Early development history of Botox (onabotulinumtoxinA).

The development of Botox (onabotulinumtoxinA) began in the 1970s as Dr. Scott was attempting to identify an injectable substance that would weaken the extraocular eye muscles in patients with strabismus as an alternative to muscle surgery. This search led to botulinum toxin type A, which was tested and developed over the next 15 years. As botulinum toxin type A moved from an experimental drug to a product in need of licensing by the Food and Drug Administration (FDA), the first manufacturing methods and quality control procedures were developed for Oculinum, the botulinum toxin type A product that would eventually be sold to Allergan and become known as Botox.

Treatment of strabismus and blepharospasm with Botox (onabotulinumtoxinA): Development, insights, and impact.

Strabismus, deviation of the ocular alignment, can adversely affect quality of life and activities of daily living. Surgery was the prior standard of care for strabismus, but up to 40% of patients required additional surgeries. This need for more effective and less invasive treatment, along with the convergence of other events such as the development of electromyography, purification of botulinum toxin A, and the finding that injection of botulinum toxin type A could paralyze the hind limbs of chicks, led Dr. Alan Scott to investigate injection of his formulation for strabismus. The positive results of initial trials in monkeys segued to human trials with observations of alignment improvements and few adverse events. The success of botulinum toxin type A in the treatment of strabismus led to interest in its use to treat other skeletal muscles, particularly in blepharospasm, a type of focal dystonia involving eyelid spasms and involuntary eye closure that lacked an effective pharmacological treatment. Patient groups helped to increase awareness of this novel treatment, and results from clinical trials confirmed its effectiveness. Dr. Scott's formulation, then known as Oculinum, received its first Food and Drug Administration approvals in 1989 for strabismus and blepharospasm. Allergan acquired Oculinum in 1991, renaming it Botox. These initial uses led to its application in a myriad of other indications as outlined in other articles of this supplement.

Activating the levator to elevate the eyelid.

PURPOSE: To demonstrate in an animal model the feasibility of elevating the eyelid in a functionally useful manner by chronically stimulating the levator palpebrae superioris (LPS) muscle with an implanted electrode. METHODS: Five rabbits were implanted with electrodes designed to stimulate the nerve innervating the LPS near its entry to the muscle. Bipolar platinum electrodes in a silicone rubber envelope with silicone-sleeved, PTFE-coated platinum lead wires were used to provide long-term stimulation with bipolar square-wave pulse trains of 0.18-0.80 mA and 200 Hz at a duty cycle of 8 seconds on and 2 seconds off. Explanted electrodes were examined for damage, and stimulated tissues were evaluated for abnormalities by light microscopy. RESULTS: We achieved mean lid elevation of 1.6 mm, approaching the diameter of the light-adapted pupil, with 0.5 mA stimulus. Stimulus currents below 1.0 mA produced no signs of discomfort. Three animals with which we attempted daily stimulation, averaged 16.1 hours per week. Experiments lasted 22 weeks on average. Lid lifting with a well-implanted platinum electrodes was stable, with no apparent tissue or electrode damage after as long as 29.1 weeks. CONCLUSIONS: Stable, functionally useful eyelid lifting was achieved with stimulation currents that caused no apparent discomfort or damage to muscles or nerves. A simple, discrete bipolar electrode was effective and survivable.

Pharmacologic injection treatment of comitant strabismus.

PURPOSE: To report the magnitude and stability of corrections in comitant horizontal strabismus achieved by injecting bupivacaine (BPX, optionally with epinephrine) and botulinum A toxin (BTXA) into extraocular muscles of alert adult subjects with electromyographic (EMG) guidance. METHODS: A total of 55 adults with comitant horizontal strabismus participated in a prospective observational clinical series. Of these, 29 previously had undergone 1 or more unsuccessful strabismus surgeries; 4 had undergone other orbital surgeries. Thirty-one patients with esodeviations received BPX injections in a lateral rectus muscle, some with BTXA in the medial rectus; 24 patients with exodeviations received BPX in a medial rectus muscle, some with BTXA in the lateral rectus muscle. A second treatment (BPX, BTXA, or both) was administered to 27 patients who had residual strabismus after the first treatment. Five patients required additional injections. Clinical alignment was measured at 6 months and yearly thereafter through 5 years' follow-up, with mean follow-up of 28 months. A successful outcome was defined as residual deviation ≤10(Δ). RESULTS: On average, presenting misalignment of 23.8(Δ) (13.4°) was reduced at 28 months by 16.0(Δ) (9.1°), with successful outcomes in 56% of patients. Of patients with initial misalignments ≤25(Δ), 66% had successful outcomes, with corrections averaging 13.2(Δ) (7.5°); of patients with larger misalignments, 40% had successful outcomes, with corrections averaging 20.9(Δ) (11.8°). Corrected alignments were stable over follow-ups as long as 5 years. CONCLUSIONS: Injection treatments resulted in stable, clinically significant corrections in comitant horizontal strabismus. Injection provides a low-cost alternative to incisional strabismus surgery, particularly where it is desirable to minimize surgical anesthesia and avoid extraocular scarring.

