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Benefits of laser phototherapy on nerve repair

Benefits of laser phototherapy on nerve repair
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  REVIEWARTICLE Benefits of laser phototherapy on nerve repair Renata Ferreira de Oliveira  & Daniela Miranda Richarte de Andrade Salgado  &  Lívia Tosi Trevelin  & Raquel Marianna Lopes  &  Sandra Ribeiro Barros da Cunha  & Ana Cecília Correa Aranha  &  Carlos de Paula Eduardo  & Patricia Moreira de Freitas Received: 16 September 2013 /Accepted: 20 January 2014 # Springer-Verlag London 2014 Abstract  Post-traumaticnerve repairrepresentsa major chal-lenge to health sciences. Although there have been great advances in the last few years, it is still necessary to findmethods that can effectively enhance nerve regeneration. La-ser therapy has beenwidelyinvestigatedasa potential methodfor nerve repair. Therefore, in this article, a review of theexisting literature was undertaken with regard to the effectsof low-power laser irradiation on the regeneration of traumatically/surgically injured nerves. The articles were se-lected using either electronicsearchengines ormanualtracingofthereferencescitedinkeypapers.Inelectronicsearches,weused the key words as  “  paresthesia  ” ,  “ laser therapy ” ,  “ low- power laser and nerve repair  ” , and  “ laser therapy and nerverepair  ” , considering case reports and clinical studies. Accord-ing to the findings of the literature, laser therapy acceleratesand improves the regeneration of the affected nerve tissues, but there are manyconflictingresults about laser therapy.Thiscan be attributed to several variables such as wavelength,radiation dose, and type of radiation. All the early in vivostudies assessed in this research were effective in restoringsensitivity. Although these results indicate a potential benefit of the use of lasers on nerve repair, further double-blindcontrolled clinical trials should be conducted in order tostandardize protocols for clinical application. Keywords  Nerverepair  .Low-powerlasertherapy .LLLT(low-levellasertherapy) Introduction  Nerve tissue injuries may occur during various dental androutine surgical procedures, resulting in classic paresthesia.Thisdeficiencyischaracterizedasasensoryneuralloss,andisan abnormality that may or may not be transitory; it implies a sensorydisorderinwhichthepatientreportsadecreaseorlack of sensitivity, tingle in the tongue, lips or cheeks, and changein taste, among other manifestations [1  –  4]. The main iatro-genic causes of paresthesia in dentistry include the removal of impacted third molars, endodontic treatments, inferior alveo-lar nerve block (local anesthesia), orthognathic surgery, im- plants, surgical removal of cysts or tumors, and facial trauma [5  –  10].For the treatment of nerve tissue injuries, the followingtherapies have been proposed: systemic drugs administration(vitamins B and C, steroidal anti-inflammatory agents), local physiotherapy, electrical stimulation, acupuncture, and moxi- bustion. The prognosis for recovery as a result of these treat-ments varies considerably, depending on the extent of thenervous/nerve tissue injuries and the suggested treatment [11  –  13]. However, there is no therapy that promotes the totalrecovery and normalization of the injured tissue.First described in 1978 [14] as an alternative for the regen-eration of the traumatized nerves, low-power laser has beenextensively studied and great advances have been achieved inthe last three decades. Some of the effects of phototherapy arean increase in cellular metabolism and an increase in DNAand RNA synthesis in the cell nucleus, with consequent cell proliferation and protein synthesis, for example, collagenfibers produced by fibroblasts [15  –  19], cell differentiation(fibroblasts into myoblasts) [20], changes in nervous/nervecell action potential [21], effects on the immune system (lym- phocyte activation) [22, 23], microcirculation stimulation and capillary formation [24], stimulation of the release of growthfactors, and increase in leukocyte activity [25, 26]. R. F. de Oliveira  : D. M. R. de Andrade Salgado :  L. T. Trevelin : R. M. Lopes :  S. R. B. da Cunha  :  A. C. C. Aranha  : C. de Paula Eduardo :  P. M. de Freitas ( * )Department of Restorative Dentistry, Special Laboratory of Lasers inDentistry (LELO), School of Dentistry, University of São Paulo,São Paulo, Brazile-mail: Lasers Med SciDOI 10.1007/s10103-014-1531-6  Some studies have assessed the effects of the