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Early and continued manual stimulation is required for long-term recovery after nerve injury
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.
... 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]. ...
Background
In a broad variety of species, muscle contraction is controlled at the neuromuscular junction (NMJ), the peripheral synapse composed of a motor nerve terminal, a muscle specialization, and non-myelinating terminal Schwann cells. While peripheral nerve damage leads to successful NMJ reinnervation in animal models, muscle fiber reinnervation in human patients is largely inefficient. Interestingly, some hallmarks of NMJ denervation and early reinnervation in murine species, such as fragmentation and poly-innervation, are also phenotypes of aged NMJs or even of unaltered conditions in other species, including humans. We have reasoned that rather than features of NMJ decline, such cellular responses could represent synaptic adaptations to accomplish proper functional recovery. Here, we have experimentally tackled this idea through a detailed comparative study of the short- and long-term consequences of irreversible (chronic) and reversible (partial) NMJ denervation in the convenient cranial levator auris longus muscle.
Results
Our findings reveal that irreversible muscle denervation results in highly fragmented postsynaptic domains and marked ectopic acetylcholine receptor clustering along with significant terminal Schwann cells sprouting and progressive detachment from the NMJ. Remarkably, even though reversible nerve damage led to complete reinnervation after 11 days, we found that more than 30% of NMJs are poly-innervated and around 65% of postsynaptic domains are fragmented even 3 months after injury, whereas synaptic transmission is fully recovered two months after nerve injury. While postsynaptic stability was irreversibly decreased after chronic denervation, this parameter was only transiently affected by partial NMJ denervation. In addition, we found that a combination of morphometric analyses and postsynaptic stability determinations allows discriminating two distinct forms of NMJ fragmentation, stable-smooth and unstable-blurred, which correlate with their regeneration potential.
Conclusions
Together, our data unveil that reversible nerve damage imprints a long-lasting reminiscence in the NMJ that results in the rearrangement of its cellular components. Instead of being predictive of NMJ decline, these traits may represent an efficient adaptive response for proper functional recovery. As such, these features are relevant targets to be considered in strategies aimed to restore motor function in detrimental conditions for peripheral innervation.
... 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). ...
It is well-known that, after nerve transection and surgical repair, misdirected regrowth of regenerating motor axons may occur in three ways. The first way is that the axons enter into endoneurial tubes that they did not previously occupy, regenerate through incorrect fascicles and reinnervate muscles that they did not formerly supply. Consequently the activation of these muscles results in inappropriate movements. The second way is that, in contrast with the precise target-directed pathfinding by elongating motor nerves during embryonic development, several axons rather than a single axon grow out from each transected nerve fiber. The third way of misdirection occurs by the intramuscular terminal branching (sprouting) of each regenerating axon to culminate in some polyinnervation of neuromuscular junctions, i.e. reinnervation of junctions by more than a single axon. Presently, "fascicular" or "topographic specificity" cannot be achieved and hence target-directed nerve regeneration is, as yet, unattainable. Nonetheless, motor and sensory reinnervation of appropriate endoneurial tubes does occur and can be promoted by brief nerve electrical stimulation. This review considers the expression of neurotrophic factors in the neuromuscular system and how this expression can promote functional recovery, with emphasis on the whisking of vibrissae on the rat face in relationship to the expression of the factors. Evidence is reviewed for a role of neurotrophic factors as short-range diffusible sprouting stimuli in promoting complete functional recovery of vibrissal whisking in blind Sprague Dawley (SD)/RCS rats but not in SD rats with normal vision, after facial nerve transection and surgical repair. Briefly, a complicated time course of growth factor expression in the nerves and denervated muscles include (1) an early increase in FGF2 and IGF2, (2) reduced NGF between 2 and 14days after nerve transection and surgical repair, (3) a late rise in BDNF and (4) reduced IGF1 protein in the denervated muscles at 28days. These findings suggest that recovery of motor function after peripheral nerve injury is due, at least in part, to a complex regulation of nerve injury-associated neurotrophic factors and cytokines at the neuromuscular junctions of denervated muscles. In particular, the increase of FGF2 and concomittant decrease of NGF during the first week after facial nerve-nerve anastomosis in SD/RCS blind rats may prevent intramuscular axon sprouting and, in turn, reduce poly-innervation of the neuromuscular junction.
