Pathophysiology, complications and management of stroke: A
review
Running head: A review on stroke
Umme Habeeba A Pathan1*, Abdul Raheem Thayyil2, Thimmasetty Juturu2, Shwetha Kamath2.
1Department of Pharmacy Practice, Bapuji Pharmacy College, SS layout, Shamnur road,
Davanagere-577004, Karnataka, India.
2 Faculty of Industrial Pharmacy, Bapuji Pharmacy College, SS layout, Shamnur road,
Davanagere-577004, Karnataka, India.
Author information
*Corresponding author
Umme Habeeba A Pathan (ORCID: 0000-0002-3819-4440)
https://orcid.org/0000-0002-3819-4440
#868/D-7 Shankar Vihar Layout near B C M Hostel, PIN; 577006, Davangere, Karnataka, India.
Tel: +919901821081
Email ID: [email protected]
Abdul Raheem Thayyil, Email ID: [email protected] ORCID: 0000-0002-3054-7758
https://orcid.org/0000-0002-3054-7758
Thimmasetty Juturu, Email ID: [email protected] ORCID: 0000-0002-3273-9569
https://orcid.org/0000-0002-3273-9569
Shwetha Kamath, Email ID: [email protected]: 0000-0002-2464-0964
https://orcid.org/0000-0002-2464-0964
ABSTRACT:Stroke is the next foremost origin of death under Non-Communicable Diseases
(NCD) after heart disease and cancer. Earlier, the detection of stroke was a failure due to its
complexity in understanding. On the pages of history, it was a serious disease known as
‘Apoplexy’, which was later recognized as stroke. This review focuses on the updated
definition, its types which are mainly two, ischemic and hemorrhagic stroke. It also covers the
risk factors like age, genetics, cardiac diseases, and symptoms that differentiate the type of stroke
which helps in diagnosing the mechanism correctly. The pathogenesis of stroke is summarized,
which paves the path for the treatment regimen and if left untreated, possible complications can
be seen. Finally, an attempt has also been made to brief the management including both non-
pharmacological therapy with stem cell transplantation, surgical therapy, and pharmacological
therapy.
Keywords: brain ischemia; complications;disease management; intracranial hemorrhages;
physiopathology; risk factors; stroke
1. Introduction
Stroke, commonly known as Cerebro-Vascular Accident (CVA), is stated as a sudden
commencement of neurological discrepancy which is attributable to a pivotal vascular basis [1-
3]. In modest words, it is a “brain attack”, which occurs when the brain fails to get adequate
blood circulation, as a result, brain cells do not get a sufficient amount of oxygen, and cells start
dying ultimately. Stroke is an overwhelming public health concern [4]. Among 33 million stroke
survivors worldwide, stroke is the second leading reason for death trailing ischemic heart
disease, and the third steering foundation of disability [5, 6]. The World Health Organization
(WHO) appraises that at regular intervals new patient gets cerebrum assault worldwide and
encounters either demise or handicap like clockwork due to the stroke [7]. By 2025, the UN
testimony summoned for a comparative reduction in hasty mortality by 25% from NCDs,
including stroke [8]. In the year 2002, stroke was the seventh leading cause of the title
‘disability-adjusted life years lost’ due to its immobile complications and this legacy will step up
to the sixth position by the year 2030 [9].
The risk factors include advanced age [10], gender [3,11,12], race [13], hypertension
[14], diabetic HbA1c [15], hyperlipidemia [16], atrial cardiopathy [17], cancer [18,19], genetic
factors [20], walking pace [21], hyper viruses [22], and, cannabis abuse [23]. Signs and
symptoms of stroke include multiple neurologic dysfunctions, hemiparesis, aphasia, dysarthria,
blurred vision, and altered levels of consciousness [24]. Alone clinical features will not
differentiate ischemic stroke from Intra-Cerebral Hemorrhage (ICH). Poorly performed scoring
systems help to improve diagnose stroke with accuracy by introducing imaging techniques [25].