phototherapyin sciatic crush injury in rats considering several parameters,such as the morphological and electrophysiological aspects,andfunctionalrecoveryafter nerve injury,and theyconcludedthat phototherapy proved to be efficient in promoting neuralrecovery independent of having been performedtranscutaneously or directly [14, 27  –  33].However, although laser therapy has been shown to accel-erate or improve the regeneration of the affected nervous/ nerve tissue injuries [31  –  42], the studies described in theliterature showed differences with respect to wavelength, ir-radiation parameters, and dosimetry used, making it difficult to obtain clear and objective information to facilitate clinicalapplication by the dental professional/dentist. In 2005 [30], a literature review was released about the use of the photother-apy to increase peripheral nerve repair. However, in the last 8 years, other trial studies have been published, highlightingimportant aspects of laser therapy in paresthesia. Thus, it isimportant to make a critical evaluation of the data obtained todate, showing which treatment protocols are most used, andwhich are capable of providing positive results in repairinginjured nervous/nerve tissue, thereby providing professionalswith guidance in selecting the appropriate treatment.For this purpose, we performed a search of the literature inthe electronic databases of Medline/Pubmed, BVS and Sci-ence Direct, using the key words  “  paresthesia  ” ,  “ laser thera- py ” ,  “ low-power laser and nerve repair  ” , and  “ laser therapyandnerverepair  ” ,consideringcasereportsandclinicalstudies(in animal models and humans). Paresthesias derived from nervous/nerve tissue injury There areseveraliatrogeniccausesofnerve tissueinjuriesthat lead to sensorineural deficiency (paresthesia) [5  –  10]. Thedamage to nerve fibers, especially the sensory type, can beclassified according to the method proposed by Seddon andSunderland [43, 44], as described in Tables 1 and 2, respectively.A peripheral nerve trauma can result in a deficiency rang-ingfromtotallossofsensitivitytoa discrete changeinclinicalcondition, which can persist for days, weeks, or become permanent [45, 46]. The spontaneous reversal may take place within a few days or months, depending mainly on the degreeof injury sustained, location, and individual capacity for re-covery [47]. Sensation may return in less severe cases(neuropraxis) [48], and it is known that in more than 96 %of the cases, spontaneous return of sensitivity may occur in upto 24 months [8]. As regards the inferior alveolar nerve, thereturnofneurosensoryfunctiondepends onregenerationofitsfibers and elimination or remission of the secondary causes of the paresthetic condition, such as hemorrhage, edema, localinflammation, compressive tumor lesion, development of fi- brous scar tissue, or infection. If there is compression due tothe presence of a foreign body after a surgical procedure,surgical re-intervention may be necessary to eliminate thisforeign body [4, 49, 50]. Conventional treatment The treatment offered for cases of paresthesia are dependent on the degree of nerve tissue impairment/injury. NeuropraxisIn cases in which nerve compression only occurs due to post-traumatic edema, it is recommended to wait for the gradualreturn of sensitivity [46, 48, 51]. If this is not successful, the use of a corticoid or a surgical decompression is recom-mended [47, 51]. The majority of dentists prescribe conventional drug treat-ment consisting of antineuritic medication (vitamins B and C)and steroidal anti-inflammatory substances, in order to try torestore the electric flow of the nerve fiber and decrease theduration of the pathology [48].One of the most indicated therapies is to use vitamin B1associated with strychnine at the dose of 1 mg/ampoule, in12 days of intramuscular injections. Another procedure is touse cortisone (100 mg) every 6 h, during the first 2 or 3 daysso that if there is improvement, there is a distance between theinitial doses.However, there is no effective treatment for paresthesia.The symptoms tend to regress within 1  –  2 months; however, Table 1  Seddon ’ s classification (1943) of the degree of involvement of the nervous tissue, according to clinical intervention [43]Classification Nomenclature Definition InterventionFirst degree Neuropraxia A conduction block without axonal degeneration. A microsurgical intervention is not indicated.Second degree Axonotmesis A more severe injury. Regeneration can take place several months later