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Recovery from Idiopathic Facial Paralysis (Bell’s Palsy) Using Photobiomodulation in Patients Non-Responsive to Standard Treatment: A Case Series Study
Recovery from Idiopathic Facial Paralysis (Bell’s Palsy) Using Photobiomodulation in Patients...
Pasquale, Claudio;Utyuzh, Anatoliy;Mikhailova, Maria Vladimirovna;Colombo, Esteban;Amaroli, Andrea
2021-08-20 00:00:00
hv photonics Article Recovery from Idiopathic Facial Paralysis (Bell’s Palsy) Using Photobiomodulation in Patients Non-Responsive to Standard Treatment: A Case Series Study 1 , 2 2 1 Claudio Pasquale * , Anatoliy Utyuzh , Maria Vladimirovna Mikhailova , Esteban Colombo and 1 , 2 Andrea Amaroli Department of Surgical and Diagnostic Sciences, University of Genoa, 16132 Genoa, Italy; esteban.colombo92@gmail.com (E.C.); andrea.amaroli.71@gmail.com (A.A.) Department of Orthopedic Dentistry, Faculty of Dentistry, First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; anatoliy.utyuzh@gmail.com (A.U.); stom-maria@mail.ru (M.V.M.) * Correspondence: clodent@gmail.com; Tel.: +39-010-353-7309 Abstract: Diminished facial movement and marked facial asymmetry can lead to a consistent psychological burden. Bell s palsy (BP) is one of the most common causes of facial nerve illness, which comes with unilateral acute facial paresis. Nowadays, no clear guidelines for treating BP are available. We carried out a case series study to test the efficacy of photobiomodulation (PBM) therapy in patients with BP non-responsive to standard treatment. The study was experimentally performed at the Department of Surgical and Diagnostic Sciences, University of Genoa (Genoa, Italy), in accordance with case report guidelines. Patients were referred to our department by colleagues for evaluation to be included in the case series because no consistent improvement was observed at least 3 months from the diagnosis of BP. All the patients interrupted their pharmacological therapy before the initiation of PBM therapy. PBM therapy (808 nm, 1 W irradiated in continuous-wave for Citation: Pasquale, C.; Utyuzh, A.; 2 2 2 60 s on spot-size 1 cm ; 1 W/cm ; 60 J/cm ; and 60 J) was administered every 2 days until complete Mikhailova, M.V.; Colombo, E.; resolution. Evaluation of the House-Brackmann scale was performed before and after treatments. Amaroli, A. Recovery from Idiopathic Fourteen patients were screened as eligible for the study. Patients were Caucasians (36% females Facial Paralysis (Bell’s Palsy) Using and 64% males) with a mean age standard deviation of 56.07 15.21 years. Eleven patients out Photobiomodulation in Patients of 14, who experienced BP a maximum of 6 months, completely recovered through PBM. The three Non-Responsive to Standard Treatment: A Case Series Study. patients that did not show improvement were those who had experienced BP for years. PBM could Photonics 2021, 8, 341. https:// be a supportive therapy for the management of BP in patients non-responsive to standard treatment. doi.org/10.3390/photonics8080341 However, randomized controlled trials are necessary to sustain our encouraging results, exclude bias, and better explain the boundary between the time from diagnosis and the recovery of BP through Received: 28 July 2021 PBM therapy. Accepted: 18 August 2021 Published: 20 August 2021 Keywords: facial nerve; facial paralysis; idiopathic facial palsy; chronic pain; low-level laser therapy; light therapy; alternative cure; inflammation; tissue regeneration Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Facial expression plays a pivotal role in social relationships and self-esteem [1]. Persis- tence of diminished facial movement and marked facial asymmetry can lead to a consistent psychological burden, social alienation, and depression for patients, which may result in Copyright: © 2021 by the authors. decreased productivity and higher health care expenses [2,3]. Licensee MDPI, Basel, Switzerland. Bell s palsy (BP) is one of the most common causes of facial nerve illness. Its incidence This article is an open access article is around 11–40 out of 100,000 individuals according to the literature [4–6]. Nowadays, the distributed under the terms and diagnosis is mainly based on exclusion criterion and functional assessments through scales conditions of the Creative Commons of severity, while the instrumental investigation is considered only because of possible Attribution (CC BY) license (https:// iatrogenic, tumoral, or traumatic origin [7]. Indeed, many conditions, such as Guillain- creativecommons.org/licenses/by/ Barré syndrome, Ramsay Hunt syndrome, reactions to intranasal influenza vaccines, Lyme 4.0/). Photonics 2021, 8, 341. https://doi.org/10.3390/photonics8080341 https://www.mdpi.com/journal/photonics Photonics 2021, 8, 341 2 of 11 