Ischemic stroke is a leading cause of disability world-wide. Mounting evidence supports neuromuscular pathology following stroke, yet mechanisms of dysfunction and therapeutic action remain undefined. The objectives of our study were to investigate neuromuscular pathophysiology following ischemic stroke and to evaluate the therapeutic effect of Robot-Assisted Mechanical massage Therapy (RAMT) on neuromuscular junction (NMJ) morphology. Using an ischemic stroke model in male rats, we demonstrated longitudinal losses of muscle contractility and electrophysiological estimates of motor unit number in paretic hindlimb muscles within 21 days of stroke. Histological characterization demonstrated striking pre- and postsynaptic alterations at the NMJ. Stroke prompted enlargement of motor axon terminals, acetylcholine receptor (AChR) area, and motor endplate size. Paretic muscle AChRs were also more homogenously distributed across motor endplates, exhibiting fewer clusters and less fragmentation. Most interestingly, NMJs in paretic muscle exhibited increased frequency of polyaxonal innervation. This finding of increased polyaxonal innervation in stroke-affected skeletal muscle suggests that reduction of motor unit number following stroke may be a spurious artifact due to overlapping of motor units rather than losses. Furthermore, we tested the effects of RAMT – which we recently showed to improve motor function and protect against subacute myokine disturbance – and found significant attenuation of stroke-induced NMJ alterations. RAMT not only normalized the post-stroke presentation of polyaxonal innervation but also mitigated postsynaptic expansion. These findings confirm complex neuromuscular pathophysiology after stroke, provide mechanistic direction for ongoing research, and inform development of future therapeutic strategies.
Significance
Ischemic stroke is a leading contributor to chronic disability, and there is growing evidence that neuromuscular pathology may contribute to the impact of stroke on physical function. Following ischemic stroke in a rat model, there are progressive declines of motor unit number estimates and muscle contractility. These changes are paralleled by striking pre- and postsynaptic maladaptive changes at the neuromuscular junction, including polyaxonal innervation. When administered to paretic hindlimb muscle, Robot-Assisted Mechanical massage Therapy – previously shown to improve motor function and protect against subacute myokine disturbance – prevents stroke-induced neuromuscular junction alterations. These novel observations provide insight into the neuromuscular response to cerebral ischemia, identify peripheral mechanisms of functional disability, and present a therapeutic rehabilitation strategy with clinical relevance.
The facial nerve is the most frequently damaged nerve in head and neck traumata. Repair of interrupted nerves is generally reinforced by fine microsurgical techniques; nevertheless, functional recovery is the exception rather than the rule. The so-called "post-paralytic syndrome", which includes synkinesia and altered blink reflexes, follows nerve injury. The aim of the present study was to investigate whether nerve-gap repair by an autologous vein, which had been filled with skeletal muscle, would improve axonal regeration, reduce neuromuscular junction polyinnervation and improve the recovery of whisking in rats with transected and sutured right buccal branches of the facial nerve. Vibrissal motor performance was examined with the use of a video motion analysis. Immunofluorescence was used to visualize and analyze target muscle reinnervation. The results taken together indicate a positive effect of muscle-vein combined conduit (MVCG) on recovery of whisking function after facial nerve reconstruction in rats. The findings support the recent suggestion that a venal graft with implantation of a trophic source, such as autologous denervated skeletal muscle, may promote the monoinnervation degree and improve the recovery of coordinated function of the corresponding muscles.
Background:
The "post-paralytic syndrome" after facial nerve reconstruction has been attributed to (i) malfunctioning axonal guidance at the fascicular (branches) level, (ii) collateral branching of the transected axons at the lesion site, and (iii) intensive intramuscular terminal sprouting of regenerating axons which causes poly-innervation of the neuromuscular junctions (NMJ).
Objective:
The first two reasons were approached by an innovative technique which should provide the re-growing axons optimal conditions to elongate and selectively re-innervate their original muscle groups.
