- Email: [email protected]
IncobotulinumtoxinA treatment of facial nerve palsy after neurosurgery
Accepted Manuscript IncobotulinumtoxinA treatment of facial nerve palsy after neurosurgery
Mihail Al'bertovich Akulov, Ol'ga Ratmirovna Orlova, Aleksandra Sergeevna Orlova, Dmitrij Jur'evich Usachev, Vadim Nikolaevich Shimansky, Sergey Vladimirovich Tanjashin, Svetlana Evgen'evna Khatkova, Anna Vladimirovna YunoshaShanyavskaya PII: DOI: Reference:
S0022-510X(17)33742-5 doi: 10.1016/j.jns.2017.08.3244 JNS 15522
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
3 May 2017 21 July 2017 22 August 2017
Please cite this article as: Mihail Al'bertovich Akulov, Ol'ga Ratmirovna Orlova, Aleksandra Sergeevna Orlova, Dmitrij Jur'evich Usachev, Vadim Nikolaevich Shimansky, Sergey Vladimirovich Tanjashin, Svetlana Evgen'evna Khatkova, Anna Vladimirovna Yunosha-Shanyavskaya , IncobotulinumtoxinA treatment of facial nerve palsy after neurosurgery. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2017), doi: 10.1016/j.jns.2017.08.3244
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy
IncobotulinumtoxinA treatment of facial nerve palsy after neurosurgery Mihail Al’bertovich Akulova, Ol’ga Ratmirovna Orlovab, Aleksandra Sergeevna Orlovac, Dmitrij Jur'evich Usacheva, Vadim Nikolaevich Shimanskya, Sergey Vladimirovich Tanjashina, Svetlana Evgen'evna Khatkovad, Anna Vladimirovna Yunosha-Shanyavskayaa
N.N. Burdenko Research Institute of Neurosurgery, Russian Academy of Sciences, 4-ja
PT
a
Tverskaja-Jamskaja str., 16-125047, Moscow, Russia
I.M. Sechenov First Moscow State Medical University, Department of Neurology, shosse
RI
b
I.M. Sechenov First Moscow State Medical University, Department of Human Pathology,
Rossolimo Str., 11-4-119021 Moscow
Federal State Automatic Institution Medical Rehabilitation Center, Ivan'kovskoe shosse, 3-
MA
d
NU
c
SC
Jentuziastov, 86-111123, Moscow, Russia
ED
125367, Moscow, Russia
Corresponding author:
EP T
Dr Mihail Al’bertovich Akulov
N.N. Burdenko Research Institute of Neurosurgery
AC C
4-ja Tverskaja-Jamskaja str. 16-125047, Moscow
Telephone: 89039607407 Email: [email protected]
Author email addresses: MA Akulov [email protected] OR Orlova [email protected] AS Orlova [email protected] 1
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy DJ Usachev [email protected] VN Shimansky [email protected] SV Tanyashin [email protected] SE Khatkova [email protected]
PT
AV Yunosha-Shanyavskaya [email protected]
Conflicts of interest: None
AC C
EP T
ED
MA
NU
SC
RI
Abstract presented as a poster at TOXINS 2017, January 18–21, 2017, Madrid, Spain.
2
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy Keywords: Botulinum toxin type A, facial nerve injury, incobotulinumtoxinA, synkinesis
Abbreviations FDI, Facial Disability Index IQR, inter-quartile range
PT
SD, standard deviation
RI
SFG, Sunnybrook Facial Grading scale
SC
ABSTRACT
Background: This study evaluates the effect of incobotulinumtoxinA in the acute and chronic
NU
phases of facial nerve palsy after neurosurgical interventions.
Methods: Patients received incobotulinumtoxinA injections (active treatment group) or
MA
standard rehabilitation treatment (control group). Functional efficacy was assessed using House-Brackmann, Yanagihara System and Sunnybrook Facial Grading scales, and Facial Disability Index self-assessment.
ED
Results: Significant improvements on all scales were seen after 1 month of incobotulinumtoxinA treatment (active treatment group, р < 0.05), but only after 3 months of
EP T
rehabilitation treatment (control group, р < 0.05). At 1 and 2 years post-surgery, the prevalence of synkinesis was significantly higher in patients in the control group compared with those receiving incobotulinumtoxinA treatment (р < 0.05 and р < 0.001, respectively).
AC C
Conclusions: IncobotulinumtoxinA treatment resulted in significant improvements in facial symmetry in patients with facial nerve injury following neurosurgical interventions. Treatment was effective for the correction of the compensatory hyperactivity of mimic muscles on the unaffected side that develops in the acute period of facial nerve palsy, and for the correction of synkinesis in the affected side that develops in the long-term period. Appropriate dosing and patient education to perform exercises to restore mimic muscle function should be considered in multimodal treatment.
3
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy
1. Introduction Facial nerve injury is one of the most common post-operative complications of surgical treatment for posterior cranial fossa and cerebello-pontine angle tumors [1]. This type of facial nerve palsy may be accompanied by multiple complications that are resistant to treatment and affect the structure and function of the mimic muscles [2,3].
PT
Patients develop unilateral paresis or palsy of the mimic muscles with functional deterioration
RI
including lagophthalmos (with the development of trophic disturbances and kerato-conjunctival xerosis), difficulty eating and drinking, and speech disturbance [4].
SC
Functional deterioration and pronounced facial asymmetry may be accompanied by severe
NU
psychological consequences for the patient, including low self-esteem, social isolation, anxiety, and depression [5,6].
MA
There are a number of treatment options for facial nerve palsy, depending on the etiology and pathogenesis of the condition and the level of pharmacologic and physical treatment
ED
modalities available [7,8]. These options can be divided into conservative treatments (pharmacologic and physical therapy) and surgical methods, and usually aim to activate the
EP T
mimic muscles on the affected side. However, a novel method using the contemporary local neuromuscular blocking agent, botulinum toxin type A, induces prolonged relaxation of the
AC C
mimic muscles on the unaffected side [9,10]. Injection of botulinum toxin into the unaffected mimic muscles is recommended during the acute phase of facial nerve palsy to reduce facial asymmetry and decrease the elevated muscle tone of the unaffected muscles [9]. It is thought that the elevated muscle tone of the unaffected muscles negatively impacts on the already overstretched muscles on the affected side, reducing the potential for recovery [11]. In addition, the resulting temporary muscle weakness on the unaffected side provides strength to the structures on the paralyzed side, promoting their function [12]. Patients develop a post-paralytic syndrome 4–6 months after facial nerve palsy, which is characterized by mimic muscle deficiency and a number of additional symptoms, including 4
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy mimic muscle contracture, pathologic synkinesis of the mimic muscles (involuntary muscle activity during voluntary contraction of unaffected muscles situated nearby), spontaneous muscle twitching, hemifacial sweating, lacrimation, and salivation [13]. These complications are caused by aberrant reinnervation and/or ephaptic transmission, during which two types of interactions between motor nerve and muscle take place. In type-1 interactions, an axon that
PT
previously innervated one muscle starts to innervate another muscle, while in type-2 interactions the axon branches out to innervate two or more muscles. These interactions may
RI
lead to the development of synkinesis, which in severe cases may induce substantial muscle
SC
contractions on one side of the face.
NU
The advantages of treating acute and chronic facial palsy with botulinum toxin include the simplicity of injection, flexibility of injection points, and the promptness and longevity of
MA
effect [14]. Previous clinical experience with botulinum toxin demonstrated its efficacy in facial nerve palsy with a reduction in facial asymmetry in the short-term and reduced rate of
ED
late complications including contractures and synkinesis [9,12–16]. The aim of our study was to evaluate the effect of local incobotulinumtoxinA injections into the mimic muscles in acute
EP T
and chronic phases of facial nerve palsy after neurosurgical interventions in comparison with
AC C
non-pharmacologic treatment with adhesive plaster traction.
2. Materials and methods 2.1. Study design and patients This single-center, open-label, single-blind, randomized study recruited patients (aged 18–65 years) in the acute phase of facial nerve palsy following surgical treatment for posterior cranial fossa and cerebello-pontine angle tumors. Patients were randomly assigned to the main active treatment group (incobotulinumtoxinA) or a control group (adhesive plaster traction) in a 2:1 ratio. The total duration of participation in the study was 2 years.