disease, sarcoidosis, cholesteatoma, tumors, and general structural lesions in the parotid gland and ear can mimic the symptoms of BP [4,5,8]. However, although these disorders can represent isolated facial nerve palsies, they usually cause additional problems that distinguish them from it [4,5,8]. Usually, BP is accompanied by unilateral acute facial paresis that evolves in 24–48 h [4] and reaches maximum facial weakness in 3–7 days [4,5,8]. The aetiology and pathophysiology of BP have long been debated. An increasing number of authors no longer speak of idiopathic facial paralysis in the current state of knowledge, but rather of herpetic facial paralysis [9]. In fact, clinical observations and experimental data seem to describe BP as a result of the reactivation of the Herpes simplex virus isoform 1 (HSV-1) and/or Herpes zoster virus (HZV) [8,10]. Corticosteroid therapy is universally recognized for improving the prognosis of BP [11,12]; its effectiveness is linked to anti-oedema activity and to the reduction of inflammation underlying the autoimmune phenomena affecting the myelin sheath. Many authors consider combining them with antiviral agents as valid [12], and the addition of antibiotic therapy may be of benefit [4]. However, a careful systematic review of the literature by Tiemstra and collaborators [4] showed the reliability of antivirals was not superior to placebo, and treatment with cor- ticosteroids seemed to have, in many cases, small or insignificant statistical reduction of symptoms after 6 months of treatment. Referring to the surgical approach, it consists of a decompression procedure and should be reserved for cases with facial nerve degeneration greater than 90% by electroneurography/electromyography analysis [4,13,14]. Additionally, published studies have suggested the benefit of acupuncture [15], but systematic reviews [2,4,5,8] have pointed out flaws in some study designs. Therefore, there is no consensus on this alternative therapy. However, recently, Xu et al. [16] showed the utilization of glucocorticoid treatment along with acupuncture to be promising. Basically, the non-univocal results generated confusion, resulting in no clear guidelines for treating BP being available nowadays [8]. Recently, Javaherian et al. [17] reviewed the possible use of photobiomodulation (PBM) in the treatment of BP and concluded a beneficial effect on recovery for patients with subacute BP; adverse effects were not described. Furthermore, in our previous systematic review [18], we showed PBM can affect the mitochondrial activity and the bioenergetics of cells, resulting in an improvement in the recovery from trigeminal diseases. Indeed, PBM, previously known as low-level laser therapy (LLLT), acts through a transfer of energy from photons, in the visible and near-infrared (NIR) range of wave- lengths, to photoacceptors [18–21]. The energy retained in the photoacceptor may then induce a photochemical reaction in the cell that increases the production of ATP, influ- encing cell metabolism [18,20]. Actually, at 800 nm, the cytochrome c oxidase (complex IV) of the mitochondrial respiratory chain has evidence of absorption of its energy peak, depending on its precise oxidation state [22,23]. Complexes I and II are not affected by those wavelengths, while complex III is poorly stimulated [18,23]. However, PBM has limitations in terms of consistency because of both the physical and physiological traits of tissue–light interactions and the features of standard delivery instruments (probes, fiber, or hand-piece (HP)) [24,25]. In this respect, a novel HP has been patented and manufactured to improve the standardization of the delivery of PBM therapy [25]. Authors have shown this HP, irradiating with a flat-top (FT) beam profile, is able to generate a homogeneous and constant power on the beam spot-area [23,25], which is not affected by the distance from the target [24,25]. In vitro evidence has shown PBM therapy irradiated with the FT-HP is more effective, predictable, and repeatable than with standard probes [24,25]. Through the use of the FT-HP, a therapy, consisting of 808 nm of wavelength and 1 W of power irradiated for 60 s in continuous-wave (CW) on a spot-size area of 1 cm to generate a 2 2 fluence of 60 J/cm and a power density of 1 W/cm , was selected and characterized on isolated mitochondrial [19,20,23,25], cellular [26,27], and animal models [28,29], as well as on humans [30,31]. Therefore, according to our previous works [25,30], we hypothesize that 808 nm 1 W, 2 2 1 W/cm , and 60 J/cm laser therapy, irradiated through the FT-HP, could support the Photonics 2021, 8, x FOR PEER REVIEW 3 of 11 isolated mitochondrial [19,20,23,25], cellular [26,27], and animal models [28,29], as well as on humans [30,31]. Photonics 2021, 8, 341 3 of 11 Therefore, according to our