Summary of prescribing information.
\r\n\tEngineering Geology studies can be conducted during different stages of the project, as it can be conducted during the planning process, or the environmental impact analysis process, or the structural design process, or during construction operations in public and private projects, in addition to the stages of economic engineering, and the type of studies after completing construction of the facility. Geological engineering includes the following areas: geological risk assessment, geotechnical engineering, material properties, land slippage and slope risk, erosion, floods, seismic studies, and water displacement.
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He has worked at the Chemical and Petroleum Engineering Department, United Arab Emirates University since 2009 as a core analysis lab engineer. He is a reviewer for the Journal of Petroleum Science and Engineering and an editorial board member for several other journals. He has edited one book and written several book chapters.",institutionString:"United Arab Emirates University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"United Arab Emirates University",institutionURL:null,country:{name:"United Arab Emirates"}}}],coeditorOne:{id:"143532",title:"Prof.",name:"Hasan",middleName:null,surname:"Arman",slug:"hasan-arman",fullName:"Hasan Arman",profilePictureURL:"https://mts.intechopen.com/storage/users/143532/images/system/143532.png",biography:"Dr. Hasan Arman has been a professor in the Geology Department at United Arab Emirates University, College of Science, since 2008. He has been head of the department since August 2018. He received his BSc and MSc from Hacettepe and Istanbul Universities, Turkey, in 1984 and 1986, respectively. He obtained a Ph.D. from the University of Arizona, USA, in 1992. He worked as a postdoc at the University of Nevada, Reno, USA, from 1992 to 1993. He worked as a researcher at Tokai University, Japan, from 1995 to 1997 on a Japanese Monbusho Scholarship. He was also a faculty member at the Civil Engineering Department, Sakarya University, Turkey, between 1993 and 2008. Dr. Arman has taught several different courses at undergraduate and graduate levels. His research interests include rock mechanics, engineering geology, environmental degradation, sustainability, water resources, global warming, climate change, and renewable and sustainable energy sources. 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The first agent, which was approved by the Food and Drug Administration in 1989, is Botox® (Allergan Inc, Irvine, CA, USA). Botulinum toxin type A (BoNT/A) is most commonly used these days: Botox®, OnabotulinumtoxinA; Dysport®, AbobotulinumtoxinA; Xeomin®, IncobotulinumtoxinA; Hengli/CBTX-A®, Chinese botulinumtoxin A; Neuronox/Meditoxin®, South Korea botulinumtoxin A, etc. Botulinum toxin type B is also frequently used: Myobloc®/Neurobloc®, RimabotulinumtoxinB.
\nThe practitioners of BoNT injection need to remember that BoNT is a protein. This means that BoNT can denature easily and contribute to the generation of neutralizing antibodies. BoNT has to be stored at 2–8 °C (36–46 °F) and administrated only for a limited time [3–5]. Freezing, light exposure, and shaking should be avoided. To reduce the incidence of antibody generation, the following are recommended: maintain at least a 3-month interval between injections; use the smallest possible dose, and avoid booster injections. Detailed prescription information for widely used BoNTs is summarized in Table 1 [3–5].
\n\n | Botox® [3] | \nDysport® [4] | \nMyobloc® [5] | \n
---|---|---|---|
Contents | \nOnabotulinumtoxinA | \nAbobotulinumtoxinA | \nRimabotulinumtoxinB | \n
\n | Human albumin | \nHuman albumin | \nHuman albumin | \n
\n | Sodium chloride | \nLactose | \nSodium succinate | \n
\n | \n | Cow’s milk proteins | \nSodium chloride | \n
Target SNARE protein | \nSNAP-25 | \nSNAP-25 | \nVAMP | \n
Storage | \nStore at 2–8°C (36–46°F) | \nStore at 2–8°C (36–46 °F) | \nStore at 2–8°C (36–46°F) | \n
\n | Inject BoNT within 24 hours | \nInject BoNT within 24 hours | \nInject BoNT within 4 hours, once diluted | \n
\n | \n | Do not freeze | \nDo not freeze | \n
\n | \n | Protect from light | \nDo not shake | \n
\n | \n | \n | Protect from light | \n
Reconstitution | \nSterile, preservative-free 0.9% sodium chloride | \nProvided as solution (pH 5.6) | \n|
\n | \n | \n | Can be diluted with normal saline | \n
Indications and usage | \nCervical dystonia | \nCervical dystonia | \nCervical dystonia | \n
\n | Blepharospasm | \nGlabella lines | \n\n |
\n | Spasticity in adult | \nUpper limb spasticity in adult | \n\n |
\n | Chronic migraine | \n\n | \n |
\n | Strabismus | \n\n | \n |
\n | Axillary hyperhidrosis | \n\n | \n |
\n | Overactive bladder | \n\n | \n |
Contraindications | \nHypersensitivity to any BoNT | \nHypersensitivity to any BoNT | \nHypersensitivity to any BoNT | \n
\n | Infection | \nInfection | \nInfection | \n
\n | \n | Allergy to cow’s milk protein | \n\n |
Limit of a total dose | \n400 Units | \n1000 Units | \nNA | \n
Minimal interval | \n3 months | \n12 weeks | \nNA | \n
Side effects | \nGeneralized weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, breathing difficulties | \n||
\n | Pain, inflammation, bleeding | \n||
\n | Flu, rhinitis, pharyngitis | \n||
Drug interactions | \nAminoglycosides and other agents interfering with neuromuscular transmission (eg. Curare-like agents) | \n||
\n | Anticholinergics | \n||
\n | Muscle relaxants | \n||
\n | Other BoNT | \n||
Cautions | \nPregnancy (Category C) | \n||
\n | Nursing mothers | \n||
\n | Pediatric/geriatric use | \n||
Immunogenicity* | \nPositive antibodies: 0.0–1.2% | \nPositive antibodies: 0.0–3.6% | \nNeutralizing activity | \n
\n | Risk factors: frequent intervals, higher doses | \n\n | - 1 years: 10% (for 36% ELISA-positive cases) | \n
\n | \n | \n | - 18 months: 18% (for 50% ELISA-positive cases) | \n
Summary of prescribing information.
