Spatial functional reorganizations can serve as potential biomarkers of post facial palsy synkinesis.

Facial palsy can result in a serious complication known as facial synkinesis, causing both physical and psychological harm to the patients. There is growing evidence that patients with facial synkinesis have brain abnormalities, but the brain mechanisms and underlying imaging biomarkers remain unclear. Here, we employed functional magnetic resonance imaging (fMRI) to investigate brain function in 31 unilateral post facial palsy synkinesis patients and 25 healthy controls during different facial expression movements and at rest. Combining surface-based mass-univariate analysis and multivariate pattern analysis, we identified diffused activation and intrinsic connection patterns in the primary motor cortex and the somatosensory cortex on the patient's affected side. Further, we classified post facial palsy synkinesis patients from healthy subjects with favorable accuracy using the support vector machine based on both task-related and resting-state functional magnetic resonance imaging data. Together, these findings indicate the potential of the identified functional reorganizations to serve as neuroimaging biomarkers for facial synkinesis diagnosis.

Prognostic value of electroneurography using the midline method for predicting the development of synkinesis after peripheral facial palsy.

OBJECTIVE: The prognostic value of electroneurography (ENoG) for predicting the incidence of synkinesis is reportedly about 40 % using the formal standard method (ENoG-SM). However, the prognostic value of ENoG using the newly developed midline method (ENoG-MM) has not been determined. The aim of this study was to demonstrate the optimal prognostic value and advantages of ENoG-MM for predicting the incidence of synkinesis. METHODS: Participants were 573 patients treated for peripheral facial palsy including Bell's palsy or Ramsay Hunt syndrome. We investigated the clinical presence of any oral-ocular or ocular-oral synkinesis from the medical records. ENoG-MM and ENoG-SM were performed 10-14 days after symptom onset. In ENoG-MM, compound muscle action potentials were recorded by placing the anode on the mental protuberance and the cathode on the philtrum. In ENoG-SM, electrodes were placed on the nasolabial fold. Synkinesis was clinically assessed at the end of follow-up or at >1 year after onset. The sensitivity and specificity of ENoG values for predicting the incidence of synkinesis were compared between ENoG-MM and ENoG-SM at every 5 % around 40 % (range, 30-50 %). RESULTS: At every 5 % of ENoG values around 40 %, ENoG-MM provided higher sensitivity and lower specificity for predicting the incidence of synkinesis compared with ENoG-SM. In particular, when the cut-off value was set at 45 %, sensitivity was 100 % and 95.3 % with ENoG-MM and ENoG-SM, respectively. CONCLUSION: In peripheral facial palsy, ENoG-MM offered higher sensitivity than ENoG-SM for predicting synkinesis. ENoG-MM is useful for screening patients at risk of developing synkinesis. In clinical practice, an ENoG-MM cut-off value of 45 % must be the optimal prognostic value because of the 100 % sensitivity.

Long-term stable efficacy of botulinum toxin A in facial movement disorders with no need for increasing dose.

ABSTRACT: Botulinum toxin A is considered an effective treatment for involuntary facial movements. We examined whether treatment efficacy maintained or changed over time with two products, Botox and Dysport, in patients with hemifacial spasm, facial synkinesis and benign essential blepharospasm.We retrospectively investigated 87 consecutive patients (51 women, 36 men) who had undergone treatment for ≥6 years. Long-term effects, as well as side effects of Botox or Dysport local injections were evaluated. The first three treatments were considered the titration period and not taken into account when testing for dose changes.Mean treatment duration was 10 years (range 6-11, SD 1.0), 2441 treatments were administered, 1162 with Botox and 1279 with Dysport, the two brands were interchanged as needed. Good to full improvement was seen in 90% of patients both with both brands. Injection doses and treatment responses were consistent during the study with both drugs. No major side effects were reported, and relatively few minor adverse events were reported, with clear reduction from the titration period (6.1%), to the remainder of the study (3.9%).Botulinum toxin (BTX-A) is a satisfactory long-term treatment without need for dose increase over. Both Botox and Dysport were effective when used interchangeably.

Long-term therapy with botulinum toxin in facial synkinesis: Retrospective data analysis of data from 1998 to 2018.

