ORIGINAL ARTICLE
Year : 2020 | Volume
: 37 | Issue : 4 | Page : 197--202
Botulinum toxin injections for neurological disorders: Experience between 1994 and 2019
Cem Boluk1, Yesim Gökçe2, Aysegül Gündüz1, Nurten Uzun Adatepe1, Feray Karaali Savrun1, Asim Kaytaz3, Meral E Kızıltan1,
1 Department of Neurology and Clinical Neurophysiology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, Turkey
2 Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, Turkey
3 Department of Otorhinolaryngology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, Turkey
Correspondence Address:
Cem Boluk
Department of Neurology and Clinical Neurophysiology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Fatih 34098, Istanbul
Turkey
Abstract
Aim: Reported results of botulinum toxin (BoNT) injections vary widely in different studies and in different neurological disorders. The aim of this study was to investigate the efficacy and safety of BoNT injections for each neurological disorder and to report our experience in this area since 1994. Materials and Methods: All patients who were injected with BoNT since 1994 were included in this retrospective study. Age, gender, etiology, specific diagnosis, time from first symptom to first injection, type of BoNT (onabotulinum toxin-abobotulinum toxin), doses, treatment response, and complications were extracted from patient files. Etiologies were classified into five main groups: hyperkinetic movement disorders, focal spasticity, painful conditions, sialorrhea, and hyperhidrosis. Positive treatment response was defined as any objective clinical improvement determined by the attending physician and declared by the patient. Results: We determined that 1792 patients were considered for BoNT injections. Among them, 341 were not found to be suitable for injections or did not accept to have the procedure done. In total, 1451 different patients were included in the study. The most common indications for BoNT injection were hyperkinetic movement disorders (72.3%) and focal spasticity (15.2%). Other disorders included painful conditions, hyperhidrosis, and sialorrhea. In 74.3% of the patients, the only injected toxin was onabotulinum toxin, whereas 10.2% of the patients were injected only with abobotulinum toxin. In 14.7% of the patients, the injection type was changed from one to the other, due to ineffectiveness or unavailability. Response rates were 95.4% for focal spasticity, 92.6% for hyperkinetic movement disorders, 81.1% for painful conditions, 66.7% for hyperhidrosis, and 63.1% for sialorrhea. Severe complications were seen in 0.6% of the patients. Conclusion: BoNT injections seem to be effective in all of the neurological disorders which we investigated. Except for mild cosmetic complications, BoNT is generally safe in experienced hands.
How to cite this article:
Boluk C, Gökçe Y, Gündüz A, Adatepe NU, Savrun FK, Kaytaz A, Kızıltan ME. Botulinum toxin injections for neurological disorders: Experience between 1994 and 2019.Neurol Sci Neurophysiol 2020;37:197-202
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How to cite this URL:
Boluk C, Gökçe Y, Gündüz A, Adatepe NU, Savrun FK, Kaytaz A, Kızıltan ME. Botulinum toxin injections for neurological disorders: Experience between 1994 and 2019. Neurol Sci Neurophysiol [serial online] 2020 [cited 2023 Mar 22 ];37:197-202
Available from: http://www.nsnjournal.org/text.asp?2020/37/4/197/305386 |
Full Text
Introduction
Since its initial approval by the United States Food and Drug Administration in 1989, the injection of botulinum toxin (BoNT) has been commonly used for treatment in various neurological diseases in addition to cosmetic purposes. In general practice, it is mainly used for hyperkinetic movement disorders (such as blepharospasm, hemifacial spasm, facial myokymia, orolingual, orofacial, and oromandibular dyskinesia, cervical dystonia, laryngeal dystonia, selected cases with tremor, focal hand dystonia and task-specific dystonia), hyperhidrosis, sialorrhea, spasticity, and selected painful conditions.[1],[2],[3],[4],[5],[6],[7]
Various treatment response and complication rates for each disorder have been reported before.[8],[9],[10] Different studies have shown that efficacy, safety, and dose selection are related to various factors besides the experience of the clinician.[11],[12]
In this study, we aimed to present the indications, efficacy, and safety of BoNT injections in different neurological disorders in our cohort and to report fully our experiences at our clinic since 1994.
