\r\n\tMain types of important health problems that occur in humans are: Wuchereria bancrofti, Brugia malayi, Brugia timori, Onchocerca volvulus, Loa loa, Mansonella ozzardi, Dipetolonema perstans, Dipetolonema streptocerca, Dirofilaria repens, Dirofilaria tenuis, Dirofilaria immitis, and Dracunculu smedinensis. \r\n\tEpidemiologically Filarisis is estimated to be prevalent in more than 120 million people worldwide. Mostly it is prevalent in hot and humid subtropical regions. Countries where filariasis may be found in Asia: Amman, China, India, Japan, Korea, Vietnam, Indonesia, Ceylon, Malaysia and Thailand; in the Mediterranean region: Spain, Italy, Macedonia; in Africa: (between 150 North and 130 South parallels) Angola, Tanzania, Ghana, Morocco, Algeria, Tunis, Egypt; and in Central America: Mexico, Honduras, Venezuela, Caribbean, Guyana. \r\n\tClinical manifestation may vary from painful inflammatory swellings of lymph nodes in acute infections to lymphedema due to blockage of lymphatic system in chronic cases. The diagnosis firstly depends on the “suggestive symptoms”. Blood tests such as Indirect Hemaglutination (IHA), Enzym-Linked Immunosorbent Assay (ELISA) are indirect diagnostic tests and PCR. Definitive diagnosis depends on direct identification of microfilariae in blood samples or involved-tissue biopsies. The treatment of choice in Filariasis is a combined regimen of diethylcarbamazine (DEC) 6 mg/kg, ivermectin 150 mg/kg and albendazole (ALB) 400 mg single-administration. Prevention: Treatment of patients with filariasis and vector control is possible
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"ae0039d441f0aea87a81d27d582721e1",bookSignature:"Prof. Tonay Inceboz",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9112.jpg",keywords:"ilariasis, morphology, vector, geographic distribution, Lymphatic system, Wuchereria bancrofti, Brugia malayi, Brugia timori, Cutaneous and ocular system, Dipetolonema streptocerca, Loa loa, Onchocerca volvulus, Serous cavity, Mansonella perstans and Mansonella ozzardi, Dirofilaria immitis, Other filariae, Dipetolonema perstans, Dipetolonema streptocerca, Dracunculus medinensis, microscopy, serology, molecular, drugs, prevention",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 10th 2019",dateEndSecondStepPublish:"October 1st 2019",dateEndThirdStepPublish:"November 30th 2019",dateEndFourthStepPublish:"February 18th 2020",dateEndFifthStepPublish:"April 18th 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Dokuz Eylül University",institutionURL:null,country:{name:"Turkey"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247865",firstName:"Jasna",lastName:"Bozic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247865/images/7225_n.jpg",email:"jasna.b@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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\n\t\t\t
1. Introduction
\n\t\t\t
The chapter will deal with the use of artificial insemination (AI) in animals and humans, both currently and in the future, with particular emphasis on comparative aspects between species. Although AI (in the form of intrauterine insemination) is not frequently used in human patients, it is the most commonly used method of breeding food production animals in developed countries, with more than 90% pigs and almost the same proportion of dairy cattle bred by this method in the European Union and North America. This chapter will explain the advantages and disadvantages of using AI, the various methodologies used in different species, and how AI can be used to improve reproductive efficiency in farm animals, sport animals, and human patients. To finish, some speculation is made about future trends for this biotechnology.
\n\t\t\t
\n\t\t\t\t
1.1. What is artificial insemination (AI)?
\n\t\t\t\t
Artificial insemination (AI) is the manual placement of semen in the reproductive tract of the female by a method other than natural mating. It is one of a group of technologies commonly known as “assisted reproduction technologies” (ART), whereby offspring are generated by facilitating the meeting of gametes (spermatozoa and oocytes). ART may also involve the transfer of the products of conception to a female, for instance if fertilization has taken place in vitro or in another female. Other techniques encompassed by ART include the following: in vitro fertilization (IVF) where fertilization takes place outside the body; intracytoplasmic sperm injection (ICSI) where a single spermatozoon is caught and injected into an oocyte; embryo transfer (ET) where embryos that have been derived either in vivo or in vitro are transferred to a recipient female to establish a pregnancy; gamete intrafallopian transfer (GIFT) where spermatozoa are injected into the oviduct to be close to the site of fertilization in vivo; and cryopreservation, where spermatozoa or embryos, or occasionally oocytes, are cryopreserved in liquid nitrogen for use at a later stage.
\n\t\t\t\t
AI has been used in the majority of domestic species, including bees, and also in human beings. It is the most commonly used ART in livestock, revolutionising the animal breeding industry during the 20th century. In contrast to medical use, where intra-uterine insemination (IUI) is used only occasionally in human fertility treatment, AI is by far the most common method of breeding intensively kept domestic livestock, such as dairy cattle (approximately 80% in Europe and North America), pigs (more than 90% in Europe and North America) and turkeys (almost 100% in intensive production). AI is increasing in horses, beef cattle and sheep, and has been reported in other domestic species such as dogs, goats, deer and buffalo. It has also been used occasionally in conservation breeding of rare or endangered species, for example, primates, elephants and wild felids. The other ARTs in animals are generally confined to specialist applications or for research purposes, since the cost would be prohibitive for normal livestock breeding. In contrast, IUI is used less often in human fertility treatments than IVF or ICSI.
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
1.2. Advantages and disadvantages of artificial insemination
\n\t\t\t\t
AI in animals was originally developed to control the spread of disease, by avoiding the transport of animals with potential pathogens to other animal units for mating and by avoiding physical contact between individuals. The use of semen extenders containing antibiotics also helped to prevent the transmission of bacterial diseases. The advantages and disadvantages of AI are as follows:
\n\t\t\t\t
Advantages:
\n\t\t\t\t
AI helps prevents the spread of infectious or contagious diseases, that can be passed on when animals are in close contact or share the same environment;
The rate of genetic development and production gain can be increased, by using semen from males of high genetic merit for superior females;
It enables breeding between animals in different geographic locations, or at different times (even after the male´s death);
Breeding can occur in the event of physical, physiological or behavioural abnormalities;
AI is a powerful tool when linked to other reproductive biotechnologies such as sperm cryopreservation, sperm sexing;
AI can be used in conservation of rare breeds or endangered species.
\n\t\t\t\t
Disadvantages:
\n\t\t\t\t
Some males shed virus in semen without clinical signs of disease (“shedders”).
Some bacterial pathogens are resistant to the antibiotics in semen extenders or can avoid their effects by forming bio-films;
There has been a decline in fertility in dairy cattle and horses associated with an increase in AI;
The focus on certain individuals may result in loss of genetic variation.
\n\t\t\t\t
\n\t\t\t\t\t
1.2.1. Viruses in semen
\n\t\t\t\t\t
Cryopreserved semen doses can be “quarantined” until the male is shown to have been free of disease at the time of semen collection. In contrast, the short shelf-life of fresh semen doses means that they must be inseminated into the female before the disease-free status of the male has been established. Breeding sires used for semen collection are tested routinely for the presence of antibodies in serum as being indicative of past infection, but some viruses, e.g. equine arteritis virus, may be shed in semen for several weeks before there is evidence of sero-conversion. In other cases, usually of congenital infection, individuals may be permanent virus “shedders” without ever developing antibodies. Semen from these individuals represents a source of pathogens for disease transmission to naive females.
\n\t\t\t\t
\n\t\t\t\t
\n\t\t\t\t\t
1.2.2. Bacteria in semen
\n\t\t\t\t\t
Normally, in a healthy male, the ejaculate itself does not contain microorganisms, but contamination occurs at semen collection from the prepuce and foreskin, the male´s abdomen and the environment. Semen processing from livestock usually takes place without access to a laminar air flow hood, resulting in potential contamination from the laboratory environment. Antibiotics are added to semen extenders to limit the growth of these contaminants and prevent disease in the inseminated female. Although the female reproductive tract has well-developed physiological mechanisms for dealing with contamination introduced during mating, these can be overwhelmed by bacteria multiplying in semen extenders or where semen is deposited in a non-physiological location.
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\n\t\t\t\t
\n\t\t\t\t\t
1.2.3. Antibiotics in semen extenders
\n\t\t\t\t\t
The addition of antibiotics to semen extenders is controlled by government directives, both nationally and internationally, which state the types of antibiotic to be used and also their concentrations. In general, there is a tendency to use broad spectrum, highly potent antibiotics in various combinations to reduce sperm toxicity. However, these antibiotics may exacerbate the development of resistance, both for the people handling the semen extenders and in the environment during the disposal of unused extenders or semen doses. The scale of the problem becomes apparent if one considers that approximately four million liters of boar semen extender containing antibiotics are used in Europe alone per year.
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\n\t\t
\n\t\t
\n\t\t\t
2. Pre-requisites for AI
\n\t\t\t
Pre-requisites for AI include a supply of semen, reliable methods for oestrus detection in the female and a means of inserting the semen into the female reproductive tract.
\n\t\t\t
\n\t\t\t\t
2.1. Collection of semen
\n\t\t\t\t
In most domestic animals, semen is collected by means of an artificial vagina, for example, bull, ram, stallion, after allowing the male to mount either an oestrous female or a phantom.
\n\t\t\t\t
The artificial vagina consists of a lubricated liner inserted into an outer jacket, the space between the two being filled with warm water. The pressure can be increased by adding air.
\n\t\t\t\t
The ejaculate is deposited into an insulated collecting vessel attached to one end of the liner.
\n\t\t\t\t
Boar and dog semen is usually collected by manual stimulation.
\n\t\t\t\t
In some species that are accustomed to being handled, it is possible to obtain semen by vaginal washing after natural mating, for example, dogs and marmoset monkeys. However, in this case the spermatozoa have already been exposed to vaginal secretions which may be detrimental to sperm survival. Human males can usually supply a sample by masturbation, except in the case of spinal injury when electroejaculation may be necessary. Some other primates can be trained to supply a semen sample on request in the same manner. For other species, for example, most non-domestic species, electroejaculation represents the only possibility for obtaining a semen sample. The problem with electroejaculation is that the secretions of the accessory glands may not be present in the usual proportions, which may have a detrimental effect on sperm survival.
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\n\t\t\t\t\t
2.1.1. Constituents of semen
\n\t\t\t\t\t
Semen consists of spermatozoa contained in a watery fluid known as seminal plasma that represents the combined secretions of the different accessory glands, such as the seminal vesicles, bulbourethral gland and prostate. The relative contributions of these different glands vary between species. In some species, such a most primates, the semen coagulates immediately after ejaculation and then liquefies over a period of approximately 30 minutes.
\n\t\t\t\t\t
In most other species, the ejaculate remains liquid, the exception being in camelids where the seminal plasma is highly viscous and does not liquefy readily in vitro. The addition of enzymes has been suggested as a means of liquefying primate or camelid semen. However, all the enzymes tested thus far (collagenase, fibrinolysin, hyaluronidase and trypsin) have been seen to cause acrosomal damage in spermatozoa (Wani et al., 2007) and are contra-indicated if the spermatozoa are to be used for AI. Recent advances have shown that camelid semen, extended 1:1 volume to volume, will liquefy in 60-90 min at 37 °C.
