Botulinum Toxin for Aberrant Facial Nerve Regeneration: Double-Blind, PlaceboControlled Trial Using Subjective Endpoints Gary
Borodic, M.D., Mary Bartley, R.N., William Slattery, M.D., Michael Glasscock, M.D., Eric Johnson, Ph.D., Carl Malazio, B.S., Michael Goodnough, Ph.D., Martin Acquadro, M.D., and Michael McKenna, M.D. Boston, Mass.; Los Angeles, Calif.; Nashville, Tenn.; and Madison, Wis. Background: Aberrant facial nerve regeneration syndrome is systematically studied by constructing a subjective questionnaire organized into pertinent domains (impairment of quality of life, social interactions, perception of self-appearance, visual function, and perception of problem severity) and by physical assessment of degree of involuntary palpebral fissure closure during routine facial movements using videotaping and a physicians grading scale.
Methods: The videotape measurements of corneal light reflex to upper lid margin distance and vertical palpebral distance were made during adynamic and active facial expression. Thirty-six patients were studied (six in an open-label pilot study design and 30 in a multicenter, double-blind, placebo-controlled trial). Botulinum toxin type A injections consistently suppressed the degree of involuntary eyelid movement associated with smiling, chewing, and puckering by each measurement and in both study designs. Results: In all subjective morbidity domains, improvement was demonstrated in the doubleblind study design (quality of life, p . 0.05; social interaction, p . 0.001; personal appearance, p . 0.001; peripheral visual impairment, p . 0.01; and perception of sever ity, p . 0.05). Correlation between degrees ofphysical impairment was significant but low comparing degree of subjective impairment to direct videotaped measurements. Correlation was more significant comparing subjective scores to the physicians grading scale assessment of degree of physical impairment. Conclusions: Impairment in quality of life, social interactions, and self-assessment of appearance closely reflected the nature of the morbidity associated with palpebral fissure asymmetry associated with aberrant facial nerve regeneration. The physicians grading scale best reflected subjective morbidity over direct videotaped measurements. (Plast. Reconstr. Surg. 116: 36, 2005.) Chronic facial nerve palsy has long been known to negatively impact a patient s ability to lead a normal existence. A frequent consequence of chronic facial palsy is aberrant facial nerve regeneration, which often results in abnormal synkinetic eyelid and upper and lower facial movements. Such abnormal movements lead to uncontrolled and involuntary closure of upper and lower eyelids, asymmetry of the
palpebral fissures, and distortion of communicative facial expression. Such physical defects From the Massachusetts Eye and Ear Infirmary, the House Ear Clinic, the Baptist Hospital, and the Food Research Division, University of Wisconsin. Received for publication July 11, 2002; revised December 1, 2004. Readers may also refer to the online version of the article at the Journal s Web site (www.plasreconsurg.org) for additional materials. DOI: 10.1097/01.PRS.0000169689.27829.C4 36
Vol. 116, No. 1 / FACIAL NERVE REGENERATION in facial movement have previously been found to be clinically significant and have been included in widely accepted methods of objectively grading the degree of facial palsy in contemporary clinical practice.1,2 In addition, ocular surface exposure, keratitis, reflex tearing (crocodile tears), and eyelid malposition further aggravate the syndrome.3,4 Direct efforts to treat exposure keratitis involve gold weight implants for animation,5,6 canthoplasty and tarsorrhaphy, corrections of lid malposition, punctal plugs, and other facial animation procedures.7,8 Although treatment of keratitis remains a priority, patients often remain impaired by abnormal facial movements that impair natural expression. The purpose of this study was to scientifically validate improvement using subjective endpoints reflecting distress created by asymmetric palpebral fissures secondary to synkinetic eyelid closure and to test the alteration in subjective morbidity in a double-blind controlled study design using botulinum toxin injections. PATIENTS AND METHODS Clinicians from three medical centers caring for a large number of facial paralysis patients agreed to participate in the study. Interviews with physicians and patients were conducted to establish a consensus of descriptive phrases and question types that closely reflected the morbidity associated with synkinetic facial movements following facial paralysis. Domains that were agreed on included quality of life, self-image, social interaction, perception of severity, impairment of peripheral vision, and perception of appearance. Protocol and informed constant were submitted and approved by the internal review board of the Baptist Hospital, House Ear Clinic, and the Massachusetts Eye and Ear Infirmary and U.S. Food and Drug Administration under Investigational New Drug 4891. A small open-label pilot study was conducted to assess results and comprehension of questionnaire and cohesiveness within morbidity domains by factor analysis. Botulinum toxin for injection was obtained from Associated Synapse Biologics, manufactured