without surgical intervention.Third degree Neurotmesis The most severe injury, with complete anatomicalsection of the neurovascular bundle or extensiveavulsion or crush injury.A microsurgical intervention is generally indicated.Fourth degreeFifth degreeLasers Med Sci  there is improvement with the use of histamine or vasodilator drugs [4].Axonotmesis or neurotmesisIn cases of sectioning of neural tissue, however, neurorrhaphytechniques that consist of the coaptation of an injured nervesegment may be used in order to restore the sensory loss or motor function [47, 52, 53]. The sooner decompression is  performed, the greater will be the probability of regenerationoccurring, because there will be a smaller quantity of scar tissue [47, 52, 54]. The indications for neural repair by neurorrhaphy include the following: observation of, or suspectedlacerationortransection ofthe nerve (theanesthesia does not improve 3 months after surgery); pain resulting fromneuroma formation; and pain caused by a foreign object or deformity of the duct, in addition to progressive decrease insensitivity or increase in pain [53]. Sensitivity may be recov-ered in approximately 01 (1 year) [4]. Neurorraphy may,however, be a very invasive method, and is indicated as thelast option in the treatment of sensorineural loss, and onlywhenthere iscompletenerve transection,sothatthe treatment of first choice is medication [48].Other therapies currently used for the treatment of paresthe-sias of the orofacial region, such as neuropraxis andaxonotmesis of different etiologies, are the following:neurorehabilitation, which seeks to restore or upgrade the sen-sorial processors and motor function [55]; eletroacupuncture,whichisbasedonthesameprinciplesasacupuncture,however,using the needles connected to an electric appliance that pro-duces electrical stimuli with an analgesic effect, when it isswitched on [11]; and moxibustion, which is a type of thermalacupuncture that consists of applying heat in body points or regions [56, 57]. However, in the scientific literature, there are still no longitudinal clinical studies that prove effectiveness of these three therapies.Among many methodologies offered to improve nerverepair, laser therapy has received increasing attention as a noninvasive technique [30] over the two last decades, and insome cases, the use of drugs has not been necessary [58, 59]. Although studies on the effects of laser therapy on peripheralnerve regeneration were published towards the end of 1970, it was only in the late 1980s that scientific interest began to beshowninthetherapeuticapproachtothistechnique,leadingtothe publication of a series of studies showing positive effectsof laser therapy on nerve regeneration [14, 15, 28, 30  –  33, 41, 42, 60  –  82]. Mechanism of action of low-level lasers Low-level laser therapy consists of releasing energy from photons absorbed through photochemical, photophysicaland/or photo biological effects on cells and tissues that donot generate heat [78, 83  –  85].Manyeffects ofLLLT(low-levellasertherapy)atacellular level have now been well elucidated, such as the stimulationof mitochondrial activity, stimulation of DNA and RNA syn-thesis, the variation of intra and extracellular pH, accelerationof metabolism, increased protein production and modulationof enzymatic activity [86  –  89]. In spite of the photochemistry, photo physical and photo biological effects of low-level laser therapy having been proved [78, 84, 85, 90], some authors agree that future studies should be conducted on low-levellaser therapy as a noninvasive treatment modality in different diseases and peripheral nerve injuries, in order to obtain protocols based on the literature, for wide acceptance andstandardization of this technique in clinical therapy [73, 74, 76, 81, 82]. Low-level laser acts by decreasing inflammation, and thus,sensitivitytopain[86,87,90  –  93].Itstimulatescirculationandcell activity, acts in biomodulation due to the increase in Table 2  Sunderland ’ s classification (1951) of the degree of involvement of the nervous tissue, according to the prognosis of regeneration [44]Classification Definition PrognosisFirst degree Nerve conduction is physiologically interrupted;however, there is no broken axon.There is no degeneration, and the spontaneous recoveryoccurs in a few days or weeks.Second degree Evident rupture of the axon with distal and proximalWallerian degeneration for one or more nodal segments.The integrity of the endoneurial tube is maintained,favoring the course