\n\t\t\t\t\t
Seminal plasma contains an energy source (often fructose), proteins and various ions such as calcium, magnesium, zinc and bicarbonate. Seminal plasma not only activates the spermatozoa, which have been maintained in a quiescent state in the epididymis, but also functions as a transport medium to convey the spermatozoa into the female reproductive tract and to stimulate the latter to allow spermatozoa to swim to the site of fertilization. It has been suggested that seminal plasma, at least in horses, is also a modulator of sperm-induced inflammation, which is thought to play an important role in sperm elimination from the female reproductive tract (Troedsson et al., 2001). Various proteins in the seminal plasma, such as spermadhesins and the so-called CRISP proteins (CRISP = cysteine-rich secretory proteins) are thought to be associated with sperm fertility. It is likely that these proteins bind to spermatozoa immediately, setting in motion a sequence of intracellular events via a second-messenger pathway. In some species, small membrane-bound vesicles have also been identified in seminal plasma, apparently originating from different accessory glands in various species. These vesicles, variously named prostasomes, vesiculosomes, or epididysomes depending on their origin, fuse with the sperm outer membrane, increasing motility and possibly being involved in sperm capacitation and acquisition of fertilizing ability. However, their exact mechanism of action has yet to be elucidated.
\n\t\t\t\t\t
Seminal factors promote sperm survival in the female reproductive tract, modulate the female immune response tolerate the conceptus, and to condition the uterine environment for embryo development and the endometrium for implantation (Robertson, 2005). The mechanism of action in the endometrium is via the recruitment and activation of macrophages and granulocytes, and also dendritic re-modelling, that improve endometrial receptivity to the implanting embryo. Cytokine release has embryotrophic properties and may also influence tissues outside the reproductive tract.
\n\t\t\t\t\t
Exposure to semen induces cytokine activation into the uterine luminal fluid and epithelial glycocalyx lining the luminal space. These cytokines interact with the developing embryo as it traverses the oviduct and uterus prior to implantation. Several cytokines are thought to be involved, for example granulocyte-macrophage colony stimulating factor (GM-CSF), a principle cytokine in the post-mating inflammatory response, targets the pre-implantation embryo to promote blastocyst formation, increasing the number of viable blastomeres by inhibiting apoptosis and facilitating glucose uptake (Robertson et al., 2001). Interleukin-6 (IL-6) and leukocyte inhibitory factor (LIF) are similarly induced after exposure to semen (Gutsche et al., 2003; Robertson et al., 1992).
\n\t\t\t\t\t
Clinical studies in humans showed acute and cumulative benefits of exposure to seminal fluid but also a partner-specific route of action. Live birth rates in couples undergoing fertility treatments are improved if women engage in intercourse close to embryo transfer (Bellinge et al., 1986; Tremellen et al., 2000). The use of seminal plasma pessaries by women suffering from recurrent spontaneous abortion is reported to improve pregnancy success (Coulam and Stern, 1993, cited in Robertson, 2005). Partner-specificity of the response is suggested by increased rates of preeclampsia in pregnancies from donor oocytes or semen when prior exposure to the donor sperm or conceptus antigens has not occurred (Salha et al., 1999).
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2.1.1.2. Semen processing
\n\t\t\t\t\t\t
Although seminal plasma plays such an important role in activating spermatozoa and in the female reproductive tract, it is detrimental to long-term sperm survival outside the body. Under physiological conditions, spermatozoa are activated by seminal plasma at ejaculation and then swim away from the site of semen deposition in the female. It is only during in vitro storage that spermatozoa become exposed to seminal plasma long-term. Thus it is customary to add a semen extender to the semen, to dilute toxic elements in seminal plasma, to provide nutrients for the spermatozoa during in vitro storage and to buffer their metabolic by-products. The addition of extender also permits the semen to be divided into several semen doses, each containing a specific number of spermatozoa that has been determined to be optimal for good fertility in inseminated females.
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2.1.2. Semen preservation
\n\t\t\t\t\t
Semen is used either immediately after collection (“fresh”) for example turkeys, human beings; after storage at a reduced temperature (“stored”) for example horses, pigs, dogs; or after freezing and thawing (“cryopreservation”) for example, bulls.
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\n\t\t\t\t\t\t
2.1.2.1. Fresh semen
\n\t\t\t\t\t\t
In contrast to animal species, human semen is not extended prior to processing (see previous section) and is not usually kept for more than a few hours before use. Poultry semen cannot be extended as much as is customary for other species since the spermatozoa are adversely affected by increased dilution. Goat semen cannot be kept at 37 °C because an enzymatic component of the bulbo-urethral gland secretion hydrolyses milk triglycerides into free fatty acids, which adversely affects the motility and membrane integrity of buck spermatozoa (Pellicer-Rubio and Combarnous, 1998). For liquid preservation, goat semen can be stored at 4 °C although fertility is retained for only 12-24h. The rate of extension used for stallion semen varies between countries but rates of 1:2, 1:3 or even 1:4 (v/v) semen:extender are common. The standard practice in some countries is to have 500 million or one billion progressively motile stallion spermatozoa for fresh or cooled semen doses respectively. Boar semen doses contain three billion progressively motile spermatozoa.
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\n\t\t\t\t\t\t
2.1.2.2. Stored semen
\n\t\t\t\t\t\t
Storing extended semen at reduced temperature helps to extend sperm life by slowing their metabolism as well as by inhibiting bacterial growth. Bacteria grow by utilizing the nutrients in semen extenders, thus competing with spermatozoa for these limited resources, and release metabolic byproducts, thus creating an environment that is not conducive to maintaining viable spermatozoa. Furthermore, as bacteria die, they may release endotoxins that are toxic to spermatozoa. However, cooled stored semen is the method of choice for breeding horses and pigs, enabling the semen dose to be transported to different locations for insemination. Stallion semen is stored at approximately 6 °C while boar semen is stored between 16 and 18 °C.
\n\t\t\t\t\t\t
Most boar semen doses are sold as cooled doses. In contrast, some stallions produce spermatozoa that do not tolerate cooling, rapidly losing progressive motility. In such cases, the only option currently is to use fresh semen doses for AI immediately after semen collection, although a new method of processing, centrifugation through a single layer of colloid, has been shown to solve the problem, as discussed later.
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2.1.2.3. Cryopreservation
\n\t\t\t\t\t\t
Semen is most useful for AI if it can be cryopreserved, since this method of preservation ideally enables the semen to be stored for an unlimited period without loss of quality until needed for AI. Since the frozen semen does not deteriorate, it can be quarantined until the male has been shown to be free from disease at the time of semen collection. However, the spermatozoa of various species differ in their ability to withstand cryopreservation: ruminant spermatozoa survive well whereas poultry spermatozoa do not, with less than 2% retaining their fertilizing ability on thawing (Wishart, 1985). For farm animal breeding, the cost of cryopreservation and the likelihood of a successful outcome following AI must be considered when deciding whether to use fresh, cooled or frozen sperm doses.
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The spermatozoa are mixed with a protective solution containing lipoproteins, sugars and a cryoprotectant such as glycerol. These constituents help to preserve membrane integrity during the processes of cooling and re-warming. However, sperm motility must also be maintained, so that the thawed spermatozoa can reach the oocytes after insemination and fertilize them. In most species, the seminal plasma is removed by centrifugation before mixing with the cryoextender, for example, stallion, boar, goat and human semen. The extended semen is packed in straws and frozen in liquid nitrogen vapour before plunging into liquid nitrogen for long-term storage. There is considerable variation in the success of sperm cryopreservation between different species, despite intensive research into the constituents of cryoextenders and the rates of cooling and re-warming. Human spermatozoa can be frozen relatively successfully using commercially available cryoextenders and programmable freezing machines.
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2.2. Oestrus detection and ovulation
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Successful AI also depends on depositing the semen in the female tract at around the time of ovulation. Like human beings, some domestic animals breed throughout the year, for example cattle and pigs, but others show a defined period of reproductive activity known as the breeding season, for example sheep and horses. The onset of the breeding season is controlled by photoperiod. Both of these patterns of reproductive behaviour are characterised by waves of ovarian activity, culminating in ovulation. However, in some other species ovulation occurs in response to the stimulus of mating, for example, cats, rabbits and camels. In spontaneously ovulating species, ovulation occurs at some time during, or shortly after, oestrus, which is the period of time when the female is receptive to the male. Since a successful outcome for AI depends on the deposition of spermatozoa at a suitable time relative to ovulation, oestrus detection is crucial if the female is to be inseminated at the correct time. Males of the same species are, of course, very good at detecting oestrus females, but since many livestock breeding units that practice AI do not have male animals in the vicinity, it is essential that husbandry personnel become good at recognising oestrous behaviour.
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Although some domestic animals may show well-developed oestrous behaviour, e.g. dairy cows, others may not. Behavioural signs of oestrus in cows include restlessness or increased activity, vocalization, chin resting, swelling of the vulva, vaginal discharge and mounting other cows, although there are breed differences in the frequency and intensity of these signs. In sheep and goats, vulval swelling and vaginal discharge may be seen, and there is usually pronounced male-seeking behaviour. When AI is to be used in sheep, it is usual to synchronize oestrus with hormones: intravaginal sponges impregnated with progestagens are inserted to suppress the ewe´s natural ovarian cycle for 12 days. On sponge removal, pregnant mare serum gonadotrophin is administered, with AI taking place at a set time thereafter. Alternatively, a vasectomised ram wearing a marker can be run with the females. When the females are in oestrus, the vasectomised ram marks them as he mounts, thus enabling them to be identified for AI. Oestrous sows and mares can be identified by the behaviour exhibited towards teaser males.
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2.2.1. Induced ovulation
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When AI is performed in species that are normally induced ovulators, such as rabbits, cats and camels, it is necessary to stimulate ovulation. The easiest way to achieve this stimulation is to mate the female with a vasectomised male, but this practice is not desirable from the point of view of disease control and necessitates having vasectomized males available. The most acceptable alternative is to administer luteinising hormone, usually in the form of human chorionic gonadotrophin. However, the major disadvantage is that repeated injections of this foreign protein may cause the female to develop antibodies, thus inactivating subsequent doses.
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2.2.2. Artificially induced ovulation
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Hormones may be administered to spontaneous ovulators to ensure that ovulation occurs at the correct time relative to AI. However, since 2006, the use of hormones in food-producing animals has been forbidden in the European Union, and local regulations may also apply in other parts of the world. Previously most dairy goats in France were inseminated out of the breeding season with deep frozen semen, after induction of oestrus and ovulation by hormonal treatments. This protocol provided a kidding rate of approximately 65% (Leboeuf et al., 2008). As an alternative to administering artificial hormones, out-of season breeding may be induced by altering the photoperiod or by introducing a buck to the herd. This practice is also widespread in intensive sheep flocks.
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2.3. Deposition of semen in the female
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There are differences between species in the site of semen deposition during natural mating. In ruminants and primates, semen is deposited in the vagina whereas in pigs, dogs, camels and horses, semen deposition is intrauterine. In most species, it is possible to pass an insemination catheter through the cervix, thus enabling semen to be deposited in the uterus during AI. Exceptions are sheep and goats, where the tightly folded nature of the cervix does not permit easy passage of an insemination catheter. The advantages of depositing the semen in the uterus are that the spermatozoa have less far to travel to reach the oviducts and fewer spermatozoa are lost through back-flow. A smaller volume of semen can be used per insemination dose than for intravaginal deposition, thus permitting an ejaculate to be divided into several AI doses, and the cervix, which can act as a barrier to the passage of spermatozoa, is bypassed. A disadvantage, particularly for human IUI, is that seminal plasma is also introduced into the uterus, unless specific steps are taken to separate the spermatozoa from seminal plasma before IUI.
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3. Species differences in the use of AI
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Despite the fact that the basic principles of AI are the same in all species, there is wide variation in the uptake of this biotechnology in different species.
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3.1. AI in cattle
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In cattle, frozen semen doses are used most widely in Europe and North America, since there are well-established protocols for cryopreserving bull semen. Semen doses typically contain approximately 15 million motile spermatozoa. In New Zealand, however, fresh semen doses are used instead, with AI occurring within 24h of semen collection.