Stroke has got extremely complex pathophysiology which involves numerous processes,
including atherosclerosis accumulation, hypertrophy of muscle, local occlusion leading to
cerebral ischemia. This cerebral ischemia is a major culprit for a cascade of unwanted reactions
leading to inflammation, mitochondrial damage, Blood-Brain Barrier (BBB) disruption,
excitotoxicity, and, cell death [26]. A serious and common complication in stroke patient
includes Stroke-Associated Pneumonia (SAP) [27], followed by dysphagia [28], circulatory
obstacles which are the second foremost source of post-stroke death [29], myocardial infarction
[30], serotonin syndrome [31,32], post-stroke fatigue [33,34],post-stroke dementia [35-37] post-
stroke epilepsy [38] post-stroke cognitive impairment [36,39] Post Stroke Cognitive Decline
(PSCD) [36,40-42], post-stroke insomnia [43], and re-admission [44].
The goal of therapy includes recombinant tissue Plasminogen Activators (rtPA) which is
a fibrinolytic therapy to improve BBB damage and reduce the hemorrhagic transformation in
clinical practice [45]. To provide neuroprotection and aiming to avoid a series of Ischemic-
Reperfusion (I/R) injury, U.S. Food and Drug Administration (USFDA) has permitted NADPH
oxidase (NOX) inhibitors, and numerous drugs [46]. To protect against vascular endothelial
dysfunction and alleviate ischemic injury, a new free radical called edaravone revealed better
effect [47]. To overcome post-stroke complications, retrievals are established like involvement in
the rehabilitation center [48]. Characteristic post-stroke care begins with hospitalization for a
week and abides by some weeks of physiotherapy, occupational therapy, and speech-language
pathology. Lifestyle modification includes exercise, which is essential for motor learning to
reduce activity limitation [49], adopting the traditional Mediterranean Diet (MeD) [50], and
having adequate sleep [51]. Stroke patients have a high mortality rate annually 30 to 50% [10].
2. Definition
The term stroke was initially proposed by William Cole in 1689 [52]. Before Cole, the stroke
was described as ‘apoplexy’ and it was first seen by Hippocrates around 400 BC [1,53].
Currently, WHO describes stroke as “quickly emerging clinical signs of focal disruption of
cerebral event, durable more than 24 hours or directing to fatality, with no seeming reason other
than that of vascular cause” [54].
3. Classification
3.1. Transient Ischemic Attack.In 2009, an expert committee of the American Heart
Association/American Stroke Association (AHA/ASA) published a scientific statement defining
Transient Ischemic Attack (TIA) and recommending evaluation. The definition proposed was “a
transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal
ischemia without acute infarction” [55].
3.2.Etiological Classification of Ischemic and Hemorrhagic Stroke.
3.2.1 Ischemic Stroke.Ischemic stroke classification is either phenotypic or causative, as per the
present approaches. Phenotypic classification lean towards unfolding the agreeing fundamental
pathologies, by not focusing on the most plausible ischemic stroke reason.While, causative
classifications accentuate on setting up the most probable reason, ignoring other related
infections [56]. The classification is summarized in Table 1.
Table 1: Ischemic stroke classification systems [34,56]
Phenotypic Classification Causative Classification
A) ASCO
1.Atherosclerosis
2.Small vessel disease
3.Cardiac pathology
4.Other causes
B) ASCOD
1.Atherosclerosis
2.Small vessel disease
3.Cardiac pathology
A) TOAST
1.Large artery atherosclerosis
2.Cardio embolism
3.Small vessel occlusion
4.Other determined etiology
5.Undetermined etiology
B) SSS-TOAST
1.Large artery atherosclerosis
2.Cardio-aortic embolism
4.Other cause
5.Dissection
3.Small artery occlusion
4.Other causes
5.Undetermined causes
a. Unknown
• Cryptogenic embolism
• Other cryptogenic
• Incomplete evaluation
b. Unclassified
C) SPARKLE
1.Largeartery disease
2.Cardio embolic
3.Smallvessel disease
4.Other rare or unusual etiologies
5.Un determined etiologies
6.Un known etiology
7.Incomplete evaluation
D) CISS
1.Large artery atherosclerosis Aortic-arch
atherosclerosis I/E artery atherosclerosis
2.Cardiogenicstroke
E) KOREAN–TOAST
1.Atherothrombosis(AT)
2.Cardioembolism
3.Small artery disease
4.Otherdetermined etiology
5.Undeterminedetiology
3.2.2. Hemorrhagic stroke. Hemorrhages in hemorrhagic stroke are classified by their underlying
vascular pathology and location. Important causes include aneurysmal Sub-Arachnoid
Hemorrhage (SAH) [57]. Bleeding in the brain especially in the spaces of epidural and subdural
is caused due to trauma and other major causes are listed in Table 2.
