Treatment With Nimodipine or FK506 After Facial Nerve Repair Neither Improves Accuracy of Reinnervation Nor Recovery of Mimetic Function in Rats.

Purpose: Nimodipine and FK506 (Tacrolimus) are drugs that have been reported to accelerate peripheral nerve regeneration. We therefore tested these substances aiming to improve the final functional outcome of motoric reinnervation after facial nerve injury. Methods: In 18 female rats, the transected facial nerve was repaired by an artificial nerve conduit. The rats were then treated with either placebo, nimodipine, or FK506, for 56 days. Facial motoneurons were pre-operatively double-labeled by Fluoro-Gold and again 56 days post-operation by Fast-Blue to measure the cytological accuracy of reinnervation. The whisking motion of the vibrissae was analyzed to assess the quality of functional recovery. Results: On the non-operated side, 93-97% of those facial nerve motoneurons innervating the vibrissae were double-labeled. On the operated side, double-labeling only amounted to 38% (placebo), 40% (nimodipine), and 39% (FK506), indicating severe misdirection of reinnervation. Regardless of post-operative drug or placebo therapy, the whisking frequency reached 83-100% of the normal value (6.0 Hz), but whisking amplitude was reduced to 33-48% while whisking velocity reached 39-66% of the normal values. Compared to placebo, statistically neither nimodipine nor FK506 improved accuracy of reinnervation and function recovery. Conclusion: Despite previous, positive data on the speed and quantity of axonal regeneration, nimodipine and FK506 do not improve the final functional outcome of motoric reinnervation in rats.

Traumatic luxation of the nose in a newborn: case report and review of the literature.

During delivery the delicate structures of the face are predominantly exposed to external force effects and hence deformities on the nose can emerge as a birth-related trauma in newborns. As self-straightening of the nasal septum commonly occurs, a conservative therapy is recommended for most cases. We report on a case where a birth-related trauma of the nose leaded to acute breathing problems in a newborn with insufficient oxygenation. An overview about the available literature is given. A cautious reposition of the nose proved to be an appropriate management for short- and long-term development.

Manual stimulation of the suprahyoid-sublingual region diminishes polynnervation of the motor endplates and improves recovery of function after hypoglossal nerve injury in rats.

BACKGROUND: Using the rat facial nerve axotomy model, the authors recently showed that manual stimulation of denervated whiskerpad muscles reduced the posttransectional polyinnervation at the neuromuscular junctions and promoted full recovery of vibrissal whisking. OBJECTIVE: Prompted by implications for rehabilitation therapy, the authors examined whether manual stimulation of denervated supra- and infrahyoid muscles would also improve recovery after unilateral lesion on the hypoglossal nerve. METHODS: Adult rats underwent transection of the right hypoglossal nerve. Half of the animals received no postoperative treatment, and the other half were subjected to daily manual stimulation of the suprahyoid/sublingual region for 2 months. Recovery was assessed by measuring the angle of tongue-tip deviation from the midline, degree of collateral axonal branching at the lesion site (counts after retrograde labeling with 2 fluorescent dyes), synaptic input to the hypoglossal motoneurons using synaptophysin immunocytochemistry, tongue-muscles motor representation in the cerebral cortex after c-Fos immunocytochemistry, and portion of polyinnervated neuromuscular junctions. RESULTS: In animals receiving manual stimulation, the tongue-tip deviation was 37.0 +/- 49.37 degrees , whereas values in control nonstimulated rats were significantly higher (50.1 +/- 9.01 degrees ; P < .05; mean +/- SD). Improved recovery was not associated with reduced collateral axonal branching; there were also no differences in tongue-muscles representation in the motor cortex. However, manual stimulation restored the total synaptic input to levels in intact animals and reduced the proportion of polyinnervated neuromuscular junctions compared with nonstimulated animals. CONCLUSION: The data show that manual stimulation of denervated muscles improves functional outcome following peripheral nerve injury. This suggests immediate potential for enhancing clinical rehabilitation strategies.

Quality of life after facial nerve repair.