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3.2. AI in pigs
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The porcine AI industry uses liquid semen that has been stored for one to several days at 16-18°C. In contrast, AI with cryopreserved boar spermatozoa results in lower farrowing rates and litter sizes than with cooled, stored spermatozoa, making the use of frozen-thawed sperm doses unattractive for commercial pig breeders. Exceptions to this rule are when semen is transported over long distances, which creates problems in temperature regulation, and in instances where it is vital that the boars can be shown to be free of disease at the time of semen collection. The ability of boar spermatozoa to survive cool storage so well is attributed to low levels of reactive oxygen species (ROS) in semen or to the efficient scavenging of ROS by anti-oxidative components in seminal plasma.
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3.3. AI in horses
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AI has increased in horses in the last 25 years. Initially, fresh semen was used for AI shortly after semen collection, but nowadays the use of cooled semen has largely replaced fresh semen in Europe and North America. The extended semen is cooled to approximately 5 , and transported in insulated containers, together with a cold pack. The fertility of the cooled semen is maintained for approximately 24h. Frozen semen doses are used infrequently, although this trend may change with the development of better freezing protocols. However, with the increased use of cooled semen, a concomitant decrease in foaling rate has been observed in several countries, such as Finland and Sweden, although the reason for this apparent decline in fertility is unknown. Unlike bulls and boars, which are selected for their semen quality as well as for their potential “genetic merit” in production characteristics (body composition, weight gain, milk production etc), the choice of stallions as breeding sires is based solely on their performance in competition. Thus, considerable variation in semen quality exists between stallions. This variation, coupled with increased use of a wider range of stallions, may be contributing to the observed decline in foaling rate. Other important considerations are the lack of established standard methods for cooling and freezing of stallion spermatozoa, for the sperm concentration in the insemination dose, or for quality control of raw or frozen/thawed spermatozoa.
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3.4. AI in sheep
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Ram semen differs from stallion and boar semen in consisting of a small volume (a few mL) of seminal plasma containing a very high concentration of spermatozoa. In Europe, reproductive research in livestock has tended to focus on cattle and pigs rather than on small ruminants, with the result that sperm handling and cryopreservation for AI is less advanced in the latter species. In addition, the anatomy of the female reproductive tract in these species presents more of a barrier to successful insemination than in cattle, since the cervix is tightly folded, making insertion of the insemination catheter difficult. Productivity in sheep and goats could be increased, by improving the quality of the spermatozoa assigned for use in AI, and improving the AI techniques in these species. Recent innovations in sheep breeding include the development of a flexible catheter at the National Center for Genetic Resource Preservation, Fort Collins, Colorado, that can be inserted through the ovine cervix, thus overcoming the barrier to effective AI in this species.
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AI in sheep and goats is traditionally performed with fresh or cooled spermatozoa, with acceptable fertility results. However, use of foreign breeds, genetic improvement and the use of “safe” semen from other countries requires the use of frozen semen, to enable analyses for contaminants or diseases in the “donor” male to be completed before the semen doses are used for AI. Although the post-thaw motility of frozen semen from goats and sheep is usually considered acceptable, low fertility has been associated with its use in AI, mainly owing to a shortened lifespan of the spermatozoa.
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3.5. Intrauterine insemination in human fertility treatment
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It is estimated that 10-20% of couples wanting to conceive are unable to do so without some assistance. In 40% of cases, sub-fertility is due to female factors, with a further 40% being due to male factors. The remaining cases may be multifactorial or idiopathic in origin. The use of IUI is generally contraindicated in male factor infertility, with IVF or ICSI being the treatments of choice. Since spermatozoa must be able to reach the site of fertilization and the products of conception must be able to reach the uterus for implantation, female factor infertility due to blockage of the oviducts is better treated by IVF or ICSI than by IUI. The patient´s own semen or donor semen may be utilized for these fertility treatments.
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4. AI - State of the art
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AI can help to improve reproductive efficiency in animals for food production or sport. We are living in a world of scarce resources where there is constant competition for water, food, land and energy. Since protein of animal origin continues to be one of the most important forms of nourishment for human beings, animals are an essential part of the ecosystem and must be husbanded in a sustainable fashion. Animal production not only “competes” with human beings for the aforementioned resources, but also produces large amounts of effluent and gaseous emissions which can affect the environment. Therefore, it is vital for the survival of the planet that all aspects of animal production are justified and optimized. Through grazing or browsing and the recycling of nutrients, animals also contribute to maintaining the landscape in a productive state.
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The production of food of animal origin is based on breeding offspring to enter various husbandry systems. Therefore, one of the first points for optimization is in increasing reproductive efficiency, using an holistic approach. Females should be bred for the first time at an appropriate age to ensure the birth of healthy offspring and optimum lactation, without compromising the health of the female. Subsequent breeding attempts should also be timed appropriately to balance the metabolic requirements of lactation and early pregnancy. Females not conceiving or showing early embryonic loss should be identified at an early stage for re-breeding or culling. However, optimizing female reproduction demands a supply of spermatozoa. The spermatozoa must be readily available (i.e. can be stored), robust, and capable of fertilization, initiation of early embryonic development and regulation of placental formation, and there must be a means of delivery to an appropriate site in the female.
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5. AI in other species
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AI in non-domestic species presents several new challenges compared with domestic species. In many cases little is known about the reproductive biology of the species in question, and handling the animals may cause them stress, with the attendant risk of injury. The animals must be managed correctly for the establishment and maintenance of pregnancy. There are reports of successful AI in deer, buffalo and camelids.
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6. Future trends in AI
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It is highly probable that the use of AI in livestock will continue to increase. AI not only facilitates more effective and efficient livestock production, but can also be coupled to other developing biotechnologies, such as cryopreservation, selection of robust spermatozoa by single layer centrifugation, and sperm sex selection.
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6.1. AI in increasing the efficiency of livestock production
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Apart from some specialist sheep or goat units focussing on milk production for cheese and intensive meat production, farming of these species tends to be confined to marginal land that is unsuitable for crop production or grazing for dairy cattle. There has been limited selection for production traits. However, there is a resurgence of interest in them now in developed countries because of growing awareness that small ruminants could represent better utilization of scare resources than larger ones, such as cattle, while producing less methane and effluent. In many developing countries, sheep and goats are better suited to the climate than cattle, and it is culturally acceptable to eat their meat and milk products. Thus it is likely that there will be an upsurge in the use of AI in sheep and goats in the future, with an emphasis on improving production traits by the introduction of superior genes. However, it is essential that any A.I. scheme aimed at large scale improvement of the national herd must be supported by improved animal husbandry and animal health, otherwise the pregnancies resulting from AI will not go to term, and the offspring will either not survive or will fail to thrive. Many of the advanced ART are of little help in areas where basic husbandry skills are inadequate.
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6.2. Biomimetic sperm selection
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One potential disadvantage of AI is that the natural selection mechanisms within the female reproductive tract to select the best spermatozoa for fertilization may be bypassed when AI is utilized. Biomimetics is the use of technologies and/or processes that mimic a naturally occurring event. Several in vitro procedures have been suggested that could be used to mimic selection of good quality spermatozoa in the female reproductive tract and thus fit the definition of biomimetics in ART. These include sperm processing procedures such as swim-up, sperm migration, filtration and colloid centrifugation (reviewed by Morrell & Rodriguez-Martinez, 2009). Of these methods, the one that is most applicable to livestock and human spermatozoa is colloid centrifugation.
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6.2.1. Density gradient centrifugation
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Human spermatozoa for fertility treatment are usually processed to remove the seminal plasma and to select those of better quality. In most cases, this is achieved either by sperm migration, in which the more motile spermatozoa are separated from the rest of the ejaculate, or by density gradient centrifugation, where the most robust spermatozoa are selected. The benefits of density gradient centrifugation are as follows (Morrell, 2006):
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Poorly motile and abnormal spermatozoa are removed,
Sources of ROS (cell debris, leukocytes, epithelial cells and dead or dying spermatozoa) are removed;
Sperm survival is improved during frozen and non-frozen storage;
Bacterial contamination is controlled without antibiotics.
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6.2.2. Single layer centrifugation
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Density gradient centrifugation is seldom used when processing animal semen because of the limited volume of semen that can be processed at one time and the time taken to prepare the different layers. A novel sperm preparation technique, Single Layer Centrifugation (SLC) through a colloid, was developed at the Swedish University of Agricultural Sciences (SLU) to select the most robust spermatozoa from ejaculates. This method is similar to density gradient centrifugation (DGC), but is better suited for animal semen since it has been scaled-up to process whole ejaculates. The major applications for SLC-selection are similar to DGC end have been reviewed extensively by Morrell & Rodriguez-Martinez (2010)
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6.3. Sex selection
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For many centuries, animal breeders and researchers have endeavoured to control the sex of the offspring born, for various reasons. Initially male offspring were preferred for meat production, because of the better feed conversion efficiency and lean-to-fat ratio of males, whereas females were preferred for dairy purposes, except that some males of high genetic merit were still required as sires. Couples may want a child of a specific sex to avoid the expression of sex-linked disorders.
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Many methods have been proposed for separating X- and Y-chromosome bearing spermatozoa, based on physical properties, e.g. size of the sperm head, or functional properties e.g. swimming speed. However, the only method which has been shown to work reliably is that of selection and separation of spermatozoa whose DNA is stained with a bis-benzimidazole dye, H33342, using the sorting capacity of a flow cytometer (Morrell et al., 1988; Johnson et al., 1989). This method functions because the X chromosome is larger than the Y, therefore taking up more of the DNA-specific stain and showing a higher fluorescence when the spermatozoa are passed through a laser beam. In bulls, for example, the difference in DNA content between the X and Y- chromosome is approximately 4.2%. However, the process of sorting sufficient numbers for an insemination dose in the flow cytometer takes too long, since the stained spermatozoa must pass one at a time through a laser beam for detection of their DNA content. Moreover, the pregnancy rate after insemination of sexed bull spermatozoa is lower than with unsexed spermatozoa, making the procedure inefficient and expensive. Experience has shown that the staining profiles are highly individual, with the result that it is not possible to separate the X- and Y-chromosome bearing spermatozoa efficiently from all males.
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Alternative methods of sex selection are also being investigated. A company in Wales, Ovasort, has identified sex-specific proteins on the sperm surface and have raised antibodies to them. It is intended to use the antibodies to aggregate spermatozoa bearing a specific sex chromosome, thus enabling them to be removed from the general population.
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A combination of ARTs would also be relevant for sperm sexing. Thus, the speed of flow sorting can be increased by first removing the dead and dying spermatozoa from the population, for example by density gradient centrifugation or single layer centrifugation. Such a combination may increase the “sortability” of sperm samples. Sufficient sexed spermatozoa may be obtained from flow sorting for IVF, thus generating embryos or blastocysts for subsequent transfer. However, methods of speeding up the selection process are needed if flow cytometry is to become useful for species other than the bovine.
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6.4. Sperm cryopreservation
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As previously mentioned, the ability of cryopreserved spermatozoa to retain their fertilizing ability varies widely between species. New cryoextenders and new protocols are being developed constantly in an effort to address this issue. One recent advance has been the introduction of dimethylsulphoxide and the amides formamide and dimethylformamide as cryoprotectants, in place of glycerol. These molecules seem to function better than glycerol for some individuals whose spermatozoa do not freeze well, for example, some stallions. One explanation for this observation is that these molecules are smaller than glycerol and therefore may cause less damage when they penetrate the sperm membrane. However, no method appears to be universally successful within one species. As far as turkey spermatozoa are concerned, it seems that the development of a successful freezing method will require more than new cryoprotectants and additives (Holt, 2000).
