Berrant Facial Nerve Regeneration, Double-blind, Placebo-controlled Trial Using Subjective...

7/31/2019 Berrant Facial Nerve Regeneration, Double-blind, Placebo-controlled Trial Using Subjective Endpoints. Plast Recons

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Botulinum Toxin for Aberrant Facial NerveRegeneration: Double-Blind, Placebo-Controlled Trial Using Subjective Endpoints

GaryBorodic,M.D.,MaryBartley,R.N.,WilliamSlattery,M.D.,MichaelGlasscock,M.D.,EricJohnson,Ph.D.,CarlMalazio,B.S.,MichaelGoodnough,

Ph.D.,MartinAcquadro,M.D.,and

MichaelMcKenna,M.D.

Boston,

Mass.;LosAngeles,Calif.;Nashville,Tenn.;andMadison,Wis.

Background:Aberrant facial nerve regeneration

syndrome is systematically studied byconstructing a subjective questionnaire organizedinto pertinent domains (impairmentof quality of life, social interactions, perceptionof self-appearance, visual function, andperception of problem severity) and by physicalassessment of degree of involuntary palpebralfissure closure during routine facialmovements using videotaping and a physiciansgrading scale.


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Methods:The videotape measurements ofcorneal light reflex to upper lid margin distanceand vertical palpebral distance weremade during adynamic and active facial expression.Thirty-six patients were studied (sixin an open-label pilot study design and 30 ina multicenter, double-blind, placebo-controlledtrial). Botulinum toxin type A injectionsconsistently suppressed the degree ofinvoluntary eyelid movement associated withsmiling, chewing, and puckering by eachmeasurement and in both study designs.Results:In all subjective morbidity domains,improvement was demonstrated in the double-blind study design (quality of life, p.0.05; social interaction, p.0.001; personalappearance, p.0.001; peripheral visual impairment,

p.0.01; and perception of sever

ity, p.0.05). Correlation between degreesofphysical impairment was significant but lowcomparing degree of subjective impairmentto direct videotaped measurements. Correlationwas more significant comparing subjectivescores to the physicians grading scale

assessment of degree of physical impairment.Conclusions:Impairment in quality of life,social interactions, and self-assessment of appearanceclosely reflected the nature of themorbidity associated with palpebral fissureasymmetry associated with aberrant facialnerve regeneration. The physicians gradingscale best reflected subjective morbidity overdirect videotaped measurements. (Plast.Reconstr.Surg.116: 36, 2005.)

Chronic facial nerve palsy has long beenknown to negatively impact a patients ability tolead a normal existence. A frequent consequenceof chronic facial palsy is aberrant facialnerve regeneration, which often results in abnormalsynkinetic eyelid and upper and lowerfacial movements. Such abnormal movementslead to uncontrolled and involuntary closureof upper and lower eyelids, asymmetry of the


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palpebral fissures, and distortion of communicativefacial expression. Such physical defects

From the Massachusetts Eye and Ear Infirmary, the House Ear Clinic, the BaptistHospital, and the Food Research Division, University ofWisconsin. Received for publication July 11, 2002; revised December 1, 2004.

Readers may also refer to the online version of the article at the JournalsWeb site (www.plasreconsurg.org) for additional materials.

DOI:10.1097/01.PRS.0000169689.27829.C4

36


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Vol.116,No.1/ FACIAL NERVE REGENERATION

in facial movement have previously been foundto be clinically significant and have been includedin widely accepted methods of objectivelygrading the degree of facial palsy in contemporaryclinical practice.1,2

In addition, ocular surface exposure, keratitis,reflex tearing (crocodile tears), and eyelidmalposition further aggravate the syndrome.3,4Direct efforts to treat exposure keratitis involvegold weight implants for animation,5,6 canthoplastyand tarsorrhaphy, corrections of lid malposition,punctal plugs, and other facial animationprocedures.7,8 Although treatment ofkeratitis remains a priority, patients often remainimpaired by abnormal facial movementsthat impair natural expression. The purpose of

this study was to scientifically validate improvementusing subjective endpoints reflecting distresscreated by asymmetric palpebral fissuressecondary to synkinetic eyelid closure and totest the alteration in subjective morbidity in adouble-blind controlled study design using botulinumtoxin injections.

PATIENTS AND METHODS

Clinicians from three medical centers caringfor a large number of facial paralysis patientsagreed to participate in the study. Interviews

with physicians and patients were conducted toestablish a consensus of descriptive phrasesand question types that closely reflected themorbidity associated with synkinetic facialmovements following facial paralysis. Domainsthat were agreed on included quality of life,self-image, social interaction, perception of severity,impairment of peripheral vision, andperception of appearance.

