Timing of appearance of the third dentition (Takahahsi et al., 2013, copy right, In Tech)
\r\n\tCongenital hearing loss means hearing loss that is present at birth. I have managed children with hearing loss for many years, and the most touching thing is the light that blooms on the face while the hearing-impaired child heard his mother's voice at first time. The scene of "happy tears" impressed me so much. To hear the voice that has not been heard is so pleasant, as if this ordinary listening experience is a supreme listening enjoyment.
\r\n\r\n\tAge-related hearing loss means a progressive loss of ability to hear high frequencies with aging, also known as presbycusis. Among them are the influence of internal and external factors such as genes, drugs and noise exposure. The studies pointed out that the brain stimulation of the hearing-impaired person is greatly reduced compared with subjects with normal hearing. The connection of auditory cortex and other brain areas has declined a lot, which is probably one of the important causes of dementia or even depression in the elderly.
\r\n\r\n\tNoise-induced hearing loss is hearing impairment resulting from exposure to loud sound. There is actually continuous and endless noise in many workplaces, which may cause chronic and cumulative damage. Some young people often work hard but easily neglect to protect themselves. In addition, in recent years, entertainment noise (such as nightclubs, concerts, and personal listening devices) has caused hearing impairment in young people. These should be avoidable and preventable.
\r\n\r\n\tHearing Science is the study of impaired auditory perception, the technologies and other rehabilitation strategies for persons with hearing loss. Public health has been defined as "the science and art of preventing disease", improving quality of life through organized efforts. To avoid the “epidemic” of hearing loss, it is necessary to promote early screening, use hearing protection, and change public attitudes toward noise.
\r\n\r\n\tBased on these concepts, the book incorporates updated developments as well as future perspectives in the ever-expanding field of hearing loss. Besides, it is also a great reference for audiologists, otolaryngologists, neurologists, specialists in public health, basic and clinical researchers.
",isbn:"978-1-83968-678-8",printIsbn:"978-1-83968-677-1",pdfIsbn:"978-1-83968-679-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"a4b7dbb02ba00e7412422cd5dbffa029",bookSignature:"Dr. Tang-Chuan Wang",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10529.jpg",keywords:"Hidden Hearing Loss, Plasticity, Electrophysiology, Otoacoustic Emission, Newborn Hearing Screening, Genetics, Aging, Hearing Aids, Noise Exposure, Occupational Hearing Loss, Epidemiology, Prevention",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 3rd 2020",dateEndSecondStepPublish:"October 1st 2020",dateEndThirdStepPublish:"November 30th 2020",dateEndFourthStepPublish:"February 18th 2021",dateEndFifthStepPublish:"April 19th 2021",remainingDaysToSecondStep:"4 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Tang-Chuan Wang is an excellent otolaryngologist-head and neck surgeon in Taiwan; a research scholar of Harvard Medical School and University of Iowa Hospitals. He worked in the Hospital of the University of Pennsylvania, Boston Children's Hospital, and Massachusetts Eye and Ear. Due to his contribution to biomedical engineering, he was invited into the executive committee of HIWIN-CMU Joint R & D Center in Taiwan.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"201262",title:"Dr.",name:"Tang-Chuan",middleName:null,surname:"Wang",slug:"tang-chuan-wang",fullName:"Tang-Chuan Wang",profilePictureURL:"https://mts.intechopen.com/storage/users/201262/images/system/201262.gif",biography:'Dr. Tang-Chuan Wang is an excellent otolaryngologist – head and neck surgeon in Taiwan. He is also a research scholar of Harvard Medical School and University of Iowa Hospitals. During his substantial experience, he worked in Hospital of the University of Pennsylvania, Boston Children\'s Hospital and Massachusetts Eye and Ear. Besides, he is not only working hard on clinical & basic medicine but also launching out into public health in Taiwan. In recent years, he devotes himself to innovation. He always says that "in theoretical or practical aspects, no innovation is a step backward". 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"47334",title:"Feasibility of Molecularly Targeted Therapy for Tooth Regeneration",doi:"10.5772/58904",slug:"feasibility-of-molecularly-targeted-therapy-for-tooth-regeneration",body:'The tooth is a complex organ that consists of enamel, dentin, cementum, and pulp. Missing teeth is frequently occurring problem in aging populations. To treat these defects, the current approach involves prostheses, autotransplantation, and dental implants. The exploration of new strategies for tooth replacement has become a hot topic. Using the foundations of experimental embryology, developmental and molecular biology, tooth regeneration is becoming realistic possibility. Several different methods have been proposed to achieve biological tooth replacement. These include scaffold-based tooth regeneration, cell pellet engineering, stimulation of the formation of a third dentition, and gene-manipulated tooth regeneration. The idea that a third dentition might be locally induced to replace missing teeth is an attractive concept (Young et al., 2005; Edward & Mason, 2006; Takahashi et al., 2008, 2013). This approach is generally presented in terms of adding molecules to induce de novo tooth initiation in the mouth. Tooth development is the result of reciprocal and reiterative signaling between oral ectoderm-derived dental epithelium and cranial neural crest cell-derived dental mesenchyme under genetic control (Thesleff, 2006). More than 200 genes are known to be expressed during tooth development (http://bite-it.helsinki.fi/). A number of mouse mutants are now starting to provide some insights into the mechanisms of supernumerary tooth formation. Multiple supernumerary teeth may have genetic components in their etiology and partially represent the third dentition in humans. Such candidate molecules might be those that are involved in embryonic tooth induction, in successional tooth formation, or in the control of the number of teeth. This means that it may be possible to induce de novo tooth formation by the in situ repression or activation of a single candidate molecule. In this review, we provide an overview of the collective knowledge of tooth regeneration, especially regarding the control of the number of teeth for molecularly targeted therapy by the stimulation of a third dentition.
It has been suggested that, in humans, a “third dentition” with one or more supernumerary teeth can occur in addition to the permanent dentition, and supernumerary teeth are sometimes thought to represent a partial post-permanent dentition (Ooe, 1969). The deciduous teeth are, ontogenetically, the first generation of teeth. The permanent teeth (except molar) belong to the second dentition. The term “third dentition” refers to the opinion that one more set of teeth can occur in addition to the permanent teeth (Figure 1). Human teeth are diphyodont excepting the permanent molars. The normal mouse dentition is monophyodont and composed of one incisor and three molars in each quadrant. The number of teeth is usually strictly determined. It was initially reported that there is an anlagen of the third dentition in some mammals (Leche, 1893). The presence of an epithelial anlagen of the third dentition was also noticed in humans (Ooe, 1969). The teeth and anlagen that appear in third dentition in serial sections of infant jaws and some fetuses have been analysed. The epithelium which is considered as the anlagen of the third dentition develops lingual to all permanent tooth germs (Ooe, 1969). Furthermore, when it appears, the predecessor (permanent tooth germ) is in the bell-shaped stage (Ooe, 1969). The timing of appearance of the third dentition seems to be after birth (Table 1). This means that we have a chance to access the formation of the third dentition in the mouth.