Table 2: Causes of intracranial hemorrhages [58].
Causes Location
Head trauma Intraparenchymal, frontal lobes, anterior
temporal lobe, subarachnoid, extra-axial
(subdural, epidural)
Hypertensive hemorrhage Thalamus, cerebellar hemisphere, pons
Transformation of prior ischemic infarction
Basal ganglion, subcortical region, lobar
Metastatic brain tumor
Lobar
Coagulopathy
Any
Drug
Lobar, subarachnoid
Arteriovenous malformation
Lobar, intraventricular
Amyloid angiopathy
Lobar
Aneurysm Subarachnoid, Intraparenchymal
3.3. Classification based on mechanism. Classification is briefed in Figure 1 [24,59,60].
Figure 1: Classification of stroke based on mechanism.
4. Risk factors
4.1. Single Risk Factors
4.1.1. Age. People over the age of 55 of either gender are in great jeopardy of getting a stroke.
The likelihood of stroke doubles every decade among this age group [10, 61].
4.1.2. Gender. Women are liable to get stroke than men because of high anxiety, depression,
pain, discomfort, and decreased mobility leading to augmented frailty and low quality of life.
Obstetric women are at high risk of developing ischemic stroke (RR=34), intracerebral
hemorrhage (RR=95), and subarachnoid hemorrhage (RR=47). Epidemiologic studies chronicled
preeclampsia and eclampsia credit for nearly 50% of obstetric strokes. Typical syndromes found
in post-delivery women are Reversible Cerebral Vasospasm Syndrome (RCVS) and Posterior
Reversible Vasospasm Syndrome (PRES) [4].As the age increases the risk of acquiring stroke
shifts from women to men [62,63].
4.1.3. Genetic factors. Around 32 stroke risk loci are present in the brain which can get changed
or mutated and lead to stroke [62]. It is a non-modifiable risk factor [63]. Genome-Wide
Association Studies (GWAS) is the fronting methodology in genetics for finding an association
between genetics and stroke [64]. Identifying stroke as a single-gene disorder has paved the path
for enhancing its therapeutic outcome[65].
4.1.5. Hypertension. Rather than saying with increased or decreased BP, it would be best to
define in terms of Blood Pressure Variability (BPV) and related metrics. The latest facts by a
sequence of studies from Korea demonstrated the multifarious relationship between BP and
Acute Ischemic Stroke (AIS). From these studies, it was noted that the tension of pulse had better
prognostic powers rather than usual measures of BP metrics. The study by P B Gorelick et al.
mentioned five systolic BP trajectory groups (low, moderate, rapidly stabilized, acutely elevated
and, persistently high) within 24h onset of stroke among 8376 Acute Ischemic Stroke (AIS)
patients. The risk worsened as vascular complications took over hypertension [14].
4.1.6. Cardiac disease. Atrial Fibrillation (AF), mitral stenosis, mitral annular calcification, left
atrial enlargement, structural abnormalities such as atrial-septal aneurysm, and myocardial
disease can lead to stroke [24]. AF is more vulnerable to an embolic stroke [66]. Embolic stroke
of undetermined cause (EUS) which contributes to 30% of cryptogenic stroke has a stronger
relationship with cardiac abnormalities especially AF and endocarditis [67].
4.1.7. Diabetes mellitus (DM). One of the macrovascular complications of DM includes stroke,
so DM is more prone to the high prevalence of getting a brain attack. In people with established
DM, higher glycated hemoglobin values are strongly related to first-ever stroke according to
systemic review and meta-analysis [15].
4.1.8. Hyperlipidemia. It is a positive risk factor for extra-cranial atherosclerosis [3]. There
existsan opposite relationship between total cholesterol in ICH and ischemic stroke. It is found
that low levels of cholesterol increase the risk of ICH whereas high levels increase the risk of
ischemic stroke [16].
