Ocular surface alterations in blepharospasm patients treated with botulinum toxin A injection

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1 Eur J Ophthalmol 2014; 24 ( 6 ): DOI: /ejo ORIGINAL ARTICLE Ocular surface alterations in blepharospasm patients treated with botulinum toxin A injection Sibel Kocabeyoglu, Hande Taylan Sekeroglu, Mehmet C. Mocan, Ersin Muz, Murat Irkec, Ali Sefik Sanac Department of Ophthalmology, Hacettepe University School of Medicine, Ankara - Turkey Purpose: To evaluate ocular surface changes secondary to periocular botulinum toxin A injection in patients with essential blepharospasm. Methods: Thirteen eyes of 13 patients with essential blepharospasm who underwent periocular botulinum toxin A injection were included in this prospective study. Patients were evaluated prior to and at 2-week and 1-, 3-, and 6-month time points following injections. Ocular surface tests were carried out in the order of tear break-up time (TBUT), lissamine green (LG) staining, Schirmer I test with anesthesia, and ocular surface disease index (OSDI) questionnaire for all patients. The Friedman test with Conover post hoc method was used for statistical comparisons of values at different time points. Results: The TBUT was found to be increased at 1 month after the injection (8.5 ± 2.1; p = 0.018) and decreased below baseline levels (6.4 ± 2.1) at the 6-month visit (5.7 ± 2.0; p = 0.018). None of the Schirmer test values at follow-up visits were significantly different as compared to baseline levels (11.3 ± 5.5), although the 2-week measurement (14.3 ± 5.6) was significantly higher as compared to that at the 6-month follow-up visit (9.6 ± 4.9; p = 0.034). There was also a significant decrease in LG staining scores at 2-week (0.6 ± 0.4; p = 0.012) and 1-month (0.6 ± 0.4; p = 0.012) time points compared to the baseline levels (1.1 ± 0.6). The OSDI scores improved at 2-week (5.4 ± 6.8; p<0.001), 1-month (3.2 ± 5.1; p<0.001), 3-month (2.5 ± 4.4; p<0.001), and 6-month (5.5 ± 5.4; p<0.001) time points as compared to baseline levels (11.6 ± 8.5). Conclusions: Botulinum toxin A injection appears to have a positive but temporary effect on ocular surface parameters in patients with blepharospasm. Keywords: Botulinum toxin, Essential blepharospasm, Ocular surface Accepted: April 14, 2014 INTRODUCTION Botulinum toxin A is currently being used for the of blepharospasm, hemifacial spasm, certain types of strabismus such as paralytic, residual, or consecutive deviations as an alternative to surgical, as well as for nystagmus, headache syndromes such as migraine, lacrimal hypersecretion syndromes, eyelid retraction, and spastic entropion. Essential blepharospasm is a focal cranial dystonia involving the eyelid and forehead muscles. Overactivity of the orbicularis oculi leads to excessive eye blinking and potentially persistent eye closure related to prolonged muscle spasms of the eyelids. Studies suggest that blepharospasm causes dry eye symptoms and a reduction in Schirmer test results (1). Botulinum toxin injection causes a temporary pharmacologic denervation of the orbicularis oculi muscle, reduction of lacrimal drainage, and improvement in dry eye symptoms (2). It has also been reported that periorbital botulinum toxin A injections increase tear secretion and decrease dry eye symptoms in patients with Sjögren syndrome associated with blepharospasm (3). In contrast, dry eye syndrome after botulinum toxin A injection for blepharospasm has been reported, and it has been suggested that dry eye appears to occur 830

2 Kocabeyoglu et al as a result of a poor blink function due to orbicularis muscle weakness and lagophthalmos (4, 5). Although the effects of botulinum toxin A injection for in many diseases and its adverse effects have been well established, there are few studies in the literature looking into its effects on the ocular surface. This study was undertaken to investigate the effect of botulinum toxin injection on ocular surface parameters in patients with essential blepharospasm. MATERIALS AND METHODS Thirteen eyes of 13 patients treated with botulinum toxin A injections were included in this prospective study. The tenets of the Declaration of Helsinki was followed throughout the study. Informed consent was obtained from all patients and the study was carried out with approval from the institutional review board. All patients underwent a complete ophthalmic examination. Subjects who used topical drugs, had a history of ocular surface surgery or ocular trauma, had coexistent corneal disease except dry eye due to essential blepharospasm, or used contact lenses were excluded from the study. Botulinum A toxin (Botox, Allergan, Inc., Irvine, California, USA) was diluted with 2.5 ml of 0.9% sodium chloride in order to obtain 4 U/0.1 ml of botulinum toxin for injection. It was administered by ASS and the dose of botulinum was 4 units per injection. Injections were performed in 4 or 5 quadrants in the periocular area depending on the region