OBJECTIVES: Treatment with botulinum toxin A (BoNT) is the therapy of choice for many patients with facial synkinesis. Repeated injections relieve hypertonicity and hyperkinesis of reinnervated mimic muscles. Aim of the study was to prove if the injection regime and dosage of BoNT change during long-time therapy. DESIGN: Retrospective analysis of patients´ data, who were treated for synkinesis with BoNT from 1998 to 2018. SETTING: Tertiary referral facial nerve centre. PARTICIPANTS: Injection pattern of BoNT was based on clinical symptoms, observations of the specialist and on previous treatment pattern. Onabotulinumtoxin (OnaBoNT), Incobotulinumtoxin (IncoBoNT) and Abobotulinumtoxin (AboBoNT) were available for treatment. Patients consulted our department for following treatment as soon as the symptoms re-occurred. MAIN OUTCOME MEASURES: Change in dosage and injection pattern, the time intervals between treatments over the entire therapy period. RESULTS: Seventy-three patients were repeatedly injected. The median number of treatments was 18, the median treatment interval was 3.0 months. During the initial treatment, orbicularis oculi and the mentalis muscles were the most frequently injected muscles (94%). During repeated treatment, the number of injected muscles increased significantly (P < .0001), whereas the dose per muscle remained stable. The initial dose was 24 U (95%-CI 22-27 U) for OnaBoNT and IncoBoNT; 69 U for AboBoNT(95%-CI 44-94 U). We observed a significant increase in dosage for OnaBoNT and IncoBoNT (P < .0001) during the long-term therapy. The time intervals between treatments were stable for all three BoNT preparations (P > .05). CONCLUSIONS: We observed significant change in treatment dose and injection pattern of BoNT in patients with facial synkinesis. These results provide an orientation in dose finding and injection regimen of BoNT in the long-term course of therapy.

Crumley's Classification of Laryngeal Synkinesis: A Comparison of Laryngoscopy and Electromyography.

OBJECTIVES/HYPOTHESIS: Applying the principles of misdirected nerve regeneration to the larynx, Roger Crumley in 1989 coined the term laryngeal synkinesis (LS) which he later (2000) classified into 4 types (type I - good voice, type II - involuntary twitches and poor voice, type III - adduction during inspiration, type IV - abduction during phonation). Neurophysiological data were not available for all LS patients at that time. The current study was undertaken to utilize and test the Crumley classification for a clinical interrater comparison and, secondly, compare predicted with actual laryngeal electromyography (LEMG) results. STUDY DESIGN: Descriptive study. METHODS: Laryngoscopic and LEMG data of patients with unilateral vocal fold paralysis (VFP) of 6 months duration or longer were combined for retrospective evaluation. Forty-five data sets were available for laryngoscopic classification by two local laryngologists and by Roger Crumley. Twenty-three data sets with complete thyroarytenoid (TA) and posterior cricoarytenoid (PCA) - EMG data were used to compare predicted with actual LEMG results. RESULTS: Local laryngologists were able to classify 24 of 45, Crumley 30 of 45 cases into one of the 4 synkinesis types. There was substantial agreement between examiners (Cohens Kappa 0.66 [P < .001]). Comparison of predicted and actual LEMG data showed only moderate agreement. EMG sykinesis rates were lower in TA than in PCA and highest in Crumley type I cases. CONCLUSION: The Crumley classification is helpful in describing and understanding synkinesis. It does not always correlate predictably with actual LEMG data. A complete LEMG mapping of all intrinsic muscles may improve understanding of chronic VFP. LEVEL OF EVIDENCE: 4. Laryngoscope, 131:E1605-E1610, 2021.

Buccinator synkinesis treated by botulinum toxin in facial palsy and hemifacial spasms.

OBJECTIVE: To assess botulinum toxin treatment for buccinator muscle synkinesis including: how often the synkinesis was troublesome; who benefitted and how from the treatment; and what were the adverse effects, ideal dosage, and injection site. SUBJECTS AND METHODS: Facial palsy (FP) patients and patients with hemifacial spasms who were attending for multiple site botulinum-toxin treatment for facial sequelae were assessed for buccinator synkinesis. The study group comprises those experiencing buccinator synkinesis with associated bothering symptoms who were willing to try injection also to the buccinator muscle. RESULTS: During 9/2017-12/2019, 126 different patients with facial sequelae were treated with multiple-site botulin-toxin injections by the author. Of them, 83 (66%) received injection also for buccinator synkinesis and 66/82 (80%) wanted to continue with the buccinator injections. The most remarkable results were seen with FP patients biting the mucus membrane of their cheek: usually the biting ceased totally. Patients with powerful hemifacial cheek spasms also experienced cessation of the spasms, contrasting any previous treatments. Adverse effects were mostly mild: slight weakness of the corner of the mouth or additional leakage of saliva or liquids. Only a few patients experienced more pronounced adverse effects. The most posterior contracting part of the buccinator muscle proved to be the best site for the injection. CONCLUSIONS: Buccinator synkinesis was very common and its treatment gave many patients additional relief from facial sequelae symptoms. Professionals treating patients with synkinesis and hemifacial spasms should add well-tolerated buccinator injections to their repertoire of injection sites.