Materials and Methods
We conducted a retrospective cohort study between 2019 and 2020. All patients who have been injected with BoNT by our experienced physicians for whatever reason at the outpatient neurology clinic since 1994 were included in the study. Age, gender, first application year, duration between the first symptom and BoNT injection, etiology, total number of BoNT injections, type of BoNT (AbobotulinumtoxinA [Dysport®, Ipsen Ltd., Slough, UK]; OnabotulinumtoxinA [Botox®, Allergan Inc., Irvine, CA]), intervals between injections, frequency of visits, total doses for each injection, complications, side effects, and treatment response were recorded. Ethical approval was not needed for this type of retrospective observational data analysis. The STROBE guideline and checklist was followed.[13]
Patients were mainly categorized into five groups: (1) hyperkinetic movement disorders, (2) focal spasticity, (3) painful conditions, (4) sialorrhea, and (5) hyperhidrosis. Specific diagnoses were additionally classified as subgroups.
Positive treatment response was defined as any objective clinical improvement determined by the attending physician and by the self-declaration of the patient after each injection. In self-declarations, the Patients' Global Impression of Change (PGIC) scale was used to assess overall response to treatment. The PGIC is a seven-point scale (1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; and 7, very much worse). The response was defined as getting 1, 2, or 3 from the PGIC scale.
Noted complications were divided into two groups: (a) mild complications (cosmetic complications, weakness, localized bruising, presyncope, pain, dry eye, mild bleedings, and ecchymosis) and (b) severe complications (hematoma, pneumothorax, respiratory problems, syncope, and convulsion).
Statistical analysis
The SPSS 21.0 (version 21.0, SPSS Inc., Chicago, IL, USA) was used for the calculation of frequency distributions and percentages. ANOVA test was used for variance analysis in terms of comparing the means of five main etiologic groups. Pearson Chi-square test was used to compare the categorical variables. Logistic regression analysis was used to evaluate the factors associated with treatment response and complications.
Results
We determined that 1792 patients were considered for injection of BoNT. After the initial clinical examination, 341 were not found to be suitable for injections due to medical causes or did not accept to have the procedure done, or they had missing data. In total, 1451 patients with 9334 injections were included in the study.
The most common cause of BoNT injections was found to be hyperkinetic movement disorders in 1049 patients (72.3%). Other groups included focal spasticity, 220 patients (15.2%); painful conditions, 131 patients (9.0%); sialorrhea, 45 patients (3.1%); and hyperhidrosis, 6 patients (0.4%).
The female/male ratio was 0.6 in the sialorrhea group and 0.8 in the focal spasticity group. The two groups have a significantly low female/male ratio when compared to the other groups (P = 0.001). The mean age at the first injection was 31.5 ± 12.9 years in the hyperhidrosis group, and it was significantly lower than the other groups (P = 0.002). The mean duration from the first complaint to the first injection was 151.1 months in the painful condition group, and it was significantly higher than the other groups (P < 0.001). The mean number of injections was 7.8 ± 5.5 applications in the hyperkinetic movement disorder groups, and it was significantly high when compared to the other groups (P < 0.001). The mean onabotulinum toxin and abobotulinum toxin doses were 221.2 ± 85.2 and 843.7 ± 318.5 units (U), respectively, in the focal spasticity group. The doses were significantly higher than the other groups (P < 0.001).
