TABLE 4.
Characteristics of included studies—Ophthalmology.
| Author; Year of publication; Trial registration | Study design; Country; Setting | Participant characteristics | Eligibility criteria | Interventions; Comparisons | Outcome measures (methods); Timepoints | Main findings | Safety | Funding; Conflict of interest |
|---|---|---|---|---|---|---|---|---|
| Demodex infestation | ||||||||
| Craig 2022; trial not registered Craig et al. (2022) | RCT (cross-over); Canada; Outpatient clinic | N = 30 enrolled (n = 30 analysed) Age in years, mean (SD) 33 (Soukoulis and Hirsch, 2004), range 20–59. Female: 18/30 |
Inclusion criteria: ≥ 18 years of age Exclusion criteria: history of contact lens wear; surgical procedures within two years prior to study; active ocular infection or corneal disease (other than mild dry eye symptoms, i.e. Ocular Surface Disease Index score ≤ 22); topical or systemic medications, or systemic conditions affecting the eye; abnormal corneal sensitivity (Cochet-Bonnet aesthesiometer measurement < 60mm). |
Intervention group 1: TTO-based eyelid wipes (5% Melaleuca alternifolia) I-Lid’n Lash® Plus, I-MED Pharma, Canada.Intervention group 2: TTO-based eyelid wipes (Melaleuca alternifolia - concentration not stated) Blephadex™ Eyelid Wipes, Lunovus, US. Intervention group 3: TTO-based eyelid wipes (Melaleuca alternifolia - concentration not stated) Oust™ Demodex®, OCuSOFT®, US. Intervention group 4: TTO-based eyelid wipes (Melaleuca alternifolia - concentration not stated) EyeCleanse™ Eyelid Cleanser Lid Wipes with Tea Tree, Chrissanthie, South Africa. Control group: Sensitive Eyes® Plus Saline Solution, Bausch and Lomb, US. Eyelid cleanser wipe or cotton pad soaked in saline solution was applied onto subjects’ closed eyelids using gentle pressure for 10 cycles of side-to-side motion, at the same time of day (within ± 1 h). Washout was 48-72 h between product application days. |
Tear film stability (assessed using either Keratograph 5 M, Oculus Optikgeraete GmbH, Germany, or Medmont Corneal Topographer E300, Medmont International, Australia) Visual acuity (six-metre best spectacle-corrected logMAR) Conjunctival hyperaemia i.e. ocular redess (Keratograph 5 M, Oculus Optikgeraete GmbH, Germany) Timepoints: before and at 10 minutes after product application. Ocular surface staining (according to Centre for Contact Lens Research staining grading scale) Timepoints: once at enrolment and then at 10 min after each product application Ocular discomfort score (patient-assessed on scale from 0 = no discomfort up to 10 = maximum tolerable discomfort). Timepoints: before product application and then every 15 s for 5 min after product application, then every 30 s for a further 5 min Time until comfortable eye-opening (patient assessed as the time elapsed after product application until they felt they could comfortably open their eyes) |
Tear film stability (i.e. tear film break up time in seconds) sig. decreased with EyeCleanse™ from 8.9 ± 4.4 to 5.6 ± 3.1, p < 0.001. All other groups showed no sig. change. Visual acuity did not significantly change in any group. Bulbar ocular redness sig. increased after applying Lid’n Lash® (0.4 ± 0.2 to 0.6 ± 0.4, p < 0.05), and EyeCleanse™ (0.4 ± 0.3 to 0.9 ± 0.6, p = 0.005). Similarly, limbal ocular redness sig. increased after applying EyeCleanse™ (0.3 ± 0.2 to 0.8 ± 0.6, p = 0.01). Both corneal and conjunctival staining scores increased from 0/100 to 3/100 10-minutes post application of EyeCleanse™ (both P<0.05). No sig. changes observed in other intervention groups. Ocular discomfort score was sig. higher than baseline (p < 0.05) 150 secs post-application of Lid’n Lash®, 60 s post Blephadex™, 120 s post Oust™ Demodex®, and 195 s post EyeCleanse™. Time until patient-reported comfortable eye-opening was sig. longer with Lid’n Lash® vs. Sensitive Eyes® Plus (6 s vs. 1 s, p < 0.05), and with EyeCleanse™ vs. Sensitive Eyes® Plus (30 s vs. 1 s, p < 0.001). |
Superior and inferior lid wiper epitheliopathy grade (according to Korb et al.) increased with EyeCleanse™ only. No other adverse or serious adverse events were recorded. |
Partial funding from Canadian Optometric Education Trust Fund. Authors state no conflicts of interest. |
