Apraclonidine: A Real Eye Opener in Botox-Induced Ptosis

Michelle Crist, O.D. VA Boston Healthcare System – West Roxbury

Abstract: With the increasing cosmetic use of Botox®, optometrists may be called upon to address post-injection complications such as temporary blepharoptosis. A case of Botox®-induced ptosis managed with Apraclonidine 0.5% is presented.

I. CASE HISTORY A 57 year-old white female presented to the emergency department with an acute onset of a right blepharoptosis the day prior. Upon admission, a diagnosis of Bell’s palsy was made with suspicion of right- sided facial weakness and the optometry service was consulted for evaluation.

Further questioning revealed a history of receiving Botox® injections on three occasions over the past year. The patient was returning for repeat injections approximately every six months, with a four month duration of efficacy. Her desire for Botox® injections arose after years of squinting caused forehead wrinkles that left the woman appearing angry. Over time, her appearance began to negatively impact her business. The most recent injection occurred 16 days prior to the onset of symptoms. The patient specifically reported that the pattern of injections into her forehead was different at her recent session in comparison to that of her previous appointments. Vision was obscured to the extent that the patient had to hold her eyelid up while driving. In addition, she experienced diminished depth perception, which was especially problematic in the setting of working with sharp tools as a dog groomer. The patient denied pain, vision loss, diplopia, dysarthria, dysphagia, confusion, peripheral weakness or nausea.

Past ocular history was significant for a vitreoretinal tuft, atrophic retinal hole and a peripapillary nevus OS, with narrow anterior chamber angles OU. The patient disclosed a medical history of migraine, hyperlipidemia, osteopenia, tubular adenoma, and depression. Current medications included calcium with vitamin D, fish oil, glucosamine and a multivitamin.

II. PERTINENT FINDINGS Visual acuity was 20/20 OD and 20/20- OS. Extraocular motilities were smooth and full. External exam showed a blepharoptosis of the right upper eyelid. There was no fatiguability of the ptosis on sustained upgaze. Pupils were equal, round and reactive to light OD and OS without a relative afferent pupillary defect. Upon testing of cranial nerve VII, the patient was found to have slight right-sided lower facial weakness with flattening of the nasolabial fold. Review of old photos suggests longstanding facial asymmetry with lower right-sided facial droop. All other cranial nerves were intact. Slit-lamp examination confirmed anatomically narrow anterior chamber angles by Von Herick, but was otherwise unremarkable. Dilated fundus exam was within normal limits. CBC, MRI and MRA were ordered by neurology on admission with no significant findings.

III. DIFFERENTIAL DIAGNOSIS A number of conditions must be considered as differential diagnoses in cases of acquired ptosis, those of which are summarized in Table 1. The three leading differentials are third nerve palsy, myasthenia gravis and Horner’s syndrome. Other differentials include trauma, Bell’s palsy, levator aponeurosis dysfunction (secondary to senescence, cicatrization, inflammation) and mechanical causes (eyelid tumors, dermatochalasis, etc). In a Bell’s palsy, orbicularis oculi weakness is present with an inability to close, rather than open, the eye. Also, typically we observe a brow- or “pseudo-” ptosis due to paralysis of the frontalis muscle that inserts into the eyebrow. A true blepharoptosis does not typically occur. The clinical scenario must be carefully considered prior to making a diagnosis, to ensure therapeutic intervention is tailored to patient needs with appropriate urgency.

IV. DIAGNOSIS AND DISCUSSION Examination findings were indicative of a post-injection Botox®-induced blepharoptosis of the right upper eyelid. There were no signs or symptoms to support other diagnoses. Cosmetic use of Botox® has increased dramatically in recent years following FDA approval for the temporary aesthetic improvement in appearance of moderate to severe glabellar lines. Periocular injection of the botulinum toxin generates a selective muscle paralysis of the corrugator and procerus muscles that excessively contract to exacerbate forehead rhytides, or wrinkles. Resultant ptosis occurs when the botulinum toxin inadvertently migrates through the orbital septum, exerting a neuromuscular blockade on the levator palpebrae superioris muscle. This effect is achieved through the inhibition of acetylcholine release into the neuromuscular junction. Toxin particles are endocytosed into the presynaptic cholinergic nerve terminal. Proteins permitting vesicle fusion with the cell membrane are cleaved by the toxin particles, thus preventing release of acetylcholine into the neuromuscular junction and subsequently decreasing muscle activity.

Seven different strains of Clostridium botulinum bacteria have been identified, named A-G for the type of neurotoxin they produce. Botulinum type A is known to be more powerful than the other strains, with a longer duration of action. While preparations of both botulinum type A and B are commercially available for use in the cosmetic arena, only type A has gained approval in the treatment of glabellar lines. Upon FDA approval in April 2002, ALLERGAN Pharmaceutical marketed Botox® and Botox® Cosmetic (both onabotulinumtoxin A), for injection into forehead muscles to temporarily improve the look of moderate to severe frown lines between the eyebrows (glabellar lines) in people 18 to 65 years of age. In 2009, the pharmaceutical company Medicis received U.S. FDA approval of Dysport® (abobotulinumtoxin A) for the same purpose. It is important to note that each product has restricted clinical utility and unique diffusion characteristics, therefore uniform dosing cannot be applied. Other therapeutic applications for botulinum toxin A include cervical dystonia, severe primary axillary hyperhidrosis, strabismus, essential blepharospasm, hemifacial spasm, acquired nystagmus, myokymia, eyelid retraction in thyroid eye disease, upper limb spasticity, and chronic migraines (Table 2). FDA approval, however, has not been obtained for all of these conditions. For the treatment of periorbital rhytides, the onset of action of Botox® typically occurs within 24- 72 hours after injection and the duration of efficacy is estimated at 3-6 months. Depending on the extent of treatment, costs can range from 300-500 dollars per session.