OBJECTIVES: Analyze the postoperative quality of life (QoL) in patients after surgical nerve repair for facial nerve lesion. STUDY DESIGN: Descriptive study using questionnaire data and medical chart review. METHODS: Forty-nine patients answered the Short Form-36 (SF-36), the European Organization for Research and Treatment (EORTC) questionnaires QLQ-C30 and QLQ-HN35, and a modification of the Acoustic Neuroma Hospital of Norway Survey. Facial function was self-evaluated by the patients using the House-Brackmann (HB) scale and the Stennert index (SI). The questionnaire data were analyzed in relation to the medical chart data. RESULTS: The follow-up time ranged from 12 to 202 months. The underlying disease was benign in 34 (61%) patients and malignant in 15 (39%) patients. Facial nerve repair was successful in all patients, with a mean HB scale of 3.1, a mean SI of 4.9, and a mean May grading of 2.7. The facial function self-evaluation was not significantly different. Seventy-five percent of the patients were satisfied with the operation. The SF-36 demonstrated a significantly lower social functioning, emotional role, general mental health, and vitality lower than in the normal German population. In the EORTC QLQ C30, emotional function was low and the insomnia rate high. EORTC QLQ HN35 showed a high rate of trouble with social eating, less sexuality, problems opening mouth, and weight gain problems. Age 45 years or older, female sex, May grading 3 or greater, SI self-assessment 5 or greater, HB self-assessment greater than 2 had a significant negative effect on some QoL items, but not factors such as type or histology of the disease or delayed reconstruction. CONCLUSIONS: Although grading of facial function after nerve repair revealed satisfying results, the patients experience a reduced QoL.

Postoperative functional evaluation of different reanimation techniques for facial nerve repair.

BACKGROUND: The facial nerve function after facial-facial nerve anastomosis, grafting, hypoglossal-facial nerve anastomosis, hypoglossal-facial interpositional jump nerve anastomosis, or a combined approach was analyzed. METHODS: Facial function was assessed after operation using a 7-point visual analog scale (VAS) and by electromyography (EMG) in 53 patients. The final result was judged by May's facial nerve grading system. RESULTS: Voluntary EMG activity occurred on average 4.52 +/- 1.31 months after operation. Initial facial movements were visible after 5.41 +/- 1.80 months. Facial function related to the VAS finally reached 44% of normal value. The result was judged May's grade I in 13%, grade II in 34%, grade III in 28%, and grade IV in 25% of patients. A significant difference in outcome between different reconstruction types was not seen. Age over 60 years was related to worse outcome. CONCLUSIONS: A correct selection of the best method in the individual situation presumed, all analyzed facial reanimation techniques seem to lead nearly similar and satisfactory results.

Lymphatic malformations of the head and neck: introduction of a disease score for children, Cologne Disease Score (CDS).

OBJECTIVE: A clinical staging system for children with lymphatic malformations that would allow for a standardized comparison of disease and treatment outcomes. METHODS: We developed an examination sheet for the determination of a disease score ranging from 0 (worst) points to 10 (best) points, Cologne Disease Score (CDS). Disfigurement, dysphagia, dysphonia, dyspnea and an observer statement towards progression were contributing to CDS. Each parameter yielded two, one or zero points. Two points were given when no limitation was seen in the patient concerning the respective item. One point was given at mild limitation and zero points were given when considerable limitation in the respective item could be observed. We evaluated 26 patients with lymphatic malformations of the head and neck retrospectively by completing one examination sheet for each patient-visit. RESULTS: Four patients had an initial CDS value of three or less points (severe disease-group). After therapy the mean value of their score increased only slightly to 3.9+/-2.6 points. Six patients had an initial CDS value of four, five or six points (advanced disease-group). After treatment their mean score value increased dramatically to 9.0+/-1.5 points (P<0.001). Sixteen patients initially had seven points or higher (moderate disease-group), they had 9.8+/-0.4 points after treatment. CONCLUSIONS: The evaluation of the CDS was easy and expeditious. The score itself was a good predictor in view of the outcome. This new disease score for paediatric patients might be appropriate to evaluate therapeutic trials in paediatric patients.

Transplantation of olfactory mucosa minimizes axonal branching and promotes the recovery of vibrissae motor performance after facial nerve repair in rats.

