Drooping of the eyelid, or ptosis, is a side effect of botulinum toxin injections, which can be caused by poor injection technique. Dr Zahida Butt describes the side effects and contraindications using apraclonidine, or Iopidine, to treat Botox-induced ptosis
The global use of botulinum toxin, or Botox, is becoming more common as an aesthetic procedure. However, one of its side effects is ptosis—the product’s effect on ocular muscles is dependent on the dosage of Botox reaching the levator palpebrae superioris muscle. The levator allows the eyelid to open properly and fully.
The incidence of ptosis after Botox injections is reported to be around 1%. The problem can occur up to two weeks after injection, usually if the Botox is incorrectly placed or resulting from unusual anatomy. Total reversal of ptosis induced by Botox can take up to three months to achieve.
Isolated case reports have shown that use of Iopidine, otherwise known as Apraclonidine 0.5%–1%, three times a day can sometimes be effective. In normal clinical practice, there is no improvement in eyelid elevation when Iopidine is administered topically but in the absence of levator function, this drug may be of some use.
Iopidine is an adrenergic agonist which selectively increases eyelid elevation in the absence of levator function, indirectly combating the effects of Botox. The Iopidine acts by selectively targeting alpha-2 adrenergic receptors on smooth muscle which results in the contraction of Müller’s muscle. This muscle joins on to the levator palpebrae superioris muscle and, on contraction, helps to elevate the eyelid by 1–3mm.
It is very important not to confuse brow ptosis, related to an excessive dose of Botox on the frontalis muscle of the forehead which causes brow droop, with true eyelid ptosis (figs 1, 2).
Iopidine is delivered as a stat dose to treat or prevent high pressure inside the eye that may occur during and after laser eye treatment. Iopidine is thought to work by acting on receptors in the walls of blood vessels in the eye. It causes the blood vessels to narrow which restricts the flow of blood through the vessels. This decreases the production of a watery fluid called aqueous humour that fills the back of the eye—this reduction in aqueous humour inflow into the eyeball decreases pressure within the eye.
Along with its required effects, Iopidine may cause some unwanted side effects. Although not all of these side effects may occur, they may need medical attention if they do.
Based on 1% Iopidine delivery, hypersensitivity occurs in up to 20% of patients, including ocular discomfort, hyperaemia, pruritis, tearing, oedema of the eyelids and conjunctiva, and foreign body sensation. In a study of 40 patients, subjects received Iopidine for 90 days—allergic reactions tended to occur 30–60 days after treatment began and resolved on discontinuation of the drug. Although up to 20% of patients developed allergic symptoms, only two patients elected to discontinue therapy for this reason.
Another double-blind, placebo-controlled study, showed that 12.9% of the 84 patients treated with one to two drops of Iopidine 0.5%, three times daily, discontinued treatment because of hypersensitivity side effects.
In terms of ocular side-effects, hyperaemia and pruritis are experienced by 10–13% of patients treated with Iopidine, while 4–6% suffer from ocular discomfort and tearing. There is a 1–5% incidence of lid oedema, blurred vision, foreign body sensation, dry eye, conjunctivitis, discharge and blanching.
Rare ocular occurrences, noted in less than 1% of patients, include: lid margin crusting, conjunctival follicles, conjunctival oedema, abnormal vision, ocular pain, keratitis, blepharitis, photophobia, corneal staining, lid erythema, blepharoconjunctivitis, irritation, corneal erosion, corneal infiltrate, keratopathy, lid scales and lid retraction. Follicular conjunctivitis and hypotony have been reported rarely and mydriasis has also been seen. Many ocular side effects are transient and may not be seen until 5–7 hours after dosing.
A 66 year old man with proliferative diabetic retinopathy and increased intraocular pressure successfully underwent trabeculoplasty to lower the pressure. He received one drop of 1% Iopidine in the left eye one hour before and immediately after the procedure. At one and two hours postoperatively, the intraocular pressure in his left eye was measured at 8mm Hg and 6mm Hg respectively.
After examination, the patient was discharged. When the intraocular pressure in the left eye was measured one and four days postoperatively, results showed 10mm Hg and 28mm Hg respectively. It was believed that the use of Iopidine almost certainly contributed to low intraocular pressure in this patient, although trabeculoplasty itself can result in an acute decrease in pressure.
Some patients experience cardiovascular side effects, with less than 3% reporting arrhythmias and peripheral oedema, and less than 2% presenting with an irregular heartbeat.
Although long term studies have not yet been carried out, systemic side effects from Iopidine are expected to be relatively infrequent relative to Clonidine, which is used orally to reduce blood pressure, as Iopidine is far less lipophilic. The relative hydrophilia of Iopidine markedly reduces the risk of central alpha adrenergic stimulation.
