Preseptal and Pretarsal Botulinum Toxin Injection in Hemifacial Spasm and Blepharospasm: A 10-Year Comparative Study

Introduction

Hemifacial spasm (HFS) and benign essential blepharospasm (BEB) are the most common and debilitating craniocervical abnormal movement disorders arising from the peripheral nervous system (PNS). HFS is characterized by involuntary unilateral eyelid twitching, which occasionally extends to the unilateral perioral and neck muscles.¹ HFS is considered a rare condition with an estimated prevalence of 14.5 per 100,000 women and 7.4 per 100,000 men globally. Asians are more affected than Western people, and most affected individuals are in early adulthood.² On the other hand, BEB is a focal dystonia characterized by the simultaneous contraction of agonist and antagonist periorbital muscles, resulting in involuntary eyelid closure.^3,4 The estimated global prevalence ranges from 20 to 133 cases per million and varies across geographical areas.⁵ The condition is thought to be due to a structural defect that leads to neurotransmitter dysregulation.⁴ However, the exact cause of BEB is not well understood, and consequently, there is no definitive cure for BEB.

The primary goal of therapy in both diseases is to reduce the abnormal muscle contractions resulting from abnormal impulse transmissions to adjacent neurons. In milder diseases, oral medication such as clonazepam, carbamazepine, gabapentin, anticholinergics, and haloperidol may be used to relieve the muscle spasm. However, the major drawbacks of most of these medications are the side effects, such as excessive sedation and fatigue associated with their long-term use. The advent of botulinum toxin has revolutionized the management of HFS and BEB. Onabotulinum toxin and Abobotulinum toxin are the most common botulinum toxins used in HFS and BEB. In addition, there are two main botulinum toxin injection techniques, specifically the pretarsal technique (PT) and the preseptal technique (PS).^6–9 However, there are comparatively few studies focusing on botulinum toxin injection techniques and the type of botulinum toxin in treating both BEB and HFS. Additionally, the number of long-term and real-world studies appears to be very scarce. Our study aimed to compare the efficacy and safety of PT and PS botulinum toxin injection techniques from our 10-year botulinum toxin clinic registry. The study results will guide doctors in administering botulinum toxin injections, particularly for Thai and Asian patients.

Materials and Methods

Study Design and Population

This is a retrospective study and data were retrieved from Maharaj Nakorn Chiang Mai Hospital botulinum toxin clinic registry from January 2011 to December 2021. Data pertinent to consecutive adult patients who were aged 18 years or over and diagnosed with HFS or BEB was prospectively collected from the registry. The study was approved by the Research Ethics Committee, Faculty of Medicine, Chiang Mai University, certificate of approval number 2565–08941.

Data Collection and Outcomes

HFS and BEB patients would have consulted experienced neurologists at the botulinum toxin clinic to have a verified diagnosis. The neurologists subsequently reviewed the clinical data and evaluated the pre-treatment modified Jankovic scale (mJS). The score is divided into five categories, ranging from 0 to 4, a zero score implying no impairment, and a score of four indicating a severe, incapacitating spasm.¹⁰ After a thorough evaluation, neurologists would administer botulinum toxin injections, the choice of the toxin type depending on their assessment. In the case of the PS injection technique, two injections were subcutaneously administered in the upper septal region, and two injections subcutaneously placed in the lower septal region of the orbicularis oculi muscles. (see Figure 1A). The PT injection technique, on the other hand, involved four separate injection sites with two injections subcutaneously administered to the medial and lateral pretarsal segments of the upper eyelid and the remaining two to the middle and lateral pretarsal segments of the lower eyelid. (See Figure 1B) Subcutaneous injections were administered in all cases with 30-gauge, 0.5-inch needles, and an insulin syringe while laying supine with their eyelids closed. In the case of HFS, botulinum toxin injections were given at the affected site in the orbicularis oris, zygomaticus major, levator labii superioris, and the mentalis muscles. A three-month follow-up was carried out in all cases to evaluate the post-treatment mJS and collect the data from the self-rating scales. The patient’s level of satisfaction was recorded using self-rating scales ranging from 0 to 10 were. A score of 0 stood for very unsatisfied and the score of 10 stood for very satisfied. At the follow-up time, other clinical outcomes, including latency to response, duration of response, adverse events and additional use of clonazepam, were also documented. Additionally, the cost of therapy per injection was investigated. Cost of therapy included botulinum toxin cost, syringe and needles, sterilization equipment, and treatment-related fees. PT and PS injection techniques, as well as botulinum toxin types (Onabotulinum toxin and Abobotulinum toxin), were also compared in terms of the aforementioned parameters.

Figure 1 Botulinum Toxin Injection Techniques and Location of Injection. (A) Preseptal injection. (B) Pretarsal injection.

