Clinical Uses of Botulinum Toxin in Ophthalmology
Botulinum toxin has found numerous uses in medicine, with new indications continuing to be added. This agent has become the treatment of choice for a number of movement disorders, and has been advocated for many other conditions such as aesthetic reduction of facial wrinkles.
Movement Disorders and Focal Dystonias
Benign Essential Blepharospasm
This cranial dystonia involves the eyelid and forehead muscles. It manifests as involuntary orbicularis muscle contraction resulting in increased frequency of blinking (Figure 3). In severe cases, blinking is repetitive and forceful, resulting in functional blindness. The etiology remains unknown, but may involve dysfunction of the central coordination of visual sensory input and motor output to the eyelids. Patients have increased sensitivity to visual stimuli and an exaggerated motor response manifested as excessive blinking and forced eyelid closure. Botulinum toxin has been used in the treatment of blepharospasm since 1983 and is the treatment of choice for controlling eyelid spasms. Studies show type A toxin to be effective in 70%–90% of patients. The average dose of toxin type A is 12.5–25 units per eye, injected into the orbicularis muscle (Figure 4). Treatment benefit lasts an average of 13 weeks. In cases where type A becomes ineffective, one can use botulinum toxin type B, using 750 to 2500 units per eye. In our experience, type B has a shorter duration of effect (8–10 weeks) and shows a greater tendency to diffuse to adjacent areas. Potential adverse effects following the use of botulinum toxin around the eye include ecchymosis, ptosis, diplopia, midfacial weakness, lagophthalmos, and dry eye. Ptosis is the most common complication related to spread of the chemodenervation to the levator muscle. It is seen in 10%–15% of treated patients. Typically, this is mild and of little or no functional consequence. In most cases, complications are mild, transient, and can be minimized with appropriate injection technique.
Blepharospasm: Clinical Exam and Injection Sites
Essential blepharospasm is characterized by bilateral, repetitive and uncontroleld clonic contractions of the arbicularis oculi muscle. When it is associated with oromandibular dystonia, as in this video, there are also midfacial and periorial spasm.
In the majority of cases, blepharospasm is managed with the injection of butolinum toxin into the affected muscles. Typically, Botox (botulinum toxin type A) is injected into the medial and lateral portions of the pretarsal orbitcularis in both the upper and lower eyelids, and often into the eyebrow, as well.
Video courtesy of Keith D. Carter, MD.
A focal movement disorder affecting the lower face, oromandibular dystonia is characterized by spasms along the sides of the nose, mouth, and chin. The condition can have a profound influence on eating and speaking. Treatment is with small doses (1–2 units, type A) of toxin into the affected facial muscles, with no more than 10 units on each side. Because these muscles are so tiny, overdosage and facial weakness, with drooling or cheek biting are potential risks. A thorough knowledge of facial anatomy and experience in injecting the face is important.
This syndrome refers to a regional dystonia consisting of the two adjacent facial dystonias, benign essential blepharospasm and oromandibular dystonia. Clinical manifestations commonly begin with orbicularis muscle spasm spreading to the lower face and even the neck after months to a few years. While the facial spasms may become less severe with botulinum toxin treatment of the orbicularis muscle alone, in most cases injection of the middle and lower facial muscles will also be required. Treatment is with small 1–2-unit injections of botulinum toxin type A into the affected facial muscles, with no more than 10 units on each side.
This neuromuscular disorder is characterized by unilateral recurrent twitches of the facial muscles innervated by the facial nerve (Figure 5a). Unlike blepharospasm, these spasms persist during sleep and are not related to hypersensory input. The anatomic basis for the spasms is usually a mechanical irritation of the facial nerve at its exit root by a sagging arterial branch. Although surgical treatment is available, most patients are treated medically with botulinum toxin, and the results are highly successful (Figure 5b). Injection is as for blepharospasm and oromandibular dystonia, with an average of 25–35 units on the affected side (see Figure 4). The duration of effect is typically about 16 weeks.