The clinical and demographical characteristics of patients according to the five main groups are shown in [Table 1]. The features of the main subgroups in the hyperkinetic movement disorder group are shown in [Table 2]. The mean BoNT doses for some specific disorders are shown in [Table 3].{Table 1}{Table 2}{Table 3}
In the hyperkinetic movement disorder group, hemifacial spasm (n = 283, 27.0%) and cervical dystonia (n = 278, 26.5%) were the most common causes. Others were blepharospasm (n = 104, 9.9%), extremity dystonia (n = 107, 10.2%), oromandibular dystonia (n = 51, 6.1%), generalized dystonia (n = 36, 3.4%), laryngeal dystonia (n = 29, 2.8%), and dystonic tremor (n = 24, 2.3%).
The most common disorders within the spasticity group were stroke (n = 115, 52.3%), multiple sclerosis (n = 34, 15.5%), and cerebral palsy (n = 29, 13.2%).
The painful conditions that were referred for BoNT were trigeminal neuralgia (n = 70, 53.4%), migraine (n = 50, 38.2%), cluster headache (n = 3, 2.3%), tension-type headache (n = 2, 1.5%), complex regional pain syndrome (n = 2, 1.5%), and fibromyalgia (n = 1, 0.8%). Cases with trigeminal neuralgia were either resistant to other medical treatments or could not use oral medications due to side effects. The causes of trigeminal neuralgia were idiopathic, classical, or secondary (attributed to multiple sclerosis). All cases with migraine had a chronic form and did not respond to medical treatments.
Causes of BoNT injections in the sialorrhea group were Parkinson's disease and other types of parkinsonism (n = 21, 46.6%), ALS (n = 14, 31.1%), cerebral palsy (n = 8, 17.7%), stroke (n = 2, 4.4%), and multiple sclerosis (n = 2, 4.4%).
The type of the BoNT was onabotulinum toxin in 74.3% (n = 1078) of all the patients, whereas abobotulinum toxin was preferred in 10.2% (n = 148). In 15.5% (n = 225) of the patients, the type of BoNT was changed from one to another for various reasons (inefficacy, unavailability, physician preference, etc.).
Response rates
The response rate was 63.1% in the sialorrhea group, and it was significantly lower than the other main groups, as shown in [Table 1] (P < 0.001). Response rates for each specific diagnosis within the hyperkinetic movement disorder and painful condition groups were as follows: hemifacial spasm (97.1%), generalized dystonia (96.7%), laryngeal dystonia (95.2%), cervical dystonia (94.6%), blepharospasm (90.2%), bruxism (88.9), dystonic tremor (86.6%), extremity dystonia (84,1%), chronic migraine (83.8%), and trigeminal neuralgia (79.5%). The response rates according to specific diagnoses are summarized in [Figure 1]. None of the variables were found to have an influence on treatment response (gender P = 0.929, etiology P = 0.915, comorbidity P = 0.970, type of BoNT P = 0.698, and dosage P = 0.882).{Figure 1}
Complication rates
Complication rates in the five main groups were as follows: 21.2% in hyperkinetic movement disorders, 6.5% in focal spasticity, 4.5% patients with sialorrhea, and 1.2% in painful conditions, respectively. The complication rate was significantly higher in the hyperkinetic movement disorder groups (P < 0.001).
Severe complications (convulsive syncope, dyspnea, respiratory failure, allergic reactions) were only seen in 9 patients with a rate of 0.6%.
None of the variables including BoNT doses were found to have an influence on complications (gender P = 0.415, etiology P = 0.578, type of BoNT P = 0.144, dosage P = 0.775, and comorbidity P = 0.952).
Discussion
This study showed that BoNT injections were effective, well-tolerated, and safe in experienced hands, regardless of the kind of neurological disorder. Hyperkinetic movement disorders constituted the vast majority of patients. The mean age at the first injection application was evidently low in the hyperhidrosis group. Duration from the first complaint to the first injection was significantly longer in the painful condition group. The mean injection number was much higher in the hyperkinetic movement disorder group. No factors were found to be associated with response rates or complications.
