\r\n\tFrom the definition of Massive MIMO, the Book covers the important aspects of channel estimation, different efficiency parameters, and various practical deployment considerations. From the beginning, a very general, yet tractable, canonical system model with spatial channel correlation is required. This model is used to realistically assess the Spectral Efficiency and Energy Efficiency and is later extended to also include the impact of hardware impairments.
\r\n\r\n\tAs an overall framework, the authors and researchers who are working in the Area of Massive MIMO and 5G are expected to submit chapters covering these areas to give insight into research about MIMO.
",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:"f6e96802bc79d6b8b0bab9ad24980cbc",bookSignature:"Dr. Sudhakar Radhakrishnan",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/7638.jpg",keywords:"Multi Antenna Systems, Diversity, Space-time Codes, Rake Receiver, MIMO Wireless Communication, SVD, Equalising MIMO Systems, Predistortion, Beam Forming Principles, Increased Spectrum Efficiency, Interference Cancellation, Beam Former",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 18th 2019",dateEndSecondStepPublish:"March 6th 2020",dateEndThirdStepPublish:"May 5th 2020",dateEndFourthStepPublish:"July 24th 2020",dateEndFifthStepPublish:"September 22nd 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:"26327",title:"Dr.",name:"Sudhakar",middleName:null,surname:"Radhakrishnan",slug:"sudhakar-radhakrishnan",fullName:"Sudhakar Radhakrishnan",profilePictureURL:"https://mts.intechopen.com/storage/users/26327/images/system/26327.jpg",biography:"Dr. Sudhakar Radhakrishnan is a researcher in the field of Image processing and contributed a lot to the society. He is an editorial board member for 3 International journals namely International Journal of Computer Theory and Engineering, International Journal of Computer and Electrical Engineering and International Arab Journal of Information technology. He is currently an Associate editor of IEEE-Access a multidisciplinary Journal published by IEEE. He is a reviewer of 16 international journals namely IEEE Transactions on Systems, Man, and Cybernetics: Systems by IEEE, International Arab Journal of Information Technology coming from Zarqa University, International Journal of Computer and Electrical Engineering published by International Association of Computer Science and Information Technology Press (IACSIT),International Journal of Computer Theory and Engineering published by International Association of Computer Science and Information Technology Press (IACSIT), Journal of Electrical and Electronics Engineering Research, Iranian Journal of Electrical and Computer Engineering, Journal of Optical Engineering, Journal of Electronic Imaging, Imaging Science Journal, International Journal of Computational Science and Engineering (IJCSE), International journal of Image mining(IJIM), Int. J. of Biomedical Engineering and Technology (IJBET) , Journal for Image Analysis & Stereology from International Society for Stereology, ETRI journal from Korea,\tAEUE- International journal of Electronics and Communications and IET Image Processing. He wrote 2 books titled 'Research issues in Image compression using Wavelet variants” .'Practicing Signals and Systems Laboratory using MATLAB” and two Book chapters titled 'Wavelet based image compression” in book titled 'Computational Intelligence Techniques in Handling Image Processing and Pattern Recognition” 'Analysis of Hand Vein image s using hybrid techniques” in Hybrid Intelligence techniques for Image Analysis and Understanding”. He edited three books titled 'Effective video coding for Multimedia applications”, 'Applications of Digital Signal Processing through practical approach” 'Recent Advances in Image and Video Coding” Wavelet theory and its applications all published by IntechOpen.He has published 100 papers in international, national journals and conference proceedings. His areas of research include Digital Image Processing, Image Analysis, Wavelet Transforms, Communication Engineering, and Digital Signal Processing",institutionString:"Dr. Mahalingam College of Engineering and Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"5",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"280415",firstName:"Josip",lastName:"Knapic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/280415/images/8050_n.jpg",email:"josip@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, copy-editing 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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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"72941",title:"Chronic Migraine",doi:"10.5772/intechopen.93314",slug:"chronic-migraine",body:'Chronic migraine (CM) is a distinct and relatively recently defined type of migraine initially recognized in patients with a large burden of disability from frequent headaches and a history of prior migraine.
The International Headache Society (IHS) defines CM as more than 15 headache days per month over a 3-month period of which more than eight are migrainous [1].
Disability rates and burden of disease among individuals with CM has more-severe impact on socioeconomic functioning and quality of life than does episodic migraine (EM) [2, 3, 4]. About 25% patients with CM report a very severe headache- related disability, as defined by the Migraine Disability Assessment Scale (MIDAS) to compare with 3% of patients with EM [2]. The proportion of patients with CM who report reduced household productivity, missed family activities and missed household work is two to three times higher than that of EM patients [4]. The annual per-person costs of CM—consisting of direct costs caused by health care utilization and treatment expenses (∼30%) and indirect costs attributable to absenteeism from work and loss of productivity (∼70%)—are about fourfold higher than those concerning with EM [5, 6].
Acknowledgment the severe effect of CM on socioeconomic functioning and quality of life, effective treatment of this disorder and preventing progression from episodic to CM—are one of most important problems in management of headache disorders.
The current definition of CM as outlined in the International Classification of Headache Disorders, 3rd edition (ICHD-3) [1] is relatively new. This definition has been tested multiple times and has gone through multiple revisions.
Although migraine as a distinct condition of headache with other accompanying symptoms has been known for thousands of years from the early writings of Aretaeus of Cappadocia in 30–90 A.D. [7]. The first formal modern definition of migraine was outlined in 1962 [8]. This first definition did not contain operational rules for migraine diagnosis and in 1988 the IHS published operational diagnostic criteria entitled the International Classification of Headache Disorders (ICHD-1) [9]. Criticism has been raised by experts that the ICHD-1 was not comprehensive enough to introduce diagnostic criteria for chronic headaches [10].
It was recognized in the 1980s that a chronic frequent headache patient population had a history of migraine [11, 12]. The daily and near daily headache patients were classified with multiple diagnoses but likely represented a single pathophysiological entity of migraine transformation with increased frequency. Recognizing this drawback, the Silberstein—Lipton criteria 1994, 1996 were proposed [13, 14]. They stipulated that chronic daily headaches defined as headaches on 15 or more days a month for at least 1 month, there was a subcategory of transformed migraine (TM) [6].
The term chronic migraine the first time in the literature was used by Manzoni et al. [15]. The results of a population study of chronic daily headache patients in Italy showed that 72% had fulfilled an IHS diagnosis of migraine [15]. For the first time CM appeared in the International Classification of Headache Disorders, 2nd edition (ICHD-2), 2004 [16]. There the CM category was defined as a complication of migraine, in patients having migraine without aura on at least 15 days per month, for at least 3 months, before the diagnosis was established. In the comments were stated that chronicity may be regarded as complication of EM and if medication overuse is present this is the most likely cause of chronic symptoms and it was suggested to code probable CM and probable medication- overuse headache (MOH). The requirement of having 15 migraine days per month was likely too stringent [17] and in a field trial of the ICHD-2 criteria [18] only 5.6% could be classified with CM, and only 10% could be classified to probable migraine with probable MOH.
Further, as it was recognized in prior studies, in the process of migraine transformation or chronification, the migraine features of some of the headaches may be lost [11, 12, 13, 14].
Recognizing the drawbacks, in an appendix to ICHD-2R the CM definition was specified by requiring only 8 days per month to meet the definition of migraine or be responsive to migraine specific medications. This criterion is still present in the ICHD-3 [1].
ICHD-3 criteria of CM include a mixture of migraine and tension-type-like headaches and do not account for patients with high-frequency migraine attacks in the absence of other types of headaches [19].
Patients with migraine on eight or more days but not 15 days with headache a month are as disabled as patients with ICHD-3 defined CM [19]. Following this data a criticism regarding the existing CM criteria was raised and suggestion to revise the CM criteria was iniciated [19].
The prevalence of CM worlwide ranges is reported to be between 0.9–5% [20], in a general population, and about 8% among patients with migraine [2, 21, 22, 23, 24]. However, the true prevalence of CM is difficult to estimate because of heterogeneus data collection instruments.
CM accounts for about one-third of chronic headache (with more than 180 days per year) in general population [23]. This headache disorder is almost three times more common in women than in men with prevalence rate peaks at the ages of 18–29 years with repeating at 40–49 years [2, 22]. Most studies suggest that annually, from about 2.5% of people with EM evolves CM [25, 26], while only a limited portion with CM revert back to EM [25, 27].
The course of CM can change—spontaneous or medically induced remission is possible. About 26% of patients can experience remission within 2 years of the onset of CM [24]. Large-scale epidemiological studies have identified various factors associated with progression from episodic to CM, and also factors that promote migraine remission [27].
Most important nonmodifiable risk factors for migraine chronification are age, female sex and low educational status [2, 7, 14, 23]. Individuals with CM have increased incidence of certain somatic and psychiatric comorbidities—in comparison with people with EM [23, 25]. However, the understanding of complex factors and mechanisms leading to an increased migraine frequency and consequently to the development of CM are only in the beginning and needs further investigations.
Generally the pathophysiology of migraine is intricate and in spite of substantial progress in recognizing its mechanisms over the past several decades, it still remains not fully elucidated. Even more, so is the pathophysiology of CM. Current evidence defines migraine as a disorder of brain dysfunction with genetic background and environmental triggering [28]. To date there is limited number of scientific studies exploring the chronic form of migraine, therefore the reasons why the disease sometimes takes a turn and attacks become more frequent are not fully clarified yet. The key components proposed in the pathogenesis of migraine chronification include atypical pain processing, central sensitization, cortical hyperexcitability and neurogenic inflammation [29] (Figure 1).