5
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy Major exclusion criteria included facial nerve paresis of non-surgical etiology, complete rupture of the facial nerve during surgical resection of the tumor, non-compliance with treatment regimen including control visits, and individual complications, intolerance, or side effects to treatment. The study protocol was approved by the local Ethical Committee of the N.N. Burdenko
PT
Research Institute of Neurosurgery, Moscow, Russia. All procedures complied with the standards established by the Declaration of Helsinki and signed, informed consent was
SC
RI
gathered from all patients.
NU
2.2. Treatment
2.2.1. Acute-phase treatment with incobotulinumtoxinA
MA
Patients in the active treatment group received the first injection of incobotulinumtoxinA (Xeomin®, Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany) 24–48 hours after
ED
the development of mimic muscle paresis or palsy. During the acute-phase treatment, incobotulinumtoxinA was injected into active muscles on the unaffected side to correct
EP T
(decrease) the tension of these muscles (Table 1). The total dose of incobotulinumtoxinA was 40–50 U per patient and the total number of injection points varied between 10 and 15.
AC C
Repeated injections were performed 4 and 8 months after the start of the study.
6
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy Table 1 Acute-phase treatment: incobotulinumtoxinA treatment of mimic muscles on the Muscle
Number of
IncobotulinumtoxinA
injection
dose per site, U
sites 2
3
Musculus corrugator supercilii
2
4 and 2, respectively
Musculus levator labii superioris alaeque nasi
1
RI
PT
Musculus frontalis
Musculus zygomaticus
1
2
1
2
1
2
1
2
1
1
1
1–2
1
2
2–4
4–5
Musculus buccinator
1
2.5
Musculus risorius
1
2
SC
Minor
2
NU
Major Musculus levator labii superioris
MA
Musculus levator anguli oris Musculus orbicularis oris
Musculus mentalis
AC C
EP T
Musculus platysma
ED
Musculus depressor labii inferioris
unaffected side.
7
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy 2.2.2 Chronic-phase treatment with incobotulinumtoxinA Treatment of synkinesis as a complication of the neurosurgery commenced 8 months after the surgery. Injections of small doses of incobotulinumtoxinA (1–1.5 U per injection point) were performed into the muscles on the affected side and symmetrically in a doubled dose into the muscles on the unaffected side.
PT
To achieve medically induced ptosis for the correction of lagophthalmos complications, neuro-ophthalmologists from the N.N. Burdenko Research Institute of Neurosurgery
RI
performed incobotulinumtoxinA injections (15 U) into the projection point of musculus
SC
levator palpebrae superioris (Fig. 1) [17]. The injection was repeated after 4–7 days with the
AC C
EP T
ED
MA
NU
same dose if the desired effect was not achieved after the first injection.
Fig. 1. IncobotulinumtoxinA injection sites on the unaffected side and drug-induced eyelid ptosis on the affected side.
8
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy 2.2.3. Adhesive plaster traction Patients in the control group received adhesive plaster traction aligned from the unaffected side to the affected side against the muscle traction of the unaffected side 24–48 hours after the development of mimic muscle paresis or palsy. Treatment continued for up to 3 months. Corrective plaster dressings (1–2 cm wide) were applied on the skin surface in the area of the
PT
contracted muscles with plaster fixation near bony structures (temporal area, zygomatic bone, and mandibula). Skin and muscles of the affected side were pulled upwards and laterally to
RI
prevent paretic muscles from stretching. Patients were instructed to perform position
SC
treatment, initially for 30–60 minutes per day, predominantly during active mimic movements
NU
(during meals or communication) [18]. Treatment time was gradually increased to 2–6 hours a day over 2 weeks depending on patients’ tolerability to treatment and convenience. Position
MA
treatment was continued for 3–4 months. 2.2.4. Physiotherapy
ED
A similar physiotherapy program was introduced in both groups and included individualized movement therapy (taking into account clinical and functional alterations), facial massage,
EP T
physical exercises performed in front of a mirror to retain functional control of the mimic muscles, and articulation exercises in front of a mirror with pronunciation of sounds, words,
AC C
and tongue-twisters.
2.3. Efficacy assessments Treatment efficacy was assessed clinically, taking parameters of neuromuscular functionality into account. Assessments were performed by an independent researcher who was blinded to the treatment administered to each patient. The severity of facial palsy was assessed using the House-Brackmann scale (6-point scale ranging from 1 [normal] to 6 [total paralysis]) [19] and the Yanagihara System (5-point facial nerve grading system ranging from 0 [normal function] to 4 [total paralysis] for 10 items [at rest, wrinkle forehead, blink, slight eye closure, tight eye 9
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy closure, eye closure on affected side, wrinkle nose, whistle, grin, depress lower lip], with a total score ranging from 0 to 40) [20]. Patients also completed the Facial Disability Index (FDI) self-assessment scale, which assesses physical function and social wellbeing on a combined scale from 0 (worst) to 200 (best) [21]. The Sunnybrook Facial Grading scale (SFG), a combined score relating to the degree of facial symmetry, normal voluntary muscle
PT
movement, and synkinesis ranging from 0 (severe impairment) to 100 (normal function) [22],
RI
was used for the assessment of facial symmetry and synkinesis.
SC
2.4. Statistical analysis
NU
Changes in mean House-Brackmann scores and Yanagihara System mean score were analyzed using one-sample t-tests with no replacement of missing data. Comparison of SFG
MA
scores was performed using the Wilcoxon signed rank test for non-parametric paired samples. Comparison between control and active treatment groups for functional improvement was
ED
performed by Student’s t-test. A p-value of < 0.05 was considered significant. All statistical
3. Results
EP T
analyses were performed using SAS version 8.2 or later (SAS Institute, Cary, NC, USA).
AC C
3.1. Patient baseline characteristics Seventy-six patients in the acute phase of facial nerve palsy following surgical treatment for posterior cranial fossa or cerebello-pontine angle tumors were evaluated. Of these, 51 patients were randomly assigned to the active treatment (incobotulinumtoxinA) group and 25 patients to the control (adhesive plaster traction) group. Age and sex distribution were similar between the groups (Table 2). The majority of patients had facial nerve palsy following surgical removal of vestibular schwannoma (48 patients, 63.2%) and the remainder following surgical removal of petro-clival meningioma (28 patients, 36.8%), with both etiologies equally distributed 10
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy between the two groups. The most common clinical symptoms were similar in both groups and included mimic muscle weakness (100% overall) and hypacusia (92.2%), while dry eye (21.1%) and facial hypesthesia (11.8%) were the least common. At baseline, dysfunction measured on the House-Brackmann scale was similar in both groups (mean [standard deviation; SD] score, 3.3 [1.0] in the active treatment group and 3.4 [0.9] in
PT
the control group). Moderate facial nerve dysfunction on the House-Brackmann scale (grade 3) was significantly more prevalent than other grades of dysfunction in both groups (р < 0.05)
RI
(Table 2). The mean (SD) score on the Yanagihara System scale was also similar for both
SC
groups, 20.1 (7.0) [range 11–31 points] and 19.9 (5.3) [range 10–32 points] in the active
AC C
EP T
ED
MA
NU
treatment and controls groups, respectively.
11
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy Table 2 Patient demographics and baseline characteristics.
Characteristic
IncobotulinumtoxinA,
Control,
Total,
n = 51
n = 25
n = 76
Male
28 (54.9)
13 (52)
41 (53.9)
Female
23 (45.1)
12 (48)
35 (46.1)
48.2 (6.4)
46.7 (7.1)
SC
PT
Sex, n (%)
32 (62.7)
16 (64.0)
48 (63.2)
19 (37.3)
9 (36.0)
28 (36.8)
51 (100)
25 (100)
76 (100)
27 (52.9)
14 (56.0)
41 (53.9)
Lacrimation
18 (35.3)
8 (32.0)
26 (34.2)
Dry eye
11 (21.6)
5 (20.0)
16 (21.1)
Facial hypesthesia
6 (11.8)
3 (12.0)
9 (11.8)
Hypacusia
47 (92.2)
23 (92.0)
70 (92.1)
Grade 1
0
0
0
Grade 2
7 (13.7)
4 (16.0)
11 (14.5)
45.3 (7.7)
RI
Age, years; mean (SD) Surgical procedure leading to symptoms, n (%)
NU
Removal of vestibular
Removal of petro-clival meningioma
MA
schwannoma
ED
Clinical symptoms, n (%)*
EP T
Mimic muscle weakness
Discomfort in the mastoid bone
AC C
area
Baseline facial nerve asymmetry on House-Brackmann scale, n (%)
12
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy IncobotulinumtoxinA,
Control,
Total,
n = 51
n = 25
n = 76
Grade 3
24 (47.1)
11 (44.0)
35 (46.1)
Grade 4
11 (21.6)
6 (24.0)
17 (22.4)
Grade 5
9 (17.6)
4 (16.0)
13 (17.1)
Grade 6
0
0
0
PT
Characteristic
RI
*Patients could have more than one symptom.
