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Tiefenbacher",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10765.jpg",keywords:"Managing Urbanization, Managing Development, Managing Resource Use, Drought Management, Flood Management, Water Quality Monitoring, Air Quality Monitoring, Ecological Monitoring, Modeling Extreme Natural Events, Ecological Restoration, Restoring Environmental Flows, Environmental Management Perspectives",numberOfDownloads:24,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 12th 2021",dateEndSecondStepPublish:"February 9th 2021",dateEndThirdStepPublish:"April 10th 2021",dateEndFourthStepPublish:"June 29th 2021",dateEndFifthStepPublish:"August 28th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A geospatial scholar working at the interface of natural and human systems, collaborating internationally on innovative studies about hazards and environmental challenges. Dr. Tiefenbacher has published more than 200 papers on a diverse array of topics that examine perception and behaviors with regards to the application of pesticides, releases of toxic chemicals, environments of the U.S.-Mexico borderlands, wildlife hazards, and the geography of wine.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"73876",title:"Dr.",name:"John P.",middleName:null,surname:"Tiefenbacher",slug:"john-p.-tiefenbacher",fullName:"John P. Tiefenbacher",profilePictureURL:"https://mts.intechopen.com/storage/users/73876/images/system/73876.jfif",biography:"Dr. John P. Tiefenbacher (Ph.D., Rutgers, 1992) is a professor of Geography at Texas State University. His research has focused on various aspects of hazards and environmental management. 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1. Introduction
Lumbar discectomy is the most commonly performed spinal operation in the United States with more than half a million procedures performed annually. In addition, spinal anesthesia for surgical analgesia in these procedures has been established as an accepted technique for many years. With the refinement in surgical technique for lumbar discectomy, that has now made the procedure relatively non-invasive, spinal anesthesia plays an even more important role.
The original laminectomy and discectomy was performed by Mixter and Barr in 1934 [1]. Most surgeons perform a modified microdiscectomy originally described by Williams [2]. With the use of high-powered microscopes, the anatomy is better visualized and incisions are much smaller with less tissue and bone disruption. There are alterations to the standard microdiscectomy including laser disc removal, endoscopic discectomy and intradiscal electrothermal treatment. However, the microdiscectomy remains the procedure with the highest success rate. Lumbar laminectomy or discectomy is performed with the patient in the prone or lateral decubitus position. A midline paramedian incision is created and the lumbodorsal fascia is incised. Periosteal dissection exposes the laminae that are removed as necessary to provide access to the thecal sac and nerve roots. The nerve roots are retraced medially to expose the posterior longitudinal ligament that covers the intervertebral discs. The discectomy is performed by incising the ligament and removing disc material with a forceps. The laminar resection can also be extended to provide canal decompression in cases of spinal stenosis.
It is important to note that the lumbar spine has the largest vertebral bodies and bears the greatest weight. The center of gravity of the body is approximately 1 cm behind the sacral promontory that, in turn, places the entire weight of the body directly on L4-5 and L5-S1. With aging, the discs tend to become less fluid and more fibrocartilagenous, with little difference between nucleus and annulus. The discs are subject to pathologic changes that may lead to herniation of the nucleus pulposus and cause compression of the neural elements.
Subsequent removal of the disc or lamina with the assistance of loops or microscopes typically has a surgical duration of approximately two hours. As such, this has made spinal anesthesia an attractive choice for the anesthetic technique in these patients. This chapter will review the evidence supporting the utilization of this technique as well as the possible risks associated with neuraxial anesthesia and prone positioning.
2. Technique of spinal anesthesia for spine surgery
Briefly, once a decision has been made to proceed with spinal anesthesia several items must be performed in order to have a successful outcome. Knowing the level of surgical anesthesia required is extremely important since this will determine whether the patient can comfortably undergo the procedure and avoid the hemodynamic consequences of surgical stimulation. Of course, it is also essential that the area of coverage will provide relief from painful stimuli as well.
Anesthesia levels for lumbar surgery can be easily achieved with hyperbaric or isobaric local anesthetics. Typically, for L1-L5 surgery a dermatomal sensory level of at least T6-T8 will be required. Though this is higher than the level of the operative site, the higher level will allow for the surgery to take place and, depending on the local anesthetic selected, allow for a slow regression of surgical anesthesia coverage. In most instances, the patient is placed in the full prone position. The prone knee chest position and the horizontal side position have also been used. These positions are of importance since the spread of local anesthetic may be different depending on this position and also the baricity of the local anesthetic solution. After placing the spinal, the patient should be positioned supine with the level allowed to set before final positioning is achieved.
Bupivacaine appears to be the agent of choice since it provides adequate duration of coverage in comparison to other agents such as lidocaine. If lidocaine is selected, it is conceivable that regression of sensory coverage could occur shortly after positioning and draping of the patient. In addition, some practitioners will also select additives to the local anesthetic though the risk/benefits of these will be discussed later. A variety of agents have been used in lumbar surgery, all with varying degrees of success including opioids, epinephrine, phenylephrine, neostigmine and clonidine. Final selection of any and all additives will depend on the clinical situation and the physical status of the patient.
In most instances, the patient will have the spinal anesthetic placed prior to prone positioning. Usually the patient will be administered 400-600 ml of a balanced salt solution to expand intravascular volume prior to spinal placement. The preference for placement of the spinal block for many practitioners is to place the patient in the seated position. The seated position allows for better delineation of the overall spinal anatomy and helps to ascertain the midline, especially in larger individuals. In some instances, the patient can be placed in the lateral decubitus position for spinal placement. The back is prepped and draped in a sterile fashion and the best interspace, either L2-3, 3-4 or 4-5, is identified and 2-4 ml of 2% lidocaine is injected to anesthetize the area where the spinal needle will be inserted. Most practitioners will use a 24g or 25g pencil-point spinal needle placed through an introducer and advanced until free flow of CSF is observed from the hub of the needle. The spinal anesthetic can also be accomplished with the use of a 22 gauge Quincke needle. Once subarachnoid placement is confirmed, either 2-3 ml of 0.5% plain bupivacaine or 1.5-2 ml of 0.75% hyperbaric bupivacaine is injected into the subarachnoid space. The patient is returned to the supine position, and once a T8-10 level is obtained, the patient is rolled into the prone position and either placed on chest rolls, a Wilson or Andrews frame and allowed to self position their upper body for comfort.
3. Baricity issues
There has been some controversy over the preferred baricity of the local anesthetic for spinal anesthesia in lumbar surgery. Jellish, et al, [3] in their prospective study effectively utilized hyperbaric bupivacaine 0.75% with dextrose 8.5% to achieve levels of T6-T10. The study patients were required to stay supine after placement of the local anesthetic for approximately 10 minutes to fix the spinal level. Fixation of a hyperbaric spinal is required since typically the patients are placed in prone position. This is of particular importance given the fact that there are times when the head-down position is transiently performed as the patient is positioned on a frame or in knee-chest position.
If a hyperbaric solution is selected and adequate time for fixation has not been performed, the solution could track cephalad and lead to a higher level than what is required. This is also accentuated since the frame and/or knee-chest position required for the surgery eliminates the lordotic curves of the spine. The fixation of a hyperbaric spinal occurs when the solution is taken up by the spinal tissue and blood, especially the dextrose solution. This results in a change in solution from hyperbaric to isobaric and subsequent positioning has little to no effect [4].
Baricity of the spinal anesthetic has also been shown to affect both the quality of the anesthetic and the level of the block. Isobaric procaine/tetracaine spinal anesthesia has the same success profile with minimal complication compared to general anesthesia for spine surgery [5]. If the sensory level is adequate and ventilation is not impaired by a high block, spinal anesthesia provides good surgical conditions for spine surgery. Subjective dyspnea associated with a high spinal level may be accentuated with the patient in the prone position. Some clinicians believe isobaric spinal anesthetics could be the best choice because the dense low thoracic block may be routinely achieved with minimal hemodynamic consequences. Also, the effect of the isobaric agent is not affected by other factors like gravity or prolonged position. As such, patients that are placed in the knee chest position can be turned prone immediately after placement of the spinal as opposed to wait times of 10 minutes or longer for the block to set with a hyperbaric technique.
Plain isobaric bupivacaine was compared to hyperbaric bupivacaine to determine quality of block and cephalad spread in patients undergoing spinal surgery [6]. A 3 mL solution of isobaric 0.5% bupivacaine was administered to one group and 2ml of 0.75% bupivacaine was administered to the second group. All injections were performed within 5 seconds with the needle bevel facing cephalad. After turning supine for 10 minutes, the patients were turned prone to begin surgery. Time of onset for sensory and motor block was more rapid with hyperbaric bupivacaine. In addition, the final level achieved was higher with hyperbaric bupivacaine, compared to isobaric solution. Maximum heart rate change was similar in both groups but maximum blood pressure change was greater with the hyperbaric solution and this required a greater need for blood pressure and heart rate treatments. The dependent movement of hyperbaric solutions, and the level of the block achieved was always several denervations higher than the equivalent dose of isobaric solution. Even though sensory block is higher with hyperbaric local anesthetics, sympathetic block could be even higher. This explains the alteration in blood pressure observed with hyperbaric spinal anesthesia that is accentuated by turning prone. Thus, when using hyperbaric bupivacaine, meticulous determination of block level must be made before positioning the patient to avoid hypotension and bradycardia.
More breakthrough pain during spinal surgery has been noted with hyperbaric bupivacaine solutions compared to isobaric. This is thought to be due to the superiority of plain bupivacaine in suppressing slow conducting repetitive stimuli that is characteristic of low back pain [7].
Rung and colleagues [8] have suggested the utilization of isobaric bupivacaine 0.5% for providing adequate anesthesia. The group felt that the isobaric nature of the medication would help avoid the issues regarding positioning and unwanted rises in anesthetic levels. In addition, they also felt that the utilization of isobaric agents would speed the procedure since the patient could first be placed in prone position and then have the anesthetic administered. This would decrease the amount of time required for preparation and speed the onset of surgery.
Another study examined the use of 15 mg of 0.5% plain bupivacaine injected at the L2-3 interspace and either placing the patient in the prone knee chest position before placement of the spinal or after spinal placement positioning the patient supine and allowing the spinal level to be obtained before positioning prone. [9] The mean drop in systolic blood pressure was 30 mmHg in prepositioned patients compared to 13 mmHg with spinal placed before positioning. More ephedrine was needed when the spinal was placed post positioning to maintain blood pressure compared to the patients who had the block placed in the horizontal side position. This same knee chest group of patients also needed more atropine or glycopyrrolate to maintain heart rate. The investigators believed that placing the spinal block in the lateral horizontal position and allowing the patient to lie supine for 20 minutes produced less hypotension and bradycardia when compared to patients who had the block placed in the prone knee chest position because these patients had more time to accommodate for vasodilation of the lower limbs. The controversy over the ideal baricity has not been settled and either agent may be appropriate for the procedure.
