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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"},{slug:"intechopen-identified-as-one-of-the-most-significant-contributor-to-oa-book-growth-in-doab-20210809",title:"IntechOpen Identified as One of the Most Significant Contributors to OA Book Growth in DOAB"}]},book:{item:{type:"book",id:"989",leadTitle:null,fullTitle:"Respiratory Diseases",title:"Respiratory Diseases",subtitle:null,reviewType:"peer-reviewed",abstract:"Medicine is an ever-changing science. 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Temporomandibular joint (TMJ) is susceptible to various diseases affecting other synovial joints. Due to its position it is exposed to trauma, and its functional link with the occlusal complex which makes it very sensitive to any occlusal disorders. Any force that overloads the TMJ complex can cause damage to the joint structures or disrupt the normal functional relationship between condyle, disc and articular eminence, resulting in dysfunction or pain, or both. Systemic joint disorders may also affect TMJ.
Diseases and functional disorders of the TMJ can be globally divided into several categories:
deviations in the form of articular surfaces,
disorders in the functions of the condyle-disc complex,
inflammatory diseases of the TMJ,
degenerative TMJ disorders,
ankylosis of TMJ.
This classification is based on the recommendations of the American Academy of Orofacial Pain 1993 [1].
The basic symptoms that accompany the diseases and dysfunction of TMJ are: pain, abnormal jaw movement, spasm of masticatory muscles and joint sounds produced by the joints during mandibular movements [2].
The pain that origins from any joints including the TMJ, is called arthralgia.
Arthralgia is triggered by receptors located in the soft tissue of the joint. Such receptors (nociceptors) contain discal ligaments, retrodiscal tissue and articular capsule. Arthralgia from the soft-tissue structures of the non-inflammatory joint represents a sharp, sudden and intense pain that is closely related to the joint movements. If, however, the inflammation of the soft-tissue structures of the affected joint has occurred, the pain will be constant and increase during mandibular movements. Course of pain can be acute or chronic [2].
Disturbed joint function is a common accompaniment to all joint disorders. TMJ dysfunction can occur in various forms but their major effects are the limitations and/or alterations of jaw movements. This is manifested by the feeling the stiffness of the joint, limited mouth opening with deviation or deflection of the mandible on the affected side and limited movement to the contralateral side [2, 3].
The sound signals produced by the joint are the most common consequence of the dysfunction of the condyle-disc complex, the morphological incompatibility of articular surfaces and their degenerative changes. The sound signals produced by the joint may occur as individual short-duration sounds at opening or when opening and closing the mouth, referred to as clicking (“click”) or as multiple, rough and scratched sounds, which are called as “crepitation” [2, 3].
The most common defects on the articular joint surfaces occur in the upper joint compartment and affect the articular eminence or the upper surface of the disc, thus preventing normal translatory movements.
Deviation can be followed by clear single sound—“click”, followed by normal opening or closing of the mouth. The click always occurs at the same level of opening or closing motion and should be distinguished from the reciprocal click in patients with disc displacement with reduction. In the disc displacement with reduction click is rarely heard at the same level of opening or closing the mouth [2, 4, 5].
These disorders are series of dysfunction that are most often the result of previous diseases, trauma, or occlusal disharmony. Disorders are caused by changes in the relationship between condyle and disc and the disturbance of their functional activity. In the normal joint the disc is bound to the medial and lateral condyle pole by discal ligaments. Therefore translational movement in the healthy joint is possible only between the condyle-disc complex and the articular eminence. The only physiological movement between condyle and disc is rotation. The amount of rotation of the disc in normal circumstances depends on the shape of the disc, the degree of interarticular pressure and the synergic function of the upper head of the lateral pterygoid muscle and the upper layer of the bilaminar zone [2, 10, 12, 13, 14, 15, 16].
In opening the mouth and moving the condyle-disk complex forward, the upper layer of the bilaminar zone is tensed and retracted (rotates) the disc in the posterior direction. The interarticular pressure increasing during the mouth opening maintained the condyle below the thin intermediate zone of the disc and prevented the thicker anterior disc border from being pulled between the condyle and eminence.
The upper layer of the bilaminar zone is the only structure that can pull the disc backwards. This force only works when the condyle is moved forward and it extends and tightens the upper layer of the bilaminar zone. There is no tension in the retrodiscal tissue during the closing of mouth. The disc rotates forward thanks to the function of the upper head of the lateral pterygoid muscle, when the mouth closing. This muscle part is activated and pulls the disc forward, while the condyle-disc complex slides back and up. The moderate rotation of the disc, which occurs in the normal joint under the mechanisms described, allows the disc and condyle to remain in intimate contact during all movements and all mandibular positions. In the healthy joint, the articular surfaces of the condyle, disc, and eminence are smooth and sliding, which ensures unobtrusive movements without any friction. The normal relationship between condyle and disc in mandibular movements is also maintained due to the specific form of disc.
The biconcave form of the disc and its thickening borders itself ensures the stability of the disc condition while the interarticular pressure increases during the opening of the mouth also helps to center the disc on the condyle. Medial and lateral discal ligaments support the maintenance of disc because they avoid any translatory movement between condyle and disc [2, 10, 12, 13, 14, 15, 16].
If, however, the form of the disc is changed and the discal ligament is elongated, the translatory movement between the condyle and the disc becomes possible. The amount of this movement depends on the change in the form of disc and the degree of elongation of discal ligament. Discal ligaments are not elastic and after elongation they retain that length.
Under the closed mouth, interarticular pressure is very low. If the disc ligaments are stretched, the disc can move on the articular surface of the condyle. Since in the closed mouths the upper layer of the bilaminar zone has no influence on the position of the disc, the tone of the upper head of the lateral pterygoid muscle may influence the disc to assume the anterior position on the condyle. Moving the disk forward is medially limited by the length of the discal ligaments and the thickness of the posterior disc border. If this condition lasts longer, the posterior disc border can be thinned, making it easier for its antero-medial dislocation. In such cases, the articular surface of the condyle no longer rests below the intermediate zone of the disc during closing mouths, but under its thinned posterior disc border or, even in the retrodiscal tissue.