The occurrence of abnormally associated movements is inevitable after facial nerve transection. The reason for this post-paralytic syndrome is poor guidance of regrowing axons, whereby a given muscle group is reinnervated by misrouted axonal branches. Olfactory ensheathing glia have been shown to reduce axonal sprouting and stimulate axonal regeneration after transplantation into the spinal cord. In the present study, we asked whether transplantation of olfactory mucosa (OM) would also reduce sprouting of a damaged peripheral pure motor nerve. The adult facial nerve was transected, and the effect of the OM placed at the lesion site was analyzed with regard to the accuracy of target reinnervation, axonal sprouting of motoneurons, and vibrissal motor performance. Accuracy of target reinnervation and axonal sprouting were studied using preoperative/postoperative labeling and triple retrograde labeling of facial motoneurons, respectively. The vibrissal motor performance was monitored using a video-based motion analysis. We show here that implantation of OM, compared with simple facial-facial anastomosis, (1) improved the protraction, amplitude, angular velocity, and acceleration of vibrissal movements up to 80% of the control values, (2) reduced the percentage of branching motoneurons from 76 to 39%, and (3) improved the accuracy of reinnervation from 22 to 49%. Moreover, we present evidence, that transplanted OM but not buccal mucous membrane induced a sustained upregulation of trophic factors at the lesion site. It is concluded that transplantation of OM to the transected facial nerve significantly improves nerve regeneration.

Increased expression of ICAM-1, VCAM-1, MCP-1, and MIP-1 alpha by spinal perivascular macrophages during experimental allergic encephalomyelitis in rats.

BACKGROUND: T-cells extravasation and CNS parenchyma infiltration during autoimmune neurodegenerative disease can be evoked by local antigen presenting cells. Studying the chemoattracting potential of spinal perivascular macrophages (SPM) during experimental allergic encephalomyelitis (EAE), we observed numerous infiltrates of densely-packed mononuclear cells. Apart from the poor spatial and optical resolution, no differentiation between the resident SPM (mabs ED1+, ED2+) and the just recruited monocytes/macrophages (mab ED1+) was possible. RESULTS: This is why we labeled SPM by injections of different fluoresecent dyes into the lateral cerebral ventricle before induction of active EAE. Within an additional experimental set EAE was induced by an intraperitoneal injection of T-cells specifically sensitized to myelin basic protein (MBP) and engineered to express the green fluorescent protein (GFP). In both experiments we observed a strong activation of SPM (mabs OX6+, SILK6+, CD40+, CD80+, CD86+) which was accompanied by a consistently increased expression of ICAM-1, VCAM-1, and the chemokines MCP-1 and MIP-1alpha. CONCLUSION: These observations indicate that SPM play a role in promoting lymphocyte extravasation.

Altered sensory input improves the accuracy of muscle reinnervation.

PURPOSE: To improve functional recovery after peripheral nerve suture, we characterized the quality of target reinnervation in rats in which the afferent trigeminal connection to facial motoneurons had been altered. METHODS: Employing an improved lesion model and a refined mode of retrograde tracer application, we studied the accuracy of reinnervation in rats which underwent buccal-buccal nerve anastomosis (BBA) alone (group 1), BBA plus excision of the ipsilateral infraorbital nerve (ION; group 2), and BBA plus excision of the contralateral ION (group 3). This was done by comparison between the number of double-labeled motoneurons after pre-operative injection of Fluoro-Gold (FG) and post-operative injection of Fast Blue (FB) into the whisker pad muscles. RESULTS: In the first group we counted 398 +/- 80 FG+FB double labeled cells (mean +/- SD; n = 9 rats), i.e., only 27% of all motoneurons that grew axons into the whisker pad had projected to these muscles before surgery. In group 2, this value was increased marginally to 436 +/- 68 (32%). In group 3,. we counted 580 +/- 63 double-labeled neurons. This is the first morphological report demonstrating significantly improved specificity of reinnervation. Indeed, 41% of the motoneurons innervating the target in group 3 belonged to the original neuron pool. These morphological findings are supported by evidence obtained from electrophysiological recordings and behavioural studies. CONCLUSIONS: The principle finding of the present study is that a peripheral lesion to the contralateral trigeminal nerve improves the quality of reinnervation of the whisker pad musculature by its original nerve. The contralateral trigeminal lesion may trigger behavioural demand and forced overuse of the axotomized facial nerve, which may be a key issue for recovery of vibrissae rhythmical whisking after facial nerve surgery.

