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Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm
Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Case study
Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm Atsushi Mizuma a,⇑, Eiichiro Nagata a, Takashi Yasuda b, Maiko Kouchi a, Taira Nakayama b, Kazunari Honma a, Kentaro Tokuoka b, Yasuhisa Kitagawa b, Shigeru Nogawa b, Shunya Takizawa a a b
Department of Neurology, Tokai University School of Medicine, Japan Department of Neurology, Tokai University Hachioji Hospital, Japan
a r t i c l e
i n f o
Article history: Received 12 April 2017 Accepted 21 June 2017 Available online xxxx Keywords: Hemifacial spasm Botulinum toxin Primary headache Tension type headache Cranio-cervical dystonia Headache impact test-6
a b s t r a c t Objective: We examined the relationship between hemifacial spasm (HFS; a form of cranio-cervical dystonia) and chronic primary headache, including tension-type headache (TTH). We also examined whether botulinum toxin A (BoNT/A) therapy for HFS ameliorates concomitant TTH. Methods: Fifty-one HFS patients receiving BoNT/A therapy were recruited. Patients’ characteristics (including age, gender, chronic headache history, exercise habits, stiff neck, cervical spondylolysis history), stress factors, worsening/new onset of headache associated with HFS, and dose of BoNT/A were examined. We diagnosed headache types according to The International Classification of Headache Disorders, 3rd edition, beta. Numerical Rating Scale (NRS) and Headache Impact Test-6 (HIT-6) scores for headache severity were compared between the 6-week baseline before BoNT/A therapy and 6week follow-up after BoNT/A therapy. Results: Of 51 patients with HFS, 17 (33.3%) reported worsening or new onset of headache (especially TTH) associated with HFS (Group-S), and 34 were not aware of headache (Group-N). Twelve patients (70.6%) in group-S reported improvement of headache after BoNT/A therapy. NRS (from 7 [5–9] to 0 [0–5], p < 0.01) and HIT-6 (from 55 [54–64] to 44 [36–52], p < 0.001) scores were significantly improved after BoNT/A therapy. Logistic regression analysis revealed significant interaction between TTH associated with HFS and the presence of stress factors (odds ratio 43.11: 2.95–629.39, p < 0.001) and history of chronic headache (odds ratio 28.53: 2.96–275.10, p < 0.001). Conclusions: Primary headache, especially TTH, is associated with HFS. BoNT/A therapy for HFS may also be indirectly effective for treatment of TTH. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Hemifacial spasm (HFS) is categorized as a form of craniocervical dystonia [1,2], and may be caused by vascular compression [2], tumor compression [1], brainstem lesions such as cerebrovascular diseases [3] and demyelinating diseases [4], and secondary factors such as trauma or peripheral facial paralysis [1,5]. However, in some cases of HFS the etiology cannot be established [1]. In these cases, medical treatment (anticonvulsants or GABAergic drugs) and/or intramuscular injection of botulinum toxin A Abbreviations: HFS, hemifacial spasm; BoNT/A, botulinum toxin type A; TTH, tension type headache; CH, chronic headache; NRS, Numerical Rating Scale; HIT-6, Headache Impact Test-6. ⇑ Corresponding author at: Department of Neurology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. E-mail address: [email protected] (A. Mizuma).
(BoNT/A) are performed to reduce spasms [1]. Though oral medications are generally ineffective [1], BoNT/A therapy can reduce spasms and improve quality of life [1,2]. Unusual involuntary movements can become major stress factors for cranio-cervical dystonia patients [2]. Furthermore, some cases of cranio-cervical dystonia (pharyngeal dystonia, spasmodic torticollis, mandibular dystonia, and lingual dystonia) are associated with secondary headache (headache attributed to cranio-cervical dystonia) due to the abnormal movements or defective posturing of the neck or head arising from muscular hyperactivity [6]. In contrast to other cranio-cervical dystonias, stress factors (via the central pain mechanism [7]) and increasing tenderness of pericranial muscles (via the peripheral pain mechanism [8]) can affect not only the severity of HFS, but also the severity of headache (especially primary headache [7,8]). However, the relationship between headache and HFS is unclear.
http://dx.doi.org/10.1016/j.jocn.2017.06.069 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mizuma A et al. Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.069
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A. Mizuma et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Tension-type headache (TTH), which is most frequent form of primary headache [9] in Japan, constitutes about 50% of chronic headache and may adversely affect work and productivity [10,11]. However, there are relatively few reports about TTH compared to migraine, and some cases may be subclinical (associated with other disorders) [11]. Although the coexistence ratio of TTH in patients with HFS is unclear, both stress factors and increasing tenderness of pericranial muscles associated with cranio-cervical dystonia (including HFS) are likely to worsen TTH. Spasmodic torticollis, which is also included in cranio-cervical dystonia, is associated with primary headache, especially migraine and TTH [12]. Recently, BoNT/A therapy has been applied to various movement disorders, such as cranio-cervical dystonia, post-stroke spasticity, and cerebral palsy [13–16]. Trials of BoNT/A therapy for treatment of primary headache have also been performed [17– 21]. However, BoNT/A was not effective for TTH [17,18], although it was effective against chronic migraine [19–21]. On the other hand, a beneficial effect on primary headache was reported in cranio-cervical dystonia patients treated with BoNT/A therapy, especially among patients receiving doses higher than 50 U for the treatment of spasmodic torticollis [12]. Hence, we speculated that facial spasm might worsen headache or cause new headache, and we hypothesized that BoNT/A therapy to treat HFS might improve not only facial spasm, but also headache. To test this idea, we examined the frequency of coexistence of chronic primary headache (CH) and HFS, and the effect on headache of BoNT/A therapy for HFS.