SC
SD, standard deviation.
NU
3.2. Efficacy after acute-phase treatment
A marked improvement in facial nerve dysfunction was shown after 1 month of treatment
MA
with incobotulinumtoxinA in the active treatment group (Fig. 2 and Table 3). Facial nerve dysfunction decreased by 1.4-fold in the active treatment group compared to baseline
ED
(p < 0.05) and by 1.3-fold compared with the control group (р < 0.05). After 3 months of incobotulinumtoxinA treatment, the decrease in facial nerve dysfunction remained at 1.4-fold
EP T
in the active treatment group compared to baseline (p < 0.05). There was no significant difference in House-Brackmann score between 1 and 3 months post-treatment in this group,
AC C
most likely due to waning of the clinical effect of the botulinum toxin at this time point. In the control group, a significant reduction in facial nerve dysfunction compared to baseline level (р < 0.05) was observed only after 3 months of rehabilitation treatment (Fig. 2 and Table 3).
13
ACCEPTED MANUSCRIPT
NU
SC
RI
PT
BoNT treatment of facial palsy
MA
Fig. 2. House-Brackmann facial asymmetry grade over time. Box whisker plots representing the spread of House-Brackmann facial asymmetry scores in
ED
patients in the active treatment and control groups. Boxes represent the spread of the scores between 25th and 75th percentile; horizontal lines represent the median score; whiskers
EP T
represent the 0 and 100th percentiles.
AC C
An improvement of 1.7-fold on the Yanagihara System scale compared to baseline was shown in the active treatment group after 1 month (р < 0.05) and of 1.9-fold after 3 months (p < 0.05). The difference in scores at 1 and 3 months post-treatment was not significant (p > 0.05).
In the control group, there was a slight improvement of 1.2-fold on the Yanagihara System scale between baseline and 1 month post-treatment (p > 0.05). However, after 3 months of treatment, a significant improvement of 1.9-fold compared to baseline (р < 0.05) was observed (Table 3).
14
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy In summary, incobotulinumtoxinA treatment of facial nerve dysfunction in the early post-operative period provided a more rapid clinical effect in comparison with traditional treatment approaches.
Table 3 House-Brackmann and Yanagihara System scale scores in the acute phase. Baseline
1 month
PT
Scale and treatment
post-treatment
RI
House-Brackmann scale
IncobotulinumtoxinA
3.3 (1.0)
Control
3.4 (0.9)
NU
Yanagihara System scale score, mean (SD)
20.1 (7.0)
MA
IncobotulinumtoxinA Control
19.9 (5.3)
2.3 (1.2)*
3.2 (1.0)
2.8 (1.0)*
35.1 (8.0)*
38.4 (7.2)*
24.5 (6.1)
36.9 (6.9)*
AC C
EP T
ED
*P < 0.05 for facial nerve dysfunction scores post-treatment vs baseline. SD, standard deviation.
15
post-treatment
2.4 (1.2)*
SC
score, mean (SD)
3 months
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy
3.3. Efficacy after chronic-phase treatment The next phase of the study evaluated long-term facial nerve dysfunction 6 months, 12 months, and 2 years after the neurosurgical intervention. A total of 64 patients completed 12 months of treatment, including 45 (88.2%) patients from the active treatment group and 19
PT
(76.0%) patients from the control group; 51 patients completed 2 years of treatment, including 37 (72.5%) and 14 (56.0%) patients in the active treatment and control groups, respectively.
RI
Of the 14 patients from the active treatment group who failed to complete 2 years of
SC
treatment, nine (64.3%) refused to continue treatment because of distant residence and transportation problems and five (35.7%) for family reasons. Of the 11 patients in the control
NU
group who discontinued treatment prematurely, the majority (five patients, 45.4%) withdrew due to low treatment efficacy, and the remainder due to distant residence (two patients,
MA
18.2%) and for family reasons (four patients, 36.3%).
Six months after the surgical intervention, there was a trend towards a lower prevalence of
ED
synkinesis in the active treatment group (23 patients, 45.1%) compared with the control group
EP T
(16 patients, 64.0%). Patients in the active treatment group continued incobotulinumtoxinA treatment with 1.5–2 U per point injected on the affected side in the area of synkinesis and 2– 4 U per injection point on the unaffected side to maintain facial symmetry.
AC C
One year after the surgical intervention, the prevalence of synkinesis was significantly lower in the group of patients who had received incobotulinumtoxinA injections compared with the control group (р < 0.05). Differences between the groups continued to increase until the end of the second year of treatment (р < 0.001) (Table 4).
16
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy Table 4 Number of patients with synkinesis in the long-term follow-up period. IncobotulinumtoxinA,
Control,
n = 51
n = 25
6 months (N = 76)
23 (45.1%) [n = 51]
16 (64.0%) [n = 25]
1 year (N = 64)
14 (31.1%)* [n = 45]
13 (68.4%) [n = 19]
2 years (N = 51)
6 (16.2%)** [n = 37]
11 (78.6%) [n = 14]
PT
Follow-up period
RI
*P < 0.05 for incobotulinumtoxinA vs control.
SC
**P < 0.001 for incobotulinumtoxinA vs control.
NU
Compared with patients in the control group, 6 months and 1 year after the neurosurgical intervention, there was a significant improvement in median SFG scores (symmetry of
MA
voluntary movement, synkinesis, composite score) for the active treatment group (р < 0.05). After 2 years, there was a significant increase in all SFG partial scores (resting symmetry,
ED
symmetry of voluntary movement, synkinesis, and composite score) in patients receiving
AC C
EP T
incobotulinumtoxinA injections (р < 0.05) (Table 5).
17
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy Table 5 Sunnybrook Facial Grading scale scores in the long-term follow-up period.
Sunnybrook Facial Grading scale
IncobotulinumtoxinA
Control
n = 51
n = 25
Resting symmetry
-5 [-10; -5]
-5 [-10; -5]
Symmetry of voluntary movement*
64 [52; 76]
60 [48; 72]
-6 [-9; 2]
-9 [-11; 4]
Median [IQR]
PT
6 months after neurosurgical intervention
RI
Synkinesis*
72 [51; 86]
SC
Composite score* 1 year after neurosurgical intervention
MA
Symmetry of voluntary movement* Synkinesis*
ED
Composite score*
2 years after neurosurgical intervention
EP T
Resting symmetry*
Symmetry of voluntary movement*
AC C
Synkinesis*
n = 45
n = 19
-5 [-10; 0]
-5 [-10; -5]
68 [62; 80]
56 [44; 72]
-5 [-7; 4]
-9 [-12; 3]
81 [56; 95]
56 [41; 63]
n = 37
n = 11
-5 [-5; 0]
-5 [-10; 0]
76 [66; 84]
56 [42; 68]
-3 [-5; 7]
-11 [-13; 0]
88 [65; 96]
47 [32; 65]
NU
Resting symmetry
Composite score*
57 [44; 69]
*P < 0.05 for incobotulinumtoxinA vs control (two-tailed probability). IQR, interquartile range.
The mean (SD) FDI score in the active treatment group was also higher than that of the control group 6 months after the neurosurgical intervention, 127.8 (19.2) and 108.2 (17.0), respectively (p < 0.05). One year after the start of treatment, the mean (SD) FDI score in the active treatment and control groups was 142.0 (19.3) and 97.6 (20.6), respectively (р < 0.05). 18
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy After 2 years of treatment, the mean FDI score in the active treatment group was 1.96-fold higher than that of patients in the control group (mean [SD] scores, 167.3 [21.4] and 85.3 [14.7], respectively, р < 0.05).
3.4. Safety
PT
Adverse events were observed in five (9.8%) patients in the active treatment group, including lip ptosis (three patients, 5.9%), which regressed within 3 months; negligible ptosis (two
RI
patients, 3.9%), which regressed within 1 month; difficulty speaking as a result of mimic
SC
muscle weakness (four patients, 7.8%); dry eye (three patients, 5.9%). Other than dry eye,
NU
which required prescription of saline eye drops, all other adverse symptoms regressed without
MA
treatment and did not require special interventions.