of contractions. Ocular surface testing of all patients was carried out before and 2 weeks, 1 month, 3 months, and 6 months after injection. Tests were carried out in the order of standard tear break-up time (TBUT) testing, lissamine green (LG) staining of the conjunctiva and cornea, and Schirmer I test with topical anesthesia, respectively. The tests were performed in exactly the same order and at the same time of day (between 9:00 AM and 10:00 AM) and in the same environmental conditions for all subjects in order to control the factors that may contribute the ocular surface integrity and alter the severity of blepharospasm. The TBUT measurement was obtained after application of sterile fluorescein strips wetted with preservative-free lubricating eyedrops (Refresh, Allergan Inc.). The patient was instructed to blink several times for a few seconds and the TBUT measured as the time between the last blink and the appearance of the first corneal dry spot. Schirmer I test was performed after instillation of a topical anesthetic (proparacaine hydrochloride 0.5%, Alcaine, Alcon Laboratories Inc., Puurs, Belgium). The sterilized strips of filter paper were placed in the inferior fornix, between the lateral third and the middle third of the eyelid, for 5 minutes with the patient looking straight ahead. Ocular surface staining was evaluated after application of LG strip in the lower conjunctival sac. Using white light, staining of the cornea and the conjunctiva was graded between grade 0 and 5 according to the Oxford Scheme (6). Patients were also assessed with the Ocular Surface Disease Index (OSDI, Allergan Inc.) questionnaire with respect to the severity of their subjective symptoms. The OSDI was developed to provide a rapid assessment of the severity of symptoms of ocular surface disease and their impact on vision-related function. Briefly, the 12 items of the OSDI questionnaire are graded on a scale of 0 to 4: 0 = the presence of symptoms none of the time; 1 = some of the time; 2 = half of the time; 3 = most of the time; 4 = all the time. The total OSDI score was calculated for each patient using the following formula: OSDI = (sum of scores for all questions answered) 25/(total number of questions answered) Thus, the OSDI was scored on a scale of 0 to 100. Only patients who reached the 6-month time point without the need for repeat botulinum A injections were included in data analysis. Statistical analysis The data were evaluated in collaboration with the Department of Biostatistics. Numerical variables were evaluated for normality of data distribution by using Kolmogorov- Smirnov test. Descriptive statistics were expressed as mean ± standard deviation or median (min-max) according to the assumption of normal distribution. Two-way analysis of variance with repeated measures was used to examine main effect (group and time) and group-by-time interaction. If there were statistically significant main effects or interactions, Bonferroni method was used as post hoc test. The Friedman test for non-normally distributed data was used with Conover post hoc method, for all pairwise multiple comparisons. Data analysis was performed by SPSS 15.0 (Statistical Package for Social Sciences, SPSS Inc., 831

3 Ocular surface alterations after botulinum toxin A injection Chicago, Illinois, USA) software package. A p<0.05 was accepted as statistically significant. RESULTS The mean age of patients (6 female, 7 male) with blepharospasm was 64.3 ± 11.0 years (range years). All the patients had bilateral blepharospasm and one of the eyes was randomly included in the study. The ocular surface parameters before and 2 weeks, 1 month, 3 months, and 6 months after the are highlighted in Table I. The increase in TBUT was significant at 1 month after the injection (8.5 ± 2.1; p = 0.018) and decreased below baseline levels (6.4 ± 2.1) at 6 months after the (5.7 ± 2.0; p = 0.018). None of the Schirmer test values at follow-up visits were significantly different as compared to baseline levels, although the 2-week measurement (14.3 ± 5.6) was significantly higher as compared to that at the 6-month follow-up visit (9.6 ± 4.9; p = 0.034). There was also a significant decrease in LG staining scores at 2-week (0.6 ± 0.4; p = 0.012) and 1-month (0.6 ± 0.4; p = 0.012) time points compared to baseline levels (1.1 ± 0.6). The OSDI scores improved at 2-week (5.4 ± 6.8; p<0.001), 1-month (3.2 ± 5.1; p<0.001), and 3-month (2.5 ± 4.4; p<0.001) time points as compared to baseline levels (11.6 ± 8.5). Changes in ocular surface parameters over 6 months are given in Figure 1. In 8 patients (61%), blepharospasm recurred within the 6-month period and necessitated Botox reinjection after the final visit. None of the subjects experienced Botox injection related adverse effects. Fig. 1 - Ocular surface parameter changes of patients with essential blepharospasm during 6 months following periocular botulinum toxin injection. BUT = break-up time; LG = lissamine green; OSDI = ocular surface disease