Detailed histological analysis of the tooth replacement in these models indicates that the successional teeth are initiated from the dental lamina epithelium, which grows from the lingual side of the deciduous tooth enamel organ, and it later elongates and buds into the jaw mesenchyme, forming successional teeth. Jarvien et al. showed that, in the ferret, Usag-1(also known as Sostdc1, Ectodin, and Wise) is expressed in the elongating successional dental lamina at the interface between the lamina and deciduous tooth, as well as the buccal side of the dental lamina, suggesting that Sostdc1 plays a role in defining the identity of the dental lamina(Jarvinen et al., 2009). Handrigan et al. analysed successional tooth formation in the snake and in lizard, and proposed that dental epithelium stem cells are responsible for the formation of successional lamina, and Wnt signaling may regulate the dental eithelial stem cell fate in these cells (Handrigan et al., 2010). Maintenance or reactivation of component dental lamina is thus pivotal for the replacement tooth and supernumerary formation.
Supernumerary teeth can be associated with a syndrome or they can be found in non-syndromic patients. Only 1% of non-syndromic cases have multiple supernumerary teeth, which occur most frequently in the mandibular premolar area, followed by the molar and anterior regions, respectively (Yusof, 1990; Yague-Garcia et al., 2009). Genetic mutations have been associated with the presence or absence of individual types of teeth.
Supernumerary teeth are associated with 8 syndromes and developmental abnormalities in which the resposible genes already have been isolated (Takahashi et al., 2013). The percentage occurrence in CCD is 22% in the maxillary incisor region and 5% in the molar region (Shafer, 1983). CCD is a dominantly inherited skeletal dysplasia caused by mutations in RUNX2 (Mundlos et al., 1997). There is a wide spectrum of phenotypic variability ranging from the full-blown phenotype to an isolated dental phenotype characterized by supernumerary tooth formation and/or the delayed eruption of permanent teeth in CCD (Takahashi et al., 2008). Runx2-deficient mice were found to exhibit lingual buds in front of the upper molars, and these were much more prominent than in wild-type mice (Aberg et al., 2004). These buds presumably represent the mouse secondary dentition, and it is likely that RUNX2 acts to prevent the formation of these buds. Runx2 regulates the proliferation of cells and may exert specific control on the dental lamina and formation of successive dentitions. Runx2 heterozygous mutant mice mostly phenocopied the skeletal defects of CCD in humans, but with no supernumerary tooth formation (Otto et al., 1997). Notably, in Runx2 homozygous and heterozygous mouse upper molars, a prominent epithelial bud regularly presents. This epithelial bud protrudes lingually with active Shh signaling, and it may represent the extension of the dental lamina for successional tooth formation in mice. Hence, although Runx2 is required for primary tooth development, it prevents the growth of the dental lamina and successional tooth formation (Otto et al., 1997).
Familial adenomatous polyposis (FAP), also named adenomatous polyposis of the colon (APC), is an autosomal dominant hereditary disorder characterized by the development of many precancerous colorectal adenomatous polyps. In addition to colorectal neoplasm, individuals can develop variable extracolonic lesions, including upper gastrointestinal polyposis, osteomas and dental anomalies (Wijn et al., 2007). Dental abnormalities include impacted teeth, congenital absence of one or more teeth, supernumerary teeth and odontomas (Wijn et al., 2007). Gardner syndrome is a variant of FAP characterized by multiple adenomas of the colon and rectum typical of FAP together with osteomas and soft tissue tumors (Chimenos-Kustner et al., 2005). Supernumerary teeth and osteomas were originally described as a part of Gardner syndrome, but they can also occur in FAP patients with or without other extracolonic lesions (Chimenos-Kustner et al., 2005; Wijn et al., 2007). FAP and Gardner syndrome are caused by a large number of germinal mutations in the Apc gene (Groden et al., 1991). Apc is a tumor suppressor gene involved in the down-regulation of free intracellular ß-catenin, the major signal transducer of the canonical Wnt signaling pathway (Groden et al., 1991). Approximately 11-27% of patients have supernumerary teeth, but, so far, no specific codon mutation of the Apc gene has been found to correlate with supernumerary teeth.
The identification of mutations in RUNX2 causing an isolated dental phenotype in CCD and in Apc causing FAP has attracted attention as a possible route towards inducing de novo tooth formation.
A number of mouse mutants provide insights into the supernumerary tooth formation (Takahashi et al., 2013). Several mechanisms by which supernumerary tooth might arise in mice have been proposed (Murashima-Suginami et al., 2008; Wang et al., 2009). One plausible explanation for supernumerary tooth formation is the rescue of tooth rudiments such as within the diastema region or maxillary deciduous incisor (Yamamoto et al., 2005; Murashima-Suginami et al., 2007; Lagronova-Churava et al., 2013). During early stages of mouse tooth development transient vestigial tooth buds develop in the diastema area; developing to the bud stage yet later regressing and disappear by apoptosis, or merge with the mesial crown of the adjacent first molar tooth organ (Yamamoto et al., 2005; Lagronova-Churava et al., 2013). The rudimentary maxillary incisor regressed by apoptotic elimination of mesenchymal cells (Murashima-Suginami et al., 2007). We demonstrated that USAG-1-deficient mouse model has supernumerary incisors in the maxillary and mandible, a fused tooth in the maxillary and mandibular molar regions, and a supernumerary tooth was also located in front of the first mandibular molar (Figure 2). Increased BMP signaling results in supernumerary teeth in the Usag-1-deficient mouse model (Murashima-Suginami et al., 2008). Recently, we claimed that gene interactions between BMP-7 and USAG-1 regulate the supernumerary maxillary incisor formation (Kiso et al., 2014). BMP-7 was co-localized with USAG-1 in the area of the maxillary rudiment incisor tooth germ in addition to the regular maxillary incisor tooth organ. USAG-1 abrogation rescued the apoptotic elimination of mesenchymal cells in the rudimentary maxillary incisor tooth primordia at E15, whereas the tooth sizes were comparable (Murashima-Suginami et al., 2007, 2008). The apoptotic mesenchymal cells in USAG-1-/-/BMP-7-/-are similar to USAG-1+/+/BMP-7+/+in contrast to that of USAG-1-/-/BMP-7+/+. These results support our interpretation that USAG-1 functions as a novel BMP-7 antagonist in the maxilla. We confirmed that increased BMP signaling in supernumerary teeth of the USAG-1 deficient mice could be prohibited by BMP-7 abrogation. In the contrast, to test whether BMP-7 has the potential to induce supernumerary tooth formation, we performed explant culture and subsequent subrenal kidney capsule culture. The incisor explants supplemented with BMP-7 in USAG-1+/-as well as USAG-1-/-have supernumerary tooth in similar numbers after 20 days culture, while these cultured explants in USAG-1+/+retained normal tooth number (Figure 2). These results demonstrated that BMP-7 can induce supernumerary tooth formation, however it is impossible to induce extra tooth by only BMP-7 (Kiso et al., 2014). While we showed that enhanced BMP signaling resulted in supernumerary teeth, we also demonstarated that BMP signaling was modulated by Wnt signaling in the Usag-1-deficient mouse model (Figure 3) (Murashima-Suginami et al., 2008). Canonical Wnt/β-catenin signaling and its down-stream molecule Lef-1 are essential for tooth development. Overexpression of Lef-1 under the control of the K14 promoter in transgenic mice leads to the development abnormal invaginations of the dental epithelium in the mesenchyme and formation of a tooth-like structure (Zhou et al., 1995). De novo supernumerary teeth arising directly from the primary tooth germ or dental lamima have been reported in Apc loss-of-function or β-catenin gain-of-function mic. It was demonstrated that mouse tooth buds expressing stabilized β-catenin give rise to extra teeth (Jarvinen et al., 2006). Conditional knockout of the Apc-gene resulted in supernumerary teeth in mice (Wang et al., 2009). Notably, adult oral tissues, especially young adult tissues, are still responsive to the loss of Apc (Wang et al., 2009). In old adult mice, supernumerary teeth can be induced on both labial and lingual sides of the incisors, which contain adult stem cells supporting the continuous growth of mouse incisors (Huysseune et al., 2004). In young mice, supernumerary tooth germs were induced in multiple regions of the jaw in both incisor and molar regions. They can form directly from the oral epithelium, in the dental lamina connecting the developing molar or incisor tooth germ to the oral epithelium, in the crown region, as well as in the elongating and furcation area of the developing root (Wang et al., 2009). Wnt/BMP signaling seems to be essential in supernumerary tooth formation (Figure 3).