Abnormal Laryngeal Electromyography Findings in Asymptomatic Adults Across the Age Spectrum.

OBJECTIVES/HYPOTHESIS: Laryngeal electromyography (LEMG) is a diagnostic tool for patients with suspected neurogenic abnormalities of the larynx. LEMG is often used with the assumption that any abnormality is symptom-/disease-related. We sought to determine the prevalence of abnormal LEMG findings in a group of healthy asymptomatic adults across a large age spectrum. STUDY DESIGN: Open, prospective study, gender-match and age balanced by decade. METHODS: Forty-six healthy participants (age 20-78) underwent LEMG, including 178 muscles. Participants had no history of voice problems, normal VHI-10, and normal flexible laryngoscopy. Qualitative and quantitative LEMG (bilateral) were performed involving the thyroarytenoid-lateral cricoarytenoid muscle complex (TA-LCA) and cricothyroid (CT) muscles. LEMG parameters included evaluation for fibrillation potentials, sharp waves, reduced recruitment, polyphasic potentials, electrical synkinesis, and measurement of turns per second. RESULTS: Of participants, 4% had at least one abnormal qualitative finding (slightly reduced recruitment or two to three discrete polyphasic potentials). There were no findings of fibrillation potentials or sharp waves. There were no abnormal qualitative findings in the CT muscles tested. Of participants, 16% had at least one abnormal synkinesis finding. LEMG qualitative abnormalities and quantitative abnormalities do not appear to correlate with gender or age. CONCLUSION: Abnormal qualitative and quantitative LEMG findings were uncommon and minor in severity in our group of asymptomatic healthy adults. The likelihood of abnormal LEMG results in asymptomatic adults was 2.2% for qualitative findings, 9.3% for synkinesis, and 5.4% for turns/s. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:2065-2069, 2021.

Syngeneic Transplantation of Rat Olfactory Stem Cells in a Vein Conduit Improves Facial Movements and Reduces Synkinesis after Facial Nerve Injury.

BACKGROUND: Posttraumatic facial paralysis is a disabling condition. Current surgical management by faciofacial nerve suture provides limited recovery. To improve the outcome, the authors evaluated an add-on strategy based on a syngeneic transplantation of nasal olfactory stem cells in a rat model of facial nerve injury. The main readouts of the study were the recording of whisking function and buccal synkinesis. METHODS: Sixty rats were allocated to three groups. Animals with a 2-mm facial nerve loss were repaired with a femoral vein, filled or not with olfactory stem cells. These two groups were compared to similarly injured rats but with a faciofacial nerve suture. Olfactory stem cells were purified from rat olfactory mucosa. Three months after surgery, facial motor performance was evaluated using video-based motion analysis and electromyography. Synkinesis was assessed by electromyography, using measure of buccal involuntary movements during blink reflex, and double retrograde labeling of regenerating motoneurons. RESULTS: The authors' study reveals that olfactory stem cell transplantation induces functional recovery in comparison to nontransplanted and faciofacial nerve suture groups. They significantly increase (1) maximal amplitude of vibrissae protraction and retraction cycles and (2) angular velocity during protraction of vibrissae. They also reduce buccal synkinesis, according to the two techniques used. However, olfactory stem cell transplantation did not improve axonal regrowth of the facial nerve, 3 months after surgery. CONCLUSIONS: The authors show here that the adjuvant strategy of syngeneic transplantation of olfactory stem cells improves functional recovery. These promising results open the way for a phase I clinical trial based on the autologous engraftment of olfactory stem cells in patients with a facial nerve paralysis.

Can the Jankovic-assessment be used as an alternative to electromyography? A cross-sectional study on facial dystonia patients treated with Botulinum toxin.