Typically during the insertion of the spinal anesthetic a pencil-point needle such as a Whitacre is used versus the standard cutting Quincke type. Obviously this is utilized to avoid undue trauma to the dura via the cutting needle and causing a potential dural tear that could interfere with surgery (cerebral spinal fluid (CSF) in the field) as well as lead to postdural puncture headaches. In addition, other studies suggest that the pencil-point needles lead to a local inflammatory response that help with rapid dural closure [10].
The appropriate level of needle insertion will obviously be determined by the procedure and what disc is affected. There have been concerns about the utilization of spinal anesthesia in patients with pre-existing spinal disease; however in a report by Hebl et al., [11] it was felt that the history of spinal surgery did not increase the risk of technical complications or block success, but did make placement potentially more difficult. The group felt that midline or lateral approach may be especially difficult if there were bone grafting or posterior fusions since success would only occur if the block was performed at areas that were unfused.
Prone (for isobaric only), sitting or lateral approaches for spinal anesthesia insertion have all been described, however is must be kept in mind that ultimately the spinal should be placed above the level of any lumbar stenosis (and below the level of the cord) since very tight stenotic lesions may affect spread of local anesthetic [12].
4. Additional issues regarding agent selection
Currently procaine, lidocaine, mepivacaine, tetracaine, ropivacaine, levobupivacaine, bupivacaine are all approved in the US for intrathecal use. As mentioned previously, bupivacaine is typically the choice of agent due to its duration of action. Ropivacaine and L-bupivacaine (S-enantiomer of bupivacaine) have a less cardiotoxic profile compared to bupivacaine; however, the overall volume utilized in spinal anesthesia is so small that this is of little concern. Tetracaine, which is an ester-based local anesthetic may also be utilized and may be in prepared in isobaric, hypobaric or hyperbaric solutions. Typically, because fixation for tetracaine takes a long time, it is not routinely utilized.
Lidocaine has a long history of safe use, but its association with transient neurologic symptoms (TNS) would make it a potentially poor choice for lumbar spine surgery. TNS, initially described in 1993[13] presents with the onset of back and leg pain post-procedure. It has been associated with positioning and can be found with all local anesthetics, but has been reported most frequently with lidocaine. Still there is no definitive proof that the local anesthetics are the source for TNS and some studies have strongly encouraged the discontinuation of this term to avoid linking the previous clinical symptoms with the use of lidocaine [14].
It is well known that determinants for level of spinal analgesia depend on the dosage administered as well as the baricity [15]. The total dose of bupivacaine administered is very important since the concentration of the medication changes after mixing with the CSF and the change in concentration has on the quality or level of the spinal anesthesia [16]. In addition, other studies have determined that there is non-homogenous spread of local anesthetics in the CSF [4]. Typically there is an epicenter of local anesthetic concentration and subsequent spread away from the site with decreasing levels of local. The decreased concentration at these sites leads to a variation in uptake of the anesthetic in the level of the cord.
5. Additives
As with most spinal anesthetics, there may be the desire to place additives to enhance the quality of the block utilized for lumbar surgery. Opioids, vasoconstrictors, alpha-2 agonists and neostigmine [17] have all been described and each has associated risk and benefits. Opioids tend to work synergistically with local anesthetics and are known to enhance the quality of the block. However, these agents are also associated with urinary retention (a controversy that will be discussed later). Concern regarding the addition of vasopressors and spinal blood flow is unfounded and their overall mechanism of action is unclear and inconsistent depending on the agent chosen [18].
Clonidine, an alpha-2 agonist, has been utilized frequently in spinal surgery. It is known to block the motor and sensory affects associated with tetracaine, but sensory affects are much longer. The proposed mechanism is related to the vasoconstrictive properties and the antinociception associated with adrenergic stimulation and activation of the descending noradrenergic pathways [18, 19]. Other investigators noted that patients who underwent spinal surgery and received 150mg of clonidine epidurally displayed lower postanesthesia care unit pain scores and less demand for analgesics as well as improved postoperative hemodynamics [20]. These results were confirmed in a study by Farmery and Wilson-MacDonald who found that utilization of an epidural catheter with clonidine after spinal surgery (under general anesthesia) led to profound and prolonged postoperative pain relief along with a reduction in postoperative nausea and vomiting [21]. The use of clonidine will be discussed further in the section regarding pain control.
6. Benefits
Some of the benefits of performing spinal anesthesia for lumbar surgery include a perceived decrease in blood loss, lower rates of thromboembolism, less hypertension or tachycardia, and better postoperative pain control. In addition, during spinal anesthesia, the patient is only mildly sedated with a benzodiazepine or propofol. This allows for a more reliably assessment of potential positioning issues that will be discussed later.
7. Blood loss
It has been observed that there is a perception of less surgical blood loss associated with cases performed under spinal anesthesia. Preload is markedly reduced during spinal anesthesia and there is a resultant drop in mean arterial pressure (MAP). This reduction will produce a decrease in vertebral interosseous pressure during neuraxial anesthesia which may lead to reduced blood pressure within the bone itself, considered the main source of bleeding during posterior lumbar spine surgery [22]. The mechanism in which spinal anesthesia may reduce blood loss may possibly be related to the fact that spinal anesthesia leads to a marked reduction in the high venous pressure that occurs in response to sympathetic activity provoked by pain produced by tissue damage during surgery [23]. On the contrary, inhalational anesthesia does not totally block these sensory signals but these signals are effectively inhibited with spinal anesthesia.
Spinal anesthesia permits spontaneous ventilation during surgery that in the prone position results in lower intrathoracic pressure compared with general anesthesia using positive pressure ventilation. The avoidance of positive pressure ventilation results in less distension of the epidural veins and a reduction in intrathoracic pressure. This reduction produces a better blood return through the vena cava and less blood flow and distention of the venous plexus for better surgical exposure [24]. The diminished blood loss observed during spinal anesthesia can facilitate removal of the disc or vertebral body and result in less surgical time observed because of reduced time to affect hemostasis.
It is also worth reviewing the hemodynamic effects of spinal anesthesia since they play a significant role in the reduction of blood loss. Spinal anesthetics are known to produce a sympathetic denervation that is more profound as the level of anesthesia progresses. When a partial sympathetectomy occurs, as is routine with a well-controlled spinal, the area of tissue above the level of sympathetic denervation displays a reflex increase in sympathetic tone. This helps to compensate for the peripheral vasodilation that subsequently occurs. Arterial and arteriole beds are affected but do not maximally vasodilate due to the maintenance of autonomous tone. Thus, it is common to see a mild decrease in total peripheral vascular resistance of approximately 15-18% assuming cardiac output is maintained [4].The venous circulation, however, is profoundly affected and since, in spine surgery, the extremities lie below the level of the heart, there is a significant amount of pooling of the blood in the dependent capacitance vessels. If normovolemia is not maintained then a significant decrease in cardiac output is seen.
8. Blood pressure and coronary circulation
There have been numerous studies comparing spinal with general anesthesia, and in most instances there has been minimal intraoperative hemodynamic differences between the two techniques. In many of the comparisons, total anesthesia times were shorter with the use of spinal as compared to general anesthesia (GA) [3, 25, 26]. (Table 1) In all of these studies it was noted that mean arterial pressure and heart rate were lower in patients receiving spinal anesthesia. The incidence of bradycardia was lower in spinal anesthesia as well as the incidence of tachycardia. The observation that spinal anesthesia maintains hemodynamic stability with little effect on heart rate was noted in a recent study by Attari, et al [27]. In this study 72 patients underwent spine surgery with half assigned to general anesthesia and the other to spinal anesthesia. Statistically significant reductions in MAP and heart rate changes were noted in the spinal group. In addition there was enhanced surgeon satisfaction as well as a reduction in postoperative pain. These results were supported in another study which compared sixty patients undergoing lumbar disk surgery [28]. This group noted like Attari, that there were less episodes of tachycardia, hypertension and better postoperative pain with less nausea/vomiting in patients undergoing spinal. However, in their study, they found that surgeon satisfaction was greater in the general anesthesia group.
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t\tSpinal\n\t\t\t
\n\t\t\t
\n\t\t\t\tGeneral\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Total anesthesia time (min)
\n\t\t\t
106.6±3.2
\n\t\t\t
131.0±4.3*\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Surgical time (min)
\n\t\t\t
67.1±2.8
\n\t\t\t
81.5±3.6*\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Blood loss (mL)
\n\t\t\t
133±13
\n\t\t\t
221±32*\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Intravenous fluids (mL)
\n\t\t\t
1329±60
\n\t\t\t
1478±79
\n\t\t
\n\t\t
\n\t\t\t
Bradycardia
\n\t\t\t
14.0%
\n\t\t\t
22.9%
\n\t\t
\n\t\t
\n\t\t\t
Hypertension
\n\t\t\t
3.3%
\n\t\t\t
26.2%*\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Tachycardia
\n\t\t\t
14.8%
\n\t\t\t
21.3%
\n\t\t
\n\t\t
\n\t\t\t
Hypotension
\n\t\t\t
54.1%
\n\t\t\t
57.4%
\n\t\t
\n\t\t
\n\t\t\t
Ephedrine required
\n\t\t\t
36.1%
\n\t\t\t
22.9%
\n\t\t
\n\t
Table 1.
Intraoperative Data for Spinal versus Genera; Anesthesia Groups
Numeric dara expressed as mean ± SEM
Bradycardia and hypotension=decreases in heart rate (HR) and mean arterial pressure (MAP) to less than 80% of baseline values; tachycardia and hypertension=HR and MAP greater than 120% of baseline values.
*P<0.05 versus spinal anesthesia group.
Jellish et al. Spinal vs General Anesthesia for Spinal Surgery. Anesth Analg 1996;83:559-64
Another recent comparative study also found the incidence of tachycardia to be higher with general anesthesia [29]. They found the incidence of bradycardia to be similar, as well as intravenous fluids and operative times. They did note a higher incidence of hypotension with spinal anesthesia compared to the other studies. This may reflect the importance of the fluid preload prior to the placement of the spinal block which was not used in that study.
