataxic gait
Facial paresis
Eye movement abnormality or diplopia
Visual field defect

The person might be present with speech problems and will have a difficulty understanding what others are saying and may be confused. Face droopiness, which is the weakness of one side of the face, is another visible clinical finding. It is usually accompanied with vision problems in either one or both eyes. The person may have a blurred, blackened or a double vision. Moreover, he may develop a sudden weakness or feeling of numbness or the arm or leg. This often affects just one side of the body. To test this, ask the person to raise both arms over the head at the same time. If one arm begins to fall, it may be a sign that they are having a stroke. They may also have a problem with maintaining balance, so they will present with a troubled walking. Furthermore, a sudden, severe headache that is accompanied by vomiting, dizziness or altered consciousness, may indicate that they are having a stroke.

WORKUP AND DIAGNOSIS

History and physical examination are the initial steps to diagnosing stroke. The most important component to obtain from the history is when was the person last seen normal and with no symptoms. Stroke treatment is most effective when given as soon as possible as it has a narrow time window of effectiveness. Quick assessment of the person with suspected acute ischemic stroke is made to determine the most suitable intervention among the available options as well as further assess the eligibility for thrombolysis.¹⁶

Usually, The National Institutes of Health Stroke Scale (NIHSS) provides a quantitative measure of stroke-related neurologic deficit, its widely used as a clinical assessment tool to evaluate acuity of stroke patients, determine appropriate treatment, and predict patient outcome. The NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patent’s ability to answer questions and perform activities. Ratings for each item are scored on a 3- to 5-point scale, with 0 as normal, and there is an allowance for untestable items. Scores range from 0 to 42, with higher scores indicating greater severity.

Immediate Diagnostic Studies:

Noncontrast brain CT or brain MRI
Blood glucose
Serum electrolytes and renal function tests
Electrocardiograph
Markers of cardiac ischemia
Complete blood count, including platelet count
Prothrombin time/international normalized ratio
Activated partial thromboplastin time
Oxygen saturation

For Selected patients, the following can be done:

Hepatic function tests.
Chest radiography if a lung disease is suspected.
Lumbar puncture (if subarachnoid hemorrhage suspected and head CT
negative for blood).
Electroencephalogram, if seizure is suspected.

Despite the desire to know the results of these tests before giving the recombinant tissue plasminogen activator, thrombolytic therapy should not be delayed while awaiting the results unless a bleeding abnormality or thrombocytopenia is clinically suspected, or the patient has received heparin or warfarin used unknown anticoagulants.

In order to be able to distinguish between ischemic stroke and hemorrhagic stroke as well as rule out other types of central nervous system lesions, neuro-images must be done. However, the choice of neuroimaging depends on its availability at the hospital, eligibility to be used for acute stroke intervention and if there are any patient contraindications present.

Clinically, the diagnosis of stroke is usually accurate but determining the pathological type of stroke is best achieved by conducting an early brain computed tomography (CT) scan or by performing an autopsy, for confirmation. A CT scan is not only needed to rule in the diagnosis of ischemic stroke, but also to exclude the presence of certain stroke mimics and detect hemorrhage. In other words, a normal CT scan does not rule out the diagnosis of ischemic stroke. ¹⁶

Although MRI scans have better resolution when compared to CT scans, they are less available and more expensive than CT scanners. Also, MRI scans cannot be performed on persons who have certain types of implanted devices (e.g., pacemakers) or in those who are claustrophobic. In addition, CT scans have a 95- 100% sensitivity of detecting subarachnoid blood in the first 12 hours; however, over time as the subarachnoid blood is cleared, its sensitivity greatly decreases to about 50% after one week and is not detectable by CT after a period of about two to three weeks, unlike ischemic stroke. ^{24, 27, 28}

According to the guidelines, it is recommended that a MRI scan is ordered if it could be obtained as quickly as a CT scan and more importantly if the patient presented within the time window of acute stroke intervention. If not, then CT is the go-to test because when the history and physical is consistent for acute, its treatments should not wait for detailed imaging. ²⁶

Middle Cerebral Artery (MCA) infarct

Figure 3. Middle Cerebral Artery (MCA) infarct ²⁹Case courtesy of Dr. Sajoscha Sorrentino.

Factors such as poor public awareness of symptoms, lack of quick detection by emergency medical services (EMS), poor coordination between EMS and the hospital emergency department or delay of diagnosis upon arrival at the emergency department are considered factors that contribute in the failure to provide prompt diagnosis and treatment of acute ischemic stroke.

STROKE MIMICS AND DIFFERENTIAL DIAGNOSIS

When evaluating a patient presenting with a suspected stroke, other possible conditions associated with the central nervous system must be ruled out as there is a large number of stroke- mimickers ^18,20-23

Seizures, status epilepticus in particular, can mimic a stroke
Subdural hematomas (SDH), intracranial hemorrhages (ICH), or masses
Demyelinating disorders like multiple sclerosis
Toxic and metabolic differentials like Sepsis, uremia, hypo and hyperglycemia, hyponatremia, and hyperkalemia can all cause symptoms that resemble a stroke
Complex migraines
Systemic infections, the commonest source is the chest.
Dementia.
Psychiatric disorders like panic disorders.
Could be associated with alcohol intoxication, an adverse effect to a secondhand medication or other encephalopathy

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