Rupture of the larynx in a newborn.

BACKGROUND: Lesions of the laryngotrachea due to repeated intubation trauma after birth are reported. CASE: A macrosomic neonate was born at term after uneventful pregnancy. On the basis of diminished uterine contractions and arrest of descent, the head was delivered by using obstetric forceps. No intubation was attempted after birth. Ten hours later, the infant developed acute life-threatening respiratory distress and subcutaneous emphysema. Intubation was impossible. Open surgical exploration of the neck revealed a rupture of the cricothyroid ligament within the larynx. The defect was closed immediately, and after artificial ventilation for 7 days, the infant was extubated. One year later, the child is developing satisfactorily, without stridor or hoarseness. CONCLUSION: In macrosomic neonates after traumatic delivery, a laryngotracheal lesion should be considered when respiratory distress syndrome combined with subcutaneous emphysema occurs.

Bezold's abscess following chronic mastoiditis in a newborn.

Despite the availability of antibiotics, acute otitis media can still lead to major complications. Bezold's abscesses are very rare complications and are usually found only in adults with well-pneumatized mastoid bones. We present the case of a 10-week-old newborn with a Bezold's abscess. It is stressed that acute otitis media can be silent and undetected in infants and can lead to major complications such as Bezold's abscess.

Reconstruction of complex peripheral facial nerve defects by a combined approach using facial nerve interpositional graft and hypoglossal-facial jump nerve suture.

OBJECTIVES/HYPOTHESIS: To describe a modified facial nerve reconstruction technique for complex defects of the facial fan after parotid surgery that avoids synkinesis between upper and lower face. STUDY DESIGN: Retrospective case series. METHODS: Patients who had undergone radical parotidectomy with a large defect of the facial fan, reconstruction of the upper face by facial nerve interpositional graft, and reconstruction of the lower face by hypoglossal-facial nerve jump nerve suture were included in this series. RESULTS: Four patients underwent the modified combined approach after tumor resection and prior to postoperative radiotherapy in three of the four cases. Surgery was combined with an upper lid weight implantation. Regeneration of the face was successful in all cases within 12 to 16 months. Most important, the separated reanimation of the upper and lower face circumvented synkinesis of the upper and lower face. This factor was essential for good functional results. Using the hypoglossal jump technique instead of a classical cross-nerve suture technique prevented the sacrifice of ipsilateral tongue function. CONCLUSIONS: The presented method offers satisfactory results for facial reanimation and avoids synkinesis between the upper and lower face. Using the jump technique instead of a classic hypoglossal transfer as it was described originally for the combined approach avoids long-term sequelae for the tongue.

Local stabilization of microtubule assembly improves recovery of facial nerve function after repair.

Within a recent study on the recovery of vibrissae motor performance after facial nerve repair in blind (strain SD/RCS) and sighted (strain SD) rats, we found that, despite persisting myotopic disorganization in the facial nucleus, the blind animals fully restored vibrissal whisking. Searching for the morphological substrates of this improved recovery, we compared the amount of cytoskeletal proteins in the leading edge of elongating axons between both strains. Since our results showed an enhanced expression of neuronal class III beta-tubulin in the blind rats, we wondered whether this was due to an increased synthesis or to a delayed turnover of microtubules. In the present report, we approached this question applying established pharmacological agents to the transected buccal branch of the facial nerve in sighted Wistar rats perturbing either microtubule assembly towards stabilization (enhanced polymerization with 10 microg/ml taxol) or towards increased synthesis (challenged by destabilization with 100 microg/ml nocodazole and 20 microg/ml vinblastine). Evaluation of the effect(s) 2 months later included estimation of (i) vibrissae motor performance by video-based motion analysis, (ii) the degree of collateral axonal branching by double retrograde neuronal labeling with crystals of Fluoro-Gold and DiI and (iii) the pattern of motor end-plate reinnervation (proportions of mono- and poly-reinnervated) in the largest extrinsic vibrissal muscle, the m. levator labii superioris. We found that only stabilization of microtubules with 10 microg/ml taxol reduced intramuscular axonal sprouting and polyinnervation of the motor end-plates, which was accompanied by improved restoration of function.

