Benefits of laser phototherapy on nerve repair

Lasers Med Sci DOI 10.1007/s10103-014-1531-6 REVIEW ARTICLE 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-traumatic nerve repair represents a major challenge to health sciences. Although there have been great advances in the last few years, it is still necessary to find methods that can effectively enhance nerve regeneration. Laser therapy has been widely investigated as a potential method for nerve repair. Therefore, in this article, a review of the existing literature was undertaken with regard to the effects of low-power laser irradiation on the regeneration of traumatically/surgically injured nerves. The articles were selected using either electronic search engines or manual tracing of the references cited in key papers. In electronic searches, we used the key words as “paresthesia”, “laser therapy”, “lowpower laser and nerve repair”, and “laser therapy and nerve repair”, considering case reports and clinical studies. According to the findings of the literature, laser therapy accelerates and improves the regeneration of the affected nerve tissues, but there are many conflicting results about laser therapy. This can be attributed to several variables such as wavelength, radiation dose, and type of radiation. All the early in vivo studies assessed in this research were effective in restoring sensitivity. Although these results indicate a potential benefit of the use of lasers on nerve repair, further double-blind controlled clinical trials should be conducted in order to standardize protocols for clinical application. Keywords Nerve repair . Low-power laser therapy . LLLT (low-level laser therapy) 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 in Dentistry (LELO), School of Dentistry, University of São Paulo, São Paulo, Brazil e-mail: pfreitas@usp.br Introduction Nerve tissue injuries may occur during various dental and routine surgical procedures, resulting in classic paresthesia. This deficiency is characterized as a sensory neural loss, and is an abnormality that may or may not be transitory; it implies a sensory disorder in which the patient reports a decrease or lack of sensitivity, tingle in the tongue, lips or cheeks, and change in taste, among other manifestations [1–4]. The main iatrogenic causes of paresthesia in dentistry include the removal of impacted third molars, endodontic treatments, inferior alveolar nerve block (local anesthesia), orthognathic surgery, implants, surgical removal of cysts or tumors, and facial trauma [5–10]. For the treatment of nerve tissue injuries, the following therapies have been proposed: systemic drugs administration (vitamins B and C, steroidal anti-inflammatory agents), local physiotherapy, electrical stimulation, acupuncture, and moxibustion. The prognosis for recovery as a result of these treatments varies considerably, depending on the extent of the nervous/nerve tissue injuries and the suggested treatment [11–13]. However, there is no therapy that promotes the total recovery and normalization of the injured tissue. First described in 1978 [14] as an alternative for the regeneration of the traumatized nerves, low-power laser has been extensively studied and great advances have been achieved in the last three decades. Some of the effects of phototherapy are an increase in cellular metabolism and an increase in DNA and RNA synthesis in the cell nucleus, with consequent cell proliferation and protein synthesis, for example, collagen fibers produced by fibroblasts [15–19], cell differentiation (fibroblasts into myoblasts) [20], changes in nervous/nerve cell action potential [21], effects on the immune system (lymphocyte activation) [22, 23], microcirculation stimulation and capillary formation [24], stimulation of the release of growth factors, and increase in leukocyte activity [25, 26]. Lasers Med Sci Some studies have assessed the effects of the phototherapy in sciatic crush injury in rats considering several parameters, such as the morphological and electrophysiological aspects, and functional recovery after nerve injury, and they concluded that phototherapy proved to be efficient in promoting neural recovery independent of having been performed transcutaneously or directly [14, 27–33]. However, although laser therapy has been shown to accelerate or improve the regeneration of the affected nervous/ nerve tissue injuries [31–42], the studies described in the literature showed differences with respect to wavelength, irradiation parameters, and dosimetry used, making it difficult to obtain clear and objective information to facilitate clinical application by the dental professional/dentist. In 2005 [30], a literature review was released about the use of the phototherapy to increase peripheral nerve