Dr.Meghana Tanwar, T18259, Dr. Sabyasachi Chakrabarty, Dr. Maneksha V, Dr. Madhavi Ramanatha Pillai
Abstract
Aims: To evaluate the safety and efficacy of Botulinum toxin type A in facial dystonias.
Methods: 26 patients with facial dystonias, treated with Botulinum toxin type A, were followed up over a period of 5 years or till they discontinued our treatment. The pre and post-injection severity of symptoms was recorded using the Jancovic Rating Scale(JRS) and the Samsung Medical Centre(SMC) systems for the phenotypes of blepharospasm(EB) and hemifacial spasm(HFS) respectively. The complications and the mean symptom-free intervals were recorded. A correlation analysis was done to identify factors which were associated with longer symptom-free intervals. p <0.05 was considered statistically significant.
Results: The mean age at first presentation was 56.62±10.56 years. The mean duration of follow-up was 1.86±2.06 years. The modal disease severity pre and post injection were 5 and 0 for EB and 2 and 0 for HFS. The mean number of symptom-free days with doses of 20, 22.5, 25, 30 and 50 units was 102.1±44.7, 132.4±35.3, 147.2±61.6, 124.4±55.1 and 142.4±59.7 respectively. The commonest complication was lagophthalmos (26.3%; n=20). Injections for primary dystonias were associated with longer disease-free intervals than those for secondary dystonias (p=0.02). There was no correlation between the dose and the mean symptom-free interval (p=0.31). There was a statistically significant increase in the efficacy with each injection at doses of 22.5U per sitting (p=0.04).
Conclusion: Botulinum toxin type A is safe and effective in the treatment of facial dystonias. It’s efficacy increases with each injection at a dose of 22.5U and is greater in primary dystonias.
Key Words :-
Facial dystonia, Blepharospasm, Hemifacial spasm, Botulinum toxin,
Body
Introduction
Facial dystonias are a group of disorders characterised by involuntary spasm of the muscles of the face and the neck. These disorders may be idiopathic or secondary to compression or a pre-existing palsy of the facial nerve. Although one may try microvascular decompression procedures in secondary compressive dystonias, there is an inherent risk of permanent nerve damage or stroke. [1] Botulinum toxin injection is an alternative to surgery but its effects are temporary. We wanted to determine the safety and efficacy of Botulinum toxin in the treatment of facial dystonias and the factors which were associated with longer disease-free intervals.
Methods
This was a retrospective, interventional study. The study adhered to the tenets of the Declaration of Helsinki. An ethical committee clearance was obtained before undertaking a review of medical records. We included patients who had been diagnosed with idiopathic and secondary facial dystonias (Essential blepharospasm, Hemifacial spasm, and Vascular Loop syndromes affecting the facial nerve), had been receiving injections of Botulinum toxin Type A in our hospital and had received atleast one injection of the drug in the past one year (May 2016 to April 2017). The records were examined for their demographic profile, the details of injection (ie dose, sites, number of previous injections, complications etc), the progression of symptoms and the average symptom-free interval. The severity of blepharospasm was graded using the Jankovic Rating Scale (JRS) and that for hemifacial spasm by the Samsung Medical centre grading system (SMC). [2], [3]
All interventions were done by a single surgeon. We used BotoGenie® (Bio Med Private Limited, Ghaziabad, Uttar Pradesh, India) in each case. BotoGenie® , a lyophilised powder with a strength of 50 IU, was reconstituted with two ml of sterile normal saline producing a final concentration of 25 IU/ml. In case of blepharospasm, injections were given to the medial and lateral pretarsal orbicularis oculi of the upper and the lower lids. The dose was varied according to the pre-injection severity and the resistance to therapy. For hemifacial spasm, injections were given in eight to ten sites, depending on the extent of involvement and the severity of disease. At each injection site 0.1 ml was injected.
The complications were recorded on the first follow-up visit (7 days post intervention) in each case.