PURPOSE: This study aims to quantitatively compare the Jankovic assessment (JA) with electromyography (EMG)-based measures for assessing changes in facial movements in patients with facial dystonia. MATERIALS AND METHODS: Thirteen patients (five males and eight females) affected with different forms of facial dystonia (hemifacial spasm and synkinesis) participated in this study. All patients were treated with Botulinum Toxin (BTX) and evaluated with the JA scale and EMG-based measures, including motor unit potentials (MUP) latency and presence of polyphasic potentials before and after BTX injection. Correlation between the JA scores and the EMG-based measures was calculated. Statistical analysis was performed with the Pearson test. RESULTS: Correlation between the JA scores and the EMG-based measures was found to be statistically significant, both before and after treatment with BTX. CONCLUSION AND RELEVANCE: JA scores significantly correlated with more objective EMG-based measures, suggesting that the JA scale can be used to assess facial movement changes, for example elicited by a treatment such as BTX injection. Thus, in facial dystonia patients, the JA scale may be used for evaluating treatment outcomes as a valid and low-cost alternative to EMG.

Decreased ACKR3 (CXCR7) function causes oculomotor synkinesis in mice and humans.

Oculomotor synkinesis is the involuntary movement of the eyes or eyelids with a voluntary attempt at a different movement. The chemokine receptor CXCR4 and its ligand CXCL12 regulate oculomotor nerve development; mice with loss of either molecule have oculomotor synkinesis. In a consanguineous family with congenital ptosis and elevation of the ptotic eyelid with ipsilateral abduction, we identified a co-segregating homozygous missense variant (c.772G>A) in ACKR3, which encodes an atypical chemokine receptor that binds CXCL12 and functions as a scavenger receptor, regulating levels of CXCL12 available for CXCR4 signaling. The mutant protein (p.V258M) is expressed and traffics to the cell surface but has a lower binding affinity for CXCL12. Mice with loss of Ackr3 have variable phenotypes that include misrouting of the oculomotor and abducens nerves. All embryos show oculomotor nerve misrouting, ranging from complete misprojection in the midbrain, to aberrant peripheral branching, to a thin nerve, which aberrantly innervates the lateral rectus (as seen in Duane syndrome). The abducens nerve phenotype ranges from complete absence, to aberrant projections within the orbit, to a normal trajectory. Loss of ACKR3 in the midbrain leads to downregulation of CXCR4 protein, consistent with reports that excess CXCL12 causes ligand-induced degradation of CXCR4. Correspondingly, excess CXCL12 applied to ex vivo oculomotor slices causes axon misrouting, similar to inhibition of CXCR4. Thus, ACKR3, through its regulation of CXCL12 levels, is an important regulator of axon guidance in the oculomotor system; complete loss causes oculomotor synkinesis in mice, while reduced function causes oculomotor synkinesis in humans.

Motor Control Deficits in Facial Synkinesis Patients: Neuroimaging Evidences of Cerebral Cortex Involvement.

Objective: Facial synkinesis is a severe sequelae of facial nerve malfunction. Once the synkinesis is established, it is extremely difficult for patients to recover. Given that the restoration of motor or sensory function after peripheral nerve injury was closely related with cortical plasticity, we investigated cortical plasticity in facial synkinesis patients by the frequency-specific data which remains largely uncharacterized. Materials and Methods: Resting-state fMRI was conducted in 20 facial synkinesis patients and 19 healthy controls, and the amplitude of low-frequency fluctuation (ALFF) in five different frequency bands (slow-6: 0-0.01 Hz; slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz; slow-3: 0.073-0.167 Hz; and slow-2: 0.167-0.25 Hz) was calculated, respectively. And the relationship between ALFF and clinical outcomes was also analyzed. Results: Comparing with the healthy controls, facial synkinesis patients showed significantly different ALFF values, mainly in the sensorimotor areas. Furthermore, increased ALFF of the ipsilateral insula in the slow-6 band was significantly related with better facial nerve function. Conclusion: Increased ALFF values in the ipsilateral insula might reflect an abnormal state of hypercompensation in motor control of facial synkinesis patients. It provided valuable spatial information about the functionally aberrant regions, which implied the possible involvement of motor control system in facial synkinesis.

Treatment Patterns and Outcomes in Botulinum Therapy for Patients With Facial Synkinesis.