4.1.9. Illicit drug use. Cannabis and its analogs are worldwide used illicit substances and drugs.
The use of this violates and has a large impact on cerebrovascular events or stroke [23]. The
violation is judged based on the hypothesis that cannabis induces transient vasoconstriction
according to a systematic review of 18 case-reports by S.A Gomez Ochoa. According to this
review, 9 case reports on the syndrome of vascular constriction allied with consumption of
cannabis by Ducros et al., [68] revealed Magnetic Resonance Imaging (MRI) scans with inner
and specific arterial constriction, Herning et al., [69] also revealed the similar findings regards
with the high vascular defiance and rate of blood flow in substance abuser and non-abuser. Wolff
et al., reinforced this above theory in his cohort analysis among young 48 patients revealing 21%
of patients had multifocal intracranial stenosis with consumption of cannabis, and also the study
supported for the fact that the stenosis is reversible. Hence due to investigative changes and
hindrance in the normal mechanism of blood flow to the brain can associate the TIA and stroke
in cannabis abusers [70].
4.1.10. Herpes virus. There is a greater risk of acquiring stroke due to herpesvirus infection as it
provokes inflammatory actions in the body. The virus aid in the series of proactive consequences
like thrombogenesis, atherosclerosis, damage to vessels, platelet aggregation, and, as a result of
these inflammatory processes there lays a huge risk for stroke [22].
4.1.11. Smoking and alcohol abuse. Smokers risk increases by two or four folds of developing
stroke than non-smokers [71]. It is found that there is a proof relating to the risk of stroke in
young men through dose-response curve [72]. As per the alcohol is concerned, more than 5
drinks of alcohol per day can increase the risk of stroke than those who do not drink [73]. 20-
30% of people are at risk to get stroke by living with smokers that are second-hand smokers [74].
4.2. Multiple Risk Factors. Stroke is increased by the presence of multiple risk factors.
Framingham profile also well known as Framingham Stroke Risk Profile (FSRP) is significant
and easily available during an outpatient office visit. This gender-specific profile includes: Age,
antihypertensive drugs, elevated systolic blood pressure, elevated serum cholesterol, glucose
intolerance, cigarette smoking, presence of Coronary Vascular Disease (CVD), left ventricular
hypertrophy, and AF [24,75]. The single and multiple risk factors are briefed in Figure 2.
Figure 2:Risk factors.
5. CLINICAL PRESENTATION
5.1 Signs and Symptoms. One of the earliest symptoms is detected by FAST which is shown in
Figure 3 [76]. Signs and symptoms account for warnings due to brain injuries and precise
discrepancies. The foremost sign is hemiparesis. Symptoms involved with vision and
consciousness are diplopia and giddiness, which is due to the impaired circulatory involvement
away from the brain. Symptoms involved with speech such as aphasia is because of circulatory
dysfunction in the left hemisphere of the brain. Additional signs include dysarthria, optic chiasm
defects, and stupor. Pain is commonly present in hemorrhagic stroke in the form of a severe
headache than with ischemic stroke [24,77].
Figure 3:FAST.
The symptoms of TIA are enumerated in Table 3.
Table 3: Symptoms associated with TIA[78].
Symptom Right carotid Left carotid Vertebrobasilar
Aphasia Possible Yes No
Ataxia No No Yes
Blindness Right Yes Right or Left side
Clumsiness Yes Left Yes
Diplopia No No Yes
Dysarthria Yes Yes No
Paralysis Left side Right side Any Limb
Paresthesia Left side Right side Any Limb
Vertigo No No Yes
5.2 Diagnosis.
5.2.1. Clinical diagnosis. Knowledge plays a significant task in clinical diagnosis. The neuro-
specialist who diagnoses and sets the treatment regimen should have sound knowledge in
neuroanatomy and vascular anatomy [79]. During clinical diagnosis, three queries oblige a
response and those are [80];
A. The process is either of the vascular origin or it just mimics a stroke.
B. Name of impaired blood vessel supply in the CNS.
C. The mechanism involved, either ischemic or hemorrhagic.
5.2.2. Radiographic diagnosis. The radiological tests include [24,79]:
A. X-Ray; Cerebral Angiography shown in Figure 4
B. Computed Tomography (CT) scan
C. Magnetic Resonance Imaging (MRI) scan
D. Diffusion-Weighted Imaging (DWI)
E. Carotid Doppler (CD)
F. The Electro Cardio Gram (ECG)
G. Trans Thoracic Echocardiogram (TTE)
H. Trans Esophageal Echocardiogram (TEE)
I. Trans Cranial Doppler (TCD)
Figure 4: Cerebral angiography showing initial blockage and cerebral ischemia.