*The incidence of antibodies are highly dependent on the methodology of the assay. Therefore, the simple comparisons between different BoNTs are illogical.
SNARE, soluble N-ethlymaleimide sensitive factor attachment protein receptor; SNAP-25, synaptosome-associated protein; VAMP, vesicle-associated membrane protein; BoNT, botulinum neurotoxin; NA, not applicable.
Early BoNTs did not overcome the following problems: short-lasting effects, necrotizing problem, and systematic toxicity [6]. However, there have been remarkable advances since Scott et al. [7] successfully improved strabismus with purified BoNT injections. Now BoNT is widely used to reduce the hyperactivity of muscles or glands mediated by Ach release [1]. For neurological disorders, BoNT can be effectively used for hyperkinetic movement disorders (dystonia, hemifacial spasm, myoclonus, myokymia, tremor, etc.), spasticity, drooling, and chronic migraines. Applications for strabismus, spasms of the gastrointestinal tract or genitourinary tract, and cosmetic work are possible.
\nIn this chapter, although there have been many guidelines published, we focus more on the practical tips for BoNT injections in the treatment of several neurological symptoms.
\nThe principle action mechanism of BoNT is to block the release of Ach from presynaptic nerve terminals. Therefore, the Ach-mediated hyperactivities of muscles and glands could be good targets for BoNT therapy. The following list shows representative indications for BoNT injection.
Hyperkinetic movement disorders\n
Dystonia (cervical dystonia, blepharospasm, oro-mandibular dystonia, limb dystonia, laryngeal dystonia, etc.)
Hemifacial spasm
Myoclonus, myokymia, tremor, dyskinesia, tics, etc.
Other neurological disorders\n
Spasticity
Headache (chronic tension type headache, chronic migraine)
Drooling, etc.
Other disorders\n
Strabismus
Hyperhidrosis
Spasm or spasticity of the gastro-intestinal and genito-urinary tracts
Cosmestic applications, etc.
The cautions and contraindications are as important as the proper indications. Patients with neurological disorders involving anterior horn cells, peripheral nerves, neuro-muscular junctions, and muscles require special care when injecting BoNT. Concomitant use of drugs, which could affect neuro-muscular transmission or cause muscle weakness, is also not recommended (Table 1) [3–5]. In addition, most BoNTs do not guarantee the safety of pregnant women, nursing mothers, and pediatric patients. Hypersensitivities to any of the BoNTs or their components and the infection of target sites are important contraindications. Especially, Dysport® is contraindicated in patients with allergies to cow’s milk protein [4]. Anti-platelet or anti-coagulation agents could cause a hematoma.
\nDespite past studies using different types of BoNT, it is unclear which one is the most effective BoNT. Furthermore, it is generally accepted that the doses between different BoNT products are not interchangeable [3–5, 8–10]. However, in real practice, patients who have been treated with different BoNT products could visit your clinic any time. In this regard, a simple conversion ratio between Botox® and Dysport® was made [11]. Based on the average recommended dose of Dysport®(500 Units) and Botox® (200 Units) for patients with cervical dystonia, a conversion ratio of 2.5:1 was assumed and it was found that Dysport® showed no inferiority to Botox® at this ratio. The ratio of 2.5:1 has the practical advantage by simplifying the interchanging process. This issue will be addressed in detail later.
\nThe widely used solvent for reconstituting BoNT is 0.9% normal saline. Hypotonic saline or distilled water is not suitable as a solvent because it could cause pain. Recently one preliminary study suggested that reconstituting BoNT with Ringer acetate could reduce the injection site pain rather than with normal saline by normalizing the pH values of the solution [12]. Myobloc® is provided as a solution (pH 5.6) that can be used as is or diluted with normal saline [5].
\nRegardless of the BoNT subtype, one unit of BoNT was defined as the calculated median intraperitoneal lethal dose (LD50) in mice. However, the biological activity varies between BoNTs. Although there is no consensus for the conversion ratio, we use the ratio of 2.5:1 for Dysport® and Botox® because the non-inferiority of Dysport® has already been proven [11]. On the assumption that the ratio of 2.5:1 is bioequivalent, the practitioner can make two kinds of solutions (Table 2). To make a solution with a high concentration, 1 ml of 0.9% normal saline is needed for 1 ample (100 Units) of Botox® and 2 ml of 0.9% normal saline for 1 ample (500 Units) of Dysport®. For a solution with a low concentration, 2 ml and 4 ml are mixed with 1 ample of Botox® and Dysport®, respectively. Then, the same volume of each solution indicates the same potency (Table 2). It means that physicians do not need complicated calculations. Because the same conversion ratio (2.5:1) is also applied to the limitations for the total doses of Dysport® (1000 Units) and Botox® (400 Units), we believe that it is very simple and practical.