| Karakurt; 2018; trial not registered Karakurt and Zeytun, (2018) | RCT (parallel); Turkey; Outpatient clinic | N = 135 enrolled (n = 135 analysed) Age in years, mean (SD) TTO group 57.52 (14.22) Control group 55.15 (13.97) Female TTO group 40/75 Control group 35/60 |
Inclusion criteria: diagnosed demodectic blepharitis based on clinical and parasitological examinations; history of regular application of eyelash-based treatments for Demodex and regular follow-up at study clinic. Exclusion criteria: other ocular or systemic disease; ocular surgery; previous systemic or topical treatment. |
Intervention group: TTO eyelid shampoo (7.5% TTO, botanical species not stated) Blefaroshampoo®, Teka, Turkey. Control group: eyelid shampoo without TTO (Blepharitis Shampoo®, Jeomed, Turkey) All subjects washed eyelids with allocated shampoo twice daily for 4 weeks. |
Demodex positivity (eight eyelashes removed by epilation method and examined under light microscope were defined as Demodex positive when larva, nymphs, or mature Demodex mites were observed in ≥1 eyelash). Average Demodex count (calculated by dividing total Demodex count by number of eyelashes on which they were observed). Ocular symptoms (itching, burning, feeling of a foreign body in the eye, eye redness, and cylindrical dandruff assessed as 0 = no symptoms, 1 = light, 2 = moderate, or 3 = severe). Timepoints: Baseline and after 4 weeks. |
Demodex positivity all subjects were Demodex positive at baseline. Number of Demodex positive subjects sig. decreased in TTO group to 48/75 after 4 weeks (p < 0.001). Similarly, the number of Demodex positive subjects decreased in control group to (53/60) after 4 weeks (p = 0.008). Full Demodex reduction achieved in 36% of TTO group and 12% of control group. Average Demodex count (in subjects who did not achieve full reduction in Demodex mites) sig. decrease within TTO group from 12.46/eyelash to 4.15/eyelash after 4 weeks (p < 0.001). Similarly, sig. decrease within control group from 11.98/eyelash to 7.91/eyelash, after 4 weeks (P=0.024). Ocular symptoms mean score of each symptom sig. decreased within TTO group (all p < 0.001). Symptom scores also decreased within control group but all p > 0.05. |
Not assessed. | Funding: Erzincan University, Coordinator of Scientific Research Projects (TSA-2017-441). Authors state no conflicts of interest. |
| Koo; 2012; trial not registered Koo et al. (2012) | RCT (parallel); Korea; Hospital clinic | N = 281 enrolled (n = 160 analysed) Age in years, mean (SD); range TTO group 53.7 (10.3); 23–85 Control group 55.6 (11.3): 25–85 Female TTO group 70/106 Control group 34/54 |
Inclusion criteria: ocular surface discomfort (e.g., dryness, pruritus, ocular pain, or visual disturbance). Exclusion criteria: eye surgery within 6 months prior to study; eyedrop use other than artificial tears; current or prior eyelid scrubbing treatment. |
Intervention group: TTO eyelid scrub (TTO, Melaleuca alternifolia), Sydney Oil Co, Australia. TTO diluted to either 50% or 10% with mineral oil. Subjects received weekly lid scrubs with 50% TTO dilution in clinic and performed twice daily lid scrubs with 10% TTO dilution performed at home, for one month. Control group: Saline eyelid scrub. Subjects received weekly lid scrubs in clinic and performed twice daily lid scrubs performed by subjects at home, for one month. |
Ocular surface discomfort index (patient questionnaire scored between 0 and 100 with higher scores meaning greater ocular discomfort). Demodex count (number of Demodex mites identified by microscopy in total of eight lashes). Timepoints: Baseline and after one month. |
Ocular surface discomfort index sig. decrease in TTO ‘good compliance’ group i.e., scrubbed eyelids >10 times/week, compared with control group (p = 0.005), and with TTO ‘poor compliance’ group i.e., scrubbing <5 times/week (p < 0.001), after 1 month. Demodex count sig. decrease in TTO good compliance group i.e., scrubbing eyelids >10 times/week, compared with control group (p = 0.003) and with TTO poor compliance group i.e., scrubbing <5 times/week (p = 0.019), after 1 month. |
Not reported as measured, but authors reported ocular irritation occurred in 5/106 subjects in TTO group. | Authors state no funding and no conflicts of interest. |
| Wong; 2019; ACTRN12618001368224 Wong et al. (2019) | RCT (parallel, within-subject design); Australia; Unclear | N = 20 enrolled (n = 20 analysed) Age in years, median 63.5; range 48–76 Female 14/20 |