We also demonstrated that Cebpb deficiency was related to the formation of supernumerary teeth(Figure 2). A total of 66.7% of Cebpb-/-12-month-olds sustained supernumerary teeth and/or odontomas in the diastema between the incisor and the first molar (Huang et al., 2012). Furthermore, it was suggested that the dental epitheilal stem cells might be contributated to supernumerary tooth formation in mice (Figure 2).
These mouse models clearly demonstrated that it was possible to induce de novo tooth formation by the in situ inhibition or activation of single molecule such as USAG-1, BMP7 or CEBPB.
Molecularly targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific types of cells by interfering with specific targeted molecules.
Most targeted therapies are either small moleclule or monoclonal antibodies. Small molecules are typically able to diffuse into cells and can act on target that are found inside the cells. Monoclonal antibodies usually can not penetorate the surface membrane and are directed against targets that are outside cells or on the surface of cells. Candidates for small molecules are identified in screeing the effect of thousands of test compounds on a specific target. The best candidates are then chemically modified to produce many closely related versions. Monoclonal antibody are prepared first by immunized animals such as mice with purified target moleclules.They are humanized by replacing the animal portion of the antibody with human portion. More than 40 molecularly targeted cancer therapy have been approved by the U.S Food and Drug Administration for the treatment of specific type of cancer. Many more are in clinical trials or preclinical testing (Forscher et al., 2014). Recent molecularly targeted therapy also has successfully been introduced into the treatment of several inflammatory rheumatic diseases such as rheumatoid arthritis (Mocsai et al., 2014).
Molecularly targeted therapy provides a unique tool for the delivery of previously identified signaling molecules in both time and space that may significantly augment our progress toward clinical tooth regeneration. Stimulation of the formation of a third dentition comprises an attractive concept (Figure 4). This approach is generally presented in terms of adding molecules to induce de novo tooth initiation in the mouth. We have a chance to access the formation of the third dentition in the mouth, because the time of appearance of the third dentition seems to be after birth. Advances in our understanding of signal transduction by Wnt/BMP signalling in the supernumerary teeth formation offer numerous opportunities for devising new targeted therapies (Figure 3).This led to a new approach of drug development whereby targeted therapy are developed by directly targeting molecules thought to be involved in the the formation of a third dentition. A mojor approach for the development targeted therapeutics has been the application of monoclonal antibody for targeting molecules such as USAG-1.
Molecularly targeted therapy seems to be a suitable approach in tooth regeneration by stimulation of the third dentition.
Multiple impacted supernumerary teeth (the third dentition) in a 13-year-old non-syndromic patient.
The third dentition develops lingual to the permanent tooth germ (D). All impacted supernumerary teeth in this patient are located to the lingual side of the permanent teeth (white arrow) (A-C). These multiple supernumerary teeth seem to be post-permanent dentition (“third dentition”). (Takahahsi et al., 2013, copy right, In Tech)
\n\t\t\t\t | \n\t\t
Timing of appearance of the third dentition (Takahahsi et al., 2013, copy right, In Tech)
Supernumerary teeth formation in mouse model
Usag-1 deficient mice (A-C) A: Oblique view of the maxillary incisors. B: Occlusal view of the mandibular incisors. C: Occlusal view of the mandibular molars. Micro-CT images of Cebpb dificient mice (D-F) A frontal view (D), a sagittal view (E) and a horizontal view (F) BMP-7 has potential to partially induce the formation of maxillary supernumerary incisors formation in vitro. The incisor explants supplemented with (H)/without (G) BMP-7 in USAG-1+/− (G, H) sagittal sections of explant. (I) Sox2 positive detal epithelial stem cells in sagittal sections of the rudimentary maxillary incisor tooth primordia at E15.
Wnt/BMP signaling in supernumerary tooth formation.
Underlined molecules are responsible genes for human syndromes or mutant mouse associated with supernumerary teeth
Molecularly targeted therapy for the tooth regeneration by stimulation of a third dentition
We have a chance to access the formation of the third dentition in the mouth, because the timing of the appearance of the third dentition seems to be after birth. The identification of mutations in RUNX2 causing an isolated dental phenotype in CCD and supernumerary tooth formation in the mouse model clearly demonstrated that it was possible to induce de novo tooth formation by the in situ inhibition or activation of a single candidate molecule. These results support the idea that the de novo inhbition or activation of candidate molecules such as RUNX2 or USAG-1 might be used to stimulate the third dentition in order to induce new tooth formation in the mouse (Figure 4). Molecularly targeted therapy seems to be a suitable approach in tooth regeneration by stimulation of the third dentition.
This work was supported by Grant-in-Aid for Scientific Research(C):22592213 and 25463081 and A-STEP (Adaptable & Seamless Technology Transfer Program through Target-driven R&D) FS stage: AS231Z01061G and AS242Z02645Q.
This chapter focuses on the treatment of acute cerebral ischemia and intracranial hemorrhage, which are two types of stroke. Stroke is characterized by a sudden loss of brain function with no established cause other than vascular origin. This applies to both ischemic stroke and intracranial hemorrhage.
\nAcute stroke suggests the following signs:
Sudden onset of symptoms and development of the clinical picture in a few seconds or minutes with further stabilization or improvement.