\nAfter injecting normal saline for reconstitution, the next step is to mix gently to minimize unnecessary destruction of the toxin. Because the available time is short after reconstitution (within 24 hours for Botox® and Dysport®) [3, 4], it is more efficient to inject BoNT after gathering sufficient numbers of patients who need BoNT treatment.
\n\n | Botox®, OnabotulinumtoxinA | \nDysport®, AbobotulinumtoxinA | \n
---|---|---|
Units per 1 ample | \n100 Units | \n500 Units | \n
Method #1 (high concentration) | \n100 Units (1 ample): 1 ml of 0.9% N/S | \n500 Units (1 ample): 2 ml of 0.9% N/S | \n
\n | → 0.1 ml solution = 10 Units of Ona-BoNT/A | \n→ 0.1 ml solution = 25 Units of Abo-BoNT/A | \n
\n | → 0.01 ml solution = 1 Unit of Ona-BoNT/A | \n→ 0.01 ml solution = 2.5 Units of Abo-BoNT/A | \n
Method #2 (low concentration) | \n100 Units (1 ample): 2 ml of 0.9% N/S | \n500 Units (1 ample): 4 ml of 0.9% N/S | \n
\n | → 0.1 ml solution = 5 Units of Ona-BoNT/A | \n→ 0.1 ml solution = 12.5 Units of Abo-BoNT/A | \n
\n | → 0.01 ml solution = 0.5 Units of Ona-BoNT/A | \n→ 0.01 ml solution = 1.25 Units of Abo-BoNT/A | \n
Practical tips of conversion between Botox® and Dysport®.
BoNT/A, botulinum neurotoxin type A.
Generally, a 1-ml syringe, which can control the volume by 0.01 ml, is preferred. The practitioner needs 0.03–0.05 ml more volume than the target volume, taking into consideration the dead space inside of the needle. After the syringe is filled properly with the BoNT solution, the practitioner should remove the air. The following are tips for removing air bubbles and aligning the needle.
Draw down the syringe quickly while holding the cap of syringe. It is based on the inertia effect, and just one time is enough to collect bubbles on top. Tapping the body is also available.
Pull slightly back, before pushing forward, the plunger of the syringe. It will be helpful in saving the BoNT in the dead space of the needle.
Rotate the bevel of the needle in the same direction with the scale marks of the syringe.
The selection of the injection needle depends on the target sites. Because most facial muscles are thin and close to the skin, a thin and short needle such as a 23- or 24-gauge needle is suitable for the delivery of BoNT solution. In contrast, neck and limb muscles are thick, large, and located relatively deep from skin. Thus, a thick and long needle such as a 21-gauge needle is necessary.
\nBoNT injection is recommended for use in only limited areas. The reasons for the limited use are because of the total dose and cost of BoNT. Therefore, determining the target is the most important procedure in treatment with BoNT.
\nDetermining target sites has the same meaning as finding symptomatic muscles. It is not difficult to locate target sites for disorders with static muscular hypertonia (such as fixed dystonia or spasticity). However, mobile hyperkinetic movement disorders are another matter. Especially for mobile dystonia, finding target muscles is not simple because the direction of abnormal movement seems to be irregular or changes every moment. Ultrasonography, computed tomography, magnetic resonance imaging, and electromyography (EMG) are supportive tools to help ascertain the target [13]. In particular, EMG can provide dynamic information and help in the precise injection of BoNT to target muscles in real time. However it should be kept in mind that EMG is not a substitute for knowledge of anatomy and is a mere supportive tool. Another important thing is to avoid BoNT injections near sites where side effects occur frequently. Particularly the procedure for head and neck requires special care.
\nPractical tips for examining patients and determining target sites are introduced below.
\nThe final posture of cervical dystonia (CD) patients consists of a combination of dystonic muscle contractions, compensatory movements, and secondary musculo-skeletal changes. Therefore, examination in various situations is helpful in differentiating target dystonic muscles from the others.
\nBefore the examination, enough exposure of the neck and adjacent muscles is very important. This procedure is essential for precise inspection. In addition, sensory trick by scarf or clothes could be eliminated. Then, the physicians should see the rotation and deviation of neck and adjacent muscles on a neutral position, and describe how they are seen. It can be summarized as the combination of turning to one side (torticollis), tilting or shifting to one side (laterocollis), bending forward (antecollis) or backward (retrocollis). Shoulder elevation is frequently accompanied.
\nHere are several methods to distinguish compensatory movements. The physicians have to tell the patients “let the neck and shoulder relax as they move”, and make them walk repeatedly. Palpation of the candidate muscles is helpful in assessing whether they are hypertrophic or contain bands. The features of dystonia such as task-specificity, overflow, and null-point could also be important clues. Especially for tremulous CD, if a tremor diminishes at a specific position, the muscles inducing that position would be affected by dystonia. Short-term follow-up can reveal critical information. The effect of BoNT for CD is generally maximized within 2 or 3 weeks after injection. Therefore, early visits can provide information whether previous target sites were appropriate as well as whether the patient is a BoNT non-responder. The dynamic progression of dystonia is another reason why follow-up is important.
\nDetermining target sites in facial involuntary movements is relatively simple compared to CD. Therefore, when BoNT is injected into the face, avoiding side effects is given much weight. The face contains other important anatomical structures such as the eye balls, lacrimal ducts, salivary glands, nerves, and vessels. The direction of the needle always must head away from the eye balls. Two canaliculi per eye exist in the medial canthus. BoNT injection into the lower canaliculus generally is avoided because it is believed to have a main role in transporting tears to the lacrimal sac and nasolacrimal duct. When injecting into the masseter muscle, it is better to preserve the lower posterior portion where the parotid gland is placed.