Apraxia of Eyelid Opening
Apraxia is an inability to perform learned complex movements in the absence of paralysis, sensory loss, or disturbance of coordination. Apraxia of eyelid opening is a poorly understood entity and generally refers to a nonparalytic inability to raise the upper eyelid in the absence of discernable orbicularis muscle contraction or levator muscle injury. Many authors inappropriately apply this diagnosis to any patient with eyelid closure associated with minimal force of orbicularis contraction, or to those who respond poorly to botulinum toxin.
The original description of this disease referred to patients with supranuclear injury in which activation of the levator muscle could not be achieved. Since that time, apraxic eyelids have been found to occur with several different disorders such as dystonic Parkinson syndrome, progressive supranuclear palsy, and isolated loss of levator muscle control. A fourth type, which can be referred to as blepharospastic apraxia, is seen in some patients with blepharospasm. Here, subclinical contractions of the pretarsal orbicularis muscle persist into the post-blink phase, suppressing levator muscle contraction. In such cases, injection of 5 units of botulinum toxin type A into the pretarsal orbicularis and Riolan’s muscles along the upper eyelid margin may show beneficial results, where routine placement of toxin as for blepharospasm will not. The frontalis sling procedure has also proven to be beneficial.
Treatment of Tics, Tremors, and Myokmia
Several investigators have reported the use of botulinum toxin for the treatment of motor tics, including those associated with Tourette syndrome. Improvement has also been demonstrated in patients with essential tremor and head movements associated with cervical dystonia. Eyelid myokymia is an uncontrollable twitching of the orbicularis muscle, typically involving the lower eyelid. The twitching is triggered by stress, fatigue, caffeine, or alcohol. In most cases it is benign and self-limiting. The mechanism is not well understood, but the affected muscle shows a slow, undulating fine movement in the most superficial muscle layers. Injection of 5 units of botulinum toxin type A into the superficial orbicularis muscle temporarily relaxes the muscle until the condition resolves spontaneously.
Facial Nerve Synkinesis
Facial synkinesis is an involuntary contraction of muscles innervated by one branch of the facial nerve when attempting to voluntarily activate muscles previously innervated by other branches. It is seen frequently following facial nerve palsy with aberrant misdirected regeneration of peripheral fibers. The condition can result in facial deformity, inappropriate eyelid closure, drooling, and twitching or muscle spasms. Botulinum toxin has been shown to be highly effective in reducing the synkinetic movements for 4–9 months. Injections are similar to the hemifacial spasm pattern (see Figure 4).
Botulinum toxin was first used in ophthalmology by Dr. Alan Scott to treat strabismus by weakening the contraction force of specific opposing muscles to straighten the eye. Injection usually requires the use of electromyographic-guided needle placement to ensure the toxin is delivered to the target muscle. For infantile esotropia it has been shown that two thirds of children receiving simultaneous bimedial rectus muscle toxin injection achieve some degree of stereopsis. One third of patients with comitant exotropia may also show improvement in their deviation. For larger-angle deviations, increasing the dose of toxin per injection may give better results, but this is associated with a higher incidence of complications such as ptosis. Botulinum toxin has also shown some benefit for traumatic paralytic strabismus, where it is used to minimize contracture of the opposing muscle until recovery. For patients who do not show recovery in 6 months, surgical correction is indicated.
The use of botulinum toxin for headache syndromes followed from observations that patients treated for forehead frown lines showed improvement in headache. Because migraine and other headaches often are associated with visual disturbances, management can be of ophthalmic significance. While botulinum toxin blocks the transmission of ACh at the neuromuscular junction, more recently, effects on noncholinergic sensory pathways have also been identified. The transmission of pain signals from the periphery to the central nervous system in migraine headache is not completely understood, but in part involves the activation of trigeminal nociceptive afferent fibers on vessel walls by tissue damage and/or extravasated algesiogenic vasoactive neuropeptides, leading to propagation of pain. Botulinum toxin has been shown to lessen the frequency and intensity of tension headaches, cervicogenic headaches, and fibromyalgia-myofascial pain syndromes, with a 40%–75% reduction in the use of chronic pain medication. While the exact dosing regimen and placement sites remain to be determined, in our experience botulinum toxin can significantly reduce the severity and frequency of painful migraine episodes for 3–9 months. We give 50–100 units of botulinum toxin type A into the frontalis muscle, staying at least 2 cm above the brow to prevent brow ptosis. In addition, we give 30–40 units into the temporalis muscle on each side, and, if needed, 20 units to the occipitalis muscle.