Continuous variables were summarised as mean and standard deviation. Categorical variables were either summarised as frequency and percentage or mode. Student’s t test (two-tailed) and χ – squared tests were used to compare the mean difference between the two groups. The effect of the drug in the two groups and genders was compared by the One way ANOVA test. The correlation between the dose and the efficacy of the drug was determined by the Spearman’s rank coefficient. A p value <0.05 was considered statistically significant.
Results
A total of 26 patients were included, out of which 3 patients had blepharospasm and 23 patients had hemifacial spasm. 7 patients had an underlying vascular loop syndrome or a secondary facial dystonia. Table 1 shows the demographic characteristics of our study participants.
A total of 76 sittings were included in our study ranging from one to nine sittings per patient. Most of the sittings involved a total dose of 25 IU (n=51; 67.1%). Figures 1 and 2 are the pre and post treatment photos in two of our participants having primary Hemifacial spasm and blepharospasm respectively.
The average disease free interval generated by these 76 sittings was 139.92 ± 58.53 days. Graph 1 shows the average symptom-free interval with each dose.
We tried to determine the pre operative factors which were responsible for longer disease-free intervals, suggestive of a better efficacy. The duration of the disease free interval was unaffected by the gender of the patient (f ratio value = 0.042; p = 0.84 ). The efficacy of the drug was unaffected by the duration of the dystonia at first presentation (p = 0.32). The first treatment with BotoGenie® gifted significantly longer disease free intervals in primary dystonias (135.11 ± 54.15 days) than in secondary dystonias (75.29 ± 48.89 days) as shown by the One way ANOVA test (f ratio value = 6.46; p = 0.02). There was no statistically significant correlation between the total dose administered in a sitting and the efficacy of the drug (ρ = 0.12; p value = 0.31). There was a statistically significant increase in the efficacy of the drug with subsequent injections at doses of 22.5 IU per sitting ( ρ = 0.66; p value = 0.04). Doses of 20, 25, 30 and 50 IU were not associated with a similar increase in efficacy with subsequent injections. (p values of 0.59, 0.26, 0.87 and 0.37 respectively)
The overall complication profile for BotoGenie® was the same for both primary and secondary dystonias. The complication rate for primary dystonias was 33.3% (n=23) and that for secondary dystonias was 42.9% (n=3). There was no systemic, life-threatening or vision threatening complication in either group. Table 2 shows the distribution of complications in the two groups.
The participants who developed lagophthalmos after the injection were treated with ocular lubricants and lid taping at bed time. This lagophthalmos disappeared spontaneously, usually within three to five weeks. None of the other complications encountered in our study needed treatment.
Discussions
There are several methods of treating facial dystonias. Tight bands across the forehead, tight glasses, glasses with a palpebral splint and dark goggles are non-pharmacological ways of treating blepharospasm. Oral benzodiazepines and GABA-B blockers may also be used. Dopamine modulating therapies may also be helpful. But these are systemic therapies which may alter cognitive function and induce somnolence.[4] Microsurgical decompression produces lasting results in vascular loop syndromes, but there is a high risk of permanent neurodeficit or stroke.[1] Alcohol or anaesthetic substances may be injected intramuscularly, but the effect fades out too rapidly to be clinically useful. Breinin and Jacoby found that cadmium and diltiazem reduced muscle contractility in vivo and in vitro, but their results were never put to clinical tests.[5]. [6] Antibiotics such as Doxorubicin may also be used as an alternative therapy. Theoretically a single local injection of Doxorubicin causes permanent cure.[7] But the most popular mode of treating a facial dystonia, irrespective of the underlying etiology, is with injections of type A botulinum toxin.
Onabotulinum toxin A, Abobotulinum toxin A, Incobotulinum toxin A and several other preparations of type A Botulinum toxin are available commercially for the treatment of facial dystonias. But one unit of a given preparation is specific and is not comparable to one unit of any other preparation due to differences in the vehicle dilution scheme, the laboratory protocols and the differences in species sensitivities.[8] Most studies on facial dystonias have been performed with Onabotulinum toxin A. BotoGenie® is different from Onabotulinum toxin type A. In this retrospective interventional study, we tried to determine whether BotoGenie® is safe and effective in the treatment of facial dystonias and the factors which affect it’s efficacy.