Manually-stimulated recovery of motor function after facial nerve injury requires intact sensory input.

We have recently shown in rat that daily manual stimulation (MS) of vibrissal muscles promotes recovery of whisking and reduces polyinnervation of muscle fibers following repair of the facial nerve (facial-facial anastomosis, FFA). Here, we examined whether these positive effects were: (1) correlated with alterations of the afferent connections of regenerated facial motoneurons, and (2) whether they were achieved by enhanced sensory input through the intact trigeminal nerve. First, we quantified the extent of total synaptic input to motoneurons in the facial nucleus using synaptophysin immunocytochemistry following FFA with and without subsequent MS. We found that, without MS, this input was reduced compared to intact animals. The number of synaptophysin-positive terminals returned to normal values following MS. Thus, MS appears to counteract the deafferentation of regenerated facial motoneurons. Second, we performed FFA and, in addition, eliminated the trigeminal sensory input to facial motoneurons by extirpation of the ipsilateral infraorbital nerve (IONex). In this paradigm, without MS, vibrissal motor performance and pattern of end-plate reinnervation were as aberrant as after FFA without MS. MS did not influence the reinnervation pattern after IONex and functional recovery was even worse than after IONex without MS. Thus, when the sensory system is intact, MS restores normal vibrissal function and reduces the degree of polyinnervation. When afferent inputs are abolished, these effects are eliminated or even reversed. We conclude that rehabilitation strategies must be carefully designed to take into account the extent of motor and/or sensory damage.

Bone marrow-derived mesenchymal stem cell transplantation does not improve quality of muscle reinnervation or recovery of motor function after facial nerve transection in rats.

Recently, we devised and validated a novel strategy in rats to improve the outcome of facial nerve reconstruction by daily manual stimulation of the target muscles. The treatment resulted in full recovery of facial movements (whisking), which was achieved by reducing the proportion of pathologically polyinnervated motor endplates. Here, we posed whether manual stimulation could also be beneficial after a surgical procedure potentially useful for treatment of large peripheral nerve defects, i.e., entubulation of the transected facial nerve in a conduit filled with suspension of isogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) in collagen. Compared to control treatment with collagen only, entubulation with BM-MSCs failed to decrease the extent of collateral axonal branching at the lesion site and did not improve functional recovery. Post-operative manual stimulation of vibrissal muscles also failed to promote a better recovery following entubulation with BM-MSCs. We suggest that BM-MSCs promote excessive trophic support for regenerating axons which, in turn, results in excessive collateral branching at the lesion site and extensive polyinnervation of the motor endplates. Furthermore, such deleterious effects cannot be overridden by manual stimulation. We conclude that entubulation with BM-MSCs is not beneficial for facial nerve repair.

Manual stimulation of facial muscles improves functional recovery after hypoglossal-facial anastomosis and interpositional nerve grafting of the facial nerve in adult rats.

The facial nerve in humans is often prone to injuries requiring surgical intervention. In the best case, nerve reconstruction is achieved by a facial-facial anastomosis (FFA), i.e. suture of the proximal and distal stumps of the severed facial nerve. Although a method of choice, FFA rarely leads to a satisfactory functional recovery. We have recently devised and validated, in an established experimental paradigm in rats, a novel strategy to improve the outcome of FFA by daily manual stimulation (MS) of facial muscles. This treatment results in full recovery of facial movements (whisking) and is achieved by reducing the proportion of functionally detrimental poly-innervated motor end-plates. Here we asked whether MS could also be beneficial after two other commonly used surgical methods of clinical facial nerve reconstruction namely hypoglossal-facial anastomosis (HFA) and interpositional nerve grafting (IPNG) which, however, seem to have a poorer outcome compared to FFA. Compared to FFA, daily MS for 2 months after HFA and IPGN did not completely restore function but, nevertheless, significantly improved the amplitude of whisker movements by 50% compared with untreated animals. Functional improvement was associated with a reduction in the proportion of polyinnervated end-plates. MS did not reduce the extent of axonal branching at the lesion site nor the subsequent misdirected axonal regrowth to inappropriate targets. Our data show that a simple approach leading to improved quality of muscle fiber reinnervation is functionally beneficial after different types of clinically relevant surgical interventions.