Bupivacaine injection remodels extraocular muscles and corrects comitant strabismus.

PURPOSE: To evaluate the clinical effectiveness and anatomic changes resulting from bupivacaine injection into extraocular muscles to treat comitant horizontal strabismus. DESIGN: Prospective, observational clinical series. PARTICIPANTS: Thirty-one comitant horizontal strabismus patients. METHODS: Nineteen patients with esotropia received bupivacaine injections in the lateral rectus muscle, and 12 patients with exotropia received bupivacaine injections in the medial rectus. Sixteen of these, with large strabismus angles, also received botulinum type A toxin injections in the antagonist muscle at the same treatment session. A second treatment was given to 13 patients who had residual strabismus after the first treatment. MAIN OUTCOME MEASURES: Clinical alignment measures and muscle volume, maximum cross-sectional area, and shape derived from magnetic resonance imaging, with follow-up examinations for up to 3 years. RESULTS: At an average of 15.3 months after the final treatment, original misalignment was reduced by 10.5 prism diopters (Δ; 6.0°) with residual deviations of 10Δ or less in 53% of patients. A single treatment with bupivacaine alone reduced misalignment at 11.3 months by 4.7Δ (2.7°) with residual deviations of 10Δ or less in 50% of patients. Alignment corrections were remarkably stable over follow-ups for as long as 3 years. Six months after bupivacaine injection, muscle volume had increased by 6.6%, and maximum cross-sectional area had increased by 8.5%, gradually relaxing toward pretreatment values thereafter. Computer modeling with Orbit 1.8 (Eidactics, San Francisco, CA) suggested that changes in agonist and antagonist muscle lengths were responsible for the enduring changes in eye alignment. CONCLUSIONS: Bupivacaine injection alone or together with botulinum toxin injection in the antagonist muscle improves eye alignment in comitant horizontal strabismus by inducing changes in rectus muscle structure and length.

Bupivacaine injection of the lateral rectus muscle to treat esotropia.

PURPOSE: We report results of a pilot trial of bupivacaine injection into extraocular muscles as a method of enlarging and strengthening the muscles to treat strabismus. METHODS: Bupivacaine, in volumes from 1.0 to 4.5 mL and concentrations from 0.75% to 3.0%, was injected into 1 lateral rectus muscle in each of 6 patients with comitant esotropia with the use of the electrical activity recorded from the needle tip to guide injection. Magnetic resonance imaging was performed before and at intervals after injection to estimate changes in muscle size. Clinical measures of alignment were made before and at intervals after injection. Two patients required a second injection for adequate effect. RESULTS: Four patients showed improved eye alignment, averaging 12(Delta), measured an average of 367 days after the last injection (range, 244-540 days). Two patients were substantially unchanged. Alignment improvement for all 6 patients averaged 8(Delta) (range, 0-14(Delta)). Volumetric enlargement of the injected muscle, computed from magnetic resonance images, was 6.2% (range, -1.5% to 13.3%). There was a positive correlation between alignment change and muscle enlargement averaging 0.65. Injection caused a retrobulbar hemorrhage in an unchanged patient that cleared without affecting vision. CONCLUSIONS: Bupivacaine injection improved eye alignment in 4 of 6 esotropic patients. There was a positive correlation between improved eye alignment and increased muscle size. Clinical and laboratory studies are underway to determine optimal dosages, effects in other strabismus conditions, and differential effects of bupivacaine on contractile and elastic muscle components.

Treating strabismus by injecting the agonist muscle with bupivacaine and the antagonist with botulinum toxin.