We included 26 patients who had a total of 76 sittings of Botulinum toxin injection for facial dystonias. We divided the patients into those with primary and secondary dystonias. The two groups were comparable with regard to their demographic profiles. Five different doses were used depending on the severity of the disease. The mean symptom-free interval post injection in our study varied from 3.4 – 4.9 months (102.1 to 147.2 days) with different doses of BotoGenie®. This is comparable to the reports of Wang X et al and is slightly greater than that reported by Anwar et al.[1], [9] There was no statistically significant improvement in the efficacy of the drug on increasing the dose. This is similar to the reports of Czyz and Ainsworth.[10],[11] At 22.5 IU/ sitting, there was a statistically significant increase in the efficacy with each subsequent dose (p value= 0.04). We have come up with a possible cause. The dose of the injection was chosen according to the severity of the spasm at every visit and we switched over to a higher dose when the spasms were resistant to the previous one. As a result, patients receiving lower doses of the drug actually had a less resistant disease and were likely to be symptom-free for a longer period of time. Anwar et al in his study noted that 23.52% of the study participants felt almost cured after three to five injections and stopped treatment.[9] In the rest of the patients, who were more resistant to therapy, the dose of the drug had to be increased and they required regular injections for prolonged periods.[9] We believe that we would have obtained the same result with a dose of 20 IU/ sitting but there were a very few sittings where this dose was used (n=4; 5.3%). Hence it could not achieve a statistical significance (p = 0.59).
In our study, the first injection of Botulinum toxin was associated with a longer disease-free interval in primary than in secondary dystonias. Oyama H et al showed that secondary hemifacial spasms caused by vertebral artery compression is more resistant to Botulinum toxin therapy because of the strong compression forces.[12] This probably accounts for this disparity in our study as well.
In our study, the commonest complication with this intervention was lagophthalmos, followed by deviation of the angle of the mouth and ptosis. But none of these complications required a major intervention. The occurence of complications following an injection of Botulinum toxin for a facial dystonia is rare. The incidence of ptosis following Botulinum toxin injection has been reported in 5.88% to 22% of cases in literature.[9], [13] Exaggerated symptoms of dry eye and features of facial weakness has also been reported. One study has also shown an improvement in the features of dry eye post injection.[14] This difference in the complication profile in different reports is probably due to different dosage schedules and/or slightly different techniques of administration.
In conclusion, we would like to say that Botulinum toxin type A is both safe and effective in the treatment of facial dystonias. It is slightly more effective in primary than in secondary dystonias. Nevertheless, keeping the complication profile in mind, we would like to suggest Botulinum toxin injections as the primary mode of treatment in all forms of facial dystonias.
References
- Wang X, Thirumala PD, Shah A, Gardner P, Habeych M, Crammond DJ et al. Effect of previous botulinum neurotoxin treatment on microvascular decompression for hemifacial spasm. Neurosurg Focus. 2013 Mar;34(3):E3. doi: 10.3171/2012.11.FOCUS12373.
- Jankovic J, Oman J. Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study. Neurology. 1987;37:616–23.
- Lee JA, Jo KW, Kong DS, Park K. Using the new clinical grading scale for quantification of the severity of hemifacial spasm: correlations with a quality of life scale. Stereotact Funct Neurosurg. 2012;90:16‐9.
- Hellman A, Torres-Russotto D. Botulinum toxin in the management of blepharospasm: current evidence and recent developments. Ther Adv Neurol Disord. 2015 Mar; 8(2): 82–91.
- Breinin GM, Sadovnikoff N, Pfeffer R, Davidowitz J, Chiarandini DJ. Cadmium Reduces Extraocular Muscle Contractility in Vitro and in Vivo. Invest Ophthalmol Vis Sci. 1985;26:1639-42.