previous works [25,30], we hypothesize that 808 nm 1 W, 2 2 1 W/cm , and 60 J/cm laser therapy, irradiated through the FT-HP, could support the re- covery of patients affected by BP. Therefore, the predictor variable of our research was recovery of patients affected by BP. Therefore, the predictor variable of our research was our PBM therapy through higher power and fluence, irradiated through the FT-HP [25]. our PBM therapy through higher power and fluence, irradiated through the FT-HP [25]. The primary endpoint was the improvement in the symptoms of BP, defined by the The primary endpoint was the improvement in the symptoms of BP, defined by the House- House-Brackmann scale, in patients with no response to standard treatment. The second- Brackmann scale, in patients with no response to standard treatment. The secondary ary endpoint was the detection of any adverse effects up to 12 months follow-up. endpoint was the detection of any adverse effects up to 12 months follow-up. 2. Materials and Methods 2. Materials and Methods 2.1. Patients’ Information and Eligibility 2.1. Patients’ Information and Eligibility Our case series study was experimentally performed at the Department of Surgical Our case series study was experimentally performed at the Department of Surgical and Diagnostic Sciences (DISC), University of Genoa (Genoa, Italy), in accordance with and Diagnostic Sciences (DISC), University of Genoa (Genoa, Italy), in accordance with case report guidelines. case report guidelines. Before arriving at the DISC, all patients were diagnosed with BP within 3 days of the Before arriving at the DISC, all patients were diagnosed with BP within 3 days of onset of symptomatology [2] by specialized physicians that followed the Guideline De- the onset of symptomatology [2] by specialized physicians that followed the Guideline velopment Group [32]. Figure 1 shows a drawing of a typical patient affected by BP. In Development Group [32]. Figure 1 shows a drawing of a typical patient affected by BP. In accordance with the medical record, information on patients was available to our team. accordance with the medical record, information on patients was available to our team. Basically, the severity of the illness was evaluated and quantified through the House- Basically, the severity of the illness was evaluated and quantified through the House- Brackmann scale [33], an accredited clinical tool employed to document the degree of fa- Brackmann scale [33], an accredited clinical tool employed to document the degree of cial paralysis and to predict the probability of recovery. Electromyography [4,13,14] ex- facial paralysis and to predict the probability of recovery. Electromyography [4,13,14] cluded management by surgery; therefore, patients were immediately treated with corti- excluded management by surgery; therefore, patients were immediately treated with costeroids and acyclovir [4,8,33,34]. Additionally, the use of eye lubricant was suggested. corticosteroids and acyclovir [4,8,33,34]. Additionally, the use of eye lubricant was sug- gested. After 2 After weeks 2 on weeks medic on atio medication, n, the patient thes patients who did who not show did not impro show vemen imprt ovement were reviewed were reviewed by speciali by zed specialized physicians physicians to careful to lycar exclude efully exclude other con other ditions conditions that mimic thatBP, mimic such BP as , such as Guillain-Barré syndrome, Ramsay Hunt syndrome, Melkersson-Rosenthal syn- Guillain-Barré syndrome, Ramsay Hunt syndrome, Melkersson-Rosenthal syndrome, dr Sjogren’s ome, Sjogr syn en’s drom syndr e, Lyme ome, L dis yme easdisease e (not endem (not endemic ic in our in count our country), ry), sarcoi sar dosi coidosis, s, stroke, stroke, mul- multiple tiple sclero scler sisosis, , chocholesteatoma, lesteatoma, tumtumors, ors, and and gener general al structur structural al lesions lesions in the in pa the rotid par g otid land gland and ear, according to the literature [4,5,8]. The use of intranasal influenza vaccines and ear, according to the literature [4,5,8]. The use of intranasal influenza vaccines was was also excluded. also excluded. Figure 1. Bell’s palsy is a unilateral facial peripheral palsy of the facial nerve that results in muscle Figure 1. Bell’s palsy is a unilateral facial peripheral palsy of the facial nerve that results in muscle weakness on one side of the face affected. The drawing shows the typical aspect and consequences weakness on one side of the face affected. The drawing shows the typical aspect and consequences of of a patient affected by it. Image created with BioRender.com. a patient affected by it. Image created with BioRender.com. Confirmation of BP was followed by cycles of administration of the previous pharma- cological cure. Photonics 2021, 8, x FOR