In a double-blind, crossover study of 20 healthy female volunteers, the use of 0.5% Iopidine did not produce any significant changes in resting or exercise heart rate or blood pressure relative to placebo. This study did not address chronic use of Iopidine in the elderly or in patients with glaucoma.
A single case of syncope and chest tightness has been associated with Iopidine. A 67 year old woman with a history of hypertension, diabetes and renal calculi was scheduled to undergo argon laser iridotomy. She had no known history of coronary artery disease or arrythmias. Her regular medications included insulin, Frusemide and Metoprolol. Around 10 minutes after the instillation of one drop of 1% Iopidine to the right eye, to prevent elevated intraocular pressure, she complained of chest tightness—her pulse was “strong and regular”.
But within one to two minutes, her pulse was undetectable and the patient lost consciousness. She was in sinus rhythm. She was successfully resuscitated following aggressive intravenous fluid therapy. Her blood glucose was 180mg/dl and her ECG was normal. The patient subsequently underwent successful argon laser iridotomy without the use of Iopidine.
There have been occasional reports of bradycardia, chest heaviness or burning, palpitations, reduced blood pressure and orthostatic hypotension, flushing and clammy palms when 1% Iopidine is administered once or twice daily for four weeks. One study showed blood pressure reduction averaged 6% and was not considered clinically significant although occasionally blood pressure decreased by 20%. Heart rate changes ranged from a 42% decrease to a 44% increase.
There have been rare occurrences of respiratory problems such as nasal congestion, rhinitis, dyspneoa, pharyngitis and asthma. Increased pharyngeal secretions, nasal burning or dryness and head cold sensations have also been reported following Iopidine therapy for up to four weeks.
Dry mouth has been reported in 10% of those treated with Iopidine and dysgeusia in around 3% of patients. Patients have also reported abdominal pain, diarrhoea, constipation, gastric discomfort, nausea, dyspepsia and vomiting.
Relating to the nervous system, lethargy affects up to 14% of patients who have been using Iopidine for up to four weeks. Abnormal coordination, asthenia, dizziness, headache, insomnia, malaise, nervousness, paraesthesia and somnolence has been seen in up to 3% of patients. Decreased libido, dream disturbances, fatigue, irritability, numbness or pain of extremities have also been noted, as has depression in less than 1% of patients.
Other side effects, such as contact dermatitis and pruritis (<3%), myalgia (0.2%) and chest pain, dry nose, facial oedema, taste perversion and parosmia (<3%) have been noted.
The respiratory, cardiovascular and nervous system side effects have been reported in patients who have used Iopidine for up to four weeks of therapy. For those receiving 1% Iopidine, more common side effects include increase in pupil size, paleness of the eye or inner lining of the eyelid and raising of the upper eyelid.
Iopidine should be used with caution in patients taking monoamine oxidase inhibitors, tricyclic antidepressants such as amitriptyline, and imipramine-related antidepressants such as mianserin.
A 15% discontinuation rate has been reported. Serious side effects are very rare but to avoid them, it would be prudent to take a full medical history and use with caution in severe kidney failure, depression, recent heart attack, high blood pressure, heart failure, angina or vasovagal attack.
Iopidine should not be used in patients with known hypersensitivity or allergy to any ingredient including benzalkonium chloride preservative, or in people with severe coronary insufficiency.
Iopidine may cause temporary blurred vision after being applied. If affected, it is best to advise patients not to drive or operate machinery until this has worn off.
The medication may also cause dizziness or fatigue so it is therefore best to caution patients regarding these side effects. Alcohol intake should also be limited while on this medication as the side effects can be potentiated.
The ptosis induced by Botox is self-limiting and therefore, even without treatment, the ptosis reversal would be complete in three to four months. The eyelid droop from Botox usually disappears in the vast majority of patients within the first two months so the drug can be discontinued before most side effects could occur.
Patients with Botox-related ptosis can be successfully treated with 0.5%–1% Iopidine. The resultant significant decrease in the amount of ptosis can help patients cope better with the disabling side effect of this cosmetic treatment.
Miss Zahida Butt is an NHS consultant ophthalmic and oculoplastic surgeon based at the Queen Elizabeth Hospital, King’s Lynn. She is also founder of The Cosmetic Clinic, King’s Lynn
1. Malhotra PS, Danahey DG and Hilger P. “Botox injections to improve facial aesthetics.” 2010 http//emedicine Medscape.com article
2. Schenfield N. “The use of Apraclonidine eyedrops to treat ptosis after the administration of Botulinum toxin to the upper face.” Dermatology Online Journal. 2005 Volume 1, Issue 1 (1) 9.