5.2.3. Diagnostic tools. Standardize neurologic evaluation is done by using stroke scales. Stroke
scale is available and is evaluated based on two criteria;
A. One which aims at cognitive and physical impairment.
B. The second which regulates the impact of strokes based on day-to-day events and
eminence of living throughout restoration from stroke [81].
5.2.4. Prognostic models. Prognostic Models can be precisely used for the purposeful sequel of a
whole retrieval in patients with ischemic stroke might be useful to neural precaution practices for
several following purposes;
A. Developed prognostic model knowledge can be useful in selecting appropriate
treatments and individualizing patient management, along with patient counseling.
B. These models also improvise rehabilitation and discharge planning.
C. In poor economical countries, the use of prognostic models would be the best clinical
choice for patients concerning precise medical circumstances, which might decrease
health concern charges and hospital stay.
But before the use of the prognostic model in the medical field, it is evaluated and the
process of evaluation is known as model validation. Models are developed by predictor
variables, for example, in a systemic review and meta-analysis done by Jampathong et al., [82]
shows 23 prognostic tools.
5.2.5. Misdiagnosis. Many other neurologic conditions that depict the same symptoms as that of
stroke are called Stroke Mimics (SM). Due to this condition often other conditions are
misdiagnosed as stroke and some of them are listed below [83];
A. Epilepsy
B. Headache
C. Metabolic abnormality
D. Tumors
E. Vertigo
6. PATHOPHYSIOLOGY.
6.1. Ischemic Stroke. The pathophysiology of ischemic stroke is exceptionally multifaceted. The
processes involved are cerebral ischemia, inflammation/cytokines storm, oxidative stress, BBB
disruption, excitotoxicity, necrosis, or apoptosisand circadian influence on the mechanism [84-
86].Cerebral ischemia is caused by thrombosis, embolism, focal hypoperfusion, lipid
accumulation in the carotid artery, and inflammatory cells [24,77,86].Cholesterol deposition in
circle of Willis (coW) is shown in Figure 5.
Figure 5: Circle of Willis of healthy brain v/s with atherosclerotic plaque.
Acute occlusion in the intracranial vessels leads to decreased blood flow to the brain
resulting in three different scenarios based on the flow of blood to the brain. First, if the cerebral
blood flow is zero then brain tissue dies within 4-10 min. Second, if the blood flow is < 16-18 ml
min-1 for 100g tissue then there is infarction within an hour. Third, if the blood flow is < 20 ml
min-1 for 100g tissue then ischemia is caused without infarction [3]. The process of
atherosclerosis leads to cerebral ischemia and is summarized in Figure 6.
Figure 6:Carotid atherosclerosis to cerebral ischemia.
Inflammation involves the accumulation of immune cells in certain regions [85]. The
essential leukocyte sub-population that controls cascade of neuroinflammatory responses
includes microglial cell instigation, brain leukocyte assault, lymphocytes, and pro-inflammatory
cytokines [87,88].It is seen that in experimental models of the brain as well as in patient with
acute stroke are linked with increased production of pro-inflammatory cytokines and chemokines
which contributes to cerebral infarct [89].There are several cytokines which comes into play
during the inflammatory response, like Tumor Necrosis Factor-𝛼 (TNF-𝛼), Interleukin-1𝛽 (IL-
1𝛽), Interleukin-6 (IL-6), and Interleukin-18 (IL-18) [90].
When blood perfusion to the brain stops, the ischemic neurons become energy-deprived
and necrosis happens. This event potentiates immune system activation causing the deposition of
inflammatory cells in the vicinity of the ischemic region [91].Earlier only bioenergetics of
mitochondria was considered, however current knowledge focus on mitochondrial damage at a
molecular level can lead to cerebral ischemia. Since mitochondria play a vital role in generating
Reactive Oxygen Species (ROS). These further damage mitochondrial DNA and disrupt electron
transport chain function causing inflammation and apoptosis [92].Stroke, which is a result of
neurological deficit have peculiar variations with the vascular system. They include altered BP,
fibrinolysis, vascular tone, cerebral vasomotor regulation, hindering coagulation, and its factors.
Day-to-day altered patterns of BP were noteworthy post-stroke because those patterns can
monitor the duration of therapy, and help in averting initiation of stroke once again [84].
Oxidative stress results from a disparity in ROS production and competence to neutralize the free
radical products in the human body [92].