4. Discussion
ED
Treatment of facial nerve palsy both in the acute and chronic periods is challenging and
EP T
requires a multimodal approach. In our opinion, the maintenance of facial symmetry and the inhibition of mimic muscle hyperactivity on the unaffected side in the acute phase of facial nerve palsy following neurosurgical intervention is one of the key factors to reduce
AC C
complications, such as synkinesis and contractures, in the longer term. This supports the utilization of botulinum toxin type A for the treatment of these pathologic conditions [23]. The main goals of rehabilitative measures in the treatment of facial nerve palsy are to: create optimal conditions to support regenerative processes and to preserve denervated muscle tissue; prevent muscle contraction on the unaffected side (‘antagonist contraction’) and of the muscles of mastication; attempt to restore involuntary movements into voluntary movements including different synergic reactions (proprioceptive facilitation and stimulation) ; increase
19
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy muscle strength through adequate exercise; prevent substitutive movements (when minimal voluntary activity reappears); and restore isolated voluntary muscle contractions [24]. In our study, patients with facial nerve palsy after the neurosurgical removal of posterior cranial fossa and cerebello-pontine angle tumors received incobotulinumtoxinA injections as a part of the rehabilitation treatment or received non-pharmacologic treatment (plaster
PT
traction) instead. The inclusion of a comparator control group using standard rehabilitation treatment in a ‘real-world’ clinical setting is a strength of our study design. The small sample
RI
size and lack of placebo control are the main limitations to our study. In addition, the
SC
observers were not blinded to the treatments patients had received. However, we
NU
demonstrated that incobotulinumtoxinA treatment enabled a more prominent therapeutic effect and more rapid functional restoration of the affected nerve and mimic muscles than
MA
treatment with adhesive plaster traction.
In conclusion, incobotulinumtoxinA treatment was a good therapeutic option in both the acute
ED
and chronic phase of facial nerve palsy. Accurate dosing and appropriate administration of incobotulinumtoxinA, with patient education to perform special exercises for the restoration
EP T
of mimic muscle function, should be considered as a part of the multidisciplinary treatment of
AC C
patients with facial nerve palsy.
Acknowledgements The authors wish to thank the patients and study investigators. The first draft manuscript was written by Mihail Al’bertovich Akulov. Editorial support with preparation of the manuscript (editing for English language) was provided by Claire Cairney, PhD, of Complete Medical Communications and funded by Merz Pharmaceuticals GmbH.
20
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy
Funding This study was funded by Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany. The funding body had no influence on the study design, the study conduct, preparation of the
AC C
EP T
ED
MA
NU
SC
RI
PT
manuscript or the decision to publish.
21
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy
References [1]
J.K. Terzis, P. Konofaos, Experience with 60 adult patients with facial paralysis secondary to tumor extirpation, Plast. Reconstr. Surg. 130 (2012) 51e–66e.
[2]
A.L. Ho, A.M. Scott, A.F. Klassen, S.J. Cano, A.L. Pusic, N. Van Laeken, Measuring
PT
quality of life and patient satisfaction in facial paralysis patients: a systematic review
RI
of patient-reported outcome measures, Plast. Reconstr. Surg. 130 (2012) 91–99. Ye.V. Saksonova, Facial nerve neuropathy, Novaja apteka 2 (2013) 94–95.
[4]
Ekman P., Psychosocial aspects of facial paralysis in: May M., ed. The Facial Nerve.
SC
[3]
F.C. Macgregor, Facial disfigurement: problems and management of social interaction
MA
[5]
NU
New York: Thieme Medical (1986) 781–787.
and implications for mental health, Aesthetic Plast. Surg. 14 (1990) 249–257. B. Ross, J.M. Nedzelski, J.A. McLean, Efficacy of feedback training in long-standing
ED
[6]
[7]
EP T
facial nerve paresis, Laryngoscope 101 (1991) 744–750. S.V. Surovyh, Combined surgical treatment of patients with facial nerve neuropathy,
[8]
AC C
avtoref. dis. na. soisk. uchen. step. kmn. (2008) 1–24. M.J. Maksimova, M.N. Sharov, M.A. Damashenko, Facial nerve neuropathy, Farmateka 14 (2011) 46–51. [9]
J. Kim, Contralateral botulinum toxin injection to improve facial asymmetry after acute facial paralysis, Otol. Neurotol. 34 (2013) 319–324.
[10]
O.R. Orlova, Ju.V. Mozolevskij, L.R. Mingazova, Facial nerve neuropathy (Bell's palsy) in: Selected lectures on neurology II. MEDpress-inform (2012) 381–394.
22
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy [11]
O.R. Orlova, N.N. Jahno, Clinical use of Botox (Botulinum Toxin-A): physician guideline, (2001) 208.
[12]
A.G. Salles, P.N. Toledo, M.C. Ferreira, Botulinum toxin injection in long-standing facial paralysis patients: improvement of facial symmetry observed up to 6 months,
[13]
PT
Aesthetic Plast. Surg. 33 (2009) 582–590. A.G. Salles, E.F. da Costa, M.C. Ferreira, A.F. Remigio, L.B. Moraes, R. Gemperli,
RI
Epidemiologic Overview of Synkinesis in 353 Patients with Longstanding Facial
SC
Paralysis under Treatment with Botulinum Toxin for 11 Years, Plast. Reconstr. Surg.
[14]
NU
136 (2015) 1289–1298.
Ye.V. Saksonova, O.R. Orlova, Application of Type A botulinum toxin in case of
G.B. Krohel, C.L. Cipollo, K. Gaddipati, Contralateral botulinum injections improve
ED
[15]
MA
facial nerve damage, Vestnik jesteticheskoj mediciny 12 (2013) 35–42.
drinking ability and facial symmetry in patients with facial paralysis, Am. J.
[16]
EP T
Ophthalmol. 139 (2005) 540.
M. de Maio, R.F. Bento, Botulinum toxin in facial palsy: an effective treatment for
[17]
AC C
contralateral hyperkinesis, Plast. Reconstr. Surg. 120 (2007) 917–927. T.V. Tabashnikova, N.K. Serova, V.N. Shimanskii, N.N. Grigor'eva, [Botulotoxin type A (lantox) for inducing temporal ptosis in neurosurgical patients], Zh. Vopr. Neirokhir. Im N. N. Burdenko 76 (2012) 43–48. [18]
O.G. Kogan, V.L. Najdin, Medical rehabilitation in neurology and neurosurgery, Moscow Medicine (1988) 206–215.
23
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy [19]
J.W. House, D.E. Brackmann, Facial nerve grading system, Otolaryngol. Head Neck Surg. 93 (1985) 146–147.
[20]
Yanagihara N., Grading of facial nerve palsy in: Fisch U., ed. Facial nerve surgery. Birmingham, AL.: Aesculapius Publishing Co. (1977) 533–535. J.M. VanSwearingen, J.S. Brach, The Facial Disability Index: reliability and validity
PT
[21]
of a disability assessment instrument for disorders of the facial neuromuscular system,
SC
[22]
RI
Phys. Ther. 76 (1996) 1288–1298.
J.G. Neely, N.G. Cherian, C.B. Dickerson, J.M. Nedzelski, Sunnybrook facial grading
K. Fujiwara, Y. Furuta, Y. Nakamaru, S. Fukuda, Comparison of facial synkinesis at 6
MA
[23]
NU
system: reliability and criteria for grading, Laryngoscope 120 (2010) 1038–1045.
and 12 months after the onset of peripheral facial nerve palsy, Auris Nasus Larynx 42
A. Baricich, C. Cabrio, R. Paggio, C. Cisari, P. Aluffi, Peripheral facial nerve palsy:
EP T
how effective is rehabilitation?, Otol. Neurotol. 33 (2012) 1118–1126.
AC C
[24]
ED
(2015) 271–274.
24
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy
Highlights
Treatment of facial nerve palsy is challenging, requiring a multi-modal approach. IncobotulinumtoxinA was effective in acute and chronic phases of facial
PT
nerve palsy. Clinical effects were more rapid compared to traditional treatment
RI
approaches.
SC
Facial asymmetry and rate of long-term contractures and synkinesis were reduced.