PURPOSE: We report the results of injection of bupivacaine (BUP) and botulinum toxin (BT) into agonist and antagonist muscles, respectively, to treat horizontal strabismus. METHODS: We treated both horizontal muscles of 7 patients with comitant horizontal strabismus, 2 patients with partial lateral rectus (LR) paralysis, and one elderly myopic patient with acquired esotropia, injecting the agonist muscle with BUP in concentrations of 0.75% to 3.0% and volumes of 3.0 to 5.0 mL, and the antagonist with BT in about half the usual therapeutic dose to prevent it from stretching the BUP-treated muscle during its regeneration following BUP myotoxicity. We reinjected BT in one patient who had an inadequate response from the initial BT dose. RESULTS: The 7 comitant patients were corrected (on average) 19.7 prism diopters (Delta), from 28.3Delta to 8.6Delta, at 193 days after injection. Muscle volume increase after BUP injection was 5.8% at 158 days. One LR palsy patient without LR atrophy was changed 55Delta; the other, with LR atrophy, was corrected 4Delta. Two patients had transient vertical deviations from the BT injection. The myopic patient with esotropia was unchanged. CONCLUSIONS: Injections of BUP and BT corrected 7 patients with comitant horizontal strabismus an average of 19.7Delta, about double the correction reported from BUP injection alone. BUP-injected muscles increased size by 5.8%. Of 2 patients with LR weakness, one without LR atrophy was changed by 55Delta, but another with LR atrophy was corrected only 4Delta.

Bupivacaine injection of eye muscles to treat strabismus.

BACKGROUND: Bupivacaine injected into animal muscles induces a cycle of myotoxicity, degeneration, regeneration and hypertrophy of muscle fibres, without adverse effects on other tissues. This induced hypertrophy can be harnessed to treat strabismus. METHODS: Bupivacaine, 4.5 ml of a 0.75% solution, was injected into the right lateral rectus (RLR) muscle of a patient who had diplopia and who showed 14-prism-dioptres oesotropia. RESULTS: RLR paresis persisted for 7 days. Then, the RLR regained its abducting ability, and progressive improvement of alignment to 4-prism-dioptres oesophoria occurred over the next 33 days, with the elimination of diplopia. Alignment remained the same at 54 days after injection. Magnetic resonance imaging showed a focal increase in the size of the injected RLR of 58% in the posterior area, with reduced change in anterior portions of the RLR. CONCLUSION: Injection of bupivacaine to induce hypertrophy of the injected muscle and thus alter eye alignment was effective in our patient. This approach can be a useful addition to the treatment of strabismus.

Development of botulinum toxin therapy.

Justinius Kerner collected data on 230 cases of botulism in the 1820s, suggested the therapeutic use of toxin, and gave a remarkably complete and accurate description of clinical botulism: its symptoms, time course, and the physical findings that the tear fluid disappears, the skin is dry, the eye, gut, and somatic muscles are paralyzed, and mucus and saliva secretion is suppressed. These effects are the clinical targets of botulinum therapy today. Inspired by Drachman's use of toxin to safely paralyze the hind limb in chicks, we worked out the procedures for its safe medical application and licensure from 1972 to 1989, applying it first to correct strabismus, blepharospasm, leg muscle spasm, and torticollis. This list is now extended by others to well over 100 uses. For many years, blepharospasm patients returning for injection around the eyes and upper face would mention as a joke that they were "back to get the wrinkles out." Working in aesthetic dermatology and ophthalmology, Alistair and Jean Carruthers could envision the intentional cosmetic application of botulinum toxin, probably its greatest single use today.

Avaliaçäo da motilidade extrinseca ocular de pacientes facectomizados sob anestesia retrobulbar / Evaluation of ocular of cataract patients operated under retrobuklbar anesthesia

Diplopia binocular persistente foi relatada como complicaçäo de cirurgia ocular sob anestesia local. A literatura revela que os anestésicos utilizados provocam efeitos tóxicos sobre a musculatura extraocular. Realizou-se estudo clínico prospectivo de avaliaçäo da motilidade ocular pré e pós-operatória de pacientes facectomizados sob anestesia retrobulbar com cloridrato de bupivacaína. O estudo revelou 7 pacientes com queixa de diplopia binocular persistente que apresentaram padräo semelhante na evoluçäo da funçäo muscular durante o período pós-operatório. O músculo reto inferior mostrou-se hipofuncionante até a primeira semana, recuperando totalmente sua funçäo entre sexta e nona semanas; inversamente, o músculo reto superior apresentou discreta hipofunçäo até a primeira semana, que se intensificou entre a sexta e nona semanas