- Jacoby J, Kahn DN, Pavlica MR, Ko K, Breinin GM. Diltiazem reduces the contractility of extraocular muscles in vitro and in vivo. Invest Ophthalmol Vis Sci. 1990 Mar 1;31(3): 569-76.
- Nguyen LT, McLoon LK, Wirtschafter JD. Doxorubicin chemomyectomy is enhanced when performed two days following bupivacaine injections: The effect coincides with the peak of muscle satellite cell division. Invest Ophthalmol Vis Sci. 1998 Jan;39(1):203-6.
- Carruthers J, Carruthers A. The evolution of botulinum neurotoxin type A for cosmetic applications. J Cosmetic Laser Ther. 2007;9: 186–92.
- Anwar MS, Zafar H. Efficacy of botulinum toxin in benign essential Blepharospasm: Desirable & undesirable effects. Pak J Med Sci. 2013 Nov-Dec; 29(6): 1389–93.
- Czyz CN, Burns JA, Petrie TP, Watkins JR, Cahill KV, Foster JA. Long-term botulinum toxin treatment of benign essential blepharospasm, hemifacial spasm, and Meige syndrome. Am J Ophthalmol. 2013;156(1):173–7.
- Ainsworth JR, Kraft SP. Long-term changes in duration of relief with botulinum toxin treatment of essential blepharospasm and hemifacial spasm. Ophthalmology. 1995;102(12):2036–40.
- Oyama H, Ikeda A, Inoue S, Nakashima Y, Shibuya M. Local injection of botulinum toxin type A for hemifacial spasm. Neurol Med Chir (Tokyo). 2002;42(6):245-9.
- Ruusavaara P, Setala K. Long-term treatment of involuntary facial spasms using botulinum toxin.Acta Ophthalmol. 1990;68(3):331–8.
- Park DI, Shin HM, Lee SY, Lew H. Tear production and drainage after botulinum toxin A injection in patients with essential blepharospasm. Acta Ophthalmol. 2013;91(2):e108–12.
Table 1 Demographics of our study participants
| Primary facial dystonia | Secondary facial dystonia | Overall | p value | |
| Age (years) * | 56.89 ± 11.32
(45 – 70) |
55.86 ± 9.90
(36 – 77) |
56.62 ± 10.56
(36 – 77) |
0.83 † |
| Gender ‡
Male Female |
10 (52.6) 9 (47.4) |
4 (57.1) 3 (42.9) |
14 (53.8) 12 (46.2) |
0.84 § |
| Phenotype ‡
Blepharospasm Hemifacial spasm Laterality ‡ Right Left |
2 (20) 17 (80)
8 (47.1) 9 (52.9) |
1 (14.3) 6 (85.7)
2 (33.3) 4 (66.7) |
3 (11.5) 23 (88.5)
10 (43.5) 13 (56.5) |
0.79 §
0.56 § |
| Duration of illness at presentation (years) * | 2.73 ± 2.71
(0.08 – 6) |
4.03 ± 5.08
(0.08 – 15) |
3.15 ± 3.46
(0.08 – 15) |
0.32 † |
| Severity at presentation ||
Blepharospasm¶ Hemifacial spasm ** |
4 2 |
6 2 |
4 2 |
– |
* Expressed in terms of Mean ± Standard deviation and (Range)
† Two-tailed Student’s t-test ‡ Expressed in terms of frequency (Percentage)
- χ – squared test. || Summarised in terms of Mode.
¶ Severity graded by Jankovic Rating Scale
** Severity graded by the Samsung Medical Centre grading system
Table 2 Complication profile of the two groups
| Primary facial dystonia * | Secondary facial dystonia * | p Value † | |
| Lagophthalmos | 18 (26.1) | 2 (28.6) | 0.8 |
| Deviation of angle of mouth | 2 (2.9) | 1 (14.3) | |
| Ptosis | 2 (2.9) | 0 (0) | |
| Persistent twitching | 1 (1.5) | 0 (0) | |
| Total | 23 (33.3) | 3 (42.9) |
* The data has been represented as frequency (percentage).
† p value has been calculated by two tailed t – test
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