Methods:
The transected facial nerve trunk was inserted into a 3-way-conduit (from isogeneic rat abdominal aorta) which should "guide" the re-growing facial axons to the three main branches of the facial nerve (zygomatic, buccal and marginal mandibular). The effect of this method was tested also on hypoglossal axons after hypoglossal-facial anastomosis (HFA). Coaptational (classic) FFA (facial-facial anastomosis) and HFA served as controls.
Results:
When compared to their coaptation (classic) alternatives, both types of 3-way-conduit operations (FFA and HFA) promoted a trend for reduction in the collateral axonal branching (the proportion of double- or triple-labelled perikarya after retrograde tracing was slightly reduced). In contrast, poly-innervation of NMJ in the levator labii superioris muscle was increased and vibrissal (whisking) function was worsened.
Conclusions:
The use of 3-way-conduit provides no advantages to classic coaptation. Should the latter be impossible (too large interstump defects requiring too long interpositional nerve grafts), this type of reconstruction may be applied. (230 words).
During nervous system development, neurons extend axons along well-defined pathways. The current understanding of axon pathfinding is based mainly on chemical signaling. However, growing neurons interact not only chemically but also mechanically with their environment. Here we identify mechanical signals as important regulators of axon pathfinding. In vitro, substrate stiffness determined growth patterns of Xenopus retinal ganglion cell axons. In vivo atomic force microscopy revealed a noticeable pattern of stiffness gradients in the embryonic brain. Retinal ganglion cell axons grew toward softer tissue, which was reproduced in vitro in the absence of chemical gradients. To test the importance of mechanical signals for axon growth in vivo, we altered brain stiffness, blocked mechanotransduction pharmacologically and knocked down the mechanosensitive ion channel piezo1. All treatments resulted in aberrant axonal growth and pathfinding errors, suggesting that local tissue stiffness, read out by mechanosensitive ion channels, is critically involved in instructing neuronal growth in vivo.
The aim of this study is to investigate the effect of sensory input on the neural plasticity in the facial nucleus following facial nerve injury. Adult male Wistar rats were randomly assigned to four groups: (1) sham control; (2) facial nerve crush (FNC); (3) nerve crush plus daily manual vibrissal stimulation (FMS); and (4) nerve crush with infraorbital nerve transection plus daily manual stimulation (FIMS). Plasticity related proteins in the facial nucleus were evaluated by western blot at 7, 14, and 28 days postsurgery (n = 6/group per timepoint). Synaptophysin-positive terminals were evaluated by immunohistochemistry in a second set of animals (n = 6/group) at 14 days. Quantitation of synaptophysin immunostaining showed that rats in the FNC group had a significantly lower mean number of pixels compared to control animals (29.1 ± 2.6 × 106 vs. 34.2 ± 2.3 × 106; P < 0.05). Values in the FMS group (33.2 ± 1.7 × 106) were similar to that of the control group, while the mean number in the FIMS group (26.5 ± 2.4 × 106) was significantly lower than in the control group. Synapsin I phosphorylation was reduced to 70–83 % in FNC rats, but increased to 121–132 % in the FMS group (P < 0.05 vs. controls). Phosphorylation of cAMP response element-binding protein was similarly reduced by facial nerve crush, which was delayed in FMS animals (P < 0.05 vs. controls at 28 days). Expression and phosphorylation of all proteins were reduced to the lowest in the FIMS group (all P < 0.05). Sensory input from the IoN have a strong effect on synaptic plasticity within the facial nucleus, which is necessary to achieve the benefit of manual stimulation.
Introduction:
The important sequelae of facial nerve palsy are synkinesis, asymmetry, hypertension and contracture; all of which have psychosocial effects on patients. Synkinesis due to mal regeneration causes involuntary movements during a voluntary movement. Previous studies have advocated treatment using physiotherapy modalities alone or with exercise therapy, but no consensus exists on the optimal approach. Thus, this review summarizes clinical controlled studies in the management of synkinesis and asymmetry in facial nerve palsy.
Materials and Methods:
Case-controlled clinical studies of patients at the acute stage of injury were selected for this review article. Data were obtained from English-language databases from 1980 until mid-2013.
Results:
Among 124 articles initially captured, six randomized controlled trials involving 269 patients were identified with appropriate inclusion criteria. The results of all these studies emphasized the benefit of exercise therapy. Four studies considered electromyogram (EMG) biofeedback to be effective through neuromuscular re-education.