Focal neurological symptoms associated with damage to certain parts of the brain: motor deficits (weakness or immobility of the limbs on one side of the body (hemiplegia or hemiparesis) or an isolated limb), loss of sensitivity (decreased sensitivity in various parts of the body), aphasia, agnosia, and vision disorders.
Symptoms suggesting a loss of function: limb tremors, convulsions, paresthesias, visual hallucinations, and flashes before the eyes.
Headache, nausea and vomiting, dysphagia, dysarthria, dysphonia, diplopia, ataxia, hiccups, one-sided acute hearing loss, respiratory disorder, convulsive syndrome, and transient loss of consciousness may be clinical manifestations of a stroke localized in the brain stem.
Symptoms such as loss of consciousness, dizziness, general weakness, confusion, urinary incontinence, syncopal condition, and tinnitus do not indicate the development of a stroke if they are not associated with focal neurological symptoms.
For the differential diagnosis of ischemic and hemorrhagic strokes, it is necessary to conduct a neuroimaging study [1]. This is the most important stage of diagnosis, because patients with ischemic and hemorrhagic strokes require different therapies in the acute period and various measures of secondary prevention [2].
\nMagnetic resonance imaging (MRI) is the most appropriate diagnostic method for patients with acute cerebral circulation disorders due to the following reasons [3]:
T1- and T2-weighted images and fluid-attenuated inversion recovery (FLAIR) sequences allow the differentiation of old foci and foci of nonvascular origin.
Diffusion-weighted images allow the identification of new ischemic foci. Low brain blood flow causes the development of cytotoxic cell edema and, as a result, a decrease in the movement of extracellular fluid, which is displayed as a hyperintensive signal on diffusion-weighted images, and a decrease in the water diffusion coefficient. These changes appear earlier than changes in T1 and T2 and FLAIR.
T* sequences are used to detect hemorrhages.
Time-of-flight (TOF) MR angiography can be used to visualize the occlusion of extra- and intracranial arteries.
When MRI is not available in an emergency or cannot be performed due to contraindications (established rhythm driver, claustrophobia, psychomotor agitation), an emergency computed tomography (CT) scan of the brain is performed without contrast. CT scan reveals an intracranial hemorrhage in the form of a hyperintensive zone in the brain parenchyma. Figure 1 shows a non-contrast CT scan with a spontaneous hyperdensity of the right cerebral hemisphere, due to a deep intracerebral hemorrhage (ICH). In the early stages of acute cerebral ischemia, CT signs of ischemia may be absent. But within 3 hours, you can see signs of ischemia, for example, the disappearance of a clear border of gray and white matter. With the occlusion of the middle cerebral artery, CT signs will appear in the form of a hyperintensive zone. CT with contrast allows you to visualize the anatomy of the arteries and perfusion.
\nNon-contrast CT scan shows a spontaneous hyperdensity of the right cerebral hemisphere.
The most common causes of ischemic stroke are common atherosclerosis, atrial fibrillation (AF), occlusion of small perforating arteries of the brain, pathology of heart valves, and infectious diseases, in young patients—cerebral artery dissection.
\nIntracerebral hemorrhages in most cases are the result of the damage to small cerebral vessels due to chronic arterial hypertension or amyloid angiopathy.
\nFor all patients in the acute stage, the following examinations should be carried out, which will determine the treatment plan: a thorough collection of anamnesis to determine the presence of hypertension, medications used, alcohol abuse, and substance abuse and a family history of stroke, oncology, and trauma; a clinical examination; blood test to detect polycythemia and plateletemia, erythrocyte sedimentation rate (ESR) to detect vasculitis, and the level of glycemia to detect diabetes or hypoglycemia, and coagulation tests. Cardiac assessment including electrocardiogram (ECG) and echocardiography (EchoCG) is quite important in all cases and Holter in selected cases. ECG recording to detect heart attacks, atrial fibrillation, continuous ECG monitoring to detect arrhythmias; monitoring of systolic, diastolic, and mean blood pressure (BP) by noninvasive method; dopplerography to detect stenoses and dissections of cervical and intracranial vessels; transthoracic EchoCG to detect blood clots, tumors, valve pathology, vegetations on the valves, reduction of ejection fraction, and the presence of an open oval window. Neuroimaging methods include MRI and CT of the brain to detect caverns, intracranial venous thromboses, cerebral microhemorrhages, arteriovenous malformations (AVM), tumors, and indirect signs of unknown injuries. Additional examinations are prescribed depending on the initial results obtained, the patient’s age, and the presumed etiology of the stroke: angiography (usually MR, CT angiography) and specific biological tests when it comes to specific causes, such as antinuclear antibodies, etc.
\nThere are neurological complications that occur in the acute phase of stroke in any type in the form of convulsive syndrome; hyper- and hypoactive delirium, especially with a pre-existing decrease of cognitive functions and the development of metabolic or infectious complications; as well as intracranial hypertension.
\nNonspecific complications include bedsores, pneumonia, urinary tract infection, hyponatremia due to inadequate secretion of antidiuretic hormone (ADH), deep vein thrombosis, and pulmonary thromboembolism. They are more likely to develop in patients with severe neurological deficits. Hyponatremia is a common accompaniment during the acute stage of stroke. Its relevance to the clinical presentation, treatment and prognosis should be mentioned.
\n\n
Hypernatremia: Na >145 mmol/l (the main reason—central DI)
Criteria: polyuria: rate of diuresis >3 ml/kg/hour
Hypernatremia: >145 mmol/l
Urine specific gravity: <1005
\nInfusion therapy:
Base 75–100 ml/hour monitoring of sodium concentration every 6 hours.
Fluid deficit replenishment: in case of polyuria—compensation of fluid loss.
\nIf ineffective, symptoms of diabetes insipidus (DI) persist—ADH\n
Desmopressin: 2–4 mcg per 24 hours
Vasomirin (nasal spray): 10 mcg
\n
Total body fluid = 0.6 × body weight
Free water deficit = (0.6 × body weight) − (0.6 × body weight) × (140/Na act)
Example: body weight = 75 kg, Na = 154 mmol/l
Free water deficit = 0.6 × 75 − [0.6 × 75 × (140/154)] = 45 − 40.9 = 4.1 l
\n
Hyponatremia: Na < 135 mmol/l
If Na <125 mmol/l, there is a high risk of neurological disorders.