repair. However, in the last 8 years, other trial studies have been published, highlighting important aspects of laser therapy in paresthesia. Thus, it is important to make a critical evaluation of the data obtained to date, showing which treatment protocols are most used, and which are capable of providing positive results in repairing injured nervous/nerve tissue, thereby providing professionals with guidance in selecting the appropriate treatment. For this purpose, we performed a search of the literature in the electronic databases of Medline/Pubmed, BVS and Science Direct, using the key words “paresthesia”, “laser therapy”, “low-power laser and nerve repair”, and “laser therapy and nerve repair”, considering case reports and clinical studies (in animal models and humans). Paresthesias derived from nervous/nerve tissue injury There are several iatrogenic causes of nerve tissue injuries that lead to sensorineural deficiency (paresthesia) [5–10]. The damage to nerve fibers, especially the sensory type, can be classified according to the method proposed by Seddon and Sunderland [43, 44], as described in Tables 1 and 2, respectively. A peripheral nerve trauma can result in a deficiency ranging from total loss of sensitivity to a discrete change in clinical condition, 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 degree of injury sustained, location, and individual capacity for recovery [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 up to 24 months [8]. As regards the inferior alveolar nerve, the return of neurosensory function depends on regeneration of its fibers and elimination or remission of the secondary causes of the paresthetic condition, such as hemorrhage, edema, local inflammation, compressive tumor lesion, development of fibrous scar tissue, or infection. If there is compression due to the presence of a foreign body after a surgical procedure, surgical re-intervention may be necessary to eliminate this foreign body [4, 49, 50]. Conventional treatment The treatment offered for cases of paresthesia are dependent on the degree of nerve tissue impairment/injury. Neuropraxis In cases in which nerve compression only occurs due to posttraumatic edema, it is recommended to wait for the gradual return of sensitivity [46, 48, 51]. If this is not successful, the use of a corticoid or a surgical decompression is recommended [47, 51]. The majority of dentists prescribe conventional drug treatment consisting of antineuritic medication (vitamins B and C) and steroidal anti-inflammatory substances, in order to try to restore the electric flow of the nerve fiber and decrease the duration of the pathology [48]. One of the most indicated therapies is to use vitamin B1 associated with strychnine at the dose of 1 mg/ampoule, in 12 days of intramuscular injections. Another procedure is to use cortisone (100 mg) every 6 h, during the first 2 or 3 days so that if there is improvement, there is a distance between the initial 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 Intervention First degree Second degree Neuropraxia Axonotmesis A conduction block without axonal degeneration. A more severe injury. Third degree Fourth degree Fifth degree Neurotmesis The most severe injury, with complete anatomical section of the neurovascular bundle or extensive avulsion or crush injury. A microsurgical intervention is not indicated. Regeneration can take place several months later without surgical intervention. A microsurgical intervention is generally indicated. Lasers Med Sci Table 2 Sunderland’s classification (1951) of the degree of involvement of the nervous tissue, according to the prognosis of regeneration [44] Classification Definition Prognosis First degree Nerve conduction is physiologically interrupted; however, there is no broken axon. Evident rupture of the axon with distal and proximal Wallerian degeneration for one or more nodal segments. Rupture of axon and endoneurial tubes, preserving the perineum. There is no degeneration, and the spontaneous recovery occurs in a few days or weeks. The integrity of the endoneurial tube is maintained, favoring the course of the regeneration process. Disorganization of the internal architecture of the funiculus hinders regeneration by stimulating fibrosis during the process, obstructing the growth of axons. Regeneration is more difficult than it is in the second and third degrees. Second degree Third degree Fourth degree Fifth degree Axons and endoneurial tubes are completely disrupted, in addition to part of the epineurium; however, the integrity of part of the epineurium is maintained, and complete section of the entire trunk does not occur. Continuity nervosa is only maintained by scar tissue. There is complete transection of the nerve trunk with a variable distance between