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6.5. Removal of viruses from ejaculates
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Viral infectivity can be removed from the semen of patients with viral infections such as HIV and hepatitis, by a sequential method of sperm preparation i.e. centrifugation on a density gradient followed by a “swim-up” (reviewed by Englert et al., 2004). Spermatozoa from virally infected men prepared by this method have been used in assisted reproduction attempts, apparently without sero-conversion of mothers or children. However, some studies with HIV report that density gradient centrifugation alone will not remove all viral infectivity (Politch et al., 2004). Since spermatozoa may function as vectors for viruses (Chan et al., 1994), further work is required to investigate how closely different viral particles are associated with the sperm membrane with putative carry-over during processing. The double method of processing has also been successful in removing equine arteritis virus from an infected stallion ejaculate in a preliminary study (Morrell & Geraghty, 2006). SLC together with swim-up was used to reduce viral infectivity from boar semen spiked with porcine circo virus 2 (Blomqvist et al., 2011).
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6.5. AI in conservation biology
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It has been suggested that AI and other forms of ART could be useful for genetic conservation and preservation of rare breeds. Many of these technologies have been successful to some degree in a research setting, but none have produced results sufficient to effect population-wide improvements in genetic management (Morrow et al., 2009). Cryopreservation of semen has been the most widely applied ART in this respect, but much of the frozen semen in so-called gene banks has never been tested for fertility. A lack of suitable females or dearth of knowledge about the reproductive biology of the species involved may contribute to this deficit. However, long-term storage of frozen gametes of unknown fertility is not a sustainable policy for the conservation of rare breeds and endangered species. The development of in vitro methods of testing sperm fertility would contribute considerably to conservation efforts. Since the semen quality in these animals may be poor (Gamboa et al., 2009), techniques such as SLC of samples prior to AI could be of considerable benefit in conservation breeding.
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7. Conclusion
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AI revolutionized animal breeding in the 20th century, particularly in combination with sperm cryopreservation. The AI industry has developed dramatically in most domestic species in the last few decades and its use is now widespread in intensive animal production. The development of other associated technologies, such as sperm selection and sex selection, are predicted to create powerful tools for the future, both for domestic livestock breeding and for the purposes of conservation. AI will continue to play a role in fertility treatment for human patients, although it may be superseded by IVF or ICSI. It has been suggested that AI (in animals) is entering a new era where it will be used for the efficient application of current and new sperm technologies (Roca, 2006). Exciting possibilities are offered by emerging techniques, such as Single Layer Centrifugation, for improving sperm quality in AI doses as well as for increasing sperm survival during cryopreservation.
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\n\t\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/16096.pdf",chapterXML:"https://mts.intechopen.com/source/xml/16096.xml",downloadPdfUrl:"/chapter/pdf-download/16096",previewPdfUrl:"/chapter/pdf-preview/16096",totalDownloads:21576,totalViews:4320,totalCrossrefCites:0,totalDimensionsCites:5,hasAltmetrics:0,dateSubmitted:"October 24th 2010",dateReviewed:"April 10th 2011",datePrePublished:null,datePublished:"June 21st 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/16096",risUrl:"/chapter/ris/16096",book:{slug:"artificial-insemination-in-farm-animals"},signatures:"Jane M. Morrell",authors:[{id:"29913",title:"Dr.",name:"Jane M.",middleName:null,surname:"Morrell",fullName:"Jane M. Morrell",slug:"jane-m.-morrell",email:"jane.morrell@slu.se",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1. What is artificial insemination (AI)? ",level:"2"},{id:"sec_2_2",title:"1.2. Advantages and disadvantages of artificial insemination",level:"2"},{id:"sec_2_3",title:"1.2.1. Viruses in semen",level:"3"},{id:"sec_3_3",title:"1.2.2. Bacteria in semen",level:"3"},{id:"sec_4_3",title:"1.2.3. Antibiotics in semen extenders",level:"3"},{id:"sec_7",title:"2. Pre-requisites for AI",level:"1"},{id:"sec_7_2",title:"2.1. Collection of semen",level:"2"},{id:"sec_7_3",title:"2.1.1. Constituents of semen",level:"3"},{id:"sec_7_4",title:"2.1.1.2. Semen processing",level:"4"},{id:"sec_9_3",title:"2.1.2. Semen preservation",level:"3"},{id:"sec_9_4",title:"2.1.2.1. Fresh semen",level:"4"},{id:"sec_10_4",title:"2.1.2.2. Stored semen",level:"4"},{id:"sec_11_4",title:"2.1.2.3. Cryopreservation",level:"4"},{id:"sec_14_2",title:"2.2. Oestrus detection and ovulation",level:"2"},{id:"sec_14_3",title:"2.2.1. Induced ovulation",level:"3"},{id:"sec_15_3",title:"2.2.2. Artificially induced ovulation",level:"3"},{id:"sec_17_2",title:"2.3. Deposition of semen in the female",level:"2"},{id:"sec_19",title:"3. Species differences in the use of AI",level:"1"},{id:"sec_19_2",title:"3.1. AI in cattle",level:"2"},{id:"sec_20_2",title:"3.2. AI in pigs",level:"2"},{id:"sec_21_2",title:"3.3. AI in horses",level:"2"},{id:"sec_22_2",title:"3.4. AI in sheep",level:"2"},{id:"sec_23_2",title:"3.5. Intrauterine insemination in human fertility treatment",level:"2"},{id:"sec_25",title:"4. AI - State of the art",level:"1"},{id:"sec_26",title:"5. AI in other species",level:"1"},{id:"sec_27",title:"6. Future trends in AI",level:"1"},{id:"sec_27_2",title:"6.1. AI in increasing the efficiency of livestock production",level:"2"},{id:"sec_28_2",title:"6.2. Biomimetic sperm selection",level:"2"},{id:"sec_28_3",title:"6.2.1. Density gradient centrifugation",level:"3"},{id:"sec_29_3",title:"6.2.2. Single layer centrifugation",level:"3"},{id:"sec_31_2",title:"6.3. Sex selection ",level:"2"},{id:"sec_32_2",title:"6.4. Sperm cryopreservation",level:"2"},{id:"sec_33_2",title:"6.5. Removal of viruses from ejaculates ",level:"2"},{id:"sec_34_2",title:"6.5. AI in conservation biology",level:"2"},{id:"sec_36",title:"7. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBellinge\n\t\t\t\t\t\t\tB. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCopeland\n\t\t\t\t\t\t\tC. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThomas\n\t\t\t\t\t\t\tT. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMazzucchelli\n\t\t\t\t\t\t\tR. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tO’Neil\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCohen\n\t\t\t\t\t\t\tM. 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Steril., 81\n\t\t\t\t\t440\n\t\t\t\t\t447 .\n\t\t\t'},{id:"B17",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRobertson\n\t\t\t\t\t\t\tS. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMayerhofer\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeamark\n\t\t\t\t\t\t\tR. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1992\n\t\t\t\t\tUterine epithelial cells synthesize granulocyte-macrophage colony-stimulating factor and interleukin-6 in pregnant and nonpregnant mice.\n\t\t\t\t\tBiol Reprod, 46\n\t\t\t\t\t1069\n\t\t\t\t\t1079\n\t\t\t\t\n\t\t\t'},{id:"B18",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRobertson\n\t\t\t\t\t\t\tS. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSjoblom\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJasper\n\t\t\t\t\t\t\tM. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNorman\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeamark\n\t\t\t\t\t\t\tR. 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A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCuello\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tParrilla\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMartinez\n\t\t\t\t\t\t\tE. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tChallenges in Pig Artificial Insemination.\n\t\t\t\t\tReprod Dom Anim,\n\t\t\t\t\t41\n\t\t\t\t\t2\n\t\t\t\t\t43\n\t\t\t\t\t53 .\n\t\t\t'},{id:"B21",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSalha\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSharma\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDada\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNugent\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRutherford\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTomlinson\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPhilips\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAllgar\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWalker\n\t\t\t\t\t\t\tJ. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999\n\t\t\t\t\tThe influence of donated gametes on the incidence of hypertensive disorders of pregnancy.\n\t\t\t\t\tHum Reprod,\n\t\t\t\t\t14\n\t\t\t\t\t2268\n\t\t\t\t\t2273 .\n\t\t\t'},{id:"B22",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTremellen\n\t\t\t\t\t\t\tK. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tValbuena\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLandera\n\t\t\t\t\t\t\tS. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBallesteros\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMartinez\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMendoza\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNorman\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRobertson\n\t\t\t\t\t\t\tS. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSimon\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tThe effect of intercourse on pregnancy rates during assisted human reproduction\n\t\t\t\t\t. Hum Reprod,\n\t\t\t\t\t15\n\t\t\t\t\t2653\n\t\t\t\t\t2658 .\n\t\t\t'},{id:"B23",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTroedsson\n\t\t\t\t\t\t\tM. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLoset\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlghamdi\n\t\t\t\t\t\t\tA. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDahms\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCrabo\n\t\t\t\t\t\t\tB. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001 Interaction between equine semen and the endometrium: the inflammatory response to semen. Anim Reprod Sci, 68\n\t\t\t\t\t273\n\t\t\t\t\t278 .\n\t\t\t'},{id:"B24",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWani\n\t\t\t\t\t\t\tN. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBillah\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSkidmore\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tStudies on liquefaction and storage of ejaculated dromedary camel (Camelus dromedarius) semen. Anim Reprod Sci,\n\t\t\t\t\t109\n\t\t\t\t\t309 EOF\n\t\t\t\t\t318 EOF .\n\t\t\t'},{id:"B25",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWishart\n\t\t\t\t\t\t\tG. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1985\n\t\t\t\t\tQuantitation of the fertilising ability of fresh compared with frozen and thawed fowl spermatozoa.\n\t\t\t\t\tBritish Poultry Science, 26\n\t\t\t\t\t375\n\t\t\t\t\t380 .\n\t\t\t'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"M. Morrell Jane",address:null,affiliation:'
Swedish University of Agricultural Sciences, Uppsala, Sweden
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Waziri and Bilkisu Y. Kaltungo",authors:[{id:"183446",title:"Dr.",name:"Musa I.",middleName:null,surname:"Waziri",fullName:"Musa I. Waziri",slug:"musa-i.-waziri"},{id:"192161",title:"Dr.",name:"Bilkisu Y.",middleName:null,surname:"Kaltungo",fullName:"Bilkisu Y. Kaltungo",slug:"bilkisu-y.-kaltungo"}]},{id:"52592",title:"Genomics Tools for the Characterization of Genetic Adaptation of Low Input Extensively Raised Chickens",slug:"genomics-tools-for-the-characterization-of-genetic-adaptation-of-low-input-extensively-raised-chicke",signatures:"Farai Catherine Muchadeyi and Edgar Farai Dzomba",authors:[{id:"183770",title:"Dr.",name:"Farai Catherine",middleName:null,surname:"Muchadeyi",fullName:"Farai Catherine Muchadeyi",slug:"farai-catherine-muchadeyi"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"75441",title:"An Integrated Approach to the Role of Neurosonology in the Diagnosis of Giant Cell Arteritis",doi:"10.5772/intechopen.96379",slug:"an-integrated-approach-to-the-role-of-neurosonology-in-the-diagnosis-of-giant-cell-arteritis",body:'\n
\n
1. Introduction
\n
Giant cell arteritis (GCA) is a primary (non-necrotizing granulomatous) vasculitis of autoimmune etiology, which especially affects extra cranial medium-sized arteries (branches of the external carotid arteries-ECAs-particularly the superficial temporal arteries-TAs) and sometimes large-sized arteries (aorta and its major branches). It is also recognized as Horton, temporal, or granulomatous arteritis. It causes narrowing of the artery, leading (by wall thickening) to partial (stenosis) or complete obstruction (occlusion) of local arterial blood flow, its clinical manifestations being expressed by signs of local ischemia [1, 2, 3, 4, 5, 6].
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GCA is the most common form of vasculitis that occurs in adults and in the elderly, being diagnosed over the age of 50’s. Women are two to three times more affected than men. It is well known that the disease can occur in every racial group but is most common in Caucasians, especially people of northern European descent, and others in northern latitudes. [1, 2, 3, 4, 5, 6].
