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Early and continued manual stimulation is required for long-term recovery after nerve injury

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Abstract

Introduction: We showed previously that manual stimulation (MS) of vibrissal muscles for 2 months after facial nerve injury (FFA) in rats improves whisking and reduces motor endplate poly-innervation. Here, we asked whether discontinuing or delaying MS after FFA would also lead to similar results. Methods: Rats were subjected to FFA and received MS for: i) 4 months ("early & continued"), ii) the first but not the last 2 months ("discontinued"), or iii) the last 2 months ("delayed"). Intact animals and those not receiving MS ("no MS") were also examined. Results: Early & continued MS restored whisking amplitude to 43°, a value significantly higher compared to the discontinued, delayed, and no MS groups (32°, 24°, and 10°). Motor end-plate poly-innervation occurred in all experimental groups, but it was significantly higher in the delayed group. Discussion: Early & continued MS results in better recovery than when it is either discontinued or delayed. This article is protected by copyright. All rights reserved.

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... Although reinnervation occurs relatively fast in our model, the proportion of poly-innervated NMJs remained significantly increased for up to three months after nerve damage. This observation is consistent with experiments showing that some facial muscles maintain a significant percentage of poly-innervated NMJs (~ 16%) after muscle reinnervation [40]. Moreover, in some frog species, there is a significant percentage of poly-innervated muscle fibers in adult stages [41]. ...
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... Video-based motion analysis of vibrissal motor performance is well established by our group Bendella et al., 2016;Bischoff et al., 2009;Grosheva et al., 2018). ...
... However, the functional capacity of the smaller numbers of motor units, whose force output is increased by the inclusion of more muscle fibers, is obviously compromised by their reduced numbers and consequent larger force increments during their progressive recruitment (Gordon et al., 2004). Extensiive intramuscular sprouting leads to transient polyneuronal innervation of hindlimb muscles (Fu and Gordon, 1997;Gorio et al., 1983;Rich and Lichtman, 1989) but polyneuronal reinnervation may remain in other muscles, including reinnervated vibrissae after facial nerve injuries (Grosheva et al., 2017). ...
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Importance Facial nerve injury leads to severe functional and aesthetic deficits. The transgenic Thy1-GFP rat is a new model for facial nerve injury and reconstruction research that will help improve clinical outcomes through translational facial nerve injury research.Objective To determine whether serial in vivo imaging of nerve regeneration in the transgenic rat model is possible, facial nerve regeneration was imaged under the main paradigms of facial nerve injury and reconstruction.Design, Setting, and Participants Fifteen male Thy1-GFP rats, which express green fluorescent protein (GFP) in their neural structures, were divided into 3 groups in the laboratory: crush-injury, direct repair, and cross-face nerve grafting (30-mm graft length). The distal nerve stump or nerve graft was predegenerated for 2 weeks. The facial nerve of the transgenic rats was serially imaged at the time of operation and after 2, 4, and 8 weeks of regeneration. The imaging was performed under a GFP-MDS-96/BN excitation stand (BLS Ltd).Intervention or Exposure Facial nerve injury.Main Outcome and Measure Optical fluorescence of regenerating facial nerve axons.Results Serial in vivo imaging of the regeneration of GFP-positive axons in the Thy1-GFP rat model is possible. All animals survived the short imaging procedures well, and nerve regeneration was followed over clinically relevant distances. The predegeneration of the distal nerve stump or the cross-face nerve graft was, however, necessary to image the regeneration front at early time points. Crush injury was not suitable to sufficiently predegenerate the nerve (and to allow for degradation of the GFP through Wallerian degeneration). After direct repair, axons regenerated over the coaptation site in between 2 and 4 weeks. The GFP-positive nerve fibers reached the distal end of the 30-mm–long cross-face nervegrafts after 4 to 8 weeks of regeneration.Conclusions and Relevance The time course of facial nerve regeneration was studied by serial in vivo imaging in the transgenic rat model. Nerve regeneration was followed over clinically relevant distances in a small number of experimental animals, as they were subsequently imaged at multiple time points. The Thy1-GFP rat model will help improve clinical outcomes of facial reanimation surgery through improving the knowledge of facial nerve regeneration after surgical procedures.Level of Evidence NA.
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Most experiments of peripheral nerve repair after injury have been conducted in the rodent model but the translation of findings from rodent studies to clinical practice is needed partly because the nerve regeneration must occur over much longer distances in humans than in rodents. The reconstruction of long distance nerve injuries still represents a great challenge to surgeons who is engaged in peripheral nerve surgery. Here we used the functional nerve conduit (collagen scaffolds incorporated with neurocytokines CNTF and bFGF) to bridge a 35 mm long facial nerve gap in minipig models. At 6 months after surgery, electrophysiology assessment and histological examination were conducted to evaluate the regeneration of peripheral facial nerves. Based on functional and histological observations, the results indicated that the functional collagen scaffolds promoted nerve reconstruction. The number and arrangement of regenerated nerve fibers, myelination, and nerve function reconstruction was better in the CNTF + bFGF conduit group than the single factor CNTF or bFGF conduit group. The functional composite conduit, which exhibited favorable mechanical properties, may promote facial nerve regeneration in minipigs effectively.