of the regeneration process.Third degree Rupture of axon and endoneurial tubes, preservingthe perineum.Disorganization of the internal architecture of thefuniculus hinders regeneration by stimulating fibrosisduring the process, obstructing the growth of axons.Fourth degree Axons and endoneurial tubes are completely disrupted, in additionto part of the epineurium; however, the integrity of part of theepineurium is maintained, and complete section of the entiretrunk does not occur. Continuity nervosa is only maintained byscar tissue.Regeneration is more difficult than it is in the secondand third degrees.Fifth degree There is complete transection of the nerve trunk with a variabledistance between neural stumps.The possibilities of regeneration and returnof function are remote.Lasers Med Sci   production of mitochondrial ATP, and leads to an increase inthe threshold of nerve terminal excitability that results in ananalgesic effect [88, 89, 94]. The mechanism whereby low- level laser exerts its effects is based on the stimulation of the Na  +/  K  +  pump in the cell membrane [95, 96]. This stimulation hyperpolarizes the membrane, increasing the nerve impulsesand pain threshold [97]. The analgesic effect is due to theincrease of ß endorphins in the cerebrospinal fluid [98], andothers, such as anti-inflammatory, vascular, myorelaxing, andhealing effects, have been attributed to the use of low-power laser. They induce arteriolar and capillary vasodilatation andneovascularization, leading to increased blood flow in theirradiated area [78, 84, 85, 99]. Laser therapy on nerve tissue The literature points out three main goals of the use of low- power lasers in the treatment of paresthesia: (1) it acceleratesinjured nerve tissue regeneration; (2) it stimulates adjacent or contralateral nerve tissues,causing themtoplaythe roleofthesectioned nerve; and (3) it biomodulates the nervous/nerveresponseleadingtonormalityoftheactionpotentialthreshold.After this, we will discuss the effects of low-intensity laser therapy in these three processes in greater detail.Accelerates injured nerve tissue regenerationInperipheralnerve injuryoccurring after axontransection, thedistal part of the axon disintegrates and undergoes Walleriandegeneration dues to loss of contact with the cell body.Calcium-dependent proteases are activated in axon distal toinjury, leading to a proteolytic process that disintegrates axo- plasm [100, 101]. The remainders of the distal part of such axons, including myelin debris, are digested by Schwann cell proliferation and macrophage invasion [102, 103]. Schwann cell myelination through partitioning-defective 3 (PAR3) pro-tein (or protease-activated receptor 3) can be regulated by a  positive sign of the injured axon or the absence of a signalnormally provided by intact axons. The importance of Schwann cells and macrophages in removing myelin mayvary over time after the injury [102]. After the lesion,Schwann cells proliferate [104], and develop very early after a neural injury [105], with the response being faster in nonmyelinating Schwann cells [106].Studies have shown that laser therapy accelerates andimproves the regeneration of affected nerve tissue, since irra-diation with laser acts in activating and/or stimulating axonsprouting, and acts directly on axons and/or on Schwann cells[34  –  37,41,82];acceleratesthemyelinationoftheregenerated nerve fibers by increasing cells metabolism; and stimulatesSchwann cells proliferation and inhibits cell degeneration[38  –  40].Stimulating adjacent nervous/nerve tissuesIt is believed that laser has the potential to regenerate nervesand/or stimulate nearby innervations in order to play the roleof compromised innervations. Another hypothesis about therole of low-power laser therapy in paresthesia is based on its potential to increase microcirculation at the irradiated site,which has been scientifically proven [107, 108]. A possible hypothesismentionedina paper published in1996[64] isthat laser irradiation can stimulatethe reinervation of the tissue, by penetrating into axons or adjacent Schwann cells, the metab-olism of the damaged sensorineural tissue, and the productionof growth-associated proteins by adjacent non-injured nerves.Similar findings were found in the study of Dahlin in 2004[109].Biomodulates the nervous/nerve responseThe beneficial effect of phototherapy with low-power laser has been shown not only in nerves treated with laser but alsoin the corresponding segments of the spinal cord, wheretreatment with laser