Mechanical stimulation of paralyzed vibrissal muscles following facial nerve injury in adult rat promotes full recovery of whisking.

Many patients suffer lifelong disabilities after peripheral nerve injury. Insufficient recovery has been attributed to excessive axonal branching, axonal regrowth to improper targets and polyneuronal reinnervation of motor endplates. We used the rat facial nerve transection/suture model to quantify the effects of mechanical stimulation on the paralyzed whisker musculature. "Manual" stimulation involved briskly stroking the whiskers by hand in a manner that specifically mimicked normal whisker movement. "Environmental" stimulation involved enhanced whisker use as rats encountered objects in an enriched environment. Manual and environmental stimulation were also combined. Video-based motion analysis of vibrissal motor performance showed that daily manual, but not environmental, stimulation for 2 months resulted in full recovery of whisking. Polyneuronal reinnervation of motor endplates was reduced but not misdirected axonal regrowth. Our findings indicate the potential of use-specific training to enhance appropriate functional outcome after peripheral nerve injury and may be useful in a clinical rehabilitation setting.

The axotomy-induced neuropeptides galanin and pituitary adenylate cyclase-activating peptide promote axonal sprouting of primary afferent and cranial motor neurones.

The neuropeptides galanin and pituitary adenylate cyclase-activating peptide (PACAP) are markedly up-regulated in response to peripheral nerve lesion. Both peptides are involved in neuronal differentiation and neurite outgrowth during development. In this study, we investigated the effects of galanin and PACAP on axonal elongation and sprouting by adult rat sensory neurones in vitro and facial motor neurones in vivo. Dissociated rat dorsal root ganglion neurones were plated on laminin substrate and analysed morphometrically. Both the mean axonal length and the number of branch points significantly increased in the presence of galanin or PACAP (2-5 microm). Effects on axonal collateralization were investigated in the rat facial nerve lesion model by direct application of the peptides to collagen-filled conduits entubulating the transected facial nerve stumps. Triple retrograde labelling of brainstem neurones confirmed that the peptides potently induce axonal sprouting of cranial motor neurones. The number of neurones regenerating into identified rami of the facial nerve increased up to fivefold. Biometrical analysis of whisking behaviour revealed that galanin and PACAP impaired the functional outcome when compared with vehicle-treated animals 8 weeks after surgery. In conclusion, although galanin and PACAP have been established as neurotrophic molecules with respect to axonal development and regeneration, their potential as treatments for peripheral nerve lesions appears limited because of the extensive stimulation of collateral axon branching. These branches are misrouted towards incorrect muscles and cause impairment in their coordinated activity.

Improved outcome of facial nerve repair in rats is associated with enhanced regenerative response of motoneurons and augmented neocortical plasticity.

Within a recent study on the vibrissae motor performance after facial nerve repair in strains of blind (SD/RCS) and sighted (SD) rats we found that, despite persisting myotopic disorganization in the facial nucleus, the blind animals fully restored vibrissal whisking. Here we searched for morphological substrates of better recovery in the regenerating motoneurons and in the cerebral motor cortex. Expression analyses of the neurite growth-related proteins f-actin, neuronal class III beta-tubulin and plasticity-related gene-1, and stereological estimates of growth cone densities revealed a more vigorous regenerative response in the proximal nerve stump of blind SD/RCS rats compared with SD animals at 5-7 days after buccal nerve transection. Using c-Fos immunoreactivity as a marker for neuronal activation, we found that the volume of the cortex acutely responding to nerve transection (facial muscles reactive volume, FMRV) in both hemispheres of intact sighted rats was twofold smaller than that measured in blind animals. One month after transection and suture of the right facial nerve (FFA) we found a twofold increase in the FMRV in both rat strains compared with intact animals. The FMRV in SD/RCS animals, but not in SD rats, returned to the values in intact rats 2 months after FFA. Our findings suggest that enhanced plasticity in the CNS and an augmented regenerative response of the injured motoneurons contribute to better functional recovery in blind rats.