Components of pathogenesis of migraine chronification. Data from Ref. [
Distinct phases of migraine are associated with different anatomical areas and driven by different processes. Prodromal symptoms that can develop prior the onset of migraine pain are believed to be a result of abnormal activity in cortical, diencephalic and/or brainstem areas. Migraine aura, experienced by approximately one third of patients, is most probably caused by cortical spreading depression (CSD)—a phenomenon defined as a slowly propagating depolarization wave followed by a prolonged period of inhibition of cortical activity [28, 30]. Going further, the pivotal process of the headache phase is activation of the trigeminovascular system. As the brain itself has been known to be rather insensate, the intracranial nociceptive impulses are generated in pain-sensitive structures like pial, arachnoid and dural blood vessels, venous sinuses as well as large cerebral arteries, all of which are innervated by nociceptive nerve fibers originating in the trigeminal ganglion. Activation of these structures by various stimuli is responsible for generation of migrainous pain and its associated features [31, 32, 33]. Extracranial afferent nociceptive innervation is largely received through the divisions of trigeminal nerve, mainly the ophthalmic, as well as the upper cervical dorsal root ganglia [34]. The intracranial and extracranial neural afferents enter caudal medulla via trigeminal tract and terminate in the spinal trigeminal nucleus caudalis and upper cervical spinal cord (C1-C3)—the trigeminocervical complex (TCC) [35, 36]. Next, the nociceptive information travels further via ascending pathways to the diencephalon and cortical areas, including insula and cingulate cortex. [28] The role of the limbic system is also significant: central pain processing and further relaying of sensory information depend largely on the thalamus [28, 37]; moreover, the amygdala and hippocampus participate in affective and cognitive perception of pain [38, 39]—features contributing to migraine notoriety as a disabling and burden-causing disease with strong emotional implications.
Under normal physiological circumstances activation of the nociceptive system is counterbalanced by pain modulation. It is known that in migraine, descending pain-modulating pathways are dysfunctional and pain inhibition is atypical, therefore susceptibility to migraine attacks is increased [40, 41]. Modulation system originates in the cerebral cortex and is carried out via cortico-trigeminal pathways with participation of brain structures, such as hypothalamus, locus coeruleus, nucleus raphe magnus and rostral ventromedial medulla. A core structure controlling pain and providing endogenous analgaesia is the periaqueductal gray matter (PAG) [42, 43]. Due to repetitive migraine attacks and prolonged exposure to pain, PAG and other structures, comprising the descending pain-modulating network, are excessively activated, which results in oxidative stress and subsequent dysfunction. Thereby adequate pain modulation is not ensured and susceptibility to generation of migraine attacks increases [42, 43, 44].
Some authors propose that migraine chronification can be seen as a threshold problem [45]. Pain threshold exists in order to protect from situations where daily non-noxious stimuli could induce pain, therefore it takes a stimulus of certain potency to actually be perceived as painful. Pain threshold is inconstant and shifts depending on cyclic changes that are thought to originate in the limbic system [46]. Those changes allow threshold fluctuations making individuals periodically more susceptible to migraine attacks. During the interictal period threshold is normal, but when it decreases sufficiently, certain events, like stress or changes in hormonal or sleep rhythm, can provoke a migraine attack [47, 48]. Frequent attacks are among the major risk factors of migraine chronification, as they shorten the interictal period thus preventing restoration of the pain threshold to normal level [27, 49]. Consequently the sensory threshold stays below-baseline for most of the time and susceptibility to migraine attacks increases. Likewise, the most common risk factors, as obesity, physical inactivity, psychiatric illnesses and stress, might affect the threshold and make individuals more prone to migraine episodes [45].
Further alteration of pain threshold and increased sensitivity to attack-inducing triggers can be influenced by central sensitization [45]. Cutaneous allodynia, which represents central sensitization, is significantly more prevalent in chronic migraine patients than those with episodic one, suggesting that frequent attacks and higher pain intensity contribute to the development of central sensitization [50, 51]. This also explains why ineffective attack management is a risk factor for chronification: if migraine attacks are not treated completely, it results in a longer and more intense state of pain, leading to pronounced central sensitization, lowered pain threshold and increased susceptibility to migraine transformation [50, 52]. Overuse of acute pain medications is another risk factor for migraine progression, as it has been shown to promote central sensitization and susceptibility to CSD [27, 53].
There has been increasing evidence on altered cortical excitability in migraine [54]. Studies with transcranial magnetic stimulation have demonstrated reduced visual suppression in CM patients compared with EM patients and healthy controls, which proves the presence of cortical hyperexcitability [42]. In addition, assessment of visual evoked potentials shows that interictal excitability of the visual cortex is persistent and matches that of a migraine attack thus creates a “never-ending” migraine [55]. The underlying mechanisms of cortical hyperexcitability have not been uncovered yet, but evidence suggests that it may be induced by dysfunction of the pain modulatory pathways [55].
Another contributor to the pathophysiology of CM is neurogenic inflammation [29, 56]. Upon nociceptive stimulation by chemical, mechanical or electrical stimuli, a number of vasoactive substances are released from the axon terminals, causing vasodilation of the blood vessels and further plasma extravasation, edema and mastocyte degranulation. This so-called “sterile inflammation” results in sensitization and activation of the trigeminal meningeal receptors [28, 56], promoting the induction of migrainous pain [56]. Among the best-studdied vasoactive substances are calcitonine gene-related peptide (CGRP), substance P, neurokinin A, serotonin (5-HT) and pituitary adenylate cyclase-activating peptide (PACAP). CGRP is one of the most significant central pronociceptive agents expressed in the trigeminovascular system and associated with pain processing and migraine symptoms. It takes part in the development of peripheral and central sensitization and enhanced abnormal pain perception [28]. Vasoactive intestinal peptide (VIP) is another important parasympathetic neurotransmitter with a headache-eliciting effect [57, 58]. These pro-inflammatory vasoactive substances have been in the spotlight of research for years with regard to their potential role as biomarkers for chronic migraine. The levels of CGRP and VIP have been measured and compared during the interictal state of episodic and chronic migraine, showing an increase of either in the latter [59]. This provides additional evidence on altered interictal activity of the trigeminovascular system in chronic migraineurs. Moreover, the role of other substances, such as leptin, adipoleptin, TNF-α and glutamate, in the processes related with persistence and progression of migraine, has been demonstrated. This provides reasonable hopes on future implementation of biomarkers for migraine chronification [57, 58, 60].
In terms of anatomic changes in migraine, white matter lesions are considered to be more common in migraineurs than in general population. Moreover, increase in lesions correlates with attack frequency [61]. Recent neuroimaging studies revealed some other neuroanatomical differences correlating with headache frequency that could even be considered indirect markers of migraine chronification: it showed that migraineurs with more frequent attacks had thicker somatosensory cortex, anterior cingulate cortex and inferior temporal gyrus, compared with those with low-frequency attacks [62]. Also correlation with thickness of left middle frontal gyrus and left central sulcus was noted. Moreover, patients with CM had volumetric changes in amygdala, hippocampus, putamen and brainstem areas [63]. These data once again prove the role of these cerebral structures in the pathogenesis of chronic migraine [64].
Genetic influence on the progression from episodic to CM is yet to be established as more large-sample studies are needed [64, 65]. However it looks that chronic migrain has a polygenetic background. Data suggest the role of certain gene groups linked to migraine and pain progression, addiction and medication overuse, hyperexcitability and oxidative stress in migraine chronification [66]. Furthermore, it is becoming clear that epigenetics is also related to migraine as to many other multifactorial diseases. Although to date there are no specific genetic studies in chronic migraine patients, there is some evidence that neuronal activity occuring during CSD may cause epigenetic changes involved in neuronal plasticity, neuroprotection and regulation of basal synaptic activity [67, 68].
Not all patients with EM progress into chronic form [69]. The American Migraine Prevalence and Prevention (AMPP) Study [70], the International Burden of Migraine Study (IBMS) [3] and the others have explored at the prevalence of different features in episodic and CM. Some of them have been found to be more prevalent in the chronic form of migraine, suggesting that these features should be seen as risk factors associated with migraine conversion that may serve as prognostic markers enabling prediction of possible migraine progression from episodic to chronic form. Knowing these factors can assist in identifying patients at risk of transformation and take appropriate measures to prevent it (Table 1).
Female sex Caucasian race Increasing age Lower level of education Lower economic status Being unmarried Unemployment | Acute medication overuse Insufficient treatment |
Psychiatric disorders Depression Anxiety Bipolar disorder Personality disorders and traits Obsessive-compulsive Avoidant Dependent Passive-aggressive Concomitant chronic pain disorders Fibromyalgia Back and neck pain Painful neuropathy Cardiovascular disorders Arterial hypertension Hypercholesterolemia Asthma Stress related with major life changes Divorce Change of employment status Grief | |
High caffeine consumption Obesity Sleep disorders Sleep apnea Snoring Sleep deprivation Excessive sleeping | |
Frequent attacks Cutaneous allodynia |
The risk factors can be divided into non-modifiable and modifiable. Some of them carry more weight in predisposing CM than the others do. The most significant risk factors are overuse of acute medication [27], ineffective acute treatment [51], obesity [71], depression [72] and stressful life events [27]. The risk factors are listed in Table 1.
Studies show that higher prevalence of CM is related to some non-modifiable demographic characteristics, such as female sex [73, 74] and Caucasian race [75]. Regarding age, CM tends to be increasingly more prevalent from 18 to 50 years in both sexes [2]. In terms of the modifiable risk factors, there is evidence for correlation between lower level of education and CM, but data are inconsistent [3, 24, 25, 75]. In addition, some studies propose lower economic status [76], being unmarried [25] and unemployed [3, 25] as risk factors for chronic migraine.