PEER REVIEW 4 of 11 Photonics 2021, 8, 341 4 of 11 Confirmation of BP was followed by cycles of administration of the previous phar- macological cure. Patients were referred to our department by colleagues for evaluation to be included Patients were referred to our department by colleagues for evaluation to be included in the case series because no consistent improvement was observed by at least 3 months in the case series because no consistent improvement was observed by at least 3 months from the diagnosis of BP. from the diagnosis of BP. Before inclusion in the case series study, the patients were re-evaluated and the Before inclusion in the case series study, the patients were re-evaluated and the House- House-Brackmann scale was re-assigned. Brackmann scale was re-assigned. Patients were considered eligible if BP was confirmed and they were negative for Patients were considered eligible if BP was confirmed and they were negative for diabetes, human immunodeficiency virus (HIV) and high blood pressure. Pregnant diabetes, human immunodeficiency virus (HIV) and high blood pressure. Pregnant women women and patients younger than 18 years were excluded. No discrimination on the and patients younger than 18 years were excluded. No discrimination on the grounds ground of sex was s of made. sex was Conversely made. Conv , because ersely, becau of 808 se nm of 808 laser nm light laser absorption light absorpt by melanin ion by mela [35], - nin [35], only Caucasian people were considered suitable for the study. The patients only Caucasian people were considered suitable for the study. The patients stopped their stopped their pharmacological treatment. pharmacological treatment. 2.2. Procedures 2.2. Procedures In accordance with our previous in vitro [23,25–27] preclinical [28,29] and clinical [30] In accordance with our previous in vitro [23,25–27] preclinical [28,29] and clinical [30] studies, an 808 nm diode laser device (Doctor Smile, LAMBDA Spa, 36100 Vicenza, Italy) studies, an 808 nm diode laser device (Doctor Smile, LAMBDA Spa, 36100 Vicenza, Italy) equipped with the AB-2799 HP (Doctor Smile, LAMBDA Spa, 36100 Vicenza, Italy) able to equipped with the AB-2799 HP (Doctor Smile, LAMBDA Spa, 36100 Vicenza, Italy) able irradiate through an FT beam profile was used. to irradiate through an FT beam profile was used. PBM therapy was administered through the power of 1 W irradiated in CW for an PBM therapy was administered through the power of 1 W irradiated in CW for an exposure time of 60 s and on a spot-size of 1 cm , which allowed generating a power exposure time of 60 s and on a spot-size of 1 cm , which allowed generating a power den- 2 2 density of 1 W/cm and a fluence of 60 J/cm (energy administered = 60 J). To complete 2 2 sity of 1 W/cm and a fluence of 60 J/cm (energy administered = 60 J). To complete the the therapy session, a total of seven points were irradiated in contact. The laser parameters therapy session, a total of seven points were irradiated in contact. The laser parameters and treatment are are shown in Figures 2 and 3. and treatment are are shown in Figures 2 and 3. Figure 2. Design of the photobiomodulation therapy irradiation area and parameters. In yellow, the frontal and lateral Figure 2. Design of the photobiomodulation therapy irradiation area and parameters. In yellow, the frontal and lateral representations of the facial nerve and its branches. The red circles along the facial nerve branches indicate the points representations of the facial nerve and its branches. The red circles along the facial nerve branches indicate the points where where the therapy was administered in every session. Image created with BioRender.com. the therapy was administered in every session. Image created with BioRender.com. Photonics 2021, 8, 341 5 of 11 Photonics 2021, 8, x FOR PEER REVIEW 5 of 11 Figure 3. Laser parameters and treatments session design. The laser therapy was irradiated through a flat-top beam profile Figure 3. Laser parameters and treatments session design. The laser therapy was irradiated through a flat-top beam profile hand-piece, every 2 days until complete resolution. Previously, we showed [25] the flat-top hand-piece * is able to maintain hand-piece, every 2 days until complete resolution. Previously, we showed [25] the flat-top hand-piece * is able to maintain constant power and beam spot size from contact to many centimeters away allowing for improved clinical consistency constant power and beam spot size from contact to many centimeters away allowing for improved clinical consistency during PBM treatments delivery. ** BP resolution was experienced after different treatment sessions, from 8 up to 18. during PBM treatments delivery. ** BP resolution was experienced after different treatment sessions, from 8 up to 18. Image