index; Sch = Schirmer test. DISCUSSION In the present study, we evaluated the effect of botulinum toxin injection on the ocular surface and on subjective symptoms. Our results showed that ocular surface test results improved 2 weeks after injection, started to deteriorate after 3 months, and almost returned to their baseline values after 6 months in blepharospasm patients. In parallel with improvements in objective test results, subjective complaints also decreased within 2 weeks and increased between 3 and 6 months postinjection. Worsening of subjective symptoms and objective findings within the 6-month follow-up period was consistent with increased frequency of blinking and the waning effect of the injections on orbicularis oculi within the same time interval. The clinical effect of botulinum toxin generally begins between 1 and 5 days and its benefits last about 3-4 months in most patients, but can vary from a few weeks to 6 months or greater (7). TABLE I - COMPARISON OF OCULAR SURFACE PARAMETERS OF PATIENTS WITH ESSENTIAL BLEPHAROSPASM BE- FORE AND AFTER BOTULINUM TOXIN A INJECTION Before 2 weeks after 1 month after 3 months after 6 months after TBUT, s 6.4 ± ± ± ± ± 2.0 LG staining, grade 1.1 ± ± ± ± ± 0.6 Schirmer test, mm 11.3 ± ± ± ± ± 4.9 OSDI score, points 11.6 ± ± ± ± ± 5.4 LG = lissamine green; OSDI = ocular surface disease index; TBUT = tear break-up time. 832

4 Kocabeyoglu et al Periodic blinking of the eyelids is crucial for drainage and turnover of the precorneal tear film (8, 9). Tears produced by the major and minor lacrimal glands spread over the ocular surface and drain through the lacrimal punctum by blinking. Several anatomic and physiologic studies have attempted to identify the role of blinking on the lacrimal pump. In a study by Wojno (10), dynamic changes in the lacrimal sac in response to blinking as a driving force of tear drainage were evaluated using fluoroscopic dacryocystography. According to their study, contraction of the canalicular system and dilation of the superior portion of the lacrimal sac in response to eyelid closure was suggested as an important factor in the lacrimal pump mechanism. Thus, blinking abnormalities such as those observed in the setting of blepharospasm can cause improper tear distribution and hence aggravation of ocular surface problems (8). Although ocular surface disease and dry eye have been reported in association with blepharospasm, the underlying mechanisms causing ocular surface disease in the setting of blepharospasm have not been clarified (11, 12). Prior studies have looked into the effect of botulinum toxin injection on the ocular surface. In a study by Matarasso (13), it was suggested that paresis of the pretarsal portion of the orbicularis oculi muscle could impair nasolacrimal outflow by inhibiting the pumping action of the orbicularis oculi muscle and alter the Schirmer test. Paralysis of the orbicularis oculi muscle acting on the canaliculi decreases the pump function during blinking and may lead to prolonged lubrication of the ocular surface. Botulinum toxin injection also impairs autonomic cholinergic transmission and inhibits lacrimal gland tear production (14, 15). As such, it is still being used in autonomic nervous system disorders relating to pathologic tearing (10). Sahlin et al (2) suggested that the injection of botulinum toxin into the medial portion of the orbicularis muscle of the lower lid or to both the upper and lower lids caused decrease in the effectiveness of the orbicularis muscle pump mechanism around the canaliculi and decreased mean blink tear output of up to 70% using the drop test 3 weeks after injection, and a subjective improvement in subjective symptoms in 70% of their patients with dry eye was noted. These results have helped clarify the relationship between excessive blinking and tear dynamics as well as their effects on ocular surface changes in patients with blepharospasm. In contrast with our results, Horwath-Winter et al (11) reported reduced Schirmer test results and increased rose Bengal staining after botulinum toxin A injection in blepharospasm. They suggested that botulinum toxin was effective in relieving blepharospasm but did not ameliorate tear function. However, the results of the current study showed that botulinum toxin A injection led to a slight but significant increase in the tear function of patients with blepharospasm. Different results reported in the literature may arise from the diversity of injection techniques and dosages of botulinum toxin. In agreement with our results, a recent study by Park et al (12) showed an increase in TBUT, lower lid tear meniscus height, and Schirmer test results in parallel with improvement in dry eye symptoms following injections in patients with essential blepharospasm. The results of their study as well as ours propose that botulinum toxin injection is an effective for dry eye symptoms related to blepharospasm. One other source of discrepancy between the results of such studies