NU
IncobotulinumtoxinA should be considered in multi-modal treatment of
AC C
EP T
ED
MA
facial palsy.
25
Mihail Al'bertovich Akulov, Ol'ga Ratmirovna Orlova, Aleksandra Sergeevna Orlova, Dmitrij Jur'evich Usachev, Vadim Nikolaevich Shimansky, Sergey Vladimirovich Tanjashin, Svetlana Evgen'evna Khatkova, Anna Vladimirovna YunoshaShanyavskaya PII: DOI: Reference:
S0022-510X(17)33742-5 doi: 10.1016/j.jns.2017.08.3244 JNS 15522
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
3 May 2017 21 July 2017 22 August 2017
Please cite this article as: Mihail Al'bertovich Akulov, Ol'ga Ratmirovna Orlova, Aleksandra Sergeevna Orlova, Dmitrij Jur'evich Usachev, Vadim Nikolaevich Shimansky, Sergey Vladimirovich Tanjashin, Svetlana Evgen'evna Khatkova, Anna Vladimirovna Yunosha-Shanyavskaya , IncobotulinumtoxinA treatment of facial nerve palsy after neurosurgery. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2017), doi: 10.1016/j.jns.2017.08.3244
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy
IncobotulinumtoxinA treatment of facial nerve palsy after neurosurgery Mihail Al’bertovich Akulova, Ol’ga Ratmirovna Orlovab, Aleksandra Sergeevna Orlovac, Dmitrij Jur'evich Usacheva, Vadim Nikolaevich Shimanskya, Sergey Vladimirovich Tanjashina, Svetlana Evgen'evna Khatkovad, Anna Vladimirovna Yunosha-Shanyavskayaa
N.N. Burdenko Research Institute of Neurosurgery, Russian Academy of Sciences, 4-ja
PT
a
Tverskaja-Jamskaja str., 16-125047, Moscow, Russia
I.M. Sechenov First Moscow State Medical University, Department of Neurology, shosse
RI
b
I.M. Sechenov First Moscow State Medical University, Department of Human Pathology,
Rossolimo Str., 11-4-119021 Moscow
Federal State Automatic Institution Medical Rehabilitation Center, Ivan'kovskoe shosse, 3-
MA
d
NU
c
SC
Jentuziastov, 86-111123, Moscow, Russia
ED
125367, Moscow, Russia
Corresponding author:
EP T
Dr Mihail Al’bertovich Akulov
N.N. Burdenko Research Institute of Neurosurgery
AC C
4-ja Tverskaja-Jamskaja str. 16-125047, Moscow
Telephone: 89039607407 Email: [email protected]
Author email addresses: MA Akulov [email protected] OR Orlova [email protected] AS Orlova [email protected] 1
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy DJ Usachev [email protected] VN Shimansky [email protected] SV Tanyashin [email protected] SE Khatkova [email protected]
PT
AV Yunosha-Shanyavskaya [email protected]
Conflicts of interest: None
AC C
EP T
ED
MA
NU
SC
RI
Abstract presented as a poster at TOXINS 2017, January 18–21, 2017, Madrid, Spain.
2
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy Keywords: Botulinum toxin type A, facial nerve injury, incobotulinumtoxinA, synkinesis
Abbreviations FDI, Facial Disability Index IQR, inter-quartile range
PT
SD, standard deviation
RI
SFG, Sunnybrook Facial Grading scale
SC
ABSTRACT
Background: This study evaluates the effect of incobotulinumtoxinA in the acute and chronic
NU
phases of facial nerve palsy after neurosurgical interventions.
Methods: Patients received incobotulinumtoxinA injections (active treatment group) or
MA
standard rehabilitation treatment (control group). Functional efficacy was assessed using House-Brackmann, Yanagihara System and Sunnybrook Facial Grading scales, and Facial Disability Index self-assessment.
ED
Results: Significant improvements on all scales were seen after 1 month of incobotulinumtoxinA treatment (active treatment group, р < 0.05), but only after 3 months of
EP T
rehabilitation treatment (control group, р < 0.05). At 1 and 2 years post-surgery, the prevalence of synkinesis was significantly higher in patients in the control group compared with those receiving incobotulinumtoxinA treatment (р < 0.05 and р < 0.001, respectively).
AC C
Conclusions: IncobotulinumtoxinA treatment resulted in significant improvements in facial symmetry in patients with facial nerve injury following neurosurgical interventions. Treatment was effective for the correction of the compensatory hyperactivity of mimic muscles on the unaffected side that develops in the acute period of facial nerve palsy, and for the correction of synkinesis in the affected side that develops in the long-term period. Appropriate dosing and patient education to perform exercises to restore mimic muscle function should be considered in multimodal treatment.
3
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy
1. Introduction Facial nerve injury is one of the most common post-operative complications of surgical treatment for posterior cranial fossa and cerebello-pontine angle tumors [1]. This type of facial nerve palsy may be accompanied by multiple complications that are resistant to treatment and affect the structure and function of the mimic muscles [2,3].
PT
Patients develop unilateral paresis or palsy of the mimic muscles with functional deterioration
RI
including lagophthalmos (with the development of trophic disturbances and kerato-conjunctival xerosis), difficulty eating and drinking, and speech disturbance [4].
SC
Functional deterioration and pronounced facial asymmetry may be accompanied by severe
NU
psychological consequences for the patient, including low self-esteem, social isolation, anxiety, and depression [5,6].
MA
There are a number of treatment options for facial nerve palsy, depending on the etiology and pathogenesis of the condition and the level of pharmacologic and physical treatment
ED
modalities available [7,8]. These options can be divided into conservative treatments (pharmacologic and physical therapy) and surgical methods, and usually aim to activate the
EP T
mimic muscles on the affected side. However, a novel method using the contemporary local neuromuscular blocking agent, botulinum toxin type A, induces prolonged relaxation of the
AC C
mimic muscles on the unaffected side [9,10]. Injection of botulinum toxin into the unaffected mimic muscles is recommended during the acute phase of facial nerve palsy to reduce facial asymmetry and decrease the elevated muscle tone of the unaffected muscles [9]. It is thought that the elevated muscle tone of the unaffected muscles negatively impacts on the already overstretched muscles on the affected side, reducing the potential for recovery [11]. In addition, the resulting temporary muscle weakness on the unaffected side provides strength to the structures on the paralyzed side, promoting their function [12]. Patients develop a post-paralytic syndrome 4–6 months after facial nerve palsy, which is characterized by mimic muscle deficiency and a number of additional symptoms, including 4
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy mimic muscle contracture, pathologic synkinesis of the mimic muscles (involuntary muscle activity during voluntary contraction of unaffected muscles situated nearby), spontaneous muscle twitching, hemifacial sweating, lacrimation, and salivation [13]. These complications are caused by aberrant reinnervation and/or ephaptic transmission, during which two types of interactions between motor nerve and muscle take place. In type-1 interactions, an axon that
PT
previously innervated one muscle starts to innervate another muscle, while in type-2 interactions the axon branches out to innervate two or more muscles. These interactions may
RI
lead to the development of synkinesis, which in severe cases may induce substantial muscle
SC
contractions on one side of the face.
NU
The advantages of treating acute and chronic facial palsy with botulinum toxin include the simplicity of injection, flexibility of injection points, and the promptness and longevity of
MA
effect [14]. Previous clinical experience with botulinum toxin demonstrated its efficacy in facial nerve palsy with a reduction in facial asymmetry in the short-term and reduced rate of
ED
late complications including contractures and synkinesis [9,12–16]. The aim of our study was to evaluate the effect of local incobotulinumtoxinA injections into the mimic muscles in acute
EP T
and chronic phases of facial nerve palsy after neurosurgical interventions in comparison with
AC C
non-pharmacologic treatment with adhesive plaster traction.
2. Materials and methods 2.1. Study design and patients This single-center, open-label, single-blind, randomized study recruited patients (aged 18–65 years) in the acute phase of facial nerve palsy following surgical treatment for posterior cranial fossa and cerebello-pontine angle tumors. Patients were randomly assigned to the main active treatment group (incobotulinumtoxinA) or a control group (adhesive plaster traction) in a 2:1 ratio. The total duration of participation in the study was 2 years.