Some modifiable lifestyle features have also been listed as risk factors of CM. First, high caffeine intake is connected with migraine transformation, especially when excessive consumption has started before the onset of chronic daily headache [77]. Second, obesity, especially in women, is more prevalent in chronic than in EM thus it can be considered a risk factor for migraine chronification [71]. In fact, similar relation also exists between increased body weight and other headache disorders like MOH and benign intracranial hypertension [78, 79]. The mechanisms linking obesity and frequent headaches are not known yet, but it may be related to hyperleptinemia [80, 81, 82]. Next, sleep disorders, including sleep apnea, snoring, disturbed sleep and oversleeping, have been found to elevate the risk for developing CM [83, 84]. Therefore it is obvious that patient education and counseling on lifestyle is extremely important, as reducing caffeine intake, normalizing body weight and sleeping patterns early enough may help to prevent migraine progression.
Another tendency is that patients with CM report various comorbidities more commonly than those with CM. According to the CaMEO study, patients with the most comorbidities were 5 times more likely to progress to CM than those with the fewest [84, 85]. Psychiatric comorbidities, especially anxiety and severe or moderate depression, are particularly prevalent in CM patients [72, 84, 86] as are some personality traits and disorders, in particular obsessive-compulsive, dependent, avoidant and passive-aggressive [87]. Chronic pain conditions, including fibromyalgia, chronic back and neck pain, are also a strong prognostic factor for migraine progression from episodic to chronic state as they are much more commonly reported by chronic migraineurs [88]. Other comorbidities such as cardiovascular disorders, asthma and allergies [25] are also considered risk factors for migraine progression. Moreover, various major life changes, like divorce, change of employment status or being recently widowed also play a role in migraine conversion, partially by accompaniment of anxiety and depression [27]. Therefore it is critically important to adequately treat these comorbidities in order to prevent migraine chronification, impaired quality of life and development of disability.
In addition to what has been set out before, some headache features have been established as risk factors too. One of the majors is headache frequency [27, 69]. Scher et al. has shown that the risk for chronification increases with the increase of headache frequency in a non-linear fashion. A minimum of three attacks per month is enough to elevate the risk for new-onset chronic headache [27]. This is based on the fact that prolonged exposure to pain induces central sensitization and decreases the attack threshold. Hence this once again emphasizes the importance of rapid and adequate treatment of migraine attacks to prevent pathophysiological alterations leading to migraine chronification.
Another specific clinical feature of migraine attack is cutaneous allodynia, which affects approximately 63% of migraineurs [89]. According to Burstein et al. and Louter et al. it is not only a clinical marker of central sensitization but can also be considered an independent predictor of migraine chronification [50, 52]. From therapeutic point of view, triptans should be administered to terminate a migraine attack within 30 minutes for subjects with cutaneous allodynia in order to minimize exposure to pathological processes leading to migraine chronification [90].
Aditionally some treatment-related factors are proven to play a role in the pathogenesis of CM. The Akershus study [91] among other data has confirmed that acute medication overuse has substantial impact to the processes leading to migraine progression. Acute medication overuse is defined as medication intake on 10–15 days per month [92]. Among the different analgesic groups opioids, barbiturates and combination drugs are associated with the highest dose-dependent risk, while triptans show moderate association with migraine progression and it is more likely in patients with higher baseline attack frequency. Interestingly, some data reports protective effect of NSAIDs against migraine progression, but only in patients with less than 10 attacks per month [79, 92]. The impact of medication overuse in migraine progression is supported by the fact, that attack frequency and disability decreases after discontinuation of acute medication, which also allows more effective preventive treatment [91].
On the other hand, the AMPP study states that ineffective or insufficient treatment can also promote chronification processes [90]. Patients using triptans are more likely to successfully abort the attacks than those using NSAIDs and simple analgesics therefore they are at less risk for chronification [51].
In conclusion it is crucial that effort is made to treat migraine attacks rapidly and adequately as well as to modify other risk factors relevant to the patient so that the pathophysiological mechanisms responsible for migraine progression from episodic into chronic form could be precluded [45, 64].
Although the most obvious difference between episodic and CM seems to be the frequency of attacks, clinical migraine features may change too as the disease progresses from less frequent to chronic form. Usually over time the pain becomes more “featureless”, thus resembling tension-type headache for most of the time with some more prominent migraine-like attacks interjected [69].
Typical migraine attacks generally manifest as severe, usually unilateral headache of throbbing quality, increasing intensity with physical activity and a combination of associated features: nausea, vomiting, hypersensitivity to visual, auditory, olfactory and cutaneous stimuli. The headache can change sides during or between the attacks [64]. The pain in patients with CM is more commonly bilateral and the associated symptoms are less pronounced than in those with EM [93]. Some patients report prodromal symptoms up to 48 hours before the onset of pain, including fatigue, asthenia, impaired concentration, irritability and other that can warn against an upcoming attack. However, it can be difficult to distinguish prodromal periods in CM as the attacks are very frequent or continuous [24].
Migraine with aura affects 20–40% of all migraineurs [93] and features a selection of transient focal neurological symptoms that usually but not invariably present before the onset of pain. The most common aura type accounting for approximately 90% is visual [84], but patients can also experience sensory, brainstem or hemiplegia-related aura [69, 84, 94]. Both types of migraine, with and without aura, can progress into chronic form.
According to the newest ICHD-3 criteria (Table 2), CM should be diagnosed when headache is experienced on 15 or more days per month over more than 3 months. The headache on 8 or more days per month should meet the criteria for migraine with or without aura and/or should be relieved by specific migraine treatment [1].
A. Headache (migraine-like or tension-type-like) on ≥15 days/month for >3 months, and fulfilling criteria B and C; |
B. Occurring in a patient who has had at least five attacks fulfilling criteria B-D for 1.1 |
C. On ≥8 days/month for >3 months, fulfilling any of the following: 1. Criteria C and D for 1.1 2. Criteria B and C for 1.2 3. Believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative; |
D. Not better accounted for by another ICHD-3 diagnosis. |
Chronic migraine diagnostic criteria, ICHD-3, 2018.
Not always it is easy for the patients to remember the exact number of days of pain per month, hence keeping a headache diary can come to help. Patients should be encouraged to not only mark the days of pain, but also elaborate what the pain was like, what features it was accompanied by, was any medication required and with what outcome. This is a good and easy tool for a physician to not only accurately know the count up of the headache days, but also make a full picture of its characteristics [95, 96].
Physician making a diagnosis should obtain a detailed history, as history is where the diagnosis of migraine lies. A thorough neurological examination, including fundoscopy, should be the following step during consultation [97].
In case of presentation of typical features of CM and normal examination, no further testing is required. However vigilance is needed to suspect any possible secondary headache causes, such as infections, tumors or hydrocephalus (Table 3), when additional investigation is warranted [29]. The set of tests required depends on clinician’s judgment in each situation and may include certain blood tests, imaging of brain, cervical spine and sinuses, scanning of cranial and extracranial arteries and performing a lumbar puncture with measuring of the CSF opening pressure. The method of choice for brain imaging is usually MRI [97]. The most consistent indicators for such conditions (“red flags”) include thunderclap headache, associated focal neurological deficit or systemic features, headache of onset in patients over the age of 50 years and more [29, 97, 98, 99].
Etiology | Examples | |
---|---|---|
Cervical pain, temporomandibular joint disorders, myofascial pain | ||
Tumor, hemorrhage, brain infection, primary benign intracranial hypertension, hydrocephalus, pituitary apoplexy | ||
Post-lumbar puncture, post-epidural/spinal analgesia, spontaneous CSF leak | ||
Meningitis, encephalitis, sinusitis, abscess | ||
Medication overuse headache, medication side-effects, substance abuse or withdrawal | ||
Uremia, hepatic encephalopathy, hypoxia | ||
Trigeminal neuralgia, occipital neuralgia | ||
Somatoform disorder, psychosis, aggravation | ||
Traumatic brain injury | ||
Stroke, dissection of carotid or vertebral arteries, giant-cell arteritis, arterial hypertension, CADASIL, venous sinuses thrombosis |
After stating that the patient has a primary headache disorder, the pattern of the headache should be established. Episodic headache occurs on less than 15 days per month while chronic headache—on 15 or more days in a month. Headaches lasting up to 4 hours are considered “short” in contrast to “long” headaches that last more than 4 hours [100]. CM should be differentiated from other chronic long-duration primary headaches (Table 3).
The main feature of new daily persistent headache is a distinct and clearly remembered onset and rapid development to an unremitting state of pain over 24 hours. This distinguishes it from chronic migraine that develops slowly over the course of months or years while attacks become more and more frequent and merged together. Besides, the localization and accompanying symptoms of new daily persistent headache are usually undefined and nonspecific, thus alleviating the differential diagnosis [29, 45, 97].
Another point to remember is the importance of assessing the patient for possible acute medication overuse, as it is one of the major risk factors for migraine progression. Sometimes it may be challenging to tell if medication overuse is a cause or a consequence of CM. The ICHD-3 criteria encourage coding both CM and MOH diagnoses in case when medication overuse is confirmed [1]. The diagnoses should be reviewed and specified later after assessing the effect of medication withdrawal: the headache may revert to episodic migraine or remain chronic. The former case would suggest that medication overuse indeed was a causative factor that had led to chronification. In the latter scenario the diagnosis of medication-overuse headache should be revoked, as it would seem that the overuse had taken place simply as a result of increased attack frequency [101]. Points of the differential diagnosis are summarized in Table 4.