neural stumps. there is improvement with the use of histamine or vasodilator drugs [4]. Axonotmesis or neurotmesis In cases of sectioning of neural tissue, however, neurorrhaphy techniques that consist of the coaptation of an injured nerve segment 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 regeneration occurring, 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 suspected laceration or transection of the nerve (the anesthesia does not improve 3 months after surgery); pain resulting from neuroma formation; and pain caused by a foreign object or deformity of the duct, in addition to progressive decrease in sensitivity or increase in pain [53]. Sensitivity may be recovered in approximately 01 (1 year) [4]. Neurorraphy may, however, be a very invasive method, and is indicated as the last option in the treatment of sensorineural loss, and only when there is complete nerve transection, so that the treatment of first choice is medication [48]. Other therapies currently used for the treatment of paresthesias of the orofacial region, such as neuropraxis and axonotmesis of different etiologies, are the following: neurorehabilitation, which seeks to restore or upgrade the sensorial processors and motor function [55]; eletroacupuncture, which is based on the same principles as acupuncture, however, using the needles connected to an electric appliance that produces electrical stimuli with an analgesic effect, when it is switched on [11]; and moxibustion, which is a type of thermal acupuncture 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. The possibilities of regeneration and return of function are remote. Among many methodologies offered to improve nerve repair, laser therapy has received increasing attention as a noninvasive technique [30] over the two last decades, and in some cases, the use of drugs has not been necessary [58, 59]. Although studies on the effects of laser therapy on peripheral nerve regeneration were published towards the end of 1970, it was only in the late 1980s that scientific interest began to be shown in the therapeutic approach to this technique, leading to the publication of a series of studies showing positive effects of 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, photophysical and/or photo biological effects on cells and tissues that do not generate heat [78, 83–85]. Many effects of LLLT (low-level laser therapy) at a cellular level have now been well elucidated, such as the stimulation of mitochondrial activity, stimulation of DNA and RNA synthesis, the variation of intra and extracellular pH, acceleration of metabolism, increased protein production and modulation of 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-level laser 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 and standardization of this technique in clinical therapy [73, 74, 76, 81, 82]. Low-level laser acts by decreasing inflammation, and thus, sensitivity to pain [86, 87, 90–93]. It stimulates circulation and cell activity, acts in biomodulation due to the increase in Lasers Med Sci production of mitochondrial ATP, and leads to an increase in the threshold of nerve terminal excitability that results in an analgesic effect [88, 89, 94]. The mechanism whereby lowlevel 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 impulses and pain threshold [97]. The analgesic effect is due to the increase of ß endorphins in the cerebrospinal fluid [98], and others, such as anti-inflammatory, vascular, myorelaxing, and healing effects, have been attributed to the use of low-power laser. They induce arteriolar and capillary vasodilatation and neovascularization, leading to increased blood flow in the irradiated area [78, 84, 85, 99]. Stimulating adjacent nervous/nerve tissues It is believed that laser has the potential to regenerate nerves and/or stimulate nearby innervations in order to play the role of compromised innervations. Another hypothesis about the role 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 hypothesis mentioned in a paper published in 1996 [64] is that laser irradiation can stimulate the reinervation of the tissue, by penetrating into axons or adjacent Schwann cells, the metabolism of the damaged sensorineural tissue, and the production of growth-associated proteins by adjacent non-injured nerves. Similar findings were found in the study of Dahlin in 2004 [109]. Laser therapy on nerve tissue Biomodulates the nervous/nerve response The literature points out three main goals of the use of lowpower lasers in the treatment of paresthesia: (1) it accelerates injured nerve tissue regeneration; (2) it stimulates adjacent or contralateral nerve tissues, causing them to play the role of the sectioned nerve; and (3) it biomodulates the nervous/nerve response leading to normality