in conjunction with Professor Eric Johnson of the University of Wisconsin, and was quantified using the standard Schantz-Kautter method of LD 50 determination.9 12 Assays were further reproduced and validated at Toxicon, Inc. Botulinum toxin manufactured in this study was conducted under U.S. Food and Drug Administration Investigational New Drug no. 4891. Botulinum A toxin was prepared in a freeze-dried form, at an activity level of 100 LD 50 units per vial (30% bioactivity). The specific activity of the botulinum was 25 LD 50 units/ng protein. Nonpreservative saline was used as the diluent. Non preservative-containing saline was used as the control injection material in the double-blind study. Inclusion criteria required that patients (1) be older than 21 years of age, (2) be female patients testing negative for pregnancy, (3) have a duration of the condition of at least 6 months, (4) have an absence of symptomatic dry eye syndrome (Schirmer test . 5 mm after 5 minutes without topical anesthetic), (5) have an absence of myopathic facial disease (e.g., myasthenia gravis)13 or other facial myopathies, (6) have an absence of myopathic or severe involutional ptosis, (7) have no concurrent use of aminoglycoside therapy, (8) have an absence of active keratitis or other ocular surface disease, (9) have an absence of muscular dystrophy, and (10) have an understanding of the internal review board approved informed consent. Injections were given at a concentration of 2.5 LD 50 units per 0.1 cc and injected at the four injection points in the periocular areas previously described for the treatment of synkinetic eyelid movements.4 Injections were made to avoid medial placement on the lower eyelid and in the midposition in the upper eyelid, as these injection sites have been associated with diplopia and ptosis, respectively.14 Thirty-gauge needles were used to make subcutaneous injections at each lid position. Videotaping was performed with a 3/4-inch UMatic system and a 1/2-inch VHS recording systems, with patients staring at a fixation light adjusted on a horizontal plane with the patient s pupils. A 30-mm strip was fixated to each patient s right brow, and measurements of the vertical palpebral distances and corneal light reflex to upper lid margin distance were interpolated from the 30-mm measurement strip. Actual measurements represent interpolation from this 30-mm strip to anatomical distances observed on
the video screen. Vertical palpebral distance and corneal light reflex to upper lid margin distance are commonly used measurements obtained by eyelid surgeons to assess the degree of clinically relevant ptosis (Fig. 1).15
Patients were asked to render three facial movements for videotaping. Smiling, puckering, and chewing were chosen to force the activation of various muscles of facial expression and to simulate a spectrum of stereotyped facial expressionistic movement and functional movements. Each movement was repeated five times for each measurement, and the measurement determination for a given time was the numerical average of the five measurements. Measurements of vertical palpebral and corneal light reflex to upper lid margin distances were obtained by blinded physician observers, as was the tabulation of questionnaire domain scores and the physicians grading scale. Age-and sex-matched controls were selected at a shopping mall and given the questionnaire to complete for validation. A ratio of 3:1 control/test subject was used in the statistical comparison. The physicians grading scale was constructed to allow an assessment of degree of synkinesis during facial expression. Generally, the instructions given to the patient were to smile or pucker their lips on at least several occasions by the treating physician. The grading would then be estimated according to the scale outlined in Table I. Safety data were collected during ophthalmology and otolaryngologic examination before treatment and after 2 weeks from the time of injection, and the complication rate was compared with placebo using Fisher s statistic. Specifically, each patient was assessed with an ocular exposure grading system based on slitlamp evidence of punctate keratopathy and subjective complaint of eye irritation (Table II). Each patient was further assessed for dePLASTIC AND RECONSTRUCTIVE SURGERY, July 2005 gree of epiphora, diplopia, ptosis, photophobia, corneal erosions, ocular motility, facial symmetry, symptoms of dry eye, and systemic complaints. Any complication that occurred was evaluated for duration and intensity. Moistening drops were conventionally recommended if ocular irritation was encountered. RESULTS Morbidity Domains
From interviews with patients and physicians, domains were identified reflecting subjective morbidity of patients experiencing synkinetic eyelid closure from chronic aberrant facial nerve regeneration. Self-image, general attitude toward quality of life, attitude regarding social interaction, perception of facial appearance, and peripheral visual function were the initial domains. It should be noted that many patients stated that reflex tearing was improved, but this morbidity issue was not dealt with in the subjective instrument. Initial Validation of Test Instrument (Small Sample in Open-Label Study Design) Once the questionnaires were completed, each domain was tested against a sample of six patients with factor analysis, test-retest reliability, and before-and-after test result after injection of botulinum toxin test article. Comparison of each domain against the age-and sexmatched controls (3:1 control/test case ratio, n . 18) yielded significant differences for all domains (p . 0.01, Fisher s). Factor analysis within each domain was used to identify deviant questions, which were removed. Botulinum injection produced substantial reduction in inFIG. 1. Diagram of corneal margin to reflect distance and vertical palpebral dis tance (measurements of palpebral asymmetry with facial movement).