Headache type/causative problem | Localization | Duration | Associated and distinguishing features | Diagnostic tests |
---|---|---|---|---|
Unilateral or bilateral |
|
| ICH-3 criteria | |
Side-locked |
|
| ICH-3 criteria Indomethacin trial [12] | |
Usually bilateral, but can be unilateral |
|
| ICH-3 criteria | |
Undefined |
|
| ICH-3 criteria | |
Daily persistent headache with a distinct and clearly remembered onset, with pain becoming continuous and unremitting within 24 hours | Undefined | Undefined | Individual approach:
|
Once the diagnosis of CM has been confirmed, standard questionnaires, such as Migraine Disability Assessment (MIDAS) or Headache Impact Test-6 (HIT-6) should be used for patient assessment in order to evaluate the burden of disease and monitor the effects of prescribed treatment [95]. Episodic and treatment-responsive migraine can be diagnosed and managed in the primary care, while chronic or refractory patients should be referred to a specialist neurologist, preferably with an expertise in the field of headache disorders [95].
There are three broad approaches to treating CM [97]:
Lifestyle and trigger management.
Acute headache treatments.
Preventive treatment.
Lifestyle modification, as well as trigger reduction can, be helpful in reducing the fequency of migraine attacks and stopping or slowing down the process of migraine chronification. That includes regularity of regimen with regard to meals, hydration, sleep and stress. It could be also helpful to detect and understand the obvious triggers. It is important to know other problems that exacerbate the tendency to headaches: such as: depression, anxiety, other pain syndromes such as fibromyalgia, localized pain in head and neck structures, and conditions that create ‘metabolic’ strain such as obesity, sleep apnoea or postural orthostatic tachycardia syndrome [102, 103]. It is particularly important to recognize and manage medication overuse (including caffeine overuse), as failure to do so will render most attempts at preventive treatment ineffective [92].
In order to identify the factors mentioned above it is very important to take a detailed history of the particular patient and to evaluate the headache questionnaires and diaries, which are suggestable in many headache centers worldwide.
The natural course of CM presents a variation in headache frequency meaning that patients can fluctuate between EM and CM [97] and exacerbations of chronic pain. Acute CM treatments are necessary to treat these conditions; e.g.,
For the patients with CM often is difficult to know when to take acute treatments. The physician should discuss this question with the patient and also explain about the possibility of co-existence of MOH, which now is considered a sequela rather than a cause of migraine and can co-exist with CM [1, 92].
In order to prevent the development of MOH, it is very important to avoid using painkillers and triptans too often in the early stages of management [104]. The detailed anamnesis and analysis of patient headache questionnaire and diary will help to understand and count the” good days and bad days “or the days with clearly exacerbated headaches. For the acute headache treatment are recommended the same groups of medications as for migraine attack treatment. This includes simple analgesics, combinated analgetics, triptans if the analgetics are not effective, and neuromodulating procedures [97, 99, 105] (Reference to section on treatment of migraine attacks to be included).
Opioids are not recommended for the treatment of acute headache because of the significant risk of medication overuse and the most protracted withdrawal [106].
Triptans are migraine-specific medications that inhibit the release of CGRP by activation of presynaptic 5HT1 receptors [107, 108]. However, patients should not take triptans more than 10 days in a month to avoid developing MOH [1].
Non-invasive stimulation procedures could be used in patients who refuse to use pharmacological migraine therapy or it is contraindicated or not tolerated. That includes external trigeminal nerve stimulation [109], single transcranial magnetic stimulation [110] and transcutaneus vagal nerve stimulation [111].
Effective acute treatment of migraine attacks may help to prevent progression from EM to CM, but rather than relying on taking drugs to stop migraine attacks after they have started, the aim of treatment for CM should be the prevention of migraine attacks [20].
The goals of CM prophylactic treatment are to prevent attacks, thereby reducing headache frequency, severity and associated disability and decreasing reliance on acute treatment, which may be contributing to concurrent MOH [92, 104]. An additional goal may be to prevent progression of EM to CM in patients with high-frequency attacks [45]. The first-line treatment of CM is pharmacological [45].
Numerous orally administered drugs are used for the prophylaxis of CM, including beta-blockers, calcium-channel blockers, tricyclic antidepressants, serotonin antagonists, antihypertensives, and antidepressants [112]. The drugs that are effective for EM are not necessarily effective for CM [54], but evidence for the efficacy of oral agents in CM is generally extrapolated from studies in patients with high-frequency EM [97, 113]. Insufficient efficacy, not suitable route and dose of drug administration and/or adverse events leading to treatment discontinuation often occur with these drugs in patients with CM [114, 115].
The only currently available evidence-based prophylactic treatment options for CM are topiramate and onabotulinumtoxinA (OBT-A) which is a formulation of botulinum toxin A administered by intramuscular injection, from more than one randomized controlled trial [97, 113].
To date, OBT-A is the only treatment specifically approved for the prevention of CM in the EU and North America (class of evidence I, level of recommendation A) [116, 117, 118, 119]. In the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials [117, 118] OBT-A has been shown to be an effective and generally well tolerated treatment for the prevention of CM, and tends to be better tolerated than various oral prophylactic treatments, including topiramate [120, 121, 122, 123]. Based on the PREEMPT clinical trial protocol, OBT-A is administered to at least 31 injection sites across 7 head and neck muscles, and is currently recommended as a second-line option for patients who have not responded adequately or are intolerant of commonly prescribed oral migraine prophylaxis [124]. Treatment should be repeated every 12 weeks. This data was confirmed in recently finished Chronic migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL) study, aim to investigate the long-term safety, efficacy and tolerability of nine cycles of repetitive BoNT-A injections. The Compel Study concluded that OBT-A treatment was well tolerated over 108 weeks, and no new safety signals were identified [125].
The molecular biological mechanism of action of OBT-A is well established, whereby it inhibits fusion of intracellular vesicles with the nerve membrane [125] by cleaving synaptosomal-associated protein (SNAP-25) [126, 127]. By impairing intraneuronal vesicular fusion, OBT-A modulates neuropeptide release and downregulates receptors and ion channels important in nociception [128, 129].
So, it is thought that OBT-A blocks release of CGRP from peripheral nociceptive neurons and interferes with transient receptor potential cation (TRP) channels in the trigeminally-innervated cranio-facial-cervical region, thereby reducing neuronal hyperexcitability and peripheral and central sensitisation [54, 130]. It is hypothesized that trigeminal-targeted preventative treatments counteract the impingement of nociceptive input from highly sensitized trigeminal neurons on brainstem second-order neurons, thus preventing central sensitisation, a key pathophysiological mechanism of CM [131].
Additionally recent clinical data demonstrates that OBT-A has been shown to reduce serum CGRP concentration in patients with CM (pretreatment median, 74.1 pg/mL; 1 month post-treatment median, 51.9 pg/mL,
There is no consensus in the literature regarding the number of OBT-A cycles required for the preventive treatment of CM. Some trials suggest an increasing efficacy with regular cycle repetition for more than 1 year, including in patients with MOH (three class II trials, level B recommendation) [133, 134, 135]. To date, no clinical features predicting responses to OBT-A (recommendation level B) have been identified [136, 137].
The adverse effects of this treatment are rare, transient and mild. The most frequently reported were neck and shoulder muscle weakness, post-application headache, palpebral pseudoptosis and other facial mimics asymmetries, in addition to pain at injection sites (class of evidence I) [117, 118, 119, 137, 138, 139].
Although not specifically licensed for CM, orally administered anticonvulsant topiramate is an effective prophylactic treatment for patients with migraine, and may be effective in patients with CM [140]. Topiramate reduced headache days versus placebo and was relatively well tolerated in patients with CM in two large randomized controlled trials [141, 142]. The initial dosage should be started slowly with 2 × 12.5 mg or 2 × 25 mg and a dose of 2 × 50 mg (if necessary up to 2 × 100 mg) per day as final target dose. Adverse events commonly associated with topiramate include paresthesia, memory and concentration disturbances, fatigue, nausea, and weight loss [143, 144].
It is thought that topiramate has dual effects on neurotransmission—enhancing inhibitory effects while minimizing excitatory effects, both of which are implicated in migraine physiology [145]. The pharmacologic mechanisms underlying this antimigraine activity may include blockade of cell membrane ion channels and neurotransmitter release (e.g., inhibition of glutamate), resulting in inhibition of neuronal hyperexcitability. Studies have demonstrated topiramate’s inhibitory effect on excitability in motor and visual cortices [54, 144, 145]. Based on this broad mechanism of action, topiramate may prevent the development of cortical spreading depression by reducing nociceptive transmission and generally inhibiting neuronal hyperexcitability [146]. Similarly, topiramate has demonstrated cognitive adverse events, which are likely a reflection of the central inhibitory effects [54]. Pooled analyses of clinical trial results suggest that preventive topiramate treatment in patients with episodic migraine may reduce the risk of headache-day increase, which in some cases may prevent migraine chronification [147].
Deeper understanding the importance of CGRP and its receptor role in CM pathophysiology and need for more effective, better tolerated prophylactic therapies for CM or high-frequency EM gave background for the development of the new class drugs—anti-CGRP/R monoclonal antibodies (mAbs).