Inclusion criteria: age ≥45 years; similar vision in both eyes; generally healthy. Exclusion criteria: active anterior segment disease except blepharitis; ocular or systemic medications that may affect tear film or ocular microbiota started within 3 months prior to study or likely to increase in dose during study; ocular surgery within 6 months prior to study; pregnant or lactating; known allergy to TTO, coconut oil or fluorescein dye; heavy make-up users; epilepsy or migraines triggered by flashing light. |
Intervention group: TTO-based eyelid wipes (Melaleuca alternifolia - concentration not stated) Blephadex™ Eyelid Wipes, Lunovus, US. Subjects used wipes on one randomly selected eye daily for 1 month. Control group: contralateral eye received no treatment. |
Demodex mite count (four lashes epilated from each eye and examined under light microscope). Ocular microbiota – bacterial colony count (swab of inferior lid margin taken, plated, cultured and CFU/mL counted). Bacterial lipase (assessed by glycerol monolaurate assay of bacterial culture). Ocular Surface Disease Index (patient questionnaire scored between 0 and 100 with higher scores meaning greater ocular discomfort). Tear film stability (assessed by Tearscope Plus non-invasive tear break up time). Tear film lipid layer thickness (assessed by Lipiview® interferometer). Tear volume (measured with Phenol red thread test in millimetres). Ocular symptoms i.e. itching, dryness and overall discomfort (assessed using VAS from 0 = no symptoms to 100 = maximum symptoms). Timepoints: Baseline and after 30 days. |
Demodex mite count sig. decreased in TTO group (median 0, IQR 2) compared with no treatment (median 2, IQR 4) after 30 days (p = 0.04). Ocular symptoms of dryness and overall discomfort both sig. decreased in TTO group, compared with no treatment (p < 0.05). No sig. difference in change between groups after 30 days (p > 0.05) for other outcomes: Ocular microbiota →Bacterial lipase →Ocular Surface Disease Index →Tear film stability →Tear film lipid layer thickness →Tear volume →Ocular symptom: itching |
No adverse events were reported throughout the study. Slight discomfort upon initial use of eyelid wipes n = 1. |
Funding: The University of New South Wales Authors state no conflicts of interest. |
| Dry eye post cataract surgery | ||||||||
| Mohammadpour; 2020; IRCT2013111313567N5 Mohammadpour et al. (2020) | RCT (parallel); Iran; Hospital clinic | N = 62 enrolled (n = 62 analysed) Age in years, mean (SD) 66.4 (8.8), range 37–82 Female 49/62 |
Inclusion criteria: signs and symptoms of dry eye after phacoemulsification cataract surgery that remained after one-month treatment with artificial tears and 1% betamethasone drops. Exclusion criteria: signs and symptoms of dry eye present prior to phacoemulsification cataract surgery; meibomian gland dysfunction; blepharitis; epithelial defects; history of trauma; uveitis; trachoma; prior ocular surgery; contact lenses; systemic disease that may cause dry eye. |
Intervention group: Eyelid shampoo (EyeSol®, Novaliq GmbH, Germany containing 1% TTO, Melaleuca alternifolia) with additional 5% TTO added + artificial tears (Artelac Eye Drops) + topical steroid drops (Betamethasone Eye Drops 0.1%). Control group: Eyelid shampoo (EyeSol®, Novaliq GmbH, Germany containing 1% TTO, Melaleuca alternifolia) + artificial tears (Artelac Eye Drops) + topical steroid drops (Betamethasone Eye Drops 0.1%) Study duration was one month. Frequency and doses of eyelid washes are not reported. |
Demodex count (assessed by microscopic examination) Refraction Corrected and uncorrected distance visual acuity Schirmer test (test strip inserted at bottom and at corner of the eye without anaesthesia to measure tear production over five minutes) Tear break-up time (calculated by observing fluorescein changes in the ocular surface) Osmolarity of tears (measured by TearLab) Ocular Surface Disease Index (patient questionnaire scored between 0 and 100 with higher scores meaning greater ocular discomfort) Timepoints: Baseline and after one month. |