\nAsymmetry and ptosis should be considered. To prevent asymmetry, injections are often given also on the contralateral side. To prevent ptosis, BoNT injections to the mid-portions of the upper eyelid and frontalis area are avoided. Especially, when the orbicularis oculi is the target, injection into the pretarsal area has stronger effects and less frequent ptosis than injections into the preseptal area [14, 15].
\nUsing overflow phenomenon and mirror movement is a good way to differentiate main symptomatic spasms from compensatory ones [16]. If hand dystonia is too complex to determine a target, an EMG-guided approach will be useful. However, it is not easy to inject only into the real target site because the hands are comprised of small muscles for delicate movements. And paralysis of specific muscle rather can cause great inconvenience in most situations except when that specific task is performed.
\nOnce the target muscles for BoNT injection have been chosen, the next step is determining how much BoNT and how many injection sites are required. The recommended volumes for several target muscles are provided in the prescription information [3–5]. However, the response varies from person to person and information for every possible indication is not included. Thus, the injection volume and site should be individualized taking into consideration race, sex, age, medical condition, etc.
\nThe followings are additional helpful tips in determining the injection volume.
For larger target muscles, a larger volume of BoNT is required.
It is safer to apply a low dose first.
Imagining the diffusion pattern of BoNT is important.
Borodic et al. [17] reported several important features for the BoNT/A diffusion pattern in the longissimus dorsi of rabbits: the diffusion of BoNT/A occurred in a dose-dependent manner; the spread pattern in the injected muscle was more linear than in a remote muscle of the same distance; lower doses did not affect a different muscle located 45 mm from the injection site while higher doses diffused even into that muscle. This study supports the concept that injection into multiple sites with lower doses could reduce side effects by preventing the diffusion of BoNT, in other words its biological effect, to other muscles beyond the injection site [18]. Therefore, Rosales et al. [19] recommended a “high potency, low dilution” of BoNT/A for oromandibular, lingual, cranial, cervical, and distal limb dystonias, which are small and localized targets. In contrast, A “low potency, high dilution” of BoNT/A is more useful for big muscles.
\nThe method of injection mainly depends on the anatomical features of target sites.
\nSuperficial fat compartments are distributed throughout the entire face excluding the upper eyelids, nose, and mouth [20]. Most facial muscles are located just beneath the skin and subcutaneous fat, whereas peri-ocular and peri-oral areas have little fatty tissue. Facial skin is relatively thin compared to the other parts. Especially, the skin thickness of the palpebral areas is only around 0.5 mm. Therefore, when the orbicularis oculi or orbicularis oris muscle is the target, the needle should be inserted horizontally to skin as much as possible although more pain at the injection site is inevitable. Smoothing out skin wrinkles is important for easy needling. Vesicle formation is also recommended in these areas because it seems to be helpful in localizing the extent of chemo-denervation. For other facial muscles, the angle between needle and skin needs to be set a little bit higher so that the needle can be inserted into a deeper location. Another important consideration in facial muscle anatomy is that the facial muscles have few muscle spindles except in jaw muscles. It refers that BoNT injections directly impact on extrafusal muscle fibers in face.
\nOn the other hand, neck and limb muscles are large and located more deeply. For effective delivery of BoNT, a long needle inserted perpendicularly to the skin is necessary. This direction of insertion is also good for reducing pain. Grasping and fixing muscles are essential for precise targeting. Postures of activating relevant muscles and imaging- or EMG-guided methods may be of great help to approach deep muscles. Before administering the BoNT solution, pulling back is required to ascertain whether the needle reaches the target muscle or adjunctive vessel.
\nTo provide the appropriate BoNT treatment, the practitioner should be well informed of the etio-pathogenesis of disorders and the anatomy of the target area, as well as the action mechanism of BoNT and methods of storage and injection. Patients must also understand that BoNT treatment is just a way to relieve symptoms, and not treatment for underlying causes. Repeated applications of BoNT are required because the effects last for 3 months on average. Paradoxically, BoNT is a reversible and very safe toxin in terms of side effects. We hope that the guides of this chapter are very helpful in understanding and using BoNT in a clinical setting.
\nStroke also known as cerebrovascular accidents is the world’s second death-perpetrating disease after cardiovascular diseases [1, 2], and it affects about 13.7 million people annually in the globe [3]. About one third of all strokes translate into fatalities, and another one third constitutes stroke survivors staying with residual disability that accounts as foremost noticeable root of long-term neurological disability in adults [4, 5] and third most common cause of all disabilities globally [6]. Stroke classically depicts a syndrome with sudden onset of acute focal injury of the central nervous system (CNS) of vascular origin that produces focal or global neurological deficit in accordance with affected area of blood supply [7]. Thus, based on the isolated territory of the brain involve, stroke can be cerebral stroke, brainstem stroke, cerebellar stroke, or thalamic stroke, while based on underline cause it can be ischemic stroke (thrombotic, embolic, lacunar, watershed, or cryptogenic) which results from brain vascular occlusion, or hemorrhagic stroke (intraparenchymal or subarachnoid) which is due to blood-related aberrations [8].