Image created with BioRender.com. created with BioRender.com. The precision of the laser therapy parameter was secured by the Pronto-250 power The precision of the laser therapy parameter was secured by the Pronto-250 power metre (Gentec Electro-Optics, Inc. G2E Quebec City, QC, Canada). metre (Gentec Electro-Optics, Inc. G2E Quebec City, QC, Canada). Adverse events due to possible undesirable thermal effects were avoided by moni- Adverse events due to possible undesirable thermal effects were avoided by monitor- toring the irradiation with a thermal camera, FLIR ONE Pro-iOS (FLIR Systems, Inc. de- ing the irradiation with a thermal camera, FLIR ONE Pro-iOS (FLIR Systems, Inc. designs, signs, 97070 Portland, OR, USA.) (dynamic range: −20 °C/+400 °C; resolution 0.1 °C) [25]. 97070 Portland, OR, USA.) (dynamic range: 20 C/+400 C; resolution 0.1 C) [25]. PBM therapy was administered every 2 days until complete resolution. Special pro- PBM therapy was administered every 2 days until complete resolution. Special tective glasses were used to keep patients and operators safe. protective glasses were used to keep patients and operators safe. The patients were screened before the irradiation of the PBM therapy, and the House- The patients were screened before the irradiation of the PBM therapy, and the House- Brackmann scale was used in the evaluation of every therapy session. Brackmann scale was used in the evaluation of every therapy session. At the end of therapy, patients were re-examined at the following follow-up visits: At the end of therapy, patients were re-examined at the following follow-up visits: day 15, 1 month, 3 months, 6 months, and 12 months. day 15, 1 month, 3 months, 6 months, and 12 months. Images were obtained by the Canon EOS 450 camera, with a 100 mm lens (Canon Images were obtained by the Canon EOS 450 camera, with a 100 mm lens (Canon Italia S.p.A, 20063 Cernusco sul Naviglio, Milan, Italy). The images were acquired in a Italia S.p.A, 20063 Cernusco sul Naviglio, Milan, Italy). The images were acquired in a standard condition of illumination, exposition, distance, and tilt angle. standard condition of illumination, exposition, distance, and tilt angle. 2.3. Outcomes 2.3. Outcomes Th The e pr predict edictor or variable variable of of our our resear resea ch rch was was the thPBM e PBM thrth ough rough higher highe power r power andand fluence flu- ence irradiated irradiated through through the FT th-HP e FT[ -25 HP ]. [The 25]. Th primary e primendpoint ary endpoint wasw the as impr the impro ovement vemen in t BP in, BP, as evaluated as evaluatby ed by the th House-Brackmann e House-Brackmanscale, n scale in , in patients patients with withno no rrespon esponse se to to standar standard d treatment. The secondary endpoint was detecting any adverse effects up to the 12-month treatment. The secondary endpoint was detecting any adverse effects up to the 12-month follow-up visit. follow-up visit. 3. Results 3.1. Participants Between January 2020 and May 2021, 14 patients were screened as eligible for the study. Patients were Caucasians (36% females and 64% males) with a mean age standard deviation of 56.07 15.21 years. Characteristics of the patients and their recovery after Photonics 2021, 8, x FOR PEER REVIEW 6 of 11 3. Results 3.1. Participants Photonics 2021, 8, 341 6 of 11 Between January 2020 and May 2021, 14 patients were screened as eligible for the study. Patients were Caucasians (36% females and 64% males) with a mean age ± standard deviation of 56.07 ± 15.21 years. Characteristics of the patients and their recovery after treatment with PBM therapy are shown in Figure 4. BP was diagnosed no more than 3 treatment with PBM therapy are shown in Figure 4. BP was diagnosed no more than 3 days after the onset of symptomatology by colleagues. Patients were immediately treated days after the onset of symptomatology by colleagues. Patients were immediately treated with corticosteroids and acyclovir through cycles of therapy from a minimum of 36 days to with corticosteroids and acyclovir through cycles of therapy from a minimum of 36 days a maximum of 75 days (Figure 4, drug administration). All the patients interrupted their to a maximum of 75 days (Figure 4, drug administration). All the patients interrupted their pharmacological therapy, according to the advice of specialized physicians, because no pharmacological therapy, according to the advice of specialized physicians, because no significant recovery was observed. In all, 68% of the patients manifested insurgence of significant recovery was observed. In all, 68% of the patients manifested insurgence of side effects because of the prolonged administration of drugs. Patients were then referred side effects because of the prolonged administration of drugs. Patients were then referred to