The brain is considered an immune restricted site because the meninges especially BBB
firmly confines the entrance of pro-inflammatory mediators from the periphery into the Central
Nervous System (CNS) [93]. But when BBB is disrupted, then it facilitates the exchange of
harmful substances like cytokines, C-Reactive Protein (CRP), matrix metalloproteinases
(MMPs), and nitric oxide (NO) in the CNS, and scavenges crucial nutrients reaching the brain
[45,91, 94].Hence, cytokines is crucial inflammatory factor which can be detected in serum and
cerebrospinal fluid during acute phase of stroke making it as on road biomarker in early
detection of stroke [95]. One such study included isolation of thrombus through standard
thrombectomy procedure in post-stroke patients up to 24 hour onset. Later, the thrombus was
studied at molecular and cellular level using machine learning that lead the way to find
prognostic inflammatory biomarkers of stroke[96].Due to lack of understanding in the
mechanism of cytokines before and after stroke, it hinder the use of cytokine as biomarker or
therapeutic target [97]. MicroRNAs have dual actions of pros and cons. Pros include that these
help in nerve development, differentiation, synaptic plasticity, apoptosis, and degeneration. But
the two among microRNAs namely microRNA-15a and microRNA-497 are
pathophysiologically active. These microRNAs impair normal defense mechanisms and interfere
in antiapoptotic action [85].
Due to increase accumulation of excitatory amino acids leads to excitotoxicity which paves
a path for cellular calcium to increase to a toxic level. When toxic levels of calcium ions are
present energy production system is imbalanced and so the Na⁺-K⁺ ATPase enzyme is inhibited.
As a result, there is a bulk entry of ions into the cell leading to either acute cell swelling or cell
death [26].Cell death can be categorized into two as necrosis and apoptosis. Necrosis is simple
tissue death with minimal damage whereas apoptosis is programmed cell death. During necrosis,
there is a chance of recovery of neuronal cells if the pressure of the mechanism is corrected at
earliest. The apoptotic form can be severe and permanent injuries are seen due to the inability to
reverse the programmed cell death [26,98-100]. The process of necrosis is summarized in Figure
7.
Figure7: Cerebral ischemia to cell death.
6.2. Hemorrhagic Stroke. Only 15% of stroke case accounts for a hemorrhagic one. Hence, the
pathophysiology of hemorrhagic stroke is not well established as that of ischemic stroke. The
only mechanism known is that the rupture of the blood vessel in the brain causes chaos in the
brain and so the brain is posturized to be in the pool of blood. As the blood fills up in the
cranium it creates increased intracranial pressure which is marked by severe headache and results
can be fatal within hours if left untreated. The blood in brain parenchyma creates a mechanical
effect that exhibits neurotoxicity and multiple organ failure due to severe internal bleeding.
Sometimes hemorrhages can develop into secondary ischemia [3,24].
7. COMPLICATIONS.
7.1. Stroke Associated Pneumonia (SAP). It is the usual complications of a stroke. SAP is likely
to develop inpatient with advancing age, increased hospital stay, and decreased human leukocyte
antigen-DR isotype (HLA-DR), stroke-induced immune depression syndrome, and Chronic
Obstructive Pulmonary Disease (COPD) [27].
7.2.Dysphagia.Post-stroke dysphagia can be seen in patients who are more prone to develop
SAP. Early dysphagia screening can be assessed within 4 hours of hospital admission and
evaluated by Speech and Language Pathologist (SLP) according to United Kingdom guidelines
within 72 hours [28].
7.3. Cardiac Complications.The cardiovascular complication is one of the main reasons for death
in stroke patients. It is well studied under a specialty called neurocardiology. The complications
are mild to moderate such as Neurogenic Stress Cardiomyopathy (NSC) and Takotsubo
cardiomyopathy. In the case of SAH, complications include cardiac arrhythmia associated with
other heart abnormalities, and increased hospital stay. The mechanism involved in brain heart
interaction is the stimulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis, catecholamine
surge, and sympathetic and parasympathetic regulations [29,101].
7.4. Depression.Post Stroke Depression (PSD) occurs around three months after the stroke, and
around 12% of male and 16% of females suffer from depression due to stroke. Depression is
likely due to decreased bioavailability of amines of several neurotransmitters like serotonin,
dopamine, and norepinephrine in the brain [87].