In one retrospective study which investigated the long-term efficacy of BoNT-A over a 10-year period in 235 patients with cervical dystonia, hemifacial spasm, blepharospasm, and other focal/segmental dystonia, response rates were reported as 96% for hemifacial spasm, 92% for blepharospasm, and 68% for cervical dystonia. Minor side effects developed in 27% of the patients at any one time.[14] These response and complication rates were similar to our study except for cervical dystonia which had a higher response rate in ours. Similarly, Jankovic reported that the complication rate with BoNT injections was 22% for cervical dystonia at the last visit.[15] In a systemic review and meta-analysis of 36 long-term studies involving 2309 individuals, any mild-to-moderate adverse events were reported in about 25% in the BoNT-A treated group (353/1425 patients). They stated that serious adverse events were seen in <1 in 1000 patients.[16] In another study, Cillino et al . recorded that 30% of the patients had one or more mild-to-moderate side effects, and none of them had any serious side effects.[17] Despite having the highest complication rates, the hyperkinetic movement disorder group had higher injection numbers than other groups. One reason could be that these patients have more necessity for BoNT injections for their treatment when compared to other groups. More medical treatment options are available for other groups of disorders. The other reason could be that this group has a higher patient number and got more injections to face area.
It is well known that formulations of onabotulinum toxin and abobotulinum toxin are different, and the total BoNT units used in clinical practice for each neurological condition differ. Some studies have investigated this difference and shown equivalence in therapeutic effect at a dose ratio (abobotulinum toxin/onabotulinum toxin units) ranging from 3:1 to as high as 6:1, with reporting different adverse effect ratios.[18],[19],[20] Marchetti et al . reported that the abobotulinum toxin-to-onabotulinum toxin ratio may vary between 2:1 and a high of 11:1 although the vast majority was about 3:1.[21] In our study, the abobotulinum toxin-to-onabotulinum toxin ratio varied between 2.9 and 4.4.
Each neurological condition may require different doses of BoNT for good clinical response. In our study, the highest dose of BoNT was used in the spasticity group with a mean of 221.2 U for onabotulinum toxin and 843.7 U for abobotulinum toxin. Randomized controlled trials regarding dose ranging of BoNT in spasticity showed that higher doses have better efficacy and longer duration of action when compared with lower doses. Simpson et al . reported that 300 U onabotulinum toxin was more effective than 150 U and Bakheit et al . reported that effect on functional disability was better at 1000 U abobotulinum toxin when compared to 500 U.[22],[23]
After spasticity, one of the highest BoNT doses (with 195 U of onabotulinum toxin and 715 U of abobotulinum toxin) was used for cervical dystonia. Similarly, in a multicenter, randomized, double-blind study, the mean adjusted dose of onabotulinum toxin was 205 U for cervical dystonia.[24] Mejia et al . reported that the mean injected dose at first and last sessions was 187 U in the movement disorder group which consisted mainly of cervical dystonia patients.[25] In another study, a mean of 795 U abobotulinum toxin was used in primary cervical dystonia patients.[26]
The lowest onabotulinum toxin dose in our study was used in laryngeal dystonia (with a mean of 7.9 onabotulinum toxin U) and with the abobotulinum toxin/onabotulinum toxin ratio of 4.4. Similarly, Blitzer and Brin, with their 210 patients' injections, showed that by injecting 7.5 U onabotulinum toxin (3.75 U for each side), all patients benefitted. They also reported that side effects did not decrease significantly by lowering the dose to 5 U.[27]
Our study showed female predominance in the painful condition and hyperkinetic movement disorder groups, whereas males were more frequent in focal spasticity. Similarly, in a multicenter study, Cillino et al . reported female dominance in both the blepharospasm and hemifacial spasm patients.[17] In another large cohort, it was recorded that 74% of the cervical dystonia patients were female.[28] On the contrary, male dominance can be clearly seen in patients with spasticity. In different studies, it was reported that 62%, 80%, and 57.5% of the patients with spasticity were male, respectively.[23],[29],[30] The main reason for this is that most studies, including our own, have mostly stroke patients in the spasticity groups. Male dominance in stroke is a well-known situation in the world and also in Turkey.[31],[32]
Limitations of the study
The study has several limitations. The first main limitation of the study is that it was retrospective. Second, the identification of responsive patients might have not been as objective as expected due to the lack of scales in some patients' files, especially within the in first years. Another limitation is a lack of comparative analysis of EMG-guided versus nonguided injections. Last but not least, due to missing data, some patients had to be excluded from the analysis.