of the action potential threshold. After this, we will discuss the effects of low-intensity laser therapy in these three processes in greater detail. Accelerates injured nerve tissue regeneration In peripheral nerve injury occurring after axon transection, the distal part of the axon disintegrates and undergoes Wallerian degeneration dues to loss of contact with the cell body. Calcium-dependent proteases are activated in axon distal to injury, leading to a proteolytic process that disintegrates axoplasm [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) protein (or protease-activated receptor 3) can be regulated by a positive sign of the injured axon or the absence of a signal normally provided by intact axons. The importance of Schwann cells and macrophages in removing myelin may vary 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 non myelinating Schwann cells [106]. Studies have shown that laser therapy accelerates and improves the regeneration of affected nerve tissue, since irradiation with laser acts in activating and/or stimulating axon sprouting, and acts directly on axons and/or on Schwann cells [34–37, 41, 82]; accelerates the myelination of the regenerated nerve fibers by increasing cells metabolism; and stimulates Schwann cells proliferation and inhibits cell degeneration [38–40]. The beneficial effect of phototherapy with low-power laser has been shown not only in nerves treated with laser but also in the corresponding segments of the spinal cord, where treatment with laser significantly decreased the degenerative changes in neurons, and the proliferation induced by both astrocytes and oligodendrocytes. This suggests a higher rate of metabolism in neurons, and an enhanced capacity to produce myelin under the influence of a laser treatment [30]. Some studies [14, 28, 31, 69] have assessed the histomorphometric evolution to determine the total surface area of the fascicle, mean axon diameter, and axonal density in the proximal, middle, and distal segments of the nerve. This examination was performed using a computerized system with an operating microscope and a video camera connected to a monitor and a computer screen with specific software that allows the quantification of myelinated and unmyelinated fibers, as well as individual evaluation of axons with determination of the radius, circumference, diameter, and area [69]. It was found that there was an increase in axon density and an increase in peroxidase enzyme in the nucleus of the motor facial nerve [15] in the groups treated with laser, when compared 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 concerning laser therapy. This may be attributed to many variables, such as wavelengths, dose, and type of radiation [14, 15, 28, 30–33, 41, 42, 61–82, 110, 111]. The present study considered 32 published articles in literature, including 3 clinical case reports, 22 in vivo studies in animal models, 3 in vitro studies, 4 in vivo studies in humans (Table 3). The differences in outcomes were found to be based on the different lasers used and parameters selected to perform treatment of paresthesia. These variables are described individually below, pointing out their relevance in each of the findings. Ref. Year Type of study No. of samples Affected site Time of study Wavelength (nm) Dose (J/cm2) Power density Irradiation time Outcome measure Results/effects Positive Positive Animal trials 14 1987 In vivo – Sciatic nerve Approx. 1 year 632.8 – – 14 min 61 1992 In vivo 12 rabbits Peronial nerve 15 days 632.8 3.82 – 3 min Eletrophysiological and morphological Eletrophysiological and morphological Eletrophysiological 28 1987 In vivo – Sciatic nerve – 632.8 – – 7 min 15 1993 In vivo 87 rats Facial nerve 14 days – – 13–120 min Counting the no. of HRP Effective 63 1995 In vivo 20 rats Sciatic nerve 28 days 361, 457,514, 633,720,1064 820 48 550 mW/cm2 85 s (per point) Effective 66 2001 In vivo 17 rats 21 days 632 180 – – 68 2001 In vivo 24 rats Sciatic nerve injury Sciatic nerve SFI, neurophysiological and histological CMAPs 10 weeks 780 – – 15 min (per area) Effective 69 2002 In vivo 820–830 Eletrophysiological, somatosensorial and histologic Histomorphometric Null Positive Effective 5 rabbits Mentual nerve 15 weeks 6 – 90 s (per point) 110 2003 In vivo 24 rats Sciatic nerve Approx. 21 days 904 0.31/2.48/19 – 15 min 70 2003 In vivo 20 rats Sciatic nerve 5 weeks 650 – – 5 min Eletrophysiological and morphological Motor test Effective 71 2004 In vivo 16 rats Median nerve injury Approx. 2 months 808 905 29 40 – – 39 s 1’12 s Functional, optical and electronic microscopy Effective 111 2005 In vivo – Sciatic nerve Approx. 