Vol. 116, No. 1 / FACIAL NERVE REGENERATION TABLE I Synkinesis Physicians Grade Description 0 Not present 1 Mild; upper lid closure 1.5 mm 2 Mild moderate; upper eyelid closure to within 1 mm of the corneal light reflex 3 Moderate; upper eyelid moves to the position of the corneal light reflex 4 Moderate severe; corneal light reflex is obliterated by upper eyelid movement 5 Severe; upper lid moves to the position of the inferior limbus at the 6-o clock position with evidence of scleral show 6 Very severe; eye closes completely with lower facial movement voluntary eyelid closure using vertical palpebral fissure and corneal light reflex to upper eyelid margin distance comparing baseline to posttreatment measurements in the open-label trial (Table III). Pearson linear correlation comparing subjective result and degree of synkinetic closure was not significant for the pilot six-patient study group. Improvement in domain scores did occur in this small group in five of six patients (Table IV). From reviewing the cross-correlation between domain scores, the self-image domain was merged into the personal appearance domain, as responses yielded similar results. Self-perception of severity of the problem was a final domain added. Complications in this group included dry eye, lagophthalmos, and ecchymosis. TABLE II Exposure Grading Scale Grade Description 0 No symptoms of exposure keratitis 1 Symptoms of transient ocular irritation that can be relieved by lubricating ophthalmic drops or ophthalmic ointment 2 No symptoms of dry eye syndrome; however, superficial Grading Scale
punctate keratopathy of less than 1/8 of the cornea; no evidence of ciliary injection of the eye 3 Symptoms of exposure keratitis (ocular irritation) associated with evidence of superficial punctate keratopathy of less than 1/8 of the cornea; no evidence of ciliary injection of the eye 4 Symptoms of exposure keratitis (pain) associated with superficial keratopathy of greater than 1/8 of the cornea on slit-lamp examination and early injection of the ciliary vessels 5 Greater than 50% of the cornea has superficial punctate keratopathy associated with ciliary injection and pain 6 Pain associated with corneal erosions, ciliary injection 7 Corneal ulceration associated with extreme pain and intense photophobia; tarsorrhaphy or extended pressure patching may be necessary Double-Blind, Placebo-Controlled Trial Thirty patients participated in this limb of the study, and there were no dropouts. The diagnosis of participants included 20 patients with chronic Bell s palsy, four patients after acoustic neuroma surgery, four patients after Ramsey-Hunt syndrome, one patient with mastoiditis, and one patient after meningioma resection. The double-blind, placebo-controlled trial demonstrated efficacy for quality of life, social interactions, perception of self-appearance, visual function, and perception of severity domains (Table V). Reduction in physical synkinesis as measured with videotaping and blinded physician assessment was demonstrated for each form of facial movement as measured by the vertical palpebral fissure and corneal to light reflex distance (Table VI). The physicians grading scale easily demonstrated reduced synkinesis (Table VII). Reflex epiphora (crocodile tears) was reported to improve in six of nine patients in the active drug group and zero of six placebotreated patients (p . 0.05, Fisher s two-tailed test). Two patients in the active drug group complained of transient increased epiphora associated with increased physical evidence of exposure keratitis on slit-lamp examination. Correlation between Degree of Facial
Movement Impairment and Subjective Morbidity Correlation between numerical tabulations for each morbidity domain and the degree of synkinetic movements measured directly on videotape derived from the double-blind study was accomplished using a total of 150 matched data entries for each of the three facial movements studied (Table VIII). Pearson correlation was low comparing videotaped measurements to subjective questionnaire performance but statistically significant for the quality of life, social interaction, and self-appearance domains. The physician s grading scale showed better correlation to the morbidity domains (Table IX). There were no major complications. Physical signs of exposure keratitis increased in the active drug group compared with the controls (p . 0.05, Fisher s). No patient exceeded grade 3 on the exposure scale (Table II). The remaining complications are outlined in Table X. All drug-related complications were transient.
