Clinical features and response to botulinum toxin in primary and secondary hemifacial spasm
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.236959
Source of Support: None, Conflict of Interest: None
Keywords: Botulinum toxin, hemifacial spasm, magnetic resonance imaging
Hemifacial spasm (HFS) is a nondystonic hyperkinetic movement disorder of adults characterized by insidious onset of painless, arrhythmic, and tonic or clonic intermittent spasms of the muscles of facial expression. The condition may be primary or secondary to facial nerve damage. Primary HFS is usually due to the compression of facial nerve at its root exit zone from the brainstem by an ectatic arterial loop arising from the vertebrobasilar system. Secondary HFS may occur due to the involvement of facial motor nucleus in the pons, or due to the injury to the nerve itself anywhere along its peripheral course by a variety of etiological conditions such as trauma, as well as by inflammation, which may be infective or noninfective, demyelination, tumors, and vascular insults. The prevalence of HFS has been estimated to be 14.5 per 100,000 women and 7.4 per 100,000 men in a large population-based study. The typical age of onset is the fifth to sixth decade. Primary HFS is commoner than secondary HFS, accounting for approximately 4/5th of the total cases. Botulinum toxin therapy has undoubtedly proved to be effective in the treatment of both primary and secondary HFS.
In this study, we have attempted to give a detailed clinical description of patients with primary and secondary HFS and their response to botulinum toxin therapy.
This retrospective study is a detailed report of 40 patients with HFS (33 primary and 7 secondary) who attended our botulinum toxin clinic over the last 18 months. The data collected included the demographic profile, clinical features of HFS, severity measured by Likert scale [a 5-point scale from 0 to 4 (0 = not affected; 4 = very severe, prolonged spasm)], etiology, magnetic resonance imaging (MRI) of the brain, including the intracranial vascular imaging, and a detailed account of the botulinum toxin sessions, dosages, response, and the side effects. Thirty-four patients (30 primary and 4 secondary) received botulinum toxin type A (Onabotulinumtoxin A) injection. Each of these patients received 8–16 units in orbicularis oculi, (which was given pretarsally at 4 sites, 2–4 units at each site), zygomaticus major (2–5 units), nasalis (2–5 units), and mentalis (2 units). Some patients also received additional injections in orbicularis oris (1–2 units), rizorius (1–2 units), and platysma (5–20 units). The data was entered into an Excel sheet, and statistical analysis was done using the SPSS (Statistical Package for the Social Sciences, IBM corporation, New York) software (version 13). The variables were expressed as mean ± standard deviation, percentage, and range. The frequencies between the various groups and the response to the therapy were compared using the chi-square test and P values ≤0.05 were considered as statistically significant.
We studied a total of 40 patients with HFS [Table 1]. Out of these, 33 patients had primary HFS and 7 patients had secondary HFS. The female patients outnumbered the male ones (23 and 17, respectively), and among them 18 had primary HFS and 5 had secondary HFS. Only 2 male patients had secondary HFS. The mean age at presentation was 48.4 ± 12.6 years, whereas the mean age at the onset of symptoms was 43.7 ± 12.2 years, and this was comparable in both the groups. The mean duration of symptoms was 57.4 ± 39.3 (6–144) months. The number of patients with the left-sided spasm was slightly higher than those with the right sided one (21 and 18 patients, respectively) and 1 patient had bilateral HFS. This slight higher left-sided preponderance was reflected in patients with primary HFS as well (18 vs, 15 patients), whereas both the sides were equally involved in secondary HFS. The onset of the spasm was from the upper