Cerebral stroke results in loss of cerebral cortex related functions that manifests as motor impairment [9, 10, 11], sensory impairment [12, 13, 14], cognitive impairment [15, 16, 17], balance impairment [18] among others. The motor function of the cerebral cortex is embedded in the motor cortex (primary motor area, premotor cortex, supplementary motor area, cingulate motor areas) located in the frontal lobe anterior to central sulcus, the motor cortex is responsible for planning, initiation, execution, and regulation of voluntary movement which is achieved through originating descending corticospinal tract and corticobulbar system to the spinal cord and brainstem respectively [19]. Cerebral cortex plays principal role in sensory/perceptual functions by providing meaning to all sensations (except sense of smell) through primary somatosensory cortex in the postcentral gyrus of the parietal lobe, and other primary cortical sensory areas such as auditory cortex in the temporal lobe and visual cortex in the occipital lobe. Cognitive function involves multifaceted domains of cognitive processes including memory, learning, attention, thought, comprehension, perception, language among others [20]. Each of these domains of cognition requires cerebral cortex, illustration can be seen in memory domain where memory acquisition involves sensory cortex, memory retrieval involves prefrontal cortex, and memory storage is distributed throughout the cortex [21]. Balance and coordination of movement involve integrated functioning of both pyramidal and extra-pyramidal systems, and the cerebral cortex is the main principal origin of pyramidal system.
The mechanism of cerebral damage after stroke determines the cerebral stroke impairments, and the mechanism of damage is relative to whether the type of stroke is ischemic or hemorrhagic. Ischemic stroke consists of five distinct pathophysiologic mechanism each of which has distinct time frame; these includes immediate (within minutes) peri-infarct depolarization and excitotoxicity, hours later by neuro-inflammation and oxidative stress, days later by apoptosis [8]. In addition to ischemia related cascade of events aforementioned, hemorrhagic stroke is associated with two additional unique pathophysiologic phases. The primary; acute phase which is due to physical effect of hematoma (mass effect) from the mass accumulated blood, and the secondary; subacute phase termed as cytotoxicity from secondary metabolites of blood components [22, 23, 24].
Recovery to some extent from post stroke impairments observed among stroke survivors was one of the early evidences that led to move away from outdated dogma widely misconceived previously that; there was no possibility for repair or change within the CNS after it had suffered a lesion; and that once there is damage such as stroke that leads to neuronal demise inadvertently, the brain structures and functions are lost forever [25, 26]. It is now well-established fact that CNS repair or change itself but it just that it relatively does not do well enough, and that functional recovery after damage relies on neuroplasticity [27, 28]. Neuroplasticity is life-long natural capability of the CNS to rearrange itself in both molecular form and function in response to new experience or stimulus. Brain plasticity is pivotal to functional recovery after cerebral stroke, and this spontaneous, endogenous and intrinsic capacity of the brain is what restorative rehabilitation approaches for stroke explore, promote and remodel in the right direction to achieve optimal functional recovery after stroke [29, 30].
There is exploding surge among scientists to pay more attention in searching for various therapeutic strategies that can enhance neuroplasticity to augment functional recovery with rehabilitation after stroke [31, 32, 33, 34]. Although this strategy is still in developmental stage but the reasons for this shift in attention are not far-fetched. Firstly, the thrombolytic/thrombectomy clinical treatment available for acute stroke has a very restrictive time window of administration of 4–5 hours of lesion onset [35]. This is in contrast to restorative/rehabilitative interventions that has unlimited therapeutic window of lifelong applicability [36]. Secondly, rehabilitation interventions are still far from sufficiency for optimal and ideal recovery from impairments after stroke [37], as about 50% of stroke survivors still leaves with residual disability and remain functionally dependent despite rehabilitative management [38]. Understanding the mechanisms of cerebral damage and their recovery after cerebral stroke is essential towards development of strategies that harness and enhance neuroplasticity in combination with rehabilitation processes [39]. This paper therefore discusses the mechanism of cerebral damage after stroke as well as elucidates the concept of neuroplasticity as key for recovery following stroke.
In ischemic stroke, irreversible cascade of damage to the brain tissue ensue once the cerebral blood flow (CBF) reduces to less than 12 ml/100 g/min of the normal range of 50–60 ml/100 g/min. Within seconds of this abrupt ischemic insult, neuronal cells in the center of ischemic region termed as ischemic prenumbra undergoes anoxic depolarization due to loss of ATP-dependent ionic pump homeostasis, and they never repolarize [40]. This necrotic core of ischemic prenumbra is enclosed by a zone of relatively lesser impacted tissue termed as ischemic penumbra, which is abridged functionally silent by the reduced blood flow but maintains metabolically active and therefore can repolarize at the expense of further energy consumption [41]. This repetitive depolarization and repolarization of ischemic penumbra are termed peri-infarct depolarization and the important period of time during which this volume of brain tissue is salvageable is referred to as the window of opportunity. The energy failure in the functioning of ATP dependent sodium potassium pump in the ischemic prenumbra results in massive uncontrolled anoxic depolarization that results in opening of voltage-gated calcium channels, mitochondrial dysfunction which further deplete energy required to maintain ion gradient, and abnormally extracellular buildup of excitatory amino acids [42, 43].
Consequently, excitatory glutamate and other excitatory amino acids such as aspartate becomes excessively released, and glutamate hyperexcitation of glutamate N-methyl-D-aspartate (NMDA) receptor, which is arguably the most calcium-influx allowing ionotropic glutamate receptor; results in massive influx of calcium ion (Ca++) into hypoxic neuron. Calcium ion triggers series of cascading events that ultimately lead to neuronal demise through activation of proteolytic enzymes, stimulation of pathogenic genes, lipid peroxidation and free radical generation [44]. For this; glutamate and other excitatory amino acids are cumulatively termed excitotoxins, and their accompanying neuronal damage termed excitotoxicity [45]. Calcium activates key number of disparaging intracellular enzymes such as proteases, kinases, lipases, and endonuclease that not only wildly permits release of cytokines and other mediators that result in the loss of cellular integrity but also orchestrated triggering of intrinsic apoptotic pathway of neuronal death. Specifically, calcium through mobilizing phospholipases hydrolyses membrane bound glycerophospholipids to yield free fatty acids, which enable free radical peroxidation of other membrane bound lipids. Calcium through mobilizing proteases lyses integral structural proteins and activates nitric oxide synthase enzyme that triggers free radical machinery [46].