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According to Hunder [7], and Jennette [8] a complete diagnosis of GCA requires the presence of American College of Rheumatology (ACR) classification modified criteria:
scalp tenderness, abnormal temporal arteries on inspection and palpation (Figure 1), reduced pulse, jaw claudication (pain in the jaw while/after chewing);
blurred vision or permanent visual loss in one or both eyes (since permanent visual loss due to ischemia is frequent, GCA should be considered an ophthalmic emergency requiring immediate management);
systemic symptoms (fatigue, weight loss, fever, pain in the shoulders and hips: polymyalgia rheumatica);
increased inflammatory markers (erythrocyte sedimentation rate greater than 50 mm/h, C reactive protein greater than 1,5 mg/dl);
representative histologic findings in temporal artery biopsy (TAB): mononuclear cell infiltration or granulomatous inflammation of the vessel wall, usually accompanied with multinucleated giant cells (Figure 2).
\n\n
Figure 1.
Giant cell arteritis (GCA) of the left superficial temporal artery (TA) shows a prominent, tender and nodular artery, that is also hypo pulsating on palpation [9].
\n
Figure 2.
The histopathological examination of the left superficial temporal artery biopsy (TAB) noted [10]. (A) Thickened vascular wall with inflammatory infiltration of multinucleated giant cells, (B) epithelioid cells and (C) dissolution of the internal elastic lamina (H&E stain).
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Several imaging techniques may be suitable in the diagnosis of GCA. [9] Compared to other imaging techniques, US is considered to be the most suitable in the evaluation of GCA patients, therefor it can easily be performed by the clinician (immediately after the general examination of patient), and it is significantly shortening the waiting period until another investigation is performed. [9, 10, 11, 12, 13, 14, 15, 16].
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\n
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2. Extracranial duplex sonography in giant cell arteritis (GCA)
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Ultrasonography (US) is a safe, noninvasive, without radiations, widespread accessible, fast, and low-cost bedside screening technique which has the unique capacity of studying real-time hemodynamics. It presents the ability to evaluate the anatomy of vessel’s wall, identifying equally parietal abnormalities (wall thickening, hypoechoic plaques, clotting, parietal hematoma, dissections) and the external diameter of the artery; it can rule out both stenosis and occlusion. Therefore, the use of US is widespread in neurological clinical practice, mainly in the evaluation of arterial atherosclerotic process but also for monitoring other diseases such as medium/large-vessel vasculitis. [17, 18, 19].
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Olah noted that for US imaging of extracranial vessels different modes are being used:
\nB-mode (brightness mode)\n
\n
The strength of the echo is recorded as a bright dot, while the location of different gray dots corresponds to the depth of the target. [17]
\n
\nb. The duplex image\n
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It associates a B-mode gray-scale image with pulse-wave (PW) Doppler flow velocities measurements.
The B-mode image represents the anatomical localization of the vessels, indicating the zone of interest where a Doppler sample volume should be placed and where the velocities are measured.
The Doppler angle can be measured correctly when the blood is parallel to the direction of the vessel. [17]
\n
\nc. Color Doppler flow imaging\n
\n
Measure mean frequency shift in each sample volume.
It represents color–coded velocity information, which is superimposed as a color flow map on a B-mode image.
In each sample volume, the color reflects the blood flow velocity in a semi quantitative manner, as well as the flow direction relative to the transducer. Blood flowing toward or away from the transducer is shown by different colors (red and blue). Moreover, fast flow is indicated by a lighter hue and slow flow by a deeper one.
The color flow map indicates the position and orientation of the vessels, as well as the site of turbulent flow or stenosis. Since color flow mapping is based on flow velocity measured by PW technology, aliasing occurs if the frequency shift is higher than half of the pulse repetition frequency (PRF). [17]
\n
\nd. Power Doppler mode\n
\n
Uses the signal intensity of the returning Doppler signal instead of frequency shift.
Power (intensity) of the signal is displayed as a color map superimposed on a B-mode image. Since the Doppler power is determined mainly by the volume rather than the velocity of moving blood, power Doppler imaging is free from aliasing artifacts and much more sensitive to detect flow, especially in the low-flow regions. However, it does not contain information about the flow direction or flow velocity. [17]
\n\n
The advantages of US over other imaging techniques in GCA are represented by its safety, accessibility, tolerability, fast (may take about 15-20 minutes, if it’s conducted by an experienced sonographer) and the more important, its high resolution (a high –frequency probe offers both an axial and a lateral resolution of 0.1 mm) [19, 20, 21, 22, 23, 24, 25, 26, 27]. The smaller the vessel diameter, the more difficult is to appreciate the vessel wall damages, so that, in this case, the most informative US data are based on Doppler spectral evaluation. This is also valid for the assessment of medium to small vessel inflammation such as intracranial vasculitis. Small vessel vasculitis (the ANCA-associated or the immune complex vasculitis) are not a domain of ultrasound. [19].
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Furthermore, US has a higher sensitivity than TAB, the last one evaluating only a restricted anatomical region in a systemic disease. Using US, we can reveal pathological characteristics in GCA: non-compressible arteries (compression sign), the wall thickening (“halo” sign), stenosis and vessel occlusion. A normal intima-media complex (IMC) of an artery is represented by US as a homogeneous, hypoechoic or anechoic echo structure delineated by two parallel hyperechoic margins. [19, 20, 21, 22, 23, 24, 25, 26, 27].
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There is imperative to underline the importance of establishing the arteries that should be routinely examined in a patient suspected for GCA and these are: the TAs, and axillary arteries. If US of these arteries does not reveal suggestive lesions, in the presence of a clear patient history and of an obvious clinical examination, other arteries should be examined: other branches of the ECAs (the internal maxillary, the facial, the lingual, the occipital arteries), the vertebral, the subclavian, the common carotid arteries-CCAs, and the internal carotid arteries-ICAs. [9, 19, 21].
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Regarding the adequate US equipment for the diagnosis of GCA, modern high-resolution linear probes providing Doppler mode should be used, especially for examination of TAs. We should take into consideration that tissue penetration increases with lower frequencies and the resolution of US increases with higher frequencies. Probes that provide frequencies >20 MHz allow the clearly visualization of the normal IMC of TAs probes with frequencies ≥15 MHz are usually used for detection of minor wall thickening. [19, 21].
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2.1 Ultrasonography (US) of the large cervical and cervico-brachial vessels
\n
In 2012, during the Chapel Hill Consensus Conference [19, 28], large vascular vasculitis (LVV) was well-defined as a vasculitis involving the aorta and its major branches, although any size of artery may be affected. This definition does not state that LVV mainly affects large vessels because in many patients, the number of medium and small arteries affected is greater than the number of large arteries involvement. For example, in GCA, only few branches of the ECAs may be affected when there is involvement of numerous small branches extending into the eye and orbit (e.g., central retinal artery, posterior ciliary arteries). [29, 30] Less frequently, the CCA and the ICA are also affected (Figures 3 and 4). [9].
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Figure 3.
Large vessels GCA; CT-angiography- occlusion of the left CCA, ECA, and ICA [9].
\n
Figure 4.
Large vessels GCA, color Doppler ultrasound in transverse view of the right CCA. Hypoechoic wall swelling with right CCA occlusion [9].
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As Sturzenegger pointed up, angiography is not able to illustrate the vessel wall, so as to diagnose the inflammation of the large cervical and cervico-brachial vessels (aorta and its supra-aortic branches), the US can be very useful, since it can define alterations of the vessel wall with the use of B-mode imaging, while Doppler spectral flow velocity evaluation can help identify the stenosis or occlusion of the vessel. [19].
\n
Color Doppler Duplex sonography (CDDS) is an excellent device used in screening the large vessels involvement. Agreeing with different authors, including Sturzenegger, there are two ultra-sonographic hallmarks of large vessels GCA:
Vessel wall thickening, that typically is homogeneous, circumferential and over long segments (Figures 4 and 5);
Large vessel GCA, color Doppler ultrasound in longitudinal view of the right CCA with hypoechoic wall swelling [4].
\n
Remarkably in some cases [9], the common carotid and the internal carotid arteries are also involved (large-vessel GCA) (Figures 3, 4, and 5).
\n
\n
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2.2 Ultrasonography (US) of the temporal arteries (TAs)
\n
Extracranial Duplex sonography investigates almost completely the whole length of the common superficial TAs, including the frontal and parietal branches, and founds that inflammation is segmental (intermittent arterial involvement) [19, 20, 21, 22, 23, 24, 25, 26, 27]. The common superficial TA derives from the ECA. It divides into the frontal and parietal ramus in front of the ear. The distal common superficial TA and the rami are localized between the two layers of the temporal fascia, which is like a bright band at ultrasound examination. [19, 20, 21, 22, 23, 24, 25, 26, 27].
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2.2.1 Technical requirements
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High-resolution color Doppler US can illustrate the vessel wall and the lumen of the TAs. One should use linear probes with a minimum gray scale frequency of 8 Mhz. Color frequency should be about 10 Mhz. [19, 20, 21, 22, 23, 24, 25, 26, 27].
\n
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2.2.2 Machine adjustments
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The pulse repetition frequency (PRF) should be about 2.5 kHz as maximum systolic velocities are rather high (20-100 cm/s). Steering of the color box and the Doppler beam should be maximal as the rami are parallel to the probe. It is important that the color covers the artery lumen exactly. [19, 20, 21, 22, 23, 24, 25, 26, 27].
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2.2.3 Sonographer training
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The sonographer should perform at least 50 Duplex ultrasound of the TAs of subjects without GCA to be sure about the appearance of normal TAs before starting to evaluate patients with GCA. [19, 20, 21, 22, 23, 24, 25, 26, 27].
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2.2.4 Sequence of the ultrasound examination
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The investigation should begin with the TA, using the longitudinal scan. The probe should then be moved along the course of the TA to the parietal ramus. On the way back one should delineate the TA in transverse scans. Using the transverse scan, one can find the frontal ramus, which should then be delineated in both scans (longitudinal and transverse). If the color signal indicates localized aliasing and diastolic flow, one should use the pw-Doppler mode to confirm the presence of stenosis. [19, 20, 21, 22, 23, 24, 25, 26, 27].
\n
In 1997 Schmidt et al. proved that the most specific (almost 100% specificity) and sensitive (73% sensitivity) sign for GCA was a concentric hypo-echogenic mural thickening, dubbed “halo”, which the authors interpreted as “vessel wall edema”. [24].
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Other positive findings for GCA are the presence of occlusion and stenosis. [19, 20, 21, 22, 23, 24, 25, 26, 27].
\n
In conclusion, there are three important items in the ultrasound diagnosis of temporal arteritis:
“dark halo” sign – a typically homogeneous, hypoechoic, circumferential wall thickening around the lumen of an inflamed TA - which represents vessel wall edema and a characteristic finding in temporal arteritis/GCA. It is well delineated toward the lumen (Figure 6).
stenosis are documented by blood-flow velocities, which are more than twice the rate recorded in the area of stenosis compared with the area before the stenosis, with wave forms demonstrating turbulence and reduced velocities behind the area of stenosis (Figure 7).
acute occlusions, in which the US image is comparable to that of acute embolism in other vessels, showing hypoechoic material in the former artery lumen with absence of color signals. [19, 20, 21, 22, 23, 24, 25, 26, 27]
\n\n
Figure 6.
Color Doppler ultrasonography (CDUS) of the right TA shows a hypoechoic halo around the lumen in transverse view (arrow). The “halo sign” corresponds to edema of the artery wall. [11].
\n
Figure 7.
Longitudinal view of the right TA by color Doppler ultrasonography (CDUS) shows a hypoechoic halo of the TA and the presence of turbulent and weak flow, suggesting the presence of stenosis. The PSV is 1 m/s, that is double compared to the segment without stenosis. [11].