This condition is referred to as a functional derangement of the disc and is initially difficult to register. Later, there is a pain, usually associated with chewing. If the anterior displacement of the disc is more pronounced, the joint function may be compromised. During the mouth opening, the condyle moves forward, a short translatory movement between the condyle and the disc is performed first, ensuring that the condyle takes its normal position below the intermediate zone of the disc. This relation of condyle and disc is then maintained during the further opening of the mouth under the action of interarticular pressure which increases at the opening of the mouth.
During the closing of the mouth the fibers of the retrodiscal tissue actively assist in restoring the condyle to the normal position, which it occupies when the mouth is opened. The interarticular pressure maintains intimate contact between the condyle and the disc during the translational closing movement and does not allow the anterior, thicken disc border thread between the condyle and the articular eminence. However, when the closing movement is complete, the interarticular pressure decreases and the tension in the retrodiscal tissue is reduced, the tone in the upper head of the lateral pterygoid muscle will have an effect on the anterior displacement of the disc [2, 10, 12, 13, 14, 15, 16].
The basic characteristic of this functional disorder is the presence of translational motion between the condyle and the disc at the beginning of the opening and at the end of the mouth closure, which does not exist in the normal joint. During this pathologic translation, increased interarticular pressure or deformed articular disc may prevent undisturbed crossing of articular surfaces. This raises the sudden, distorted movement of the condyle that skips the barrier to take normal position below the intermediate zone of the disc. This sudden skip of the condyle motion usually accompanies a characteristic sound, which is referred to as a “click” at the mouth opening. After this sound, normal relation between condyle and disc is established during further movement of the opening.
This condyle-disc interact is presented during mouth closing all the way till the very end. However, when the mouth is closed and the interarticular pressure decreased, the disc is again displaced forward (and medially) under the tone of the upper head of the lateral pterygoid muscle.
If the displacement is small this shift is usually not followed by a characteristic sound. A single “click” at the mouth opening indicates an early stage of dysfunction.
If the condition is prolonged, the dysfunction is increased. Continuously anteriorly displaced disc leads to permanent elongation of the discal ligaments, including the lower layer of the retrodiscal tissue. The posterior disc border continues to thinning, and the condyle lies practically on the retrodiscal tissue when the mouth closed. Morphological changes in the disc in the area where the condyle is now positioned may cause a secondary “click” in the final stages of closing the mouth just before the condyle takes the final position. Disc is most often moved forward, or anteromedial, but it also appeared the medial, lateral and even posterior displacement of the disc. Displacements of the articular disc represent a series of pathological conditions that progressively worsen over time. These conditions usually begin with disc displacement with reduction, which is usually not accompanied by pain or major function disorders. In some patients, this condition aggravates, takes a heavier form of dysfunction, disc displacement without reduction, while in others the level of the displacement of the disc is prolonged for long time (Figure 1). The reason for these differences is not always clear. The presence of various factors that may contribute to the development of dysfunction, such as loss of lateral teeth, systemic stability of the ligaments or the presence of parafunctional activities, has certainly a significant influence. In diagnosing disc displacement, clinical examination is not always sufficient to determine the actual condition, especially in cases where dysfunction does not cause greater discomfort. Special X-ray techniques, such as arthrography or MRI, are often needed to confirm a clinical diagnosis. However, it must be emphasized that the painless joint with mild mouth signaling is not an indication of the use of complicated and expensive X-ray methods. The clinician must determine whether arthrography or MRI is crucial for determining the correct treatment [8, 9, 10].
The position of TMJ disc during mouth opening and closing in three different conditions: healthy joint, anterior disc displacement with reduction (ADDWR) and anterior disc displacement without reduction (ADDWOR).
In this disorder when the mouth is closed, disc does not take a normal position between condyle and articular eminence, but is displaced forward, or forward and medial, and during opening of the mouth it returns to approximately normal position on the condyle [2, 10, 12, 13, 14, 15, 16, 17]. In some cases, this may be accompanied by increased muscular activity, pain, and limitation of mandibular movements.
The following clinical sign that can be easily detected in these patients is the deviation of the middle line of the mandible to the affected joint at the earliest stage of mouth opening. This is because of the temporary blockade of condyle translation caused by disc displacement. When the disc takes a normal position in relation to the condyle, during mouth opening, the translational movement forward and down as well as the middle line of the mandible return to normal. The deviation from the deflection of the mandible should be distinguished. Deviation is the initial turning of the mandible to the affected joint due to a temporary obstacle. The mandible returns to the central position when the obstacle passes (Figure 2). In the deflection, the middle line of the mandible moves from the beginning to the end of the movement of the opening to the affected side and does not return to the center (Figure 3).
Mandibular deviation during mouth opening associated with disc displacement with reduction.
Mandibular deflection during mouth opening associated with disc displacement without reduction (affected right side).
Pain is not always a companion to the anterior disc displacement. If present, it is usually stimulated by tensed disc ligaments or it is caused by the condyle pressure on the retrodiscal tissue.
The amount of mandibular movements in this disorder is usually normal and in fact the diameter of the maximum opening of the mouth may be greater than normal. Limited opening of the mouth, if present, is the most common consequence of muscular spasm caused by pain, rather than mechanical obstruction of the articular disc [5, 10, 12, 13, 14, 15, 16, 17].
Sensitivity of the joint to palpation in patients with single or reciprocal click, even in the absence of pain, indicates that there was no adaptation of the joint tissue to this condition. The patient should be aware that the dysfunction has a progressive course and that painful sensations may also occur, especially when it comes to patient with parafunctions [16, 17, 18].
If the disc displacement with reduction is accompanied by pain, all management measures should be taken to alleviate or eliminate pain and second to improve function.