Protocol and informed constant were submittedand approved by the internal reviewboard of the Baptist Hospital, House Ear

Clinic, and the Massachusetts Eye and Ear Infirmaryand U.S. Food and Drug Administrationunder Investigational New Drug 4891. Asmall open-label pilot study was conducted toassess results and comprehension of questionnaireand cohesiveness within morbidity domainsby factor analysis.

Botulinum toxin for injection was obtainedfrom Associated Synapse Biologics, manufactured


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in conjunction with Professor Eric Johnsonof the University of Wisconsin, and wasquantified using the standard Schantz-Kauttermethod of LD 50 determination.9 12 Assayswere further reproduced and validated at Toxicon,Inc. Botulinum toxin manufactured in

this study was conducted under U.S. Food andDrug Administration Investigational New Drugno. 4891. Botulinum A toxin was prepared in afreeze-dried form, at an activity level of 100 LD50 units per vial (30% bioactivity). The specificactivity of the botulinum was 25 LD 50units/ng protein. Nonpreservative saline wasused as the diluent. Nonpreservative-containingsaline was used as the control injectionmaterial in the double-blind study.

Inclusion criteria required that patients (1)be older than 21 years of age, (2) be femalepatients testing negative for pregnancy, (3)have a duration of the condition of at least 6months, (4) have an absence of symptomaticdry eye syndrome (Schirmer test .

5 mm after5 minutes without topical anesthetic), (5) havean absence of myopathic facial disease (e.g.,myasthenia gravis)13 or other facial myopathies,(6) have an absence of myopathic orsevere involutional ptosis, (7) have no concurrentuse of aminoglycoside therapy, (8) havean absence of active keratitis or other ocularsurface disease, (9) have an absence of musculardystrophy, and (10) have an understandingof the internal review boardapproved informedconsent.

Injections were given at a concentration of 2.5LD 50 units per 0.1 cc and injected at the fourinjection points in the periocular areas previouslydescribed for the treatment of synkinetic eyelidmovements.4 Injections were made to avoid medialplacement on the lower eyelid and in themidposition in the upper eyelid, as these injectionsites have been associated with diplopia andptosis, respectively.14 Thirty-gauge needles wereused to make subcutaneous injections at each lidposition.

Videotaping was performed with a 3/4-inch U-

Matic system and a 1/2-inch VHS recording systems,with patients staring at a fixation light adjustedon a horizontal plane with the patientspupils. A 30-mm strip was fixated to each patientsright brow, and measurements of the verticalpalpebral distances and corneal light reflexto upper lid margin distance were interpolatedfrom the 30-mm measurement strip. Actual measurementsrepresent interpolation from this30-mm strip to anatomical distances observed on


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the video screen. Vertical palpebral distance andcorneal light reflex to upper lid margin distanceare commonly used measurements obtained byeyelid surgeons to assess the degree of clinicallyrelevant ptosis (Fig. 1).15


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Patients were asked to render three facialmovements for videotaping. Smiling, puckering,and chewing were chosen to force theactivation of various muscles of facial expressionand to simulate a spectrum of stereotypedfacial expressionistic movement and functionalmovements. Each movement was repeated fivetimes for each measurement, and the measurementdetermination for a given time was thenumerical average of the five measurements.Measurements of vertical palpebral and corneallight reflex to upper lid margin distanceswere obtained by blinded physician observers,as was the tabulation of questionnaire domainscores and the physicians grading scale.

Age-and sex-matched controls were selectedat a shopping mall and given the questionnaireto complete for validation. A ratio of 3:1 con-trol/test subject was used in the statisticalcomparison.

The physicians grading scale was constructed

to allow an assessment of degree ofsynkinesis during facial expression. Generally,the instructions given to the patient were tosmile or pucker their lips on at least severaloccasions by the treating physician. The gradingwould then be estimated according to thescale outlined in Table I.

Safety data were collected during ophthalmologyand otolaryngologic examination beforetreatment and after 2 weeks from the timeof injection, and the complication rate wascompared with placebo using Fishers statistic.

Specifically, each patient was assessed with anocular exposure grading system based on slitlampevidence of punctate keratopathy andsubjective complaint of eye irritation (TableII). Each patient was further assessed for de-

PLASTIC AND RECONSTRUCTIVE SURGERY, July2005

gree of epiphora, diplopia, ptosis, photophobia,corneal erosions, ocular motility, facialsymmetry, symptoms of dry eye, and systemic

complaints. Any complication that occurredwas evaluated for duration and intensity. Moisteningdrops were conventionally recommendedif ocular irritation was encountered.

