Purpose: To trial topical insulin drops to promote healing in neurotrophic keratitis that has
been refractory to conventional management versus tarsorrhaphy.
Hypothesis: Topical insulin might promote re-epithelialization in the setting of neurotrophic
keratitis (Stage 2 or 3) with persistent epithelial defect refractory to conventional
treatments and be a non-inferior treatment to tarsorrhaphy.
Justification: Several experiments support the use of insulin for the promotion of corneal
epithelial healing. In vitro experiments with immortalized corneal epithelial cells suggest
that insulin improves epithelial cell migration. A rabbit model showed improvement in corneal
hypoesthesia after topical insulin exposure. These results suggest that early hypoesthesia
may be reversible, and thereby improve epithelial wound healing. Another rabbit model showed
that topical insulin might alter the corneal surface by increasing the tensile strength of
corneal wounds. Finally, the presence of insulin receptors on the cornea and lacrimal gland
suggests that insulin may contribute to corneal wound healing.
Few case studies describe the use of topical insulin in the absence of other concurrent
treatments for neurotrophic keratitis.
Objectives: Through use of topical insulin, promotion of corneal healing in cases where
conventional methods have failed. These include topical antibiotics, preservative free
artificial tears, and bandage contact lens for at least 2 weeks. This study will evaluate
topical insulin as a salvage treatment in patients who otherwise would require tarsorrhaphy.
Research Method: Patients will be recruited in Vancouver, Edmonton, Toronto, Ottawa, Halifax,
and Montreal. Patients with neurotrophic corneal ulcers will be identified through the
Ophthalmology on call resident clinics in each location and directly referred to a physician
in their city who is participating in this study. At least 12 patients will be enrolled in
each group (as per power calculation).
Baseline demographic information will be collected (age, gender, medical comorbidities,
ocular comorbidities, current medications, and previous and current eyedrops). Baseline
ocular examination will consist of a complete ophthalmologic exam, including visual acuity,
intraocular pressure, dilated fundus exam or BScan imaging, corneal sensation, eyelid
measurements (palpebral fissure, presence of entropion or ectropion, and lagophthalmos), and
anterior segment exam and photography. Corneal sensation will be measured in group quadrants
and centrally and quantified with cochet bonnet esthesiometry.
Patients will be randomized to one of two groups: Permanent medial tarsorrhaphy or topical
insulin drops.
Patients will stop all other topical medication before commencing use of insulin eyedrops.
Topical insulin will be compounded under sterile conditions at a local pharmacy at a
concentration of 25 IU / ml in sterile balanced saline solution (0.9%). Topical insulin will
be administered four times per day to the affected eye.
Patients will be followed up every 3 days after initiation of therapy, or as needed. Each
follow up visit will include an ophthalmologic exam with repeat measurements of the
epithelial defect, visual acuity, IOP, and anterior segment exam.
The primary outcome will be time to re-epithelialization of neurotrophic ulcer, defined as
<0.5mm of remaining epithelial defect. There will also be an evaluation of the percentage of
patients healed at each follow up time point. Subgroup analysis will analyze time to
re-epithelialization in patients with diabetes separate from patients without diabetes.
The trial will be terminated early if the patients should develop adverse side effects,
including allergy, worsening of symptoms, infection, or worsening of keratitis.
Plan for Data Analysis: Statistical analysis to determine the rate of improvement of
neurotrophic keratitis by photograph analysis, corneal sensation in four quadrants and
centrally, and visual acuity testing.