The benefit of the use of some intraoral devices in the management of patients with disc displacement with reduction is still subject of discussion. Most commonly applied intraoral devices are repositioning splint and stabilization splint [18, 19, 20, 21, 22, 23]. Recently in the literature, the modified mandibular splint has been mentioned, which achieves significant success rate in eliminating joint sounds and patients had no complications because of occlusal changes [24].
The basic aim of the repositioning therapy is to temporarily stabilize the mandible in an appropriate anterior position that allows the disc, if possible, to take a normal position on the condyle, and that the retrodiscal tissue releases the pressure and thus eliminates the pain and clicking sounds of the joint. Much more important is moving the condyle forward, which should enable the adaptive and regenerative processes in the retrodiscal tissue. Why this adaptation occurs in some patients, and in others not, it is not yet clarified. The goal of repositioning therapy is, therefore, to eliminate pain and allow relaxation and regeneration, actually transformation of the retrodiscal tissue [10, 18, 19, 20, 22, 23] (Figures 4–6).
Mandibular protrusion position, about 2–3 mm in front of the maximal intercuspal position, the reciprocal sounds are unheard in patient with disc displacement with reduction.
Stone cast model with repositioning splint (contact position).
Stone cast model with repositioning splint.
Repositioning therapy may, however, also have some consequences. Therefore, repositioning therapy can be considered as a temporary treatment that reduces pain and joint sounds in a relatively short period of time. The results of long-term use of the repositioned splint are, however, not encouraging, especially in terms of eliminating the sound signals. In spite of these shortcomings, repositioning therapy has its place within the noninvasive (conservative) methods of treating patients with anterior disc displacement with reduction [18, 19, 20, 22, 23].
Some authors recommend that treatment begins by introducing a stabilization splint during a certain time because adverse long-term effects are minimized. A stabilization splint is applied in the upper jaw at night and, preferably, 1–2 hours during the day for several weeks (Figures 7 and 8). If there is no symptom reduction during stabilization splinting therapy, repositioning therapy should be continued. Before performing a repositioning splint, it is good to perform a test that will show whether the mandibular repositioning eliminates the sounds and the amount of propulsion required. This is done by maximizing the mouth opening in order to reduce the disc to a normal position. At the upper dental arch, place several layers of wax for the shaping, then the mandible is easily brought to the protrusion position, about 2–3 mm in front of the maximal intercuspal position. If the sounds are heard when reaching the mandible in that position, it is unlikely that the repositioning therapy will be successful in correcting the condyle-disc relationship. Clicking in the early (initial) mouth opening phase has a better prognosis than clicking at later stages. It indicates a minor disorder, a smaller amount of disc displacement, and less damage to the discal ligaments.
Stabilization splint in patient with disc displacement with reduction.
Fabricated stabilization splint.
After 2–3 months of application the repositioning splint worn 24 hours a day including when the patient is eating (if possible), if the pain is significantly reduced or eliminated, the anterior repositioning splint should be reconverted to the stabilization splint. Treatment is considered successful if the patient does not have any pain, regardless of whether the joint sounds are present. If pain occurs again, the treatment with anterior reposition of mandible should be repeated. However, before recreating the repositioning splint, it is necessary to check whether there are additional factors that jeopardize treatment (bruxism, harmful habits) and whether the patient wears a splint as instructed by the physician. Certainly, the patient should be warned of the need for maximum control of parafunctional activities, eliminating bad habits, avoiding strong and long-lasting chewing, hard food, etc. [12, 20, 22, 23].
Disc displacement with reduction sometimes requires immediate treatment, even though the patient does not complain on pain. In patients with intermittent joint blockades, treatment should begin immediately, as such conditions can lead to serious injuries to the joint, most often the disc displacement without reduction. All pain-related disc displacements require treatment.
This condition is characterized by anterior or antero-medial disc displacement in closed mouth conditions, where the disc does not return to the normal condyle relationship during mouth opening or condyle translation. Translational movements of the condyle are limited or disabled as it cannot pass under the dislocated and deformed disc. Pressed disc changes its shape, from biconcave to biconvex, and the anterior disc connection is relaxed. The contact between the condyle, the disc, and the articular eminence is lost, the space which normally occupies the disc is reduced, and the deformed disc is below the condyle. This results in restricted translation of the condyle in the affected joint, limited opening of the mouth, and sometimes with complete blockade of the mouth opening (“closed lock”).
Due to more efficient approach to therapy and overall prognosis, the state of anterior disc displacement without reduction can be divided into two stages—acute and chronic.
Normal range of mouth opening in healthy person.
Limited mouth opening in patient with disc displacement without reduction.
Since limited mouth opening can be the result of muscular spasm, differential diagnosis should determine the true cause of this occurrence. It is known that contraction of the mandibular elevator muscles may limit vertical movements of mandible but does not significantly affect the lateral and protrusive range of motion. On the contrary, the intracapsular cause of mandibular movement restraints, such as disc displacement without reduction, leads to obstruction of all translational motion of the condyle in the affected joint and thus to the limitation of mouth opening, propulsion and lateral movement to the opposite side. If the movements of the mandible are not limited by the presence of strong pain, the intracapsular cause of mandibular obstruction usually permits the opening of the mouth by a pure rotation range of 25 mm. In cases of spasms or painful contraction of the mandibular elevator muscles, mouth opening may, however, be limited to several millimeters [5, 12, 25, 26].