IMPORTANCE: In the last decade, there has been a significant increase in the number of practitioners administering botulinum toxin for facial synkinesis. However, there are few resources available to guide treatment patterns, and little is known about how these patterns are associated with functional outcomes and quality of life. OBJECTIVE: To evaluate botulinum treatment patterns, including the dosing and frequency of muscle targeting, for treatment of facial synkinesis and to quantify patient outcomes. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study of 99 patients treated for facial synkinesis was conducted from January 2016 through December 2018 at the Vanderbilt Bill Wilkerson Center in Nashville, Tennessee, a tertiary referral center. INTERVENTION: Onabotulinum toxin A treatment of facial synkinesis. MAIN OUTCOMES AND MEASURES: Patient-reported outcomes on the Synkinesis Assessment Questionnaire and botulinum treatment patterns, including the dosages and frequency of injection for each facial muscle, were compared at the initiation of treatment and at the end of recorded treatment. RESULTS: In total, 99 patients (80 female patients [81%]) underwent botulinum injections for treatment of facial synkinesis. The median (interquartile range) age was 54.0 (43.5-61.5) years, and the median (interquartile range) follow-up was 27.1 (8.9-59.7) months. Most patients underwent injections after receiving a diagnosis of Bell palsy (41 patients, 41%) or after resection of vestibular schwannoma (36 patients [36%]). The patients received a total of 441 treatment injections, and 369 pretreatment and posttreatment Synkinesis Assessment Questionnaire scores were analyzed. The mean botulinum dose was 2 to 3 U for each facial muscle and 9 to 10 U for the platysma muscle. The dose increased over time for the majority of all muscles, with steady state achieved after a median of 3 treatments (interquartile range, 2-3). Linear regression analysis for cluster data of the mean total questionnaire score difference was -14.2 (95% CI, -17.0 to -11.5; P < .001). There was a significant association of postinjection questionnaire score with younger patients, female sex, total dose, and synkinesis severity. Oculo-oral synkinesis may respond more to treatment compared with oro-ocular synkinesis. CONCLUSION AND RELEVANCE: Patients with facial synkinesis responded significantly to botulinum treatment. Treatment began with 6 core facial muscles that were injected during most treatment sessions, and dosages increased after the first injection until steady state was achieved. Those with a greater degree of morbidity, younger patients, and females showed significant improvement, and the larger the dose administered, the greater the response. Oculo-oral synkinesis may be more responsive than oro-ocular synkinesis. LEVEL OF EVIDENCE: 3.

Decreased Distance between Representation Sites of Distinct Facial Movements in Facial Synkinesis-A Task fMRI Study.

This study aimed to investigate the cortical functional alterations in patients with unilateral facial synkinesis using the task-designed functional magnetic resonance imaging. Fourteen unilateral synkinesis followed by peripheral facial nerve palsy patients and eighteen healthy adults were recruited in this study. Four facial motor tasks, i.e. left/right blinking and left/right smiling, were performed by each subject during the scans. Based on the activation maps, the spatial distance between the representation sites in the contralateral pre-/post-central gyrus of left or right blinking and smiling tasks (i.e. left/right B-S-distance) were calculated. Patients with unilateral facial synkinesis showed decreased B-S-distances during blinking and smiling tasks on the affected half face (9.68 ±â€¯3.92 mm) compared to both average distances in healthy controls (14.95 ±â€¯5.55 mm; p = 0.002) and unaffected half face tasks in patients (16.19 ±â€¯7.87 mm; p = 0.011). These findings demonstrated cortical reorganization in facial synkinesis and suggested a conceivable mechanism corresponding to the simultaneous facial movement. This potentially provides a new modulation target for preventive, therapeutic and rehabilitative maneuver of this disease.

Congenital Oculonasal Synkinesis.

A 4-year-old girl with maxillary hypoplasia, intermittent exotropia, and high myopia displayed congenital oculonasal synkinesis. We examine the implications for pathogenesis of these disparate craniofacial findings.

Synkinesis Between Orbicularis Oculi and Procerus Muscles: Video Presentation of an Unusual Type of Aberrant Innervation after Cosmetic Rhinoplasty.

BACKGROUND: Synkinesis is a recognized complication following peripheral facial nerve paralysis. Different types of synkinesis have been described, with oral-ocular and ocular-oral synkinesis being the most common. Ocular-nasal synkinesis has been reported in two patients following cosmetic rhinoplasty. However, synkinesis between the orbicularis oculi and procerus muscles has not been reported by now. METHODS: This is an interventional case report. RESULTS: Two women, aged 42 and 37 years, presented with unilateral contraction of the medial eyebrow muscles (procerus) with spontaneous or voluntary blinking, 4 and 5 months after cosmetic rhinoplasty, respectively. Both were successfully treated with injection of botulinum toxin A. CONCLUSIONS: Surgical trauma is inevitable during every procedure, including rhinoplasty, and may damage the fine structures including branches of the facial nerve innervating the muscles. Gentle tissue handling may minimize iatrogenic injury to the fine motor branches of the facial nerve and prevent subsequent aberrant innervation and synkinesis. Botulinum toxin A injection can effectively, yet temporarily, resolve the unintentional contractions and provide significant patient comfort. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the table of contents or the online instructions to authors www.springer.com/00266 .