face in 31 patients, whereas 6 patients had the involvement of lower face first. This was similarly present in patients with primary HFS (26 vs. 5 patients), and interestingly, predominant upper face onset was found in patients with secondary HFS also (5 vs. 1 patient). Only 3 patients had simultaneous onset in the upper and lower face, out of which 2 had primary and 1 had secondary HFS. The median duration of progression from the upper face to the lower face or vice versa was 12 (1–96) months; however, the spasm did not progress in 4 patients, as it was restricted to the upper face in 3 and to the lower face in 1 patient. The click in the ipsilateral ear was felt by 17 patients, primarily in those who had primary HFS (15 patients). The overall severity, as assessed by the 5-point Likert scale, was predominantly mild, i.e., mildly disturbing to the patient but not affecting function (n = 18, 45%); 12 patients (36%) experienced moderate-to-severe spasm in the primary HFS category. Interestingly, the spasm was less intense in patients with secondary HFS as the majority of patients reported a very mild-to-mildly severe facial spasm. The spasm became aggravated during periods of stress, while speaking to someone, and when someone cautiously looked at their face, in a majority of the patients (60–65%). This was followed by an increase in HFS on going out in the sun, reading, and watching television (35–40%) [Table 2]. This distinction was not apparent in patients with secondary HFS who reported a similar effect by stress, eating, speaking, and sun exposure, with none reporting aggravation while reading or watching television. Sleep was the most important relieving factor, as experienced by a majority of the patients in both the groups (n = 30, 75%) followed by wearing dark goggles (n = 3, 7.5%). Hypertension was also present in 11 (27.5%) of our patients, majority of whom were primary cases (n = 82.4%). Hearing loss was reported by 4 patients that included 2 patients in each group. There was a vascular loop at the 5th nerve exit zone, a schwannoma involved the 8th nerve, Ramsay–Hunt syndrome, and an unknown cause in 1 patient each, respectively. MRI brain of 22 patients was available for review. It was abnormal in 4 out of 15 patients with primary HFS, showing bilateral flow voids across the 7th and 8th nerve complex, vertebrobasilar dolichoectasia, vascular loop across the 5th nerve entry zone, and an ipsilateral frontal cavernous angioma in 1 patient each, respectively. MRI brain was done in 6 patients of the secondary HFS group, where it was abnormal in 1 patient where it showed a schwannoma involving the left 7th and 8th cranial nerve [Figure 1]. In one of the patients with a secondary HFS, MRI was not done because he had a history of metallic orthopedic implant instituted following a fracture. His computed tomography (CT) of the head was normal.
The group with secondary HFS included 7 (17.5%) patients. Five of them had a Bell's palsy, one had a left-sided Ramsay-Hunt syndrome, and a patient had a schwannoma involving the left 7th and 8th cranial nerve, who presented with facial spasm from the outset followed by same-sided hearing loss without any weakness of facial musculature. This patient underwent a gamma knife ablation of the lesion; however the lesion was persisting even after 2 years with a mild spasm involving the left orbicularis oculi. One patient had sequential but bilateral HFS initially involving the left side of the face following a left-sided hemiparesis, which subsided spontaneously over a year, and now she presented with a right-sided HFS, following the development of a right-sided Bell's palsy. The median interval between the facial weakness and the onset of HFS was 6 (2–300) months. Other notable findings were the predominant upper face onset, mild severity of spasms, worsening by similar conditions as for primary HFS except reading and watching television, and with similar relieving factors as for primary HFS [Table 2].