The manual rearrangement therapist performs it by pressing the thumb to the lower teeth or the lower alveolar ridge of the affected side pulling the lower jaw downwards and separating the condyle from the articular eminence, thus providing a space for restoring the disc. If the reposition succeeds, as it can be seen from the considerably increased range of mouth opening, propulsion, and movement on the contralateral side, immediate repositioning splint should be introduced to prevent disc re-displacement. This splint should be made in advance and now modified so as to stabilize the mandible in the propulsive position 2–3 mm in front of the maximal intercuspal position. The patient needs to carry a splint constantly during the day and night, even during the meal, for the first 2–4 days before beginning only night-time use for at least 10 days. Also, a diet with only soft food should be prescribed. The patient should report at least once a week to evaluate the condition and eventually adjust the splint. If the disc is in the optimal position after this period, the repositioning splint can be replaced by a stabilization splint. If the joint blockade is repeated in spite of applied therapy, it is necessary to reanalyze the degree of dysfunction (the amount of disc displacement, possibility of its restoration) in order to establish a definitive therapy plan. The frequency of temporary joint blockades or long period disc displacement without reduction significantly reduces the chance for successful treatment (reposition) due to irreversible changes in joint tissue. Single, sudden joint blockade accompanied by limited mouth opening and intense pain has a much better prognosis, especially if the blockade is a consequence of a sudden trauma that has affected a healthy joint. The patient should be advised to use soft food and to maximally reduce the range of mandibular movements. If the attempt of manual reposition of the disc displacement fails, other alternatives should be considered [5, 12, 25, 26, 27].
The diagnosis of the dislocated disc is also confirmed by some radiographic methods that allow the analysis of soft tissue of the joint (arthrography, MRI) [8, 9, 10].
In patients with chronic disc displacement without reduction, the disc is deformed and its last attachment is non-functional, so returning it to normal position is impossible.
This disorder was previously referred to as “subluxation”.
Usually both joints are included, but hypermobility may be unilateral if it is the result of the joint hypomobility of the opposite side.
When the hypermobility of TMJs is part of the general (systemic) hypermobility of all the joint structures, it can be considered benign and no intervention should be undertaken [28, 29]. However, the joint hypermobility can lead to more difficult conditions, such as recurrent mandibular dislocation.
In the literature, it is referred as a mouth closure or “open lock”“[2, 33, 34].
If manual repositioning fails in the attempt, it is recommended to trigger the vomiting reflex by touching the soft palate by mirror. This inhibits the activity of the elevators and increases the chances of its manual repositioning. If the dislocation of the condyle-disc complex often repeats (becoming a chronic phenomenon), it is best to train the patient how to bring the mandible back to normal position using exercises like joint hypermobility [2, 33, 34].
Surgical intervention can be undertaken if this condition is often repeated and accompanied by pain. It usually consists of eminectomy (reduction of peak articular eminence) or eminoplasty (a surgical increase in inclination of the articular eminence) to prevent subsequent dislocations [35, 36].
Depending on the tissue in which the process takes place, inflammation of the TMJ is referred to as capsulitis, synovitis and retrodiscitis.
Capsulitis (inflammation of the external fibrotic layer of the joint capsule) and synovitis (inflammation of the synovial membrane) have almost the same clinical picture and are considered to be a unique clinical entity.
In the case of acute persistent pain, injection of corticosteroids (methylprednisolone 5–20 mg with 0.5 ml local anesthetic using 23–27 gauge, 05–1 inch needle) into the joint or joint area can reduce the pain and the inflammation. It should be cautious with corticosteroids because of the potential for damage to joint tissue. It is not recommended to administer more than three injections at short intervals [11]. Corticosteroids should not be given if acute purulent infection is present.
If the inflammation is a consequence of chronic, repeated microtrauma or it has been secondary due to disc displacement, specific therapy is used to remove the source of the microtrauma or to allow the replacement of the dislocated disc [11, 37, 38, 39]. The use of stabilization splint for several weeks during the night, in these cases, reduces bruxism, reduces pressure on the joint and eliminates muscular spasm. Reposition splint therapy can help in cases where the primary cause is anterior disc displacement. This therapy minimizes the trauma of the discal ligaments.
Condyle pressure on richly vascularized retrodiscal tissue with a lot of nerves located behind an articular disc can lead to inflammation and swelling with significant functional disturbances.
Degenerative diseases of the TMJ differ significantly from those that have been written since they primarily damage bony articular surfaces of condyle and fossa. Some classifications characterize these diseases commonly referred to as arthritides [42]. The different types are: osteoarthritis, osteoarthrosis, polyarthritides.
Degenerative diseases of the joint systems may be of local character, then they only affect specific joint structures such as TMJ or may, however, be part of the general systemic disease of all joints in the body (polyarthritis).
Osteoarthritis is one of the most common arthritides affecting the TMJ. Osteoarthritis usually develops gradually and is limited in character. Degenerative processes in the TMJ even without a certain therapy end in about 3 years. The pain is reduced and the joint function somewhat regenerates, the volume of mandibular movements increases, and the creptions become less expressive. However, structural changes in the bone components of the joint are definitive. This stabilized condition is sometimes referred to as osteoarthrosis after the inflammatory process retreated and when pain is no longer present [11, 37, 39, 40, 42, 43, 44, 45, 46].
Changes in TMJ in lateral phases of disease can be observed on radiographic images, especially on the articular surfaces of the condyle in the form of the flattened surface, the presence of osteophytes, the cystic formation in the subchondral bone and the reduction of the joint space [12, 44].
The patient needs to take soft, almost fluid food; to avoid any function during the painful stages of the disease. Antirheumatics, NSAID, naproxen (Naprosyn) 500 mg two times per day for minimum of 3 weeks [11] or combination anxiolytic agent diazepam (Valium) 2.5 mg four times per day for 1 week than 5 mg four times per day for 2 weeks to and NSAID Ibuprofen 600 mg four times per day for 3 weeks are prescribed to reduce the pain and inflammation of the joints. The use of muscle relaxants cyclobenzaprine (Flexeril) 10 mg every night or sedatives clonazepam (Klonopin) 0.25 mg every night, increased by 0.25 each week to a maximum of 1 mg per day in patients with muscular spasms is suggested. Corticosteroid injections (methylprednisolone 5–20 mg with 0.5 ml local anesthetic using 23–27 gauge, 05–1 inch needle) help in cases of intense pain [11, 12, 37, 39, 40, 44]. Since mechanical overload of the joint is the main cause of osteoarthritis, it is recommended to use a stabilizing splint during the night and, preferably, 1–2 hours during the day for 6–8 weeks [12]. If the pain is unbearable, if it does not decrease after the above mentioned treatment, the possibility of surgery is considered.