2.4. Quantitative evaluation of headache We used Numerical Rating Scale (NRS) [25] and Headache Impact Test-6 (HIT-6) [26] for quantitative evaluation of headache. We also set two investigation periods: a 6-week baseline period (pre-treatment period) and a 6-week follow-up period after BoNT/A therapy (post-treatment period) according to the previous report [27]. Scores were based on the patients’ subjective opinions during the specified periods. 2.5. Primary and secondary outcome Primary endpoint was worsening or new onset of headache accompanied by HFS. Secondary endpoint was clinical outcome defined in terms of NRS and HIT-6 scores and safety (side effects such as severe facial motor palsy, ptosis, lacrimation, etc.) after BoNT/A therapy. 2.6. Statistical analysis The chi-square test and t test were used for categorical data. For the analysis of the improvement of NRS and HIT-6 score, we used the Wilcoxon signed-rank test. We also used multivariable logistic regression to assess the relative risks of variables for worsening/ new onset of headache accompanied by HFS. Statistical analyses were performed using SPSS 23.0 (SPSS, Inc. Chicago, IL, USA). The significance level was set at P < 0.05.
2. Materials and methods
3. Results
2.1. Study design and ethics considerations
3.1. Association of HFS with headache
This study was a retrospective study and the subjects were recruited from patients with HFS who had visited at our neurology clinic at Tokai University Hospital for BoNT/A therapy between April 2015 and July 2015 (the period corresponds to one course of BoNT/A therapy). This study was approved by the Tokai University Ethics Committee (No. 16R-062). Informed consent was obtained from all recruited patients. Types of headache were diagnosed according to the criteria of The International Classification of Headache Disorders, 3rd edition (ICHD-III beta) [6].
Of the 51 patients with HFS, 17 patients (33.3%) reported worsening or new onset of headache accompanied by HFS (Group-S). Among these 17 patients, 15 had TTH and the other 2 had TTH and migraine (one ‘‘migraine without aura” and one ‘‘chronic migraine” according to ICHD-III beta). Of these 17 patients, 13 (72.2%) had headache at the ipsilateral side from HFS. The headache type associated with HFS was infrequent episodic TTH or frequent episodic TTH in all cases. The remaining 34 of the 51 patients were not aware of headache, regardless of CH history (Group-N).
2.2. Patient population
3.2. Patients’ characteristics
Fifty-one patients (41 females [80.4%]; mean age ± standard deviation, 64 years ± 14) who met the following inclusion criteria were recruited: received BoNT/A therapy at least once and continuing BoNT/A therapy. We excluded patients with blephalospasm, Meige syndrome, spasmodic torticollis, and medication-overuse headache [22]. Patients who had been treated for headache or microvascular compression before receiving BoNT/A therapy were also excluded from this study.
Table 1 summarizes the characteristics of patients and the dose of BoNT/A in each group. Patients were younger in group-S than in group-N (57 ± 17 vs. 68 ± 11, p < 0.05). CH history (70.6% vs. 17.6%, p < 0.001) was more frequent in group-S than in group-N. Stiff neck (82.4% vs. 52.9%, p < 0.05) and stress factors (88.2% vs. 32.4%, p < 0.001) were also more frequent in group-S than in group-N. Fig. 1 shows the distribution of patients by CH history and worsening or new onset of TTH. Twelve patients (70.6%) reported worsening of TTH accompanied by HFS among 17 patients with a history of CH. Five patients (14.7%) reported novel onset of TTH accompanied with HFS among 34 patients without a history of CH. There was no significant difference of injection site (0.625– 22.5 U of intramuscular injection per muscle) or total dosage of BoNT/A (20.73 ± 13.33 U vs. 17.07 ± 10.68 U) between the two groups.
2.3. Data collection The following patient data were collected from medical records at our clinic: age, gender, chronic headache (CH) history, exercise habits (defined as previously reported [23]), stiff neck (subjective or objective symptom [muscle tenderness]), history of cervical spondylolysis (diagnosed by an orthopedic surgeon based on clinical symptoms or imaging inspections), stress factors (defined as both ‘‘stressful life events” and ‘‘minor life events” [24]), worsening of headache in parallel with HFS or new onset of headache accompanied by HFS, and details of BoNT/A treatment for HFS (injection site and total dosage during the investigation period).