Four anti-CGRP/R antibodies are approved in the US and Europe for the prophylactic treatment of CM: erenumab (Aimovig) [148, 149], which targets the CGRP receptor, fremanezumab (Ajovy) [150, 151] and galcanezumab (Emgality) [152, 153] which target the CGRP ligand; and fourth anti-CGRP/R antibody against the CGRP ligand, eptinezumab (VYEPTI
Drug | Manufacturer | Target | Dose of administration | Route of administration | Dosing |
---|---|---|---|---|---|
Erenumab (Aimovig) | Amgen and Novartis Pharmaceu-ticals | CGRP receptor | 70 mg | Once monthly | Autoinjector 70 mg/mL |
140 mg | Some patients may need 140 mg SC once monthly | Autoinjector 140 mg/mL | |||
Fremanezumab (Ajovy) | Teva | CGRP ligand | 225 mg | Once monthly | Syringe or autoinjector 225 mg/1.5 mL |
675 mg | Every 3 months (q) | ||||
Galcanezumab (Emgality | Eli Lilly and Company | CGRP ligand | 240 mg(2 consecutive 120 mg SC injections) loading dose once, maintainance dose 120 mg monthly | Once monthly | Single-dose prefilled pen 120 mg/mL and single-dose prefilled syringe 100 mg/mL and 120 mg/mL |
Eptinezumab (VYEPTI | Alder Biopharma-ceuticals and Lundbeck Seattle BioPharma-ceuticals Inc. | CGRP ligand | 100 mg IV every 3 months (q) | Every 3 months (q) | Injectable solution 100 mg/ml |
300 mg IV every 3 months (q) | Some patients may benefit from a 300 mg IV dose q3 months |
Brief review of administration of CRRP/R monoclonal antibodies.
The anti-CGRP/R antibodies are highly specific for their CGRP/R target, have no ability to cross the blood brain barrier, and bypass liver metabolism so CNS-related effects and hepatotoxicity are unlikely [158]. Their long half-lives allow for dosing once a month for erenumab and galcanezumab, or and once every 3 months, for fremanezumab [159, 160, 161] and eptinezumab [162].
This very promising treatment with mABs for CM is proved in clinical trials [163].
A phase III RCT, the HALO CM, evaluated the efficacy of fremanezumab in subjects aged 18–70 years with CM with duration of treatment 3 months [160]. Patients (n = 1130) were randomized to monthly subcutaneous injections of fremanezumab 225 mg (loading dose of 675 mg), to quarterly fremanezumab 675 mg, or placebo for 3 months. Exclusion by preventive failure of ≥2 drugs. During 12-week period, there was a reduction in the average number of headache days per month in the fremanezumab 675 mg (LSMD −1.8; SE 0.3;
The Prevention of Migraine via Intravenous ALD403 Safety and Efficacy–2 (PROMISE-2) study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study with duration of treatment 12 weeks [167]. Adults with CM (n = 1072) were randomly assigned to receive IV eptinezumab 100 mg, eptinezumab 300 mg, or placebo administered on day 0 and week 12. Exclusion is by preventive failure of ≥2 drugs. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) over weeks 1–12. Treatment with eptinezumab 100 and 300 mg was associated with significant reductions in MMDs across weeks 1–12 compared with placebo (placebo −5.6, 100 mg −7.7,
Clinical question | Recommendation | Strength of the recommendation | |
---|---|---|---|
1. When should treatment with anti-CGRP monoclonal antibodies be offered to patients with migraine? | |||
In patients with CM who have failed at least two of the available medical treatments or who cannot use other preventive treatments because of comorbidities, side effects or poor compliance, we suggest the use of erenumab, fremanezumab, or galcanezumab | Experts’ opinion | ||
2. How should other preventive treatments be managed when using anti-CGRP monoclonal antibodies in patients with migraine? | |||
In patients with CM who are on treatment with any oral drug with inadequate treatment response we suggest to add erenumab, fremanezumab, or galcanezumab and to consider later withdrawal of the oral drug In patients with chronic migraine who are on treatment with OBT-A with inadequate treatment response we suggest to stop OBT-A before initiation of erenumab, fremanezumab, or galcanezumab In patients with CM who are on treatment with erenumab, fremanezumab, or galcanezumab and who may benefit from additional prevention we suggest to add oral preventive drugs | Experts’ opinion | ||
3. When should treatment with anti-CGRP monoclonal antibodies be stopped in patients with migraine? | |||
In patients with CM, we suggest to consider to stop treatment with erenumab, fremanezumab, and galcanezumab after 6–12 months of treatments | Experts’ opinion | ||
4. Should medication overuse be treated before offering treatment anti-CGRP monoclonal antibodies to patients with chronic migraine? | |||
In patients with CM and medication overuse, we suggest to use erenumab, fremanezumab, and galcanezumab before or after withdrawal of acute medications | Experts’ opinion | ||
5. In which patients anti-CGRP monoclonal antibodies are not to be used? | |||
In patients with migraine, we suggest to avoid anti-CGRP monoclonal antibodies in pregnant or nursing women, in individuals with alcohol or drug abuse, cardio and cerebrovascular diseases, and with severe mental disorders | Experts’ opinion | ||
6. Should binding and/or neutralizing antibodies be monitored? | |||
In patients with migraine on treatment with anti-CGRP monoclonal antibodies, we suggest not to test binding and/or neutralizing antibodies in daily clinical practice; we suggest to further study the possible implications of binding and/or neutralizing antibodies | Experts’ opinion |
The strategy of combining different prophylactic drugs is not supported by high-level evidence [168]. However, the so-called rational polytherapy—the association of effective drugs with different mechanisms—can be used in monotherapy-refractory patients [169]. Regarding comparative efficacy, one single-center double-blind RCT showed equivalence between OBT-A (100 units at fixed points plus 100 units at “follow the pain” points) and topiramate (maximum dose of 200 mg), with better tolerability and adherence in the OBT-A [121] while one single-center open-label study showed comparable efficacy between amitriptyline (25–50 mg/day) and OBT-A (250 U/15 sites), also with better tolerability and compliance in the group treated with OBT-A [122].
Preclinical data suggest that anti-calcitonin gene-related peptide monoclonal antibodies and OBT-A have synergistic effects within the trigeminovascular system. Of note, findings indicate that fremanezumab—an antibody targeting the calcitonin gene-related peptide—mainly prevents the activation of Aδ-fibers, whereas botulinum toxin type A prevents the activation of C-fibers [168]. There is currently only indirect preclinical evidence to support a rationale for dual therapy with anti-calcitonin gene-related peptide monoclonal antibodies and OBT-A for CM prevention [170]. Rigorous studies evaluating clinical efficacy, safety, and cost-effectiveness of dual therapy with mAbs are needed.
CM is underdiagnosed and, thus, untreated disease. Only 20% of patients who meet the criteria for CM are properly diagnosed [65].Treatment options are available for these patients, but only if the patients are properly identified [171]. Successful management of CM will help properly diagnose this disease, optimize treatment and thus reduce the global burden of it. Important components of CM management involve correct diagnosis, optimal treatment plan, patient education, treatment of MOH and comorbid conditions and monitoring of patients response to treatment plan.
It is important for all physicians who are treating the patient to understand the treatment plan, in order to monitor the patient’s response to treatment, using as well as continual assessment of the patient’s Health-Related Quality of Life (HRQOL) [95]. Preventive therapy for migraines may take up to 6–8 weeks to begin to demonstrate efficacy, and up to 6 months before full efficacy is established [172]. Support and close follow-up are essential for patients, particularly in the first 3 months of treatment [172].
Additionally, physicians should try to identify and reduce aggravating risk factors, such as triggers of migraine or other behavioral habits that may have contributed to the patient’s headaches (Section 7.1).
Thus, multimodal treatment concepts are superior to simple drug treatment in severely affected patients [95].
Box 1 contains the key components of chronic migraine management for physicians [95].
Important components of chronic migraine management*.
Complete and correct diagnosis |
Referral to headache specialist/neurologist to confirm CM diagnosis and provide a treatment plan |
Management of overuse of acute headache pain medications: providing limits to acute and rescue therapy |
Patient education about CM and importance of treatment compliance |
Explaining realistic expectations to patients |
Consideration of important exacerbating factors |
Treatment of comorbid conditions |
Nonpharmacotherapy, including trigger management and behavioral therapy |
CM, chronic migraine; HIT-6, headache impact test-6; HRQoL, health-related quality of life; MIDAS, migraine disability assessment.
*With permission: Diener et al. [95].
CM is associated with higher burden of disease, more severe psychiatric comorbidity, greater use of healthcare resources, and higher total costs than EM. The current definition of CM has gone through multiple revisions, but the discussion about it is still continuing,
The pathophysiology of CM is not fully understood. However, recent advances in electrophysiology and neuroimaging have indicated that atypical pain processing, central sensitization, cortical hyperexcitability and neurogenic inflammation are important in the development of this disorder. The most significant risk factors such as overuse of acute medication, ineffective acute treatment, obesity, depression and stressful life events have been associated with migraine progression.
Unfortunately, CM is still undertreated because of its poor treatment response and limited therapy options. The currently available evidence-based prophylactic treatment options for CM are topiramate and OBT-A. According to the results of the clinical studies the new class of drugs—anti-CGRP/R monoclonal antibodies seems to be a very promising treatment for CM. Complete and correct diagnosis, optimal treatment plan, management of acute medication overuse and exacerbating factors, patient education and monitoring of the patient’s response to treatment plan are the most important components for the successful CM management.
The next years seem to be inspiring for the field, as current research areas are being extended and novel areas are being covered, ultimately broadening our understanding of the complex syndrome of CM.
The authors declare that they have no conflict of interest related to the publication of this chapter.