Osteoarthrosis is a non-inflammatory degenerative process that changes the morphology of joint components and mainly affects the articular surfaces of the TMJ and the subchondral bone. When bony changes are active, the condition is called osteoarthritis. As remodeling occurs the condition can become stable, yet the bony morphology remains altered [12, 45, 46].
Systemic polyarthritis can also involve the TMJ. The clinical picture is similar to that of localized osteoarthritis of TMJ.
Therapy of TMJ disease in these cases is palliative. It is recommended to rest the joints, take antiflogistics, analgesics and sedatives to relieve pain. The most common recommended drugs are NSAID, naproxen (Naprosyn) 500 mg two times per day for minimum of 3 weeks [11] or combination anxiolytic agent diazepam (Valium) 2.5 mg four times per day for 1 week than 5 mg four times per day for 2 weeks to and NSAID Ibuprofen 600 mg four times per day minimum for 3 weeks. In some patients, treatment may be attempted by stabilization occlusal split during the night for several weeks, which significantly reduces muscle hyperactivity, which relieves pain. Although there is an obvious occlusion instability, the use of irreversible occlusal therapy should be considered well and, of course, do not undertake anything to relieve the underlying disease and eliminate the inflammation in TM joints. If occlusal therapy is necessary because of the occlusion stabilization, the position of the condyle in relation to the articular eminence should be well analyzed. In cases of extreme damage of the TM joints and complete occlusion disorders, orthognathic surgery is indicated [12, 45, 46, 47, 48].
Ankylosis is defined as immobilization or concrescence of the joint structures, caused by degenerative diseases, hemarthrosis secondary to joint injuries or surgical interventions. Inability or restriction of movement in the TMJ may be caused by fibrosis or bone tissue, which is less frequent [49, 50].
Hyperplasia of the fibrous tissue in the joint can lead to the ankylosis of the condyle, disc or retrodiscal tissue for the posterior wall of the joint capsule, articular fossa or the articular eminence.
Fibrosis may also occupy the joint capsule (capsular fibrosis), forming the binder fibers of the fibrous tissue inside the capsule, and may also cause general capsular thickening. This condition is characterized by a painless limitation of the mandible movement on the opposite side.
In a clinical finding, one-sided ankylosis is dominated by a poorer development of the affected side—the middle of the chin and the bite center are moved to that side. In the case of bilateral ankylosis, there is a so-called “ bird’s face” appearance. The lower jaw is generally undeveloped. Due to the inability to open the mouth, hygiene is usually poor, with a consequent set of teeth caries [50].
The signs and symptoms of disease and dysfunction of TMJ are different in various disease groups and depend on the duration of the disease and its chronicity and as well as on the individual sensitivity of the patient. Proper identification of symptoms and precise diagnosis are therefore essential for future treatment.
I confirm that there is no conflict of interest.
Ischemia-reperfusion (I/R) injury is a phenomenon in which cellular damage in a hypoxic organ is accentuated following the oxygen restoration [1, 2, 3], being a major pathophysiological event and cause of morbidity and mortality in liver resections and transplantation [4]. Despite the attempts to solve this problem, hepatic I/R is an unresolved problem. In addition, hepatic steatosis is a major risk factor for liver surgery, as it is associated with an increased complication index and postoperative mortality after major liver resection and transplantation, since steatotic livers show impaired regenerative response and reduced tolerance to I/R injury compared with non-steatotic ones. Of note, the prevalence of steatosis ranges from 24 to 45% of the population and consequently a further increase in the number of steatotic livers submitted to surgery is to be expected [5]. These observations highlight the need to develop protective strategies in liver surgical conditions.
\nThe mechanisms involved in liver I/R injury are complicated, mainly including microcirculation failure and oxidative stress [4]. A wide range of strategies has been attempted in order to mitigate I/R injury, mainly pharmacological treatments focused on gene therapy, improvement of preservation solutions, among others. However, an effective treatment is still lacking [4] since is difficult to achieve by targeting individual mechanism. Surgical strategies such as the ischemic preconditioning (IPC) technique noted for its effectiveness, as it activates several protective pathways against I/R injury in experimental models should be considered. IPC can be either applied directly to the target organ [6] or remotely (RIPC) to a distant vascular bed [7]. The benefits of the IPC and RIPC observed in experimental models of hepatic warm and cold ischemia [8, 9] prompted human trials of ischemic preconditioning. However, controversial results have been showed in the clinical practice. Therefore, the present chapter aims to describe the current knowledge of the IPC and RIPC in liver resections and liver transplantation of both steatotic and non-steatotic livers. In addition, the scientific controversies regarding the possible beneficial effects of these techniques, in experimental, translational and clinical studies in the setting of liver surgery will be discussed.
\nPreconditioning the liver with ischemia involves a brief period of portal triad clamping usually between 5 and 15 min followed by a brief period of reperfusion (10–20 min) before a prolonged period of ischemia [10] (Figure 1). The exact mode of action of the IPC in the prevention of post-operative hepatic complication has not yet been fully comprehended. The molecular basis for IPC consists of a sequence of events in which in response to the triggers of IPC, a signal must be generated and transduced into an intracellular message leading to the effector mechanism of protection [11, 12]. As in the pathophysiology of hepatic I/R, in the modulation of hepatic injury induced by IPC, there is a complex interaction between different mechanisms and cell types [13].
\nSchematic illustration of ischemic preconditioning and remote ischemic preconditioning.
Over the years, studies with experimental animal models have reported numerous positive effects of IPC on the alleviation of hepatic I/R injury and improvements of post-operative liver functioning. Various combinations of ischemia and reperfusion periods have been tested showing similar beneficial effects: lower aminotransferase levels, reduced hepatocellular injury, and higher survival rates [14]. IPC protected against mitochondrial ROS and thus reduce the oxidative stress-mediated damage in liver I/R injury [15, 16, 17, 18]. However, Rüdiger et al. showed that IPC is beneficial in liver submitted to an ischemic period of up to 75 min, but not for more prolonged ischemia [19].