Patients undergoing lumbar procedures under spinal anesthesia seemed to have similar or better hemodynamic variables than patients having the procedure under general anesthesia. Less intraoperative hypertension is noted and less tachycardia is observed with spinal anesthesia. Tetzloff, et al. [30]. using power spectral heart rate data which included low frequency, high frequency and the ratios of low/high frequency demonstrated that with spinal dermatomal levels below T8, the prone position resulted in a significant increase in heart rate with spinal anesthesia and a significant decrease in blood pressure with general anesthesia. Low frequency and low frequency/high frequency ratios were unchanged in the spinal anesthesia group. The preservation of low frequency heart rate variation may reflect better presentation of cardiac sympathetic activity with spinal anesthesia. Low thoracic levels of spinal anesthesia preserve the sympathetic efferent signals to the myocardium more than general anesthesia. Placing a patient in the prone position may reduce venous return and preload which is better tolerated with a spinal anesthetic.
Given the fact that many of the patients presenting for spinal surgery may have co-morbidities such as coronary artery disease, one may be concerned regarding the presence of hypotension. It has been noted that the decrease in MAP results in a significant decrease in coronary blood flow. One investigator found that there was a 48% decrease in myocardial oxygen supply during spinal anesthesia but there was also a 53% decrease in myocardial oxygen requirements [31]. There are three reasons for the decrease in myocardial oxygen requirement that include the reduction in afterload, preload and heart rate. Heart rate reduction is related to both the vagal predominance that occurs after sympathetectomy as well as the decrease in right atrial pressures and pressures in the great veins (via intrinsic chronotropic stretch receptors) which leads to bradycardia [4].
9. Pain control
Improving postoperative analgesia in spine surgery patients is also a challenge. Though many of the patients who receive spinal anesthesia for their spine procedure have reduced pain scores and analgesia requirements in the immediate postoperative period, their analgesic requirements are similar to general anesthesia patients 24 hours after surgery. Several studies comparing the two anesthetics demonstrated that patients who had spinal anesthesia had lower pain scores and analgesic requirements [3, 25, 29]. In many of the studies the lower pain scores may result from two different mechanisms. Patients who received spinal anesthesia had much lower initial pain scores than general anesthesia patients. There may be a preemptive effect in which spinal anesthesia attenuates pain by inhibiting afferent nociceptive pathways [32]. Also, since sensory recovery will lag behind motor recovery after spinal block, the patients receiving neuroaxial anesthesia likely had residual blockade even though motor function had returned.
Pain after spine procedures is a combination of musculoskeletal, usually derived from surgical trauma and neuropathy that is radiating and burning in nature and is secondary to the nerve compression or injury that required the laminectomy or discectomy. This type of pain responds poorly to opioids but has been shown to be relieved with the administration of epidural clonidine [33].
Sympathetic hyperactivity is reduced from the administration of epidural clonidine through three mechanisms. It may inhibit nociceptor neurotransmitter release in the dorsal horn and sympathetic outflow in the spinal cord intermediolateral column. In addition, it may inhibit norepinephrine release from sympathetic terminals in the periphery. Clonidine may also be absorbed into the systemic circulation where it reaches alpha 2 adrenoreceptors of the dorsal horn and provides analgesia by increasing the antinoceptive threshold of the spinal cord which activates the descending noradrenergic pathway to inhibit small diameter afferent induced substance P release [19].
The addition of epidural clonidine to spinal anesthetics for spine surgery has been found to reduce pain in patients receiving rescue analgesics to increase the time to the first rescue dose of analgesics for pain. Clonidine prolongs sensory and motor block associated with intrathecal bupivacaine [34]. Patients who received epidural clonidine along with their spinal anesthetic required their first analgesia dose 3.7 hours after surgery [20]. Another study showed that by using a small dose combination of epidural morphine and clonidine for postoperative analgesia after lumbar disc surgery reduced pain with movement after surgery[35]. These patients experienced a frequent incidence of difficult micturition not observed when epidural clonidine was administered without added opioids.
The infiltration of local anesthetics into the surgical wound has also been noted to prolong postoperative analgesia after lumbar spine surgery. The infiltration of 0.375% bupivacaine subcutaneously has been noted to produce an analgesic effect which lasted approximately 13 hours [36]. With the use of newer local anesthetics that have a timed release, this type of analgesia could be even more prolonged [37].
The success rate of the spinal anesthetic in patients with spinal pathology is also a consideration. Some practitioners have noted ineffective spread or patchy block with spinal anesthesia after previous spine surgery. There are a number of problems that could affect the spread of the local anesthetic including altered anatomy which may make placement of the spinal more difficult. Insertion of a spinal needle through the site of a fusion may be complicated by scar tissue and bone graft material. Intradural scarring commonly referred to as arachnoiditis, characterized by an inflammation of the pia arachnoid membrane surrounding the spinal cord may alter the anatomy of the subarachnoid space and limit the spread of local anesthetics [38]. Most investigators have noted a high success rate of spinal anesthesia after previous spinal surgery with failure rates of less than 1% [26].
10. Venous thromboembolism
Finally, spinal anesthesia for lumbar spine surgery also decreases the incidence of lower extremity thromboembolic complications [39]. The most likely explanation is the modulation of the hypercoagulable state that occurs after surgery. Neuraxial anesthesia with local anesthetics has been shown to enhance fibrinolytic activity, reduce antithrombin III activity to normal levels and attenuate increases in postoperative platelet activity [40].
11. Postoperative nausea
Many studies have noted a reduced incidence in postoperative nausea and vomiting. The increased need for narcotic analgesics in patients receiving GA may be a contributing factor to the higher amount of emetic symptoms with GA. In addition, anesthetic factors such as the use of N2O (nitrous oxide) or the administration of certain pungent inhalational anesthetics could produce more nausea after surgery. The incidence of nausea and vomiting has also been demonstrated to be less with low level T-8 or bolus spinal anesthesia compared to GA because of improved gastric emptying.
12. Post-anesthesia care unit (PACU)
Hemodynamics in the PACU have been noted to be better with spinal anesthesia compared to GA. Both heart rate and blood pressure have been noted to be higher in GA patients upon admit to PACU. (Figure 1) This may be due to the increased sympathetic activity during emergence from anesthesia and possibly undertreated pain with opioids or other analgesics prior to emergence. Patients who had spinal anesthesia were much less hypertensive throughout their recovery room stay.
Figure 1.
Heart rate (HR) and mean arterial pressure (MAP) values at admission (admit) and at 10, 20 and 30 min after adimission to the postanesthesia care unit (PACU). Intergroup differences in HR (A) were noted at PACU admission but did not persist through 20-min time point. Intergroup differences in MAP (B) were also observed at PACU admission and were still present 30 min after admission. *Significant difference compared to spinal group at a P<0.001 level.
13. Rare complications
Complications associated with spinal anesthesia for lumbar surgery have been relatively rare. There have been no reports of post-dural puncture headache even when a dural tear occurred during surgery [9].A possible explanation is that surgery near the spinal cord elicits inflammatory responses that help seal any small puncture site. In addition, the presence of small amounts of post-procedural blood may serve to seal the site similar to applying a blood patch. Other complications associated with spinal anesthesia may play a role in these lumbar cases and will be discussed further.
14. Neurological complications
In general, spinal anesthesia has a long history of safety. In the widely quoted study by Dripps and Vandam, properly performed spinal anesthesia is safe. A study which reviewed over 10,000 spinal anesthetics failed to find any major neurologic sequelae [41]. However, in a retrospective study by Hebl et al, [11], one of the major findings was that the patient population with pre-existing spinal stenosis or disk disease had an increased risk of worsening pre-existing deficits or development of new deficits after neuraxial blockade. In addition, those patients with multiple neurologic diagnoses have even higher risk. It was noted that the frequency of persistent postoperative neurologic deficits was approximately 1.1% (95% CI 0.5-2%) with prior epidemiological investigations being somewhere between 1:1000 to 1:10,000.
The group went on to propose that the neurological problems seen may have been the result of a “double-crush” phenomenon [42].In double-crush syndrome there is a pre-existing lesion (proximal) and distal to the lesion there is another compression that renders the nerve vulnerable to further injury. Neuraxial anesthesia may add insult by the additive effects of neural ischemia and local anesthetic toxicity. In spinal anesthesia, local anesthetic toxicity resulting from maldistribution and high concentrations is well known. This toxicity has resulted in cauda equina syndrome seen with microcatheters utilized for continuous spinal anesthesia [43]. Though these studies are worrisome, there have yet to be reports of neurological complications from spinal anesthesia used for lumbar spine surgery.
15. Cardiac arrest
Though it has been mentioned previously that there is less observed bradycardia during spinal anesthesia for spine surgery, there still exists the concern for profound bradyarrhythmias and cardiac arrest. In a review of studies about cardiac arrest during spinal anesthesia, investigators found an overall incidence of 0.07% (7 for every 10,000 patients) [44]. More than half were in patients under the age of thirty and this may explain the paucity of events during lumbar surgery with an older patient population. The mechanism proposed is a result of the blockade of sympathetic efferents that leads to bradyarrhythmias via vagal predominance. The presence of vagal mediated bradycardia and decreased venous return from venodilation combines to cause further issues. It is well known that right atrial pressures are decreased in low spinals (36%) and high spinals (up to %53) [45]. This decrease in preload elicits reflexes that cause severe bradycardia [46]:
Firing of low pressure baroreceptors in the right atrium
Bezold-Jarisch reflex
The Bezold-Jarisch reflex (BJR) is triggered by the stimulation of intracardiac mechanoreceptors that subsequently lead to bradycardia, hypotension and vasodilation [47]. According to Mackey [46] and Kinsella [48], the mechanoreceptors associated with BJR are usually triggered by distention, but when there is a decrease in venous return (as seen with prone position and spinal anesthesia), along with an increase in inotropic state (compensatory response to decreased preload), the walls of the ventricle may deform and trigger the mechanoreceptors similar to what is seen during distention. This results in a paradoxical vasodepressor response. This vasodepressor response along with the pre-existing bradycardia may lead to cardiac arrest. It is interesting to note that the BJR is also triggered by spinal anesthesia via 5-HT3 receptors in the vagal nerve endings. The 5-HT3 trigger can be abolished by the administration of ondansetron, an antagonist to 5-HT3.
Risk factors identified by Pollard [44] that are associated with cardiac arrest include the following:
Baseline heart rate <60
ASA status I
Use of beta blocking drugs
Sensory level above T6
Age <50 years
Prolonged PR interval
Recommendations include the maintenance of preload whenever possible, followed by a step-wise escalation of pharmacological intervention starting with atropine (0.4-0.6 mg), then ephedrine (25-50 mg) and finally, if still not responsive, epinephrine (0.2-0.3 mg) intravenously.