Conclusion
This study with its considerably high patient number and length of experience showed a very satisfactory treatment response and complication rates. Indications for BoNT injections are wide and are becoming wider gradually with the management of various clinical conditions. Its benefits may be increased by individualized treatment models rather than standard protocol. Further studies may pay particular attention to the factors which we did not investigate such as optimal treatment intervals, dilution scheme, technical factors, and immunogenicity.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
| 1 | Kenney C, Jankovic J. Botulinum toxin in the treatment of blepharospasm and hemifacial spasm. J Neural Transm (Vienna) 2008;115:585-91. |
| 2 | Bentivoglio AR, Fasano A, Ialongo T, Soleti F, Lo Fermo S, Albanese A. Fifteen-year experience in treating blepharospasm with Botox or Dysport: Same toxin, two drugs. Neurotox Res 2009;15:224-31. |
| 3 | Vogt T, Lüssi F, Paul A, Urban P. Long-term therapy of focal dystonia and facial hemispasm with botulinum toxin A. Nervenarzt 2008;79:912-7. |
| 4 | Jankovic J. Botulinum toxin in clinical practice. J Neurol Neurosurg Psychiatry 2004;75:951-7. |
| 5 | Bakheit AM. Botulinum toxin in the management of childhood muscle spasticity: Comparison of clinical practice of 17 treatment centres. Eur J Neurol 2003;10:415-9. |
| 6 | Ranoux D, Attal N, Morain F, Bouhassira D. Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann Neurol 2008;64:274-83. |
| 7 | Sürmelioğlu Ö, Dağkıran M, Tuncer Ü, Özdemir S, Tarkan Ö, Çetik F, et al . The Effectiveness of botulinum toxin Type A injections in the management of Sialorrhea. Turk Arch Otorhinolaryngol 2018;56:111-3. |
| 8 | Ramirez-Castaneda J, Jankovic J. Long-term efficacy and safety of botulinum toxin injections in dystonia. Toxins (Basel) 2013;5:249-66. |
| 9 | Ababneh OH, Cetinkaya A, Kulwin DR. Long-term efficacy and safety of botulinum toxin A injections to treat blepharospasm and hemifacial spasm. Clin Exp Ophthalmol 2014;42:254-61. |
| 10 | Safarpour Y, Jabbari B. Botulinum toxin treatment of movement disorders. Curr Treat Options Neurol 2018;20:4. |
| 11 | Mclellan K, Das RE, Ekong TA, Sesardic D. Therapeutic botulinum type A toxin: Factors affecting potency. Toxicon 1996;34:975-85. |
| 12 | Francisco GE. Botulinum toxin for post-stroke spastic hypertonia: A review of its efficacy and application in clinical practice. Ann Acad Med Singapore 2007;36:22-30. |
| 13 | von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, et al . The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. PLoS medicine 2007;4(10):e296. |
| 14 | Hsiung GY, Das SK, Ranawaya R, Lafontaine AL, Suchowersky O. Long-term efficacy of botulinum toxin A in treatment of various movement disorders over a 10-year period. Mov Disord 2002;17:1288-93. |
| 15 | Jankovic J. Botulinum toxin therapy for cervical dystonia. Neurotox Res 2006;9:145-8. |
| 16 | Naumann M, Jankovic J. Safety of botulinum toxin type A: A systematic review and meta-analysis. Curr Med Res Opin 2004;20:981-90. |