3.3. Effect of BoNT/A therapy on headache Twelve patients (70.6%) reported improvement of headache (degree and/or frequency) after BoNT/A therapy in group-S. Fig. 2 showed the transition of headache during the investigation
Please cite this article in press as: Mizuma A et al. Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.069
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A. Mizuma et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx Table 1 Characteristics of the included patients with facial spasm (n = 51).
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Age, years Female, n [％]2 CH history, n [％]2 Exercise habits, n [％]2 Stiff Neck, n [％]2 Cervical spondylosis, n [％]2 Stress factors, n [％]2 BoNT/A dose, U1 BoNT/A injection site, n [%]2
Frontalis muscle Orbicularis oculi Orbicularis oris Risorius muscle/zygomatic major/zygomaticus minor/ Triangularis muscle
Group-S* (n = 17)
Group-N** (n = 34)
P
57 ± 17 15 [88.2] 12 [70.6] 3 [17.6] 14 [82.4] 9 [52.9] 15 [88.2] 20.73 ± 13.33 3 [17.6] 17 [100.0] 9 [52.9] 14 [82.4] 3 [21.4]
68 ± 11 26 [76.7] 5 [14.7] 15 [44.1] 18 [52.9] 7 [20.6] 11 [32.4] 17.07 ± 10.68 4 [11.8] 34 [100.0] 15 [44.1] 22 [64.7] 3 [8.8]
0.018 NS <0.001 NS 0.041 0.019 <0.001 NS NS NS NS NS NS
Abbreviations: TTH, tension-type headache; CI, confidence interval; CH, chronic headache; BoNT/A; Botulinum toxin type A. 1 t-test. 2 v2 test. * Symptomatic group; group of patients with TTH (worsening or new onset accompanied by facial spasm). ** Non-symptomatic group; group of patients with TTH (stable) or without TTH.
Fig. 1. Distribution of study patients by CH history and worsening or new onset of TTH. Twelve patients (70.6%) reported worsening of TTH accompanied by HFS among 17 patients with a history of CH. Five patients (14.7%) reported new onset of TTH accompanied by HFS among 34 patients without a history of CH. Of the 17 patients with CH, 15 had TTH and the other 2 patients had combined headache (TTH and migraine).
period. The baseline values of NRS and HIT-6 score before BoNT/A therapy were 7 (median; interquartile range [IQR] 5–9) and 55 (54–64), respectively. Sixteen patients (94.1%) in group-S reported moderate or severe headache (over 4 points) on NRS. Thirteen patients (76.5%) in group-S had a score of over 50 on HIT-6, indicating that their headache had some impact on quality of life. NRS was significantly improved from 7 (5–9) to 0 (0–5) after BoNT/A therapy (p < 0.01). HIT-6 score was also improved from 55 (54–64) to 44 (36–52) after BoNT/A therapy (p < 0.001). Notably, 6 patients (46.2%) showed improvement to less than 49 points, indicating that their headache had little impact on their quality of life, among the 13 patients who initially scored over 50 on HIT-6. No worsening of facial spasm and no major adverse effects of BoNT/A therapy (severe facial motor palsy, ptosis, and lacrimation) were seen during the investigation period.
3.4. Other medications Ten patients took nonsteroidal anti-inflammatory drugs from 1 to 6 times a month in group-S. One patient was taking amitriptyline for chronic migraine. Drug dosage and frequency of medication in these patients were decreased in parallel with the improvement of HFS by BoNT/A therapy. 3.5. Relative risk for worsening/new onset of TTH accompanied by HFS The influence of several factors on worsening/new onset of TTH accompanied by HFS was estimated by logistic regression analysis (Table 2). There were significant interactions between HFSassociated TTH and the presence of stress factors (odds ratio [OR]: 43.11, 95% confidence interval [CI]: 2.95–629.39, p < 0.001) and CH history (OR: 28.53, 95% CI: 2.96–275.10, p < 0.001). How-
Please cite this article in press as: Mizuma A et al. Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.069
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A. Mizuma et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Fig. 2. Effect of BoNT/A therapy on headache scores in group-S (n = 17). (a) 16 patients (94.1%) in group-S reported moderate or severe headache (over 4 points) on NRS. NRS was significantly improved from 7 (5–9) to 0 (0–5) after BoNT/A therapy (p < 0.01). (b) 13 patients (76.5%) scored over 50 on HIT-6 (s). The HIT-6 score was also improved from 55 (54–64) to 44 (36–52) after BoNT/A therapy (p < 0.001). Notably, 6 patients (46.2%) improved to less than 49 points, which suggests their headache would have little impact on their quality of life, among the 13 patients with HIT-6 scores over 50 (;).