16. Urinary retention
Urinary retention has also been associated with spinal anesthesia. However, in several studies the incidence of urinary retention was not different with spinal or general anesthesia. In most situations when spinal anesthesia is associated with urinary retention, opioids were added to the local anesthetic [49]. Subarachnoid opioids clearly increase the incidence of urinary retention, as well as respiratory depression, drowsiness and pruritis. We tend not to utilize opioids as part of the spinal anesthetic.
17. Other potential problems
17.1. Prone positioning issues
Positioning related neurologic injury has also been noted to occur more frequently during spinal surgery in the prone positioned patient [50].The most prevalent is injury to the brachial plexus. Injury to the brachial plexus is attributed to its long and superficial course in the axilla and its attachment to two firm points of fixation, the vertebrae proximally and the axillary fascia distally in the arm. The plexus also passes directly beneath the clavicle and above the first rib (Figure 2). This close proximity to freely moving bony structures makes this nerve bundle prone to stretching and compression from arm malposition. Brachial plexus injury occurs most frequently when the patient is in the prone position, especially when the arms are adducted more than 90°. In this position traction on the plexus and compression between the clavicle and first rib is responsible for the neurologic deficit. If patients are placed in the lateral decubitus position, they may be subject to brachial plexus injury from compression when the dependent arm and shoulder are positioned between the thorax and the table.
Figure 2.
Possible areas of injury to the brachial plexus: (A) neck rotation away from arm may cause stretch and compression between clavicle and first rib; (B) injury to plexus at humeral head; (C) compression or ulnar nerve in cubital tunnel.
The eyes and ears are also of concern in prone positioned patients. Pressure on the globe or hypotension, with venous congestion, could result in increased intraocular pressure and possible blindness related to ischemic injury to the optic nerves. There have been reports of increased extraocular pressure resulting from using a cushion or horseshoe head-rest to position the face [51, 52].In addition, ECG monitoring wires or oral gastric tubes, if present, could migrate under the head during prone positioning. The face could lie directly on these objects causing pressure induced ischemia to the face or eyes. These problems are avoided with the use of spinal anesthesia. The patient may be only mildly sedated and using their upper body can help to self-position with their head on a pillow or cushion. If abnormal positioning occurs, the patient will feel discomfort and alert the practitioner to the problems. They can also move their arms and head to avoid prolonged abnormal or awkward position that could produce injury.
17.2. Sedation issues
A spinal anesthetic with an awake or sedated patient who is spontaneously breathing may not be ideal for all spine surgeries. Prone positioning on different positioning systems can affect cardiac output with the possibility of a significant decrease in stroke volume and cardiac index in conjunction with the development of increased vascular and pulmonary resistance [53] (Figure 3). Patients with normal cardiac status can usually tolerate these changes. However, patients with compromised cardiac status might not be able to tolerate supine to prone positioning, especially with decreased sympathetic tone. A large drop in blood pressure or cardiac output could affect consciousness and spontaneous breathing.
Figure 3.
Description of the five different positioning systems used in this study. The type of body support each positioner provides and lower extremity position in relation to the heart are also described.
In addition, surgeries that may last more than 2-3 hours may not be conducive for spinal anesthesia. The tolerance for prone positioning on a frame in an awake or mildly sedated patient is approximately 2 hours. Patients become restless and tend to begin to adjust position in order to relieve the strain of maintaining one position for a prolonged period of time. A cooperative surgeon who can perform the procedure in a reasonable amount of time is imperative.
We also believe one to two level laminectomies or discectomies are ideal for this technique. Larger laminectomies for multi-level fusions would be too prolonged to be well tolerated in the spontaneously breathing sedated patient. Body habitus must also be considered in selecting the appropriate patient for spinal anesthesia for spine surgery. Large, obese patients with protuberant abdomens may not tolerate prone positioning well, especially if breathing spontaneously. Their ability to breathe against the restrictive effects of a large abdomen, especially if not adequately decompressed by the positioning system, could cause the patient undue anxiety and intolerance because of the inability to adequately deep breath.
18. Summary
Spinal anesthesia is an appropriate technique for lumbar spine procedures of two to three hours duration. An appropriate patient and cooperative surgeon will also facilitate the use of this anesthetic technique. The ability of the patient to self-position and guard against position related injury is of major benefit. A better postoperative experience with less pain, nausea and hemodynamic stability make this technique superior to general anesthesia for overall patient satisfaction and reduced morbidity. Short term pain control is definitely improved with spinal anesthesia and new and improved methods for providing longer term analgesia may make this anesthetic technique even more beneficial, especially if contemplating same day discharge and reduced hospital stay.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/47182.pdf",chapterXML:"https://mts.intechopen.com/source/xml/47182.xml",downloadPdfUrl:"/chapter/pdf-download/47182",previewPdfUrl:"/chapter/pdf-preview/47182",totalDownloads:4933,totalViews:984,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"September 13th 2013",dateReviewed:"June 9th 2014",datePrePublished:null,datePublished:"September 3rd 2014",dateFinished:"July 8th 2014",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/47182",risUrl:"/chapter/ris/47182",book:{slug:"topics-in-spinal-anaesthesia"},signatures:"W. Scott Jellish and Steven Edelstein",authors:[{id:"169252",title:"Dr.",name:"W. Scott",middleName:null,surname:"Jellish",fullName:"W. Scott Jellish",slug:"w.-scott-jellish",email:"wjellis@lumc.edu",position:null,institution:null},{id:"170262",title:"Dr.",name:"Steven",middleName:null,surname:"Edelstein",fullName:"Steven Edelstein",slug:"steven-edelstein",email:"sedelst@lumc.edu",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Technique of spinal anesthesia for spine surgery",level:"1"},{id:"sec_3",title:"3. Baricity issues",level:"1"},{id:"sec_4",title:"4. Additional issues regarding agent selection",level:"1"},{id:"sec_5",title:"5. Additives",level:"1"},{id:"sec_6",title:"6. Benefits",level:"1"},{id:"sec_7",title:"7. Blood loss",level:"1"},{id:"sec_8",title:"8. Blood pressure and coronary circulation",level:"1"},{id:"sec_9",title:"9. Pain control",level:"1"},{id:"sec_10",title:"10. Venous thromboembolism",level:"1"},{id:"sec_11",title:"11. Postoperative nausea",level:"1"},{id:"sec_12",title:"12. Post-anesthesia care unit (PACU)",level:"1"},{id:"sec_13",title:"13. Rare complications",level:"1"},{id:"sec_14",title:"14. Neurological complications",level:"1"},{id:"sec_15",title:"15. Cardiac arrest",level:"1"},{id:"sec_16",title:"16. Urinary retention",level:"1"},{id:"sec_17",title:"17. Other potential problems",level:"1"},{id:"sec_17_2",title:"17.1. Prone positioning issues",level:"2"},{id:"sec_18_2",title:"17.2. Sedation issues",level:"2"},{id:"sec_20",title:"18. Summary",level:"1"}],chapterReferences:[{id:"B1",body:'Mixter WJ, Barr JS. Rupture of the intervertebral disk with involvement of the spinal cord. NEJM 1934;211:210-15.'},{id:"B2",body:'Williams RW. Microlumbar discectomy: A conservative surgical approach to a virgin herniated lumbar spine. Spine 1978;3:175-82.'},{id:"B3",body:'Jellish WS, Thalji Z, Stevenson K, et al. 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J Neurolog Spine 2010;13:552-8.'},{id:"B51",body:'Bekar A, Tureyen K, Aksoy K. Unilateral blindness due to patient positioning during cervical syringomyelia surgery, unilateral blindness after prone positioning. Neurosurg Anesth 1996;8:227-9.'},{id:"B52",body:'Grossman W, Ward WT. Central retinal artery occlusion after scoliosis surgery with a horse shoe headrest: Case report and literature review. Spine 1993;18:1226-28.'},{id:"B53",body:'Dharmavarm S, Jellish WS, Nockels RS. Effect of prone positioning on hemodynamic and cardiac function during lumbar spine surgery. The Spine Journal 2006;31:1388-93.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"W. Scott Jellish",address:"wjellis@lumc.edu",affiliation:'
Department of Anesthesiology, Loyola University Medical Center, Maywood, USA
Department of Anesthesiology, Loyola University Medical Center, Maywood, USA
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1. Introduction
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Cerebral ischemia is the main disorder of cerebrovascular diseases; currently, according to data from the World Health Organization, it is the second main cause of death worldwide [1] and the third principal cause of disability. In the last 40 years alone, the incidence of this condition has more than doubled in people from low and middle-revenue countries [2].
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The increment in the incidence of this condition is due to increased risk factors as diabetes mellitus, hypertension, obesity, hyperlipidemia, and increased longevity of the population [3]. These factors allow the development of atherosclerosis, which is the main cause of ischemia [4]; thereby, it is considered that for the coming years this scenario will be maintained while strategies to reduce these factors are progressing.
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Stroke is distinguished by the brusque reduction of blood flow; therefore, the levels of oxygen and glucose are also reduced significantly, to the point of altering the metabolic activities of the neural tissue [5]. As a consequence of the latter, the low production of ATP and the acidification of the environment induce the depolarization of the membranes causing the intracellular increase of Ca2+ that is added to the one released by the endoplasmic reticulum and mitochondria [6].
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Neuronal depolarization causes the release of glutamate which, when bound to its ionotropic N-methyl-D-aspartate (NMDA) and -amino-3-hydroxy-5-methyl-4-isoxazolpropionic (AMPA) receptors, achieves greater depolarization and, as a consequence, conditions of excitotoxicity [7]. These conditions are coupled with the production of free radicals [8] and lead to cell death by the activation of molecules that induce necrosis and apoptosis [9].
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Along with the lesion caused by the decrease in blood flow, the immune response is added to the events involved in both the detriment of the tissue and its protection.
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2. Immunological response in stroke
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Inflammation is usually present before the development of arterial obstruction that gives rise to the ischemic event. The development of atherosclerosis is accompanied by the production of oxygen free radicals (ROS), expression of cell adhesion molecules, and production of proinflammatory cytokines as IL-1β and tumor necrosis factor-α (TNF-α) by endothelial cells [10].
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Shortly after occlusion, endothelial cells express a greater amount of intercellular adhesion molecules (ICAM), deposition of mannose binding lectin molecules that trigger activation of the complement pathway [11], producing higher amounts of ROS. The overproduction of ROS activates the prostaglandin pathway that stimulates the production of matrix metalloproteinases (MMP) that even though degrading constituents of the extracellular matrix, reshape the vascular endothelium seeking to protect of the blood brain barrier (BBB) [12].