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
No neurological deterioration
Acute neurological deterioration
Hyponatremia: no longer than 24 hours acute not prolonged reducing the level of sodium
Negative fluid balance: IV 3% NaCl—4 ml/kg during 15–30 min
2/3 of physiological need for fluid + furosemide 1 mg/kg
Intravenous (IV): only sodium solutions
Monitoring: fluid balance, diuresis, sodium in plasma/urine, and urine specific gravity
Central salt wasting syndrome
Restoring of fluid deficit
Positive sodium balance
Rehydration
HyperHAES: 0.25 ml/kg/hour or 0.9%NaCl
Fludrocortisone: 0.4 mg per 24 hours
Acute hyponatremia correction rate (<48 h): ≤24 mmol/l/24 hours
Chronic hyponatremia correction rate (>48 h): ≤0.5 mmol/l/hour, but ≤10 mmol/l/24 hours
In the presence of an accompanying potassium deficit: ≤4 mmol/l/25 hours
Stroke patients should be treated in specialized departments. For every 24 patients treated in a specialized rather than general ward, one death and one disability are prevented [4]. This does not depend on the age, type, and severity of stroke [4, 5]. Therefore, specialized departments are very important for the treatment of stroke patients [1, 4]. For all strokes with persistent neurological deficits, the treatment aimed at stabilizing the patient’s condition, controlling vital functions, and actively curating problems that may worsen recovery is indicated. This is the main component of the stroke treatment program [6, 7].
\nIn the detection and treatment of emergency life-threatening conditions (risk of aspiration, epileptic status, respiratory failure, etc.), the patency of the upper respiratory tract should be ensured in the case of deprivation of consciousness to the level of coma, respiratory failure of central origin, or local causes leading to respiratory disorders.
\nThe stabilization of most physiological parameters, blood pressure, saturation (more than 93%), glycemic level (less than 180 mg), body temperature (below 37.50°C), and hydration, is necessary in the first few days to prevent negative dynamics in the penumbra zone.
\nA normal respiratory function with adequate blood oxygenation is necessary in the acute period of stroke to maintain an adequate oxygen delivery to brain cells, but there is no conclusive evidence that all patients with stroke receive oxygen therapy with a positive result [4]. In cases of hypoxemia, improved blood oxygenation is achieved by oxygen therapy via a nasal catheter and noninvasive or invasive ventilation.
\nComplications of acute stroke include neurogenic stressful cardiomyopathy, paroxysmal sympathetic hyperactivity, atrial fibrillation, acute heart failure, myocardial infarction, and sudden death [1, 2]. The frequency of these complications explains the need for a constant monitoring for 2–3 days.
\nMany stroke patients are in a state of dehydration, which leads to a worse outcome of the disease [1, 2]. Despite limited clinical data, the administration of infusion therapy (0.9% sodium chloride solution) is considered part of the overall treatment of stroke, especially in patients with an increased risk of dehydration due to depression of consciousness or respiratory disorders. Experience in the treatment of hyperglycemia recommends avoiding the introduction of glucose solutions in the early period of stroke and strict control of the level of glycemia [4].
\nAccording to the literature, there are no mechanisms for autoregulation of cerebral blood flow in the penumbra zone. Therefore, a decrease in blood pressure in the first hours after a stroke before the penumbra zone appears can cause significant hypoperfusion, which worsens the development of the ischemia zone. Therefore, in the acute period, it is not necessary to aggressively treat arterial hypertension if there are no concomitant life-threatening conditions, such as aortic dissection or intracranial hematoma [2, 4].
\nIn practice, blood pressure correction is usually started when the systolic blood pressure exceeds 220 mm Hg and diastolic blood pressure exceeds 120 mm Hg. However, in many clinics, antihypertensive therapy is performed only in cases of heart failure, acute renal failure, aortic arch dissection, or malignant hypertension. When conducting a thrombolytic therapy (TLT), it is common practice to maintain blood pressure below 185 mm Hg. The intravenous administration of labetalol (10 mg bolus, followed by an infusion of 0.1–0.3 mg/kg/hour) or urapidil (12.5 mg bolus for 20 seconds, followed by an infusion of 6–30 mg/hour) is often used.
\nHyperglycemia occurs in 60% of stroke patients who have not previously suffered from diabetes [2, 7]. Hyperglycemia after a stroke is usually associated with a large volume of infarction and cortical damage and is associated with an adverse outcome of the disease [4]. Currently, the routine use of insulin infusions in patients with moderate hyperglycemia is not recommended. The European Stroke Association recommends maintaining glycemia below 180 mg/dl (10 mmol/l) [4].
\n\nBody temperature control: hyperthermia is associated with an increase in the size of the infarction zone and a worsening of the outcome of the disease [8]. Fever is associated with a worse clinical outcome [9]. When the body temperature increases, it is necessary to quickly exclude concomitant infections and, if necessary, treat them.
\nThe prevention of trophic disorders in the form of bedsores is carried out by establishing an early enteral nutrition through a nasogastric probe with an adequate calorie of nutritional mixtures: early mobilization, anti-bedsore mattresses, suitable beds, and nursing care.
\n\nAspiration pneumonia: diagnosis of dysphagia (special examination of the function of swallowing by doctors, nurses, or speech therapists) [10, 11] or use of a nasogastric probe if necessary.
\nDeep vein thrombosis and pulmonary embolism: low-molecular-weight heparins (LMWH) in prophylactic doses reduce the risk of thromboembolic complications without affecting mortality [2]. Their use slightly increases the risk of intracranial hemorrhages. The use of LMWH is recommended only if the patient has risk factors for deep vein thrombosis and pulmonary embolism, such as lower limb immobilization, in the first few hours after a stroke [2], and not earlier than 24 hours in patients with intracranial hemorrhage [9]. A recent study of Clots in Legs Or sTockings after Stroke (CLOTS) [12] has shown that an intermittent pneumatic compression reduces the risk of deep vein thrombosis and can improve stroke survival in patients who cannot go to the toilet with an assistant.
\n\nRehabilitation: it is an important issue both in acute phase and in chronic phase. Points to be covered are position turning to avoid pressure sores, chest physiotherapy to minimize lung complication, swallowing assessment and training, limb movements to prevent deep vein thrombosis, speech therapy, early mobilization, etc. All should be started as early as possible. Rehabilitation should begin as soon as the patient’s condition stabilizes: passive measures to minimize contractures, bedsores, and pneumonia. A coordinated multidisciplinary approach to patient management with the help of constantly trained staff is important, which leads to a reduction in mortality and disability.
\nThe intravenous administration of a recombinant tissue plasminogen activator (tPA) increases the chances of a favorable outcome approximately 8 times within 3 months if performed in the first 90 minutes, 2 times when performed within 91–180 minutes after a stroke, and 1.4 times when performed in 181–270 minutes [6, 13]. The mortality does not change when administered up to 270 min after stroke onset, but increases with later administration of tPA [6]. Indications and contraindications for thrombolytic therapy are noted in Tables 1 and 2, respectively.
\nNo. of wording | \n
---|
\n
| \n
Indications for thrombolytic therapy.
No. of wording | \n
Cerebral \n
| \n
Contraindications for thrombolytic therapy.