Conclusion:
Synkinesis and inconsistency of facial muscles could be treated with educational exercise therapy. EMG biofeedback is a suitable tool for this exercise therapy.
Object:
Facial nerve injury results in facial palsy that has great impact on the psychosocial conditions of affected patients. Reconstruction of the facial nerve to restore facial symmetry and expression is still a significant surgical challenge. In this study, the authors assessed a hypoglossal-facial nerve anastomosis method combined with neurotrophic factor gene therapy to treat facial palsy in adult rats after facial nerve injury.
Methods:
Surgery consisted of the interposition of a predegenerated nerve graft (PNG) that was anastomosed with the hypoglossal and facial nerves at each of its extremities. The hypoglossal nerve was cut approximately 50% for this anastomosis to conserve partial hypoglossal function. Before their transplantation, the PNGs were genetically engineered using lentiviral vectors to induce overexpression of the neurotrophic factor neurotrophin-3 (NT-3) to improve axonal regrowth in the reconstructed nerve pathway. Reconstruction was performed after facial nerve injury, either immediately or after a delay of 9 weeks. The rats were followed up for 4 months postoperatively, and treatment outcomes were then assessed.
Results:
Compared with the functional innervation in control rats that underwent facial nerve injury without subsequent treatment, functional innervation of the paralyzed whisker pad by hypoglossal motoneurons in rats treated 4 months after nerve reconstruction was evidenced by the retrograde transport of neuronal tracers, the recording of muscle action potentials conducted by the PNG, and the recovery of facial symmetry. Although a better outcome was observed when reconstruction was performed immediately after facial nerve injury, reconstruction with NT3-treated PNGs significantly improved functional reinnervation of the paralyzed whisker pad even when implantation occurred 9 weeks posttrauma.
Conclusions:
Results demonstrated that hypoglossal-facial nerve anastomosis facilitates innervation of paralyzed facial muscle via hypoglossal motoneurons without sacrificing ipsilateral hemitongue function. Neurotrophin-3 treatment through gene therapy could effectively improve such innervation, even after delayed reconstruction. These findings suggest that the combination of surgical reconstruction and NT-3 gene therapy is promising for its potential application in treating facial palsy in humans.
Deafferentation of motoneurons after facial nerve injury is a well-documented phenomenon but whether synaptic inputs to facial motoneurons are completely restored after reinnervation is unknown. Here, we tested the hypothesis that deficits in motor performance after transection/suture of the facial nerve (facial-facial anastomosis, FFA) in adult rats are associated with incomplete recovery of synaptic inputs. At 2 months after FFA, we found, in congruence with previous results, that the amplitude of whisking had recovered to only 31 % of control (sham operation). In the same FFA-treated rats, estimates of number of chemically defined synaptic terminals in the facial nucleus by immunohistochemistry and stereology showed a significant loss, compared with sham controls, of glutamatergic terminals (-26 %) and cholinergic perisomatic boutons (-31 %), but not inhibitory (GABA/glycinergic) terminals (-14 %). Synaptic deficits were accompanied by persistent microgliosis in the facial nucleus but soma area, dendritic arbor volume, and total number of motoneurons were normal. Correlation analyses revealed significant co-variations of whisking amplitude with number of glutamatergic and cholinergic synapses. Compared with 2 months, analyses of animals at 4 months after FFA showed no attenuation of the functional deficit and structural aberrations with one exception, increase of inhibitory terminal numbers beyond control level (+11 %) leading to further reduction of the excitatory/inhibitory terminal ratio. We suggest that deficits in motoneuron innervation in the regenerated facial nucleus-reduced glutamatergic and cholinergic input and reduced excitatory/inhibitory terminal ratio-could attenuate the motor output and, thus, negatively impact the functional performance after facial nerve regeneration.
In the visual system of primates, different neuronal pathways are specialized for processing information about the spatial coordinates of objects and their identity - that is, 'where' and 'what'. By contrast, rats and other nocturnal animals build up a neuronal representation of 'where' and 'what' by seeking out and palpating objects with their whiskers. We present recent evidence about how the brain constructs a representation of the surrounding world through whisker-mediated sense of touch. While considerable knowledge exists about the representation of the physical properties of stimuli - like texture, shape and position - we know little about how the brain represents their meaning. Future research may elucidate this and show how the transformation of one representation to another is achieved.