\n
Related ultrasound patterns can be found in other arteries: the facial, the internal maxillary, the lingual, the occipital, the distal subclavian and the axillary arteries.
\n
The best time to perform ultrasound investigation is before initiating the corticosteroid treatment, or in the first 7 days of treatment, since with corticosteroid therapy the” halo” revealed by TAs ultrasound disappears within 2-3 weeks. The wall inflammation, stenosis, or occlusions of the larger arteries (CCA, ICA) remain for months, despite corticosteroid treatment. However, the diagnosis process should not postpone the initiation of therapy. Ultrasound may also detect inflamed TAs in patients with clinically normal TAs. Some patients with the clinical image of polymyalgia rheumatica, but with hidden TAs may be diagnosed using ultrasonography. [9, 10, 11, 12, 13, 14, 15, 16, 19, 20, 21, 22, 23, 24, 25, 26, 27].
\n
In 2010, Arida et al. [26] evaluated a number of studies that examined the sensitivity and specificity of the “halo” sign confirmed by TA ultrasound (US) for GCA diagnosis versus the American College of Rheumatology (ACR) 1990 criteria for the classification of this vasculitis (used as a reference standard). Only 8 studies involving 575 patients, 204 of whom received the final diagnosis of GCA, achieved the technical quality criteria for US. This meta-analysis disclosed a sensitivity of 68% and a specificity of 91% for the unilateral “halo” sign, as well as 43% and 100%, respectively, for the bilateral “halo” sign in TA US for GCA diagnosis when the 1990 ACR criteria are used as the reference standard. The authors established that the halo sign in US is of great utility in diagnosing GCA. [19, 20, 21, 22, 23, 24, 25, 26, 27].
\n
In the case of consistent clinical and sonographic results, temporal arteries biopsy (TAB) does not appear to be useful and justified. [19, 27].
\n
Sturzenegger affirmed that differential diagnosis with arteriosclerosis is important in patients over 50 years, taking into consideration that GCA with large vessels disease disturbs almost exclusively this category of patients. There are some characteristic features of the arteriosclerotic wall: the thickening usually appears less homogeneous; there are calcified arteriosclerotic plaques ulcers; stenosis extends over shorter segments, they are not concentric, not tapering, and location of lesions differs (e.g., mainly bifurcations). [19].
\n
Besides, agreeing to Sturzenegger, differential diagnosis with the other LVV, especially Takayasu arteritis, has to be reflected:
Takayasu arteritis usually affects women below the age of 40 years;
symptoms like tender scalp or polymyalgia syndrome are exceptional;
the involvement of CCA is more frequent in Takayasu arteritis, while the involvement of temporal artery in Takayasu arteritis is not known;
US image of wall thickening (“halo”) is brighter in TA than in GCA probably due to a larger mural edema in GCA which is a more acute disease than TA. Reflected. [19, 20, 21, 22, 23, 24, 25, 26, 27]
\n\n
\n
\n
\n
2.3 Color Doppler imaging (CDI) of orbital (retro-bulbar) vessels
\n
Approximately 25% of patients with temporal artery biopsy (TAB) - proven GCA have ophthalmologic complications: usually unilateral visual loss (due to the vasculitic involvement of orbital vessels:
of posterior ciliary arteries (PCAs) - represented by arteritic anterior ischemic optic neuropathies (A-AION), or
of central retinal artery (CRA) - represented by central retinal artery occlusion (CRAO). [31, 32, 33, 34, 35]
\n\n
Schmidt compared the results of TAs-US examinations with the occurrence of visual ischemic complications (A-AION, CRAO, branch retinal artery occlusion, diplopia, or amaurosis fugax) in 222 consecutive patients with newly diagnosed, active GCA. [21, 22, 23, 24].
\n
However, findings of TAs US did not correlate with eye complications. [21, 22, 23, 24].
\n
This is the reason why we always have to exam the orbital (retrobulbar) vessels in GCA patients or in patients with unilateral abrupt visual loss [9, 10, 11, 12, 13, 14, 15, 16] (Figure 8A,B).
\n
Figure 8.
Color Doppler imaging (CDI) of orbital (retro-bulbar) vessels: (A). central retinal artery (CRA); (B). posterior ciliary arteries (PCAs) [15].
\n
\n
2.3.1 Orbital (retrobulbar) vessels
\n
The ophthalmic artery (OA) branches in several arteries, including (Table 1):
the central retinal artery (CRA) (Figure 8 A), and
the posterior ciliary arteries (nasal and temporal branches-nPCAs, tPCAs) [28, 31, 32] (Figure 8B), (Table 1). [15, 28, 31, 32]
\n\n
\n
\n
\n
\n
\n
\n
\n\n
\n
Parameter
\n
OA
\n
CRA
\n
PCA (temporal)
\n
PCA (nasal)
\n
SOV (superior ophthalmic vein)
\n
\n\n\n
\n
PSV (cm/s)
\n
45,3 ± 10,5
\n
17,3 ± 2,6
\n
13,3 ± 3,5
\n
12,4 ± 3,4
\n
10,2 ± 3,8
\n
\n
\n
EDV (cm/s)
\n
11,8 ± 4,3
\n
6,2 ± 2,7
\n
6,4 ± 1,5
\n
5,8 ± 2,5
\n
4,3 ± 2,4
\n
\n
\n
RI
\n
0,74 ± 0,07
\n
0,63 ± 0,09
\n
0,52 ± 0,10
\n
0,53 ± 0,08
\n
\n
\n\n
Table 1.
Normal flow velocities and Resistance Index in orbital vessels [15, 31, 32].
Note: These are the normal flow velocities and resistances index in orbital vessels which are generally accepted by the specialists.
\n
OA finishes in the a. supra-trohlearis and A. dorsalis nasi.
\n
\n
\n
2.3.2 Probe selection
\n
Standard neurovascular ultrasound machines equipped with linear-array transducers emitting 6-12 MHz (up to 15 MHz) are adequate for identifying (by Color Doppler sonography), and measuring (by spectral analysis pulsed Doppler sonography) the blood flow in the orbital vessels: the OA, the CRA and central retinal vein (CRV), PCAs, and the superior ophthalmic vein (SOV). [28, 31, 32].
\n
The CRA, a distal branch of the OA, enters the optic nerve (ON) approximately 1-1.5 cm distal from the bulbus coming from the dorsolateral direction. Parallel to this is the CRV.
\n
The PCAs are located near the optic nerve (ON) (the nasal-nPCA and the temporal-tPCA branches). [28, 31, 32].
\n
If the vessels are difficult to display, the power should be elevated for a short time if the clinical question is important. [28, 31, 32].
\n
\n
\n
2.3.3 Arterial blood supply of the anterior part of the optic nerve
\n
The optic nerve head (ONH) consists of (from anterior to posterior):
the surface nerve fiber layer - mostly supplied by the retinal arterioles. The cilioretinal artery, when present, usually supplies the corresponding sector of the surface layer. [36, 37, 38, 39, 40]
the prelaminar region - situated anterior of the lamina cribrosa. It is supplied by centripetal branches from the peripapillary choroid. [36, 37, 38, 39, 40]
the lamina cribrosa region - supplied by centripetal branches from the posterior ciliary arteries (PCAs), either directly or by the so-called arterial circle of Zinn and Haller (when is present). [36, 37, 38, 39, 40]
the retrolaminar region - is the part of the ONH that lies immediately behind the lamina cribrosa. It is supplied by two vascular systems: the peripheral centripetal and the axial centrifugal systems. The previous represents the main source of stream for this part. It is formed by recurrent pial branches arising from the peripapillary choroid and the circle of Zinn and Haller (when present, or the PCAs instead). In addition, pial branches from the central retinal artery (CRA) also supply this part. The latter is not present in all eyes. When present, it is formed by inconstant branches arising from the intraneural part of the CRA.
\n\n
From the description of the arterial supply of the ONH given above, it is obvious that the PCAs are the main source of blood supply to the ONH. [36, 37, 38, 39, 40].
\n
\n
\n
2.3.4 Pathophysiology of factors controlling blood flow in the optic nerve head (ONH)
\n
The blood flow in the ONH depends upon [36, 37, 38, 39, 40]:
resistance to blood flow - depends upon the condition and caliber of the vessels supplying the ONH, which in turn are influenced by: the efficiency of auto-regulation of the ONH blood flow, the vascular variations in the arteries feeding the ONH circulation, and the rheological properties of the blood.
arterial blood pressure (BP) - both arterial hypertension and hypotension can influence the ONH blood flow in several ways. In an ONH, a fall of blood pressure below a critical level of auto-regulation would decrease its blood flow. Decrease of BP in the ONH may be due to systemic (nocturnal arterial hypotension during sleep, intensive antihypertensive medication, etc.) or local hypotension.
intra-ocular pressure (IOP) - there is an opposite relationship between intra-ocular pressure and perfusion pressure in the ONH.
\n\n
The blood flow in the ONH is calculated by using the following formula:
\n
Perfusion pressure = Mean BP minus intraocular pressure (IOP).
\n
Mean BP = Diastolic BP + 1/3 (systolic - diastolic BP) [6, 13].
\n
\n
\n
\n
\n
3. Anterior ischemic optic neuropathies (AIONs)
\n
AION is the consequence of an acute ischemic disorder (a segmental infarction) of the ONH supplied by the PCAs. Blood supply interruption can occur with or without arterial inflammation. Therefore, AION is of two types: non-arteritic AION (NA-AION) and arteritic AION (A-AION). The prior is far more common than the last, and they are distinct entities etiologically, pathogenically, clinically and from the management point of view. [36, 37, 38, 39, 40].
\n
A history of amaurosis fugax before an abrupt, painless, and severe loss of vision of the involved eye, with concomitant diffuse pale optic disc edema is extremely suggestive of A-AION. None of these symptoms are found in NA-AION patients. [36, 37, 38, 39, 40].
\n
\n
3.1 Spectral Doppler analysis of the orbital (retro-bulbar) vessels in A-AION
\n
In acute stage, blood flow cannot be detected in the PCAs in the clinically affected eye of any of the GCA patients with A-AION. Low end diastolic velocities (EDV) and high resistance index (RI) are identified in all other orbital vessels (including the PCAs in the opposite eye) of all A-AION patients. [9, 10, 11, 12, 13, 14, 41].
\n
Over 7 days, Spectral Doppler analysis of the orbital vessels highlights blood flow alterations in all A-AION patients even with a high-dose corticosteroids therapy. Severely reduced blood flow velocities (especially EDV) in the PCAs of the affected eye (both nasal and temporal branches), compared to the unaffected eye, are observed. An increased RI in the PCAs is noted (the RI is higher on the clinically affected eye as compared to the unaffected eye). [9, 10, 11, 12, 13, 14, 41] (Figure 9A,B).
\n
Figure 9.
CDI of the PCAs in A-AION: (A). Decreased EDV in the nasal PCAs of the clinically affected right eye, and (B) of the clinically unaffected left eye.
\n
Fewer abnormalities are detected in the CRAs: high RI are measured in both sides, with decreased peak systolic velocities (PSV) in the CRA of the clinically affected eye. [9, 10, 11, 12, 13, 14, 41].
\n
Similar abnormalities are noted in the OAs: high RI are measured in both sides. [9, 10, 11, 12, 13, 14, 41].
\n
At 1 month, after treatment with high-dose corticosteroids, CDI examinations of orbital blood vessels reveals that blood flow normalization is slow in all A-AION patients. [9, 10, 11, 12, 13, 14, 41].
\n
In conclusion, the Spectral Doppler Analysis of the orbital vessels in A-AION indicates (after several days of corticosteroid treatment) low blood velocities, especially EDV, and high RI in all orbital vessels, in both orbits. These signs represent characteristic signs of the CDI of the orbital vessels in A-AION. [9, 10, 11, 12, 13, 14, 41].
\n
\n
\n
3.2 Spectral Doppler analysis of the orbital (retro-bulbar) vessels in NA-AION
\n
In contrast, the patients with NA-AION present the following characteristics in acute stage, and at 1 week of evolution:
minor reduction of PSV in PCAs (nasal and temporal) in the affected eye, compared to the unaffected eye.
slight decrease of PSV in CRA of the affected eye, due to papillary edema. [9, 10, 11, 12, 13, 14, 41]:
in OAs, PSV are variable: normal to decreased, according to ipsilateral ICAs status.
\n\n
Severe ICA stenosis (≥70% of vessel diameter) combined with an insufficient Willis polygon led to diminish PSV in ipsilateral OA. [9, 10, 11, 12, 13, 14, 41].
\n
In 1 month, CDI examinations of orbital blood vessels reveal that blood flow normalization is reached. The exceptions are the cases with severe ipsilateral ICA stenosis/occlusion. [9, 10, 11, 12, 13, 14, 41].
\n
In conclusion, in NA-AION, blood velocities and RI in PCAs are preserved. Similar results were obtained in other studies. [9, 10, 11, 12, 13, 14, 41].
\n
Fluorescein angiogram and CDI of the orbital vessels data support the histopathological evidence of involvement of the entire trunk of the PCAs in the A-AION (impaired optic disc and choroidal perfusion in the patients with A-AION). On the other hand, in the NA-AION, the impaired flow to the optic nerve head (ONH) is distal to the PCAs themselves, possibly at the level of the para-optic branches (only 1/3 of the flow of the PCAs). [36, 37, 38, 39, 40].
\n
These branches supply the ONH directly (impaired optic disc perfusion, with relatively conservation of the choroidal perfusion). [36, 37, 38, 39, 40].
\n
Extremely delayed or absent filling of the choroid has been depicted as a fluorescein angiogram characteristic of arteritic AION and has been suggested as one useful factor by which A-AION can be differentiated from NA-AION. [36, 37, 38, 39, 40].
\n
\n
\n
\n
4. Central retinal artery occlusion (CRAO)
\n
CRAO is the result of an abrupt diminuation of blood flow in CRA, severe enough to cause ischemia of the inner retina. Due to the fact that there are no functional anastomoses between choroidal (PCAs) and retinal circulation (CRA), CRAO determines severe and permanent loss of vision. Therefore, it is very important to identify the cause of CRAO, in order to protect the contralateral eye. Frequently, the site of the blockage is within the optic nerve substance and for this reason, it is generally not visible on the ophthalmoscopy. The majority of CRAO are caused by thrombus formation due to systemic diseases, including GCA. For this reason, all patients with CRAO should undergo a systemic evaluation. [42, 43, 44].
\n
\n
4.1 Spectral Doppler analysis of the orbital (retro-bulbar) vessels in CRAO
\n
The patients with an unilateral CRAO present at the Spectral Doppler analysis of the retrobulbar vessels the following aspects [9, 15, 16]:
an elevated RI in the CRAs (the RI is higher on the affected side, than it is on the unaffected side); with severe diminished blood flow velocities (especially EDV) in the CRA.
fewer abnormalities are observed in the PCAs, and in the OAs (Figure 10).
\n\n
Figure 10.
CDI of orbital vessels revealed severely diminished EDV and high RI in both CRAs (a, b) despite the fact that the left eye had the normal aspect at ophthalmoscopy. Fewer abnormalities were observed in the PCAs (c, d). [15].
\n
\n
\n
\n
5. US and others imaging techniques
\n
Other imaging techniques, such as high-resolution magnetic resonance imaging (MRI), magnetic resonance-angiography (MR-A), computer tomography angiography (CT-A), positron emission tomography (PET) provide valuable information regarding the structure of large vessels, highlighting with much greater precision the thoracic aorta, compared with US. [45, 46, 47].
\n
There are few studies that compared US with other imaging techniques. Some of them indicated that there is a good correlation between US and PET, even though PET might have a little more sensitivity for vertebral arteries examination. [45, 46] 18F-fluorodeoxyglucose-positron emission tomography/ computed tomography (FDG-PET/CT) has a higher sensitivity for detection of large arteries and aortic involvement - analysis of the arterial wall. [45, 46] The diagnostic power of high-resolution MRI and color-coded duplex US of extra-cranial arteries in detecting GCA are equivalent [47].
\n
The disadvantages of this techniques are: they are more expensive, hardly accessible, some of them are limited by invasiveness, nephrotoxicity (angiography) and exposure to high radiations (CT,PET), this is why they might be unnecessary (excepting those patients with exclusively thoracic aorta involvement) and are not accepted as diagnostic methods in GCA. They should only be used when interventions are required [45, 46, 47].
\n
All these imaging techniques should always be performed by well-trained specialists, using suitable equipment and operational protocols. [45, 46, 47].
\n
Nevertheless, US is particularly useful in examining the orbital vessels. [9, 10, 11, 12, 13, 14, 15, 16, 28, 31, 32, 41].
\n
The diagnostic work-up of AION benefits from the combined used of fluorescein angiography and noninvasive multimodal imaging, including CDI of the orbital vessels and structural Optical Coherence Tomography (OCT) of the optic nerve head (ONH) and OCT angiography [10, 48]. They provide very detailed information regarding the structural (retinal nerve fiber layer-RNFL-thickness/optic disc edema) and vascular impairments (microvascular defects-vessel tortuosity, and vessel density reduction) of the ONH, respectively [10, 48].
\n
\n
\n
6. Conclusions
\n
US should be used as a first-line diagnostic investigation for patients presenting with clinical and biological features suggestive for GCA, taking into consideration that it has a high sensitivity to detect vessel wall thickening (dark hallo sign) in the case of large/medium vessels. In a few cases of our studies, the CCAs and the ICAs were also involved.
\n
In consequence, in our department, CCDS has emerged as a safe and reliable alternative to TAB as a point of care diagnostic tool in the management of temporal arteritis.
\n
The eye involvement in GCA is frequent and consists in A-AIONs or CRAO, with abrupt, painless, and severe loss of vision of the involved eye.
\n
Because findings of TAs US do not correlate with eye complications in GCA, CDI of the orbital vessels is of critical importance, in order to quickly differentiate the mechanism of eye involvement (arteritic, versus non-arteritic). This US tehnique may be helpful to detect the blood flow in the orbital vessels, especially in cases of opacity of the medium, or when the clinical appearance of ophthalmologic complications in temporal arteritis is athypical.
\n
The Spectral Doppler Analysis of the orbital vessels in GCA with eye involvement reveals low blood velocities, especially EDV, and high RI in all orbital vessels, in both orbits, for all patients (especially on the affected side).
\n
A huge advantage of CDI of orbital vessels is that it provides immediate information that can be used to inform treatment decisions, including a potential reduction in loss of sight and avoidance of unnecessary long-term steroid treatment by early exclusion of mimics.
\n
\n\n',keywords:"giant cell arteritis (GCA), temporal arteries (TAs), temporal artery biopsy (TAB), “dark halo” sign, ultrasonography (US), arteritic anterior ischemic optic neuropathies (A-AION), central retinal artery occlusion (CRAO), color Doppler imaging (CDI) of the orbital vessels, end diastolic velocities (EDV), resistance index (RI)",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75441.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75441.xml",downloadPdfUrl:"/chapter/pdf-download/75441",previewPdfUrl:"/chapter/pdf-preview/75441",totalDownloads:11,totalViews:0,totalCrossrefCites:0,dateSubmitted:"November 4th 2020",dateReviewed:"February 3rd 2021",datePrePublished:"February 26th 2021",datePublished:null,dateFinished:"February 26th 2021",readingETA:"0",abstract:"Giant cell arteritis (GCA) is a primary vasculitis that affects especially extracranial medium-sized arteries, such as superficial temporal arteries (TAs). Three findings are important for the ultrasound (US) diagnosis of TA: „dark halo” sign, which represents vessel wall edema, stenosis, and acute occlusions. US has a high sensitivity to detect vessel wall thickening in the case of large vessels GCA. The eye involvement in GCA is frequent and consists in arteritic anterior ischemic optic neuropathies or central retinal arterial occlusion, with abrupt, painless, and severe loss of vision of the involved eye. Because findings of TAs US do not correlate with eye complications in GCA, color Doppler imaging of the orbital vessels is of critical importance (it reveals low end diastolic velocities, and high resistance index), in order to quickly differentiate the mechanism of eye involvement (arteritic, versus non-arteritic). The former should be treated promptly with systemic corticosteroids to prevent further visual loss of the fellow eye.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75441",risUrl:"/chapter/ris/75441",signatures:"Dragoș Cătălin Jianu, Silviana Nina Jianu, Georgiana Munteanu, Traian Flavius Dan, Anca Elena Gogu and Ligia Petrica",book:{id:"10304",title:"Giant-Cell Arteritis",subtitle:null,fullTitle:"Giant-Cell Arteritis",slug:null,publishedDate:null,bookSignature:"Dr. Imtiaz A. Chaudhry",coverURL:"https://cdn.intechopen.com/books/images_new/10304.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"66603",title:"Dr.",name:"Imtiaz",middleName:"A.",surname:"Chaudhry",slug:"imtiaz-chaudhry",fullName:"Imtiaz Chaudhry"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Extracranial duplex sonography in giant cell arteritis (GCA)",level:"1"},{id:"sec_2_2",title:"2.1 Ultrasonography (US) of the large cervical and cervico-brachial vessels",level:"2"},{id:"sec_3_2",title:"2.2 Ultrasonography (US) of the temporal arteries (TAs)",level:"2"},{id:"sec_3_3",title:"2.2.1 Technical requirements",level:"3"},{id:"sec_4_3",title:"2.2.2 Machine adjustments",level:"3"},{id:"sec_5_3",title:"2.2.3 Sonographer training",level:"3"},{id:"sec_6_3",title:"2.2.4 Sequence of the ultrasound examination",level:"3"},{id:"sec_8_2",title:"2.3 Color Doppler imaging (CDI) of orbital (retro-bulbar) vessels",level:"2"},{id:"sec_8_3",title:"Table 1.",level:"3"},{id:"sec_9_3",title:"2.3.2 Probe selection",level:"3"},{id:"sec_10_3",title:"2.3.3 Arterial blood supply of the anterior part of the optic nerve",level:"3"},{id:"sec_11_3",title:"2.3.4 Pathophysiology of factors controlling blood flow in the optic nerve head (ONH)",level:"3"},{id:"sec_14",title:"3. Anterior ischemic optic neuropathies (AIONs)",level:"1"},{id:"sec_14_2",title:"3.1 Spectral Doppler analysis of the orbital (retro-bulbar) vessels in A-AION",level:"2"},{id:"sec_15_2",title:"3.2 Spectral Doppler analysis of the orbital (retro-bulbar) vessels in NA-AION",level:"2"},{id:"sec_17",title:"4. Central retinal artery occlusion (CRAO)",level:"1"},{id:"sec_17_2",title:"4.1 Spectral Doppler analysis of the orbital (retro-bulbar) vessels in CRAO",level:"2"},{id:"sec_19",title:"5. US and others imaging techniques",level:"1"},{id:"sec_20",title:"6. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'\nGonzalez-Gay M.(2005) The diagnosis and management of patients with giant cell arteritis. J Rheumatol 2005;32:1186-1188.\n'},{id:"B2",body:'\nSalvarani C, Cantini F, Hunder GG (2008): Polymyalgia rheumatica and giant-cell arteritis. Lancet 2008, 372:234-245.\n'},{id:"B3",body:'\nMelson MR, Weyand CM, Newman NJ, Biousse V. The diagnosis of giant cell arteritis. Rev Neurol Dis 2007: 4(3): 128 - 42.\n'},{id:"B4",body:'\nHayreh SS, Podhajsky PA, Raman R, Zimmerman B. Giant cell arteritis: validity and reliability of various diagnostic criteria. AmJOphthalmol 1997: 123(3): 285- 96.\n'},{id:"B5",body:'\nLevine SM, Hellmann DB. (2002) Giant cell arteritis. Curr Opin Rheumatol 2002;14:3-10.\n'},{id:"B6",body:'\nGonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ, et al. Epidemiology of giant cell arteritis and polymyalgia rheumatica Arthritis Rheum 2009, 61:1454-1461.\n'},{id:"B7",body:'\nHunder G.G., et al. (1990) - The American College of Reumatology 1990 criteria for the classification of giant cell arteritis, Arteritis Rheum. 1990; 33:1122-28.\n'},{id:"B8",body:'\nJennette J et al-Revised international Chapell Hill consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65:1-11.\n'},{id:"B9",body:'\nJianu DC, Jianu SN, Petrica L, Serpe M - Advances in the Diagnosis and Treatment of Vasculitis - Luis M Amezcua-Guerra (Ed.)-Chapter 16, Large Giant Cell Arteritis with Eye Involvement, InTech, Rijeka, Croatia,2011, pg 311-330.\n'},{id:"B10",body:'\nStanca HT, Suvac E, Munteanu M, Jianu DC, Motoc AGM, Rosca GC, Boruga O - Giant cell arteritis with arteritic anterior ischemic optic neuropathy. Rom J Morphol Embryol 2017, 58 (1): 281-285.\n'},{id:"B11",body:'\nJianu DC, Jianu SN. Chapter 8-The role of Color Doppler Imaging in the study of optic neuropathies. In: Jianu DC, Jianu SN, editors. Color Doppler Imaging. Neuro-ophthalmological correlations. Timisoara, Romania: Mirton: 2010. p. 154- 74.\n'},{id:"B12",body:'\nJianu DC, Jianu SN– Updates in the diagnosis and treatment of vasculitis - Lazaros Sakkas and Christina Katsiari (Ed.) - Chapter 5, Giant Cell Arteritis and arteritic anterior ischemic optic neuropathies InTech, Rijeka, Croatia, 2013, pg 111- 130.\n'},{id:"B13",body:'\nJianu DC, Jianu SN, Petrica L, Motoc AGM, Dan TF, Lazureanu DC, Munteanu M - Clinical and color Doppler imaging features of one patient with occult giant cell arteritis presenting arteritic anterior ischemic optic neuropathy. Rom J Morphol Embryol 2016, 57(2): 579-583.\n'},{id:"B14",body:'\nJianu DC, Jianu SN, Munteanu M, Petrica L-Clinical and ultrasonographic features in anterior ischemic optic neuropathies –Vojnosanitetski Pregled (Military Medical and Pharmaceutical Journal of Serbia) 2018, August, Vol.75 (No.8): p.773-779.\n'},{id:"B15",body:'\nJianu DC, Jianu SN. Chapter 6-The role of Color Doppler Imaging in the study of central retinal artery obstruction. In: Jianu DC, Jianu SN, editors. Color Doppler Imaging. Neuro-ophthalmological correlations. Timisoara, Romania: Mirton: 2010. p. 125-142.\n'},{id:"B16",body:'\nJianu DC, Jianu SN, Munteanu M, Vlad D, Rosca C, Petrica L - Color Doppler imaging features of two patients presenting central retinal artery occlusion with and without giant cell arteritis. Vojnosanitetski Pregled (Military Medical and Pharmaceutical Journal of Serbia) 2016 April Vol.73 (No.4), 397-401.\n'},{id:"B17",body:'\nLaszlo Olah. Chapter 1 Ultrasound principles pg 1-14, in Manual of Neurosonology, L Csiba, and C Baracchini (ed), Cambridge University Press, Cambridge, United Kingdom, 2016.\n'},{id:"B18",body:'\nMassimo Del Sete and Valentina Saia. Chapter 5A. Atherosclerotic carotid disease. Carotid ultrasound imaging, pg 57-63, in Manual of Neurosonology, L Csiba, and C Baracchini (ed), Cambridge University Press, Cambridge, United Kingdom, 2016.\n'},{id:"B19",body:'\nMathias H. Sturzenegger. Chapter 8 Cervical artery vasculitides pg 300-305, in Manual of Neurosonology, L Csiba, and C Baracchini (ed), Cambridge University Press, Cambridge, United Kingdom, 2016).\n'},{id:"B20",body:'\nDuftner C, Dejaco C, Moller-Dohn U. Ultrasound definitions for vasculitis in cranial and large vessel giant cell arteritis: results of a Delphi survey of the OMERACT ultrasound large vessel vasculitis group. Ann Rheum Dis2016;75(Suppl 2):626. Doi:10.1136/annrheumdis-2016-eular.5487.\n'},{id:"B21",body:'\nSchmidt WA. Role of ultrasound in the understanding and management of vasculitis. Ther Adv Musculoskelet Dis 2014; 6: 39-47.\n'},{id:"B22",body:'\nWolfgang A. Schmidt Ultrasound in the diagnosis and management of giant cell arteritis. Rheumatology 2018; 57: ii22-ii31 doi:10.1093/rheumatology/kex461.\n'},{id:"B23",body:'\nSchmidt WA.Takayasu and temporal arteritis, in Baumgartner R.W. (ed.): Handbook on Neurovascular Ultrasound. Front.Neurol.Neurosci.Basel, Karger, 2006, 21:96-104.\n'},{id:"B24",body:'\nSchmidt WA, Kraft HE, Vorpahl K, et al.Color duplex ultrasonography in the diagnosis of temporal arteritis. N Engl J Med 1997, 337:1336-1342.\n'},{id:"B25",body:'\nMonti S, Floris A, Ponte C et al. The use of ultrasound to assess giant cell arteritis: review of the current evidence and practical guide for the rheumatologist. Rheumatology 2018;57:227-35.\n'},{id:"B26",body:'\nArida A, Kyprianou M, Kanakis M, Sfikakis PP. The diagnostic value of ultrasonography-derived edema of the temporal artery wall in giant cell arteritis: a second meta-analysis. BMC Musculoskelet Disord 2010, 11:44.\n'},{id:"B27",body:'\nJared Ching, Sonja Mansfield Smith, Bhaskar Dasgupta, Erika Marie Damato, The Role of Vascular Ultrasound in Managing Giant Cell Arteritis in Ophthalmology https://doi.org/10.1016/j.survophthal.2019.11.004Get rights and content.\n'},{id:"B28",body:'\nMario Siebler. Chapter 25 Neuro-orbital ultrasound, pg 300-305 in Manual of Neurosonology, L Csiba, and C Baracchini (ed), Cambridge University Press, Cambridge, United Kingdom, 2016).\n'},{id:"B29",body:'\nMartínez-Valle F, Solans-Laqué R, Bosch-Gil J, et al.(2010): Aortic involvement in giant cell arteritis. Autoimmun Rev 2010, 9:521-524.\n'},{id:"B30",body:'\nAgard C, Barrier JH, Dupas B, et al. Aortic involvement in recent-onset giant cell (temporal) arteritis: a case-control prospective study using helical aortic computed tomodensitometric scan. Arthritis Rheum 2008, 59:670-676.\n'},{id:"B31",body:'\nPichot O, Gonzalvez B, Franco A, Mouillon M. Color Doppler ultrasonography in the study of orbital and ocular vascular diseases. J Fr Ophtalmol; 2001, 19(1): 19-31.\n'},{id:"B32",body:'\nLieb WE, Cohen SM, Merton DA, Shields JA, Mitchell DG, Goldberg BB. Color Doppler imaging of the eye and orbit. Technique and normal vascular anatomy. Arch Ophthalmol 1991; 109(4): 527- 31.\n'},{id:"B33",body:'\nGonzalez-Gay MA, Garcia-Porrua C, Llorca J, Hajeer AH, Branas F, Dababneh A, et al.(2000) Visual manifestations of giant cell arteritis: trends and clinical spectrum in 161 patients. Medicine (Baltimore) 2000;79:283-92.\n'},{id:"B34",body:'\nSingh AG, Kermani TA, Crowson CS, Weyand CM, Matteson EL, Warrington KJ. Visual manifestations in giant cell arteritis: Trend over 5 decades in a population-based cohort. J Rheumatol 2015: 42(2): 309-15.\n'},{id:"B35",body:'\nHayreh SS, Podhajsky PA, Zimmerman B. Occult giant cell arteritis: ocular manifestations. Am J Ophthalmol 1998: 125(4): 521- 6.\n'},{id:"B36",body:'\nBiousse V: Newman NJ. Ischemic Optic Neuropathies. N Engl J Med 2015: 372(25): 2428- 36.\n'},{id:"B37",body:'\nArnold AC.Chapter 191 - Ischemic optic neuropathy, in Ianoff M., Duker J.S., ed., Ophtalmology, second edition, Mosby, 2004:1268-1272.\n'},{id:"B38",body:'\nCollignon-Robe NJ, Feke GT, Rizzo JF. Optic nerve head circulation in nonarteritic anterior ischemic optic neuropathy and optic neuritis, Ophthalmol. 2004; 111: 1663-72.\n'},{id:"B39",body:'\nHayreh SS. Ischemic optic neuropathies-where are we now? Graefes Arch Clin Exp Oplnhalmol 2013: 251(8): 1873-84.\n'},{id:"B40",body:'\nHayreh SS. Management of ischemic optic neuropathies. Inidian J Ophthalmol 2011:59(2): 123- 36.\n'},{id:"B41",body:'\nTranquart F, Aubert-Urena AS, Arsene S, Audrierie C, Rossazza C., Pourcelot L. Echo-Doppler couleur des arteres ciliaires posterieures dans la neuropathie optique ischemique anterieure aigue, J.E.MU. 1997; 18(1):6871.\n'},{id:"B42",body:'\nDuker JS. Chapter 114 - Retinal arterial obstruction, in Yanoff M., Duker J.S., ed., Ophtalmology, second edition, Mosby, 2004:856-63.\n'},{id:"B43",body:'\nAhuja RM, Chaturvedi S, Elliot A, et al. Mechanism of retinal arterial occlusive disease in African, American and Caucasian patients, Stroke 1999, 30(8): 479-84.\n'},{id:"B44",body:'\nConnolly BP, Krishnan A, Shah GK, Whelan J, Brown GC, Eagle RC, et al. Characteristics of patients presenting with central retinal artery occlusion with and without giant cell arteritis. Can J Ophthalmol 2000; 35(7): 379-84.\n'},{id:"B45",body:'\nCzihal M, Tato F, Forster S et al. Fever of unknown origin as initial manifestation of large vessel giant cell arteritis: diagnosis by colour-coded sonography and 18-FDG-PET. Clin Exp Rheumatol 2010;28:549-52.\n'},{id:"B46",body:'\nGermano G, Macchioni P, Possemato N et al. Contrast enhanced ultrasound of the carotid artery in patients with large vessel vasculitis: correlation with positron emission tomography findings. Arthritis Care Res 2017;69:143-9.\n'},{id:"B47",body:'\nBley TA, Reinhard M, Hauenstein C et al. Comparison of duplex sonography and high-resolution magnetic resonance imaging in the diagnosis of giant cell (temporal) arteritis. Arthritis Rheum 2008; 58: 2574-8.\n'},{id:"B48",body:'\nPierro L, Arrigo A, Aragona E, Cavalleri M, Bandello F. Vessel Density and vessel tortuosity quantitative analysis of A-AIONS and NA-AIONS: an OCT-Angiography Study. Journal of Clinical Medicine 2020;Apr 12;9 (4)1094 doi: 10.3390/jcm9041094\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Dragoș Cătălin Jianu",address:"dcjianu@yahoo.com",affiliation:'
Department of Neurology, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
Department of Neurology, Clinical Emergency County Hospital, Timisoara, Romania
Department of Nephrology, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
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