botulinum toxins - botulinum toxin type A - hemifacial spasm
toxinas botulínicas - toxina botulínica tipo A - espasmo hemifacial
Hemifacial spasm (HFS) is a craniofacial movement disorder characterized by involuntary
contractions of the muscles on one side of the face[1 ]. The most common site for the contractures is the orbicularis oculi muscle, but
the corrugator supercilii, frontalis muscle, orbicularis oris, zygomaticus major and
platysma can also be affected[2 ]. The condition is believed to be mainly due to a peripheral dysfunction of the facial
nerve, occasionally associated with nerve compression by a blood vessel or tumor[3 ],[4 ]. The pathophysiology, however, has yet to be fully elucidated as the condition can
occur in the absence of structural alterations[3 ]. In a recent study, Wilkinson and Kaufmann[5 ] showed that HFS may be associated with central nervous system changes. Accordingly,
one previous study from our group found similar profiles of obsessive and psychiatric
symptoms in cases of HFS and blepharospasm, which is recognized as a movement disorders
of pure central origin.[6 ] The mean annual incidence is 0.81 per 100,000 women and 0.74 per 100,000 men. Because
of this low incidence, there are few studies comparing the efficacy of different therapies[7 ]. Anticonvulsants such as carbamazepine and clonazepam should only be used for mild
presentations, as results are typically unsatisfactory[8 ]. Microvascular surgery is another form of treatment and has a success rate ranging
from 38.2% to 87% according to the literature. However, it is an invasive procedure
that can lead to severe complications and is contraindicated for elderly individuals,
patients with severe systemic diseases and patients whose symptoms are not caused
by vascular compression. It is therefore not the therapy of first choice in most cases[9 ]. Botulinum toxin type A (BTX-A) has been used to treat HFS since the 1980s and provides
symptom relief and improved quality of life in about 85% to 95% of cases[10 ]. It is currently considered the gold standard for treatment of HFS as it can be
administered in outpatient units, is less invasive than other therapies, and is well
tolerated[11 ]. Botulinum toxin type A is an exotoxin that causes presynaptic blocking at the neuromuscular
junction by inhibiting the release of acetylcholine[12 ]. As the effect of the toxin is reversible and, consequently temporary, patients
must have regular injections to control the clinical manifestations of the disease[13 ]. It is therefore essential to investigate the efficacy and duration of the effect
of BTX-A injections during treatment of HFS. However, few studies have analyzed the
long-term efficacy of the toxin in the treatment of HFS in Brazil. In light of this,
the present study sought to describe five years of experience with the use of BTX-A
to treat HFS in a tertiary academic hospital.
METHODS
Patients
The study was carried out with patients seen in the Movement Disorders Outpatient
Unit in the Neurology Service, Hospital de Clínicas, Federal University of Paraná
(HC/UFPR), between January 2009 and December 2013. The inclusion criteria were as
follows: 1) age 18 years or older; 2) clinically confirmed diagnosis of HFS; 3) regular
follow up during the study period; and 4) signed voluntary consent to treatment with
BTX-A. Exclusion criteria were: 1) incomplete medical records; 2) fewer than two BXT-A
applications; and 3) an interval of more than one year between injection sessions.
Using these criteria, of an initial sample of 136 patients treated with BTX-A in the
period investigated, 100 were included in the study. The study was approved by the
HC/UFPR Committee for Ethics in Human Research.
Botulinum toxin A
The study was retrospective, carried out with using demographic and clinical data
from medical records of patients diagnosed with HFS. Ninety-five patients had primary
FHS and five had postparalytic hemifacial spasm. All patients had neuroimaging tests
(brain CT scan, complemented by brain MRI in 50 cases). Information about each injection
session included date, dose, subjective latency to clinical improvement, duration
of the beneficial effect of BTX-A, and efficacy using the Columbia University Rating
Scale[14 ]. This scale is used in routine evaluation in the Botulinum Toxin Outpatient Clinic
of HC-UFPR. Patients were assigned values to the results of the treatment between
0% and 100%, where 0% corresponded to no improvement and 100% to complete improvement
and a return to normal function.