Physical trauma is the third leading cause of facial nerve damage, which can disrupt communication, social interaction and emotional expression. The objective of this report was to investigate the effects of facial muscle exercise as a stand-alone treatment in a young adult with unilateral facial nerve damage 13-years post-onset.
This single case study examines the long-term results of a 7-week intensive facial exercise programme followed by a 16-week moderate facial exercise programme.
Intensive exercise increased facial strength and upper lip elevation on the affected side and upper and lower lip strength on the affected and non-affected sides. With subsequent moderate exercise followed by 24 weeks of rest, strength was maintained but not increased.
With intensive facial exercise, muscle weakness resulting from facial nerve damage sustained during childhood can be improved years after injury.
Many treatment techniques, including exercise, electrical stimulation, biofeedback, and neuromuscular retraining, have been described for the treatment of patients with facial paresis. The degree of nerve injury determines the recovery of the facial muscles. Patients with a Sunderland third-degree injury benefit most from therapy to maximize facial nerve function. Following a facial nerve palsy, many patients present with facial muscle weakness in addition to aberrant synkinetic movements. Therefore therapy must be directed toward control of voluntary movement and decreasing synkinesis. Neuromuscular reeducation involves selective muscle control to decrease synkinesis and increase muscle excursion. Muscle reeducation using surface electromyographic (EMG) biofeedback and home exercises has been shown to be efficacious in the treatment of facial palsies. Neuromuscular retraining can be beneficial in maximizing facial recovery by initially decreasing aberrant synkinetic muscle activity and then increasing voluntary movement and excursion.
The purpose of this study was to investigate the effects of platelet-rich plasma (PRP) and neural-induced human mesenchymal stem cells (nMSCs) on axonal regeneration from a facial nerve axotomy injury in a guinea pig model.
Prospective, controlled animal study.
Experiments involved the transection and repair of the facial nerve in 24 albino guinea pigs. Four groups were created based on the method of repair: suture only (group I, control group); PRP with suture (group II); nMSCs with suture (group III); and PRP and nMSCs with suture (group IV). Each method of repair was applied immediately after nerve transection. The outcomes measured were: 1) functional outcome measurement (vibrissae and eyelid closure movements); 2) electrophysiologic evaluation; 3) neurotrophic factors assay; and 4) histologic evaluation.
With respect to the functional outcome measurement, the functional outcomes improved after transection and reanastomosis in all groups. The control group was the slowest to demonstrate recovery of movement after transection and reanastomosis. The other three groups (groups II, III, and IV) had significant improvement in function compared to the control group 4 weeks after surgery (P < .05). On the electrophysiologic evaluation, there was significantly better performances in groups II, III, and IV when compared to group I with respect to the amplitude and excitation area of the compound motor action potentials (MAPs) 4 and 6 weeks after surgery (P < .05); group IV had the best performance. A Western blot assay showed that group II had marked expression of several neurotrophic factors. Groups II, III, and IV demonstrated better results in axon counts and myelin thickness when compared with group I. Based on quantitative histology analysis, group IV had the greatest myelinated axon fibers compared to the other groups (P < .05).
The use of PRP and/or nMSCs promotes facial nerve regeneration in an animal model of facial nerve axotomy. The use of nMSCs showed no benefit over the use of PRP in facial nerve regeneration, but the combined use of PRP and nMSCs showed a greater beneficial effect than use of either alone. This study provides evidence for the potential clinical application of PRP and nMSCs in peripheral nerve regeneration of an acute nerve injury. Laryngoscope, 2010.