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To evaluate the range and incidence of facial palsy etiologies in cases presenting to a tertiary facial nerve center, and to review the broad and evolving spectrum of diagnostic and management approaches to the condition. Retrospective chart review. Records of patients referred for facial weakness between 2003 and 2013 were reviewed for cases of facial palsy. Cases of muscle dysfunction and primary hemifacial spasm were excluded. The remainder were analyzed by age, sex, and diagnosis. Diagnostic and treatment strategies were reviewed. There were 1,989 records that met inclusion criteria. Bell's palsy accounted for 38% of cases, acoustic neuroma resections 10%, cancer 7%, iatrogenic injuries 7%, varicella zoster 7%, benign lesions 5%, congenital palsy 5%, Lyme disease 4%, and other causes 17%. Sixty-one percent of patients were female. Mean age at presentation was 44.5 years (±18.6 years). Diagnoses were revealed primarily by history, though serial physical examinations, radiography, and hematologic testing also contributed. Management strategies included observation, physical therapy, pharmacological therapy, chemodenervation, facial nerve exploration, decompression, repair, and the full array of static and dynamic surgical interventions. Bell's palsy remains the most common facial palsy; females present more often for evaluation. Comprehensive diagnostic investigation is mandatory in atypical cases, and thorough management must be multidisciplinary. The algorithms presented herein outline a single center's approach to the facial palsy patient, providing a framework that clinicians caring for these patients may adapt to their specific settings. 2b Laryngoscope, 2013.
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Purpose Peripheral nerve trauma results in functional loss in the innervated organ, and recovery without surgical intervention is rare. Many surgical techniques can be used for repair in experimental models. The authors investigated the source and the delivery method of stem cells in experimental outcomes seeking to clarify whether stem cells must be differentiated in the injured facial nerve and improve the regenerative process. Methods The following key words were used: “nervous regeneration”, “nerve regeneration”, “facial nerve regeneration", “stem cells”, “embryonic stem cells”, “fetal stem cells”, “adult stem cells”, “facial nerve”, “facial nerve trauma” and “facial nerve traumatism”. The search was restricted to experimental studies that applied stem cell therapy and tissue engineering for nerve repair. Results Eight studies meeting the inclusion criteria were reviewed. Different sources of stem/precursor cells were explored (BMSC, ADSC, DPC, NSC) for their potential application in the scenario of facial nerve injuries. Different material conduits (vases, collagen, PGLA) were used as bridges. Immunochemistry and electrophysiology are the principal methods for analyzing regenerative effects. Although recent studies have shown that stem cells can act as a promising bridge for nerve repair, considerable optimization of these therapies will be required for their potential to be realized in a clinical setting. Conclusion Based on these studies, the use of stem cells derived from different sources presents promising results related to facial nerve regeneration and demonstrates effective functional results. The use of tubes also optimizes the nerve repair, thus promoting greater myelination and axonal growth of peripheral nerves.
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Facial nerve trauma can be a devastating injury resulting in functional deficits and psychological distress. Deciding on the optimal course of treatment for patients with traumatic facial nerve injuries can be challenging, as there are many critical factors to be considered for each patient. Choosing from the great array of therapeutic options available can become overwhelming to both patients and physicians, and in this article, the authors present a systematic approach to help organize the physician's thought process.
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Objectives The objectives of this study were to study the safety profile and role of mononuclear stem cells in the rehabilitation of posttraumatic facial nerve paralysis not improving with conventional treatment. Study Design This is a prospective nonrandomized controlled trial. Study Setting This study is conducted at Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh between July, 2007 and December, 2008. Patients We included eight patients of either sex aged between 18 and 60 years of posttraumatic facial nerve paralysis not improving with conventional treatment presented to PGIMER, Chandigarh between July 2007 and December 2008. Methods All patients underwent preoperative electroneuronography (ENoG), clinical photography, and high-resolution computed tomography (HRCT) temporal bone. All patients then underwent facial nerve decompression and stem cell implantation. Stem cells processing was done in well-equipped bone marrow laboratory. Postoperatively, all patients underwent repeat ENoG and clinical photography at 3 and 6 months to assess for objective and clinical improvement. Clinical improvement was graded according to modified House–Brackmann grading system. Intervention Done All patients of posttraumatic facial nerve paralysis who were not improving with conventional surgical treatment were subjected to facial nerve decompression and stem cell implantation. Main Outcome Measures All patients who were subjected to stem cell implantation were followed up for 6 months to assess for any adverse effects of stem cell therapy on human beings; no adverse effects were seen in any of our patients after more than 6 months of follow-up. Results Majority of the patients were male, with motor vehicle accidents as the most common cause of injury in our series. Majority had longitudinal fractures on HRCT temporal bone. The significant improvement in ENoG amplitude was seen between preoperative and postoperative amplitudes on involved side which was statistically significant (0.041). Clinical improvement seen was statistically significant both for eye closure (p < 0.010) and for deviation of angle of mouth (p < 0.008) at 6-month follow-up in 85% of our patients, far better than the results of previous conventional surgeries. Conclusion Stem cell therapy can be used safely in human beings without any adverse effects on humans, and it appears to be a promising modality for rehabilitation of patients with posttraumatic facial nerve paralysis not improving with conventional surgical treatment but few more clinical series are required for validation.
Article
The patient with facial paralysis presents a daunting challenge to the reconstructive surgeon. A thorough evaluation is key in directing the surgeon to the appropriate treatment methods. Aggressive and immediate exploration with primary repair of the facial nerve continues to be the standard of care for traumatic transection of the facial nerve. Secondary repair using dynamic techniques is preferred over static procedures, because the outcomes have proved to be superior. However, patients should be counseled that facial movement and symmetry are difficult to mimic and none of the procedures described is able to restore all of the complex vectors and overall balance of facial movement and expression.