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The release of chemokines such as CCL2 allows endothelial permeability [13], leading to the translocation of P-selectin from Weibel-Palade bodies, as well as the expression of ICAM-1 and vascular cell adhesion molecule (VCAM)-1 and E-selectin, on the endothelial surface [14]. Theses phenomena, together with the damage of the extracellular matrix facilitate the extravasation of macromolecules and water, which causes the development of vasogenic edema [15]. Peripheral immune cells then enter the injured cerebral parenchyma [16] facilitating the loss of the integrity of the BBB.
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Neutrophils are the first leukocytes that migrate to the cerebral parenchyma; they have been detected since the first hour after ischemia and reach their maximum peak in 1–3 days [17]. In the clinic, it has been observed that the higher blood neutrophil count is associated with higher infarction volumes in patients with acute stroke [18].
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The second cell type that enters the neural tissue are monocytes, these infiltrate within 24 h of the onset of the ischemic event reaching its peak on day 3 [19]; their differentiation process toward macrophages and their activation will be determined by the molecular environment to which they arrive. This process is similar to that experienced by T lymphocytes, which reach the parenchyma 24–96 h post-ischemia [20].
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At the same time, the cells of the injured cerebral parenchyma release damage associated molecular patterns (DAMPs) that activate the microglia. Depending on the activation environment, the microglia can acquire a proinflammatory (M1) or anti-inflammatory (M2) phenotype [21]. In the M1 phenotype, the microglia acquires phagocytic capacity, produces NO, free radicals, and proinflammatory cytokines (e.g. TNF-α, IL-12 and IL-6) [22]. Some regions in the ischemic penumbra present an activation of M2 microglia distinguished by the production of anti-inflammatory and repair molecules, such as insulin growth factor 1 (IGF-1), IL-10, and arginase 1 [23].
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Some researchers suggest that the M2 phenotype is initially activated during the acute phase in the peripheral zone to the infarction [24], since it has been determined that the levels of IL-10, TGF-β, and CD206 increase from the first day after the lesion and reach the maximum point between 4 and 6 days, possibly trying to keep the viability of tissue. In addition, TGF-β induces the anti-inflammatory phenotype of microglia, related with enhanced proliferation and neuroprotection [25, 26].
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In contrast, some authors suggest that the first response is proinflammatory [27], due to the loss of regulatory mechanisms; when a stroke occurs there is an important activation of the M1 microglial phenotype [28].
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Although contradictory, both positions could be correct. The fact is that, M1 and M2 phenotypes actively participate in the response observed after ischemic event; however, in normal conditions, there is an important prevalence of the M1 phenotype leading the response to a proinflammatory reaction that, instead of helping, promotes more damage.
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On the other hand, perivascular macrophages and monocytes of peripheral origin that arrive at the injured parenchyma induce the synthesis of chemokines like CXCL1 and CXCL2, which are fundamental for recruiting more neutrophils to the injury site [29, 30]. The dendritic cells (DC) present a greater expression of the major histocompatibility complex II (MHCII) and the co-stimulant molecule CD80. This causes an important enhance in the interaction of T cells around and within the damaged areas inducing then a stronger immune response [31].
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When T lymphocytes are activated by antigen-presenting cells (APCs) toward a Th1 phenotype, the secretion of proinflammatory cytokines like as IFN-γ, TNF, and LT-α [lymphotoxin] increases. This cytokine profile, intensify proinflammatory response and thereby, tissue damage. Contrarily, when T cells are activated toward a Th2 phenotype they produce anti-inflammatory cytokines such as IL-4 and IL-10 [32]. These cytokines have been associated with tissue protection mechanisms and even increased neurogenesis. This immune response that exerts protective effects and limits the damage caused by ischemia [19] can be stimulated by immunomodulatory molecules such as copolymer-1.
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3. Copolymer-1
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Copolymer-1 [Cop-1], also known as glatiramer acetate (GA) or copaxone [trade name], is a blend of peptides formed by random sequences of four amino acids: glutamic acid, lysine, alanine, and tyrosine; these have a variable length from 45 to 200 amino acid residues and a molecular weight of 4000–9000 Da [33].
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Cop-1 was originally synthesized from mylelin basic protein (MBP) to identify the precise immunogenic sequence and provoke experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS); however, it did not present encephalitogenic characteristics [34]; on the contrary, it has suppressive and protective effects on EAE [35]. In the clinic, copaxone is able to diminish the relapse rate and improve the disability of patients with relapsing-remitting MS [36]. Copaxone obtained its approvement by the Food and Drugs Administration [FDA] of U.S.A. in 1996 and in Europe in 2001 [33].
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At this time, the exact mechanism by which Cop-1 exerts its protective effects is not known at all. Studies carried out in EAE suggest that Cop-1 has greater affinity for the MHCII binding site of APC when competing with peptide complexes derived from the MBP, specifically with the epitope 82–100 [37]. This competition may also be present among the complexes for the TCR binding site of the lymphocytes [38] that, when activated, induces a Th2 response [39].
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The Cop-1 response is distinguished by increased synthesis of IL-4, IL-5, IL-10, IL-13, and TGF-β [33, 40, 41, 42, 43]. Cop-1 has also been observed to increase the presence of regulatory T lymphocytes [44] and regulatory CD8+ T lymphocytes in patients with multiple sclerosis [45, 46].
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Another important effect of copolymer-1 is the production of growth factors, among which stand out; the brain derived neurotrophic factor [BDNF] [47, 48], IGF-1, [49] and neurotrophins NT-3 and NT-4 [47]. It is known that, in addition to inducing neuroprotection and neurorestoration, these growth factors are related to mechanisms such as memory and learning.
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The molecular basis by which Cop-1 exerts its neuroprotective effect has been evaluated in several in-vitro assays. The most explanatory results have been obtained in the analysis of the effect of Cop-1 on APC such as monocytes, microglia, and astrocytes.
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It has been showed that through the blockade of the nuclear factor kappa B [NF-kB], Cop-1 reduces the expression of the chemokine CCL5 [RANTES], which is upregulated by the presence of IL-1β [50] and TNF-α in human astroglial cells [51]. A similar effect has also been observed on the monocyte chemotactic protein-1 [MPC-1] and adhesion molecules VCAM-1 and selectin E in endothelial cells as well as COX2 and iNOS [52].
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It has also been observed that Cop-1 induces differentiation of type II monocytes independently of the binding of Cop-1 to MHCII. Weber et al. demonstrated that this differentiation is due to the fact that Cop-1 reduces the phosphorylation of the transcription factor STAT-1 by stimulating the expression of IL-10 and TGF-β [53].
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On the other hand, it has also been observed that Cop-1 has a direct effect on glial cells [microglia and astrocytes] which are activated in conjunction with T cells reducing STAT-1 and STAT-3 phosphorylation through increased expression of cytokine signaling suppressor (SOCS-1) and independently of IFNϒR, accompanied by a reduction of IL-12 by CD4+ T lymphocytes [54].
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Even though the molecular pathways by which Cop-1 acts are not yet completely established, the microenvironment induced by this compound is capable of allowing neuroprotection since it reduces the deleterious scenario that leads to neural death. Additionally, the new conditions could facilitate tissue restoration through the synthesis of growth factors.
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4. The effect of copolymer-1 on inflammatory diseases
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The beneficial effects showed by copaxone in patients with MS, even though the knowledge of its immunomodulatory mechanisms is partial, encouraged the evaluation of its effect in other experimental models.
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In the model of optic nerve lesion—which tries to reproduce the characteristics of secondary degeneration—Cop-1 demonstrated an interesting neuroprotective effect. Kipnis et al. [55] evaluated the effect of adoptive anti-Cop-1 T cell transfer and immunization with Cop-1 immediately after causing optic nerve contusion in Lewis rats; their results were very encouraging as they observed reduction in axonal degeneration, accumulation of T lymphocytes in injured areas and obtained a significant increase in IL-10 and BDNF in-vitro. In contrast, using a model of axon transection of the optic nerve, Blair and coworkers [56] found no beneficial effects of Cop-1. The difference in the results may be due to the different inflammatory response evoked by the type of injury (contusion or transection). Inflammation is more pronounced after contusion as compared to the one observed after a transection. It should be an issue to be studied by future investigations.
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Parkinson’s disease presents gradual reduction of dopaminergic neurons in the region of the substantia nigra and the striatum in the brain, it is not known the reason that causes the death of these neurons, but the pathology is characterized by a significant increase in oxidative stress, mitochondrial dysfunction, neuroinflammation, and cell death [57]. Patients with PD present an increase in TNF-β, IL-1β, and IL-6 and other inflammatory cytokines resulting from the activation of the macrophages and microglia towards a proinflammatory phenotype capable of releasing NO and superoxide radicals that further damage neural tissue facilitating disease progression [58].
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In the traditional model to induce Parkinson’s disease in mice [induction by 1-1-methyl-1,2,3,6-tetrahydropyridine], it was observed that Cop-1 reduces the degeneration of dopaminergic cells. This effect is achieved since Cop-1 induces the up-regulation in the protein expression of tyrosine hydroxylase [59, 60]. Additionally, it has been reported an increase in glial cell-derived neurotrophic factor (GDNF), reduction of activated microglia markers, and restoration of BDNF [61]. Based in these findings, several research groups consider COP-1 as a pharmacological alternative for this pathology which should be deeply studied [62].
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Copolimer-1 has also been tested in models of Alzheimer’s disease (AD). AD is a pathology that produces deposits of the β-amyloid protein, dystrophic neurites, loss of synapses and neurons, and elevated gliosis [63]. From the early stages of the pathology, it has been observed microgial activation toward a M2 neuroprotective phenotype that is modified as the disease progresses [64]. In advanced stages, a proinflammatory microenvironment characterized by the presence of cytokines such as IL-1β, TNF-α, IL-6 has been reported [65].
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After Cop-1 administration, microglia modulation toward a M2 phenotype is observed, in such a way as to promote neuronal survival and neural tissue repair in AD models [66]. Butovsky and coworkers showed that Cop-1 immunizations lead to enhanced infiltration of monocyte-derived macrophages into neural tissue with an anti-inflammatory profile expressing minor levels of TNF-α and high levels of IL-10, TGF-β1, and IGF1. In this scenario, phagocytosis of preformed fibrillar amyloid-β by bone marrow-derived macrophages increased dramatically after the administration of Cop-1. Also, to demonstrate benefits on the preservation of cognitive function, the investigation showed an important synaptic protection, plaque removal, restriction of astrogliosis, and modulation of the immune molecular environment [67, 68].