Patients being followed during this period used onabotulinumtoxinA, Botox® (Allergan Pharmaceuticals, CA, USA). The protocol used to administer BTX-A in our
service is the protocol advocated by the Brazilian Ministry of Health[15 ]. Botulinum toxin type A is diluted 2:1 with saline solution and injected in doses
of 1 to 5 IU in the orbicularis oculi, procerus, corrugator supercilii, risorius,
orbicularis oris, and platysma muscles. The dose administered varied during the treatment
according to the response reported by each patient, the presence of side effects and
clinical assessment, but in general, we used 5 units per injection around the eye,
except, in the inferior muscle orbicularis oculi – 2 units, 2 units per injection
around the mouth and chin, and, when necessary 5 units in the platysma muscle. The
intervals between injection sessions varied according to the patient’s response to
the therapy.
Statistical analysis
The data collected were recorded on a Microsoft Excel® spreadsheet and exported for analysis with the Statistica package from Statsoft® . The descriptive analysis of the efficacy and safety of BTX-A and the demographic
variables included percentages and mean and standard deviation as appropriate.
RESULTS
Of the initial sample of 136 patients, six were excluded because they had had less
than two BTX-A injection sessions during the study period and 30 because their medical
records were incomplete. Hence, 100 patients were included in the statistical analysis.
Mean patient age was 63.1 years, standard deviation (SD) of 12.4 years. Most patients
were females (72%), and the left hemiface was more frequently affected (61% of cases).
Overall, 550 doses were administered to the 100 patients in the study period. Mean
follow-up was 2.6 years (SD 1.4), and the mean number of injection sessions per patient
was 5.5 (SD 2.3). Mean BTX-A dose was 28 IU (SD 8.6), and mean interval between injections
was 5.8 months (SD 2.1). For 30% of the patients the final dose was higher than the
initial, while for 35% it was lower due to the patient’s response and occurrence of
temporary side effects. Observed onset latency was around 7.1 days (SD 3.9), and mean
effect duration 3.1 months (SD 1). On a subjective scale of 0% to 100% improvement,
the effect of administration of BTX-A was 81% (SD 5.6%).
Temporary side effects were observed following 6.7% of the injection sessions, and
37% of the patients presented with temporary adverse reactions at least once during
follow-up ([Figure ]). However, most of the side effects observed were minimal, the most common being
eyelid ptosis, which was observed in 36.11% of the patients ([Figure ]). There were no reports of any systemic or severe adverse effects. The overall success
rate was 94.73% (of all the injection sessions). Twenty-one applications (3.82%) resulted
in a short-term effect of less than one month, seven (1.27%) had no effect and one
(0.18%) had a slight effect.
Figure HFS treatment with BTX-A: transitory side effects.HFS: hemifacial spasm; BTS-a: botulinum
toxin type A.
Comparison of the main results with the findings of three clinical trials in the literature
failed to reveal any significant differences ([Table ]).
Table
HFS -Treatment with BTX-A: Literature review.
Characteristics
Batisti et al.
Barbosa et al.1☐
Defazio et al.1☐
Thussu et al.1☐
Number of patients
100
54
65
27
Mean age
63.08
48.3
56
47.78
Gender (F%)
72
75.9
70
70.4
Side (L%)
61
61.1
-
51.85
Follow-up (years)
2.64
5.88
-
-
Number of doses evaluated by study
550
808
239
45
Average applications per patient
5.48
14.96
-
1.67
Average dose per application
27.98
Beginning 34.47
Beginning 17.5
74.37
End 37.61
End 15.9
Increase of dose (%)
30
11.1
-
-
Reduction of dose (%)
35
40.7
-
-
Latency (days)
7.1
-
-
11.63
Average duration of effect (months)
3.14
Beginning 3.42
3.5
4.46
End 3.22
Subjective evaluation (0–100%)
81
Beginning 83.18
96
-
End 78.53
Adverse effects on total applications (%)
6.73
-
-
4.37
Adverse effects of patients (%)
37
64.8
36.9
-
The results were compared with three clinical trials. HFS: hemifacial spasm; BTX-A:
botulinum toxin type A;. (F%): corresponds to female percentage of the subjects; Side
(L) corresponds to left side affected subjects. In two studies, the average dose application
was evaluated on the first and last reported dose. The increase or reduction of dose
refers to a difference between the administration of the first and last dose of the
Botulinum Toxin Type A.