Prior excitotoxicity activates microglia and astrocytes which are the brain resident innate immunity to reacts and release cytokines, chemokines (chemotaxis cytokines), and matrix metalloproteases (MMPs). This constitutes neuro-inflammation, and microglia activation institutes the initial vital neuro-inflammatory response in acute stroke, which together with blood-borne innate immune cells and later adaptive immune cells support the course. This neuro-inflammatory response supposedly aims to reduce injury processes but this response under stroke pathology develops improperly more reactive and aggressive to yield numerous inflammatory mediators that trigger apoptosis and orchestrate lethal neuronal injury [47, 48]. Activated microglia becomes phagocytes that can release plethora of substances, some of which are neuroprotective such as neurotropic factors; nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), insulin-like growth factor I (IGF-I), and growth associated protein (GAP-43/B-50), while some are neurotoxic such as tumor necrosis alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Blood–brain barrier (BBB) which confers brain with protection against systemic toxins is disrupted by matrix metalloproteinases (MMPs) with MMP-2 (gelatinase A) and MMP-9 (gelatinase B) being the leading concerns in cerebral ischemia [49]. MMP-2 that is normally expressed at low levels becomes increased during cerebral ischemia to galvanizes MMP-9, which abolishes components of the basement membrane in the vascular wall leading to BBB distraction, thus allowing further infiltration of inflammatory mediators and other potential toxins [50].
Oxidative stress signifies disparity in the high-level oxidants (free radicals) with respect to corresponding nonconforming low level of antioxidants. Long term cerebral hypo-perfusion produces abnormal proportions of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) oxidants through several mechanisms of injury, such as mitochondrial inhibition, calcium ions overload, ischemia–reperfusion injury, and neuroinflammation [51]. During cerebral ischemia, there is mitochondrial inhibition of oxidative phosphorylation due to the lack of sufficient oxygen, and the oxygen depleted cell shift to glycolytic pathway of ATP generation that results in lactate and hydrogen ion (H+) build-up in the mitochondria and the consequent reversal of the H+ uniporter on the mitochondrial membrane that results in superfluous cytosolic H+ buildup and acidosis [52]. Acidosis partly lead to oxidative stress by supplying excessive H+ for the successive progression in the generation of hydrogen peroxide (H2O2) and the final hydroxyl radicals (∙OH) either in the turnout of transition metal ions (Fenton reaction) or in the presence of superoxide radical (Haber-Weiss reaction), with this effect more pronounced in neurons due to inherently low anti-oxidant defense. In addition, the compelling protein and lipid oxidant peroxynitrite (OONO_) of RNS is favorably generated in the oxygen depleted cell by the reaction of nitric oxide (NO) and superoxide (O2∙−), thereby also contributing to oxidative stress.
Calcium overloads, as a result of glutamate mediated NMDA receptor excitotoxicity, also contributes in neuronal oxidative stress at cytosolic and mitochondrial level. At cytosolic level, excessive calcium ion activation of key intracellular enzymes such as neuronal nitric oxide synthase (nNOS) via Ca2+ binds calmodulin to induce subsequent downstream effect, as nNOS catalysis results in generation of nitric oxide (NO) free radical from L-arginine [53, 54]. At the mitochondrial level, excessive calcium ion influx into mitochondrial matrix leads to the inner mitochondrial accumulation of momentous level of Ca2+ via mitochondrial calcium uniporter (MCU) which proliferates disturbance of usual bio-energetic, mitochondrial ROS, and membrane permeability [55].
Apoptosis is a physiological mechanism of cell death through programmed cellular machinery of either extrinsic or intrinsic pathways [56]. Under stroke pathology, neuronal demise by necrosis preponderance in the ischemic prenumbra is marked by excitotoxicity, while additional process of neuronal demise by apoptosis which is more delayed and predominant in the ischemic penumbra occur in a fashion where apoptosis becomes dysregulated [57]. Thus, while the neurons within the core infarct die by immediate necrosis due to insufficient ATP, the penumbra die by ATP requiring process of apoptosis, supporting the established evidence that cellular demise after cerebral ischemia transpires through both necrosis and apoptosis [58]. Multiple pre-existing pathophysiologic mechanisms that can induce apoptosis after cerebral ischemia includes pro- calcium influx, pro-inflammatory cytokines and oxidative stress [59]. Apoptosis can be caspase-dependent or caspase-independent, and the most common is caspase-dependent which is initiated and triggered through distinctively intrinsic (or mitochondrial) pathway or extrinsic (or death receptor) pathway. Both intrinsic and extrinsic pathways share similar terminal phase termed execution phase where caspase 3 leads to the destruction of cellular components and cell death [60].