Using a vital nerve terminal dye (4-Di-2-ASP) and fluorescently tagged alpha-bungarotoxin to stain postsynaptic acetylcholine (ACh) receptors, we viewed the same muscle fibers at multiple times in the sternomastoid muscle of living mice during the process of reinnervation following nerve crush. Soon after axons reenter the muscle, they precisely reoccupy the original endplate sites. However, in contrast to normal adult muscle, during the first several weeks of reinnervation, anatomical and physiological measures show that many of the endplate sites are innervated by more than one axon. Typically, one axon reinnervates the original endplate site by growing up the old Schwann cell tube while another originates as a sprout from a nearby endplate. Within 2 weeks after reinnervation nerve terminal staining shows that most of the sprouts have regressed and physiological evidence of multiple innervation has returned to the normal low level. By repeatedly observing the same endplates during the period of synapse elimination, we could directly view this phenomenon. At some endplates, nerve terminal boutons in one region of the endplate were eliminated at the same time a sprout entering that area regressed. These unoccupied sites seemed permanently eliminated as they are not subsequently occupied by sprouts from the axon remaining at the endplate. We were surprised to find that there is a corresponding permanent loss of ACh receptors within the muscle fiber membrane precisely underneath the eliminated nerve terminals. The decrease in receptors at sites of synapse elimination is due to both a selective loss of ACh receptors already incorporated into these sites and to a lack of insertion of new receptors at the same regions. These sites of pre- and postsynaptic loss, however, maintain cholinesterase staining in the basal lamina for long periods. Control experiments showed that endplates that were permanently denervated, incompletely reoccupied by reinnervating axons, or stained and viewed multiple times in normal muscle do not lose postsynaptic receptor regions. Interestingly, receptors appear to be eliminated before there is any obvious change in the staining of the overlying nerve terminal. Because of the lag between receptor and nerve terminal loss, we could predict which synaptic boutons would be eliminated by looking for lightly stained receptor regions. One interpretation of these data is that the removal or redistribution of relevant postsynaptic molecules by one innervating axon may instigate the elimination of competing terminals.
The present study examined how facial nerve regeneration shapes movement representation patterns in previously disconnected motor cortices. Electrical microstimulation was used to bilaterally map the motor cortices of adult rats subjected to unilateral facial nerve lesion and reanastomosis stamps at the stylomastoid foramen level. The motor cortex output patterns of two groups of experimental hemispheres (contralateral to lesioned side) were compared before and after facial nerve reinnervation. The motor cortex output patterns in the control hemispheres (ipsilateral to the lesioned side) were used as reference. Before facial nerve reinnervation, the motor cortex forelimb and eye output area extended into the vibrissa area; such enlargement did not occupy the medial part of the former vibrissa area where ipsilateral vibrissa or neck movements were represented. After facial nerve reinnervation, the contralateral vibrissa movement reorganized into a shrunken cortical area corresponding to the medial portion of the former vibrissa representation, i.e., where the ipsilateral vibrissa and neck movements were mainly represented prior to facial nerve reinnervation. The enlargement of the forelimb and eye representation remained unchanged, even after the vibrissa motor innervation was reactivated. Before facial nerve reinnervation into expanded forelimb and eye representations, a minimal current was required to evoke these movements, which did not vary from the normal range. A higher current was necessary to evoke the ipsilateral vibrissa and neck movements in the medial part of the vibrissa representation than the threshold needed to elicit the vibrissa movement normally represented in this cortical region. After facial nerve reinnervation, the overall current required to evoke movement remained the same as that which evoked movement before the vibrissa motor innervation was reactivated.