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Another pathology that evidenced the beneficial effects produced by Cop-1 is amyotrophic lateral sclerosis (ALS). This is a neurodegenerative disease known by the progressive depletion of the upper and lower motor neurons [69]. During pathogenesis, glutamate excitotoxicity, structural and functional anomalies of mitochondria, damaged axonal structure, and oxidative stress conducted by free radicals are strongly observed [70].
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In this case, Angelov and colleagues showed—in mouse models—that the administration of Cop-1 promotes the survival of motor neurons [71].
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The beneficial effects of Cop-1 on ALS have been assessed in a Phase II trial conducted by Mosley. This investigation evaluated the cytokine response of ALS patients treated with copaxone and showed that copaxone is capable of inducing a temporary change in cytokines from Th1 to Th2 phenotype [72].
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Copaxone is also tested in other pathologies at clinical settings. For instance, a phase III study on optic neuritis is now being conducted to evaluate the thickness of the layer of nerve fiber of the retina after 6 months of treatment. The results of this study have not been published. Finally, copaxone has been tested in Crohn’s disease and various types of carcinomas, studies where copaxone is in evaluation processes [73].
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The ability of Cop-1 to modify the proinflammatory milieu and to stimulate the production of growth factors encourages the idea of testing this compound on other pathologies with characteristics of secondary degeneration caused by inflammation. In line with this, the use of Cop-1 after stroke envisions an optimistic result.
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5. Effect of copolymer-1 on stroke
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As copolymer-1 has been shown to have beneficial effects in various models where neuroinflammation is a detrimental determinant, our group decided to evaluate its neuroprotective effect on cerebral ischemia. For this purpose, we used the median transient cerebral artery obstruction (tMCAO) model. Sprague-Dawley male rats were used. After being subjected to ischemia for 90 min, the rats were immunized in the interscapular region with a dose of 200 μg of Cop-1.
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In the first study, the animals were evaluated for neurological deficit at day 1 and day 7 post-ischemia using the Zea Longa scale [74]. Then, a histological analysis was performed using hematoxylin and eosin staining to determine neuroprotection. The results indicated that Cop-1 is able to avoid up to 85.1% increase in infarct size (4.8 ± 1.5 for Cop-1 vs. 32.2 ± 8 for control group; p = 0.004 mean ± SD; Figure 1A) and is able to reduce neurological deficit on day 7 post-ischemia.
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Figure 1.
Neuroprotective effect of the copolymer-1. (A) Infarction size reduction. (B) Effect of the copolymer-1 on the neurological deficit. n = 8. Each bar represents mean ± SEM. Two-way repeated measure ANOVA. Sidak’s post hoc multiple comparisons test. *p < 0.05; **p < 0.0.
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This neuroprotective effect may be due to the reduction of the proinflammatory cytokines TNF-α and IL-1β and the increase of IL-4, as was observed by the Manguin group in a model of ischemia in diabetic mice [75]. Additionally, the production of neurotrophic factors—known to be implicated in the processes of neural survival and proliferation of neuron precursor cells—could also be involved [76].
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On the other hand, recovery from neurological deficit can be achieved by diverse mechanisms; for instance, neuroprotection exerted by Cop-1 could be limiting tissue damage caused by inflammation, this could allow the proper functioning of remaining neuronal connections. Functional recovery could also be the result of neurogenesis induced by Cop-1. Neurogenesis is a phenomenon that can replace neurons that died during the ischemic insult by allowing the substitution of neuronal circuits and thus neurorestoration.
\n
Our study provided evidences about the neuroprotective effect of Cop-1; however, the fact that Cop-1-induced T cells are able to produce neurotrophic factors, led us to think that, it was imperative to investigate if behind the clinical recovery there was also a possible neurogenesis phenomenon.
\n
In the following study, we evaluated whether Cop-1 induces neurogenesis in the two neurogenic niches of the adult brain: in the subventricular (SVZ) and the subgranular zone of the dentate hippocampus gyrus (SGZ) [77]. To accomplish the evaluation, we performed an immunofluorescence technique using a double marking of 5-bromo-2′-deoxyuridine (BrdU) and doublecortin (Dcx) at 7 and 60 days after ischemia.
\n
The results were very encouraging, the neurological recovery caused by Cop-1 was observed from day 7 post-ischemia as in the first experiment [78] and was improving even in the chronic phase at 60 days (Figure 1B). The number of neuroblasts in the groups treated with Cop-1 was significantly higher in the two neurogenic niches at both 7 and 60 days in the SVZ and SGZ (Figure 2). This neurogenic phenomenon correlated with the clinical recovery of treated rats. Simultaneously, an important increase of NT-3 was observed in the area of the ischemic penumbra [79].
\n
Figure 2.
Effect of copolymer-1 on neurogenesis at 7, 14, and 60 days. (A) Neurogenesis in SVZ at 7 and 60 days. (B) Neurogenesis in SGZ at 7 and 60 days. (C) Neurogenesis in SVZ and SGZ at 14 days. n = 8 in A and B. n = 5 in C. Each bar represents mean ± SEM. Two-tailed Mann-Whitney U test. Dunn’s post hoc multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001. SVZ: Subventricular zone and SGZ: Subgranular zone.
\n
Cop-1-induced neurogenesis has been evaluated in other animal models such as EAE [47], Alzheimer [66], and recently in the model of permanent cerebral ischemia in diabetic male mice C57Bl6 [75]. Regarding the latter, it is important to mention that, in a previous experiment carried out by the same group, they did not observe improvement in the neurological function nor reduction in the volume of the infarction. These findings could be the result of the use of inappropriate evaluation techniques [80] as in their most recent study, they observed a reduction in infarct size of up to 30–40% and an increase in neurogenesis 7 days after permanent ischemia in the SVZ. In addition, they found a reduction of proinflammatory cytokines such as TNF-α, IL-1β, and a significant increase of IL-4 and IL-10 [75].
\n
Neurogenesis is a mechanism widely regulated by signals that stimulate the stem cells of neurogenic niches [81]; many of these signals are produced by the choroid plexus (CP), which is a complex structure of cells considered an interface that mediates communication between the immune system and the cerebral parenchyma [82]. Therefore, trying to analyze the mechanism by which Cop-1 induces neurogenesis, we evaluate whether Cop-1 modifies the microenvironment of CP, 14 days after tMCAO.
\n
In the third investigation, we evaluated neurological recovery—which was observed according to our previous experiments [78, 79], neurogenesis and the expression of proinflammatory (IL-1β, TNF-α, INF-ϒ, and IL-17) and anti-inflammatory cytokines (IL-4 and IL-10) as well as the concentration of growth factors (BDNF, NT-3 and IGF-1) at the CP (Figure 3).
\n
Figure 3.
Effect of the copolymer-1 on the expression of growth factors and IL-10. Gene expression of: (A) BDNF; (B) NT-3; (C) IGF-1; and (D) IL-10. Bars represent mean ± SEM of 5 rats from each group. *p < 0.05, **p < 0.001. Mann-Whitney U test. Dunn’s post hoc multiple comparison test.
\n
In this experiment, we again proved a significant increase of neurogenesis in the groups treated with Cop-1 in both, the SVZ and SGZ [83]. This data was similar to that previously reported [79]. As for the expression of proinflammatory cytokines, we only found significant differences in the expression of IL-17, which was observed reduced in the groups treated with Cop-1. With respect to anti-inflammatory cytokines, only IL-10 was significantly increased. In this investigation, we also found a significant increase of growth factors (BDNF, NT-3, and IGF-1) in the CP [83].
\n
Both growth factors and IL-10 have been reported to be directly involved in the stimulation of SVZ and SGZ stem cells; specifically, IL-10 has been observed to induce stem cell proliferation but not differentiation in primary cultures [84]. Moreover, IL-10 has immunomodulatory capacity as it inhibits the synthesis and release of proinflammatory cytokines such as TNF-α, IL-6, and IL-1β that are known to affect neurogenesis [85]. Moreover, growth factors such as NT-3 maintain viable stem cells from neurogenic niches facilitating plasticity [86]. BDNF promotes the proliferation and survival of neuroblasts [87] and IGF-1 promotes stem cell differentiation and migration of neuroblasts [88]. Therefore, this investigation allowed to demonstrate that Cop-1 is capable of raising the expression of IL-10 and growth factors, which have beneficial effects on neurogenesis.
\n
In order to know if Cop-1 modulates the number of leukocytes in CP and to know if these intervene in the synthesis and release of growth factors and IL-10, we evaluated the cell types present in the cerebrospinal fluid in animals submitted to tMCAO and Cop-1 therapy. The results showed a significant increment in CD8+ T cells, which positively linked with the increase in growth factors and IL-10 [unpublished data].
\n
The increase in CD8+ T lymphocytes has been observed as an effect of copaxone immunization in patients with MS [46]. In addition, experiments performed in the EAE model have considered these cells indispensable for the development of the beneficial effect of Cop-1 [89]. However, it is necessary to identify the nature of these cells and whether the type of CD8 T lymphocytes is of a regulatory phenotype.
\n
Finally, the combination of Cop-1 with other strategies like polyunsaturated fatty acids has shown optimistic results as together, they have a greater capacity to significantly reduce the size of the infarction in the tMCAO model [unpublished data].
\n
\n
\n
6. Conclusion
\n
The existing evidence of the effect of Cop-1 in the tMCAO model has been very encouraging, as it shows a significant neurological recovery. This beneficial effect could be caused by modulatory mechanisms that allow the increase of IL-4 and the reduction of TNF-α and IL-1β at the lesion site, promoting then neuroprotection. Additionally, neurological recovery could also be reinforced by the changes induced by Cop-1 at the CP as the increase of IL-10 and growth factors in this site stimulate neurogenesis after ischemia. We consider that more investigations are needed in order to analyze in greater detail the mechanism by which Cop-1 acts so that in the medium term, it may be considered as a pharmacological alternative for patients suffering from a cerebrovascular event.
\n
\n\n',keywords:"cerebral ischemia, copaxone, neurogenesis, protective autoimmunity, neuroregeneration, neuroprotection",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/71298.pdf",chapterXML:"https://mts.intechopen.com/source/xml/71298.xml",downloadPdfUrl:"/chapter/pdf-download/71298",previewPdfUrl:"/chapter/pdf-preview/71298",totalDownloads:256,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 22nd 2019",dateReviewed:"January 24th 2020",datePrePublished:"March 2nd 2020",datePublished:"November 26th 2020",dateFinished:"March 2nd 2020",readingETA:"0",abstract:"Stroke is a pathology of great relevance worldwide as it currently occupies the second motif of death and the third reason of disability. Although exits some therapies that are used successfully in the clinic, a very high percentage of patients do not have the opportunity to benefit from them; therefore, it is imperative to propose other alternatives that may favor more patients. In this chapter, we briefly review the inflammatory response induced by stroke and also its deleterious and protective effects. We will describe the characteristics of copolymer-1 and the effects that this compound has shown in models of cerebral ischemia.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/71298",risUrl:"/chapter/ris/71298",signatures:"María Yolanda Cruz Martínez, Melanie Tessa Saavedra Navarrete and José Juan Antonio Ibarra Arias",book:{id:"8087",title:"Neuroprotection",subtitle:"New Approaches and Prospects",fullTitle:"Neuroprotection - New Approaches and Prospects",slug:"neuroprotection-new-approaches-and-prospects",publishedDate:"November 26th 2020",bookSignature:"Matilde Otero-Losada, Francisco Capani and Santiago Perez Lloret",coverURL:"https://cdn.intechopen.com/books/images_new/8087.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83880-440-4",printIsbn:"978-1-83880-439-8",pdfIsbn:"978-1-83969-261-1",editors:[{id:"193560",title:"Dr.",name:"Matilde",middleName:null,surname:"Otero-Losada",slug:"matilde-otero-losada",fullName:"Matilde Otero-Losada"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"72488",title:"Dr.",name:"José Juan Antonio",middleName:null,surname:"Ibarra Arias",fullName:"José Juan Antonio Ibarra Arias",slug:"jose-juan-antonio-ibarra-arias",email:"jose.ibarra@anahuac.mx",position:null,institution:{name:"Universidad Anáhuac",institutionURL:null,country:{name:"Mexico"}}},{id:"312349",title:"Ms.",name:"Melanie Tessa",middleName:null,surname:"Saavedra Navarrete",fullName:"Melanie Tessa Saavedra Navarrete",slug:"melanie-tessa-saavedra-navarrete",email:"melaniesaavedra1@gmail.com",position:null,institution:null},{id:"312580",title:"Dr.",name:"Maria Yolanda",middleName:null,surname:"Cruz Martinez",fullName:"Maria Yolanda Cruz Martinez",slug:"maria-yolanda-cruz-martinez",email:"yolanda.cruz@anahuac.mx",position:null,institution:{name:"Universidad Anáhuac",institutionURL:null,country:{name:"Mexico"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Immunological response in stroke",level:"1"},{id:"sec_3",title:"3. Copolymer-1",level:"1"},{id:"sec_4",title:"4. The effect of copolymer-1 on inflammatory diseases",level:"1"},{id:"sec_5",title:"5. Effect of copolymer-1 on stroke",level:"1"},{id:"sec_6",title:"6. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'\nOMS. Top 10 causas de muerte. Datos del observatorio mundial de la salud [GHO]. 2018. Available from: http://www.who.int/en/news-room/fact-sheets/detail/the-top-10-causes-of-death\n\n'},{id:"B2",body:'\nOMS. Noncommunicable Diseases. World Health Organization [Internet]. 2018. Available from: https://www.who.int/nmh/publications/ncd-profiles-2018/en/ [Accessed: 03 November 2019]\n'},{id:"B3",body:'\nBoehme AK, Esenwa C, Elkind MS. Stroke risk factors, genetics, and prevention. Circulation Research. 2017;120(3):472-495\n'},{id:"B4",body:'\nBanerjee C, Chimowitz MI. 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Glatiramer acetate attenuates the activation of CD4[+] T cells by modulating STAT1 and -3 signaling in glia. Scientific Reports. 2017;7:40484. DOI: 10.1038/srep40484\n'},{id:"B55",body:'\nKipnis J, Yoles E, Porat Z, Cohen A, Mor F, Sela M, et al. T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: Possible therapy for optic neuropathies. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(13):7446-7451. DOI: 10.1073/pnas.97.13.7446\n'},{id:"B56",body:'\nBlair M, Pease ME, Hammond J, Valenta D, Kielczewski J, Levkovitch-Verbin H, et al. Effect of glatiramer acetate on primary and secondary degeneration of retinal ganglion cells in the rat. Investigative Ophthalmology & Visual Science. 2005;46(3):884-890. DOI: 10.1167/iovs.04-0731\n'},{id:"B57",body:'\nDionisio PA, Oliveira SR, Gaspar MM, Gama MJ, Castro-Caldas M, Amaral JD, et al. Ablation of RIP3 protects from dopaminergic neurodegeneration in experimental Parkinson’s disease. Cell Death & Disease. 2019;10(11):840. DOI: 10.1038/s41419-019-2078-z\n'},{id:"B58",body:'\nKim YS, Joh TH. Microglia, major player in the brain inflammation: Their roles in the pathogenesis of Parkinson’s disease. Experimental & Molecular Medicine. 2006;38(4):333-347. DOI: 10.1038/emm.2006.40\n'},{id:"B59",body:'\nBenner EJ, Mosley RL, Destache CJ, Lewis TB, Jackson-Lewis V, Gorantla S, et al. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(25):9435-9440. DOI: 10.1073/pnas.0400569101\n'},{id:"B60",body:'\nLaurie C, Reynolds A, Coskun O, Bowman E, Gendelman HE, Mosley RL. CD4+ T cells from copolymer-1 immunized mice protect dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Journal of Neuroimmunology. 2007;183(1-2):60-68. DOI: 10.1016/j.jneuroim.2006.11.009\n'},{id:"B61",body:'\nChurchill MJ, Cantu MA, Kasanga EA, Moore C, Salvatore MF, Meshul CK. Glatiramer acetate reverses motor dysfunction and the decrease in tyrosine hydroxylase levels in a mouse model of Parkinson’s disease. Neuroscience. 2019;414:8-27. DOI: 10.1016/j.neuroscience.2019.06.006\n'},{id:"B62",body:'\nvon Euler Chelpin M, Vorup-Jensen T. Targets and mechanisms in prevention of Parkinson’s disease through immunomodulatory treatments. Scandinavian Journal of Immunology. 2017;85(5):321-330. DOI: 10.1111/sji.12542\n'},{id:"B63",body:'\nWyss-Coray T, Rogers J. Inflammation in Alzheimer disease—A brief review of the basic science and clinical literature. Cold Spring Harbor Perspectives in Medicine. 2012;2(1):a006346. DOI: 10.1101/cshperspect.a006346\n'},{id:"B64",body:'\nFan Z, Brooks DJ, Okello A, Edison P. An early and late peak in microglial activation in Alzheimer’s disease trajectory. Brain. 2017;140(3):792-803. DOI: 10.1093/brain/aww349\n'},{id:"B65",body:'\nDani M, Wood M, Mizoguchi R, Fan Z, Walker Z, Morgan R, et al. Microglial activation correlates in vivo with both tau and amyloid in Alzheimer’s disease. Brain. 2018;141(9):2740-2754. DOI: 10.1093/brain/awy188\n'},{id:"B66",body:'\nButovsky O, Koronyo-Hamaoui M, Kunis G, Ophir E, Landa G, Cohen H, et al. Glatiramer acetate fights against Alzheimer\'s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(31):11784-11789. DOI: 10.1073/pnas.0604681103\n'},{id:"B67",body:'\nButovsky O, Talpalar AE, Ben-Yaakov K, Schwartz M. Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Molecular and Cellular Neurosciences. 2005;29(3):381-393. DOI: 10.1016/j.mcn.2005.03.005\n'},{id:"B68",body:'\nKoronyo Y, Salumbides BC, Sheyn J, Pelissier L, Li S, Ljubimov V, et al. Therapeutic effects of glatiramer acetate and grafted CD115[+] monocytes in a mouse model of Alzheimer’s disease. Brain. 2015;138(Pt 8):2399-2422. DOI: 10.1093/brain/awv150\n'},{id:"B69",body:'\nMorrice JR, Gregory-Evans CY, Shaw CA. Animal models of amyotrophic lateral sclerosis: A comparison of model validity. Neural Regeneration Research. 2018;13(12):2050-2054. DOI: 10.4103/1673-5374.241445\n'},{id:"B70",body:'\nZarei S, Carr K, Reiley L, Diaz K, Guerra O, Altamirano PF, et al. A comprehensive review of amyotrophic lateral sclerosis. Surgical Neurology International. 2015;6:171. DOI: 10.4103/2152-7806.169561\n'},{id:"B71",body:'\nAngelov DN, Waibel S, Guntinas-Lichius O, Lenzen M, Neiss WF, Tomov TL, et al. Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(8):4790-4795. DOI: 10.1073/pnas.0530191100\n'},{id:"B72",body:'\nMosley RL, Gordon PH, Hasiak CM, Van Wetering FJ, Mitsumoto H, Gendelman HE. Glatiramer acetate immunization induces specific antibody and cytokine responses in ALS patients. Amyotrophic Lateral Sclerosis. 2007;8(4):235-242. DOI: 10.1080/17482960701374601\n'},{id:"B73",body:'\nClinical Trials. Glatiramer Acetate. 2019. Available from: https://clinicaltrials.gov/ct2/results?cond=&term=glatiramer+acetate&cntry=&state=&city=&dist\n\n'},{id:"B74",body:'\nLonga EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989;20(1):84-91. DOI: 10.1161/01.str.20.1.84\n'},{id:"B75",body:'\nMangin G, Poittevin M, Charriaut-Marlangue C, Giannesini C, Merkoulova-Rainon T, Kubis N. Glatiramer acetate reduces infarct volume in diabetic mice with cerebral ischemia and prevents long-term memory loss. Brain, Behavior, and Immunity. 2019;80:315-327. DOI: 10.1016/j.bbi.2019.04.009\n'},{id:"B76",body:'\nMirzadeh Z, Merkle FT, Soriano-Navarro M, Garcia-Verdugo JM, Alvarez-Buylla A. Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell Stem Cell. 2008;3(3):265-278. DOI: 10.1016/B978-0-12-800763-1\n'},{id:"B77",body:'\nWinner B, Winkler J. Adult neurogenesis in neurodegenerative diseases. Cold Spring Harbor Perspectives in Biology. 2015;7(4):a021287. DOI: 10.1101/cshperspect.a021287\n'},{id:"B78",body:'\nIbarra A, Avendano H, Cruz Y. Copolymer-1 [cop-1] improves neurological recovery after middle cerebral artery occlusion in rats. Neuroscience Letters. 2007;425(2):110-113. DOI: 10.1016/j.neulet.2007.08.038\n'},{id:"B79",body:'\nCruz Y, Lorea J, Mestre H, Kim-Lee JH, Herrera J, Mellado R, et al. Copolymer-1 promotes neurogenesis and improves functional recovery after acute ischemic stroke in rats. PLoS One. 2015;10(3):e0121854. DOI: 10.1371/journal.pone.0121854\n'},{id:"B80",body:'\nPoittevin M, Deroide N, Azibani F, Delcayre C, Giannesini C, Levy BI, et al. Glatiramer acetate administration does not reduce damage after cerebral ischemia in mice. Journal of Neuroimmunology. 2013;254(1-2):55-62. DOI: 10.1016/j.jneuroim.2012.09.009\n'},{id:"B81",body:'\nFaigle R, Song H. Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochimica et Biophysica Acta. 2013;1830(2):2435-2448. DOI: 10.1016/j.bbagen.2012.09.002\n'},{id:"B82",body:'\nBaruch K, Schwartz M. CNS-specific T cells shape brain function via the choroid plexus. Brain, Behavior, and Immunity. 