Demodex count sig. lower in TTO group (0.94 ± 2.26), compared with control group (2.65 ± 3.34), after one month (p = 0.024). Tear break-up time sig. improved in TTO group (8.27 ± 3.91), compared with control group (6.55 ± 2.6), after one month (p < 0.05). Osmolarity of tears sig. improved in TTO group (291.12 ± 12.6), compared with control group (306.38 ± 10.15), after one month (p = 0.018). Ocular Surface Disease Index score sig. lower in TTO group (21.87 ± 19.09), compared with control group (31.54 ± 22.57), after one month (p < 0.05). No sig. difference between groups in refraction, corrected and uncorrected distance visual acuity or Schirmer test, after one month (p > 0.05). Note: no sig. difference between TTO and control group at baseline for any measured outcome (p > 0.05). |
Not assessed. | Authors state no funding and no conflicts of interest. |
| Meibomian gland dysfunction | ||||||||
| Zarei–Ghanavati; 2021; IRCT20201219049753N1 Zarei-Ghanavati et al. (2021) | RCT (parallel, within-patient design); Iran; Hospital clinic | N = 40 enrolled (n = 40 analysed) Age in years, mean (SD) 49.2 (21.2), range 28–70 Female 17/40 |
Inclusion criteria: age 18–70 years; diagnosed MGD (‘mainly’ based on Japanese MGD Working Group criteria). Exclusion criteria: systemic medication use affecting tear production; topical medication use (e.g., steroids) within 4 weeks prior to study; ocular surgery; other ocular or systemic disease involving ocular surface (e.g., Sjogren syndrome, chemical damage, radiation to head, etc…); infectious keratoconjunctivitis; contact lenses. |
Intervention group: TTO eyelid shampoo (EyeSol®, Novaliq GmbH, Germany containing 1% TTO, Melaleuca alternifolia). Control group: Johnson’s® baby shampoo, Johnson & Johnson. Subjects washed eyelashes and eyelid margins daily for 60–90 s using the shampoo allocated to the right/left eye and the other shampoo on the opposite eye, for three months. |
5-Item Dry Eye Questionnaire score (patient questionnaire; higher score = greater dry eye severity) Meibomian gland expressibility (scored according to number of glands from which fluid could be expressed: 0=all glands expressible, 1=3-4 glands expressible, 2=1-2 glands expressible, 3=no glands expressible) Plugging (i.e., oil droplets on eyelid margin) Capping (i.e., elevations of meibomian gland orifices) Eyelid margins: →Foamy tear →Conjunctival hyperaemia →Telangiectasia Tear break-up time (measured as interval between last blink and appearance of first dry spots on cornea) Meibum quality (scored as 0 = clear fluid, 1 = cloudy fluid, 2 = viscous fluid containing particulate matter, 3 = densely opaque, inspissated, toothpaste-like; then summed across the 8 glands tested) Trichiasis/distichiasis Oxford staining (score from 0-15; higher scores indicating more severe staining of cornea) Schirmer test (using Schirmer1 test) Timepoints: Baseline and after 1 and 3 months. |
5-Item Dry Eye Questionnaire score sig. decrease in TTO group, compared with control group, after 3 months (p < 0.001). Meibomian gland expressibility sig. reduced in TTO group, compared with control group, after 3 months (p = 0.001). Plugging sig. reduced in TTO group, compared with control group, after 3 months (p = 0.001). Capping sig. reduced in TTO group, compared with control group, after 3 months (p = 0.050). Eyelid margins: →Foamy tear sig. reduced in TTO group, compared with control group, after 3 months (p < 0.001). →Conjunctival hyperaemia no sig. difference between groups after 3 months (p = 0.187). →Telangiectasia sig. decreased in TTO group, compared with control group (p < 0.001). Tear break-up time increased to sig. greater extent in TTO group, compared with control group, after 3 months (p < 0.001). Meibum quality no sig. difference between groups after 3 months (p = 0.060). Trichiasis and distichiasis no sig. difference between groups after 3 months (p > 0.99). Oxford staining no sig. difference between groups after 3 months (p = 0.192). Schirmer test no sig. difference between groups after 3 months (p = 0.191). |
More subjects in TTO group, compared with control, complained of ocular irritation (21 vs. 12, p = 0.002). No allergic reaction or contact dermatitis observed during the 3-month treatment period. |
Authors state no funding and no conflicts of interest. |
Abbreviations: CFU, colony forming units; IQR, inter-quartile range; LogMAR, logarithm of the minimum angle of resolution; MGD, meibomian gland dysfunction; RCT, randomised controlled trial; SD, standard deviation; TTO, tea tree oil; US, United States; VAS, visual analogue scale.