| 17 | Cillino S, Raimondi G, Guépratte N, Damiani S, Cillino M, Di Pace F, et al . Long-term efficacy of botulinum toxin A for treatment of blepharospasm, hemifacial spasm, and spastic entropion: A multicentre study using two drug-dose escalation indexes. Eye (Lond) 2010;24:600-7. |
| 18 | Marion MH, Sheehy M, Sangla S, Soulayrol S. Dose standardisation of botulinum toxin. J Neurol Neurosurg Psychiatry 1995;59:102-3. |
| 19 | Whurr R, Brookes G, Barnes C. Comparison of dosage effects between the American and the British botulinum toxin A product in the treatment of spasmodic dysphonia. Mov Disord 1995;10:56. |
| 20 | Ranoux D, Gury C, Fondarai J, Mas JL, Zuber M. Respective potencies of Botox and Dysport: A double blind, randomised, crossover study in cervical dystonia. J Neurol Neurosurg Psychiatry 2002;72:459-62. |
| 21 | Marchetti A, Magar R, Findley L, Larsen JP, Pirtosek Z, Růzicka E, et al . Retrospective evaluation of the dose of Dysport and BOTOX in the management of cervical dystonia and blepharospasm: the REAL DOSE study. Mov Disord. 2005;20:937-44. doi: 10.1002/mds.20468. |
| 22 | Simpson DM, Alexander DN, O'Brien CF, Tagliati M, Aswad AS, Leon JM, et al . Botulinum toxin type A in the treatment of upper extremity spasticity: A randomized, double-blind, placebo-controlled trial. Neurology 1996;46:1306-10. |
| 23 | Bakheit AM, Thilmann AF, Ward AB, Poewe W, Wissel J, Muller J, et al . A randomized, double-blind, placebo-controlled, dose-ranging study to compare the efficacy and safety of three doses of botulinum toxin type A (Dysport) with placebo in upper limb spasticity after stroke. Stroke 2000;31:2402-6. |
| 24 | Comella CL, Jankovic J, Shannon KM, Tsui J, Swenson M, Leurgans S, et al . Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia. Neurology 2005;65:1423-9. |
| 25 | Mejia NI, Vuong KD, Jankovic J. Long-term botulinum toxin efficacy, safety, and immunogenicity. Mov Disord 2005;20:592-7. |
| 26 | Haussermann P, Marczoch S, Klinger C, Landgrebe M, Conrad B, Ceballos-Baumann A. Long-term follow-up of cervical dystonia patients treated with botulinum toxin A. Mov Disord 2004;19:303-8. |
| 27 | Blitzer A, Brin MF. Laryngeal dystonia: A series with botulinum toxin therapy. Ann Otol Rhinol Laryngol 1991;100:85-9. |
| 28 | Jankovic J, Adler CH, Charles D, Comella C, Stacy M, Schwartz M, et al . Primary results from the cervical dystonia patient registry for observation of onabotulinumtoxina efficacy (CD PROBE). J Neurol Sci 2015;349:84-93. |
| 29 | Kaji R, Osako Y, Suyama K, Maeda T, Uechi Y, Iwasaki M, et al . Botulinum toxin type A in post-stroke lower limb spasticity: A multicenter, double-blind, placebo-controlled trial. J Neurol 2010;257:1330-7. |
| 30 | Dunne JW, Heye N, Dunne SL. Treatment of chronic limb spasticity with botulinum toxin A. J Neurol Neurosurg Psychiatry 1995;58:232-5. |
| 31 | Appelros P, Stegmayr B, Terént A. Sex differences in stroke epidemiology: A systematic review. Stroke 2009;40:1082-90. |
| 32 | Köseoğlu Toksoy C, Bölük C, Türk Börü Ü, Akın S, Yılmaz AY, Duman SC, et al . Stroke prevalence in a coastal town on the black sea coast in Turkey: Community based study. Neurol Res Int 2018;2018:8246123. |
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