Ultra-Long-Term Therapy of Benign Essential Blepharospasm with Botulinumtoxin A-30 Years of Experience in a Tertiary Care Center.

Aim of this study was to investigate the long-term results of botulinum toxin A (BoNT-A) injections for the treatment of benign essential blepharospasm (BEB) and to report our experience with (ultra-)long-term treatment with onabotulinumtoxin-A. We conducted a retrospective cross-sectional analysis at a university hospital. Patients with BEB and BoNT-A treatment were assigned to the Total Blepharospasm Group, patients with ≥21 onabotulinumtoxin-A injections to the Ona Long-Term Group. The Total Blepharospasm Group (n = 1940) included 33,933 BoNT-A injections. The age of patients at symptom onset was (mean ± SD) 58.0 ± 13.1 years, and 70.4% were female. The Ona long-term group (n = 234) included 10,632 onabotulinumtoxin-A injections. In this group, patients received 45.4 ± 22.9 injections with a mean dose of 22.2 IU ± 0.5. The duration of treatment was 12.6 ± 5.4 years, ranging from 2.9 to 30.0 years. The effect-duration-dose quotient did not change during long-term treatment. The observed side effects were comparable in type and frequency to other studies, even with the (ultra-)long treatment with onabotulinumtoxin-A. Our results, based on one of the largest patient populations and a treatment duration of up to 30 years, impressively demonstrate that onabotulinumtoxin-A is a safe and effective therapy for essential blepharospasm, even in the ultra-long term.

Clinical and pharmacological properties of incobotulinumtoxinA and its use in neurological disorders.

BACKGROUND: IncobotulinumtoxinA (Xeomin(®)) is a purified botulinum neurotoxin type A formulation, free from complexing proteins, with proven efficacy and good tolerability for the treatment of neurological conditions such as blepharospasm, cervical dystonia (CD), and post-stroke spasticity of the upper limb. This article provides a comprehensive overview of incobotulinumtoxinA based on randomized controlled trials and prospective clinical studies. SUMMARY: IncobotulinumtoxinA provides clinical efficacy in treating blepharospasm, CD, and upper-limb post-stroke spasticity based on randomized, double-blind, placebo-controlled trials with open-label extension periods (total study duration up to 89 weeks). Adverse events were generally mild or moderate. The most frequent adverse events, probably related to the injections, included eyelid ptosis and dry eye in the treatment of blepharospasm, dysphagia, neck pain, and muscular weakness in patients with CD, and injection site pain and muscular weakness when used for treating spasticity. In blepharospasm and CD, incobotulinumtoxinA was investigated in clinical trials permitting flexible intertreatment intervals based on the individual patient's clinical need; the safety profile of intervals shorter than 12 weeks was comparable to intervals of 12 weeks and longer. There were no cases of newly formed neutralizing antibodies during the Phase III and IV incobotulinumtoxinA trials. Phase III head-to-head trials of incobotulinumtoxinA versus onabotulinumtoxinA for the treatment of blepharospasm and CD have demonstrated therapeutic equivalence of both formulations. Additional Phase III trials of incobotulinumtoxinA in conditions such as lower-limb spasticity, spasticity in children with cerebral palsy, and sialorrhea in various neurological disorders are ongoing. CONCLUSION: IncobotulinumtoxinA is an effective, well-tolerated botulinum neurotoxin type A formulation. Data from randomized clinical trials and further observational studies are expected to help physicians to optimize treatment by tailoring the choice of formulation, dose, and treatment intervals to the patient's clinical needs.

Botulinum toxin in hemifacial spasm: the challenge to assess the effect of treatment.

Hemifacial spasm is characterized by intermittent tonic or clonic contractions of the muscles supplied by the facial nerve. Although vision is less impaired than in patients with blepharospasm, the disease can impose significant psychosocial burden on patient's life. Botulinum toxin (BoNT) is the well-established pharmacotherapy of choice, but evidence from controlled clinical trials is sparse. There is a broad variety of rating scales used in clinical studies with BoNT and obviously no consensus has been reached how to assess treatment outcome in hemifacial spasm. Clinical rating scales focusing on objective function were used in a couple of controlled studies with BoNT and were appropriate to discriminate between BoNTA and placebo. But it has not been shown that they would be sensitive enough to detect minor differences between several BoNT formulations. Although most of the clinical scales consist of a five-point rating, the descriptors for the ordinal numbers are not necessarily the same so that the results of different clinical studies are not comparable to each other. The main disadvantage of clinical scales is that they do not take into account patient's perspective of disability and impact on daily life. For this reason some clinical studies applied health-related quality of life (HRQoL) questionnaires to assess efficacy, and one research group worked on the development of disease-specific tools. Although these HRQoL questionnaires have been validated and a good correlation to disease severity could be demonstrated, they are far from having become an established variable for efficacy assessment in hemifacial spasm trials. The challenge remains to establish tools which are appropriate to rate BoNT treatment effects in hemifacial spasm. Currently, it is virtually impossible to identify one rating scale which can cover all relevant aspects of the disorder. In consequence we recommend the implementation of a combination of different rating scales which address functional impairment as well as those issues which are most important to patients. Further research is needed to standardize and validate rating scales for hemifacial spasm in clinical studies.

Difficulties with differentiating botulinum toxin treatment effects in essential blepharospasm.