Botox® is not ideal for everyone and does not come without risks. While most side effects are mild and transient, others can be potentially life threatening in certain individuals. Its use is contraindicated in patients with the following neurologic diseases: multiple sclerosis, myasthenia gravis, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) and Lambert-Eaton syndrome. Serious drug interactions can occur with medications that already interfere with neuromuscular transmission, therefore Botox® should be avoided in patients concurrently taking: aminoglycosides (amikacin, gentamicin, tobramycin, etc), cholinesterase inhibitors (donepezil, neostigmine, pyridostigmine, etc.), magnesium sulfate, penicillamine, quinine and calcium channel blockers. Botox® is compounded with human albumin, therefore reports advise against the use of this agent in people with a true allergy to eggs.

Clinical trials reveal blepharoptosis as the second most frequently encountered adverse effect (behind headaches) of Botox® injections for eyebrow wrinkles, with an incidence of 2-4%. This outcome can occur up to two weeks after injection, with resolution typically by six weeks. Further potential complications of periocular botulinum toxin use are summarized in Table 3. A Botox®-related ptosis can be iatrogenically induced in situations of inexperience or poor technique. Avoidance of unwanted sequelae can be achieved through careful attention to the periorbital anatomy. All injections to facial musculature must be restricted to at least 1 cm above the eyebrow, without crossing laterally past the midpupillary line or injecting too deep as to prevent intraorbital spread.

V. TREATMENT, MANAGEMENT Apraclonidine is an α2-adrenergic agonist that stimulates contraction of Muller’s muscle to raise the upper eyelid 1-3 mm. Recalling our patient, external exam showed a blepharoptosis of the right upper eyelid. At presentation, palpebral fissure height measured 4.0 mm OD with pupillary axis involvement and 8.0 mm OS (Figure 1-2). Two drops of Apraclonidine 0.5% were instilled into her right eye. After 30 minutes, palpebral fissure height was 6.5mm OD with clearance of the pupil and 8.0 mm OS (Figures 3-4). The patient was instructed to use one drop of Apraclonidine 0.5% as needed in the effected eye, not to exceed dosing of three times per day. One month later the patient reported that she was no longer dependent on the eye drop. Her ptosis, when present, was worse upon wakening and with fatigue. During her symptomatic period, one drop of Apraclonidine effectively lifted her eyelid for five hours.

Apraclonidine ophthalmic solution is commercially available in two formulations: Iopidine 0.5% which is used in lowering intraocular pressure in patients with ocular hypertension or glaucoma; and Iopidine 1.0% for prevention and control of post-operative spikes in IOP following various laser procedures (Figure 5-6). It should be avoided in patients with known allergy to its active ingredients (including benzalkonium chloride, BAK) and in those taking MAO-inhibitors and tricyclic antidepressants. The drug has been reported to cause contact dermatitis, mydriasis, and unpredictable variations in blood pressure or heart rate. Therefore, Apraclonidine should not be used in patients with narrow angles or uncontrolled cardiovascular disease. In theory, other sympathomimetic agents (e.g., brimonidine, phenylephrine, naphazoline) may have similar effects on a Botox®-induced blepharoptosis, however this has not been studied. Patients must be advised of the off-label usage of these eye drops in the management of their condition.

Without insurance, the cost of a five milliliter bottle of Iopidine is around $140 while Apraclonidine is available for about $90. While price may be an issue for some patients, we were able to provide both aesthetic and visual remediation to our patient with only minimal incurrence of risk.

VI. CONCLUSION During recent years, the Botox® Boom has fueled a therapeutic demand for the cosmetic use of the most potent of all biological toxins known to affect humans. It has gained popularity due to its safety profile and relatively low expense in comparison to more invasive surgical procedures. Optometrists may be called upon to address post-injection complications such as temporary blepharoptosis in this “cosmetically-sensitive” patient population. Our case demonstrates the effectiveness of the off-label use of just one of several sympathomimetic agents that may be employed in the management of this condition. Minimal literature is published on this topic; therefore additional studies are necessary to establish clinical guidelines and optimal dosing of Apraclonidine in the temporary relief of Botox®-induced ptosis.

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Table 1. Differential Diagnosis of Acquired Ptosis.

Differential Diagnosis of Acquired Ptosis

Third Nerve Palsy Myasthenia Gravis Horner's Syndrome

Trauma Levator Bell's palsy aponeurosis (pseudoptosis)

Mechanical dysfunction

Table 2. Ophthalmic uses of Botox

Ophthalmic uses of Botox

• Strabismus • Acquired nystagmus • Essential blepharospasm • Hemifacial spasm • Aberrant regeneration of CN VII • Myokymia • Reduction of periorbital rhytides • Eyelid retraction in thyroid eye disease

Table 3. Complications of periocular Botox® use

• Ptosis • Exposure keratopathy Side Effects of • Diplopia Periocular Botox • Pain/tenderness at injection sites • Headache

Figure 1-2. Ptosis prior to instillation of Apraclonidine. At presentation, palpebral fissure height measured 4.0 mm OD with pupillary axis involvement and 8.0 mm OS.

Figure 3-4. 30 minutes after instillation of Apraclonidine. Palpebral fissure height was 6.5mm OD with clearance of the pupil and 8.0 mm OS

Figure 5-6. Apraclonidine ophthalmic solution is commercially available as brand name Iopidine 0.5% and in generic form.