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To determine the procedure-specific incidence, risk factors, and injury patterns in patients with iatrogenic facial nerve injury as seen at a tertiary care facial nerve center. Retrospective chart review. Facial Nerve Center patient records from 2002 to 2012 were reviewed for cases of iatrogenic facial nerve injury. These were analyzed by type of inciting procedure, injury location, patient demographics, and referral pattern. Out of 1,810 patient records, 102 were identified that involved iatrogenic facial nerve injury. Oral and maxillofacial surgical procedures accounted for 40% of injuries, resections of head and neck lesions 25%, otologic procedures 17%, cosmetic procedures 11%, and other procedures 7%. The most common operation resulting in facial nerve injury was temporomandibular joint replacement. The most frequent pattern of injury was total hemifacial weakness. Iatrogenic facial nerve injury occurs most commonly in temporomandibular joint replacement, mastoidectomy, and parotidectomy. Direct visualization of the nerve may decrease the incidence of injury, and early referral for facial nerve exploration may result in improved outcomes. 2b. Laryngoscope, 124:260–265, 2014
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Introduction: Given the morbidity caused by facial nerve paralysis, there have been consistent approaches to treatment over the past 20 years in reanimation of the facial nerve. Treatment depends on accurate clinical examination, a good understanding of the anatomic course, and appropriate diagnostic tests. There are various options when it comes to dynamic facial nerve reanimation that range from nerve grafting, nerve anastomosis, crossover techniques and muscle transfer to microneurovascular muscle flaps, and-recently-potentially new concepts with microelectromechanical systems (MEMS) technology. The various dynamic facial nerve treatment modalities are discussed. Methods and results: A comprehensive review of the literature was performed detailing various techniques used for dynamic rehabilitation following facial nerve injury and their known results and complications. Conclusions: Currently, techniques have been attempted to achieve adequate dynamic facial reanimation of the paralyzed facial nerve. Despite the advances that have occurred in the last few years, it has been classically very difficult to achieve a House-Brackmann grade better than grade III. Outcomes are improving. Ultimately, the approach depends on the surgeon's experience.
Article
Functional recovery is typically poor after facial nerve transection and surgical repair. In rats, whisking amplitude remains greatly diminished after facial nerve regeneration, but can recover more completely if the whiskers are periodically mechanically stimulated during recovery. Here we present a robotic whisk assist system for mechanically driving whisker movement after facial nerve injury. Movement patterns were either pre-programmed to reflect natural amplitudes and frequencies, or movements of the contralateral (healthy) side of the face were detected and used to control realtime mirror-like motion on the denervated side. In a pilot study, twenty rats were divided into nine groups and administered one of eight different whisk assist driving patterns (or control) for 5- 20 minutes, five days per week, across eight weeks of recovery after unilateral facial nerve cut and suture repair. All rats tolerated the mechanical stimulation well. Seven of the eight treatment groups recovered average whisking amplitudes that exceeded controls, although small group sizes precluded statistical confirmation of group differences. The potential to substantially improve facial nerve recovery through mechanical stimulation has important clinical implications, and we have developed a system to control the pattern and dose of stimulation in the rat facial nerve model.
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Introduction: Facial nerve dysfunction can be attributed to several different causes. Several techniques have been developed to help treat the appearance and functional limitation of patients with sequelae of facial nerve dysfunction. There are options regarding static techniques of facial nerve injury treatment that range from facial musculature plication or shortening, fascial sling suspension via allograft or autograft, injectables and implants (ENDURAGen, AlloDerm, LifeCell, Bridgewater, New Jersey, USA) to techniques such as brow lift, open and endoscopic facelifts, and various eyelid surgeries with upper and lower lid procedures. In this review the various static facial nerve treatment modalities are discussed. Methods and results: A comprehensive review of the literature was performed detailing the most common static facial nerve treatment modalities and their known results and complications. Conclusions: There are individual issues associated with facial palsy for which individual solutions must be carefully tailored. Despite the presence of many surgical options, the results of reconstruction are limited. With the rapid advancement of surgical techniques, approaches to the management of facial nerve dysfunction have expanded, helping surgeons to improve and utilize alternative techniques for the treatment of patients with acute and chronic facial paralysis.
Article
Nerve conduit provides a promising strategy for nerve regeneration, and the proper microenvironment in the lumen could improve the regeneration. Our previous work had demonstrated that linear ordered collagen scaffold (LOCS) could effectively guide the oriented growth of axons. Laminin is known as an important nerve growth promoting factor and can facilitate the growth cone formation. In addition, ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) can effectively improve the nerve regeneration after nerve injuries. However, in practice, diffusion caused by the body fluids is the major obstacle in their applications. To retain CNTF or BDNF on the scaffolds, we produced collagen binding CNTF (CBD-CNTF), collagen binding BDNF (CBD-BDNF) and laminin binding CNTF (LBD-CNTF), laminin binding BDNF (LBD-BDNF) respectively. In this work, we developed laminin modified LOCS fibers (L × LOCS) by chemical cross-linking LOCS fibers with laminin. Collagen binding or laminin binding neurotrophic factors were combined with LOCS or L × LOCS, and then filled them into the collagen nerve conduit. They were found to guide the ordered growth of axons, and improve the nerve functional recovery in the rat facial nerve transection model. The combination of CNTF and BDNF greatly enhanced the facial nerve regeneration and functional recovery.