2013;34:11-16. DOI: 10.1016/j.bbi.2013.04.002\n'},{id:"B83",body:'\nCruz Y, Garcia EE, Galvez JV, Arias-Santiago SV, Carvajal HG, Silva-Garcia R, et al. Release of interleukin-10 and neurotrophic factors in the choroid plexus: Possible inductors of neurogenesis following copolymer-1 immunization after cerebral ischemia. Neural Regeneration Research. 2018;13(10):1743-1752. DOI: 10.4103/1673-5374.238615\n'},{id:"B84",body:'\nPereira L, Font-Nieves M, Van den Haute C, Baekelandt V, Planas AM, Pozas E. IL-10 regulates adult neurogenesis by modulating ERK and STAT3 activity. Frontiers in Cellular Neuroscience. 2015;9:57. DOI: 10.3389/fncel.2015.00057\n'},{id:"B85",body:'\nCunha C, Brambilla R, Thomas KL. A simple role for BDNF in learning and memory? Frontiers in Molecular Neuroscience. 2010;3:1. DOI: 10.3389/neuro.02.001.2010\n'},{id:"B86",body:'\nDelgado AC, Ferron SR, Vicente D, Porlan E, Perez-Villalba A, Trujillo CM, et al. Endothelial NT-3 delivered by vasculature and CSF promotes quiescence of subependymal neural stem cells through nitric oxide induction. Neuron. 2014;83(3):572-585. DOI: 10.1016/j.neuron.2014.06.015\n'},{id:"B87",body:'\nSnapyan M, Lemasson M, Brill MS, Blais M, Massouh M, Ninkovic J, et al. Vasculature guides migrating neuronal precursors in the adult mammalian forebrain via brain-derived neurotrophic factor signaling. The Journal of Neuroscience. 2009;29(13):4172-4188. DOI: 10.1523/jneurosci.4956-08.2009\n'},{id:"B88",body:'\nYuan H, Chen R, Wu L, Chen Q , Hu A, Zhang T, et al. The regulatory mechanism of neurogenesis by IGF-1 in adult mice. Molecular Neurobiology. 2015;51(2):512-522. DOI: 10.1007/s12035-014-8717-6\n'},{id:"B89",body:'\nTyler AF, Mendoza JP, Firan M, Karandikar NJ. CD8[+] T cells are required for glatiramer acetate therapy in autoimmune demyelinating disease. PLoS One. 2013;8(6):e66772. DOI: 10.1371/journal.pone.0066772\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"María Yolanda Cruz Martínez",address:null,affiliation:'
Centro de Investigación en Ciencias de la Salud (CICSA), Facultad de Ciencias de la Salud, Universidad Anáhuac México, Estado de México, Mexico
Centro de Investigación en Ciencias de la Salud (CICSA), Facultad de Ciencias de la Salud, Universidad Anáhuac México, Estado de México, Mexico
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More and more people nowadays see nanoparticle applications in various fields such as automotive, agriculture, medicine, machining, and so on. The addition of different nanoparticles to fluids has shown enormous advantages, particularly for improving the efficiency and therefore lowering the energy consumption of processes for addressing a wide range of global challenges related with energy and environmental problems. Nanoparticles are of great scientific interest as they are in that nanofluid with unusual effects, and ultra-small sizes will be a new area for researchers and definitely offer novel mechanisms and technologies in the future. In this chapter, the authors will mainly present the characteristics as well as latest advances in applications of nanofluids in machining practices. Nanoparticle additives contribute to reduce friction coefficient, lower the energy consumption, and significantly extend tool life by lowering thermal stress, from which the surface quality of manufactured parts improves. Moreover, the nanoparticle application in some of the green technologies as MQL and MQCL using vegetable oils not only brings out superior cooling and lubricating properties and minimizes the use of cutting fluids, but also creates new solutions for machining, especially for difficult-to-cut materials.",signatures:"Tran The Long and Tran Minh Duc",authors:[{id:"290751",title:"Dr.",name:"Tran",surname:"Long",fullName:"Tran Long",slug:"tran-long",email:"tranthelong@tnut.edu.vn"}],book:{title:"Advances in Microfluidic Technologies for Energy and Environmental Applications",slug:"advances-in-microfluidic-technologies-for-energy-and-environmental-applications",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"224066",title:"Dr.",name:"Voon Loong",surname:"Wong",slug:"voon-loong-wong",fullName:"Voon Loong Wong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/224066/images/system/224066.png",biography:"Dr. Wong Voon Loong obtained his Bachelor Degree of Chemical Engineering with First Class Honours (Book Prize Winner) from Universiti Tunku Abdul Rahman in 2010. He continued his studies at the University of Nottingham and graduated with a PhD Degree in Chemical Engineering in 2015. Wong Voon Loong’s research focuses on multiphase flow and transport phenomena in microfluidic systems. Currently, he is also involved as a key team member of research projects in the field of solar photovoltaic, particles synthesis for wastewater treatment and drug delivery system. He\ncurrently serves as an Assistant Professor at Heriot Watt University\nMalaysia Campus.",institutionString:"Heriot-Watt University Campus",institution:null},{id:"295581",title:"Prof.",name:"Rui",surname:"Lima",slug:"rui-lima",fullName:"Rui Lima",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"310629",title:"Mr.",name:"Chin-Ang",surname:"Isaac Ng",slug:"chin-ang-isaac-ng",fullName:"Chin-Ang Isaac Ng",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Heriot-Watt University",institutionURL:null,country:{name:"United Kingdom"}}},{id:"310630",title:"Ms.",name:"Lui-Ruen",surname:"Irene Teo",slug:"lui-ruen-irene-teo",fullName:"Lui-Ruen Irene Teo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Heriot-Watt University",institutionURL:null,country:{name:"United Kingdom"}}},{id:"310631",title:"Ms.",name:"Ci-Wei",surname:"Lee",slug:"ci-wei-lee",fullName:"Ci-Wei Lee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Heriot-Watt University",institutionURL:null,country:{name:"United Kingdom"}}},{id:"311626",title:"Ms.",name:"Inês",surname:"Maia",slug:"ines-maia",fullName:"Inês Maia",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"311627",title:"Mr.",name:"Cesar",surname:"Rocha",slug:"cesar-rocha",fullName:"Cesar Rocha",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Minho",institutionURL:null,country:{name:"Portugal"}}},{id:"311628",title:"Dr.",name:"Pedro",surname:"Pontes",slug:"pedro-pontes",fullName:"Pedro Pontes",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Lisbon",institutionURL:null,country:{name:"Portugal"}}},{id:"311629",title:"Dr.",name:"Vanessa",surname:"Cardoso",slug:"vanessa-cardoso",fullName:"Vanessa Cardoso",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Minho",institutionURL:null,country:{name:"Portugal"}}},{id:"311630",title:"Prof.",name:"J. 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The Open Access model is applied to all of our publications and is designed to eliminate subscriptions and pay-per-view fees. This approach ensures free, immediate access to full text versions of your research.
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Permanent and unrestricted online access to your work
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Exceeds 20 pages (for chapters in Edited Volumes), an additional fee of 40 GBP per page will be required
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Open Access Funding
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Indexing and listing across major repositories, see details ...
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Dissemination and Promotion
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Proven world leader in Open Access book publishing with over 10 years experience
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+5,200 OA books published
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Most competitive prices in the market
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Fully compliant with OA funding requirements
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Optimized processes, enabling publication between 8 and 12 months
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Personal support during every step of the publication process
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+146,270 citations in Web of Science databases
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Currently strongest OA platform with over 150 million downloads
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 128,000 international scientists and researchers.
\n\n
The Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
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OAPF Publishing Options
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1,400 GBP Chapter - Edited Volume
\n\t
10,000 GBP Monograph - Long Form
\n\t
4,000 GBP Compacts Monograph - Short Form
\n
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
\n\n
Services included are:
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An online manuscript tracking system to facilitate your work
\n\t
Personal contact and support throughout the publishing process from your dedicated Author Service Manager
\n\t
Assurance that your manuscript meets the highest publishing standards
\n\t
English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
\n\t
XML Typesetting and pagination - web (PDF, HTML) and print files preparation
\n\t
Discoverability - electronic citation and linking via DOI
\n\t
Permanent and unrestricted online access to your work
What isn't covered by the Open Access Publishing Fee?
\n\n
If your manuscript:
\n\n
\n\t
Exceeds 20 pages (for chapters in Edited Volumes), an additional fee of 40 GBP per page will be required
\n\t
If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
\n
\n\n
Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\n\n
Open Access Funding
\n\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
\n\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\n\n
Added Value of Publishing with IntechOpen
\n\n
Choosing to publish with IntechOpen ensures the following benefits:
\n\n
\n\t
Indexing and listing across major repositories, see details ...
\n\t
Long-term archiving
\n\t
Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
\n\t
Dissemination and Promotion
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Benefits of Publishing with IntechOpen
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Proven world leader in Open Access book publishing with over 10 years experience
\n\t
+5,200 OA books published
\n\t
Most competitive prices in the market
\n\t
Fully compliant with OA funding requirements
\n\t
Optimized processes, enabling publication between 8 and 12 months
\n\t
Personal support during every step of the publication process
\n\t
+146,270 citations in Web of Science databases
\n\t
Currently strongest OA platform with over 150 million downloads
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