Hemorrhagic transformation is more often observed in patients with large strokes and of old age [7]. The earlier the tPA is introduced, the more likely the beneficial effect is, and despite the fact that the probability of a favorable effect is also present when used later than 3 hours from a stroke, it is significantly reduced. The dose is 0.9 mg/kg (10% intravenous bolus, 90%—within an hour microjet). In Japan, the recommended dose is lower—0.6 mg/kg. Thus, thrombolytic therapy is recommended as early as possible after the onset of a stroke, no later than 4.5 hours. Restrictions apply both to contraindications [increased risk of hemorrhage, delay of more than 4.5 hours, blood pressure (BP) above 185 mm Hg, blood glucose above 4 G/l] and strict rules of use (only by a doctor trained in the management of stroke patients and only in the stroke department) [6].
\nOther ways to achieve rapid recanalization are currently being investigated and do not change the existing recommendations: other thrombolytic drugs, MRI patient selection criteria, intra-arterial thrombolytic therapy, and ultrasound-assisted intravenous thrombolysis. Mechanical thrombextraction is considered a promising technique in addition to intravenous thrombolysis in patients with proximal occlusions. In patients receiving oral anticoagulants, mechanical thrombectomy is often the only recommended recanalization strategy.
\nAspirin at a starting dose of 300 mg and then 75–150 mg daily prevents 9 cases of disability and death per 1000 patients. Aspirin should be prescribed 24 hours after any thrombolytic therapy. Recently, a Clopidogrel in High-Risk Patients with Acute Nondisabling of Cerebrovascular Events (CHANCE) study showed that patients with small strokes and transient ischemic attack (TIA) who received a loading dose of clopidogrel for 24 hours, against the background of aspirin, and then for 90 days on 75 mg of aspirin and 75 mg of clopidogrel had better outcomes without the risk of bleeding.
\nLow-molecular-weight heparins do not have advantages, because a decrease in the frequency of early recurrent strokes is balanced by an increase in the frequency of hemorrhagic transformations. There is no reason to recommend heparin in the acute stage of ischemic stroke, even in patients with atrial fibrillation.
\nExperimental studies have shown that potential neuroprotectors are effective, but this is not confirmed in the human population. Many neuroprotective agents have been developed based on a cascade of biochemical events leading to cell death. We report below the current clinical status of drugs that have been developed as neuroprotective agents (Table 3) [14].
\nCategory, mechanism | \nDrug name, name of multicenter study, and its results | \nCategory, mechanism | \nDrug name, name of multicenter study, and its results | \n
---|---|---|---|
Ca2+ channel blocker | \nNimodipine: no benefit (VENUS) | \nNoncompetitive NMDA antagonist | \nDizocilpine, discontinued Dextrorphan, no benefit | \n
Na+ channel blocker | \nLifarizine, no benefit; lubeluzole, no benefit; fosphenytoin, discontinued | \nCompetitive NMDA antagonist | \nSelfotel: discontinued | \n
GABA agonist | \nClomethiazole: no effect | \nAMPA/KA receptor antagonist | \nNBQX, discontinued YM872, RCT | \n
Free radical scavenger | \nEdaravone, clinical use; ebselen, phase III; NXY059: phase III; tirilazad, discontinued | \nMetabotropic receptor antagonist | \nGroups I, II, and III: RCT being planned | \n
Growth factor | \nbFGF: abandoned AX200 (filgrastim, G-CSF analogue), phase II | \nLMWH-CoA reductase inhibitor | \nLovastatin, phase II; simvastatin, phase III | \n
Growth factors, oxygen delivery | \nHuman chorionic gonadotropin (hCG)/erythropoietin (Ntx-265): phase II | \nHemodiluting agent | \nAlbumin: phase III (ALIAS) | \n
Ganglioside | \nNo benefit | \nMembrane stabilizer | \nCiticoline (CDP choline): phase III | \n
MgSO4\n | \nFAST-MAG: ongoing (IMAGE) | \nIron chelator | \nDeferoxamine mesylate: phase II | \n
Opioid receptor antagonist | \nNalmefene: no benefit | \nMetal ion chelator | \nDP-b99: phase III | \n
Polyamine receptor antagonist | \nEliprodil: discontinued | \nAntibiotic, pleiotropic protective effects | \nMinocycline: phase III | \n
Glycine antagonist | \nACEA-1021, no benefit; gavestinel, no benefit | \nOthers | \nPiracetam: phase III | \n
Neuroprotective drugs developed so far and results of clinical trials.
VENUS, very early nimodipine use in stroke; NMDA, N-methyl-D-aspartic acid; GABA gamma-aminobutyric acid; AMPA, amino-hydroxy-methyl-isoxalone propionic acid; KA, kainate; NBQX, 2,3dihydroxy-6-nitro-7-sulfamoyl-benzo [f]quinoxaline-2,3-dione; RCT, randomized controlled trial; bFGF basic fibroblast growth factor; ALIAS, albumin in acute stroke; FAST-MAG, Field Administration of Stroke Therapy—Magnesium; ACEA-1021, 5-nitro-6,7-dichloro-1,4dihydro-2,3-quinoxalinedione.
Hypothermia is a potential opportunity to provide neuroprotection, but due to side effects and the need for intensive therapy, it can only be used in severe cases, especially in patients with malignant heart attacks, and currently requires randomized trials [8, 15].
\nDecompressive neurosurgery (hemispherectomy) reduces mortality and disability in patients younger than 60 years old who recently suffered a massive stroke in the middle cerebral artery basin [16]. In order to be effective, the operation must be performed before the development of a malignant brain attack. The best selection criterion is the volume of damage on a diffusion-weighted MRI within 24 hours; a volume greater than 145 cm3 is a good predictor of malignant infarction. Therefore, the best candidates for surgical treatment are patients younger than 60 years with a lesion volume of more than 145 cm3 on diffusion-weighted MRI (6.50). The effectiveness of hemispherectomy is great—every second death is prevented. Results of the Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery II (DESTINY II) study also showed effectiveness in patients over 60 years of age [3].
\nIt is necessary to control blood pressure (BP). Lowering blood pressure in the first hours can prevent or slow down the growth of hematoma, as well as reduce the risk of repeated hemorrhage.
\nAn early decrease in blood pressure can cause cerebral ischemia in low-perfused and hypometabolic regions of the brain adjacent to the hematoma.
\nEuropean recommendations are based on the evidence of a low level of significance (class 4) [9]:
No specific drug is recommended.
In patients with a history of primary arterial hypertension or signs (ECG, changes in the fundus vessels) of chronic hypertension, systolic pressure above 180 mm Hg or diastolic pressure above 105 mm Hg and in patients without a history of hypertension, the target blood pressure is 170/100 or average 125 mm Hg.
In patients without a history of arterial hypertension (systolic blood pressure above 160 mm Hg and/or diastolic blood pressure above 95 mm Hg), the target blood pressure is 150/90 mm Hg or BP mean 110 mm Hg.
Avoid lowering blood pressure by more than 20%. These targets should be revised for patients who are being monitored for intracranial pressure (ICP) and are experiencing intracranial hypertension in order to maintain adequate cerebral perfusion pressure (greater than 70 mm Hg).