A total of 34 patients received botulinum toxin therapy [Table 3]. Out of these, 30 patients had primary HFS and 4 had secondary HFS. Six patients (3 in each group) who did not receive the botulinum toxin treatment had very mild-to-mild intermittent spasms, which were not interfering in their activities. The patients in the primary group had botulinum toxin sessions ranging from 1–5 with a median of 2 sessions; the mean dose of the toxin that they received was 21.86 ± 4.19 units (range: 10–30 units); the mean onset latency and mean peak effect latency was 6.63 ± 9.15 (range: 1–15 days) and 10.08 ± 7.94 days (range: 1–30 days), respectively; the mean duration of peak effect was 82.3 ± 51.9 days (median: 75 days; range: 30–210 days); and the mean total duration of response was 112.6 ± 55.7 days (median: 90 days; range: 30–240 days). Primary HFS patients experienced toxin related side effects in a total of 6 sessions out of 65 sessions in the form of ptosis and excessive lacrimation on 2 occasions each, and drooping of the angle of mouth and diplopia on 1 occasion each. The patients in the secondary group had 1–3 sessions (median: 1.5); the mean dose of the toxin that they received was 17 ± 4.16 (range: 12–22) units; the mean onset latency and mean peak effect latency was 9.25 ± 4.34 (range: 5–15 days), and 14.50 ± 4.12 days (range: 10–20 days), respectively; the mean duration of peak effect was 130 ± 62.4 days (median: 150 days; range: 60–180 days); and the mean total duration of response was 135 ± 63.6 days (median: 135 days; range: 90–180 days). Patients with secondary HFS experienced side effects in 5 out of 7 sessions in the form of ptosis on 3 occasions and an angle droop and excessive lacrimation on one occasion each. These side effects disappeared within 15–30 days in all the patients from both the groups. Two patients in the primary group had complete remission after a single session over a follow-up period of 2 and 4 years, respectively, whereas 1 patient in the secondary group had complete remission after a single session over a follow-up period of 1 year, and another patient has been still experiencing 75% benefit after a single session, which was conducted one and a half years back; both of these patients had Bell's palsy as their primary etiology. Two patients in the primary group did not respond well to the therapy. In one of these, the response lasted for only 10 days, and in the second patient, only 10% relief occurred after the first injection, and 45% relief after the second injection with escalation of doses. One patient, although experiencing a relief for 2 months with regular sessions of botulinum toxin, gives credit to concomitant oxcarbamazepine (600 mg/d) for his relief and is not willing discontinue the oral medication to observe the isolated effect of the toxin.
Majority of our patients had their disease onset in the 5th decade with the number of female patients being slightly more than the male ones. These figures were similar to the findings seen in several large series on primary HFS reported previously., The average duration of symptoms was 57 months in our study. This duration varied from 43 to 137 months in different studies.,,,, Involvement of the left side was slightly more than the right (1.2:1) in our study, which is similar to the findings of three other large series.,, This slightly higher left-sided predominance has been attributed to the higher prevalence of vascular anomalies on the left side of the vertebrobasilar arterial system.
Only one patient had bilateral HFS, which was similar to the very low prevalence rate of bilateral HFS reported in other studies as well. Wang et al., described 5 patients (3%) with bilateral HFS in their series of 158 patients; Moller and Moller  described 1 (0.6%) patient in their series of 143 patients; Ehni and Woltman  described 5 cases (5%) amongst their 106 patients.
Among our primary HFS cases, majority (78%) had onset on the upper face, 5 patients (15%) on the lower face, and 2 patients (6%) had a simultaneous onset. These findings were similar to that described in the series by Felicio et al., where there was upper face onset in 83% and lower face onset in 17% of the patients. Other studies also showed a predominant upper facial onset.,,, The explanation for the predominant upper face involvement at the onset is the somatotopical organization of the fibres in the facial nerve at its root exit zone, with the fibres for the upper face being more dorsally located than that of the lower face. The latter fibres are more ventral, and, therefore, the dorsal fibres get compressed by the ecstatic vascular loops first. However, it appears interesting to note that a majority of the patients with primary HFS have normal brain and vascular imaging; the other factors that may be responsible for an initial upper face onset of HFS need to be determined.
Although the simultaneous onset of upper and lower parts of the face is considered to be more characteristic of secondary HFS, it was seen in 2 of our primary cases as well. Batla et al., found this simultaneous onset of HFS in 26% of their 252 cases with primary HFS.
In secondary cases, especially the postparalytic ones, where the facial nerve is involved in its course in the temporal bone anywhere from the internal auditory meatus to the stylomastoid foramen, the fibres are more diffusely arranged, and hence, the simultaneous involvement of upper and lower face occurs in these cases. This mechanism was postulated by Colosimo et al., who found simultaneous onset of HFS in 72% of their 50 cases with secondary HFS. Though the numbers are few, our secondary HFS cases showed a predominant upper face onset and only one case had the simultaneous onset of facial spasms. Our results appear similar to the results reported in two other series. Batla et al., described 69 cases of secondary HFS, in which 75% had an upper face onset and 23% had a simultaneous onset; and, Felicio et al., also found that 84% patients had upper face onset of HFS among 39 cases of postparalytic HFS. The mean duration of progression from the upper to lower face was 12 months; it was 20 months in the series by Batla et al.