5
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy Major exclusion criteria included facial nerve paresis of non-surgical etiology, complete rupture of the facial nerve during surgical resection of the tumor, non-compliance with treatment regimen including control visits, and individual complications, intolerance, or side effects to treatment. The study protocol was approved by the local Ethical Committee of the N.N. Burdenko
PT
Research Institute of Neurosurgery, Moscow, Russia. All procedures complied with the standards established by the Declaration of Helsinki and signed, informed consent was
SC
RI
gathered from all patients.
NU
2.2. Treatment
2.2.1. Acute-phase treatment with incobotulinumtoxinA
MA
Patients in the active treatment group received the first injection of incobotulinumtoxinA (Xeomin®, Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany) 24–48 hours after
ED
the development of mimic muscle paresis or palsy. During the acute-phase treatment, incobotulinumtoxinA was injected into active muscles on the unaffected side to correct
EP T
(decrease) the tension of these muscles (Table 1). The total dose of incobotulinumtoxinA was 40–50 U per patient and the total number of injection points varied between 10 and 15.
AC C
Repeated injections were performed 4 and 8 months after the start of the study.
6
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy Table 1 Acute-phase treatment: incobotulinumtoxinA treatment of mimic muscles on the Muscle
Number of
IncobotulinumtoxinA
injection
dose per site, U
sites 2
3
Musculus corrugator supercilii
2
4 and 2, respectively
Musculus levator labii superioris alaeque nasi
1
RI
PT
Musculus frontalis
Musculus zygomaticus
1
2
1
2
1
2
1
2
1
1
1
1–2
1
2
2–4
4–5
Musculus buccinator
1
2.5
Musculus risorius
1
2
SC
Minor
2
NU
Major Musculus levator labii superioris
MA
Musculus levator anguli oris Musculus orbicularis oris
Musculus mentalis
AC C
EP T
Musculus platysma
ED
Musculus depressor labii inferioris
unaffected side.
7
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy 2.2.2 Chronic-phase treatment with incobotulinumtoxinA Treatment of synkinesis as a complication of the neurosurgery commenced 8 months after the surgery. Injections of small doses of incobotulinumtoxinA (1–1.5 U per injection point) were performed into the muscles on the affected side and symmetrically in a doubled dose into the muscles on the unaffected side.
PT
To achieve medically induced ptosis for the correction of lagophthalmos complications, neuro-ophthalmologists from the N.N. Burdenko Research Institute of Neurosurgery
RI
performed incobotulinumtoxinA injections (15 U) into the projection point of musculus
SC
levator palpebrae superioris (Fig. 1) [17]. The injection was repeated after 4–7 days with the
AC C
EP T
ED
MA
NU
same dose if the desired effect was not achieved after the first injection.
Fig. 1. IncobotulinumtoxinA injection sites on the unaffected side and drug-induced eyelid ptosis on the affected side.
8
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy 2.2.3. Adhesive plaster traction Patients in the control group received adhesive plaster traction aligned from the unaffected side to the affected side against the muscle traction of the unaffected side 24–48 hours after the development of mimic muscle paresis or palsy. Treatment continued for up to 3 months. Corrective plaster dressings (1–2 cm wide) were applied on the skin surface in the area of the
PT
contracted muscles with plaster fixation near bony structures (temporal area, zygomatic bone, and mandibula). Skin and muscles of the affected side were pulled upwards and laterally to
RI
prevent paretic muscles from stretching. Patients were instructed to perform position
SC
treatment, initially for 30–60 minutes per day, predominantly during active mimic movements
NU
(during meals or communication) [18]. Treatment time was gradually increased to 2–6 hours a day over 2 weeks depending on patients’ tolerability to treatment and convenience. Position
MA
treatment was continued for 3–4 months. 2.2.4. Physiotherapy
ED
A similar physiotherapy program was introduced in both groups and included individualized movement therapy (taking into account clinical and functional alterations), facial massage,
EP T
physical exercises performed in front of a mirror to retain functional control of the mimic muscles, and articulation exercises in front of a mirror with pronunciation of sounds, words,
AC C
and tongue-twisters.
2.3. Efficacy assessments Treatment efficacy was assessed clinically, taking parameters of neuromuscular functionality into account. Assessments were performed by an independent researcher who was blinded to the treatment administered to each patient. The severity of facial palsy was assessed using the House-Brackmann scale (6-point scale ranging from 1 [normal] to 6 [total paralysis]) [19] and the Yanagihara System (5-point facial nerve grading system ranging from 0 [normal function] to 4 [total paralysis] for 10 items [at rest, wrinkle forehead, blink, slight eye closure, tight eye 9
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy closure, eye closure on affected side, wrinkle nose, whistle, grin, depress lower lip], with a total score ranging from 0 to 40) [20]. Patients also completed the Facial Disability Index (FDI) self-assessment scale, which assesses physical function and social wellbeing on a combined scale from 0 (worst) to 200 (best) [21]. The Sunnybrook Facial Grading scale (SFG), a combined score relating to the degree of facial symmetry, normal voluntary muscle
PT
movement, and synkinesis ranging from 0 (severe impairment) to 100 (normal function) [22],
RI
was used for the assessment of facial symmetry and synkinesis.
SC
2.4. Statistical analysis
NU
Changes in mean House-Brackmann scores and Yanagihara System mean score were analyzed using one-sample t-tests with no replacement of missing data. Comparison of SFG
MA
scores was performed using the Wilcoxon signed rank test for non-parametric paired samples. Comparison between control and active treatment groups for functional improvement was
ED
performed by Student’s t-test. A p-value of < 0.05 was considered significant. All statistical
3. Results
EP T
analyses were performed using SAS version 8.2 or later (SAS Institute, Cary, NC, USA).
AC C
3.1. Patient baseline characteristics Seventy-six patients in the acute phase of facial nerve palsy following surgical treatment for posterior cranial fossa or cerebello-pontine angle tumors were evaluated. Of these, 51 patients were randomly assigned to the active treatment (incobotulinumtoxinA) group and 25 patients to the control (adhesive plaster traction) group. Age and sex distribution were similar between the groups (Table 2). The majority of patients had facial nerve palsy following surgical removal of vestibular schwannoma (48 patients, 63.2%) and the remainder following surgical removal of petro-clival meningioma (28 patients, 36.8%), with both etiologies equally distributed 10
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy between the two groups. The most common clinical symptoms were similar in both groups and included mimic muscle weakness (100% overall) and hypacusia (92.2%), while dry eye (21.1%) and facial hypesthesia (11.8%) were the least common. At baseline, dysfunction measured on the House-Brackmann scale was similar in both groups (mean [standard deviation; SD] score, 3.3 [1.0] in the active treatment group and 3.4 [0.9] in
PT
the control group). Moderate facial nerve dysfunction on the House-Brackmann scale (grade 3) was significantly more prevalent than other grades of dysfunction in both groups (р < 0.05)
RI
(Table 2). The mean (SD) score on the Yanagihara System scale was also similar for both
SC
groups, 20.1 (7.0) [range 11–31 points] and 19.9 (5.3) [range 10–32 points] in the active
AC C
EP T
ED
MA
NU
treatment and controls groups, respectively.
11
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy Table 2 Patient demographics and baseline characteristics.
Characteristic
IncobotulinumtoxinA,
Control,
Total,
n = 51
n = 25
n = 76
Male
28 (54.9)
13 (52)
41 (53.9)
Female
23 (45.1)
12 (48)
35 (46.1)
48.2 (6.4)
46.7 (7.1)
SC
PT
Sex, n (%)
32 (62.7)
16 (64.0)
48 (63.2)
19 (37.3)
9 (36.0)
28 (36.8)
51 (100)
25 (100)
76 (100)
27 (52.9)
14 (56.0)
41 (53.9)
Lacrimation
18 (35.3)
8 (32.0)
26 (34.2)
Dry eye
11 (21.6)
5 (20.0)
16 (21.1)
Facial hypesthesia
6 (11.8)
3 (12.0)
9 (11.8)
Hypacusia
47 (92.2)
23 (92.0)
70 (92.1)
Grade 1
0
0
0
Grade 2
7 (13.7)
4 (16.0)
11 (14.5)
45.3 (7.7)
RI
Age, years; mean (SD) Surgical procedure leading to symptoms, n (%)
NU
Removal of vestibular
Removal of petro-clival meningioma
MA
schwannoma
ED
Clinical symptoms, n (%)*
EP T
Mimic muscle weakness
Discomfort in the mastoid bone
AC C
area
Baseline facial nerve asymmetry on House-Brackmann scale, n (%)
12
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy IncobotulinumtoxinA,
Control,
Total,
n = 51
n = 25
n = 76
Grade 3
24 (47.1)
11 (44.0)
35 (46.1)
Grade 4
11 (21.6)
6 (24.0)
17 (22.4)
Grade 5
9 (17.6)
4 (16.0)
13 (17.1)
Grade 6
0
0
0
PT
Characteristic
RI
*Patients could have more than one symptom.