Article
Facial nerve lesions elicit long-lasting changes in vibrissal primary motor cortex (M1) muscular representation in rodents. Reorganization of cortical representation has been attributed to potentiation of preexisting horizontal connections coming from neighboring muscle representation. However, changes in layer 5 pyramidal neuron activity induced by facial nerve lesion have not yet been explored. To do so, the effect of irreversible facial nerve injury on electrophysiological properties of layer 5 pyramidal neurons was characterized. Twenty-four adult male Wistar rats were randomly subjected to two experimental treatments: either surgical transection of mandibular and buccal branches of the facial nerve (n=18) or sham surgery (n=6). Unitary and population activity of vibrissal M1 layer 5 pyramidal neurons recorded in vivo under general anesthesia was compared between sham-operated and facial nerve-injured animals. Injured animals were allowed either one (n=6), three (n=6), or five (n=6) weeks recovery before recording in order to characterize the evolution of changes in electrophysiological activity. As compared to control, facial nerve-injured animals displayed the following sustained and significant changes in spontaneous activity: increased basal firing frequency, decreased spike-associated local field oscillation amplitude, and decreased spontaneous theta burst firing frequency. Significant changes in evoked-activity with whisker pad stimulation included: increased short latency population spike amplitude, decreased long latency population oscillations amplitude and frequency, and decreased peak frequency during evoked single-unit burst firing. Taken together, such changes demonstrate that peripheral facial nerve lesions induce robust and sustained changes of layer 5 pyramidal neurons in vibrissal motor cortex.
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To review the current literature to assess the effectiveness of rehabilitation treatment for peripheral facial nerve palsy. A review of the literature was conducted using the following database: PubMed, EMBASE, PEDro, and Scopus. All randomized or quasi randomized controlled trials, case control, cohort studies and case series greater than 6 published between 1990 and 2010 in the English language were included. All types of peripheral facial nerve palsy were included. We considered all the exercises or rehabilitation programs provided by a physiotherapy in outpatient or home setting and excluded trials in which a drug therapy or surgical intervention was investigated. Three reviewers independently selected the articles. To rate the methodological quality of the studies the American Academy of Neurology classification of evidence for therapeutic intervention (Classes I-IV) was applied. Peripheral injury of the VIIth cranial nerve can have serious repercussions on the patient's functioning and quality of life. The recovery rate is related to the preservation of the nerve and to the cause of palsy. We obtained a third level of recommendation (level C); mime therapy could be effective to improve functional outcome in these patients. Evidence of specific treatment addressed to specific cause is lacking; likewise, no evidence is available on timing of intervention with respect to time of onset. Well-designed randomized controlled trials are required to evaluate the effect of rehabilitation in patients with facial palsy.
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PURPOSE: Synthetic conduits have been considered a viable option in nerve reconstructive procedures. They address the goal of entubulization and eliminate the disadvantages of autografts. However, despite all successful reports, none has contained regeneration characteristics, such as growth factors or essential cells, for nerve repair. The authors evaluated the capability of adipose-derived stem cells in Gore-Tex tubes to enhance facial nerve repair. MATERIALS AND METHODS: Undifferentiated mesenchymal stem cells were extracted from the autogenous adipose tissues of 7 mongrel dogs. The frontal branch of the facial nerve was transected. A gap size of 7 mm was repaired with an expanded polytetrafluoroethylene tube filled with undifferentiated adipose-derived stem cells encapsulated in alginate hydrogel. The control sides were repaired with the tube and alginate alone. The healing phase was 12 weeks. RESULTS: Except in 2 control sides, an organized neural tissue was formed within the tubes. Compared with the normal nerve diameter, there was a decreased ratio of 29% and 39% in the experimental and control groups, respectively. Neurofilament-positive axon counts were 67% of normal values in the 2 groups. There was no significant difference between groups in histomorphometric parameters. Nerve conduction velocity in the experimental group (28.5 ± 3.5 m/s) was significantly greater than in the control group (16.2 ± 7 m/s). The experimental group also exhibited a greater maximal amplitude of action potential (1.86 ± 0.24 mV) than the control group (1.45 ± 0.49 mV). CONCLUSIONS: Addition of stem cells in the Gore-Tex tube enhanced the neural repair from a functional standpoint. However, for better functional and histologic results, differentiated Schwann cells and other mediators may be warranted.
Article
It is believed that a major reason for the poor functional recovery after peripheral nerve lesion is collateral branching and regrowth of axons to incorrect muscles. Using a facial nerve injury protocol in rats, we previously identified a novel and clinically feasible approach to combat axonal misguidance – the application of neutralizing antibodies against neurotrophic factors to the injured nerve. Here, we investigated whether reduced collateral branching at the lesion site leads to better functional recovery. Treatment of rats with antibodies against nerve growth factor, brain-derived neurotrophic factor, fibroblast growth factor, insulin-like neurotrophic factor I, ciliary neurotrophic factor or glial cell line-derived neurotrophic factor increased the precision of reinnervation, as evaluated by multiple retrograde labelling of motoneurons, more than two-fold as compared with control animals. However, biometric analysis of vibrissae movements did not show positive effects on functional recovery, suggesting that polyneuronal reinnervation – rather than collateral branching – may be the critical limiting factor. In support of this hypothesis, we found that motor end-plates with morphological signs of multiple innervation were much more frequent in reinnervated muscles of rats that did not recover after injury (51% of all end-plates) than in animals with good functional performance (10%). Because polyneuronal innervation of muscle fibres is activity-dependent and can be manipulated, the present findings raise hopes that clinically feasible and effective therapies could be soon designed and tested.