40 TABLE III Changes in Involuntary Eyelid Closure in Open-Label Pilot Group PLASTIC AND RECONSTRUCTIVE SURGERY, July 2005 Smiling Puckering Corneal Light Reflex Margin Distance (mm) 1.4 . 3.3 (p . 0.01)* 2.2 . 0.75 (p . 0.02) Vertical Palpebral Distance (mm) 2.22 . 0.47 (p . 0.01) 3.29 . 0.82 (p . 0.01) * Paired t test. TABLE IV Domain Result (mean score) in Open-Label Trial (n . 6)* Preinjection (SD) Postinjection (SD) Self-image Personal appearance Visual Social interaction 41.33 (24.9) 57.7 (28.2) 39.3 (15.3) 52.0 (28.3) 71 (22.2) 71.5 (21.9) 62.7 (27.6) 71.3 (26.4) * Polarity: The greater score reflects improvement. Higher numbers indicate closer to normal response. p . 0.05, Wilcoxon.
DISCUSSION With increasing pressure to provide evidencebased justification for therapies, particularly in the realm of plastic surgery based procedures, the medical profession has relied on double-blind, placebo-controlled trials as the highest standard of evidence. Such trials are further validated when endpoints are both objective (measured) and subjective (patient response based), with statistically significant correlation. The study described in this article elevated the evidence for botulinum application synkinetic movements associated with aberrant facial nerve regeneration beyond case reports and case series. Originally, botulinum toxin received licensing approval for the treatment of blepharospasm and disorders based on abnormalities of the seventh cranial nerve, a commingled study group consisting of patients with Meige syndrome, essential blepharospasm, and hemifacial spasm, and probably on small numbers of patients with facial muscle synkinesis resulting from aberrant facial nerve regeneration. The endpoint was originally an investigator s four-point, five-step grading scale, with no subjective input. This study demonstrated efficacy with both independent static subjective and objective endpoints in a doubleblinded study design. Other contemporary applications of facial botulinum toxin injection are currently undergoing scrutiny using double-blinded controlled trials. Over the past 5 years, botulinum toxin has been advocated for the treatment of essential headache disorders (tension headache and migraine) on the basis of observations and even multiple open-label studies.16 19 However, when this indication was evaluated with large, randomized, doubled-blind, controlled trials, the endpoints failed to show differences between treatment and control groups; therefore, the efficacy could not be established.20 Although this indication may require subgroup identification, botulinum toxin for the treatment of headache remains unproven therapy and is controversial based on evidence from clinical studies. In the recent literature, multiple studies have been published on the application of botulinum toxin for glabellar, frontal, and temporal dynamic rhytides.21,22 Studies conducted used three-point, four-step grading scales designed to quantitate investigators objective assessment of degree of rhytides and patient global self-assessment of severity of rhytides without reference to other components of
morbidity, such as influences on social interaction, behavioral changes, and attitudes regardTABLE V Results of Double-Blind, Placebo-Controlled Trial Using Subjective Questionnaire * Baseline (SD) Postinjection (SD) Wilcoxon (p) Quality of life Social Personal appearance Visual Severity 5.01 (1.81) 39.51 (10.5) 30.15 (4.6) 15.96 (5.77) 10.73 (3.2) 3.12 (2.94) 24.34 (13.13) 15.55 (9.1) 11.13 (7.06) 7.66 (3.6) 0.05 0.001 0.001 0.01 0.05 * Polarity: The lower score . 30, control/treatment ratio tatistically significant differences and quent values for control or reflects improvement, closer to normalcy. n (1:1). None of the placebo groups demonstrated any s there were no differences between baseline and subse active drug groups.