Ipsilateral ear click is not a very well reported phenomenon or even rarely reported in several series. We found that the characteristic ear click was present in 42% of our cases; Batla et al., reported a click in 22% of their cases; Wang et al., found a click in only 4% of hteir cases. This ear click may arise due to the clonic contractions of the stapedius muscle leading to compression and rarefaction of air in the middle ear.
Majority of our primary cases fell in the mild-to-moderately severe category of spasms on the 5-point Likert scale, which appears to be similar to the data presented by Batla et al. Mental stress and speaking were the leading precipitating factors, followed by eating, reading, watching television, and going out in the sun, whereas sleep was the most important and prominent relieving factor. These also appear similar to the findings in other series., A large study reported an association between hypertension and HFS, where the authors found that 40% of their patients were hypertensive. In other studies, this association between hypertension and HFS is reported to be observed in approximately 20–40% cases., We found hypertension in 27.5% of our cases. The etiological factors responsible for these associations are small vessel vasculopathy in the brainstem secondary to chronic hypertension; or, hypertension occurring secondary to the compression of 9th and 10th cranial nerves by the ectatic vascular loops, leading to alterations in the response of vasomotor centre in the medulla. Hypertension may itself weaken the vessel walls of large arteries leading to secondary ectasias.
Some of the results of our secondary cases also merit attention here. Predominant upper face onset has already been discussed above. The average interval from the occurrence of facial weakness to the onset of spasm was 6 months. This latency was approximately 29 months in the study by Felicio et al. The intensity of spasms in our secondary cases was very mild-to-mild in comparison to our primary cases. This observation was contrary to the findings in another series which also used the Likert grading to rate the severity of spasm. In the latter study, the authors found mild and moderately severe grades of HFS in the majority of secondary cases similar to their observation in the cases with primary HFS. None of our secondary cases reported worsening of the severity of HFS with reading or watching television, although these have been reported in approximately 25% of the cases in another series.
Twenty-two patients were investigated with an MRI brain and an intracranial MR angiography to identify the etiology. Out of these, only 5 (12%) patient showed an abnormality that could result in HFS. Of these, 3 had a vascular abnormality, 1 had a schwannoma of the 7th and 8th nerve complex, and 1 had an ipsilateral frontal cavernous angioma. MRI was normal in all the patients with secondary HFS, except in 1 patient who had a schwannoma. Ectatic vessels were seen in only 13 (8%) out of 165 scans in another Indian series. In the series of Wang et al., MRI was abnormal in 27 (19.8%) out of 96 scans. Out of these, 19 cases had vascular abnormalities of the vertebrobasilar system. Felicio et al., found vascular abnormalities in only 10 (7%) patients in their series of 348 cases. Overall, we can say that significant MRI findings may be seen in 10–20% of the cases of HFS.
Botulinum toxin therapy has now been established as the standard of care in patients with HFS [Table 4].,,,,,,,,,,,,,,,,,,,,,,,, This therapy is not curative but provides a temporary relief lasting for a couple of months, and therefore, most of the patients require a long-term treatment at regular intervals depending on their response rate. Only one placebo controlled trial by Yoshimura et al., was conducted in which none of the patient responded to the placebo. This trial clearly showed the superiority of botulinum toxin over the placebo in patients with HFS.
Ninety-one percent of our patients in the primary HFS group received botulinum toxin with an average dose of approximately 22 units and a total duration of response of approximately 16 weeks. We found an excellent response rate in 93% of our patients. As seen in [Table 4], majority of the small and large series report a response duration of 12–16 weeks, a few studies mention a response duration of 18–20 weeks,,,,, and only 1 showed an average response duration of 9.3 weeks. The response rates in these studies ranged from 75 to 96%. The doses used varied from 9.3–34.5 U.