7.5. Serotonin Syndrome (SS). It is purely Adverse Drug Reaction (ADR) caused by an increased
amount of serotonin in the brain which was earlier taken to enhance the activity of the brain. So
it is necessary to have attention while prescribing dopaminergic drugs in stroke patients if not the
stroke may worsen with life-threatening condition SS [31].
7.6. Fatigue.Post Stroke Fatigue (PSF) is also one of the consequences of stroke which is related
to inactivity. PSF is assessed by different Patient-Reported Outcome Measures (PROMs)
[33,34].
7.7. Dementia.Post Stroke Dementia (PSD) can be due to vascular dementia or Alzheimer’s
Disease (AD). Other contributing factors are recurrent stroke, severe neurologic deficits, multiple
infarctions, cerebral atrophy, and cerebral micro-bleeds that can precipitate PSD [35,39].
7.7. Epilepsy.Post Stroke Epilepsy (PSE) is likely due to abnormal release of glutamate after
stroke. These are the seizures arising from the neuronal deficit purely. According to Golvic et.al.,
2018 [38]seizures can be seen post-stroke rather than because of 5 predictive factors and they are
the severity of a stroke, large artery atherosclerosis, early seizures, cortical involvement, and
Middle Cerebral Artery (MCA) territory infarct
7.8. Post Stroke Cognitive Decline (PSCD).PSCD can be easily found in elderly, rural, fewer
years of education, diabetes, recurrent stroke, physical inactivity, and smoking. This can be a
lethal complication as cognitive decline will eventually take away sensory as well as motor
actions leaving the patient to be bed-ridden and have increased morbidity and mortality [40].
7.9 Stroke related sarcopenia. There are several fragilities in muscles and progressive decline in
muscle mass and its function which lead to sarcopenia with advancing age[102].
8. MANAGEMENT.
8.1. Non- Pharmacological Treatment.Surgical intervention in the case of ischemic stroke,
craniectomy is used to release high pressure due to cerebral edema by large ischemic infarction.
To prevent the recurrence of stroke carotid endarterectomy of ulcerated narrowed carotid is the
best option as secondary prevention of stroke. But compared to endarterectomy, carotid stenting
is less invasive but investigational. In case of hemorrhagic rupture of aneurysm or Arterio-
Venous Malformation (AVM) clips are placed to avoid re-bleeding. Surgical decompression of
hematoma is considered only when pharmacological therapy fails or during life-threatening
conditions [24]. Conventional therapies include speech therapy, mirror therapy, occupational
therapy [103], and stem cell transplantation [104,105].Particularly, Bone Marrow Mesenchymal
Stem Cells (BMSCs) are frequently studied due to its paracrine effect and exosomes plays vital
role in paracrine effect. Compared to stem cell therapy, exosomes therapy has shown lesser risk
of rejection and has novel approach of treatment in stroke [106]. The Chinese Cochrane
databases include some herbs in prevention of stroke [107].
8.2. Pharmacological Treatment. The immediate drug of therapy given within hours of the onset
of stroke is rtPA [108,109]. It reduces associated disability when given as early as possible but
caution must be taken. When there is delayed administration of rtPA then other drugs like
retinoic acid and, ascorbic acid, etc. can alleviate the overdue adverse effects of rtPA [45].
Mechanism of Granulocyte-Colony Stimulating Factor (G-CSF) is the novel
advancement in the therapy for stroke depicted in mouse model. The FDA approved G-CSF
drugs has many neuroprotective actions like neurogenesis, angiogenic actions, and anti-apoptotic
actions[110]. Another novel approach is nerinetide, which is aneicasopeptide that interferes with
post-synaptic density protein 95 (PSD-95) resulting in neuroprotective action. Efficacy and
safety of nerinetide for the treatment of acute ischemic stroke in patients who underwent
endovascular thrombectomy was carried out by ESCAPE-NA1 randomized clinical trial [111].
The other treatments include antiplatelet agents, antihypertensive agents, statins, which
are generally given to remove the threat in the form of a clot, hypertension, and cholesterol
deposition, respectively. Neuro-protectants like antioxidants and FDA approved NADPH
Oxidase inhibitors (NOX inhibitors) are also used. NOX inhibitors obstruct ROS production and
prevent inflammatory processes. The drugs for ischemic stroke are listed in Table 4.