The INTERACT 2 study recently showed that in patients with intracerebral hematoma, an intensive reduction in blood pressure with targets below 140 mm Hg within an hour slightly improves the outcome and is well tolerated by the patient.
\nIn patients with intracerebral hematoma, complications such as deep vein thrombosis and pulmonary embolism are feared. A small study conducted on patients with intracerebral hematoma showed that the use of intermittent pneumatic compression is more effective than the use of compression knitwear alone [17]. The CLOTS study [12] showed that the use of compression knitwear is ineffective, but only 232 patients with intracerebral hematoma were included out of 2518 stroke patients. The expediency of using heparin and low-molecular-weight heparins is justified only in cases where the probability of bleeding risk is less than the possible benefit of prescribing drugs. In clinical practice, low doses of fractionated or low-molecular-weight heparin can be prescribed after 24 hours [16]. According to the results of the CLOTS 3 study [12], intermittent pneumatic compression is effective.
\nICP negatively affects the functional outcome. The superiority of invasive ICP monitoring over clinical observation and neuroimaging has not been proven. Ways to reduce ICP by medication help to buy time to prepare for surgical decompression, if it is planned. In the acute phase of intracranial hemorrhage, it is recommended to avoid corticosteroids. These recommendations are based on low confidence data. For the medical treatment of ICH, glycerol, mannitol, HAES, and short-term hyperventilation (confidence class 4) are used. For example, mannitol (20%) at a dose of 0.75–1.0 g/kg can be administered as an intravenous bolus followed by 0.25–0.5 g/kg every 3–6 hours, depending on the neurological status and fluid balance.
\nIn the acute stage, every patient with intracranial hemorrhage and an INR greater than 1.4 should receive intravenous vitamin K and drugs that replace the deficiency of clotting factors, despite the reason for taking oral anticoagulants (including patients with artificial valves). The goal is to prevent the growth of hematoma volume. In European protocols, it is recommended to use a concentrated prothrombin complex or SPP together with the intravenous administration of vitamin K [18]. Doses of concentrated prothrombin complex: 10–20 U/kg, if the INR is less than 3.5; or 20–30 units/kg, if the INR exceeds 3.5; together with 10 mg of vitamin K in/B.
\nRecombinant factor VIIa is not recommended for routine use outside of clinical trials.
\nThere is currently no antidote for patients with intracranial hematoma receiving new oral anticoagulants. This limits the use of these drugs.
\nThere are no specific recommendations for the treatment of hemorrhage on the background of antiplatelet drugs. Studies of the use of thrombosis have not proved its effectiveness [6, 13].
\nIn patients with intracranial hemorrhage with increased ventricles and obstruction of the third and fourth ventricles, according to some data, it is recommended to use a recombinant tissue plasminogen activator inserted directly into the ventricular system, which can improve the functional outcome [9].
\nThe removal of a blood clot should be considered in cases where there is neurological dysfunction or neuroimaging data about occlusion of cerebrospinal fluid spaces subtentorially. According to European recommendations, ventricular drainage and hematoma removal should be performed when the size of the hematoma is more than 2–3 cm in diameter or in the presence of hydrocephalus, even if the favorable outcome is doubtful due to old age or coma.
\nDynamic monitoring and conservative medical treatment are the first stage in the treatment of patients with intracranial hematoma. A special analysis of subgroups from the STICH study and a recent meta-analysis showed that craniotomy should be considered as a treatment option in cases of depression of consciousness (from 12 to 9 points on the Glasgow scale) [19] or in cases of superficial intracranial hemorrhage (less than 1 cm from the surface and does not reach the basal ganglia) [20, 21, 22]. With deep-seated hematomas, craniotomy does not bring a positive result. The STICH II study showed that early surgical treatment did not increase mortality and disability within 6 months, but slightly improved survival in patients with spontaneous intracranial hemorrhage in the absence of intraventricular hemorrhage.
\nSinus thrombosis is the cause of approximately 1% of strokes. It occurs due to the occlusion of the venous sinuses and/or cortical veins. This can lead to a venous infarction with petechial hemorrhages or a perivascular venous infarction. Usually, the cause of sinus thrombosis is congenital and acquired prothrombotic disorders, such as pregnancy and infections, including infections of the central nervous system as well as ear, sinuses, mouth, face, or neck. Also the predisposing factors are various diagnostic and therapeutic procedures, such as surgery, lumbar puncture, jugular vein catheterization, and administration of certain medications, especially oral contraceptives, hormone replacement therapy, steroids, and antitumor drugs [23].
\nThe clinical picture may be different, but sinus thrombosis should be excluded in young patients with recent headache and stroke-like symptoms, transient neurological deficits, convulsions, or lobar intracranial hemorrhages. This is especially true for patients with intracranial hypertension and patients with signs of hemorrhagic infarctions, especially if they are numerous and correspond to certain vascular pools.
\nThe gold standard for diagnosing sinus thrombosis is MRI, which provides direct visualization of occluded veins, sinuses, and blood clots [23]. Sometimes CT is used for diagnostics, but if MRI is available, this is not the method of choice for diagnostics. On CT, you can see a hyperintensive shadow of a blood clot in the occluded sinus, the so-called cord symptom.
\nThe available research data on the treatment of venous thrombosis recommend the use of heparin, as it reduces the risk of death and severe disability without the risk of intracranial hematoma. It has been shown that anticoagulant therapy leads to an absolute reduction in the risk of death and disability by 13% and a relative reduction in the risk by 54%, as well as a positive effect of using heparin without increasing the risk of intracranial hemorrhage.
\nAccording to European recommendations [18], venous thrombosis should be treated with low-molecular-weight heparins subcutaneously or intravenous heparin; doses are selected by body weight. The presence of intracranial hemorrhage accompanying venous thrombosis is not a contraindication to a heparin therapy [18].
\nThere is no data from randomized controlled trials on the efficacy and safety of systemic or local thrombolytic therapy in patients with cerebral vein thrombosis and sinus thrombosis. A recently published systematic review of thrombolytic therapy in patients with cerebral vein thrombosis and sinus thrombosis suggests a favorable effect in comatose patients [24].
\nAccording to European protocols [18], there is insufficient data to recommend the use of systemic or local thrombolytic therapy in patients with cerebral vein thrombosis and sinus thrombosis. Thrombolytic therapy may be an option if the patient’s condition worsens despite an adequate anticoagulant therapy.
\nAfter the acute phase, they switch to oral anticoagulant therapy. The Target INR is 2.0–3.0. In cases of cerebral vein thrombosis and sinus thrombosis during pregnancy, oral anticoagulants are not prescribed due to their possible teratogenic effects and the ability to penetrate the placenta. In these cases, anticoagulant therapy is continued with heparin. There is no available data from controlled studies concerning the optimal duration of anticoagulant therapy in patients with cerebral vein thrombosis and sinus thrombosis. MRI data from 33 patients showed that recanalization occurs within 4 months after cerebral vein thrombosis and sinus thrombosis, regardless of further anticoagulation therapy [25].