RESULTS

MorbidityDomains


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From interviews with patients and physicians,domains were identified reflecting subjectivemorbidity of patients experiencing synkineticeyelid closure from chronic aberrant facialnerve regeneration. Self-image, general attitudetoward quality of life, attitude regardingsocial interaction, perception of facial appearance,and peripheral visual function were theinitial domains. It should be noted that manypatients stated that reflex tearing was improved,but this morbidity issue was not dealtwith in the subjective instrument.

InitialValidationofTestInstrument(SmallSampleinOpen-LabelStudy

Design)

Once the questionnaires were completed,each domain was tested against a sample of sixpatients with factor analysis, test-retest reliability,and before-and-after test result after injectionof botulinum toxin test article. Comparisonof each domain against the age-and sexmatchedcontrols (3:1 control/test case ratio, n

.

18) yielded significant differences for alldomains (p.0.01, Fishers). Factor analysiswithin each domain was used to identify deviantquestions, which were removed. Botulinuminjection produced substantial reduction in in-FIG. 1. Diagram of corneal margin to reflect distance and vertical palpebral distance (measurements ofpalpebral asymmetry with facial movement).


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TABLE ISynkinesis Physicians Grading Scale

Grade Description

0 Not present

1 Mild; upper lid closure 1.5 mm

2 Mildmoderate; upper eyelid closure to within 1 mm ofthe corneal light reflex

3 Moderate; upper eyelid moves to the position of thecorneal light reflex

4 Moderatesevere; corneal light reflex is obliterated byupper eyelid movement

5 Severe; upper lid moves to the position of the inferiorlimbus at the 6-oclock position with evidence of scleralshow

6 Very severe; eye closes completely with lower facialmovement

voluntary eyelid closure using vertical palpebralfissure and corneal light reflex to uppereyelid margin distance comparing baseline toposttreatment measurements in the open-labeltrial (Table III). Pearson linear correlation

comparing subjective result and degree of synkineticclosure was not significant for the pilotsix-patient study group. Improvement in domainscores did occur in this small group infive of six patients (Table IV). From reviewingthe cross-correlation between domain scores,the self-image domain was merged into thepersonal appearance domain, as responsesyielded similar results. Self-perception of severityof the problem was a final domain added.Complications in this group included dry eye,lagophthalmos, and ecchymosis.

TABLE IIExposure Grading Scale

Grade Description0 No symptoms of exposure keratitis1 Symptoms of transient ocular irritation that can berelieved by lubricating ophthalmic drops or ophthalmicointment2 No symptoms of dry eye syndrome; however, superficial


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punctate keratopathy of less than 1/8 of the cornea; noevidence of ciliary injection of the eye3 Symptoms of exposure keratitis (ocular irritation)associated with evidence of superficial punctatekeratopathy of less than 1/8 of the cornea; no evidenceof ciliary injection of the eye4 Symptoms of exposure keratitis (pain) associated withsuperficial keratopathy of greater than 1/8 of thecornea on slit-lamp examination and early injection ofthe ciliary vessels5 Greater than 50% of the cornea has superficial punctatekeratopathy associated with ciliary injection and pain6 Pain associated with corneal erosions, ciliary injection7 Corneal ulceration associated with extreme pain andintense photophobia; tarsorrhaphy or extended pressurepatching may be necessary

Double-Blind,Placebo-ControlledTrial

Thirty patients participated in this limb ofthe study, and there were no dropouts. The

diagnosis of participants included 20 patientswith chronic Bells palsy, four patients afteracoustic neuroma surgery, four patients afterRamsey-Hunt syndrome, one patient with mastoiditis,and one patient after meningiomaresection.

The double-blind, placebo-controlled trialdemonstrated efficacy for quality of life, socialinteractions, perception of self-appearance, visualfunction, and perception of severity domains(Table V). Reduction in physical synkinesisas measured with videotaping and

blinded physician assessment was demonstratedfor each form of facial movement asmeasured by the vertical palpebral fissure andcorneal to light reflex distance (Table VI). Thephysicians grading scale easily demonstratedreduced synkinesis (Table VII).

Reflex epiphora (crocodile tears) was reportedto improve in six of nine patients in theactive drug group and zero of six placebotreatedpatients (p.0.05, Fishers two-tailed

test). Two patients in the active drug groupcomplained of transient increased epiphora associatedwith increased physical evidence ofexposure keratitis on slit-lamp examination.

CorrelationbetweenDegreeofFacial


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MovementImpairmentandSubjectiveMorbidity

Correlation between numerical tabulationsfor each morbidity domain and the degree ofsynkinetic movements measured directly onvideotape derived from the double-blind studywas accomplished using a total of 150 matcheddata entries for each of the three facial movementsstudied (Table VIII). Pearson correlationwas low comparing videotaped measurementsto subjective questionnaire performancebut statistically significant for the quality of life,social interaction, and self-appearance domains.The physicians grading scale showedbetter correlation to the morbidity domains(Table IX).

There were no major complications. Physicalsigns of exposure keratitis increased in the active

drug group compared with the controls (p

.0.05, Fishers). No patient exceeded grade 3on the exposure scale (Table II). The remainingcomplications are outlined in Table X. Alldrug-related complications were transient.


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40TABLE IIIChanges in Involuntary Eyelid Closure in Open-Label Pilot GroupPLASTIC AND RECONSTRUCTIVE SURGERY, July2005SmilingPuckeringCorneal 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 ttest.TABLE IVDomain Result (mean score) in Open-Label Trial(n.6)*

Preinjection(SD)Postinjection(SD)Self-imagePersonal appearanceVisualSocial interaction41.33 (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 indicatecloser to normal response. p.0.05, Wilcoxon.


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DISCUSSION

With increasing pressure to provide evidence-based justification for therapies, particularlyin the realm of plastic surgery basedprocedures, the medical profession has reliedon double-blind, placebo-controlled trials asthe highest standard of evidence. Such trialsare further validated when endpoints are bothobjective (measured) and subjective (patientresponse based), with statistically significantcorrelation. The study described in this articleelevated the evidence for botulinum applicationsynkinetic movements associated with aberrantfacial nerve regeneration beyond casereports and case series. Originally, botulinumtoxin received licensing approval for the treatmentof blepharospasm and disorders basedon abnormalities of the seventh cranial nerve,a commingled study group consisting of patientswith Meige syndrome, essential blepharospasm,and hemifacial spasm, and probablyon small numbers of patients with facial musclesynkinesis resulting from aberrant facial nerve

regeneration. The endpoint was originally aninvestigators four-point, five-step gradingscale, with no subjective input. This study demonstratedefficacy with both independent staticsubjective and objective endpoints in a doubleblindedstudy design.

Other contemporary applications of facialbotulinum toxin injection are currently undergoingscrutiny using double-blinded controlledtrials. Over the past 5 years, botulinum toxinhas been advocated for the treatment of essential

headache disorders (tension headache andmigraine) on the basis of observations andeven multiple open-label studies.1619 However,when this indication was evaluated with large,randomized, doubled-blind, controlled trials,the endpoints failed to show differences betweentreatment and control groups; therefore,the efficacy could not be established.20Although this indication may require subgroupidentification, botulinum toxin for the treatmentof headache remains unproven therapyand is controversial based on evidence fromclinical studies.

In the recent literature, multiple studieshave been published on the application of botulinumtoxin for glabellar, frontal, and temporaldynamic rhytides.21,22 Studies conductedused three-point, four-step grading scales designedto quantitate investigators objective assessmentof degree of rhytides and patientglobal self-assessment of severity of rhytideswithout reference to other components of


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morbidity, such as influences on social interaction,behavioral changes, and attitudes regard-

TABLE VResults of Double-Blind, Placebo-Controlled Trial Using Subjective Questionnaire*

Baseline (SD) Postinjection (SD) Wilcoxon (p)Quality of lifeSocialPersonal appearanceVisualSeverity5.01 (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)

0.050.0010.0010.010.05

* Polarity: The lower score reflects improvement, closer to normalcy. n.30, control/treatment ratio (1:1). None of the placebo groups demonstrated any statisticallysignificant differences and there were no differences between baseline and subsequent values for control or active drug groups.


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patient. An approach to scientifically validatingtherapeutic intervention for a specific disorderstarts with a morbidity hypothesis and a measurablephysical defect. For synkinetic eyelidclosure associated with chronic facial palsy, palpebralfissure size changes are physical defectsconveniently measured. Both ophthalmic plasticsurgeons and their patients have long appreciatedthe necessity for symmetric palpebralfissures and upper facial structures to achievenormal facial appearance. Asymmetry causesperception of disfigurement, which influencesconscious and subconscious self-image, socialbehavior, and perception of appearance. The

TABLE VIIPhysicians Grading Scale Result in Double-Blind Control(Placebo Shown)

Placebo Control(SD)Active Drug(SD)

BaselinePosttreatment4.07 (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 assesssuch morbidity categories. In ophthalmic practice,ptosis is probably the most common cause

of palpebral fissure asymmetry and causes notonly disfigurement but also defects in functionalmeasured visual fields,15 a well-acceptedmeasurement of visual function. Thus, a subjectiveendpoint assessing peripheral visionshould be included because of the involuntarynature of palpebral fissure closure.

Comparisons in correlation of objective measurementsto subjective morbidity could providesome useful information on the most appropriateobjective endpoints for scalevalidations. Grading scales and objective endpoints

used as outcome measurements in practiceor studies should have a statistically significantand highest possible correlation tosubjective morbidity. Impairment in social interactionand perception of self-image (appearance)demonstrated the highest correlationto measured asymmetry, compared withperipheral visual function. The interpretationof this finding is that vision obstruction appearsto be less significant than impact on selfimage


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and impairment in social interaction.The subjective morbidity endpoints also moresignificantly correlated to a physicians gradingscale of objective changes compared with directmeasurements of asymmetry from photographicmethods. This finding reinforces theuse of physician grading scales as useful endpointsfor clinical studies for facial disfigurement.Reasons for disparity between objectiveendpoints (photographic measurements andgrading scales) and subjective morbidity includethe following: (1) sampling of the defectis 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 orexocrine gland secretion; (4) there is no accountingfor symptoms of dry eye or exposurekeratitis, which often may accompany the syndrome;and (5) there is a disparity in personalitytypes within any population.

Historically, efforts to quantify the degree ofphysical impairment associated with facial nerveparalysis is a topic well addressed in the medical

literature.1,2,23,24 The House-Brackmann classificationprovides a quick and meaningful scale onthe physical degree of impairment in patientswith facial paralysis, yet the actual subjective morbidityrelated to this impairment was not initiallyidentified. The House-Brackman classification incorporatedreflex synkinesis in the scale. House


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PLASTIC AND RECONSTRUCTIVE SURGERY, July2005

TABLE VIIISignificant Pearson Correlation of the Domain Response and Severity of Synkinesis during Various Facial Movements (n.60)

Smile Pucker ChewVP MCRD VP MCRD VP MCRD

Quality of life 0.262* 0.298* 0.281* 0.280* 0.355 0.364Social 0.321 0.292* 0.328 0.253* 0.394 0.345Personal appearance 0.434 0.355 0.467 0.411 0.489 0.426Visual 0.293* Severity 0.302*

VP, vertical palpebral distance; MCRD, lid margin to corneal light reflex distance.

* p.0.05. p.0.01. p.0.005.Brackman classifications have recently been analyzedfor correlation to social and psychologicalmorbidity.13,25

Among hemifacial involuntary movement disorders,aberrant facial nerve regeneration demonstratesthe least period effect, that is, the moment-to-moment variation in intensity of theinvoluntary spasms. This situation makes physicalmeasurement of palpebral fissure asymmetrymore consistent than many facial movement disordersand allows an increased probability ofidentifying statistically significant correlations.Other facial spastic diseases such as hemifacialspasm and Meige syndrome would be muchmore difficult to assess with subjective-objectivecorrelations because of the large degree of period

effect associated with deformity.

Perhaps in the future, assessing facial disfigurementand movement dysfunction with computerimage analysis24 may provide more globalobjective anatomical scales. However, suchmeasurements will need further programmingdevelopment and need to account for baselinefacial contour variability.


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Improvement in reflex tearing was seen inmost patients in whom the active drug was administered.To the best of the authors knowledge,this is he first controlled evidence of efficacyto this component of the aberrant facialnerve regeneration syndrome. Botulinum toxin

TABLE IXCorrelation of Domain Results with PhysiciansGrading Scale*

PearsonCorrelation

Quality of life 0.583Social interaction 0.637Visual function 0.502Severity 0.566Personal appearance 0.507

* p.

0.001 for all domains.has long been known to suppress autonomicfunction at the axon terminal and/or ganglioniclevel.3 Cholinergic suppression of the gland canoccur from the outer upper eyelid injection, impairingstimulation of the gland with facial movements.As the eccrine sweat gland are also cholinergicallyinnervated, botulinum toxin hasbeen efficacious for Freys syndrome.26 However,caution must be advocated in applying botulinumtoxin in certain instances in which reflextearing may be protective and beneficial, such aspatients with substantial dry eye syndrome or

evidence of neurotrophic keratitis associatedwith the facial nerve palsy.