Vol. 116, No. 1 / FACIAL NERVE REGENERATION TABLE VI Objective Measurement of Reflex Eyelid Closure (Double-Blind, Placebo-Controlled Trial, Multicenter; Control Group Not Shown Baseline Postinjection (mm) (Drug) Wilcoxon Vertical palpebral distance * Smiling 3.18 (1.57) 1.13 (0.67) p . 0.005 Puckering 4.69 (1.47) 0.90 (0.74) p . 0.005 Chewing 2.91 (1.61) 0.61 (0.99) p . 0.011 Corneal light reflex to upper eyelid margin distance Smiling 2.39 (1.86) 0.46 (0.6) p . 0.013 Puckering 3.37 (1.75) 0.63 (0.76) p . 0.005 Chewing 1.96 (1.53) 0.41 (0.52) p . 0.008 * There were no differences between baseline (preinjection) for control and active drug groups. One of the control-placebo facial measurements showed a significant worsening after placebo injection during smiling measurements [baseline 2.64 (1.7), 3.66 postinjection (1.79), p . 0.033, Wilcoxon]. None of the placebo group demonstrated any statistically significant differences and there were no differences between baselines for control and active drug groups. ing quality of life.22 This study, unlike others previously published, uses the conventional investigators grading scale, a direct physical measurement, and newly developed multiple domain subjective static endpoints that attempt to globally capture and quantitate morbidity. Although the facial plastic surgeon views favorable results based on anatomical improvement, success with any surgical intervention is inevitably a subjective judgment made by the
patient. An approach to scientifically validating therapeutic intervention for a specific disorder starts with a morbidity hypothesis and a measurable physical defect. For synkinetic eyelid closure associated with chronic facial palsy, palpebral fissure size changes are physical defects conveniently measured. Both ophthalmic plastic surgeons and their patients have long appreciated the necessity for symmetric palpebral fissures and upper facial structures to achieve normal facial appearance. Asymmetry causes perception of disfigurement, which influences conscious and subconscious self-image, social behavior, and perception of appearance. The TABLE VII Physicians Grading Scale Result in Double-Blind Control (Placebo Shown) Placebo Control (SD) Active Drug (SD) Baseline Posttreatment 4.07 (1.44) 4.42 (1.42) 4.33 (1.59) 0.467 (1.06)* * p . 0.001, Wilcoxon, two-sided signed rank. subjective domains were fashioned to assess such morbidity categories. In ophthalmic practice, ptosis is probably the most common cause of palpebral fissure asymmetry and causes not only disfigurement but also defects in functional measured visual fields,15 a well-accepted measurement of visual function. Thus, a subjective endpoint assessing peripheral vision should be included because of the involuntary nature of palpebral fissure closure. Comparisons in correlation of objective measurements to subjective morbidity could provide some useful information on the most appropriate objective endpoints for scale validations. Grading scales and objective endpoints used as outcome measurements in practice or studies should have a statistically significant and highest possible correlation to subjective morbidity. Impairment in social interaction and perception of self-image (appearance) demonstrated the highest correlation to measured asymmetry, compared with peripheral visual function. The interpretation of this finding is that vision obstruction appears to be less significant than impact on selfimage
and impairment in social interaction. The subjective morbidity endpoints also more significantly correlated to a physicians grading scale of objective changes compared with direct measurements of asymmetry from photographic methods. This finding reinforces the use of physician grading scales as useful endpoints for clinical studies for facial disfigurement. Reasons for disparity between objective endpoints (photographic measurements and grading scales) and subjective morbidity include the following: (1) sampling of the defect is confined to a only one region of the face; (2) there is no accounting for actual facial weakness; (3) there is no accounting for lacrimal or exocrine gland secretion; (4) there is no accounting for symptoms of dry eye or exposure keratitis, which often may accompany the syndrome; and (5) there is a disparity in personality types within any population. Historically, efforts to quantify the degree of physical impairment associated with facial nerve paralysis is a topic well addressed in the medical literature.1,2,23,24 The House-Brackmann classification provides a quick and meaningful scale on the physical degree of impairment in patients with facial paralysis, yet the actual subjective morbidity related to this impairment was not initially identified. The House-Brackman classification incorporated reflex synkinesis in the scale. House
PLASTIC AND RECONSTRUCTIVE SURGERY, July 2005 TABLE VIII Significant Pearson Correlation of the Domain Response and Severity of Synkinesi s during Various Facial Movements (n . 60) Smile Pucker Chew VP MCRD VP MCRD VP MCRD Quality of life 0.262* 0.298* 0.281* 0.280* 0.355 0.364 Social 0.321 0.292* 0.328 0.253* 0.394 0.345 Personal appearance 0.434 0.355 0.467 0.411 0.489 0.426 Visual 0.293* Severity 0.302* VP, vertical palpebral distance; MCRD, lid margin to corneal light reflex distan ce. * p . 0.05. p . 0.01. p . 0.005. Brackman classifications have recently been analyzed for correlation to social and psychological morbidity.13,25 Among hemifacial involuntary movement disorders, aberrant facial nerve regeneration demonstrates the least period effect, that is, the momentto-moment variation in intensity of the involuntary spasms. This situation makes physical measurement of palpebral fissure asymmetry more consistent than many facial movement disorders and allows an increased probability of identifying statistically significant correlations. Other facial spastic diseases such as hemifacial spasm and Meige syndrome would be much more difficult to assess with subjective-objective correlations because of the large degree of period effect associated with deformity. Perhaps in the future, assessing facial disfigurement and movement dysfunction with computer image analysis24 may provide more global objective anatomical scales. However, such measurements will need further programming development and need to account for baseline facial contour variability.