Blepharospasm is a focal dystonia in which the extraocular muscles contract repetitively, leading to excessive blinking and forced eyelid closure. Botulinum toxin type A (BoNTA) is the primary symptomatic treatment for blepharospasm and its effects have been evaluated using numerous rating scales. The main scales in use today were initially used to determine whether BoNTA treatment was superior to placebo, and most controlled trials have confirmed this. More recently, these scales have been used to determine whether there are efficacy differences between different BoNTs in blepharospasm. However, although the scales used in these trials are able to differentiate the effects of BoNT from placebo, they may not be sensitive enough to differentiate between BoNTs. Most of the scales include only four possible points for each item, which would necessitate a 25% greater improvement in one group than the other to detect any differences. Current scales are also relatively insensitive to patients with mild disability who may experience mainly psychosocial problems related to their blepharospasm. Clinical trials comparing BoNTs that include substantial numbers of mildly affected patients may be unlikely to find differences because the scales do not adequately measure mild symptoms. Additional challenges with evaluating blepharospasm include the lack of precision and objectivity of current measures, symptom variability, the need to evaluate aspects of the disorder that are most important to patients, and the different types of blepharospasm. Although no single scale may be able to capture all relevant aspects of blepharospasm, more sensitive and patient-centered scales are needed.

Double-blind, randomised, parallel group pilot study comparing two botulinum toxin type A products for the treatment of blepharospasm.

Botulinum neurotoxins (BoNTs) are the primary treatment for focal dystonias such as blepharospasm. Several different BoNT products are available in various countries. Given the variability in manufacturing, formulation, and unit doses of BoNTs, it is important to compare the profiles of products from different manufacturers. This double-blind, randomised, parallel-group pilot study compared the efficacy and safety of the BoNT type A product Xeomin® from Merz to BOTOX® from Allergan. Subjects (n = 65) were randomly assigned to receive one or the other BoNTA in a 1:1 proportion at a dose equal to that of their most recent treatment (≥20 U/eye). Symptoms were assessed on the Blepharospasm Disability Index (BSDI), Jankovic Rating Scale (JRS), and Patient Global Assessment (PGA) scale at 4 and 8 weeks. Both BoNTA products reduced scores on the BSDI and JRS (no statistically significant difference, tendency toward greater improvements with BOTOX® than Xeomin® at 4 and 8 weeks). A post hoc analysis showed a significantly greater number of BOTOX® treated patients reaching a responder threshold of 4 points on the total BSDI score and 0.67 points on the BSDI mean item score. No significant differences between products were noted in PGA and adverse events at the doses used in this study.

Long-term follow-up of patients with frontalis sling operation in the treatment of essential blepharospasm unresponsive to botulinum toxin therapy.

OBJECTIVE: Botulinum toxin is the treatment of choice in patients with essential blepharospasm, but about 4% of patients show no sufficient effect. Many of these patients try to open their eyes by innervating their frontalis muscle. This led to the idea of performing frontalis suspension, normally used for certain types of ptosis. We set out to evaluate the long-term results, complication rates and patient acceptance of this intervention. METHODS: Frontalis sling operation was carried out on 252 eyes of 132 blepharospasm patients between 1992 and 2004. In all patients botulinum toxin treatment was administered before surgery with no or only brief and incomplete effect even with increasing toxin doses. In 120 patients surgery was performed under local anaesthesia, while 12 patients were operated upon under general anaesthesia (mostly bilateral). Silk sutures were employed in the first 14 eyes, and in all others we used Gore-Tex suture material. RESULTS: The duration of follow-up was 3-154 months; 60 patients were followed up for at least 5 years. Seventy-three per cent of patients reported an improvement after surgery. Long-term subjective improvement showed a median of 50% on a scale ranging from 0%=no improvement to 100%=no complaints. No serious corneal complications occurred, although slight overcorrection is desirable in the first days after surgery for a satisfactory long-term result. Seven per cent of operations had to be revised due to suture granulomas or extruded suture material. The effect of surgery generally remained stable over the years, with most patients needing additional treatment with botulinum toxin. In cases of decreasing effect (5% of eyes), the sutures were tightened under local anaesthesia. CONCLUSION: Frontalis suspension can be considered as a minimally invasive but very effective and even reversible procedure in "poor responders" to botulinum toxin, with good long-term effect and good acceptance by the patients. Additional treatment with botulinum toxin is required in most patients in order to increase the desirable imbalance between the frontalis and the orbicularis muscle.

Cyclic vertical deviation after ocular myositis and treatment by recession of the inferior rectus muscle.

BACKGROUND: Cyclic strabismus is a rare disorder in which strabismus and orthotropia regularly alternate over a period of mostly 48 h. It may occur spontaneously, upon squint surgery, or in association with lesions of the central nervous system. In most cases the deviations are convergent. METHODS: Clinical case report. RESULTS: A 34-year-old woman with bilateral recurrent ocular myositis for 2 years had developed cyclic vertical deviation 6 months after clinical remission. A hypotropia of the left eye alternated with an orthotropia, following a 48-h rhythm. Three months after recession of the inferior rectus muscle the alternating squint had disappeared. DISCUSSION: The aetiology of cyclic eye deviations, most of them occurring in a constant rhythm, is not known. The association with lesions of the central nervous system indicates a primary central dysregulation of a "biological clock". Their well-known occurrence, however, after squint surgery and, as in the present case, after orbital myositis, suggests that alteration of peripheral structures may contribute to a central dysregulation. Squint surgery seems to be the treatment of choice, even in rare cases with vertical deviations.