involves the type of Schirmer test utilized. Although there are several variations in the technique of performing the Schirmer test, we chose to use Schirmer I test with anesthesia to evaluate the basal tear secretion as described in previous studies (16, 17). Reflex secretion is more likely to be influenced by environmental and psychogenic stimuli as well as the type of dry eye (aqueous deficient vs evaporative) (16, 18). The results of the present study should be viewed in context of certain limitations: small number of patients and brief follow-up period. Cumulative effects of botulinum toxin on the ocular surface following consecutive injections and long-term results could be evaluated in future studies. It should be noted that in the current study fluorescein strips were wetted with low-viscosity preservative-free artificial tears for the measurement of TBUT. This approach was chosen to get consistent results in all study subjects. Since the study included a single cohort of patients receiving one type of modality (botulinum toxin injections) and no other artificial tear was introduced as part of the study intervention, the results obtained with our technique are not biased by wetting the strips with artificial tears instead of saline. However, the authors advocate the use of saline as a wetting solution for fluorescein strips in studies investigating the effect of different types of artificial tears on the ocular surface of dry eye patients to prevent potential study design flaws. In conclusion, our results suggest that injection of botulinum toxin appears to transiently improve ocular surface parameters in patients with blepharospasm. This effect could be mediated possibly through decreasing clearance and increasing ocular surface contact of ocular tears as 833

5 Ocular surface alterations after botulinum toxin A injection well as relieving excessive blinking and muscle spasms of the eyelids. Although these effects may be inconsequential in patients without dry eye disease, they may have clinical implications in those with impaired ocular surface health. ACKNOWLEDGEMENT The authors thank Jale Karakaya, Department of Biostatistics, for assistance with statistical analysis of the data. Financial Support: No financial support was received for this submission. Conflict of Interest Statement: None of the authors has conflict of interest with this submission. Address for correspondence: Prof. Dr. Murat Irkec Department of Ophthalmology Hacettepe University Ankara Turkey mirkec@isnet.net.tr REFERENCES 1. Price J, O Day J. A comparative study of tear secretion in blepharospasm and hemifacial spasm patients treated with botulinum toxin. J Clin Neuroophthalmol 1993;13: Sahlin S, Chen E, Kaugesaar T, Almqvist H, Kjellberg K, Lennerstrand G. Effect of eyelid botulinum toxin injection on lacrimal drainage. Am J Ophthalmol 2000;129: Spiera H, Asbell PA, Simpson DM. Botulinum toxin increases tearing in patients with Sjögren s syndrome: a preliminary report. J Rheumatol 1997;24: Shorr N, Seiff SR, Kopelman J. The use of botulinum toxin in blepharospasm. Am J Ophthalmol 1985;99: Mauriello JA Jr. Blepharospasm, Meige syndrome, and hemifacial spasm: with botulinum toxin. Neurology 1985;35: Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5: Dutton JJ, Fowler AM. Botulinum toxin in ophthalmology. Surv Ophthalmol 2007;52: Doane MG. Interactions of eyelids and tears in corneal wetting and the dynamics of the normal human eyeblink. Am J Ophthalmol 1980;89: Doane MG. Blinking and the mechanics of the lacrimal drainage system. Ophthalmology 1981;88: Wojno TH. Results of lacrimal gland botulinum toxin injection for epiphora in lacrimal obstruction and gustatory tearing. Ophthal Plast Reconstr Surg 2011;27: Horwath-Winter J, Bergloeff J, Floegel I, Haller-Schober EM, Schmut O. Botulinum toxin A in patients suffering from blepharospasm and dry eye. Br J Ophthalmol 2003;87: 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: e Matarasso SL. Decreased tear expression with an abnormal Schirmer s test following botulinum toxin type A for the of lateral canthal rhytides. Dermatol Surg 2002;28: Boroojerdi B, Ferbert A, Schwarz M, Herath H, Noth J. Botulinum toxin of synkinesia and hyperlacrimation after facial palsy. J Neurol Neurosurg Psychiatry 1998;65: Riemann R, Pfennigsdorf S, Riemann E, Naumann M. Successful of crocodile tears by injection of botulinum toxin into the lacrimal gland: a case report. Ophthalmology 1999;106: Kozobolis VP, Detorakis ET, Tsopakis GM, Pallikaris IG. Evaluation of tear secretion and tear film stability in pseudoexfoliation syndrome. Acta Ophthalmol Scand 1999;77: Kozobolis VP, Christodoulakis EV, Naoumidi II, Siganos CS, Detorakis ET, Pallikaris LG. Study of conjunctival goblet cell morphology and tear film stability in pseudoexfoliation syndrome. Graefes Arch Clin Exp Ophthalmol 2004;242: Li N, Deng XG, He MF. Comparison of the Schirmer I test with and without topical anesthesia for diagnosing dry eye. Int J Ophthalmol 2012;5: