Neuromodulation with Botulinum Toxin in Eyelid-Associated Ocular Surface Disease

Summary

Ocular surface disease (OSD) encompasses dry eye disease and eyelid-related disorders. Botulinum toxin, by reducing eyelid muscle tension, modulates eyelid tone and function, alleviating symptoms of eyelid-associated OSD (EAOSD), such as abnormal blink patterns and incomplete lid sealing. This paper explores botulinum toxin's role in treating EAOSD.

Abstract

Ocular surface disease (OSD) encompasses a range of conditions that not only include the well-described dry eye disease (DED) components - such as hyperosmolarity, inflammation, ocular surface damage, and neurosensory compromise - but also eyelid-related disorders. These can stem from anatomical abnormalities or as consequences of DED, leading to various mechanical and inflammatory issues. These may include friction between the eyelids and the globe; irregular blink mechanics; and incomplete protection or even frank exposure of the ocular surface. Eyelid-associated ocular surface disease (EAOSD) includes conditions such as superior limbic keratoconjunctivitis, orbicularis oculi spasm (Jumping Orbicularis Sign), lid wiper epitheliopathy, and tight eyelid syndrome. Botulinum toxin, produced by the bacterium Clostridium botulinum, works by blocking the release of acetylcholine at the neuromuscular junction, leading to temporary muscle weakening. When mindfully injected into the orbicularis oculi, frontalis, or tarsal plate, botulinum toxin may reduce muscle tension around the eyelids, which improves eyelid tone and anatomic apposition between the eyelid and ocular surface tissues. Botulinum toxin can also be used to address abnormal blink patterns, incomplete blinking, nocturnal lid seal insufficiency, and lagophthalmos. Such interventions may alleviate symptoms associated with EAOSD. This paper examines the applications of botulinum toxin in the treatment of EAOSD. Other applications of botulinum toxin for addressing photophobia and excess trigeminal nerve tone are separately addressable topics.

Introduction

While many practitioners and patients are familiar with dry eye disease (DED) and its associated pathophysiology - such as hyperosmolarity, inflammation, and neurosensory dysfunction - less attention has been given to how eyelid abnormalities contribute to ocular surface disease (OSD)¹. Eyelid-associated ocular surface disease (EAOSD) represents a complex interplay of anatomical, mechanical, and inflammatory factors that can cause or exacerbate OSD^2,3.

Disorders of the eyelids, whether stemming from anatomical anomalies or as sequelae of DED, can exacerbate the symptoms of OSD by causing friction between the eyelids and the ocular surface, irregular blink dynamics, and incomplete eyelid closure, all of which can lead to or worsen ocular surface damage^4,5,6. Common conditions of EAOSD may include superior limbic keratoconjunctivitis (SLK), orbicularis oculi spasm, lid wiper epitheliopathy (LWE), and tight eyelid syndrome (TES), each presenting unique challenges in both diagnosis and treatment^2,3,4,7.

Botulinum toxin (Botox), well-known for its cosmetic applications, has gained attention in the field of eye care for its potential to address the underlying mechanisms of certain eyelid-related disorders. In the context of OSD, eyelid or periorbital Botox injections have demonstrated several benefits, including reducing inflammation in intractable DED, elevating tear meniscus height, decreasing tear osmolarity, and improving both the signs and symptoms associated with blepharospasm^8,9,10. Botox injections have also been shown to enhance tear retention in severe dry eye cases, serve as a potential alternative to punctal plugs, and alleviate photophobia related to DED^11,12,13.

By temporarily paralyzing the orbicularis oculi, frontalis, or tarsal plate, botulinum toxin may alter blink patterns, reduce spasm-related eyelid movements, improve tear retention, and improve ocular surface protection^{13,14,15,16,17}. The growing body of evidence supporting the efficacy of Botox in the management of EAOSD highlights its potential as an alternative to traditional dry eye medications and procedures, offering a promising option for patients and an opportunity for integration into clinical practice^{13,14,15,16,17}.

This paper explores the therapeutic use of Botox for various types of EAOSD. We detail procedural techniques, including dosing, injection sites, and patient selection, for conditions such as SLK, orbicularis oculi spasm, LWE, and TES. We aim to provide practical guidance for dry eye practitioners on using Botox in the management of EAOSD.

Diagnosis of EAOSD
The diagnosis of EAOSD relies on the identification of key ocular signs, many of which are directly linked to the effects of mechanical friction between the eyelids and the ocular surface. In friction-related conditions such as SLK, slit lamp examination may show evidence of atypical eyelid-globe interaction, characterized by fluorescein staining of the superior cornea and lissamine green staining of the superior bulbar conjunctiva³. Friction-related disease may also present with staining along the upper eyelid margin after eversion, particularly near the lid margin and adjacent to the line of Marx in the lid wiper region². Mucous plaques-composed of mucin, epithelial debris, lipids, and proteins-can develop on the cornea in friction-related conditions like SLK, reflecting tear-film instability and excess mucus accumulation¹⁸. Patients experiencing increased friction between the upper eyelid and the globe may also exhibit a reduced and rapid tear breakup time (TBUT), often linked to meibomian gland dysfunction (MGD), decreased meibum secretion, and poor lipid layer stability⁴. Such findings are characteristic signs associated with EAOSD. These clinical features are hallmark signs of EAOSD. When lid margin misalignment contributes to friction, a wooden Q-tip can be placed into the eyelid crease to gently rotate the lid margin into a more anatomical position, perpendicular to the globe. If this manipulation relieves symptoms, it may support the diagnosis of friction-related EAOSD. While EAOSD symptoms often resemble those of dry eye, they are driven by a distinct underlying mechanism involving friction-induced microtrauma between the eyelids and ocular surface during blinking^3,6,19.

Consenting for the procedure
Obtain informed consent before administering botulinum toxin injections for EAOSD. Inform the patient about the purpose of the procedure, the mechanism of action of botulinum toxin, and how it reduces mechanical friction to promote ocular surface healing. The temporary nature of the treatment should be emphasized, including the anticipated need for repeat injections every 3-4 months to maintain therapeutic effects. The consent process should include:

A thorough review of the patient's medical history, including allergies, medications, previous botulinum toxin treatments, and relevant health conditions (e.g., neurological disorders).
Discussion of treatment goals and expected outcomes.
Explanation of potential risks and side effects, such as localized bruising, eyelid ptosis, mild discomfort at the injection site, or asymmetry.
Inform the patient that serious complications are rare when performed by an experienced practitioner.
Presentation of alternative treatment options to ensure an informed decision.
An opportunity for the patient to ask questions and express concerns.
Completion of a signed consent form documenting the patient's understanding and agreement to the procedure.

Protocol

The study received approval from the Colorado Multiple Institutional Review Board, conforms to the tenets of the Declaration of Helsinki, and informed consent was obtained from all participants.

1. Clean procedure set-up

1. Gather the necessary instruments and materials, including a sterile insulin syringe preloaded with botulinum toxin diluted to 4 units/0.1 mL in bacteriostatic saline. Prepare commercial-grade eyelid wipes for initial cleaning, alcohol pads for additional skin preparation, and 4 inch x 4 inch aesthetic gauze for post-injection compression. Ensure all materials are sterile and within expiration dates.
2. Confirm that the patient has signed the informed consent form prior to starting the procedure.

2. Patient instructions

1. Instruct patients to arrive with a clean face free from makeup, lotions, or creams around their eyes on the day of the procedure. If the patient is taking blood-thinning medications such as aspirin or NSAIDs, advise them to consult their physician about temporarily suspending these drugs to reduce the risk of bruising.
2. Post-procedure, advise patients to avoid applying makeup, eyelid creams, or contact lenses for 24 h to 48 h to minimize irritation and infection risk. Ask the patient to apply a cold compress to reduce mild swelling or bruising, but avoid applying direct pressure to the treated area.
3. Counsel patients to avoid strenuous exercise, saunas, and exposure to hot environments for at least 24 h after injection. Inform them to monitor for unusual symptoms such as significant swelling, drooping eyelids, or vision changes and to contact their healthcare provider immediately if these occur.
4. Explain that botulinum toxin effects typically begin to appear within 3 to 7 days, reaching maximal effect at 14 days. Recommend repeat injections every 3 to 4 months for sustained results and schedule follow-up visits to assess treatment efficacy and manage any concerns.

3. Injection procedure

1. Cleanse the eyelids and periorbital area thoroughly using commercial-grade eyelid wipes, wiping gently but completely across the skin surface. Follow this with alcohol pads, swiping gently to further disinfect the skin and reduce infection risk.
2. Identify injection sites by examining the eyelid area under a slit lamp at 16x magnification. Identify the area of greatest friction, as indicated by lissamine green and fluorescein staining, and locate the lid wiper region aligned with this area. Use this site to guide precise injection placement. Avoid injecting the medial third or the temporal third of the upper eyelid to prevent incomplete lid closure.
3. Using aseptic technique, load a sterile insulin syringe with botulinum toxin diluted to 4 units/0.1 mL in bacteriostatic saline. Inject only 1 unit (0.025 mL) at the predetermined site by inserting into the orbicularis oculi muscle within the anterior lamella of the upper eyelid.
4. Immediately after injection, apply light pressure with a 4 inch x 4 inch gauze pad to minimize bleeding and ensure patient comfort.
5. Repeat the injection for additional sites as clinically indicated, taking care not to exceed three injection sites to avoid the risk of incomplete eyelid closure or ptosis.

4. Safety and waste disposal

1. Maintain strict sterile technique throughout the procedure to prevent infection. Handle botulinum toxin carefully, avoiding skin contact and inhalation. Take care to inject the toxin precisely into the orbicularis muscle, just beneath the dermis, at the identified sites and specified volumes to minimize diffusion. Avoid injecting close to the levator palpebrae muscle to prevent ptosis. Maintain steady needle control and use slow injection techniques to reduce spread to surrounding muscles.
2. Dispose of used syringes, needles, gauze, and any remaining botulinum toxin according to institutional and regulatory guidelines for neurotoxic waste. Use designated sharps containers for needles and syringes, and ensure unused toxins are disposed of safely to prevent environmental contamination or accidental exposure.

5. Post-procedure care

1. Monitor the patient immediately post-injection for any adverse reactions such as redness, swelling, or excessive bruising.
2. Reiterate post-procedure care instructions verbally and in writing, emphasizing avoidance of makeup, physical strain, and exposure to heat for 24 h. Schedule a follow-up appointment within 7 to 14 days to assess treatment outcomes and address any complications or patient concerns.

6. Post-procedure examination

1. After botulinum toxin injections for EAOSD, perform a thorough post-procedure examination to evaluate the treatment's effectiveness and monitor for potential complications. Immediately following the injection, inspect the treated area for any signs of swelling, redness, or bruising. While minor pinpoint bleeding is normal, address excessive bleeding promptly.
2. At the follow-up, re-examine the ocular surface to evaluate the therapeutic response. Assess tear breakup time (TBUT) to determine any improvement in tear film stability and use fluorescein and lissamine green staining to monitor tissue response. Eyelids should be everted immediately after lissamine green instillation to assess the superior tarsal conjunctiva for improvements as done in²⁰.
3. Patient-reported outcomes are a vital component of the follow-up. Ask patients about any changes in symptoms, such as reduced pain during blinking, decreased foreign body sensation, and improved vision.

Results

Figure 1 shows examples of the upper eyelid area treated with Botox injections. Among our three patients who underwent botulinum toxin injection for EAOSD (Table 1, Figure 2, Figure 3, and Figure 4), all demonstrated clinical improvement in ocular surface health without any changes to their existing OSD regimens. Post-injection findings included reduced superior corneal and conjunctival...

Discussion

Botulinum neurotoxin, the most potent toxin known to humans and the causative agent of botulism, is produced by the anaerobic, spore-forming, gram-positive bacterium Clostridium botulinum²¹. It functions by blocking the release of acetylcholine at cholinergic presynaptic nerve terminals and neuromuscular synapses, leading to temporary paralysis of the affected tissues²¹. Type A is the most potent exotoxin and is the most commonly used botulinum toxin type in commer...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
4x4 esthetic gauze	Graham Spa Essentials	52509	Nonwoven esthetic wipes, 4"x4", 200 wipes per package
Alcohol prep pads	Curad	CUR090737RB	Medium, 2-ply, 100-count
Commercial grade cleansing wipe	MYZE	—	Daily Lid Wipe for eyelid hygiene
Cosmetic Botulinum Toxin	AbbVie	NDC 0023-923201	Botox for injection, 100 units/vial
Insulin syringe	Brandzig	CMP2602	1 mL 31G x 8mm insulin syringe with fixed needle