\nAccording to European protocols [18], anticoagulants can be prescribed for 3 months if cerebral vein thrombosis occurred due to transient factors and for 6–12 months in patients with idiopathic thrombosis and congenital “moderate” thrombophilia.
\nThe preventive use of anticonvulsants is controversial. Some studies have shown that sensory and motor deficits, parenchymal lesions on MRI/CT, and cortical vein thrombosis can be independent predictors of early symptomatic epileptic seizures [26]. According to European recommendations [18], prophylactic administration of anticonvulsants is possible for patients with local neurological deficits and foci of parenchymal lesions. Treatment can be continued for a year. Despite the fact that 50% of patients with venous thrombosis experience brain edema, mild edema can be relieved by isolated administration of heparin to restore venous outflow. Steroids are not recommended for the treatment of intracranial hypertension due to their unproven effectiveness. In severe cases, with the threat of transtentorial dislocation, surgical decompression is considered the only lifesaving method of treatment.
\nThe incidence of strokes in the postoperative period in patients with coronary artery bypass grafting (CABG) is about 2%, and a higher incidence of strokes is observed in patients after valve replacement operations and other cardiac surgeries [3]. The causes of stroke after cardiac surgery include perioperative embolism from the aortic arch or heart chambers, systemic hypoperfusion, ischemia associated with occlusion of large vessels, or a combination of these factors [3]. Risk factors for stroke after cardiac surgery are old age; a history of strokes, hypertension, and diabetes mellitus; the presence of noise in the projection of the carotid arteries; the use of bronchodilators and diuretics; high serum creatinine levels; recovery of large vessels; the use of inotropes after artificial circulation; and the duration of artificial blood circulation.
\nCurrently, there are no special recommendations for the treatment of patients with stroke after CABG [3]. Moreover, patients with stroke after CABG are treated as patients with acute stroke with loading doses of aspirin (160–320 mg) [3].
\nCarotid endarterectomy is the standard method for treating carotid artery stenosis [3]. It is recommended for 70–99% of patients with symptomatic stenosis. It is confirmed that surgical treatment of asymptomatic stenosis reduces the risk of ipsilateral stroke; however, the absolute advantage of this method has not been proven. Currently, stenting is not recommended for revascularization of the carotid arteries.
\nThe pathophysiological mechanism of stroke in carotid revascularization may be associated with hemodynamic cerebral ischemia or arterio-arterial embolism. The latter mechanism may be more frequent during stenting due to endovascular access.
\nIntracranial hemorrhage can be a severe side effect of thrombolytic therapy in ACS. The risk of intracranial hemorrhage depends on the previous episodes in the history, age, and mode of thrombolytic therapy. Usually, the risk of intracranial hemorrhage during thrombolytic therapy of acute myocardial infarction is 0.5–1%.
\nThere are no special recommendations for the treatment of ischemic stroke in ACS in European protocols. In the presence of ACS, the protocols of the European Stroke Organization recommend lowering blood pressure [4, 6]. An anticoagulant therapy is not recommended, while a combination of clopidogrel and aspirin is recommended in terms of cardiac causes [4, 7].
\nCardio-cerebral embolism is considered to be the cause of at least 20% of ischemic strokes, and non-valvular AF is the most common cause, associated with a fivefold increase in the risk of stroke, and accounts for 25% of all strokes in patients older than 80 years [3]. Long-term thromboprophylaxis is necessary to prevent strokes in patients with AF. Recently, for patients who cannot be treated with warfarin and clopidogrel, it has been shown that clopidogrel and aspirin therapy reduces the risk of vascular accidents [7]. Oral direct thrombin inhibitors such as dabigatran have been shown to be effective in preventing stroke and systemic embolism with a risk of intracranial hemorrhage comparable to that of warfarin. Stroke in patients with AF can be divided into three groups:
Ischemic stroke in patients with insufficient therapy, i.e., not receiving anticoagulants, despite scores on the CHADS2 scale greater than 2 [3]
Ischemic stroke that developed despite warfarin therapy
Intracranial hemorrhage that occurred in a patient receiving anticoagulants
The incidence of intracranial hemorrhage increases 7–10 times compared to patients who do not receive oral anticoagulants and is 1.8% per year in patients at risk of stroke [7].
\nIn the acute phase of stroke, heparin is not recommended; its use leads to a slight decrease in repeated strokes, an indefinite decrease in mortality, and a disability with an increase in the frequency of intracranial hemorrhages [7].
\nThe connection between the brain and the heart reflects a complex multidirectional complex regulation of systemic hemodynamics and organ autoregulation of local perfusion, which is especially pronounced in a cerebral catastrophe. Arrhythmias, in particular AF, often accompany the development of stroke, while myocardial infarction, Takotsubo syndrome, and sudden death are rare, although they are also described in strokes [27, 28, 29]. Sometimes stroke patients are found to have high levels of troponin, indicating myocardial damage.
\nTo ensure adequate treatment, a rapid diagnosis of stroke and its nature and cause is necessary. Specialized stroke departments allow for effective treatment and specific therapy.
\nThe authors declare no conflict of interest.
\nWe would like to thank our teachers—neurologists, anesthesiologists, and neurosurgeons—of Russian Polenov’s Neurosurgical Institute, the first institute of neurological surgery in the world founded in 1926 in St. Petersburg (Petrograd) in Russia.
\nACS | acute coronary syndrome |
AF | atrial fibrillation |
ADH | antidiuretic hormone |
aPTT | activated partial thromboplastin time |
AVM | arteriovenous malformation |
BP | blood pressure |
CT | computed tomography |
CABG | coronary artery bypass grafting |
DI | diabetes insipidus |
DWI | diffusion-weighted imaging |
ECG | electrocardiogram |
EchoCG | echocardiography |
ESR | erythrocyte sedimentation rate |
LMWH | low-molecular-weight heparins |
ICH | intracranial hemorrhage |
ICP | intracranial pressure |
INR | international normalized ratio |
MCA | medium cerebral artery |
MRI | magnetic resonance imaging |
NIHSS | National Institutes of Health Stroke Scale |
SAH | subarachnoid hemorrhage |
SIADH | syndrome of inappropriate antidiuretic hormone secretion |
tPA | tissue plasminogen activator |
TLT | thrombolytic therapy |
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\\n\\nParts of the Rules of Attribution are based on Work Attributing Creative Commons Materials published by the Australian Research Council Centre of Excellence for Creative Industries and Innovation, in partnership with Creative Commons Australia, which can be found at creativecommons.org.au licensed under Creative Commons Attribution 2.5 Australia license, and Best practices for attribution published by Creative Commons, which can be found at wiki.creativecommons.org under the Creative Commons Attribution 4.0 license.
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\n\nIn case you reuse or republish any of the Works licensed under CC licenses, you must abide by the guidelines outlined below:
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\n\nA Book in its entirety or a significant part of a Book cannot be translated freely without specific written consent by the publisher. Further information can be obtained at permissions@intechopen.com.
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