SC
SD, standard deviation.
NU
3.2. Efficacy after acute-phase treatment
A marked improvement in facial nerve dysfunction was shown after 1 month of treatment
MA
with incobotulinumtoxinA in the active treatment group (Fig. 2 and Table 3). Facial nerve dysfunction decreased by 1.4-fold in the active treatment group compared to baseline
ED
(p < 0.05) and by 1.3-fold compared with the control group (р < 0.05). After 3 months of incobotulinumtoxinA treatment, the decrease in facial nerve dysfunction remained at 1.4-fold
EP T
in the active treatment group compared to baseline (p < 0.05). There was no significant difference in House-Brackmann score between 1 and 3 months post-treatment in this group,
AC C
most likely due to waning of the clinical effect of the botulinum toxin at this time point. In the control group, a significant reduction in facial nerve dysfunction compared to baseline level (р < 0.05) was observed only after 3 months of rehabilitation treatment (Fig. 2 and Table 3).
13
ACCEPTED MANUSCRIPT
NU
SC
RI
PT
BoNT treatment of facial palsy
MA
Fig. 2. House-Brackmann facial asymmetry grade over time. Box whisker plots representing the spread of House-Brackmann facial asymmetry scores in
ED
patients in the active treatment and control groups. Boxes represent the spread of the scores between 25th and 75th percentile; horizontal lines represent the median score; whiskers
EP T
represent the 0 and 100th percentiles.
AC C
An improvement of 1.7-fold on the Yanagihara System scale compared to baseline was shown in the active treatment group after 1 month (р < 0.05) and of 1.9-fold after 3 months (p < 0.05). The difference in scores at 1 and 3 months post-treatment was not significant (p > 0.05).
In the control group, there was a slight improvement of 1.2-fold on the Yanagihara System scale between baseline and 1 month post-treatment (p > 0.05). However, after 3 months of treatment, a significant improvement of 1.9-fold compared to baseline (р < 0.05) was observed (Table 3).
14
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy In summary, incobotulinumtoxinA treatment of facial nerve dysfunction in the early post-operative period provided a more rapid clinical effect in comparison with traditional treatment approaches.
Table 3 House-Brackmann and Yanagihara System scale scores in the acute phase. Baseline
1 month
PT
Scale and treatment
post-treatment
RI
House-Brackmann scale
IncobotulinumtoxinA
3.3 (1.0)
Control
3.4 (0.9)
NU
Yanagihara System scale score, mean (SD)
20.1 (7.0)
MA
IncobotulinumtoxinA Control
19.9 (5.3)
2.3 (1.2)*
3.2 (1.0)
2.8 (1.0)*
35.1 (8.0)*
38.4 (7.2)*
24.5 (6.1)
36.9 (6.9)*
AC C
EP T
ED
*P < 0.05 for facial nerve dysfunction scores post-treatment vs baseline. SD, standard deviation.
15
post-treatment
2.4 (1.2)*
SC
score, mean (SD)
3 months
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy
3.3. Efficacy after chronic-phase treatment The next phase of the study evaluated long-term facial nerve dysfunction 6 months, 12 months, and 2 years after the neurosurgical intervention. A total of 64 patients completed 12 months of treatment, including 45 (88.2%) patients from the active treatment group and 19
PT
(76.0%) patients from the control group; 51 patients completed 2 years of treatment, including 37 (72.5%) and 14 (56.0%) patients in the active treatment and control groups, respectively.
RI
Of the 14 patients from the active treatment group who failed to complete 2 years of
SC
treatment, nine (64.3%) refused to continue treatment because of distant residence and transportation problems and five (35.7%) for family reasons. Of the 11 patients in the control
NU
group who discontinued treatment prematurely, the majority (five patients, 45.4%) withdrew due to low treatment efficacy, and the remainder due to distant residence (two patients,
MA
18.2%) and for family reasons (four patients, 36.3%).
Six months after the surgical intervention, there was a trend towards a lower prevalence of
ED
synkinesis in the active treatment group (23 patients, 45.1%) compared with the control group
EP T
(16 patients, 64.0%). Patients in the active treatment group continued incobotulinumtoxinA treatment with 1.5–2 U per point injected on the affected side in the area of synkinesis and 2– 4 U per injection point on the unaffected side to maintain facial symmetry.
AC C
One year after the surgical intervention, the prevalence of synkinesis was significantly lower in the group of patients who had received incobotulinumtoxinA injections compared with the control group (р < 0.05). Differences between the groups continued to increase until the end of the second year of treatment (р < 0.001) (Table 4).
16
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy Table 4 Number of patients with synkinesis in the long-term follow-up period. IncobotulinumtoxinA,
Control,
n = 51
n = 25
6 months (N = 76)
23 (45.1%) [n = 51]
16 (64.0%) [n = 25]
1 year (N = 64)
14 (31.1%)* [n = 45]
13 (68.4%) [n = 19]
2 years (N = 51)
6 (16.2%)** [n = 37]
11 (78.6%) [n = 14]
PT
Follow-up period
RI
*P < 0.05 for incobotulinumtoxinA vs control.
SC
**P < 0.001 for incobotulinumtoxinA vs control.
NU
Compared with patients in the control group, 6 months and 1 year after the neurosurgical intervention, there was a significant improvement in median SFG scores (symmetry of
MA
voluntary movement, synkinesis, composite score) for the active treatment group (р < 0.05). After 2 years, there was a significant increase in all SFG partial scores (resting symmetry,
ED
symmetry of voluntary movement, synkinesis, and composite score) in patients receiving
AC C
EP T
incobotulinumtoxinA injections (р < 0.05) (Table 5).
17
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy Table 5 Sunnybrook Facial Grading scale scores in the long-term follow-up period.
Sunnybrook Facial Grading scale
IncobotulinumtoxinA
Control
n = 51
n = 25
Resting symmetry
-5 [-10; -5]
-5 [-10; -5]
Symmetry of voluntary movement*
64 [52; 76]
60 [48; 72]
-6 [-9; 2]
-9 [-11; 4]
Median [IQR]
PT
6 months after neurosurgical intervention
RI
Synkinesis*
72 [51; 86]
SC
Composite score* 1 year after neurosurgical intervention
MA
Symmetry of voluntary movement* Synkinesis*
ED
Composite score*
2 years after neurosurgical intervention
EP T
Resting symmetry*
Symmetry of voluntary movement*
AC C
Synkinesis*
n = 45
n = 19
-5 [-10; 0]
-5 [-10; -5]
68 [62; 80]
56 [44; 72]
-5 [-7; 4]
-9 [-12; 3]
81 [56; 95]
56 [41; 63]
n = 37
n = 11
-5 [-5; 0]
-5 [-10; 0]
76 [66; 84]
56 [42; 68]
-3 [-5; 7]
-11 [-13; 0]
88 [65; 96]
47 [32; 65]
NU
Resting symmetry
Composite score*
57 [44; 69]
*P < 0.05 for incobotulinumtoxinA vs control (two-tailed probability). IQR, interquartile range.
The mean (SD) FDI score in the active treatment group was also higher than that of the control group 6 months after the neurosurgical intervention, 127.8 (19.2) and 108.2 (17.0), respectively (p < 0.05). One year after the start of treatment, the mean (SD) FDI score in the active treatment and control groups was 142.0 (19.3) and 97.6 (20.6), respectively (р < 0.05). 18
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy After 2 years of treatment, the mean FDI score in the active treatment group was 1.96-fold higher than that of patients in the control group (mean [SD] scores, 167.3 [21.4] and 85.3 [14.7], respectively, р < 0.05).
3.4. Safety
PT
Adverse events were observed in five (9.8%) patients in the active treatment group, including lip ptosis (three patients, 5.9%), which regressed within 3 months; negligible ptosis (two
RI
patients, 3.9%), which regressed within 1 month; difficulty speaking as a result of mimic
SC
muscle weakness (four patients, 7.8%); dry eye (three patients, 5.9%). Other than dry eye,
NU
which required prescription of saline eye drops, all other adverse symptoms regressed without
MA
treatment and did not require special interventions.