Table 2 Relative risks of variables for worsening/new onset of TTH in patients accompanied by facial spasm. Variable
Odds ratio
95％ CI
P
Increased age (per 1 year) Female CH history Stiff Neck Cervical spondylosis Stress factors
0.95 0.86 28.53 0.73 0.98 43.11
0.89–1.02 0.08–9.75 2.96–275.10 0.08–7.03 0.10–9.77 2.95–629.39
0.156 0.921 <0.001 0.785 0.987 <0.001
Multiple stepwise regression analysis. Abbreviations: TTH, tension-type headache; CI, confidence interval; CH, chronic headache.
ever, increased age (OR: 0.95, 95% CI: 0.89–1.02, p = 0.156), female sex (OR: 0.86, 95% CI: 0.08–9.75, p = 0.921), stiff neck (OR: 0.73, 95% CI: 0.08–7.03, p = 0.785), and cervical spondylolysis (OR: 0.98, 95% CI: 0.10–9.77, p = 0.987) were not associated with significantly increased risk for worsening or new onset of TTH associated with HFS. 4. Discussion Cranio-cervical dystonia can cause secondary headache due to abnormal movements or defective posturing of the neck or head as a result of muscular hyperactivity [6]. However, it is not known whether HFS is also related to the pathophysiology of headache. In this study, we examined the frequency of TTH coexistence in patients with HFS. We also evaluated the effect on headache of BoNT/A therapy for HFS. A major finding of this study was the higher frequency of TTH (33.3%) among HFS patients compared to the prevalence in the
Japanese population (21.7%) [11]. However, HFS patients rarely complain about headache, possibly because it is masked by other major symptoms. It seems noteworthy that new onset of TTH was seen in 14.7% of HFS patients with no history of CH. This result may support our hypothesis that HFS contributes to primary headache. From the results of multivariate analysis, not only CH history, but also stress factors were associated with TTH accompanied by HFS, regardless of the existence of stiff neck and spastic muscles (BoNT/A injection points). In general, TTH is considered to involve both central and peripheral pain mechanisms [7,8]. Stress factors are considered to be associated with both of them [28]. In patients with TTH, stress factors affect the descending pain-inhibitory system through the cerebral limbic system [28], and anti-anxiety agents or antidepressants could suppress this mechanism [28]. On the other hand, it was not clear from previous trials whether reducing muscle stiffness by BoNT/A therapy contributed to the improvement of TTH [17,18]. BoNT/A therapy for facial spasm might contribute to the improvement of TTH via reduction of stress from facial spasm, rather than by reducing muscle stiffness. As for the peripheral pain mechanism, stress factors are also related to muscle exhausion and the release of acetylcholine from presynaptic nerve terminals [28]. Released acetylcholine causes continuous contraction of muscle fibers and finally worsening of TTH owing to release of inflammatory factors such as prostaglandin E2 [28]. Reducing stress factors by BoNT/A therapy can prevent muscle exhausion and release of inflammatory factors. Indeed, efficacy of BoNT/A therapy was seen in terms of the NRS and HIT-6 scores in this study. Finally, an important feature of our study is the evaluation of headache using two types of scales (NRS and HIT-6). Nevertheless, our study has several limitations. The number of subjects is small
Please cite this article in press as: Mizuma A et al. Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.069
A. Mizuma et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
and recruited patients were limited to those receiving BoNT/A. Hence, selection bias may have affected the results. Furthermore, the severity of HFS was assessed only in terms of the dose of BoNT/A, because there is no appropriate index for HFS, in contrast to the Jankovic Rating Scale and Blepharospasm Disability Index in patients with blepharospasm [29]. Further, we could not evaluate the risk factors of TTH in detail because this study was retrospective. A prospective study would be desirable to check our findings. In conclusion, primary headache, especially TTH, often coexists with HFS. BoNT/A therapy for HFS may also be indirectly effective for improving TTH. Conflict of interest statement No conflict. Source of funding No funding. Acknowledgments None. References [1] Abbruzzese G, Berardelli A, Defaze G. Hemifacial spasm. Handb Clin Neurol 2011;100:675–80. [2] Kenney J, Jankovic J. Botulinum toxin in the treatment of blepharospasm and hemifacial spasm. J Neural Transm 2008;115:585–91. [3] Vermersch P, Petit H, Marion MH, Montagne B. Hemifacial spasm due to pontine infarction. J Neurol Neurosurg Psychiatry 1991;54:1018. [4] Mehanna R, Jankovic J. Movement disorders in multiple sclerosis and other demyelinating diseases. J Neurol Sci 2013;328:1–8. [5] Nussbaum M. Hemifacial spasm associated with benign parotid tumor. Ann Othol Rhinol Laryngol 1977;86:73–4. [6] Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33:629–808. [7] Spierings EL, Ranke AH, Honkoop PC. Precipitating and aggravation factors of migraine versus tension-type headache. Headache 2001;41:554–8. [8] Jensen R, Rasmussen BK, Pedersen B, Olesen J. Muscle tenderness and pressure pain thresholds in headache. A population study. Pain 1993;52:193–9. [9] Takashima T, Ishizaki K, Fukuhara Y, et al. Population-based door-to-door survey of migraine in Japan: the Daisen study. Headache 2004;44:8–19. [10] Schwartz BS, Stewart WF, Lipton RB. Lost workdays and decreased work effectiveness associated with headache in the workplace. J Occup Environ Med 1997;39:320–7.