DISCUSSION
Our study demonstrated that mean improvement on a subjective functional improvement
scale was 81%, and mean effect duration was 12.56 weeks. These findings corroborate
those published studies.[16 ],[17 ],[18 ],[19 ],[20 ],[21 ],[22 ],[23 ],[24 ]. The success rate in the present study was 94.73% when injections that did not produce
any effect or produced a short-term or minor effect were excluded. This success rate
is similar to that reported in two other studies (90%[23 ] and 98%[24 ]). These data indicate that even in a teaching hospital, where there is a wide range
of health professionals at different stages of their education and very often with
little experience, the results are similar to those of other research centers that
specialize in administration of the toxin. In this case series of HFS, the affected
side of the face was the left side, predominantly in females patients. These data
corroborate the findings of previously-published studies.[16 ],[17 ] The high incidence of left HFS could be explained by congenital malformations in
the vascular system located primarily on the left-hand side[25 ]; however, to the authors’ knowledge, there are no studies with statistically significant
results that support this hypothesis.
Mean patient age was similar to that in a study carried out in southeast Brazil[26 ]. According to Thussu et al.[18 ], the response to therapy is not influenced by variables such as age group, gender,
side of the face affected, age of onset and duration of symptoms prior to treatment
with BTX-A. Mean latency (7.1, SD 3.94) was very similar to that observed by Kollewe
et al.[27 ] and Lin et al.[28 ], who reported figures of 7.1 days (SD 2.3) and 5.0 days (SD 4.7), respectively.
However, in another study, symptoms in HFS patients were reported to disappear between
seven and 30 days after injection of BTX-A, with a mean of 11.63 days (SD 7.07)[18 ]. This difference may be a result of the difference in sample size and the variability
in patient response.
The mean time between patient visits was 23.04 weeks. Patients therefore remained
without the benefit of BTX-A injections for approximately 10 weeks. This discrepancy
between effect duration and the interval between injections in our service is a result
of administrative and financial problems, as the number of physicians is not proportional
to the number of patients seen, resulting in longer waiting times. However, if the
mean effect duration of BTX-A injections is known, a return visit can be scheduled
based on this and the interval can be increased or decreased according to the observed
response of each patient to the therapy. To improve the quality of life of HFS patients
and the service they receive, return visits should be scheduled for three months after
injection of the toxin.
Although no systemic or severe side effects were observed in our study, at least one
adverse effect was reported by 37% of the patients followed up. The most common complaint
was ptosis, reflecting the findings of Rieder et al[20 ]. According to the literature, the frequency of adverse events varies from 20%[29 ] to 64.8%[17 ],[30 ]. This variation is probably a result of the fact that some studies are based on
patient-reported data and others on a physician’s clinical diagnosis. In various studies,
ptosis was the most common adverse effect and no systemic or major adverse events
were reported[17 ],[29 ],[30 ]. The total incidence of adverse effects in the present study was probably lower
because of information bias, as the incidence of side effects was determined based
on information supplied by patients during their return visits. Another important
point is that all patients with HFS were injected by fellows of the movement disorders
unit or neurology residents from our institution.
Injection of BTX-A proved unsuccessful in 1.27% of cases. Nevertheless, a recent study
by Czyz et al.[29 ] showed that even with long-term follow-up there were no reports of resistance to
BTX-A. This difference may be because ours is a tertiary center, where cases of HFS
tend to be more severe and complex. Nevertheless, as there are few cases of resistance
to BTX-A described in the literature, the pathophysiology of this resistance has yet
to be clarified. A study carried out at Ohio State University College of Medicine
showed that there was no statistically significant difference in the correlation between
the incidence of side effects, dose and effect duration between the first and last
injection[29 ]. We could not make this comparison in our study because of confounding factors and
selection bias, as not all of the patients were followed up from the beginning of
the BTX-A therapy.
Although various studies have shown that BTX-A is the gold standard for treatment
of HFS, few have investigated resistance to BTX-A or whether the dose needs to be
increased in the long term. New long-term, prospective clinical trials should therefore
be carried out to assess the efficacy of the toxin in this regard. This study is in
accordance with several studies published previously, however, it is necessary to
emphasize that the botulinum toxin application was by neurology medical residents
and fellows of the movement disorders unit.
In conclusion, the findings of the present study show that treatment of HFS with BTX-A
was effective, long-lasting and well-tolerated by patients. Furthermore, there were
no reports of severe or permanent adverse effects that would prevent the treatment
being continued.