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Unilateral facial nerve transection induces plastic reorganization of the somatotopic order in the primary motor cortex area (MI). This process is biphasic and starts with a transient disinhibition of connections between cortical areas in both hemispheres. Little is known about the underlying mechanisms. Here, cortical excitability has been studied by paired pulse electrical stimulation, applied either within the MI or peripherally to the trigeminal nerve, while the responses were recorded bilaterally in the MI. The ratios between the amplitudes of the second and first evoked potentials (EPs or fEPSPs) were taken as measures of the inhibitory capacity in the MI ipsilateral or contralateral to the nerve injury. A skin wound or unilateral facial nerve exposure immediately caused a transient facilitation, which was followed by a reset to some level of inhibition in the MI on both sides. After facial nerve transection, the first relatively mild reduction of inhibition started shortly (within 10 min) after denervation. This was followed by a second step, involving a stronger decrease in inhibition, 40–45 min later. Previous publications have proved that sensory nerve injury (deafferentation) induces disinhibition in corresponding areas of the sensory cortex. It is now demonstrated that sham operation and, to an even greater extent, unilateral transection of the purely motoric facial nerve (deefferentation), each induce extended disinhibition in the MIs on both sides.
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Facial paralysis is a clinical entity associated with significant morbidity, which has a treatment paradigm that is continually evolving. Surgical management of the paralyzed face poses significant challenges to achieve the goal of returning patients to their premorbid states. Here we attempt to review the advances in facial reanimation, in particular with regards to chronic facial paralysis. These include recent developments in static and dynamic rehabilitation including advances like artificial muscles for eyelid reconstruction, dynamic muscle transfer for the eye, and orthodromic temporalis tendon transfer.
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We have recently shown that manual stimulation of target muscles promotes functional recovery after transection and surgical repair to pure motor nerves (facial: whisking and blink reflex; hypoglossal: tongue position). However, following facial nerve repair, manual stimulation is detrimental if sensory afferent input is eliminated by, e.g., infraorbital nerve extirpation. To further understand the interplay between sensory input and motor recovery, we performed simultaneous cut-and-suture lesions on both the facial and the infraorbital nerves and examined whether stimulation of the sensory afferents from the vibrissae by a forced use would improve motor recovery. The efficacy of 3 treatment paradigms was assessed: removal of the contralateral vibrissae to ensure a maximal use of the ipsilateral ones (vibrissal stimulation; Group 2), manual stimulation of the ipsilateral vibrissal muscles (Group 3), and vibrissal stimulation followed by manual stimulation (Group 4). Data were compared to controls which underwent surgery but did not receive any treatment (Group 1). Four months after surgery, all three treatments significantly improved the amplitude of vibrissal whisking to 30° versus 11° in the controls of Group 1. The three treatments also reduced the degree of polyneuronal innervation of target muscle fibers to 37% versus 58% in Group 1. These findings indicate that forced vibrissal use and manual stimulation, either alone or sequentially, reduce target muscle polyinnervation and improve recovery of whisking function when both the sensory and the motor components of the trigemino-facial system regenerate.
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To systematically review the existing literature on outcomes and management of facial paralysis resulting from intratemporal blunt trauma. Systematic review of the literature. A systematic literature review identified twenty-eight articles meeting our inclusion criteria. Outcome variables analyzed included severity of paralysis, time of onset of paralysis, surgical or non-surgical management, steroid use, and final facial nerve function. The majority of the studies were classified as level 4 evidence as defined by the Oxford Centre for Evidence-Based Medicine. There was marked variation in the quality of the studies with inconsistent outcome measures, diagnostic testing, and follow-up, thus ruling out a formal meta-analysis. In an exploratory pooling of data, 612 cases had sufficient follow-up and facial movement grading for some evaluation of trends. In 189 patients that were followed observationally, 66% achieved an outcome equivalent to House-Brackmann (HB) I, 25% achieving HB II-V, and two patients a HB VI score. Among 83 patients treated with steroids, 67% achieved HB I, 30% HB II-V, and no patients with HB VI. . In 340 patients treated surgically, 23% achieved HB I post-operatively, 58% were graded as HB II-V, and 9% with HB grade VI postoperatively. No patient presenting with partial paralysis had a HB VI outcome. The role of surgery versus non-surgical interventions for this clinical entity remains inconclusive. Level 4 evidence studies predominate and are further hindered by poor description of outcome measures and incomplete data reporting. Exploratory pooling of data without formal metaanalysis suggests the need to compare any intervention to the natural course of healing which overall appears to be favorable.
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Facial paralysis is a devastating and debilitating condition for which a range of management options exists; all of them continue to have limitations. We review the recent scientific literature and highlight key developments and opportunities for further exploration with the goal that this may help direct clinical practice and research endeavor. We reviewed recent findings in the evaluation of facial paralysis, pharmacological management, nerve injury prevention and treatment. This includes review of novel techniques using photography and videography. Review of surgical and adjunctive techniques identifies several refinements of existing techniques, some novel techniques, and the value of adjunctive materials and therapies. Management of facial paralysis remains an area of active investigation and innovation. The challenge to researchers and care providers will be to continue to explore and refine management strategies while maintaining rigorous and standardized means of evaluation and follow-up, such that outcomes may be determined and reported accurately and in a way that they can be transferred to other clinical practices. Further study of the role of growth factors and stem cells in facial nerve regeneration is critical, and is the most likely means of surmounting the remaining barriers to successful outcomes in alleviating the ravages of this devastating malady.