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Please cite this article in press as: Mizuma A et al. Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.069
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Case study
Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm Atsushi Mizuma a,⇑, Eiichiro Nagata a, Takashi Yasuda b, Maiko Kouchi a, Taira Nakayama b, Kazunari Honma a, Kentaro Tokuoka b, Yasuhisa Kitagawa b, Shigeru Nogawa b, Shunya Takizawa a a b
Department of Neurology, Tokai University School of Medicine, Japan Department of Neurology, Tokai University Hachioji Hospital, Japan
a r t i c l e
i n f o
Article history: Received 12 April 2017 Accepted 21 June 2017 Available online xxxx Keywords: Hemifacial spasm Botulinum toxin Primary headache Tension type headache Cranio-cervical dystonia Headache impact test-6
a b s t r a c t Objective: We examined the relationship between hemifacial spasm (HFS; a form of cranio-cervical dystonia) and chronic primary headache, including tension-type headache (TTH). We also examined whether botulinum toxin A (BoNT/A) therapy for HFS ameliorates concomitant TTH. Methods: Fifty-one HFS patients receiving BoNT/A therapy were recruited. Patients’ characteristics (including age, gender, chronic headache history, exercise habits, stiff neck, cervical spondylolysis history), stress factors, worsening/new onset of headache associated with HFS, and dose of BoNT/A were examined. We diagnosed headache types according to The International Classification of Headache Disorders, 3rd edition, beta. Numerical Rating Scale (NRS) and Headache Impact Test-6 (HIT-6) scores for headache severity were compared between the 6-week baseline before BoNT/A therapy and 6week follow-up after BoNT/A therapy. Results: Of 51 patients with HFS, 17 (33.3%) reported worsening or new onset of headache (especially TTH) associated with HFS (Group-S), and 34 were not aware of headache (Group-N). Twelve patients (70.6%) in group-S reported improvement of headache after BoNT/A therapy. NRS (from 7 [5–9] to 0 [0–5], p < 0.01) and HIT-6 (from 55 [54–64] to 44 [36–52], p < 0.001) scores were significantly improved after BoNT/A therapy. Logistic regression analysis revealed significant interaction between TTH associated with HFS and the presence of stress factors (odds ratio 43.11: 2.95–629.39, p < 0.001) and history of chronic headache (odds ratio 28.53: 2.96–275.10, p < 0.001). Conclusions: Primary headache, especially TTH, is associated with HFS. BoNT/A therapy for HFS may also be indirectly effective for treatment of TTH. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Hemifacial spasm (HFS) is categorized as a form of craniocervical dystonia [1,2], and may be caused by vascular compression [2], tumor compression [1], brainstem lesions such as cerebrovascular diseases [3] and demyelinating diseases [4], and secondary factors such as trauma or peripheral facial paralysis [1,5]. However, in some cases of HFS the etiology cannot be established [1]. In these cases, medical treatment (anticonvulsants or GABAergic drugs) and/or intramuscular injection of botulinum toxin A Abbreviations: HFS, hemifacial spasm; BoNT/A, botulinum toxin type A; TTH, tension type headache; CH, chronic headache; NRS, Numerical Rating Scale; HIT-6, Headache Impact Test-6. ⇑ Corresponding author at: Department of Neurology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. E-mail address: [email protected] (A. Mizuma).
(BoNT/A) are performed to reduce spasms [1]. Though oral medications are generally ineffective [1], BoNT/A therapy can reduce spasms and improve quality of life [1,2]. Unusual involuntary movements can become major stress factors for cranio-cervical dystonia patients [2]. Furthermore, some cases of cranio-cervical dystonia (pharyngeal dystonia, spasmodic torticollis, mandibular dystonia, and lingual dystonia) are associated with secondary headache (headache attributed to cranio-cervical dystonia) due to the abnormal movements or defective posturing of the neck or head arising from muscular hyperactivity [6]. In contrast to other cranio-cervical dystonias, stress factors (via the central pain mechanism [7]) and increasing tenderness of pericranial muscles (via the peripheral pain mechanism [8]) can affect not only the severity of HFS, but also the severity of headache (especially primary headache [7,8]). However, the relationship between headache and HFS is unclear.
http://dx.doi.org/10.1016/j.jocn.2017.06.069 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mizuma A et al. Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.069
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A. Mizuma et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Tension-type headache (TTH), which is most frequent form of primary headache [9] in Japan, constitutes about 50% of chronic headache and may adversely affect work and productivity [10,11]. However, there are relatively few reports about TTH compared to migraine, and some cases may be subclinical (associated with other disorders) [11]. Although the coexistence ratio of TTH in patients with HFS is unclear, both stress factors and increasing tenderness of pericranial muscles associated with cranio-cervical dystonia (including HFS) are likely to worsen TTH. Spasmodic torticollis, which is also included in cranio-cervical dystonia, is associated with primary headache, especially migraine and TTH [12]. Recently, BoNT/A therapy has been applied to various movement disorders, such as cranio-cervical dystonia, post-stroke spasticity, and cerebral palsy [13–16]. Trials of BoNT/A therapy for treatment of primary headache have also been performed [17– 21]. However, BoNT/A was not effective for TTH [17,18], although it was effective against chronic migraine [19–21]. On the other hand, a beneficial effect on primary headache was reported in cranio-cervical dystonia patients treated with BoNT/A therapy, especially among patients receiving doses higher than 50 U for the treatment of spasmodic torticollis [12]. Hence, we speculated that facial spasm might worsen headache or cause new headache, and we hypothesized that BoNT/A therapy to treat HFS might improve not only facial spasm, but also headache. To test this idea, we examined the frequency of coexistence of chronic primary headache (CH) and HFS, and the effect on headache of BoNT/A therapy for HFS.