our department. Therefore, when included in the study, the elapsed time from the to our department. Therefore, when included in the study, the elapsed time from the di- diagnosis of BP was from a minimum of 3 months to a maximum of 4 years (Figure 4, “time agnosis of BP was from a minimum of 3 months to a maximum of 4 years (Figure 4, “time after a diagnosis” column). Consequently, patients had interrupted their pharmacological after a diagnosis” column). Consequently, patients had interrupted their pharmacological treatment from a minimum of 15 days up to a maximum of years (Figure 4, “time after treatment from a minimum of 15 days up to a maximum of years (Figure 4, “time after a a diagnosis” vs. “drug administration” column). Concerning the 14 enrolled patients, diagnosis” vs. “drug administration” column). Concerning the 14 enrolled patients, a spe- a specialized physician confirmed the diagnosis of BP and the House-Brackmann scale cialized physician confirmed the diagnosis of BP and the House-Brackmann scale was re- was re-evaluated and confirmed (Figure 4, “House-Brackmann scale before”). No familial evaluated and confirmed (Figure 4, “House-Brackmann scale before”). No familial pre- predisposition was described by patients. disposition was described by patients. Figure 4. The figure shows the baseline information about the 14 patients enrolled for the case series Figure 4. The figure shows the baseline information about the 14 patients enrolled for the case study. The 14 patients received Bell’s palsy diagnosis months before to be included in the study series study. The 14 patients received Bell’s palsy diagnosis months before to be included in the (time after diagnosis). The 14 patients followed the therapy as indicated in the column “drug ad- study (time after diagnosis). The 14 patients followed the therapy as indicated in the column “drug ministration” and interrupted it before the PBM dosing. The House-Brackman score was evaluated administration” and interrupted it before the PBM dosing. The House-Brackman score was evaluated before (House-Brackman scale before) and after (House-Brackman scale after) the laser treatment before (House-Brackman scale before) and after (House-Brackman scale after) the laser treatment (n (n° treatments). treatments). 3.2. Primary and Secondary Endpoints Evaluation Concerning the primary endpoint, 11 out of 14 patients (patients 1–11) completely recovered after treatment with PBM (Figure 4, “House-Brackmann scale after”; Figure 5). The three patients that did not show improvement (patients 12–14) were those who had experienced palsy for years. Variable numbers of treatments (Figure 4, “n treatment”) were necessary to reach complete recovery (House-Brackmann scale I), according to the severity of the disease rather than the time elapsed from the diagnosis. However, after Photonics 2021, 8, x FOR PEER REVIEW 7 of 11 3.2. Primary and Secondary Endpoints Evaluation Concerning the primary endpoint, 11 out of 14 patients (patients 1–11) completely recovered after treatment with PBM (Figure 4, “House-Brackmann scale after”; Figure 5). The three patients that did not show improvement (patients 12–14) were those who had experienced palsy for years. Variable numbers of treatments (Figure 4, “n° treatment”) were necessary to reach complete recovery (House-Brackmann scale I), according to the severity of the disease rather than the time elapsed from the diagnosis. However, after a long time, the therapy also appeared ineffective for moderate and moderately severe House-Brackmann scale score III and IV, respectively (patients 12–14). Photonics 2021, 8, 341 7 of 11 In patients 1–11, after three sessions, there was already an evident improvement ob- served in the closure of the eye and in the partial restoration of the symmetry of the mouth, especially in the expression of the smile. As regards the secondary endpoint, no recrudes- a long time, the therapy also appeared ineffective for moderate and moderately severe cence of the disease or adverse effect was evidenced during follow-up. The ineffectiveness House-Brackmann scale score III and IV, respectively (patients 12–14). of PBM therapy in patients 12–14 was also confirmed during follow-up. Figure 5. The figure shows the patient n° 9 of Figure 4, before (A,A’); House-Brackman scale value Figure 5. The figure shows the patient n 9 of Figure 4, before (A,A’); House-Brackman scale value V) V) and after 9 treatments of PBM (B,B’); House-Brackman scale value I). and after 9 treatments of PBM (B,B’); House-Brackman scale value I). 