In our study, 2 patients with primary HFS did not respond well to botulinum toxin; however, the others who responded well had a consistent response over the subsequent sessions without any significant increase in dosages. Repeat injections were not associated with a higher incidence and a greater duration of complications. In a large series from Thailand by Poungvarin et al., 2% of the 251 cases did not respond at all to the therapy. In the series by Mauriello et al., 13 out of the 119 cases did not show a satisfactory response. Flander et al., in their series of 65 patients, found a consistent response with repeated injections over a period of 8 years. Similar observations were also reported by Defazio et al., (65 cases, 10 years) as well as Barbosa et al., (54 cases, 12 years). In the series by Chen et al., involving 137 patients, who injected repeatedly over 3 years, a consistent effect with the first 4 consecutive injections was observed. A good response rate with nearly constant doses of botulinum toxin over time gives a fairly good idea regarding the very low level of primary and secondary resistance to botulinum toxin in the treatment of HFS.
In one study by Polo et al., there was the requirement of a significant increase in the doses for injection of orbicularis oculi in the first 3 years, in both the primary (7.5→15 units) and secondary HFS (7.5→17.5 units) groups. In our study, we used 8–16 units for orbicularis oculi from the beginning. The majority of the patients responded well to the initial and subsequent injections without any changes in the dosages in the primary HFS group; however, patients in the secondary group reported a higher incidence of ptosis with this dose. Probably lesser doses of the toxin injected in the orbicularis oculi would suffice in the secondary group.
Complete remission is an infrequent phenomenon observed in HFS cases; data regarding this aspect is scant in literature. In our series, 3 patients (2 cases with primary HFS and 1 case with postparalytic HFS) were in complete remission after a single dose of botulinum toxin, and 1 case of secondary HFS had still been having 75% relief after a period of 1.5 years. In another series by Mauriello et al., 5 patients attained complete remission.
Our secondary cases also responded well to botulinum toxin therapy, requiring a mean dose of approximately 17 units, resulting in a total response duration of approximately 19 weeks. Oyama et al., reported a series of 5 cases, in which 3 patients had a vascular loop (2 of them having persistent post-decompression HFS), 1 was a postoperative case of schwannoma, and 1 was a case of posttraumatic facial nerve palsy; all of these received botulinum toxin with an onset latency of 2–4 weeks and a response duration of 16 weeks. In the series by Wang et al., 6 out of 25 patients who underwent vascular decompression required botulinum toxin following their surgery. This shows that patients with postparalytic HFS and persistent spasms after vascular decompression or surgical resection of the tumor also respond well to botulinum toxin therapy.
The side effects of the injection were few and transient in our primary HFS group and were seen in only 9.2% of all sessions. Out of these, ptosis and excessive lacrimation were seen in 3% of the patients, respectively; drooping of the angle of mouth and diplopia were observed in 1.5% of the patients, respectively; and all of them completely reversed by 2–4 weeks. Side effects have been reported to be in the range of 4–65% in various studies, the most common being ptosis, and all were transient. No systemic side effects have ever been reported. We observed more side effects (transient) in our secondary cases even if they received significantly lower mean dosages (mean dose: 17 ± 4.16 unit) than in the primary HFS cases (mean dose: 21.86 ± 4.19 unit). Oyama et al., also reported a higher incidence of facial nerve paresis (30%) and diplopia (10%) in their secondary HFS patients even if the dosages used were lower (mean dose: 9.6 U) than those typically used for HFS in USA.
Ipsilateral ear clicks are fairly common in patients with HFS. Patients with secondary HFS can have their onset from the upper face similar to that seen in primary HFS, hence, it is important to obtain details of the relevant history to rule out secondary causes in all patients with HFS. Botulinum toxin is effective in both primary and secondary HFS but not without complications. The effects of botulinum toxin therapy are short lasting and the treatment does not offer a permanent cure; however, remission can occur in some patients in both primary and secondary cases. The doses required for secondary HFS may be less than that seen in the primary cases. Pretarsal injections in orbicularis oculi are effective and associated with less side effects.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]