CM | chronic migraine |
HIS | the International Headache Society |
EM | episodic migraine |
MIDAS | Migraine Disability Assessment |
ICHD-3 | International Classification of Headache Disorders, 3rd edition |
ICHD-1 | International Classification of Headache Disorders, 1st edition |
ICHD-2 | Classification of Headache Disorders, 2nd edition |
MOH | medication-overuse headache |
CSD | cortical spreading depression |
VIP | vasoactive intestinal peptide |
CGRP | calcitonin gene-related peptide |
HIT-6 | Headache Impact Test-6 |
5HT1 | serotonin 1a |
OBT-A | onabotulinumtoxinA |
FDA | U.S. Food & Drug Administration |
EMA | European Medicines Agency |
HRQoL | health-related quality of life |
Antimicrobial resistance is a global public health crisis. According to Public Health England [1], each year approximately 25,000 people die across Europe due to hospital-acquired infections caused by antibiotic-resistant and MDR bacteria such as
Félix d’Herelle, known as the father of bacteriophage (or phage) therapy [3], brought an evolutionary discovery of phages as therapeutics for various infections and conditions. Phage therapy was widely enforced in the 1920s and 1930s to combat the bacterial infections. However, in the 1940s, the newly discovered antibiotics replaced the phage therapy (except Russia, Georgia and Poland) [4].
The emergence of MDR bacteria prompted a renewal of the interest to the phage therapy as an alternative treatment to overcome a broad spectrum of resistant bacterial infections. Phage therapy and phage cocktails that contain a mixture of different bacteria-specific phages, drawn interest within molecular biology and modern medical research as potential antimicrobials that could tackle the crisis of antimicrobial resistance. Nonetheless, the phage therapy remains controversial due to its disadvantages such as bacteriophage resistance: bacteria-phage evolutionary arms race that could put a burden on a long-time application of phage therapy as an anti-infectious agent [5].
Phage therapy has many advantages, primary because phages are very specific (generally limited to one species) and easy to obtain as they are widely distributed in locations populated by bacterial hosts including soil and seawater, and they do not have any known chemical side effects like antimicrobials [6].
Understanding host-phage interactions and ‘the war between bacteria and phages’ are steps towards designing engineering ‘broad-spectrum phage’ that can overcome the limitations of phage therapy and potentially overcome a wide range of resistant bacterial infections [6].
Phages are obligate intracellular parasites that distinctively infect bacterial cells. Although phages are very specific to their host, generally limited to one species, they pose an enormous threat to bacteria as in some habitats they outnumber their hosts by nearly 10-fold number [7]. Phages are the most abundant, ubiquitous and diversified organisms in the biosphere [8, 9]. Phage-host interaction and fight for the survival led to the evolution of bacterial and viral genomes and, therefore, to the evolution of resistance mechanisms. Bacteria, continuously, evolve many molecular mechanisms, driven by gene expression to prevent phage infection. These evolving phage-resistance mechanisms in bacteria induce the parallel co-evolution of phage diversity and adaptability [10, 11]. The co-evolving genetic variations and counteradaptations, in bacteria and phages, drive the evolutionary phage-host arm race [11, 12].
Leigh Van Valen, an evolutionary biologist, metaphorised the co-evolutionary arm race and proposed the Red Queen hypothesis [13].
‘It takes all the running you can do, to stay in the same place’ the Red Queen says to Alice in
The Red Queen hypothesis proposes that to survive, microorganisms must constantly adapt, evolve and thrive against ever-evolving antagonistic microorganisms within the same ecological niche [14].
Bacteria have developed various anti-phage mechanisms including non-adaptive defences (non-specific) and adaptive defences associated with Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) along with CRISPR-associated (Cas) proteins [7, 15, 16, 17, 18].
The non-specific adaptations (analogues to innate immunity in multicellular organisms) act as primary mechanisms to evade viral infection, and they include mechanisms that inhibit phage adsorption and prevent nucleic acid entry, superinfection exclusion systems, restriction-modification systems and abortive infection [7, 19].
On the other hand, the adaptive resistance (analogues to the acquired immunity in multicellular organisms) serves as a second line of defence, which is very efficient and phage-specific.
Interestingly, it was observed that the bacterial anti-phage mechanisms are generally present in a genomic array, known as ‘defence islands’ [20]. The ‘defence islands’ are enriched in putative operons and contain numerous overrepresented genes encoding diverged variants of antiviral defence systems. Moreover, scientific evidence and characteristic operonic organisation of ‘defence islands’ show that many more anti-phage mechanisms are yet to be discovered [21, 22, 23, 24].
Although bacteria have developed several resistance mechanisms against phages, phages can circumvent bacterial anti-phage mechanisms on the grounds of their genomic plasticity and rapid replication rates. These counterstrategies include point mutations in specific genes and genome rearrangements that allow phages to evade bacterial antiviral systems such as CRISPR/Cas arrays by using anti-CRISPR proteins and abortive infection by hijacking bacterial antitoxins, as well as escaping from adsorption inhibition and restriction-modification mechanisms [15, 16, 17, 18].
This chapter will comment on the genetic basis of bacterial resistance to phages and different strategies used by phages to evade bacterial resistance mechanisms.
Phage adsorption to host-specific receptors on the cell surface is the initial step of the infection and host-phage interaction. Depending on the nature of bacteria, whether it is Gram-positive or Gram-negative proteins, lipopolysaccharides, teichoic acids and other cell surface structures can serve as irreversible phage-binding receptors [19]. These receptors might be present in the cell wall, bacterial capsules, slime layers, pili or flagella [25].
Bacteria have acquired various barriers to inhibit phage adsorption, such as blocking of phage receptors, production of extracellular matrix (e.g. capsule, slime layers) and production of competitive inhibitors [26, 27, 28, 29, 30, 31]. The diversity of phage receptors in the host is influenced by co-evolutionary adaptations of phages to overcome these barriers [32]. This includes diversity-generating retroelements (DGRs) and phase variation mechanisms causing phenotypical differences within the bacterial colony [7, 33, 34].
Phase variation is a heritable, yet reversible process regulating gene expression in bacteria; genes can switch between a functional (expression) and a non-functional state leading to phenotypical variations within the bacterial population even when strains have identical genotype. Sørensen et al. [35] investigated the underlying resistance mechanism of
DGRs are genetic elements diversifying DNA sequences and the proteins they encode ultimately mediating the evolution of ligand-receptor interactions. Error-prone DGRs and random mutations in the bacterial genes encoding cell surface receptors lead to the alternation and change in the structural composition of the phage receptors, making them non-complementary to the phage’s anti-receptors, known as receptor-binding proteins (RBP) [34] (Figure 1(1)).
Bacterial defence mechanisms preventing phage adsorption and phage’s counteradaptations. (1) Phage adsorption to a host-specific receptor site on a host cell surface. Bacterium evolves phage resistance by the modification of these cell surface receptors; phage is incapable of binding to the altered receptor. (2) Phage’s adaptation to these modifications through mutations in receptor-binding protein gene that leads to the co-evolution of bacterial genetic variation. Bacteria are also capable of producing proteins that mask the phage recognition site receptors (3 and 4), thus making the receptor inaccessible for phage adsorption [
Yet, phage’s replication is exceedingly error-prone, therefore causing many random mutations in the genes encoding the RBP or tail fibres. Phages also possess DGRs that mediate phage’s tropism by accelerating the variability in the receptor-coding genes through reverse transcription process [37]. The changes in the nucleotide sequence in the RBP-coding gene may ultimately lead to the adaptation to the modified receptor (Figure 1(2)), thus the ability to adsorb and infect the bacterial cell.
Unsurprisingly, bacteria also exhibit different strategies to block their receptors [28, 29, 30, 31].
Figure 1(4) demonstrates the findings from studies conducted on
Receptors located on bacterial cell surface serve a vital role in bacterial metabolism; they may function as membrane porins, adhesions or chemical receptors [19]. Therefore, mutation or complete loss of the receptor might be lethal for bacteria. To inhibit phage adsorption, bacteria can produce surface molecules, such as exopolysaccharides.
Exopolysaccharides are extracellular polysaccharides acting as a physical barrier, composing slime or capsules surrounding bacterial cells that lead to inaccessible host receptors for efficient phage adsorption [39] (Figure 2). Studies conducted by Looijesteijn et al. [40] shown that exopolysaccharides
Bacterial strategies to inhibit phage adsorption and phage strategies to access host receptors. Some bacteria are capable of the production of exopolysaccharides, which act as an outer shield, protecting a cell from the phage infection [
Nevertheless, some phages evolved mechanisms allowing them to recognise these extracellular matrixes and degrade them by utilising hydrolases and lyases (Figure 2) [15, 16, 17, 18]. The polysaccharide-degrading enzymes allow phages to gain access to the receptor that may lead to the viral propagation. They are commonly present bound to the RBPs or exist as free soluble enzymes from previously lysed bacterial cells [41].
If phage bypasses primary antiviral strategies, it is now able to initiate infection by adsorption to a specific receptor site on a host cell surface through phage RBP [42, 43]. Upon interaction with the cell receptors, the phage injects its genetic material (single or double-stranded DNA or RNA) into the cytoplasm of the host. Depending on the nature of the phage and growth conditions of the host cell, it follows one of the two life cycles: lytic or lysogenic (Figure 3).
Lytic and lysogenic life cycles of a temperate coliphage λ that infects
In the lytic cycle, virulent phages degrade host’s genome leading to the biosynthesis of viral proteins and nucleic acids for the assembly of phage progeny. Eventually, the bacterial cell lysis, releasing a multitude of newly assembled phages, is ready to infect a new host cell [46].