4. Discussion In patients 1–11, after three sessions, there was already an evident improvement observed in the closure of the eye and in the partial restoration of the symmetry of the BP usually resolves within weeks or months [2]. However, in approximately 25% of mouth, especially in the expression of the smile. As regards the secondary endpoint, patients, moderate-to-severe facial damage and discomfort may persist [36]. Precocious no recrudescence of the disease or adverse effect was evidenced during follow-up. The pharmacological treatment of BP seems to support recovery from the illness, but system- ineffectiveness of PBM therapy in patients 12–14 was also confirmed during follow-up. atic reviews [2,4,5,8] show a positive contribution is of modest extent. Meanwhile, a sur- gical approach appears controversial [2]. Alternative approaches have been proposed 4. Discussion [37,38], but in this case, the effective improvement with respect to placebo is still under BP usually resolves within weeks or months [2]. However, in approximately 25% of evaluation [38]. Recently, PBM was proposed as an approach in the treatment of BP [17]. patients, moderate-to-severe facial damage and discomfort may persist [36]. Precocious Tanganelli et al. [39], on a single patient, concluded that a single session of PBM therapy pharmacological treatment of BP seems to support recovery from the illness, but systematic was an effective option for those affected by BP. Kumar [40] concluded, in a study on five reviews [2,4,5,8] show a positive contribution is of modest extent. Meanwhile, a surgical patients, that class IV level laser therapy can support the medical management of BP, in- approach appears controversial [2]. Alternative approaches have been proposed [37,38], cluding cases with adverse effects from corticosteroids. However, their recovery was but in this case, the effective improvement with respect to placebo is still under eval- uation [38]. Recently, PBM was proposed as an approach in the treatment of BP [17]. Tanganelli et al. [39], on a single patient, concluded that a single session of PBM therapy was an effective option for those affected by BP. Kumar [40] concluded, in a study on five patients, that class IV level laser therapy can support the medical management of BP, including cases with adverse effects from corticosteroids. However, their recovery was prevalently a partial result [40]. Aghamohamdi et al. [41] showed that the House- Brackmann grading scale ameliorates to grade I (18 cases), grade II (six cases), and grade IV (six cases) through 12 sessions of PBM on 30 patients with diabetes. Lastly, Ordahan and Karahan [42] observed positive effects of PBM associated with expression exercises on 23 patients treated in the subacute phase of the disease. Likewise, our data confirmed the consideration of PBM as a suitable therapy for BP management. Indeed, our data for the first time pointed out that PBM can support the recovery of patients affected by BP who Photonics 2021, 8, 341 8 of 11 had no response to pharmacological treatment, even when the irradiation began months after the diagnosis. Essentially, patients with House-Brackmann scale scores from IV–VI, who started PBM therapy at 3, 4, and 6 months after the diagnosis, recovered to a score of I, after 6–18 treatment sessions. With some limitations due to the experimental setup of a case series, data pointed out that, if the same PBM therapy parameter was irradiated, the number of treatments necessary to reach complete recovery were in accordance with the severity of the disease rather than the time elapsed from the diagnosis, assuming no more than 6 months had passed after the diagnosis of BP. Literature suggests the Herpes virus can affect neural dysfunction through activation of apoptotic pathways and intra-axonal degradation [43,44]. The expressions of p53 proteins, modulators of apoptosis (PUMA), and the selective androgen receptor modulator (SARM) pathway seem to be a consequence, triggering axon degeneration [43,44]. Furthermore, the regulation of extracellular signal-regulated kinase (ERK) and aquaporin-1 (AQP1) proteins can modulate morphological changes in Schwann cells, supporting the progression of facial nerve oedema [45]. In this context, authors have shown that PBM can regulate p53 and PUMA in human dermal fibroblasts and human acinar cells [46,47], as well as AQP1, mediating its effects on human erythrocytes [48]. Recent evidence by authors [2,49] converged with the hypothesis that cases of BP unable to be resolved could be correlated with ischaemia and its sequelae, followed by anomalies to the facial nerve sheath that hamper recovery. In this case, PBM could also serve as a promising therapeutic strategy as observed for functional recovery after global cerebral ischaemia [50]. Additionally, our team previously demonstrated the effectiveness of the therapy employed for BP (808 nm, 1 W; 60 J/cm ) in promoting angiogenesis [51]. Additionally, we recently reviewed the consistent support of PBM in endothelial dysfunc- tion [52]. However, in our