significantly decreased the degenerativechanges in neurons, and the proliferation induced by bothastrocytes and oligodendrocytes. This suggests a higher rateof metabolism in neurons, and an enhanced capacity to pro-duce myelin under the influence of a laser treatment [30].Some studies [14, 28, 31, 69] have assessed the histomorphometric evolution to determine the total surfacearea of the fascicle, mean axon diameter, and axonal densityinthe proximal,middle,anddistalsegmentsofthenerve.Thisexamination was performed using a computerized systemwith an operating microscope and a video camera connectedto a monitor and a computer screen with specific software that allows the quantification of myelinated and unmyelinatedfibers, as well as individual evaluation of axons with determi-nation of the radius, circumference, diameter, and area [69]. It was found that there was an increase in axon density and anincrease in peroxidase enzyme in the nucleus of the motor facial nerve [15] in the groups treated with laser, when com- pared with the control groups (not submitted to laser therapy)  —  these are findings consistent with those of other studies [34  –  40].Many studies have reported conflicting results concerninglaser therapy. This may be attributed to many variables, suchaswavelengths,dose,andtypeofradiation[14,15,28,30  –  33,41, 42, 61  –  82, 110, 111]. The present study considered 32  published articles in literature, including 3 clinical case re- ports, 22 in vivo studies in animal models, 3 in vitro studies, 4in vivo studies in humans (Table 3). The differences in out-comes were found to be based on the different lasers used and parametersselectedtoperformtreatmentofparesthesia.Thesevariables are described individually below, pointing out their relevance in each of the findings. Lasers Med Sci  Table 3  Summary of experimental studies of phototherapy effects on nerve regeneration Ref. Year Type of study No. of samplesAffected site Time of study Wavelength (nm) Dose (J/cm 2 ) Power density Irradiation time Outcome measure Results/effectsAnimal trials14 1987 In vivo  –   Sciatic nerve Approx. 1 year 632.8  – –   14 min Eletrophysiological andmorphologicalPositive28 1987 In vivo  –   Sciatic nerve  –   632.8  – –   7 min Eletrophysiological andmorphologicalPositive61 1992 In vivo 12 rabbits Peronial nerve 15 days 632.8 3.82  –   3 min Eletrophysiological Positive15 1993 In vivo 87 rats Facial nerve 14 days 361, 457,514,633,720,1064  – –   13  –  120 min Counting the no. of HRP Effective63 1995 In vivo 20 rats Sciatic nerve 28 days 820 48 550 mW/cm 2 85 s (per point) SFI, neurophysiological andhistologicalEffective66 2001 In vivo 17 rats Sciatic nerveinjury21 days 632 180  – –   CMAPs Effective68 2001 In vivo 24 rats Sciatic nerve 10 weeks 780  – –   15 min (per area) Eletrophysiological,somatosensorial and histologicEffective69 2002 In vivo 5 rabbits Mentual nerve 15 weeks 820  –  830 6  –   90 s (per point) Histomorphometric Effective110 2003 In vivo 24 rats Sciatic nerve Approx. 21 days 904 0.31/2.48/19  –   15 min Eletrophysiological andmorphological Null70 2003 In vivo 20 rats Sciatic nerve 5 weeks 650  – –   5 min Motor test Effective71 2004 In vivo 16 rats Median nerveinjuryApprox.2 months808 29  –   39 s Functional, optical and electronicmicroscopyEffective905 40  –   1 ’ 12 s111 2005 In vivo  –   Sciatic nerve Approx. 8 weeks 905  – –   72 s Eletrophysiological andmorphological Negative904 2 min73 2007 In vitro 24 rats Fibular nerve 8 weeks 901 nm  –   10 m/W 10 min Histopathological Effective74 2007 In vivo 20 rats Sciatic nerve 3 months 780 nm  –   200 m/W 15 min SFI, electrophysiologicalMorphology,Effective42 2008 In vivo 16 rats Inferior alveolar nerve3 weeks  –   5  –   1 min Histological analyses Effective76 2009 In vivo 12 rats Sciatic nerve 21 days 660 4 0.0413 W/cm2 96.7 s (per point) SFI, histological andhistomorphometricPositive (histomorphometricchanges) null (functionalrecovery)77 2009 In vivo 12 rats Sciatic nerveinjury20 days 660 4 0.0413 W/cm 2  –   SFI Effective78 2010 In vivo 27 rats Sciatic nerveinjury21 days 660 10  –   20 s SFI 660 nm more effective than830 nm830 10 38.66 s79 2010 In vivo 64 rats Sciatic nerveinjury10 days 660/780 10/60/120  –   0.3 a 2 min SFI Effective33 2010 In vivo 40 rats Sciatic nerve 12 weeks 660  –   24 mW  –   Tibialis anterior muscle weight;electrophysiology;immunohistochemistry;histopathological observation;RT-PCR Effective L  a  s  e r  s M e  d   S  c i   
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