Improvement in reflex tearing was seen in most patients in whom the active drug was administered. To the best of the authors knowledge, this is he first controlled evidence of efficacy to this component of the aberrant facial nerve regeneration syndrome. Botulinum toxin TABLE IX Correlation of Domain Results with Physicians Grading Scale* Pearson Correlation Quality of life 0.583 Social interaction 0.637 Visual function 0.502 Severity 0.566 Personal appearance 0.507 * p . 0.001 for all domains. has long been known to suppress autonomic function at the axon terminal and/or ganglionic level.3 Cholinergic suppression of the gland can occur from the outer upper eyelid injection, impairing stimulation of the gland with facial movements. As the eccrine sweat gland are also cholinergically innervated, botulinum toxin has been efficacious for Frey s syndrome.26 However, caution must be advocated in applying botulinum toxin in certain instances in which reflex tearing may be protective and beneficial, such as patients with substantial dry eye syndrome or evidence of neurotrophic keratitis associated with the facial nerve palsy. CONCLUSIONS This study concludes that botulinum toxin injections are efficacious for synkinetic movements after facial paralysis and that there are wide variations in personal perception of the degree of impairment as reflected by the level of Pearson correlation between subjective impairment and objective physical assessment of the degree of impairment measured with videotaping analysis (Table V). This significant but relatively lower correlation probably can be explained by occupation, personality, cultural differences, and sampling limitations outlined above. Others have found a similar degree of TABLE X Drug-Related Complications
Active Drug Placebo Induced lagophthalmos 8/15 0/15 (p . 0.01, Fisher s) Increased physical signs of exposure 7/15 0/15 (p . 0.01, Fisher s) New complaints of dry eye 2/15 0/1 Induced transient ptosis 0/15 1/15 Induced epiphora 2/15 0/15 Edema 1/15 0/15 Diplopia 1/15 0/15
Vol. 116, No. 1 / FACIAL NERVE REGENERATION correlation when comparing psychological distress to more objectively determine physical impairment by means of facial movement assays, the House-Brackmann classification, and other facial grading systems.13,25 Although more valid than objective endpoints, the larger variations in measurement of subjective endpoints requires studies with more subjects in the test groups to assess the influence of any therapeutic intervention. The results further concluded that impairment of social interaction, perception of selfappearance, and quality of life were the strongest subjective domains reflecting the morbidity associated with synkinetic eyelid closure found with aberrant facial nerve regeneration, as these domains correlated best with degree of physical impairment and showed the greatest differences in the double-blind study design. Visual impairment, although statistically significant in the afflicted group compared with controls, did not achieve the same degree of correlation to measurements of physical defect. Gary E. Borodic, M.D. Beyer, Townsend & Borodic, P.C. 100 Charles River Plaza Boston, Mass. 02114 REFERENCES 1. House, J. W. Facial nerve grading scale. Laryngoscope 93: 1056, 1983. 2. Croxson, G., May, M., and Mester, S. J. Grading facial nerve function: House Brackmann versus Burres-Fisch methods. Am. J. Otol.
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