Statistical Analysis

Clinical data are presented as numbers and proportions, mean and standard deviation (SD), or median and interquartile range (IQR) as appropriate. Comparisons between groups were performed using Student’s t-test, Mann–Whitney U-test, Chi-square test or Fisher’s exact test as appropriate. A two-sided test at a p-value of < 0.05 was used to indicate statistical significance. All statistical analyses were performed using licensed Stata statistical software version 16.0 (Stata Statistical Software: Release 16.0, Stata Corporation, College Station, TX, 2019).

Results

Demographic Data and Difference of mJS by Injection Techniques

During this 10-year-period, 180 patients who met the inclusion criteria were included in the study. 28 patients had incomplete data and were excluded. Out of those remaining, 152 patients, 117 (77.0%) patients had HFS. In 60.7% of HFS patients, 71 out of 117, were treated using the PS method. HFS patients in the PS group had a shorter disease duration before botulinum toxin administration than the PT group (2.8±1.0 vs 3.4±1.1 years, P-value = 0.009). There is no evidence of any differences between the two groups in the remaining characteristics, including age, gender, symptomatic left-side, pre-treatment mJS, or type of botulinum toxin used. On the contrary, 65.7% of BEB patients (23 out of 35) were injected using the PT technique and had a higher pre-treatment mJS, compared to the PS group (3.3±0.8 vs 2.5±0.5 points, P-value = 0.004). There were no significant differences in the remaining parameters for BEB patients (Table 1). The difference between pre-treatment and post-treatment mJS is lower in the PS group than in the PT group in both HFS and BEB (1.5±0.8 vs 1.8±0.6, P-value <0.001 and 1.8±0.8 vs 3.1±0.9, P-value <0.001, respectively) (Table 2).

Table 1 General Demographic Data of HFS and BEB Categorized by PS and PT Injection Techniques

Table 2 Mean Difference of Pre- and Post-Treatment Modified Jankovic Scales of HFS and BEB Categorized by PS and PT Injection Techniques*

Clinical Outcomes of Preseptal and Pretarsal Botulinum Toxin Injection Techniques in HFS and BEB

A statistical difference in latency to response was observed in both diseases. HFS patients in the PS group had a longer duration of latency to the first response (1.3±0.9 vs 1.2±0.9 weeks, P-value <0.001), in comparison to the PT group of BEB patients (1.0±0.4 vs 1.4±0.8 weeks, P-value <0.001). In addition, BEB patients treated with the PS technique had a more sustained maximal response and higher post-treatment mJS (12 (9, 12) vs 9 (8,12) weeks, P-value <0.001 and 1 (0, 1) vs 0 (0, 1), P-value <0.001, respectively). There was no evidence of any statistical difference between the two techniques in these parameters in HFS patients. A higher proportion of additional clonazepam used was found in HFS patients treated with the PS injection method but it did not result in different daily doses of the medication used. In both conditions, the injection by PS technique used less total dose per injection of onabotulinum toxin, resulting in lower medication cost per visit. Contrarily, the PS technique using more abobotulinum toxin per visit than the PT injection method (Table 3).

Table 3 Clinical Outcomes of HFS and BEB Categorized by PS and PT Injection Techniques*

Safety and Adverse Events

Considering all 2192 botulinum toxin injection sessions, there was a higher incidence of adverse events in the PS group than in the PT group (9.4% vs 5.2%, P-value <0.001). Ptosis, ecchymosis and irritation occurred significantly more frequently in the PS group than in the PT group (3.3% vs 2.5%, P-value = 0.013, 0.5% vs 0.0%, P-value = 0.031, and 5.0% vs 2.3%, P-value 0.011, respectively). In this registry, 1633 sessions of onabotulinum toxin injection and 559 sessions of abobotulinum toxin injection were administered. There was no difference in overall adverse events between onabotulinum toxin and abobotulinum toxin sessions (Table 4).

Table 4 Safety and Adverse Events of Botulinum Toxin Injection Classified by Injection Techniques and Type of Botulinum Toxin Used

Discussion

HFS and BEB are regarded as two of the most problematic movement diseases since they interfere with everyday life and cause cosmetic concerns. Since the adoption of botulinum toxin for the treatment of HFS and BEB in 1984–1985,^11,12 extensive studies have demonstrated its efficacy and safety. To date, three A subtypes (onabotulinum toxin, incobotulinum toxin, and abobotulinum toxin) and one B subtype (rimabotulinum toxin) have been approved for clinical use.¹³