8 weeks 905 904 – – 72 s 2 min Eletrophysiological and morphological Negative 73 2007 In vitro 24 rats Fibular nerve 8 weeks 901 nm – 10 m/W 10 min Histopathological Effective 74 2007 In vivo 20 rats Sciatic nerve 3 months 780 nm – 200 m/W 15 min Effective 42 2008 In vivo 16 rats 3 weeks – 5 – 1 min 76 2009 In vivo 12 rats Inferior alveolar nerve Sciatic nerve SFI, electrophysiological Morphology, Histological analyses 21 days 660 4 0.0413 W/cm2 96.7 s (per point) SFI, histological and histomorphometric Positive (histomorphometric changes) null (functional recovery) 77 2009 In vivo 12 rats 20 days 660 4 0.0413 W/cm2 – SFI Effective 78 2010 In vivo 27 rats Sciatic nerve injury Sciatic nerve injury 21 days 660 830 10 10 – 20 s 38.66 s SFI 660 nm more effective than 830 nm 79 2010 In vivo 64 rats 10 days 660/780 10/60/120 – 0.3 a 2 min SFI Effective 33 2010 In vivo 40 rats Sciatic nerve injury Sciatic nerve 12 weeks 660 – 24 mW – Tibialis anterior muscle weight; electrophysiology; immunohistochemistry; histopathological observation; RT-PCR Effective Effective Effective Lasers Med Sci Table 3 Summary of experimental studies of phototherapy effects on nerve regeneration Table 3 (continued) Ref. Year Type of study No. of samples Affected site Time of study Wavelength (nm) Dose (J/cm2) Power density Irradiation time Outcome measure Results/effects 81 2011 In vivo 36 rats Median nerve 16 weeks 810 175 21 mW/cm2 82 2011 In vivo 12 rats Sciatic nerve 8 weeks 660 3.84 0.0032 W/cm2 31 2011 In vitro 20 rats Sciatic nerve 21 days 904 nm 4 J/cm2 0.0413 W/cm2 32 2012 In vivo 50 rats Sciatic nerve 15 days 660 e 808 10 ou 50 30 mW 830 6 437 mW/cm2 90 s (per point) VAS, objective and subjective tests Effective (tingling and numbness) 820 48 550 mW/cm2 85 s (per point) mechanoreceptor and temperature tests Effective (mechanoreceptor) null (temperature) 820–830 – 550 mW/cm2 90 s (per point) VAS, temperature and objective tests (2 points) Effective 780 – – – Effective Approx. 7 weeks 820–830 – – 90 s VAS, temperature, mechanoreceptor VAS, objective tests Approx. 4 months Around 8– 201 days 670 7 – – Not informed Effective 660/690 790/830 4/140 4/140 – – – – Not informed Effective 20 days 810 1e4 50 mW 8 s (1 J/cm2) e 32 s (4 J/cm2) MTT assay and real-time PCR analysis Positive 1,182 s Grip strength test; electrophysiology; immunohistochemistry; 5 min SFI, eletrophysiological and histomorphometric 32 s per point Histological; analyzed and quantified Schwann cells, myelinic axons with large diameter and neurons 9 s (10 J/cm2) e 47 s SFI, histological and histomorphometric (50 J/cm2) Effective Positive Effective Positive Clinical trials and case reports (On patients) Inferior, mentual 20 weeks and lingual alveolar nerve Inferior, alveolar Around 36– nerve and 69 days lingual nerve 62 1993 In vivo 40 patients 64 1996 In vivo 13 patients 65 2000 In vivo 6 patients 67 2001 Case report 6 patients 72 2006 In vivo 4 patients 75 2008 Case report 1 patient Lips, chin, gum and oral region Nerve 80 2011 Case report 25 patients Not informed 41 2012 In vitro – Sural nerve Inferior and 35 days mentual alveolar nerve Lingual nerve 165 days Effective Lasers Med Sci Lasers Med Sci Variables that influence laser therapy Wavelength Among the studies analyzed in this critical review, the wavelengths most frequently used in the repair of nerve tissue ranged between the red and near infrared (660–905 nm) spectral bands. From an analysis of studies, it was determined that in the past, helium–neon laser (He–Ne), emitted in the red region of electromagnetic spectrum, was the most studied wavelength used in biomodulation of the nervous/nerve response in the neural repair process [30, 58]. At present, new wavelengths are being used, with lasers emitting radiation at the wavelength of 650–950 nm, since both red and infrared wave lengths have shown significant results in neural regeneration [32, 66, 71, 81]. In general, considering the in vivo (animal models) and in vitro results of this review [14, 15, 28, 31–33, 41, 42, 61, 63, 66, 68–71, 73, 74, 76–79, 81, 82, 110, 111], the wavelengths used vary from 361 to 1,064 nm and the majority of the results have proved that laser therapy was effective. In the study of Begis et al. [110], laser therapy showed null results, in other words, no statistical significance was observed in studied groups. The authors explained that although earlier studies suggested that laser stimulates the cell proliferation, the effect on nerve regeneration is debatable. According to the authors, the biological effects of laser may not only be related to the nerve lesion injury but also to the wavelength, the irradiation dose, and beam emission mode (continuous or pulsed), and because different procedures have been used in different studies, the results were not similar. In the work of Reis et al. [76], the result of the action of low-power laser therapy at wavelength 660 nm was positive when the histomorphometric changes in myelin sheath area were observed, in which there was a statistically significant increase, when compared with the control group. However, in the functional analysis (Sciatic Functional Index), this study did not achieve significant improvement in the study group compared with the control group. According to the authors, this was because, after neural cell injury, there is the onset of degeneration processes, characterized by an engorgement of the cells. These changes, in spite of the production of neurotransmitters with the aim of increasing protein synthesis (actin and tubulin), are related to the regeneration of the cytoskeleton axons, and affect intracellular transport and the growth cone. It is probable that the period of 7 days after the lesion would be marked by these events, but the use of laser therapy within 24 h of the injury could reduce the immediate loss of the function, confirming the allegation of Dahlin et al. [109]; however, this did not occur in the above-mentioned study. In the work of Chen et al. [11], the result of the laser therapy was negative. The authors reported that the treatment with pulsed laser at a wavelength of 904 and 905 nm, with the emission time of 72 s at 905 nm and 2 min at 904 nm, not only decreased the success rate of regeneration but also inhibited the axonal growth of the nerve. They also reported that according to the literature and their study, laser irradiation shows two effects: it may promote nerve regeneration and may also prevent nerve recovery, demonstrating the importance of using safe stimulation protocols; otherwise, inappropriate laser stimulation may irreversibly damage some nervous/nerve tissues, retarding the nerve regeneration process. Laser at a wavelength in the red spectrum was used in various studies in humans and in animal models [14, 15, 28, 32, 33, 66, 67, 70, 75, 77, 78, 80, 82]. The red laser wavelength ranged from 632.8 to 690 nm, and in 90 % of the studies in which it was used, the results showed the effectiveness of the laser for the treatment of paresthesia. In only one study [76], conducted with an animal model (in vivo), laser therapy showed null results for SFI (sciatic functional index) in the evaluation period, as described above. Studies that compared laser at the red and infrared wavelengths reported distinct and inconclusive results [32, 78, 80]; however, in one of them [80], there was no difference among the treatments and in the other, two [32, 78] phototherapy at the red and infrared wavelengths (660, 808, and 830 nm) were effective, but the best result was expressed with the wavelength of 660 nm [32, 78]. Laser in the infrared spectral range was also used in both human and animal models (in vivo) and (in vitro) [15, 31, 32, 41, 61–65, 69, 71–74, 78, 81, 110, 111]. Wavelengths ranged from 790 to 1,064 nm, and in some of the studies analyzed, the result obtained showed the effectiveness of laser for the treatment of paresthesia. Some authors [71] reported that laser induces a faster increase in the rate of recovery of injured function, in addition to a faster increase in the rate of recovery of muscle mass and nerve fiber regeneration. The studies conducted by Bagis et al. [110] may have shown the result of the null effect of laser therapy for the same reason previously mentioned, in other words, due to the type of lesion induced in the sample. The study conducted by Chen et al. [111], however, did not show positive results for the laser treatment on nerve repair possibly due to the use of a pulsed laser (wavelength at 904 and 905 nm) with a power output that may have oscillated and interfered in the neural regeneration. However, this hypothesis must be assessed in future studies, because this condition was described and assessed only in this study. In the study of Gigo-Benato et al. [71], both types of emission were used, and better results were shown in the continuous emission mode. Considering that without exception, all published studies that used continuous emission led to positives results, this type of light emission must be the first choice for promoting peripheral nerve repair [30]. Nevertheless, this hypothesis cannot be confirmed, since further studies should still be conducted to prove the real effectiveness of laser with the emission in continuous mode in comparison Lasers Med Sci with the pulsed mode. Based on literature review that was carried out in this article, we can only say that up to now, in the majority of published studies, laser was used in the continuous mode and was shown to have positive results. Therefore, this mode is the first choice for promoting peripheral nerve repair. Nervous/nerve tissue affected In human studies, the sites most affected were the inferior alveolar nerve, mental nerve, and lingual nerve, and in one of the studies, paresthesia in the lower lip, chin, and gum was assessed. The in vivo studies in animal models show a tendency to evaluate injury in the sciatic, median, and facial nerves. Only one of the selected articles [80] did not report the site/location affected by the injury. Although many studies reported greater difficulty in recovery from paresthesia after neurotmesis [10], in one of the in vivo, animal model studies assessed [68], the use of infrared laser was effective after complete transection and anastomosis of the sciatic nerve, in agreement with the findings of other studies about total neural injury and sensory recovery posttrauma [52–54]. In an in vivo study (animal model) [15], laser was used to repair induced injury to the facial nerve, using different wavelengths (361, 457, 633, 720, and 1,064 nm), power (from 8.5 to 40 mW), and irradiation times (13– 120 min) and the authors concluded that the best result was obtained at the following parameters: wavelength of 633 nm, 8.5 mW, 90 min, 45.9 J, and 162.4 J/cm2. In addition, it was concluded that the laser emitting in the red spectral band is more efficient than infrared laser, and this finding coincides with those of other studies analyzed in this review [32, 78]. Neurosensory tests As regards neurosensory tests conducted to evaluate treatment, the most frequently used were VAS (visual analog scale) [62, 65, 67, 72, 76–78], SFI (sciatic functional index) [32, 63, 64, 77–79], temperature tests [64, 65, 67], needle-stick test [62, 65], mechanoreceptor test [65, 67], and other tests, such as the two points discrimination [65], motor and muscle function test [70, 81], analyzing the degree of tingling and numbness [62], and computer analysis [31, 41, 71, 75, 76, 81, 82], counting the degree of peroxidase (Horse Radish Peroxidase or HRP) [15], Compound Muscle Action Potentials or CMPs [66], neurophysiological [63], electrophysiological [14, 28, 33, 61, 68, 79, 81, 82, 109, 110], both objective and subjective tests [62, 65, 72], and histomorphometric [14, 28, 31, 32, 69, 76] and histopathological [31–33, 41, 73] analyses. Only two studies did not mention the type of tests performed [75, 80]. Each clinical test is specific for different nervous/ nerve fibers, and these tests are extremely important because they are able to quantify the evolution of the paresthesia within a determined period of time [47, 54, 112]. Subjective clinical tests to assess the functionality of the trigeminal nerve branches are divided into two categories: the mechanoceptive tests (connected to tactile stimuli), which are based on the patient’s decision-making capacity, in a blind test, to identify the contact simultaneously at two close points, or describe the trajectory of a brush tip passing over the surface of the skin; and the nociceptive tests (connected to potential pain causing stimuli), which include thermal tests, or light punctures of the skin or mucosa, and pulp vitality test [54, 113]. Neuroelectrical tests can be used to evaluate disorders of the inferior alveolar nerve, allowing a satisfactory measurement of the degree of nerve involvement and assess which groups of nerves were most affected [113]. Lee et al. [114] reported that thermal images are an effective and safe way to diagnose a state of paresthesia. A study published by Khullar et al. [64] has highlighted the need for standardization of neurosensory testing to evaluate the results promoted by laser therapy. The authors conducted two tests—mechanoreceptor and temperature tests—to assess the effectiveness of infrared laser in the treatment of paresthesia caused by injury to the inferior alveolar and lingual nerves. When using mechanoreceptor tests, infrared laser therapy was found to be effective, but when using the temperature test, there was no significant difference in improvement between the two groups (treated/or not treated with low-power laser). Irradiation parameters When evaluating the irradiation parameters described in selected articles, it was found that some data, such as the repetition rate (Hz), the frequency of application, the time of exposure, and the diameter of the laser output beam (equipment spot size), were not described. Power was one of the parameters that varied widely from 5 to 416 mW in animal studies [15, 31–33, 41, 63, 66, 68–71, 73, 74, 76–79, 81, 82]. Yet in human studies, there was no significant variation, with 70 mW being the power most used [62, 64, 65, 72] and the lowest being 3 mW [67]. The energy density used varied widely in both human studies and animal models. The highest energy density used in a study with human beings was 140 J/cm2 and the lowest was 4 J/cm2, and both the highest and lowest