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Investigators have long sought realistic methods to accelerate regeneration following nerve injury. Herein, we investigated the degree to which manual target muscle manipulation and brief electrical stimulation of the facial nerve, alone or in combination, affects recovery following rat facial nerve injury. Prospective, randomized animal study. Sixty rats were randomized to three groups: brief electrical stimulation (BES), mechanical stimulation of the whisker pad (MEC), or both (COMBO). Animals underwent facial nerve transection and immediate microsurgical repair. In BES and COMBO groups, transection was preceded by 1-hour (3 V, 20 Hz square wave) electrical stimulation. Animals were tested weekly, with 5-minute recording sessions of whisker movement. In the MEC and COMBO groups, animals received 5 minutes of daily massage to the left whisker pad throughout the recovery period. Whisking behavior was analyzed for comparisons. The BES and MEC groups demonstrated improved functional recovery in all whisking parameters compared with the COMBO group or historical controls at most time points between postoperative weeks 1 and 7. After 12 weeks, functional recovery remained superior in the BES and MEC groups compared with the COMBO and control groups, although the effect was no longer statistically significant. We observed an accelerative recovery effect of either electrical nerve stimulation or massage of the whisker pad on whisking behavior. The combination of both interventions had a negating effect on the acceleration of recovery. The potential clinical utility of these modalities bears consideration, and their negating interaction warrants further study.
Article
To establish whether daily mechanical stimulation improves functional recovery of whisking after facial nerve transection injury and repair in rats. Forty rats underwent facial nerve transection injury and repair and subsequent quantitative facial movement testing. Animals were randomized into 2 experimental groups (n = 20 each). Both groups received daily 5-minute manual stimulation of their whiskers, with one group undergoing whisker protraction and the other, whisker retraction. Rats were tested on postoperative weeks 1, 4 through 8, and 15 via a validated, quantitative whisking kinematics apparatus. Whisks were counted and analyzed for whisking amplitude, velocity, and acceleration. Animals receiving manual stimulation by passive protraction of their whiskers demonstrated significantly improved functional recovery at multiple time points during the 15 weeks compared with historical controls (P < .005; 1-tailed t test). Recovery was similar in the protraction and retraction groups, trending toward better whisking recovery in the protraction group. Daily mechanical whisker stimulation via either protraction or retraction significantly improves recovery of whisking after facial nerve transection and repair. This finding supports the role of early soft-tissue manipulation after facial nerve repair and may have clinical implications for the postoperative management of patients after facial nerve manipulations.
Article
The Facial Grading Scale (FGS) is a quantitative instrument used to evaluate facial function after facial nerve injury. However, quantitative improvements in function after facial rehabilitation in people with chronic facial paralysis have not been shown. The objectives of this study were to use the FGS in a large series of consecutive subjects with facial paralysis to quantitatively evaluate improvements in facial function after facial nerve rehabilitation and to describe the management of chronic facial paralysis. The study was a retrospective review. A total of 303 individuals with facial paralysis were evaluated by 1 physical therapist at a tertiary care facial nerve center during a 5-year period. Facial rehabilitation included education, neuromuscular training, massage, meditation-relaxation, and an individualized home program. After 2 months of home exercises, the participants were re-evaluated, and the home program was tailored as necessary. All participants were evaluated with the FGS before the initiation of facial rehabilitation, and 160 participants were re-evaluated after receiving treatment. All participants underwent the initial evaluation at least 4 months after the onset of facial paralysis; for 49 participants, the evaluation took place more than 3 years after onset. Statistically significant increases in FGS scores were seen after treatment (P<.001, t test). The average initial score was 56 (SD=21, range=13-98), and the average score after treatment was 70 (SD=18, range=25-100). A limitation of this study was that evaluations were performed by only 1 therapist. For 160 patients with facial paralysis, statistically significant improvements after facial rehabilitation were shown; the improvements appeared to be long lasting with continued treatment. The improvements in the FGS scores indicated that patients can successfully manage symptoms with rehabilitation and underscored the importance of specialized therapy in the management of facial paralysis.
Article
The optimal timing for surgical exploration of traumatic facial paralysis to best preserve facial function is currently controversial. This article reviews the final outcomes of facial function in patients with traumatic intratemporal facial nerve injury according to the timing of surgical exploration. We performed a retrospective review of 58 patients with complete facial nerve paralysis caused by temporal bone fractures as a result of head trauma between 1998 and 2007. Patients were divided into three groups according to the type of trauma. The only difference between patients in each group was the timing of the surgical exploration. Characteristics assessed in the study included type of trauma, location of facial nerve injury, timing of surgical intervention, audiometric findings, surgical approach, and long-term follow-up of recovery of facial nerve function, as assessed by two facial nerve grading systems. The final functional gains in early-operated patients were 3.7 +/- 0.59 on the House-Brackmann (HB) scale and 75.6 +/- 10.88 on the Sunnybrook scale. The outcome in late-operated patients was 2.17 +/- 0.52 on the HB scale and 34.7 +/- 16.95 on the Sunnybrook scale, and that of nonoperated patients was 2.0 +/- 0.63 on the HB scale and 26.8 +/- 6.27 on the Sunnybrook scale. This study demonstrated that some patients with traumatic facial nerve paralysis who had nerve conduction studies consistent with a poor prognosis regained considerable facial function after early surgical intervention. However, late exploration after facial nerve paralysis did not result in positive outcomes, regardless of the type of temporal bone fracture or the site of injury, and no difference was observed compared with conservative treatment.
