Purpose
To report the clinical success and incidence of adverse events of repetitive botulinum toxin treatment of 15 years or greater.
Design
Retrospective cohort study.
Methods
The study sample consisted of 37 patients from a clinical practice, 11 male and 26 female. Inclusion criteria consisted of patients treated a minimum of 15 consecutive years for facial dystonia. Seven patients had hemifacial spasm, 4 Meige syndrome, and 26 benign essential blepharospasm. Main outcome measures consisted of treatment efficacy and adverse events.
Results
Mean treatment duration was 19.4 years (SD 2.2) with an average of 62 (SD 22) treatments of 70.2 (SD 20.8) neurotoxin units. Mean duration of treatment efficacy was 127 days (SD 37) with a 5% physician-reported minor adverse event rate and no major adverse events over each patient’s clinical course. Patients reported no major and 20% incidence of minor adverse events over the treatment course.
Conclusion
Results suggest that long-term botulinum toxin treatment produces clinical success in the alleviation of facial dystonia symptoms. Treatment produced a low incidence of major adverse events and minor adverse events. Previous studies may under-report clinical success and over-report adverse events because of study design.
Benign essential blepharospasm (BEB) and hemifacial spasm are 2 of the most common movement disorders that affect the face. Blepharospasm affects approximately 32 out of 100 000 people, typically during the fifth through sixth decade of life, affecting women more frequently than men in a 3:1 ratio. Clinical findings include excessive blinking, photophobia, and persistent eye closure secondary to involuntary spasms and/or contractions of the orbicularis oculi and surrounding muscles. A majority of blepharospasm patients also have involuntary movements of the paranasal muscles, mouth, and jaw. A subset of patients may display forceful contractions of the jaw and tongue, as well as chin thrusting, consistent with oromandibular dystonia.
The etiology of BEB is not known. Similar movement disorders can be pharmacologically produced with levodopa and neuroleptic antipsychotic drugs, both acutely and after long-term therapy. A small number of patients with lesions of the rostral midbrain or caudal diencephalon were reported with movements similar to those in cranial dystonia. These findings lead to an etiology hypothesis of supranuclear disinhibition of the facial nucleus and brainstem reflexes; however, no specific abnormalities have been found on brain imaging or at autopsy in most patients with BEB.
There have been various proposed treatment options for BEB since its classification. These have included oral medications such as anticholinergics, dopamine agonists, presynaptic monoamine-depleting agents, botulinum toxin injections, and, in refractory cases, surgical disruption of the facial nerve fibers. Botulinum toxin therapy is currently the most common treatment modality. There have been multiple studies published in the peer-reviewed literature that show both efficacy and safety of treatment. There has been suggestion that long-term botulinum toxin treatment might result in the production of anti-acetylcholinesterase antibodies, thereby decreasing the effectiveness of treatment over time.
The combination of BEB and oromandibular dystonia has been classified as a form of segmental dystonia called cranial dystonia, or “Meige syndrome.” The symptoms of Meige syndrome typically peak in the sixth decade of life and appear to be more common in women than in men (3:2 to 2:1 ratio), with a prevalence of 5 to 10 cases per 100 000 people. Similar to BEB, the etiology is speculative and the primary treatment is botulinum toxin injections.
Hemifacial spasm is characterized by unilateral intermittent clonic or tonic contractions of the muscles of facial expression supplied by the facial nerve. Hemifacial spasm most commonly has an insidious or subacute onset in the third to seventh decade of life, with a peak in middle age affecting women more frequently than men (2:1), but is less common than BEB, affecting 10 out of 100 000 people. The most likely etiology is microvascular compression at the facial nerve root exit zone from the brainstem, or less commonly at its entry point into the internal auditory meatus. It is usually chronic and progressive and may cause patients significant social disability. There are microsurgery treatment options available but, because of potential complications, patients may elect for a less invasive treatment modality.
Multiple studies have been published pertaining to the efficacy and safety of botulinum toxin treatment for various neuromuscular disorders. Currently the longest reported follow-up period to monitor efficacy and adverse events of botulinum toxin therapy was published by Mejia and associates in 2005. The study contained a sample size of 45 with an average treatment duration of 15.8 years. However, the majority of the patients in the study (31) had cervical dystonia, craniocervical dystonia, or cranial dystonia; only 4 patients had BEB and 1 hemifacial spasm.
The purpose of this study is to report the incidence of adverse events and clinical success of long-term botulinum toxin treatment for BEB, hemifacial spasm, and Meige syndrome with a minimum 15-year duration of continuous treatment. We hypothesize that the continual, long-term treatment of BEB, hemifacial spasm, and Meige syndrome with botulinum toxin produces clinical success in reduction of symptoms with a low incidence of adverse events, and previous studies may have under-reported efficacy and over-reported adverse events because of study design.