In hemorrhagic stroke, the mechanism of damage begins with additional process of mass effect from the mass accumulated blood, and cytotoxicity from the secondary metabolites of blood components, in addition to shared common damaging caused by ischemia such as excitotoxicity, neuroinflammation, oxidative/nitrosative stress, and apoptosis. The initial bleed from the cerebral hemorrhage causes immediate physical disruption of the cellular cytoarchitecture of the brain and increases local pressure which can cause compressions, hypothetically disrupting blood flow and principally causing brain herniation [61]. The subsequent expansion of hematoma causes mass effect of hematoma growth leading to further rise in intracranial pressure, brain herniation, and impacted blood flow that is correlated with neurologic deterioration and degraded clinical outcomes. Depending on the dynamic of hematoma expansion (growth), the primary damage ensues within minutes to hours subsequent to the onset of bleeding and is basically due to mechanical damage associated with the mass effect [62].
Secondary injury after cerebral hemorrhage termed as cytotoxicity occurs due to series of events initiated by the prior primary injury mechanism (mass effect), that is specifically due to body response to the hematoma for instance inflammatory response, and from the multiple blood components released from hematoma [61]. The extravasated blood components released from hematoma being implicated to cumulatively imposed cellular toxicity includes; majorly the erythrocytes and plasma proteins, and the damage-associated molecular patterns (DAMPs) which are nucleic acids, extracellular matrix components, proteins, lipid mediators, ATP and uric acid released from necrotic tissues [63]. At the early stage of cytotoxicity, the toxicity of extravasated blood plasma components such as coagulation factors, complement components, and immunoglobulins are known to be the main contributing factor of cellular damage. Subsequently, erythrocytes lysis leads to release of its major intracellular component hemoglobin (Hb), which when metabolize via hemoglobin metabolic pathway release degradation products; heme and iron (Fe). Both Hb and its degradation products are potent cytotoxic chemicals capable of causing death to many brain cells through mechanism of free radical generation with substantial increase oxidative stress and subsequent damage to DNA [62].
The ultimate goal of stroke management is to promote optimal recovery of lost functions and reduce further injury. This recovery depends majorly on brain plasticity; a spontaneous regeneration process that encompasses neural plastic changes in the lesioned hemisphere to reestablish its structural and functional reorganization. Brain plasticity under pathological condition completely differs from plasticity under properly functioning brain. For instance, plasticity in normally functioning brain is a prerequisite basis of learning and memory that involves plastic adaptation such as long-term potentiation (LTP). This is opposed to plastic changes observed using MRI in cerebral stroke pathology, that involves modification in intracortical myelin, augmented neurogenesis, improved spine density in neuronal dendrites and alterations in astrocyte volume [64].
Stroke recovery to certain extent also depends on severity extent of the initial injury deficit as the severity of the damage is inversely related to the prognosis for recovery [65]. But it was also observed that recovery differs even among post stroke patients with similar clinically assessed severity. This apparently stress the recovery role of other brain endogenous survival mechanism such as extent to which collateral circulation bypass to supply blood to the perilesional neurons, angiogenesis, inhibitory neurotransmitters that counteract excitotoxicity, and multiple representations of the same function in different cortical areas [66]. Appropriate rehabilitation and drug treatment that target underline cause of stroke are also critical to recovery after post stroke cerebral damage. Rehabilitation aims to maximize optimum recovery of lost functions as a result of impairments deficit after stroke but overall, brain plasticity underlies recovery promoted by rehabilitation [67, 68, 69].
Recovery from stroke has also been attributed to be dependent on resolution of early local processes in the brain that includes resolve of perilesional edema, re-emergence of circulation within the ischemic penumbra, resolution of remote functional depression of neurological function induced by process of diaschisis [70]. As previously stated stroke recovery majorly depends on brain reorganization process of plasticity which in turn dictates recovery promoted by rehabilitation. Mechanism through which rehabilitation mediates brain plasticity to promote recovery has been studied and explained. Rehabilitation such as physical therapists stroke interventions modifies neurotrophic factor expression in the CNS especially brain derived neurotrophic factor (BDNF), which in turn upon binding with its tyrosine kinase B (TrkB) cognate receptor recruits a cascade of signaling pathways that ultimately mediates activity-associated plasticity of neurons [71, 72]. Activity-associated plasticity signifies a means of functional and structural neuroplasticity that is tailored by the depolarizing behavior of neurons, and the mechanisms governing activity-associated plasticity includes LTP and activity-associated development of corticospinal circuitry among others [72]. Therefore, through brain plasticity after cerebral stroke, reorganization by recruiting cortical or subcortical structures to adopt the function of the injured tissue, reinforcement of remaining synaptic pathways and then creating new connections, recruitment of other pathways that are functionally alike the damaged tissue but anatomically distinct, strengthening of existing but weaker and functionally silent connections, can all be achieved to recover lost cerebral functions [73].
Neuroplasticity is a general term that covers all available processes of neuronal reorganization possible [66], such as neurogenesis, synaptogenesis, dendritic arborization, axonal sprouting, LTP, recruitment of other pathways, reinforcement of functionally silent synapses. Neurogenesis is the process of generating of neurons of neural cell types from precursors neural stem cells and/or neural progenitor cells (NPCs) [74]. Synaptogenesis is a broad term that encompasses the complex process of synaptic contacts formation, maturation and maintenance which form the basis for establishing neural circuits [75]. Dendritic arborization describes a process of neuronal dendrites tree-like branching out to make new synaptic connection through mechanisms of dendrite morphogenesis [76]. Sprouting is a form of plastic changes in the synapses in which there is axonal synaptic reorganization to modify the efficacy of synapses [77]. LTP is the fundamental form of synaptic plasticity where synapses become strengthened and this forms the cellular basis of learning and memory [78].