4. Discussion
ED
Treatment of facial nerve palsy both in the acute and chronic periods is challenging and
EP T
requires a multimodal approach. In our opinion, the maintenance of facial symmetry and the inhibition of mimic muscle hyperactivity on the unaffected side in the acute phase of facial nerve palsy following neurosurgical intervention is one of the key factors to reduce
AC C
complications, such as synkinesis and contractures, in the longer term. This supports the utilization of botulinum toxin type A for the treatment of these pathologic conditions [23]. The main goals of rehabilitative measures in the treatment of facial nerve palsy are to: create optimal conditions to support regenerative processes and to preserve denervated muscle tissue; prevent muscle contraction on the unaffected side (‘antagonist contraction’) and of the muscles of mastication; attempt to restore involuntary movements into voluntary movements including different synergic reactions (proprioceptive facilitation and stimulation) ; increase
19
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy muscle strength through adequate exercise; prevent substitutive movements (when minimal voluntary activity reappears); and restore isolated voluntary muscle contractions [24]. In our study, patients with facial nerve palsy after the neurosurgical removal of posterior cranial fossa and cerebello-pontine angle tumors received incobotulinumtoxinA injections as a part of the rehabilitation treatment or received non-pharmacologic treatment (plaster
PT
traction) instead. The inclusion of a comparator control group using standard rehabilitation treatment in a ‘real-world’ clinical setting is a strength of our study design. The small sample
RI
size and lack of placebo control are the main limitations to our study. In addition, the
SC
observers were not blinded to the treatments patients had received. However, we
NU
demonstrated that incobotulinumtoxinA treatment enabled a more prominent therapeutic effect and more rapid functional restoration of the affected nerve and mimic muscles than
MA
treatment with adhesive plaster traction.
In conclusion, incobotulinumtoxinA treatment was a good therapeutic option in both the acute
ED
and chronic phase of facial nerve palsy. Accurate dosing and appropriate administration of incobotulinumtoxinA, with patient education to perform special exercises for the restoration
EP T
of mimic muscle function, should be considered as a part of the multidisciplinary treatment of
AC C
patients with facial nerve palsy.
Acknowledgements The authors wish to thank the patients and study investigators. The first draft manuscript was written by Mihail Al’bertovich Akulov. Editorial support with preparation of the manuscript (editing for English language) was provided by Claire Cairney, PhD, of Complete Medical Communications and funded by Merz Pharmaceuticals GmbH.
20
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy
Funding This study was funded by Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany. The funding body had no influence on the study design, the study conduct, preparation of the
AC C
EP T
ED
MA
NU
SC
RI
PT
manuscript or the decision to publish.
21
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy
References [1]
J.K. Terzis, P. Konofaos, Experience with 60 adult patients with facial paralysis secondary to tumor extirpation, Plast. Reconstr. Surg. 130 (2012) 51e–66e.
[2]
A.L. Ho, A.M. Scott, A.F. Klassen, S.J. Cano, A.L. Pusic, N. Van Laeken, Measuring
PT
quality of life and patient satisfaction in facial paralysis patients: a systematic review
RI
of patient-reported outcome measures, Plast. Reconstr. Surg. 130 (2012) 91–99. Ye.V. Saksonova, Facial nerve neuropathy, Novaja apteka 2 (2013) 94–95.
[4]
Ekman P., Psychosocial aspects of facial paralysis in: May M., ed. The Facial Nerve.
SC
[3]
F.C. Macgregor, Facial disfigurement: problems and management of social interaction
MA
[5]
NU
New York: Thieme Medical (1986) 781–787.
and implications for mental health, Aesthetic Plast. Surg. 14 (1990) 249–257. B. Ross, J.M. Nedzelski, J.A. McLean, Efficacy of feedback training in long-standing
ED
[6]
[7]
EP T
facial nerve paresis, Laryngoscope 101 (1991) 744–750. S.V. Surovyh, Combined surgical treatment of patients with facial nerve neuropathy,
[8]
AC C
avtoref. dis. na. soisk. uchen. step. kmn. (2008) 1–24. M.J. Maksimova, M.N. Sharov, M.A. Damashenko, Facial nerve neuropathy, Farmateka 14 (2011) 46–51. [9]
J. Kim, Contralateral botulinum toxin injection to improve facial asymmetry after acute facial paralysis, Otol. Neurotol. 34 (2013) 319–324.
[10]
O.R. Orlova, Ju.V. Mozolevskij, L.R. Mingazova, Facial nerve neuropathy (Bell's palsy) in: Selected lectures on neurology II. MEDpress-inform (2012) 381–394.
22
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy [11]
O.R. Orlova, N.N. Jahno, Clinical use of Botox (Botulinum Toxin-A): physician guideline, (2001) 208.
[12]
A.G. Salles, P.N. Toledo, M.C. Ferreira, Botulinum toxin injection in long-standing facial paralysis patients: improvement of facial symmetry observed up to 6 months,
[13]
PT
Aesthetic Plast. Surg. 33 (2009) 582–590. A.G. Salles, E.F. da Costa, M.C. Ferreira, A.F. Remigio, L.B. Moraes, R. Gemperli,
RI
Epidemiologic Overview of Synkinesis in 353 Patients with Longstanding Facial
SC
Paralysis under Treatment with Botulinum Toxin for 11 Years, Plast. Reconstr. Surg.
[14]
NU
136 (2015) 1289–1298.
Ye.V. Saksonova, O.R. Orlova, Application of Type A botulinum toxin in case of
G.B. Krohel, C.L. Cipollo, K. Gaddipati, Contralateral botulinum injections improve
ED
[15]
MA
facial nerve damage, Vestnik jesteticheskoj mediciny 12 (2013) 35–42.
drinking ability and facial symmetry in patients with facial paralysis, Am. J.
[16]
EP T
Ophthalmol. 139 (2005) 540.
M. de Maio, R.F. Bento, Botulinum toxin in facial palsy: an effective treatment for
[17]
AC C
contralateral hyperkinesis, Plast. Reconstr. Surg. 120 (2007) 917–927. T.V. Tabashnikova, N.K. Serova, V.N. Shimanskii, N.N. Grigor'eva, [Botulotoxin type A (lantox) for inducing temporal ptosis in neurosurgical patients], Zh. Vopr. Neirokhir. Im N. N. Burdenko 76 (2012) 43–48. [18]
O.G. Kogan, V.L. Najdin, Medical rehabilitation in neurology and neurosurgery, Moscow Medicine (1988) 206–215.
23
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy [19]
J.W. House, D.E. Brackmann, Facial nerve grading system, Otolaryngol. Head Neck Surg. 93 (1985) 146–147.
[20]
Yanagihara N., Grading of facial nerve palsy in: Fisch U., ed. Facial nerve surgery. Birmingham, AL.: Aesculapius Publishing Co. (1977) 533–535. J.M. VanSwearingen, J.S. Brach, The Facial Disability Index: reliability and validity
PT
[21]
of a disability assessment instrument for disorders of the facial neuromuscular system,
SC
[22]
RI
Phys. Ther. 76 (1996) 1288–1298.
J.G. Neely, N.G. Cherian, C.B. Dickerson, J.M. Nedzelski, Sunnybrook facial grading
K. Fujiwara, Y. Furuta, Y. Nakamaru, S. Fukuda, Comparison of facial synkinesis at 6
MA
[23]
NU
system: reliability and criteria for grading, Laryngoscope 120 (2010) 1038–1045.
and 12 months after the onset of peripheral facial nerve palsy, Auris Nasus Larynx 42
A. Baricich, C. Cabrio, R. Paggio, C. Cisari, P. Aluffi, Peripheral facial nerve palsy:
EP T
how effective is rehabilitation?, Otol. Neurotol. 33 (2012) 1118–1126.
AC C
[24]
ED
(2015) 271–274.
24
ACCEPTED MANUSCRIPT BoNT treatment of facial palsy
Highlights
Treatment of facial nerve palsy is challenging, requiring a multi-modal approach. IncobotulinumtoxinA was effective in acute and chronic phases of facial
PT
nerve palsy. Clinical effects were more rapid compared to traditional treatment
RI
approaches.
SC
Facial asymmetry and rate of long-term contractures and synkinesis were reduced.
NU
IncobotulinumtoxinA should be considered in multi-modal treatment of
AC C
EP T
ED
MA
facial palsy.
25