revision of the literature on trigeminal nerve damage [18], a close connection between mitochondrial bioenergetics and PBM was demonstrated, which should also be kept in mind for BP. In support of this assumption, Moriyama and collaborators [53] “observed that the gene expression in BP changes with the degree of facial nerve palsy. Especially, muscle, neuron, and energy category genes tended to fluctuate with the degree of facial nerve palsy”. Furthermore, Persson et al. [54] suggested that the activity of sodium and calcium channels contributes to axonal degeneration after mitochondrial dysfunction. Particularly in BP with House-Brackmann score > IV, facial nerve conduction may be largely abolished, leading to very little metabolic energy production with a consistent consequence on nerve and muscle regeneration. This can, in part, explain the total or partial unresponsiveness of our patients to not only the pharmacological cure but also the effectiveness of our PBM therapy [53]. 2 2 In fact, we previously showed the ability of 808 nm 1 W, 1 W/cm and 60 J/cm to modulate the calcium homeostasis affecting mitochondria bioenergy production [26,27], through the mitochondrial respiratory chain [23,25,55,56], cell metabolism [26,50], and inflammatory cell pathways [57], to promote cell proliferation [50,55,57], tissue regener- ation [28,30,58], and release of neurotransmitters [59]. Lastly, the target of PBM therapy and the alteration of energy category genes in both moderate and severe BP could also explain why our PBM therapy was unsuccessful if performed more than 1 year after the onset of palsy. Likewise, Moriyama et al. [53] concluded that both facial nerve neurorrhaphy and nerve grafting fail in patients that had experienced BP for 1 year or more. The main limitation of our study is that, because of the case series design, our data have no control and comparative statistical analysis cannot be performed [60]. Therefore, our work has a risk of bias and is limited in the sample size calculation. Photonics 2021, 8, 341 9 of 11 However, the medical history of our patients may support the assumption that the influence of drugs or natural recovery on the results could probably be excluded. 5. Conclusions 2 2 In conclusion, PBM through 808 nm 1 W, 1 W/cm and 60 J/cm laser therapy, irradiated with the FT-HP, complied with both the primary and secondary endpoints. It is noteworthy that the relatively higher energy used in our work was supported by the flat-top hand-piece feature, which, as shown in our previous work [25], has a uniform distribution of the power density compared to Gaussian beam profile of standard both fibers and hand-pieces; thermal increase is limited. Therefore, PBM could be a supportive therapy for the management of BP in patients non-responsive to standard treatment. However, randomized controlled trials are necessary to sustain our encouraging results and exclude bias, as well as better explain the boundary between the time from diagnosis and the recovery of BP through PBM therapy. Author Contributions: Conceptualization, C.P. and A.A.; methodology, C.P. and A.A.; software, M.V.M. and A.A.; validation, C.P. and A.A.; formal analysis, A.A.; investigation, C.P. and A.U.; resources, C.P.; data curation, A.A. and E.C.; writing—original draft preparation, C.P. and A.A.; writing—review and editing, C.P., A.U., M.V.M., E.C. and A.A.; supervision, A.U. and A.A.; project administration, A.A.; funding acquisition, C.P. and A.A. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: This study followed the Declaration of Helsinki with regard to medical protocol and ethics, and the Regional Ethical Review Board of DISC, University of Genoa approved the study (Unige-DISC-protocol number 0015094). Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Data Availability Statement: Data available on request from the authors. Acknowledgments: We express our deepest appreciation to Alberico Benedicenti, Valentino Valentini and Davina Bartoli for their support in the diagnosis. Conflicts of Interest: The authors declare no conflict of interest. References 1. Pouwels, S.; Beurskens, C.H.; Luijmes, R.E.; Ingels, K.J. Clinical importance of smiling in patients with a peripheral facial palsy. J. Plast. Reconstr. Aesthet. Surg. 2016, 69, 1305–1306. [CrossRef] 2. Zhang, W.; Xu, L.; Luo, T.; Wu, F.; Zhao, B.; Li, X. The etiology of Bell’s palsy: A review. J. Neurol. 2020, 267, 1896–1905. [CrossRef] 3. Nellis, J.C.; Ishii, M.; Byrne, P.J.; Boahene, K.D.O.; Dey, J.K.; Ishii, L.E. Association among facial paralysis, depression, and of quality of life in facial plastic surgery patients. JAMA Facial Plast. Surg. 2017, 19, 190–196. [CrossRef] 4. Tiemstra, J.D.; Khatkhate, N. Bell’s palsy: Diagnosis and management. Am. Fam. 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