Table 4: Treatment of ischemic stroke
Drug Class/ Category Drug Dose per day Mechanism of action
Recombinant tissue
plasminogen activators
[86, 93, 112-116]
Alteplase 0.9mg kg-1 IV It enhances the conversion of
plasminogen to plasmin by
binding to fibrin, initiating
fibrinolysis by proteolysis
Anticoagulant agents
[117-119]
Warfarin 2-5 mg orally It blocks the regeneration of
vitamin K(1) epoxide which is
coagulant
Antiplatelet agents
[117,120,121]
Aspirin
Clopidogrel
325 mg
75 mg
Inhibits both prostaglandin
synthesis and platelet aggregation
Inhibits CYP2Y12 adenosine
phosphate (ADP) platelet receptors
Non-VKA Oral Anti-
Coagulants (NOACs)
[122]
Dabigatran
Apixaban
Rivaroxaban
150mg twice daily
2.5 mg twice daily
15 mg twice daily
These are direct thrombin
inhibitors which prevents
thrombus development
Antihypertensive agents
(ACE inhibitors)
Perindopril 3.5mg Reduces plasma level of
angiotensin, a potent
vasoconstrictor
Statins Atorvastatin 80mg Inhibits HMG-CoA reductase
which is important enzyme in
cholesterol synthesis
NOX inhibitors [46] Apocynin
Diphenyleneiodoni
um
Ebselen
50 mg kg-1 IV
150 mg twice daily
Inhibits ROS production which is
responsible for oxidative stress in
stroke
Antioxidants (nootropics
or Neuro-Trophic
Factors-NTFs) [123]
Edaravone
Cerebro-protein
hydrosylate
30 mg
60-180mg
It suppresses free radicals and
inhibits endothelial cell injury.
As of now, no confirmed pharmacologic treatment is there for ICH. Medical guidelines
are there for monitoring BP, ICP (Intra-Cranial Pressure), other complications, and acutely ill
patients in the neuro-intensive care unit [24].
9. LIFESTYLE MODIFICATION.
9.1. Physiotherapy.Difficulty in walking or motor inactivity is majorly seen in a post-stroke
patient. Stroke patients need to adapt ‘exercise’ in their life provided with the true guidance of a
physiotherapist. Rehabilitation after stroke has given significant outcomes in motor functions
after stroke.49Gait training is done to improve walking post-stroke with the help of a treadmill
[57,124-126].
9.2. Adequate Sleep. Damage to certain regions of the brain can interfere with sleep patterns. So,
it is necessary to have an adequate amount of sleep for the improvement of sleep after stroke.
Neuroplasticity and activity the of brain are improved by sleep [51].
9.3. Mediterranean Diet (MeD Diet).It is a diet including a principal source of monounsaturated
fats, vegetables, olive oil, limited consumption of meat and dairy products, and moderate use of
fish and alcohol. This diet has attained greater attention with prolonged survival and a lower risk
of neurodegenerative disorders. The benefit of the MeD diet is assessed by REGARDS (Reasons
for Geographic And Racial Differences in Stroke) study. In this study, the inverse relationship
between adherence to the MeD diet and the occurrence of ischemic stroke was documented [50].
9.4. Fasting for 11- 20 h. Changes in diet style during the holy month Ramadan that is no fluid or
food intake affects 24-hourly rhythm pattern and influences the control of the appearance of
stroke [84].
9.5. Dairy Products.Milk and other dairy product consumptions are inversely related to the
occurrence of stroke [127].
10. CONCLUSION
Stroke which is also known as Cerebrovascular Disorder is a medical emergency. Despite people
managing their physic and mental health through a workout, there are still more people like
obese, altered food taste which is high in calories leading to devastating conditions like stroke.
People should know the signs and symptoms of stroke since it is a medical emergency and to
cope up earliest. The risk factors are the various entrances for the commencement of stroke
through which one can be able to prevent if aware of it. In the section of risk factors of stroke,
genetics are yet to be explored. The complication being disability is itself directing stroke
patients mentally to die hence it is needed to look to remove this disability by various
rehabilitation centers of stroke. The proper diagnosis is also needed for this condition as there are
two main types, misdiagnosis can lead to the noxious effect. To be specific with the noxious
effect is that the therapy given for ischemic stroke includes blood thinners if given for
hemorrhage can kill patients in seconds. Lifestyle modifications should be followed by stroke hit
patient as it is meant to ease the life after stroke and mostly towards the correction of symptoms
like motor dysfunction.
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