Article
Topical application of basic fibroblast growth factor (bFGF) hydrogel facilitates faster healing from traumatic facial paralysis due to continuous release of bFGF. bFGF is considered a potent agent to facilitate recovery from neuronal damage; however, exogenously applied bFGF does not work well because of its short acting time. To enhance the effects in vivo, we developed a new drug delivery system by embedding bFGF in a gelatin hydrogel that degrades slowly. In this study, the effects of bFGF-hydrogel on traumatic facial nerve paralysis were investigated in guinea pigs. The intratemporal facial nerve was exposed and clamped at the vertical portion using micro needle forceps. The animals were then subjected to one of the following three procedures: group A, no further treatment; group B, one-shot application of bFGF to the nerve; and group C, application of bFGF-hydrogel instead. Six weeks later, facial nerve functions were evaluated by three test batteries: observation of facial movements, electrophysiological testing, and histological study. The results for groups A and B were similar in the three tests, indicating that one-shot application of bFGF did not benefit facial nerve recovery. In contrast, group C achieved better results in all tests.
Article
The outcome of peripheral nerve injuries requiring surgical repair is poor. Recent work suggested that electrical stimulation (ES) of the proximal nerve stump to produce repeated discharges of the parent motoneurons for one hour could be a beneficial therapy if delivered immediately prior to reconstructive surgery of mixed peripheral nerves. We tested whether ES has a positive influence on functional recovery after repair of a purely motor nerve, the facial nerve. Electrical stimulation (20 Hz) was delivered to the proximal nerve stump of the transected facial nerve for 1 hour prior to nerve reconstruction by end-to-end suture (facial-facial anastomosis, FFA). For manual stimulation (MS), animals received daily rhythmic stroking of the whisker pads. Restoration of vibrissal motor performance following ES or MS was evaluated using video-based motion analysis. We also assessed the degree of collateral axonal branching at the lesion site, by counting motoneuronal perikarya after triple retrograde labeling, and estimated the quality of motor end-plate reinnervation in the target musculature. Outcomes at 4 months were compared to animals receiving sham stimulation (SS) or MS. Neither protocol reduced the degree of collateral sprouting. ES did not improve functional outcome and failed to reduce the proportion of polyinnervated motor end-plates. By contrast, MS restored normal whisking function and reduced polyinnervation. Whereas acute ES is not beneficial for facial nerve repair, MS provides long-term benefits.
Article
We have shown that manual stimulation of rat whisker-pad muscles following facial-facial-anastomosis (FFA) restores normal whisking by lowering the proportion of polyinnervated motor endplates. Here we examined whether manual stimulation of the orbicularis oculi muscle (OOM) after FFA would also improve outcome. Blink responses to standardized air puffs were analyzed using video-based motion analysis. Two months after FFA, blink capacity was impaired, as indicated by a largely increased minimum distance between the eyelids after air-puff stimulation compared with intact rats (2.7 +/- 0.4 vs. 0.2 +/- 0.01 mm). Manual stimulation reduced this deficit by a factor of two (1.3 +/- 0.5 mm). The functional improvement after manual stimulation was associated with a 2-fold decrease in the proportion of polyinnervated OOM endplates (21 +/- 10% vs. 42 +/- 10% without manual stimulation, 0% in intact rats). We conclude that manual stimulation is a noninvasive and simple procedure with immediate potential for clinical rehabilitation of eyelid closure following facial nerve injury.
Article
Combining neurotrophic factor support and neural stem cell (NSC) transplantation may improve regeneration of the peripheral nervous system. Objectives. We constructed a biodegradable nerve conduit (NC) filled with NSCs overexpressing glia-derived neurotrophic factor (GDNF), which is known to protect facial motoneurons, and tested the effect of this NC on facial nerve regeneration. Primary cultured NSCs were transduced with a lentiviral vector encoding enhanced green fluorescent protein (EGFP) and GDNF. GDNF expression was confirmed by Western blotting and ELISA. Sprague Dawley (SD) rats were subjected to right facial nerve transection, and polyglycolic/polyglycolic acid (PLGA) NCs filled with NSCs-GDNF were used to bridge the nerve gap (n=24). In vivo GDNF expression was confirmed by real-time PCR. NCs containing NSCs, transgenic Schwann cells (SCs-GDNF), or empty NCs served as controls (n=24 per group). Facial nerve regeneration was assessed 2-12 weeks after surgery, by electrophysiological testing, immunohistochemical staining, and morphometric analysis of axons. NSCs exhibited sustained and robust GDNF expression in culture and following implantation. Nerve action potential amplitude, axonal area, and axonal number were significantly greater in the NSCs-GDNF group than in the NSCs or empty NC groups. Axonal area and number were also greater in the NSCs-GDNF group than the SCs-GDNF group, although this was not statistically significant. The enhanced regeneration observed in the NSCs-GDNF group was accompanied by increased labeling for S100, NF, and βIII tubulin.
Article
Normal rats show two types of rhythmical vibrissal movement, one synchronized precisely with alpha waves (about 9 Hz) of the thalamocortical system, and the other often synchronized with theta waves (about 7 Hz) of the septohippocampal system. The alpha-synchronized vibrissal movements appear while the rat stands still with a slow respiratory pattern, and are of small amplitude (a fine tremor). The theta-synchronized vibrissal movements appear during exploratory sniffing behavior, and are of large amplitude. Thus, a group of facial motoneurons which constitute the final common pathway for vibrissal movement apparently receive input convergently from these two neural systems.
Article
Certain muscles of the mouse and rat have been studied in order to assess how far a signal from denervated muscle can spread to elicit terminal sprouting from intact endplates. Denervation of the muscles surrounding the rat foot 4th lumbrical muscle caused no terminal sprouting in the 4th lumbrical itself. In the hemidenervated mouse gluteus maximus terminal sprouting was restricted to the central region of the muscle where innervated and denervated fibres intermingle. There was no enhancement of such sprouting if the underlying and closely apposed gluteus medius was simultaneously denervated. Hemidenervation of the mouse diaphragm and interscutularis, where intact endplates lie near to denervated muscle fibres, produced no terminal sprouting. Hemidenervation of the mouse platysma, where intact endplates often lie adjacent to denervated muscle fibres, similarly produced no significant response. However, all muscles were capable of producing extensive terminal sprouting in response to paralysis induced by botulinum toxin. The stimulus for terminal sprouting produced by an inactive muscle fibre must therefore be effective only on the fibre's own terminal or immediately adjacent terminals.
Article
A fine (approx. 9 c/sec) tremor of the jaw and/or vibrissae was observed in normal rats while they were standing still and not showing gross bodily movement. The tremor was distinctly different in frequency, intensity, and behavioral context, from movements involved in gnawing, tooth chattering, or exploratory sniffing. Individual tremor movements (recorded as EMG) occurred in synchrony with individual bursts of multiunit activity (MUA) recorded in the ventrobasal complex of the thalamus and with individual 'spikes' in the cortical (frontal-occipital) EEG. Single trains of this rhythmical activity often lasted more than a minute. The phase relationships between EMG and MUA differed among individuals, but tended to remain consistent within each individual. Movement artifacts were ruled out since (1) the moments of occurrence of individual tremor movements and MUA bursts were interdigitated rather than simultaneous, and (2) during high amplitude EMG bursts accompanying sni ffing (associated with EEG theta rhythm), tooth chattering, eating or licking, no corresponding activity in the MUA was observed. We also ruled out the possibility that the neural activity was generated by reafference, for (1) during vigorous non-tremor sniffing movements of the vibrissae, or chattering or chewing movements of the jaws, the rhythmical MUA was absent (although the units did discharge if the vibrissae contacted an obstacle or were brushed by the experimenter), (2) rhythmical MUA often continued both during brief pauses in the motor tremor, and in its absence, and (3) injection of Xylocaine s.c. into the face abolished sensory responses of the thalamic units, but the rhythmical MUA persisted. We discuss evidence which suggests that (1) the rhythmical cortical EEG waves are the equivalent in the rat of the alpha (mu) rhythm, and (2) the existence of parallels between alpha-tremor and Parkinsonian tremor in terms of their mechanisms and functions.
Article
To study the process of recovery from facial palsy experimentally, the location of cranial motoneurons supplying the posterior belly of the digastric muscle (PDG) and the extratemporal portion of the facial nerve trunk was examined in a double-labeling paradigm using two retrograde tracers in the adult guinea pig of which the facial nerve had been surgically injured. In different stages after the induced facial palsy had recovered functionally (4-13 weeks after the surgical operation), wheat germ-agglutinated horseradish peroxidase (WGA-HRP) was injected into the PDG and Fluoro-Ruby (FR) was applied to the proximal cut end of the extratemporal portion of the facial nerve trunk. Distribution of neurons retrogradely labeled with WGA-HRP and/or FR was plotted in the brainstem and compared with that of the controls. In the intact cases, HRP-labeled neurons were restrictedly seen in the accessory facial nucleus (Acs7), while FR-labeled neurons were found within the main facial nucleus (FMN). In the axotomized cases: (1) HRP-labeled neurons were seen diffusely in the Acs7 as well as in the FMN, where normal myotopical representation no longer seemed to be maintained. (2) FR-labeled neurons were also observed diffusely in the FMN and the Acs7. (3) A considerable number of neurons were doubly labeled with WGA-HRP and FR in both the Acs and the FMN in cases with shorter survival periods (4-7 weeks), but not in cases with longer survival periods (12-13 weeks). Thus, new findings show that connections are temporarily maintained by single, facial motoneurons with axon collaterals to multiple muscle targets in adult mammals.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
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Rehabilitation for peripheral facial paralysis is often neglected and patients are left untreated. This article explains how nonsurgical rehabilitation, specifically facial neuromuscular retraining, restores function in these patients. Patients with facial paralysis resulting from viral causes, postsurgical tumor resection, traumatic injury, or congenital paresis may be candidates for treatment. Typical patients present with flaccid paralysis acutely and may develop abnormal movement patterns (synkinesis) as recovery progresses. Neuromuscular retraining is effective. It provides specific strategies that inhibit synkinesis based on individual function and unique facial nerve and muscle properties. Successful rehabilitation results in improved patient satisfaction, self-esteem, and quality of life. Electrical stimulation should not be used at any time in facial rehabilitation. There is evidence that it may be contraindicated, and it is unnecessary. The imperative in treating synkinesis is to inhibit abnormally contracting muscles, not stimulate flaccid ones. The unfounded use of electrical stimulation is an unnecessary expense for patients and third-party payers.
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