The motor and sensory innervation of the muzzle, with special reference to the mystacial region, has been described in the albino mouse. Both extrinsic and intrinsic muscles of the mystacial region are innervated by branches of the facial nerve. The innervation of the intrinsic musculature represented by the follicular muscles was studied in detail. The facial nerve sends longitudinal branches between the horizontal rows of mystacial follicles. Each longitudinal branch gives off medial and lateral ramifications penetrating into the interfollicular space, where they anastomose with the ramification coming from the neighbouring longitudinal branch and then innervate the extremities of the follicular muscle. In addition there are two marginal branches: one on the medial side of the row A follicles; the other on the lateral side of the row E follicles. The sensory innervation of the muzzle is provided by all three divisions of the trigeminal nerve. The mystacial region, characterized by a typical pattern of vibrissal sinus follicles, is innervated by the n. infraorbitalis, the main branch of the n. maxillaris. The infraorbital nerve sends five bands of nerve fascicles to the mystacial region, each of them, the 'row nerves', passing rostrad along the medial side of the row of follicles it will innervate. The principal branches of the row nerves are follicular nerves which penetrate the posteromedial aspect of the follicle. The row nerves give off other tiny ramifications, the skin nerves, innervating the skin of the mystacial region. Some rami of the skin nerves (1-5) penetrate, as conus nerves, the uppermost part of the follicle, the conical body.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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)
A macaque monkey with a preexisting facial nerve injury showed a synkinesis of perioral muscles with blinking and thus provided a serendipitous model for a multiphasic analysis of this common neurologic syndrome. The amplitude of the paretic eyelid in spontaneous and air-puff-induced blinks was about one-third that of the normal eyelid. Despite the blink hypometria, induced blink durations remained matched for the two lids. EMG confirmed co-contraction of the zygomaticus and orbicularis oculi muscles on the affected side during blinking, with silence of the zygomaticus on the normal side. Neuroanatomic investigation showed that, on the affected side, some zygomaticus motoneurons were in the somatotopically correct nuclear subdivisions but that the majority were in the dorsal subdivision, which normally innervates the orbicularis oculi. This study supports the contention that some orbicularis oculi motoneurons are incorrectly rerouted to supply the perioral musculature following recovery from a peripheral seventh-nerve injury. This same pattern of relative weakness in eyelid muscles and the stereotyped co-contraction of lid and perioral muscles with blinking occurs in humans, suggesting that aberrant reinnervation may be the mechanism for this clinical phenomenon.
The "terminal' Schwann cells that sit atop the neuromuscular junction sense neuromuscular transmission and respond to perturbations of this transmission by extending long processes. These processes have the ability to induce nerve growth and serve as substrates to guide this growth. These processes thus play major roles in muscle reinnervation and in sprouting. An absence of nerve sprouting is correlated with the apoptotic death of terminal Schwann cells at denervated endplates in neonatal muscles. Thus, Schwann cells appear to participate actively in the maintenance and repair of neuromuscular synapses.
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.
The calcium flow inhibitor, nimodipine, has been shown to promote motor neuron survival in the facial nucleus after intracranial facial nerve transection. However, it has not been known whether the neuroprotective effects primarily involve survival of nerve cell bodies or outgrowth and/or myelination of nerve fibers. Here, we studied the effects of nimodipine in a different injury model in which the facial nerve was unilaterally crushed intracranially. This lesion caused complete anterograde degeneration and partial retrograde degeneration that were studied with a combination of several stereological methods. Nimodipine did not attenuate the modest lesion-induced neuronal loss (13%) but accelerated the time course of functional recovery and axonal regrowth, inducing increased numbers and sizes of myelinated axons in the facial nerve. It is interesting to note that nimodipine also enlarged the axons and the myelin sheaths in the nonlesioned facial nerve, which points to the possibility of using this substance for new clinical applications to promote axonal growth and remyelination.
A major reason for the insufficient recovery of function after motor nerve injury are the numerous axonal branches which often re-innervate muscles with completely different functions. We hypothesized that a neutralization of diffusable neurotrophic factors at the lesion site in rats could reduce the branching of transected axons. Following analysis of local protein expression by immunocytochemistry and by in situ hybridization, we transected the facial nerve trunk of adult rats and inserted both ends into a silicon tube containing (i) collagen gel with neutralizing concentrations of antibodies to NGF, BDNF, bFGF, IGF-I, CNTF and GDNF; (ii) five-fold higher concentrations of the antibodies and (iii) combination of antibodies. Two months later, retrograde labelling was used to estimate the portion of motoneurons the axons of which had branched and projected into three major branches of the facial trunk. After control entubulation in collagen gel containing non-immune mouse IgG 85% of all motoneurons projecting along the zygomatic branch sprouted and sent at least one twin axon to the buccal and/or marginal-mandibular branches of the facial nerve. Neutralizing concentrations of anti-NGF, anti-BDNF and anti-IGF-I significantly reduced sprouting. The most pronounced effect was achieved after application of anti-BDNF, which reduced the portion of branched neurons to 18%. All effects after a single application of antibodies were concentration-dependent and superior to those observed after combined treatment. This first report on improved quality of reinnervation by antibody-therapy implies that, in rats, the post-transectional collateral axonal branching can be reduced without obvious harmful effects on neuronal survival and axonal elongation.