CONCLUSIONS

This study concludes that botulinum toxininjections are efficacious for synkinetic movementsafter facial paralysis and that there arewide variations in personal perception of thedegree of impairment as reflected by the levelof Pearson correlation between subjective impairmentand objective physical assessment ofthe degree of impairment measured with videotaping

analysis (Table V). This significantbut relatively lower correlation probably can beexplained by occupation, personality, culturaldifferences, and sampling limitations outlinedabove. Others have found a similar degree of

TABLE XDrug-Related Complications


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ActiveDrug PlaceboInduced lagophthalmos 8/15 0/15 (p.0.01, Fishers)Increased physical signs ofexposure 7/15 0/15 (p.0.01, Fishers)New complaints of dry eye 2/15 0/1Induced transient ptosis 0/15 1/15Induced epiphora 2/15 0/15Edema 1/15 0/15Diplopia 1/15 0/15


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correlation when comparing psychological distressto more objectively determine physicalimpairment by means of facial movement assays,the House-Brackmann classification, andother facial grading systems.13,25 Althoughmore valid than objective endpoints, the largervariations in measurement of subjective endpointsrequires studies with more subjects inthe test groups to assess the influence of anytherapeutic intervention.

The results further concluded that impairmentof social interaction, perception of selfappearance,and quality of life were the strongestsubjective domains reflecting the morbidity associatedwith synkinetic eyelid closure found withaberrant facial nerve regeneration, as these domains

correlated best with degree of physicalimpairment and showed the greatest differencesin the double-blind study design. Visual impairment,although statistically significant in the afflictedgroup compared with controls, did notachieve the same degree of correlation to measurementsof physical defect.

GaryE.Borodic,M.D.Beyer,

Townsend&Borodic,P.C.100CharlesRiverPlazaBoston,Mass.02114

REFERENCES

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11: 240, 1990.3. Boroojerdi, B., Ferbert, A., Schwarz, M., Herath, H., andNoth, J. Botulinum toxin treatment of synkinesiaand hyperlacrimation in facial palsy. J.Neurol.Neurosurg.Psychiatry65: 111, 1998.4. Borodic, G. E., Pearce, L. B., Cheney, M., et al.Botulinumtoxin for the treatment of aberrant facial nerveregeneration. Plast.Reconstr.Surg.91: 1042, 1993.5.Foda, H. M. Surgical management of lagophthalmos inpatients with facial palsy. Plast.Reconstr.Surg.20: 391,1999.6.Abell, K. M., Baker, R. S., Cowen, D. E., and Porter, J. D.

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prophylactic treatment in primary headache disorders.Headache43: 853, 2003.17. Dodick, D. W.Botulinum neurotoxin for the treatmentof migraine and other primary headache disorders:From bench to bedside. Headache43: S25, 2003.18. Binder, W. J., Brin, M. F., Blitzer, A., Schoenrock, L. D.,and Pogoda, J. M. Botulinum toxin type A (BOTOX)for the treatment of migraine. Cephalgia20: 422, 2000.19. Smuts, J. A., and Barnard, P. W.

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forehead rhytides. Dermatol.Surg.29: 461, 2003.22. Carruthers, J. A., Lowe, N. J., Menter, M. A., et al.Amulticenter, double blind, randomized placebo controlledstudy of the efficacy and safety of botulinumtoxin type A in the treatment of glabellar lines. J.Am.Acad.


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Dermatol.46: 840, 2002.23. Jensen, C., Devriese, P. P., Jennekens, F. G., and Wijnne,H. J. Lip-length and snout indices in Bells palsy: Acomparison with the House grading scale. ActaOtolarygol.111: 1065, 1991.24. Neely, J. G., Cheung, J. Y., Wood, M., Byers, J., and Rogerson,A. Computerized quantitative dynamic analysisof facial motion in paralyzed and synkinetic face.Am.J.Otol.13: 97, 1992.25. VanSwearingen, J. M., Cohn, J. F., Turnbull, J., Mrzai, T.,and Johnson, P. Psychological distress: Linking impairmentwith disability in facial neuromotor disorders.Otolaryngol.HeadNeckSurg.18: 790, 1998.26. Dulguerov, P., Quinodoz, D., Cosendai, G., Piletta, P.,and Lehmann, W. Frey syndrome treatment with

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