HFS is characterized by involuntary unilateral eyelid twitching, which occasionally extends to the unilateral perioral and neck muscles. In most cases, the underlying pathology is the impingement of aberrant and ectatic blood vessels on the facial nerves at the nerve exit site.^1,2 Neurovascular decompression is considered the treatment of choice but carries worrisome risks. In 1984, botulinum toxin was initially administered to three patients, followed by 15 patients in one observational trial in 1985.^11,12 Since then, several studies have examined its effectiveness and also adverse effects.^14–16 However, the degree of improvement across HFS studies varies. The mJS (scale 0–4 from no to severe symptoms), global clinical improvement scale (scale 0–3 ranging from no improvement to complete improvement), Fahr-Marsden scale (scale 0–4 ranging from no dystonia to resting dystonia), HFS rating scale (scales 0–4 from no spasm to severe spasm), and visual analog scale (VAS) were examples of clinical scales used for evaluation of severity and comparative parameters after treatment.^10,17 The mJS was implemented in our research due to its applicability. Our study revealed that the PT technique was more effective for treating HFS as shown by the greater difference between pre-and post-treatment mJS. This finding was compatible with previous studies. Çakmur et al demonstrated that the patients injected with the PT technique had lower post-treatment scores (score 0 to 4, from no spasm to severe spasm) and a higher score from the modified Toronto Western Spasmodic Torticollis Rating Scale (TWSTR) (score −1 to 5, from worse response to striking improvement).⁹ Lolekha et al demonstrated that the PT group had favorable outcomes, as shown by considerably lower post-treatment mJS.¹⁸ Patients treated with the PS technique had higher self-reporting scales but the differences were not statistically significant, however, this pattern was consistent with earlier research. Our findings showed the latency to response in the PS group was longer than in the PT group. Contrarily, the previous studies showed no difference between the two techniques.⁹ In our study, the peak response lasted roughly 10 weeks in both the PS and PT groups. However, a previous study reported a shorter response duration in the PS group.⁹ Differences between observational and randomized-controlled trials may account for inconsistent results. In the PT group, the rescue dosage of clonazepam was considerably lower. We also showed that independent of botulinum toxin type, the cost per session of PT was less than the PS technique.

In the case of BEB, the PT technique also demonstrated favorable outcomes, specifically a higher mean difference of pre-and post-treatment mJS and a higher self-reporting scale, both compatible with previous studies.^9,19 Most studies showed that the PT injection carried shorter latency to response duration and more extended maximum response. No additional clonazepam use was reported in BEB patients in our study. Intriguingly, the cost per session of PT was lower than that of PS, demonstrating the same trend as HFS.

The PT approach is associated with a lower incidence of adverse events. Irritation, ptosis, and ecchymoses were less frequently reported in the PT group, again findings which were coherent with previous studies.^9,14,19 We also analyzed the differences between botulinum toxin types, but there were no significant differences in the occurrence of adverse events. We may assume that, regardless of the types of botulinum toxin, all adverse effects were mediated by different techniques.

The orbicularis oculi muscle is the muscle primarily affected in both HFS and BEB. The muscles can be divided into two groups, the orbital and palpebral parts, the latter being further subdivided into preseptal and pretarsal subparts. Even though both subparts are responsible for eyelid closures, there are histologically different. The pretarsal subpart has more skeletal muscles and a higher innervation density per region than the preseptal subpart, resulting in greater responsiveness to botulinum toxin therapy.^6,14 Furthermore, the pretarsal component contains a higher proportion of type 2 muscle fibers, which are generally shorter in length, resulting in greater botulinum toxin injection penetration than the preseptal subpart, which contains significantly larger type 1 fibers.^6,20

Similar to earlier studies, the PS injection presents a greater risk of adverse effects, including ptosis, irritation, tears, and ecchymosis.^7,8,18 The preseptal subpart of orbicularis oculi is located closer to the muscle that assists with eyelid elevation, the levator palpebrae, and an injection of botulinum toxin at the location might result in ptosis. Histologically, the preseptal component includes more adipose tissue, resulting in inadequate support for the eyelid muscles.^20,21 Ecchymosis was reported when utilizing the PS approach, as shown in earlier investigations. This observation can be explained by the abundance of underlying subdermal capillaries in the preseptal subpart. Our findings indicate that all botulinum toxin-associated problems were related to injection technique, not the kind of toxin.

The cost per session for onabotulinum toxin is greater in both HFS and BEB due to the significantly larger doses required to achieve the desired therapeutic effect. Contrarily, injections in the PT technique of abobotulinum toxin appeared cheaper than the PS technique. A previous study showed that the PT technique is cheaper than PS in all HFS, BEB, and cervical dystonia.²² The differences may result from variations in dosage, injection site, and treatment costs across studies.

Although our study was a long-term and real-world registry of botulinum toxin injection in a university-based clinic, there were some limitations. First, the natural characteristics of a retrospective observational study would involve some missing data. Second, we used mJS and self-reporting scales to define the clinical outcomes, which might bring a minor variation when comparing findings with other studies. Lastly, the ability for peer review was limited as there are few studies focusing on the cost-effectiveness and cost-safety associated with botulinum toxin type and injection technique. We believe that a well-designed study on the cost-effectiveness and cost-safety of individual injection techniques is warranted.

Conclusion

The PT botulinum toxin injection is efficacious in both HFS and BEB, resulting in greater patient satisfaction with a lower incidence of adverse events in comparison to the PS technique. In addition lower dosage and cheaper cost per session were observed in the PT group. Further cost-effective and cost-safety studies are required.