densities were shown to be effective in repairing nerve tissue [80]. In studies using an animal model, the energy density was higher than 180 J/cm2 [66], and the lowest was 3.84 J/cm2 [82]. In some studies, the use of low densities of 0.31–19 J/cm2 in laser treatment showed that the effect was null [76, 109]. On the other hand, in the study by Gigo-Benato et al. [79], the results showed that the use of low or moderate energy density, considered from 10 to 60 J/cm2, at a wavelength of 660 nm, were shown to be more effective than the energy density of 120 J/cm2, which is used at the wavelength of 780 nm, when the parameter for the prevention of muscle atrophy was Lasers Med Sci evaluated. In the literature, the energy density of <10–150 J/ cm2 and the time between <1 and 90 min [30, 79] have been shown to be effective in promoting nerve regeneration. Another important fact to consider as regards sensorineural recovery with laser therapy is the time of treatment. In one study [84], a crush injury was performed in the peroneal nerve of rabbits. It was observed that 15 daily transcutaneous laser irradiations at 632.8 nm on the injured nerve, starting on the first day after operation, allowed significant increase in neural recovery in the group treated with laser, after motor-evoked potential evaluation, when compared with the control group, as shown in other studies [15, 25, 28, 61, 68, 70, 71, 73, 74, 78, 79, 81, 82, 110, 111]. In another study [63], 20 rats were submitted to sciatic nerve injury (axonotmesis), of which 10 received daily treatment with 830-nm laser for a period of 28 days. After SFI (Sciatic Functional Index) evaluation, it was observed that laser therapy promoted a functional increase in the nerve; however, in the motor-evoked potential assessment, no significant differences in improvement were found when compared with the control group. In the study of Reis et al. [76], 12 rats were subjected to sciatic nerve injury (neurotmesis). Of these, six received daily treatment with 660nm laser for a period of 20 consecutive days. Histomorphometric evaluation showed that positive results in nerve regeneration were obtained, with a statistically significant increase in the area of the myelin sheath when compared with the control group. However, the SFI (Sciatic Functional Index) test showed no improvement in the study group in comparison with the control group. In the in vivo retrospective studies evaluated in this research, all were shown to be effective in the recovery of sensitivity [32, 33, 42, 62, 64, 65, 67, 72, 75, 80]; however, when the temperature test was evaluated in the study [72], no significant differences were observed. The follow-up periods in the studies reviewed in this research ranged from 8 to 201 days. Eight days was the minimum time observed to obtain significant clinical improvement in the return of sensitivity (8 days), and 201 days was the maximum time observed to achieve sensory recovery after treatment with laser therapy [80]. In this study of Yoshimoto et al. [80], the author stated that infrared laser at a wavelength of 790–820 nm was used during post-operative control, and recommended that it should start on the day after surgery, and continue on alternate days during the period of nervous/nerve tissue repair. However, in his study, it is not clear whether laser irradiation was performed during the period of 8 days in the shortest time observed for neural recovery, and it is also not clear whether he used laser therapy up until 201 days in the case in which the longest sensorineural recovery time was observed. Information about the frequency of laser therapy irradiations that were applied during the total period observed in the study was also not explained. Some authors reported that in patients who used no technique to accelerate sensory return, and who took only the conventional medication, such as corticosteroid therapy, it may take up to approximately 6.6 months to acquire complete sensory normality [8, 47, 48]. Studies affirmed that milder cases of neural lesion (neuropraxic), associated with the degree of injury sustained, location, and individual capacity of recovery, help and influence spontaneous neural return [8, 45–48, 109]. Final considerations Finally, in the literature, it may be seen that there are many differences among the results found, especially with respect to the lasers used and parameters selected for use in paresthesia. However, there is a large body of evidence that laser therapy accelerates and improves the regeneration of affected nerve tissues. The literature still lacks protocols and double-blind controlled clinical trials verifying these effects, and this should be the focus of future research. 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