Methods
This study is a retrospective cohort study of patients under the care of a single oculofacial plastic surgery group. The Mount Carmel Health System Institutional Review Board granted exempt status for the study according to Title 45 of the Code of Federal Regulations (45 CFR 46.101[b][4]). Patients undergoing current treatment were selected for the study if they met the following inclusion criteria: (1) 18 years of age or greater; (2) BEB, hemifacial spasm, or Meige syndrome; (3) request for botulinum toxin treatment; (4) minimum of 1 botulinum toxin treatment per year; and (5) 15 or more years of consecutive botulinum toxin treatments. There were no specifics related to sex, ethnicity, or socioeconomic status targeted. The following exclusion criteria were also applied: (1) less than 18 years of age; (2) participation in another study; (3) muscular spasm not consistent with BEB, hemifacial spasm, or Meige syndrome; (4) any gap in treatment longer than 1 year; (5) conditions that could be a contraindication to botulinum toxin treatment (prior allergic reaction, injection into areas of infection/inflammation, pregnancy, breastfeeding, diseases of the neuromuscular junction [myasthenia gravis or Eaton-Lambert], peripheral neuropathic diseases [amyotrophic lateral sclerosis], or aminoglycosides or agents that interfere with neuromuscular transmission). There were no control subjects in this study.
Therapeutic intervention consisted of subcutaneous botulinum toxin injections. The vast majority of patients received onabotulinumtoxinA (Botox; Allergan, Irvine, California, USA), with only 6 patients (26 out of 2281 treatments) receiving 5 or fewer rimabotulinumtoxinB (Myobloc; Elan Pharmaceuticals, San Diego, California, USA) injections during their treatment course because of unavailability of Botox. For data calculation purposes, a conversion factor of 33:1 was used for patients who received Myobloc. The injection patterns were modified based on patient response after each of the first 3 treatments and throughout the treatment course as required. Follow-up intervals were customized per individual patient based on treatment efficacy. The treatment interval was determined by physician-observed clinical success of treatment at a predetermined follow-up date and/or patient-reported return of symptoms.
The injected botulinum toxin volume, number of injection sites, and duration of effect was calculated from the fourth treatment (hereby referred to as “initial treatment”) to the last treatment of record to limit the effect of treatment titration during initial visits. During the course of treatment both physician- and patient-reported adverse events were recorded. Physician-reported adverse events had to be personally viewed by the physician and recorded in the patient chart. Patient-reported adverse events could be reported by the patient at the time of examination or any other time via telephone or e-mail. For purposes of analysis all recorded adverse events were grouped into major and minor categories. Major adverse events were those that required intervention by the physician or medical management. Minor adverse events were those that resolved spontaneously or resolved with nonprescription treatment (ie, artificial tears, cold compresses).
Statistical analysis was conducted with SPSS 20 (IBM Corporation, Somers, New York, USA). It was determined that the use of multiple comparison correction was not required for the data set prior to analysis. Scaled data were compared using an independent-samples t test. Nonparametric categorical data were analyzed with Fisher exact test. All statistical testing was 2-tailed and conducted at the 0.05 alpha level.
Results
Thirty-seven patients met the inclusion criteria for the study. The sample consisted of 11 male and 26 female patients with an average age of 58.2 years (SD 10.5) at initial treatment and 79.1 years (SD 10.5) at last treatment. Patient diagnosis included 26 BEB, 7 hemifacial spasm, and 4 Meige. Over the course of the study period, patients received a total of 2281 botulinum toxin treatments with 23 140 individual injection sites. The average duration of treatment was 19.4 years (range 15.6-24.5, SD 2.2), with an average of 62 treatments (range 34-158, SD 22). The average treatment volume was 70.2 units (range 7.5-190.0, SD 20.8), with a mean of 10 treatment sites (range 1-35, SD 3). The average time between treatments was 127 days (range 12-358, SD 37). All patients received a minimum of 1 treatment per year as defined in the study inclusion criteria.
The average treatment dose at the initial (fourth) treatment was 69.6 units (SD 24.7) vs the average dose at the last treatment of 67.0 units (SD 23.5), resulting in a statistically nonsignificant mean difference of 2.6 units (SD 20.2, CI -4.2 to 9.3, P = .445) over the course of treatment. The average treatment duration between the initial (fourth) and subsequent (fifth) treatment was 135 days (SD 53) vs the average duration between the last and previous-to-last treatment being 140 days (SD 59). This produced a mean difference in treatment duration of 5 days (SD 82, CI -32.5 to 22.5, P = .716) that was not statistically significant.
Physician- and patient-reported adverse events are summarized in Table 1 , with ptosis and diplopia being the most common reported by physician and patient. The adverse event category of “other” includes dry eye symptoms, nonspecific ocular surface irritation, photosensitivity, and eye pain. There were no major adverse events reported by physician or patients during the study treatment period. There was a 5% incidence (6 events out of 111 individual treatments) of physician-reported minor adverse events over the first 3 treatments and 5% incidence (100 out of 2170) over the fourth to final treatment. There was no statistically significant difference between occurrence incidences ( P = .6427). There was a 41% incidence (45 events out of 111 individual treatments) of patient-reported minor adverse events over the first 3 treatments and 20% incidence (436 out of 2170) over the fourth to final treatment. The difference in incidence was highly significant at P = .0001 ( Table 2 ).