2.4. Quantitative evaluation of headache We used Numerical Rating Scale (NRS) [25] and Headache Impact Test-6 (HIT-6) [26] for quantitative evaluation of headache. We also set two investigation periods: a 6-week baseline period (pre-treatment period) and a 6-week follow-up period after BoNT/A therapy (post-treatment period) according to the previous report [27]. Scores were based on the patients’ subjective opinions during the specified periods. 2.5. Primary and secondary outcome Primary endpoint was worsening or new onset of headache accompanied by HFS. Secondary endpoint was clinical outcome defined in terms of NRS and HIT-6 scores and safety (side effects such as severe facial motor palsy, ptosis, lacrimation, etc.) after BoNT/A therapy. 2.6. Statistical analysis The chi-square test and t test were used for categorical data. For the analysis of the improvement of NRS and HIT-6 score, we used the Wilcoxon signed-rank test. We also used multivariable logistic regression to assess the relative risks of variables for worsening/ new onset of headache accompanied by HFS. Statistical analyses were performed using SPSS 23.0 (SPSS, Inc. Chicago, IL, USA). The significance level was set at P < 0.05.
2. Materials and methods
3. Results
2.1. Study design and ethics considerations
3.1. Association of HFS with headache
This study was a retrospective study and the subjects were recruited from patients with HFS who had visited at our neurology clinic at Tokai University Hospital for BoNT/A therapy between April 2015 and July 2015 (the period corresponds to one course of BoNT/A therapy). This study was approved by the Tokai University Ethics Committee (No. 16R-062). Informed consent was obtained from all recruited patients. Types of headache were diagnosed according to the criteria of The International Classification of Headache Disorders, 3rd edition (ICHD-III beta) [6].
Of the 51 patients with HFS, 17 patients (33.3%) reported worsening or new onset of headache accompanied by HFS (Group-S). Among these 17 patients, 15 had TTH and the other 2 had TTH and migraine (one ‘‘migraine without aura” and one ‘‘chronic migraine” according to ICHD-III beta). Of these 17 patients, 13 (72.2%) had headache at the ipsilateral side from HFS. The headache type associated with HFS was infrequent episodic TTH or frequent episodic TTH in all cases. The remaining 34 of the 51 patients were not aware of headache, regardless of CH history (Group-N).
2.2. Patient population
3.2. Patients’ characteristics
Fifty-one patients (41 females [80.4%]; mean age ± standard deviation, 64 years ± 14) who met the following inclusion criteria were recruited: received BoNT/A therapy at least once and continuing BoNT/A therapy. We excluded patients with blephalospasm, Meige syndrome, spasmodic torticollis, and medication-overuse headache [22]. Patients who had been treated for headache or microvascular compression before receiving BoNT/A therapy were also excluded from this study.
Table 1 summarizes the characteristics of patients and the dose of BoNT/A in each group. Patients were younger in group-S than in group-N (57 ± 17 vs. 68 ± 11, p < 0.05). CH history (70.6% vs. 17.6%, p < 0.001) was more frequent in group-S than in group-N. Stiff neck (82.4% vs. 52.9%, p < 0.05) and stress factors (88.2% vs. 32.4%, p < 0.001) were also more frequent in group-S than in group-N. Fig. 1 shows the distribution of patients by CH history and worsening or new onset of TTH. Twelve patients (70.6%) reported worsening of TTH accompanied by HFS among 17 patients with a history of CH. Five patients (14.7%) reported novel onset of TTH accompanied with HFS among 34 patients without a history of CH. There was no significant difference of injection site (0.625– 22.5 U of intramuscular injection per muscle) or total dosage of BoNT/A (20.73 ± 13.33 U vs. 17.07 ± 10.68 U) between the two groups.
2.3. Data collection The following patient data were collected from medical records at our clinic: age, gender, chronic headache (CH) history, exercise habits (defined as previously reported [23]), stiff neck (subjective or objective symptom [muscle tenderness]), history of cervical spondylolysis (diagnosed by an orthopedic surgeon based on clinical symptoms or imaging inspections), stress factors (defined as both ‘‘stressful life events” and ‘‘minor life events” [24]), worsening of headache in parallel with HFS or new onset of headache accompanied by HFS, and details of BoNT/A treatment for HFS (injection site and total dosage during the investigation period).
3.3. Effect of BoNT/A therapy on headache Twelve patients (70.6%) reported improvement of headache (degree and/or frequency) after BoNT/A therapy in group-S. Fig. 2 showed the transition of headache during the investigation
Please cite this article in press as: Mizuma A et al. Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.069
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A. Mizuma et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx Table 1 Characteristics of the included patients with facial spasm (n = 51).
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Age, years Female, n [％]2 CH history, n [％]2 Exercise habits, n [％]2 Stiff Neck, n [％]2 Cervical spondylosis, n [％]2 Stress factors, n [％]2 BoNT/A dose, U1 BoNT/A injection site, n [%]2
Frontalis muscle Orbicularis oculi Orbicularis oris Risorius muscle/zygomatic major/zygomaticus minor/ Triangularis muscle
Group-S* (n = 17)
Group-N** (n = 34)
P
57 ± 17 15 [88.2] 12 [70.6] 3 [17.6] 14 [82.4] 9 [52.9] 15 [88.2] 20.73 ± 13.33 3 [17.6] 17 [100.0] 9 [52.9] 14 [82.4] 3 [21.4]
68 ± 11 26 [76.7] 5 [14.7] 15 [44.1] 18 [52.9] 7 [20.6] 11 [32.4] 17.07 ± 10.68 4 [11.8] 34 [100.0] 15 [44.1] 22 [64.7] 3 [8.8]
0.018 NS <0.001 NS 0.041 0.019 <0.001 NS NS NS NS NS NS
Abbreviations: TTH, tension-type headache; CI, confidence interval; CH, chronic headache; BoNT/A; Botulinum toxin type A. 1 t-test. 2 v2 test. * Symptomatic group; group of patients with TTH (worsening or new onset accompanied by facial spasm). ** Non-symptomatic group; group of patients with TTH (stable) or without TTH.
Fig. 1. Distribution of study patients by CH history and worsening or new onset of TTH. Twelve patients (70.6%) reported worsening of TTH accompanied by HFS among 17 patients with a history of CH. Five patients (14.7%) reported new onset of TTH accompanied by HFS among 34 patients without a history of CH. Of the 17 patients with CH, 15 had TTH and the other 2 patients had combined headache (TTH and migraine).
period. The baseline values of NRS and HIT-6 score before BoNT/A therapy were 7 (median; interquartile range [IQR] 5–9) and 55 (54–64), respectively. Sixteen patients (94.1%) in group-S reported moderate or severe headache (over 4 points) on NRS. Thirteen patients (76.5%) in group-S had a score of over 50 on HIT-6, indicating that their headache had some impact on quality of life. NRS was significantly improved from 7 (5–9) to 0 (0–5) after BoNT/A therapy (p < 0.01). HIT-6 score was also improved from 55 (54–64) to 44 (36–52) after BoNT/A therapy (p < 0.001). Notably, 6 patients (46.2%) showed improvement to less than 49 points, indicating that their headache had little impact on their quality of life, among the 13 patients who initially scored over 50 on HIT-6. No worsening of facial spasm and no major adverse effects of BoNT/A therapy (severe facial motor palsy, ptosis, and lacrimation) were seen during the investigation period.
3.4. Other medications Ten patients took nonsteroidal anti-inflammatory drugs from 1 to 6 times a month in group-S. One patient was taking amitriptyline for chronic migraine. Drug dosage and frequency of medication in these patients were decreased in parallel with the improvement of HFS by BoNT/A therapy. 3.5. Relative risk for worsening/new onset of TTH accompanied by HFS The influence of several factors on worsening/new onset of TTH accompanied by HFS was estimated by logistic regression analysis (Table 2). There were significant interactions between HFSassociated TTH and the presence of stress factors (odds ratio [OR]: 43.11, 95% confidence interval [CI]: 2.95–629.39, p < 0.001) and CH history (OR: 28.53, 95% CI: 2.96–275.10, p < 0.001). How-
Please cite this article in press as: Mizuma A et al. Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.069
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A. Mizuma et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Fig. 2. Effect of BoNT/A therapy on headache scores in group-S (n = 17). (a) 16 patients (94.1%) in group-S reported moderate or severe headache (over 4 points) on NRS. NRS was significantly improved from 7 (5–9) to 0 (0–5) after BoNT/A therapy (p < 0.01). (b) 13 patients (76.5%) scored over 50 on HIT-6 (s). The HIT-6 score was also improved from 55 (54–64) to 44 (36–52) after BoNT/A therapy (p < 0.001). Notably, 6 patients (46.2%) improved to less than 49 points, which suggests their headache would have little impact on their quality of life, among the 13 patients with HIT-6 scores over 50 (;).
Table 2 Relative risks of variables for worsening/new onset of TTH in patients accompanied by facial spasm. Variable
Odds ratio
95％ CI
P
Increased age (per 1 year) Female CH history Stiff Neck Cervical spondylosis Stress factors
0.95 0.86 28.53 0.73 0.98 43.11
0.89–1.02 0.08–9.75 2.96–275.10 0.08–7.03 0.10–9.77 2.95–629.39
0.156 0.921 <0.001 0.785 0.987 <0.001
Multiple stepwise regression analysis. Abbreviations: TTH, tension-type headache; CI, confidence interval; CH, chronic headache.
ever, increased age (OR: 0.95, 95% CI: 0.89–1.02, p = 0.156), female sex (OR: 0.86, 95% CI: 0.08–9.75, p = 0.921), stiff neck (OR: 0.73, 95% CI: 0.08–7.03, p = 0.785), and cervical spondylolysis (OR: 0.98, 95% CI: 0.10–9.77, p = 0.987) were not associated with significantly increased risk for worsening or new onset of TTH associated with HFS. 4. Discussion Cranio-cervical dystonia can cause secondary headache due to abnormal movements or defective posturing of the neck or head as a result of muscular hyperactivity [6]. However, it is not known whether HFS is also related to the pathophysiology of headache. In this study, we examined the frequency of TTH coexistence in patients with HFS. We also evaluated the effect on headache of BoNT/A therapy for HFS. A major finding of this study was the higher frequency of TTH (33.3%) among HFS patients compared to the prevalence in the
Japanese population (21.7%) [11]. However, HFS patients rarely complain about headache, possibly because it is masked by other major symptoms. It seems noteworthy that new onset of TTH was seen in 14.7% of HFS patients with no history of CH. This result may support our hypothesis that HFS contributes to primary headache. From the results of multivariate analysis, not only CH history, but also stress factors were associated with TTH accompanied by HFS, regardless of the existence of stiff neck and spastic muscles (BoNT/A injection points). In general, TTH is considered to involve both central and peripheral pain mechanisms [7,8]. Stress factors are considered to be associated with both of them [28]. In patients with TTH, stress factors affect the descending pain-inhibitory system through the cerebral limbic system [28], and anti-anxiety agents or antidepressants could suppress this mechanism [28]. On the other hand, it was not clear from previous trials whether reducing muscle stiffness by BoNT/A therapy contributed to the improvement of TTH [17,18]. BoNT/A therapy for facial spasm might contribute to the improvement of TTH via reduction of stress from facial spasm, rather than by reducing muscle stiffness. As for the peripheral pain mechanism, stress factors are also related to muscle exhausion and the release of acetylcholine from presynaptic nerve terminals [28]. Released acetylcholine causes continuous contraction of muscle fibers and finally worsening of TTH owing to release of inflammatory factors such as prostaglandin E2 [28]. Reducing stress factors by BoNT/A therapy can prevent muscle exhausion and release of inflammatory factors. Indeed, efficacy of BoNT/A therapy was seen in terms of the NRS and HIT-6 scores in this study. Finally, an important feature of our study is the evaluation of headache using two types of scales (NRS and HIT-6). Nevertheless, our study has several limitations. The number of subjects is small
Please cite this article in press as: Mizuma A et al. Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.069
A. Mizuma et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
and recruited patients were limited to those receiving BoNT/A. Hence, selection bias may have affected the results. Furthermore, the severity of HFS was assessed only in terms of the dose of BoNT/A, because there is no appropriate index for HFS, in contrast to the Jankovic Rating Scale and Blepharospasm Disability Index in patients with blepharospasm [29]. Further, we could not evaluate the risk factors of TTH in detail because this study was retrospective. A prospective study would be desirable to check our findings. In conclusion, primary headache, especially TTH, often coexists with HFS. BoNT/A therapy for HFS may also be indirectly effective for improving TTH. Conflict of interest statement No conflict. Source of funding No funding. Acknowledgments None. References [1] Abbruzzese G, Berardelli A, Defaze G. Hemifacial spasm. Handb Clin Neurol 2011;100:675–80. [2] Kenney J, Jankovic J. Botulinum toxin in the treatment of blepharospasm and hemifacial spasm. J Neural Transm 2008;115:585–91. [3] Vermersch P, Petit H, Marion MH, Montagne B. Hemifacial spasm due to pontine infarction. J Neurol Neurosurg Psychiatry 1991;54:1018. [4] Mehanna R, Jankovic J. Movement disorders in multiple sclerosis and other demyelinating diseases. J Neurol Sci 2013;328:1–8. [5] Nussbaum M. Hemifacial spasm associated with benign parotid tumor. Ann Othol Rhinol Laryngol 1977;86:73–4. [6] Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33:629–808. [7] Spierings EL, Ranke AH, Honkoop PC. Precipitating and aggravation factors of migraine versus tension-type headache. Headache 2001;41:554–8. [8] Jensen R, Rasmussen BK, Pedersen B, Olesen J. Muscle tenderness and pressure pain thresholds in headache. A population study. Pain 1993;52:193–9. [9] Takashima T, Ishizaki K, Fukuhara Y, et al. Population-based door-to-door survey of migraine in Japan: the Daisen study. Headache 2004;44:8–19. [10] Schwartz BS, Stewart WF, Lipton RB. Lost workdays and decreased work effectiveness associated with headache in the workplace. J Occup Environ Med 1997;39:320–7.
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Please cite this article in press as: Mizuma A et al. Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.069