\nIPC modulates several molecular pathways involving in I/R. When long periods of liver ischemia occur in hepatectomy or transplantation, the lack of oxygenation induces the rapid ATP consume to generate energy for cellular metabolism, resulting in adenosine production. The accumulation of adenosine provokes its transformation to hypoxanthine and xanthine leading to ROS production. IPC (5 min of ischemia/10 min reperfusion) modulates oxidative stress since reduces the accumulation of xanthine and the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO). IPC (5 min of ischemia/10 min reperfusion) inhibits this ROS generating system, xanthine/XOD [11, 12, 13]. The activation of adenosine receptor A2 induced by IPC stimulates the activity of various intracellular kinases, like protein kinase C (PKC)-specifically PKC-δ- and p38 mitogen-activated protein kinase (p38MAPK) [20]. The activation of p38 and c-Jun N-terminal kinase (JNK-1) induced by IPC (10 min of ischemia/10 min reperfusion) is associated with increased cyclin D1 expression and entry into the cell cycle [21]. In addition to this, activation of p38 by different pharmacological strategies mimicking IPC effects, including agonists of the adenosine A2 receptor, carbon monoxide (CO), NO, and atrial natriuretic peptide (ANP) has been considered to be a crucial mechanism of hepatoprotection in the setting of liver surgery [22]. Moreover, autophagic flux is enhanced by liver IPC (10 min of ischemia/10 min reperfusion), since endothelial nitric oxide synthase (eNOS)-derived NO activates autophagy via phosphorylation of p38 MAPK [23]. On the other hand, the mechanism involved in the benefits of IPC might be different dependently of the type of the liver [1]. Indeed, in the presence of steatosis, IPC (5 min of ischemia/10 min reperfusion) reduces MAPK activation (JNK and p38), and this is associated with protection against hepatic I/R injury [24, 25]. The involvement of sirtuin-1 (SIRT1) induction in the benefits of IPC (5 min of ischemia/10 min reperfusion) on normothermic hepatic conditions has been reported [26]. Thus, SIRT1 inhibition decreased the expression of extracellular signal-regulated protein kinases (ERK) and augmented p38 protein levels [26]. ERK activation during IPC (5 min of ischemia/10 min reperfusion) protects against I/R injury in steatotic livers, by inhibiting apoptosis [27], whereas treatment with a p38 activator abolished the benefits of IPC on hepatic damage [24]. In addition, inactivation of GSK-3β by IPC (10 min of ischemia/10–15 min reperfusion) induces β-catenin signaling and subsequently up-regulates anti-apoptotic factors, such as Bcl-2 and survivin, leading to a significant amelioration of liver I/R injury [28, 29]. Figure 2 shows some of the protective mechanisms of IPC in the hepatic I/R injury.
\nProtective mechanisms propose of ischemic preconditioning and remote ischemic preconditioning in the hepatic ischemia-reperfusion injury. A2-R: adenosine 2 receptor; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATF-2: activating transcription factor-2; ATP: adenosine triphosphate; cGMP: guanosine 3′,5′-cyclic monophosphate; eNOS: endothelial nitric oxide synthase; ER: endoplasmic reticulum; ET-1: endothelin-1; GSH: glutathione; HO-1: heme oxygenase-1; HSF-1: heat shock transcription factor-1; HSP72: heat-shock protein 72; IL: interleukin; iNOS: inducible nitric oxide synthase; JNK: jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MEF2c: myocyte enhancer factor-2; MIF: macrophage migration inhibitory factor; NF-κB: factor nuclear factor-kappa B; NO: nitric oxide; PI3K: phosphatidylinositol 3-kinase; PKC: protein kinase C; PLC: phospholipase C; ROS: reactive oxygen species; STAT3: signal transducer and activator of transcription-3; TNF: tumor necrosis factor; X/XOD: xanthine/xanthine oxidase.
The beneficial effects of IPC (10 min of ischemia/5 min reperfusion) in liver partial hepatectomy (PH) have been shown to be linked to better ATP recovery, NO production, antioxidant activities, and regulation of endoplasmic reticulum stress. All of this limited mitochondrial damage and apoptosis. In addition, the ERK1/2 and p38 MAPK activation induced by IPC in PH favors liver regeneration [30]. Furthermore, IPC (10 min of ischemia/10 min of reperfusion) can initiate hepatocyte proliferation action by a signaling mechanism involving TNF-α/IL-6 signal pathway [31]. In contrast, Qian et al. found that IPC impaired residual liver regeneration after major PH without portal blood bypass in rats. In this case, IPC was of 5 min ischemia/10 min reperfusion [32]. Another study testing regenerative capacity of the liver after IPC (10 min ischemia/10 min reperfusion) and PH showed that, despite IPC decreased hepatic injury, it did not influence the regeneration up to 48 h [33].
\nIn a reduced-size orthotopic liver transplantation (ROLT) rat model, IPC (10 min ischemia/10 min reperfusion) has been suggested that potentiates hepatocyte proliferation via TNF-α/IL-6-dependent pathway [34]. In addition, authors described that IPC inhibits IL-1 through NO, increases HGF, and reduces TGF-β to finally promote regeneration [34]. In addition, by another pathway independent of NO, IPC induced over-expression of heat shock protein 70 (HSP70) and heme-oxigenase-1 (HO-1) [35]. HO-1 protects against I/R injury, whereas the benefits resulting from HSP70 are mainly related to hepatocyte proliferation [35]. In addition, when steatotic grafts from living donors were transplanted applying IPC, the incidence of necrosis was reduced and the expression of both pro-autophagic beclin-1 and LC3 was increased [36]. On the other hand, in a rat model of ROLT with 70 or 90% hepatectomy, IPC (10 min ischemia/15 min reperfusion) impaired hepatic proliferative response by decreasing IL-6 and blunting cell cycle progression through a mechanism at least partially independent of STAT3 [37].
\nIPC (5 min ischemia/10 min reperfusion) has protected liver grafts in an experimental model of orthotopic liver transplantation (OLT) by modulation of xanthine/XOD system [38]. IPC reduced cAMP generation, thus ameliorating hepatic injury and survival of recipients with steatotic grafts [39]. In addition, AMPK activation by IPC (5 min ischemia/10 min reperfusion) increased the accumulation of adiponectin in steatotic liver grafts. This increased resistin and activated PI3K/Akt pathway, thus protecting steatotic livers against damage that follows transplantation [40]. However, it should be noted that in experimental liver transplantation from cadaveric donors, brain death abrogates the benefits of IPC (5 min ischemia/10 min reperfusion) in both steatotic and non-steatotic liver transplantation [41, 42]. Indeed, in the setting of liver transplantation, the inflammatory response induced by brain dead, present in the liver before the induction of IPC, would interact with various mechanistic aspects of IPC and block the eventual IPC response. Thus, Jimenez-Castro et al. have demonstrated that the treatment with acetylcholine protected liver grafts from the deleterious effects induced by brain death [41]. Under these conditions, the application of IPC was useful to improve the post-operative outcomes after transplantation.
\nIn addition to the liver, the benefits of IPC in experimental models of warm ischemia and liver transplantation have been observed in extrahepatic organs. Thus, IPC protects against lung damage associated with liver transplantation. The application of IPC in liver before I/R can prevent the release of both TNF and xanthine/XOD from the liver to the circulation. This regulated the P-selectin up-regulation and the neutrophil accumulation in remote organs such as lung and splanchnic organs [43].
\nThe benefits of IPC observed in experimental models of hepatic resections and liver transplantation [8, 9] prompted human trials of IPC. The benefits of this surgical strategy have been evidenced in patients submitted to liver resections, protecting both steatotic and non-steatotic livers [44]. However, different results have been reported on the effects of IPC in the clinical practice of liver transplantation [45, 46].
\nThe first clinical trial testing IPC in patients undergoing major PH was reported by Clavien et al. [47]. Authors conclude that IPC (10 min ischemia/10 min reperfusion) is a protective strategy against hepatic ischemia in humans, particularly in young patients requiring a prolonged period of inflow occlusion and in the presence of steatosis [44, 47]. Other clinical trials also suggest that IPC (10 min ischemia/10 min reperfusion) provides both better intraoperative hemodynamic stability and anti-ischemic effects compared with intermittent clamping [48, 49]. Regarding the molecular basis of IPC (10 min ischemia/10 min reperfusion) in clinical PH, its beneficial effects have been shown to be linked to the down-regulation of potentially cytotoxic functions of PMNLs elicited by the Pringle Maneuver [50]. In addition, IPC (10 min ischemia/15 min reperfusion) increased the generation of adenosine and attenuated the degradation of purines in patients undergoing PH. Moreover, IPC appeared to attenuate apoptotic response of the liver remnant after resection [51]. Other clinical trial revealed that IPC (10 min ischemia/10 min reperfusion) stimulated the expression of the IL-1-RA, inducible nitric oxide synthase (iNOS), and Bcl-2 which decreased the inflammatory response and abrogated liver I/R injury [52]. Interestingly, since the ischemic period and pathophysiology are similar in partial hepatectomy and living donor liver transplantation, IPC could reduce damage and improve liver regeneration failure, a relevant risk factor in living donor liver transplantation [34]. Moreover, IPC could be implemented as an appropriate surgical strategy for the use of suboptimal livers, such as steatotic ones, in the clinical practice. Different results indicate that in patients with liver cirrhosis, IPC (5 min ischemia/5 min reperfusion) has been a suitable method to decrease liver I/R injury [53, 54]. Recently, the protective mechanism of IPC in patients with liver cirrhosis subjected to PH has been associated with changes in MAPK pathways [54]. In contrast, IPC applied for 15 min followed by 5 min reperfusion did not improve liver tolerance to I/R injury after PH in patients with liver cirrhosis [55]. In fact, RIPC did not induce changes in the postoperative levels of transaminases, bilirubin, and albumin nor reduced the morbidity and mortality rates and the duration of hospitalization [55].
\nClinical trials in liver transplantation report different results on the effects of IPC against hepatic I/R injury. An IPC of 10 min ischemia/10 min reperfusion before liver transplantation reduced inflammatory response, improved ischemia tolerance, and decreased early graft function [56]. However, although the application of IPC (10 min ischemia/15 min reperfusion) reduced hepatocellular necrosis, it showed no clinical benefits [57]. In the largest prospective randomized trial of 10 min period IPC in liver transplantation from cadaveric donors, I/R injury was greater when IPC was applied [45], and it was called the “IPC paradox.” This was in accordance with the results obtained in experimental model of liver transplantation from cadaveric donors indicating that brain death abrogates the benefits of IP on post-operative outcomes [41, 42]. In fact, a microarray analysis in a randomized trial of 10 min IPC in deceased donor liver transplantation identified alteration of the expression of different antioxidant, immunological, lipid biosynthesis, cell development and growth transcripts, which are associated with hepatic damage [58].
\nRIPC is a surgical technique by which preconditioning of one organ or vascular bed provides protection to distant organs or vascular beds during a sustained period of ischaemia (Figure 1). Few experimental and clinical studies, most of them from the last years, have addressed the effects of RIPC in livers submitted to I/R.
\nWhen RIPC is applied in the hind limb, it reduced hepatic warm I/R injury of mice, rats, and rabbits. RIPC (5–10 min ischemia/5–10 min reperfusion) has been shown to improve hepatic oxygenation and microcirculation and to reduce hepatic acidosis and damage [59, 60]. RIPC (4 min ischemia/4 min reperfusion) induced eNOS activation, leading to NO production to preserve sinusoidal structure and blood flow [61]. In addition, RIPC (5 min ischemia/5 min reperfusion) regulated the expressions of iNOS and eNOS and the expressions of miR-34a, miR-122, and miR-27b injury related miRs in fatty livers, thus attenuating I/R injury [62, 63]. RIPC (10 min ischemia/10 min reperfusion) also induced the up-regulation of HO-1, induced autophagy, and then reduced the damaged mitochondria to inhibit apoptosis and eventually protect hepatic cells from I/R injury [64, 65]. Moreover, RIPC (5 min ischemia/5 min reperfusion) reduced neutrophil activation and adhesion and TNF-α [66]. Controversial results have been described in a rat model in which RIPC protocol included 3 cycles of 10 min ischemia interspersed with 10 min of reperfusion periods [67]. Regarding the hemodynamic and microcirculatory alterations, RIPC protocol had beneficial effect; however, the histopathological findings were paradox [67, 68]. In addition to RIPC in the hind limb, when RIPC (5 min ischemia/5 min reperfusion) is applied in kidney, it has also been shown to protect liver against I/R injury, improving blood flow, histology, and redox-state [69]. Figure 2 shows some of the protective mechanisms of RIPC in the hepatic I/R injury.
\nA recent study in mice showed that RIPC (3 cycles of 5 min of ischemia each followed by 5 min of reperfusion) applied in the right femoral vascular bundle did not affect regeneration after 70%-PH [70]. However, of clinical interest, the same protocol of RIPC improved liver weight gain and hepatocyte mitoses after 90%-PH [70].
\nIn an experimental model of OLT, RIPC based on 4 cycles of 5 min of ischemia and 5 min of reperfusion was applied on the infrarenal aorta. The results suggested that RIPC might confer potent protection against the detrimental effects of I/R injury including apoptosis and inflammation [71]. In addition, authors suggest that HO-1 overexpression could play an orchestrating role in RIPC (5 min ischemia/5 min reperfusion)-mediated organ protection [71]. In addition, a recent study showed that the same protocol of RIPC also exhibits protective effects, as indicated by increased portal venous flow and microcirculation, as well as decreased AST and ALT levels and a reduced Suzuki score in a model of OLT [72]. Authors suggest that the RIPC inhibited the macrophage migration inhibitory factor (MIF), which resulted in the modulation of further downstream pro-survival mechanisms (iNOS, RISK-, SAFE-pathways), protecting graft injury [72].
\nOnly three studies dated in 2017 and 2018 have addressed the effects of RIPC in the clinical liver surgery.
\nIn major HP, RIPC was shown to reduce liver I/R injury as indicated by a reduction in post-operative transaminases and increased ICG clearance [73]. To induce RIPC, a tourniquet was inflated to induce 10 min of ischemia and then deflated for 10 min to reperfuse the leg. This was repeated twice prior to commencing the operation. RIPC has potential to reduce liver injury following PH [73]. In addition, other clinical trial where RIPC was induced by three cycles of 5 min of ischemia of right upper limb followed by 5 min of reperfusion showed hepatic cytoprotective effects assessed by cholinesterase and bilirubin levels during liver resection [74]. Authors suggest that a shorter protocol of RIPC is safe and of equal effect, although the mechanisms of this effect must be investigated in future studies [74].
\nThe first trial to investigate the feasibility of RIPC in liver transplant recipients was addressing by Robertson et al. [75]. The trial involved randomization of adult recipients undergoing deceased donor liver transplantation. To induce RIPC, a tourniquet was inflated for 5 min and then deflated for 5 min to reperfuse the leg. This was repeated twice and completed prior to the transplant procedure. Authors demonstrated that RIPC is feasible, acceptable to patients and safe in this group of patients but clinical benefits within the first 3 months post transplantation were not detected [75]. Authors suggest that 5 min cycles are insufficient to create localized ischemia in the limb [75].
\nSurgical strategies such as the induction of IPC or RIPC could be of clinical interest in human liver resections and liver transplantation in both steatotic and non-steatotic livers. Both IPC and RIPC are easy to apply, inexpensive and does not require the use of drugs with potential side effects, but it requires a period of pre-ischemic manipulation for organ protection. These preconditioning techniques have been demonstrated to be promising tools for the reduction of hepatic I/R injury in different warm and cold ischemia models. Therefore, the potential applications of IPC and RIPC in human liver surgery are numerous. The benefits of IPC and RIPC have been evidenced in patients submitted to partial hepatectomy in both steatotic and non-steatotic livers. In our view, IPC and RIPC could resolve, at least partially, the lack of liver grafts available for transplant, since it can improve the post-operative outcome of liver grafts from extended criteria donors. However, controversial results on the effects of IPC and RIPC have been reported in the clinical practice of liver transplantation. It should be considered that the underlying mechanisms of both IPC and RIPC and their relevance in liver surgery remain poorly understood. Indeed, as stated along this chapter, most of the experimental studies have been focused on the molecular changes occurring during IPC and RIPC in non-brain-dead donors. Moreover, most of the experimental studies of IPC and RIPC have been performed only in I/R injury models, without hepatic resections or liver transplantation. The tolerance to I/R injury induced by either IPC or RIPC is dependently of the number of cycles of I/R and their duration as well as the surgical procedures. The clinical application of strategies designed at benchside will depend on the use of experimental models of IPC and RIPC that resemble as much as possible the clinical conditions. Multidisciplinary research groups should devote additional efforts to better understand the molecular mechanisms of IPC and RIPC during the different clinical liver surgery setting to ultimately develop useful surgical strategies aimed at reducing I/R damage.
\nThis research was supported by the Ministerio de Economía y Competitividad (project grant SAF-2015-64857-R) Madrid, Spain; the European Union (FondosFeder, “una manera de hacer Europa”); by CERCA Program/Generalitat de Catalunya; by the Secretaria d’Universitats i Recerca (Grant 2017SGR-551) Barcelona, Spain. J Gracia-Sancho received continuous funding from the Instituto de Salud Carlos III (currently FIS PI17/00012) and the CIBEREHD, from Ministerio de Ciencia, Innovación y Universidades.
\nThe authors declare that they have no conflict of interest.
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