Neuroplasticity is regulated by the corresponding cascade of intracellular events that translates into plastic changes. However, the plastic changes may either be adaptive, where it is related with an upsurge in function or maladaptive where it is linked with adverse consequences such as loss of function or augmented damage [79, 80]. This brings about the concept that not all plasticity effect positively on clinical status, that maladaptive plastic changes from dysregulated neuroplasticity result in an aberrant neural organization [79]. Typical example of situation where neuroplasticity becomes maladaptive can be seen in new onset of seizures after long period of cerebral trauma, where aberrant progressive plastic changes in the brain in the form of inappropriate synaptogenesis and axonal sprouting accounts for this late development. Neuroplasticity can also be seen as structural where the plastic changes involves the organization and number of synapses such as synaptogenesis, axonal sprouting and dendritic arborization, or functional where the plastic changes involves the efficacy and strength of synaptic connections such as LTP.
The basis of plastic changes that allows for neuroplasticity to become realistic depend upon factors such as neuronal excitability, which define the ability of a nerve to produce an action potential and in turn depends on the permeability, electrical and chemical state of the neuron [81]. This is then followed by adaptive changes termed plasticity, in which there are stable functional transformations that occur in specific neuronal systems as a result of specific stimuli or the combination of stimuli [82]. Furthermore, it has been revealed that effective and repeated action potentials are required from the presynaptic neuron to stimulate the postsynaptic to cause a change in the strength of an interneuron connection [83]. Cumulatively, the aforementioned process leads to biochemical changes, and anatomical adaptations which reinforce the connections between neighboring neurons, thus accounting for molecular, cellular, systems, and behavioral perspectives of explaining neuroplasticity [84].
The strength of the excitation impulse must exceed the threshold value to increase the synaptic efficacy and the stability of the connections between neurons. Nevertheless, when neurons are stimulated only with subthreshold stimuli, the overall activity of the synapse may decrease [85]. Studies conducted on unilateral lesion of the hippocampus results in the formation of new synapses (synaptogenesis) by the axons from the remaining contra-lateral hippocampal system [86]. Thus, the postsynaptic portion of a synapse continues to function properly despite the degeneration of the presynaptic region, and the surviving axons form new synapses. The fibers that form the (new) synapses are homologous to the damaged synapses, which may significantly facilitate the restoration of normal function.
Table 1 summarized various strategies that were found to enhance neuroplasticity and the mechanism through which modulate neuroplasticity.
Strategy | Proposed mechanism reported to modulate and promote neuroplasticity | References |
---|---|---|
Transcranial direct current stimulation (noninvasive) | Modification of neuronal membrane potentials, consequently persuading neuronal excitability which form part of the basis of neuroplasticity. | [87, 88] |
Deep brain stimulation (invasive) | This by stimulating neuronal network connected to the stimulated region, the pathological neuronal network becomes altered by changes in the neurochemical components thereby inducing morphological changes in both the dendrites (dendritic arborization) and axons (axonal sprouting). | [89] |
Functional Electrical Stimulation (FES noninvasive) | Hypothesized to modulate neuroplasticity through repeated generation of neurons synaptic activity that might facilitate synaptic remodeling, leading to neural reorganization. | [90] |
Aerobic Exercise | Aerobic exercise is linked with surge in neurogenesis and angiogenesis, together with rise in neurotrophic molecules especially BDNF and other growth factors implicated in neurite outgrowth and synaptic plasticity | [91, 92] |
Brain-derived neurotropic factor (BDNF) therapy | By binding of BDNF to its TrkB cognate receptor, two distinctive intracellular signaling pathways namely phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) becomes initiated, thereby regulating transcriptional gene activity of neurite outgrowth and neurogenesis. | [93, 94] |
Statins | Proposed mechanism by which statins modulates neuroplasticity involves indirect effect through statin-mediated increase in proteins such as endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), tissue plasminogen activator (tPA), and brain-derived neurotropic factor (BDNF) among others. | [95] |
Erythropoietin (EPO) therapy | EPO and EPO receptor (EPOR) that both becomes upregulated in response to cerebral ischemia, when supplemented act to indirectly augment neurogenesis through EPO-mediated increase in the expression vascular endothelial growth factor (VEGF) and brain-derived neurotropic factor (BDNF). | [96] |
Phosphodiesterase type 5 inhibitors (PDE-5 inhibitors) | PDE-5 inhibitors competitively inhibit phosphodiesterase enzymes responsible for converting cyclic guanylyl monophosphate (cGMP) back to GMP, thus fostering cGMP accumulation which has diverse cellular effect in the brain including angiogenesis, and neurogenesis which are requirements of neuroplasticity | [97] |
Vascular endothelial growth factor (VEGF) therapy. | Proposed mechanism through which VEGF modulates neuroplasticity involves mediating the PI3K–AKT–nuclear factor kappa B signaling pathway; an intracellular pathway that regulate transcriptional factors involves in neurogenesis | [98, 99] |
Various strategies that were found to enhance neuroplasticity.
Advancement in the understanding of mechanism of cerebral damage after stroke and brain neuroplasticity have continue to be a cutting-edge landmark information towards reducing human disability as a result of stroke. Strategies aimed at harnessing and augmenting neuroplasticity in complement with neurorehabilitation offers reasonable level of hope to maximize stroke recovery and diminish cerebral stroke induced neurological impairments. Although these strategies are rapidly evolving towards achieving clinical viability and success, more is needed to be done especially pertaining to outcome measures of neuroplasticity that rely on biomarkers of neuroplasticity rather than functional or behavioral outcome.
The authors declare no conflict of interest.
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