Hyperhidrosis and Lacrimal Hypersecretion Syndromes
The observation that some patients with hemifacial spasm treated with botulinum toxin experienced decreased facial sweating on the treated side, lead to its use in the management of hyperhidrosis of the face (eg, Frey syndrome), as well as the axilla and palms. In Frey syndrome, a common consequence of a parotidectomy, gustatory facial sweating results from aberrant regeneration of facial nerve secretomotor fibers that attach to sweat glands of the check. For treatment with botulinum toxin, postganglionic sympathetic cholinergic nerves to eccrine sweat glands are targeted in the affected areas. A dosage of 0.5–0.8 U/cm2 is injected intradermally at 10–25 sites. While the reported experience is limited, in one large clinical trial 82% of treated patients showed greater than 50% reduction in sweating compared to baseline. The benefits typically last for 3–4 months. Gustatory epiphora, often called crocodile tears, is a rare condition that may occur because of proximal facial nerve injury with aberrant regeneration of secretomotor fibers, originally destined for the salivary glands, that attach to the lacrimal gland. This can be very troublesome and embarrassing to affected patients. Lacrimal hypersecretion is a more common problem that may be secondary to ocular surface irritation, such as with trichiasis and eyelid malpositions, corneal exposure, or blepharitis. Primary idiopathic lacrimal hypersecretion, often intermittent, may also be seen in the absence of any obvious ocular surface abnormality. Injection of 2.5–5 units of botulinum toxin type A into the palpebral lobe of the lacrimal gland results in a clinically significant reduction in tear production and improvement in symptoms in the majority of patients. Relief of epiphora lasts 3–4 months.
Upper eyelid retraction associated with thyroid eye disease may result in corneal exposure and, in some cases, corneal ulceration. Surgical recession gives excellent results in 90%–95% of patients, but is not usually recommended until the ophthalmopathy is stable. Botulinum toxin type A (5–10 units) injected into the levator muscle, either transcutaneously or transconjunctivally, can provide significant improvement in eyelid retraction. A drop in eyelid position of 2–4 mm is typical, and results last for 12–14 weeks. Overcorrection can result in visually significant ptosis and diplopia from weakening of the superior rectus muscle.
Spastic entropion can be seen with any horizontal lid laxity where fixation of the anterior and posterior lamellae is disrupted. Occasionally after ocular surgery in patients with pre-existing lid laxity, ocular irritation can cause orbicularis muscle spasm resulting in entropion. Relief can be achieved by weakening the pretarsal orbicularis muscle with 5 units of botulinum toxin type A, eliminating the entropion for up to 3–4 months.
The utility of botulinum toxin in facial rejuvenation has grown dramatically in recent years. Initially treatment was for dynamic glabellar folds, treated with 20–40 units of botulinum toxin type A into the corrugator muscle in a V-shaped pattern, to include both the transverse and oblique heads, between the eyebrows. The aesthetic use of this drug has now expanded to off-label applications of many other areas of the face, including “crows feet” (lateral periocular rhytids), transverse brow and forehead furrows, “smoker’s lines” (perioral rhytids), “marionette lines” (mesolabial folds), and platysmal bands (Figure 6 shows three patterns of injection). Botulinum toxin is also useful in creating a “chemical brow lift” by targeting the brow depressors (depressor supercilii medially, and tail of the orbicularis laterally). Treatment strategies for aesthetic uses vary widely, but it is important to approach each patient judiciously. While side effects are temporary they can result in significant morbidity and patient dissatisfaction.