In contrast, temperate phages might enter the lytic or lysogenic cycle, if the host cell exists in adverse environmental conditions that could potentially limit the number of produced progeny (Figure 3 demonstrates typical lifecycle of temperate phage using coliphage λ as an example) [44, 45]. In the lysogenic phase, repressed phage genome integrates into the bacterial chromosome as a prophage. This process causes the proliferation of prophage during replication and binary fission of bacterial DNA.
Prophage only expresses a repressor protein-coding gene. The repressor protein binds to the operator sites of the other genes and ultimately inhibits synthesis of phage enzymes and proteins required for the lytic cycle.
When the synthesis of the repressor protein stops or if it becomes inactivated, a prophage may excise from the bacterial chromosome, initiating a lytic cycle (induction) which leads to the multiplication and release of virulent phages and lysis of a host cell [44, 45].
If the phage remains in the nearly dormant state (prophage), the lysogenic bacterium is immune to subsequent infection by other phages that are the same or closely analogous to the integrated prophage by means of Superinfection exclusion (Sie) systems [47].
Sie systems are membrane-associated proteins, generally, phage or prophage encoded, that prevent phage genome entry into a host cell [47]. Figure 4 shows the role of Sie system (proteins Imm and Sp) in blocking phage T4 DNA entry into Gram-negative
Superinfection exclusion systems preventing phage DNA entry in Gram-negative
The evolution of bacterial genomes allowed bacteria to acquire vast mechanisms interfering with every step of phage infection. In a case where a phage succeeded to inject its viral nucleic acid into a host cell, bacteria possess a variety of nucleic acid degrading systems such as restriction-modification (R-M) systems and CRISPR/Cas that protect bacteria from the phage invasion.
It has been reported that R-M systems can significantly contribute to bacterial resistance to phages [49].
R-M systems incorporate activities of methyltransferases (MTases) that catalyse the transfer of a methyl group to DNA to protect self-genome from a restriction endonuclease (REase) cleavage and REases, which recognise and cut foreign unmethylated double-stranded DNA at specific recognition sites, commonly palindromic. To protect self-DNA from the degradation, methylases tag sequences recognised by the endonucleases with the methyl groups, whereas unmethylated phage (nonself) DNA is cleaved and degraded (Figure 5) [26, 27, 50, 51, 52].
General representation of the bacterial restriction-modification (R-M) systems providing a defence against invading phage genomes. R-M systems consist of two contrasting enzymatic activities: a restriction endonuclease (REase) and a methyltransferase. REase recognises and cuts nonself unmethylated double-stranded DNA at specific recognition sites, whereas MTase adds methyl groups to the same genomic recognition sites on the bacterial DNA to protect self-genome from REase cleavage [
R-M systems are diverse and ubiquitous among bacteria. There are four known types of R-M within bacterial genomes (Figure 6). Their classification is mainly based on R-M system subunit composition, sequence recognition, cleavage position, cofactor requirements and substrate specificity [26, 27, 50, 51].
Four distinct types of restriction-modification (R-M) systems. (a) Type I R-M system is composed of three subunits forming a complex: hsdR (restriction), hsdM (modification) and hsdS (specificity subunit that binds to an asymmetrical DNA sequence and determines the specificity of restriction and methylation). Two hsdM subunits and one hsdS subunit are involved in methylation of self-DNA. On the other hand, two complexes of hsdR, hsdM and hsdS (where each complex consists of two hsdR, two hsdM and one hsdS subunit) bind to the unmethylated recognition sites on phage DNA and cleave the DNA at random, far from their recognition sequences. Both reactions—methylation and cleavage—require ATP. (b) Type II R-M system is composed of two distinct enzymes: palindromic sequence methylating methyltransferase (mod) and endonuclease (res) that cleave unmethylated palindromic sequences close to or within the recognition sequence. (c) Type III R-M system is formed of methyltransferase (mod) and endonuclease (res) that form a complex. Methyltransferase transfers methyl group to one strand on the DNA, whereas two methyltransferases (endonuclease complexes) act together to bind to the complementary unmethylated recognition sites to cleave the DNA 24–26 bp away from the recognition site. (d) Type IV R-M system contains only endonuclease (res) that recognises methylated or modified DNA. Cleavage occurs within or away from the recognition sequences [
Due to the diversity of R-M systems, phages acquired several active and passive strategies to bypass cleavage by REases. Passive mechanisms include reduction in restriction sites, modification and change of the orientation of restriction sites, whereas more specific, active mechanisms include masking of restriction sites, stimulation of MTase activity on phage genome or degradation of an R-M system cofactor (Figure 7) [15, 16, 17, 18].
Phage’s passive and active strategies to bypass restriction-modification (R-M) systems. (a) Phages that possess fewer restriction sites in their genome are less prone to DNA cleavage by the host restriction endonuclease (REase). (b) Occasionally phage DNA might be modified by bacterial methyltransferase (MTase) upon successful injection into a host cell. Methylated recognition sites on viral DNA are, therefore, being protected from the cleavage and degradation by REase, leading to the initiation of the phage’s lytic cycle. In addition, some phages encode their own MTase that is cooperative with the host REase; thus viral DNA cannot be recognised as nonself. (c) Some phages, for example, coliphage P1, while injecting its DNA into a host cell, it also co-injects host-genome-binding proteins (DarA and DarB) that mask R-M recognition sites. (d) Phages such as Coliphage T7 possess proteins that can mimic the DNA backbone. Ocr, a protein expressed by Coliphage T7, mimics the DNA phosphate backbone and has a high affinity for the EcoKI REase component, thereby interfering with R-M system. (e) In addition, some phages (e.g. Ral protein of Coliphage λ) can also stimulate activity of the bacterial modification enzyme in order to protect own DNA from the recognition by the bacterial REase as nonself. The peptide Stp encoded by Coliphage T4 can as well disrupt the structural conformation of the REase-MTase complex [
Fewer restriction sites in the evading genome lead to the selective advantage of this phage as its DNA is less prone to cleavage and degradation by the host REase (Figure 7a). Also, some phages incorporate modified bases in their genomes that may lead to successful infection of the host cell as REase may not recognise the new sequences in the restriction sites. A decrease in the effective number of palindromic sites in DNA or change in the orientation of restriction-recognition sites can affect R-M targeting. Alternatively, the recognition sites within the viral genome can be too distant from each other to be recognised and cleaved by the REase [15, 16, 17, 18, 53].
Interestingly, phage genome might be methylated by bacterial MTase upon successful injection into a host cell. Methylated recognition sites on viral genomes are therefore being protected from the cleavage and degradation by REase, leading to the initiation of the phage’s lytic cycle. Viral progeny remains insensitive to this specific bacterial REase until it infects a bacterium that possesses a different type of REase, in which case the new progeny will become unmethylated again and will, therefore, be sensitive to the R-M system of the cognate bacterium [28, 29, 30, 31].
The fate of the host cell chiefly confides in the levels of R-M gene expression and ultimate proportion of the R-M enzymes and their competition for the sites in the invading phage genome [52].
Furthermore, some phages encode their own MTase that is cooperative with the host REase, and thereby viral DNA cannot be recognised as nonself. Phages can also stimulate the activity of host modification enzymes that can rapidly methylate viral DNA, thus protecting it from the activity of REase.
Alternatively, phages can bypass R-M systems by masking restriction sites. For example (Figure 7c), coliphage P1, while injecting its DNA into a host cell, it also co-injects host-genome-binding proteins (DarA and DarB) that mask R-M recognition sites [53, 54].
As shown on an example of a Coliphage T7 (Figure 7d), some phages code for proteins that directly inhibit REase. Coliphage T7 possesses proteins that can mimic the DNA backbone. Ocr, a protein expressed by Coliphage T7, directly blocks the active site of some REases by mimicking 24 bp of bent B-form DNA, and it has a high affinity for the EcoKI REase component, thereby interfering with R-M system [53].
Lastly, phage-bacteria arm race allowed phages to gain capabilities of degrading necessary cofactors of R-M systems. For instance, coliphage T3 encodes S-adenosyl-l-methionine hydrolase that destroys an essential host R-M cofactor (the S-adenosyl-l-methionine). The removal of this necessary co-factor will lead to the inhibition of the REase, thereby successfully infecting the host cell [15, 16, 17, 18].
CRISPR along with CRISPR-associated (Cas) proteins is the type of adaptive heritable ‘immunity’ of bacteria, thus very specific and effective; and it is prevalent within the bacterial domain [55]. The CRISPR are DNA loci consisting of short palindromic repeats (identical in length and sequence), interspaced by segments of DNA sequences (spacer DNA) derived from previous exposures to phages. The spacer DNA sequences act as a ‘memory’, allowing bacteria to recognise and destroy specific phages in a subsequent infection. Genes encoding Cas proteins are adjacent to CRISPR loci [56].
Although some studies have suggested that CRISPRs can be used for pathogen subtyping [57], it has been found that CRISPR typing is not useful for the epidemiological surveillance and outbreak investigation of
The CRISPR/Cas phage resistance is mediated in three-step stages: adaptation (acquisition), where spacer phage-derived DNA sequences are incorporated into the CRISPR/Cas system; expression, where
CRISPR/Cas systems have been classified into three major types: Types I, II and III, which are further divided into subtypes that require different types of Cas proteins. Although the CRISPR/Cas array is diverse among the bacteria and it is continuously co-evolving in response to the host-phage interactions, the defence activity in all three types of the CRISPR is comparable [21, 22, 23] Figure 8 illustrates the defence mechanisms in three distinct CRISPR/Cas arrays.
Image showing mechanisms of adaptation, expression and interference in three different types of CRISPR/Cas arrays. Type I and Type II CRISPR/Cas arrays rely on the protospacer adjacent motif (PAM), contained within phage nucleic acid, to ‘select’ the phage-derived protospacer. Next steps in the adaptation stage are similar in all three types; protospacer is incorporated by Cas 1 and Cas2 proteins into the bacterial genome at the leader end of the CRISPR loci to form a new spacer. In expression step, CRISPR loci are transcribed into pre-crRNA. The crRNA processing and interference stage is distinct in each type of the CRISPR/Cas system. In Type I, the multisubunit CRISPR-associated complex for antiviral defence (CASCADE) binds crRNA to locate the target, and with the presence of Cas3 protein, the invading target genome is degraded whereas in Type II, Cas9 protein is essential in the processing of the crRNA. TracrRNA recognises and attaches to the complementary sequences on the repeat region that is then cut by RNase III in the presence of Cas9. Lastly, in Type III, processing of pre-crRNA into crRNA is dependent upon the activity of Cas6. Mature crRNA associated with Csm/Cmr complex targets foreign DNA or RNA for the degradation [
The Type II, CRISPR/Cas9, which was first identified in
In the adaptation stage, phage-derived protospacer (snippet of DNA from the invading phage) is incorporated into the bacterial genome at the leader end of the CRISPR loci. In expression phase, the
To bypass CRISPR/Cas that has an incredibly dynamic rate of evolution, phages acquired array of strategies to succeed in propagation; this includes mutations in the protospacers or in the PAM sequences and expression of anti-CRISPR proteins, and even some phages encode their own functional CRISPR/Cas systems [15, 16, 17, 18, 63].
Phages can evade interference step of Type I and Type II CRISPR/Cas system by a single point mutation or deletion in their protospacer region or in the PAM sequence (Figure 9). Phages with single-nucleotide substitutions or deletions positioned close to PAM sequence can bypass the CRISPR/Cas activity and complete their lytic cycles; in contrast, phages with multiple mutations at PAM-distal protospacer positions do not [15, 16, 17, 18, 28, 29, 30, 31].
Evasion by mutation. Mutations in the phage protospacers or in the PAM sequences allow the phage to escape interference step of the CRISPR/Cas system that would lead to the degradation of the phage genome [
In some circumstances, however, although the phage successfully evades CRISPR/Cas interference, the host cell may survive by the acquisition of new spacer sequences (derived from invading phage) into their own CRISPR/Cas system. This new spacer provides the bacterium with an accelerated spectrum of phage resistance [15, 16, 17, 18].
Prophages integrated within
Anti-CRISPR proteins expressed against CRISPR subtype I-F systems. Temperate phages such as
Prophages do not only contribute to bacterial resistance to invading phages, they can also encode proteins that contribute to bacterial virulence and antimicrobial resistance [58, 66].
Bacteria can also resist phages by possessing phage-inducible chromosomal islands (PICI) which prevent phage replication. Nevertheless, phages evolved their genomes to overcome this very specific antiviral strategy. For example,
Phage-encoded CRISPR/Cas systems in
Abortive infection (Abi) systems promote cell death of the phage-infected bacteria, inhibiting phage replication and providing protection for bacterial populations [68].
Abi systems require both toxins and antagonistic antitoxins. Antitoxins are proteins or RNAs that protect bacterial cell from the activity of toxins in a typical cell life cycle, whereas toxins are the proteins encoded in toxin-antitoxin locus that disrupt cellular metabolism (translation, replication and cell wall formation), causing cell death. During an infection, the expression of the antitoxin encoding gene is suppressed, leading to the lethal activation of the toxin [69]. Figure 12 illustrates the mechanism of Abi systems in
Abortive infection (Abi) systems in
Interestingly, phages evolved an array of tactics to circumvent Abi systems. This includes mutations in specific phage genes and encoding own antitoxin molecules that suppresses bacterial toxin [15, 16, 17, 18]. Figure 13 provides a broad overview of the strategies employed by the phages to by-pass Abi systems.
Escaping abortive infection mechanisms. (a) In a typical cell life cycle, antitoxins protect bacterial cell from the activity of toxins. (b) During phage infection, the expression of antitoxin encoding gene is suppressed, leading to the lethal activation of the toxin. (c) Mutations in certain phage genes can lead to escaping Abi systems activity, thereby a successful viral propagation without killing the host cell. (d) Some phages encode molecules that functionally replace the bacterial antitoxins, thus suppressing toxin activity and avoiding host cell death [
Bacteria-phage interaction is therefore very complex, and it is crucial to understand the molecular basis of this interaction and how bacteria and phages ‘fight’ each other. It has been reported that Anderson Phage Typing System of
The rapid emergence and dissemination of MDR bacteria seriously threaten global public health, as, without effective antibiotics, prevention and treatment of both community- and hospital-acquired infections may become unsuccessful and lead to widespread outbreaks.
Carbapenems and colistin are antibiotics of last resort, generally reserved to treat bacteria which are resistant to all other antibiotics. Until not long ago, colistin resistance was only described as chromosomal, however, in 2016 Liu et al. reported the emergence of the first plasmid-mediated colistin resistance mechanism, MCR-1, in Enterobacteriaceae [72]. Furthermore, the increasing occurrence of colistin resistance among carbapenem-resistant Enterobacteriaceae has also been reported [73]. This is of significant concern as infections caused by colistin and carbapenem-resistant bacteria are very challenging to treat and control, as the treatment options are greatly limited or non-existent. Thus, the discovery and development of alternative antimicrobial therapeutics are the highest priorities of modern medicine and biotechnology.
Phages should be considered as great potential tools in MDR pathogens as they are species-specific (specificity prevents damage of normal microbiota), thus harmless to human; they have fast replication rate at the site of infection, and their short genomes can allow to further understand various molecular mechanisms implied to ‘fight’ bacteria. In addition, this understanding can enable scientists to ‘manipulate’ viral genomes and engineer a synthetic phage that combines the antibacterial characteristics of multiple phages into a single genome.
The escalating need for new antimicrobial agents attracted new attention in modern medicine, proposing several potential applications of phages as antibacterial therapeutics including phage therapy, phage lysins and genetically-engineered phages.
Phage therapy utilises strictly lytic phages that have bactericidal effect. As phages are host-specific, ‘phage cocktails’ containing multiple phages can broaden range of target cells. Nevertheless, selection of suitable phages is at the paramount to the successful elimination of clinically important pathogens, and it includes avoidance of adverse effects, such as anaphylaxis (adverse immune reaction) [74].
In order to hydrolyse and degrade the bacterial cell wall, phages possess lysins.
The spectrum of efficiency of natural lysins (derived from naturally occurring phages) is generally limited to Gram-positive bacteria; however, recombinant lysins have shown an ability to destabilise the outer membrane of Gram-negative bacteria and ultimately lead to rapid death of the target bacteria [74].
Bioengineered phages have the potential to solve inherent limitations of natural phages such as narrow host range and evolution of resistance. Various genetic engineering methods have been proposed to design phages with extended antimicrobial properties such as homologous recombination, phage recombineering of electroporated DNA, yeast-based platform, Gibson assembly and CRISPR/Cas genome editing [75].
Engineering of synthetic phages could be tailored to enhance the antibiotic activity, to reverse antibiotic resistance or to create sequence-specific antimicrobials [74].
The antagonistic host-phage relationship has led to the evolution of exceptionally disperse phage-resistance mechanisms in the bacterial domain, including inhibition of phage adsorption, prevention of nucleic acid entry, Superinfection exclusion, cutting phage nucleic acids via restriction-modification systems and CRISPR, as well as abortive infection.
Evolvement of these mechanisms has been induced by constant parallel co-evolution of phages as they attempt to coexist. To survive, phages acquired diverse counterstrategies to circumvent bacterial anti-phage mechanisms such as adaptations to new receptors, digging for receptors and masking and modification of restriction sites and point mutations in specific genes and genome rearrangements that allow phages to evade bacterial antiviral systems such as CRISPR/Cas arrays, as well as mutations in specific genes to bypass abortive infection system. Conclusively, the co-evolving genetic variations and counteradaptations, in both bacteria and phages, drive the evolutionary bacteria-host arm race.
Besides, accumulating evidence shows that phages contribute to the antimicrobial resistance through horizontal gene transfer mechanisms. Indeed, many bacterial strains have become insensitive to the conventional antibiotics, posing a growing threat to human; and although in the past, western counties withdrew phage therapy in response to the discovery of therapeutic antibiotics, now, phage therapy regains an interest within the research community. There are apparent advantages of phage therapy, such as specificity, meaning only target bacteria would encounter lysis, but not healthy microbiota inhabiting human’s system. Additionally, ‘phage cocktails’, containing multiple bacteria-specific phages, could overcome the issue of phage-resistance as phages do adapt to these resistance mechanisms. However, ‘phage cocktails’ would require large numbers of phages that would have to be grown inside pathogenic bacteria in the laboratory, putting laboratory staff and the environment at risk.
Alternatively, building up the understanding of host-phage interactions and ‘the war between bacteria and phages’ could potentially lead to defeating antimicrobial resistance by designing synthetic phages that can overcome the limitations of phage therapy.
Dr Manal Mohammed is funded by a Quinton Hogg start-up award, University of Westminster.
abortive infection capsular polysaccharides clustered regularly interspaced short palindromic repeats crispr RNA diversity-generating retroelement deoxyribonucleic acid multidrug-resistant O-methyl phosphoramidate methyltransferase protospacer adjacent motif phage-inducible chromosomal island PICI-like element receptor-binding protein restriction endonuclease restriction-modification ribonucleic acid superinfection exclusion trans-activating crRNA
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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. 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