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Abstract
Background/aims It is unclear whether a reduction in tear secretion contributes to the discomfort experienced by those with prosthetic eyes. Tear secretion has hitherto only been measured with the Schirmer test which may be affected by the pooling of tears behind the prosthesis. In this study, direct imaging of the lacrimal gland has been performed to measure tear secretion in anophthalmic sockets. The relation between the area of meibomian glands and dry eye symptoms was also assessed.
Methods 12 patients were included. The amount of tear secretion was measured by direct imaging of the lacrimal gland while the presence of meibomian glands was determined using meibography. The 5-item Dry Eye Questionnaire was used to assess symptoms of dry eye.
Results No difference was found in tear secretion between the anophthalmic socket and the contralateral eye. The area of meibomian glands was significantly reduced in eyelids on the side of the prosthetic eye, compared with the contralateral eye. Seven patients reported symptoms indicative of dry eye in the anophthalmic socket, compared with only two in the contralateral eye.
Conclusions The effects of an eye prosthesis on meibomian glands may contribute to the frequently perceived symptoms of dry eye despite unaffected in tear secretion.
- Tears
- Prosthesis
- Lacrimal gland
- Eye Lids
Data availability statement
All data relevant to the study are included in the article.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Many patients with prosthetic eyes suffer from dry eye symptoms in the anophthalmic socket.
WHAT THIS STUDY ADDS
This study shows that the tear secretion from the lacrimal gland is preserved while the meibomian glands are significantly affected on the anophthalmic side.
HOW THIS STUDY MIGHT AFFEXT RESEARCH, PRACTICE OR POLICY
Future treatment strategies for dry anophthalmic socket syndrome should include treatment for meibomian gland dysfunction rather than aqueous tear deficiency.
Introduction
Discharge and symptoms of dry eye are sources of discomfort for many patients with a prosthetic eye.1–6 The UK National Artificial Eye Questionnaire study revealed a significant negative correlation between comfort in the anophthalmic socket and increased use of lubricating eye drops.6 The pathophysiology behind dry anophthalmic socket syndrome (DASS) is multifactorial and studies have shown that increased conjunctival inflammation, meibomian gland dysfunction, loss of goblet cells, blepharitis, reduced tear meniscus, eyelid laxity and lagophthalmos all contribute to the condition.2 3 7–14 The diagnostic criteria for DASS are subjective symptoms of dry eye in the anophthalmic socket (Ocular Surface Disease Index≥13, modified Symptom Assessment Questionnaire iN Dry Eye without vision-related items score≥13 or 5-item Dry Eye Questionnaire (DEQ-5) score≥6), together with at least one of the following: anterior or posterior blepharitis, tear film hyperosmolarity, meibomian gland abnormalities, reduced tear meniscus, clinical conjunctival socket inflammation or conjunctival inflammation indicated by increased matrix metalloproteinase-9 levels.5
It is unclear whether a reduction in tear secretion contributes to the symptoms of dry eye and such measurements are not included in the diagnostic criteria for DASS.5 It is known that decreased corneal sensitivity results in reduced tear production in diabetic patients and after laser-assisted in situ keratomileusis (LASIK).15 16 The impact of the removal of an eye, and thus the neural input from the cornea and retina, on tear production, is the subject of debate in the literature. Shashidahr et al found no signs of lacrimal gland atrophy in a mouse model following enucleation.17 Some studies in humans have shown a reduction in tear volume in the anophthalmic socket, compared with the contralateral eye, while others have found an unchanged or increased volume.2–4 13 14 18 19 The Schirmer test has been used in all these studies and it can be questioned whether this is a suitable method of measuring tear secretion in anophthalmic sockets. A tear pool may be formed behind the eye prosthesis, especially hollow glass prostheses, which may be absorbed by the paper strip when performing the Schirmer test, making the results unreliable.4 The results of this test have been shown to bear no relation to tear meniscus height or symptoms of dry socket and is the reason Rokohl et al recommended that the Schirmer test should not be used when evaluating anophthalmic sockets.4 5
The question of whether tear secretion is affected in the anophthalmic socket thus remains unanswered. In the present study, tear secretion was measured in anophthalmic sockets using an objective imaging technology called direct assessment of tear secretion (DATS).20 The status of meibomian glands was evaluated by meibography while symptoms of dry eye were assessed using the DEQ-5.21
Materials and methods
Patients
Patients were recruited from the routine follow-up programme at the Ocularist Service in Stockholm and the St Erik Eye Hospital, Stockholm, during August 2023. Inclusion criteria were age over 18 years with anophthalmic sockets and wearing an eye prosthesis. Exclusion criteria were previous irradiation therapy, disease or medication that could affect tear production such as mucous membrane disease, Sjögren’s syndrome or anticholinergic medication.
A total of 13 adult patients were recruited. One patient was excluded due to ruthenium plaque treatment prior to enucleation. Another patient was discovered to have a phthisical eye under a shell prosthesis and was included in the meibography examination but excluded from the DATS measurements and the DEQ-5 questionnaire. In the third and fourth patient, the upper eyelids could not be fully everted and only the lower eyelids were examined with meibography. Thus, 10 patients underwent meibography on the upper eyelid and 12 on the lower eyelid. 11 patients underwent DATS and completed the DEQ-5 questionnaire. Patient characteristics are presented in table 1.
Patient characteristics
The study was carried out in accordance with the principles laid down in the Declaration of Helsinki as amended in 2013.
Procedure
The right eye was always examined first to randomise the order in which the anophthalmic socket and the contralateral eye were examined. First, DATS was performed on both eyes, as described in Section 2.3, without a topical anaesthetic. Second, the subject’s anamnesis was taken, including the DEQ-5 questionnaire (in Swedish). Third, an external ophthalmological examination was performed including assessment of post-enucleation socket syndrome, lagophthalmos, eyelid malposition and blepharitis, taking great care not to manipulate the eyelids. Fourth, DATS was repeated in the presence of a topical anaesthetic (Minims oxybuprocaine hydrochloride 0.4%, Bausch and Lomb, Surrey, UK). This ensured sufficient time between the two DATS measurements so that they would not affect each other (approximately 10 min). Finally, meibography was performed, as described in Section 2.5, including an assessment of giant papillary conjunctivitis.
Direct assessment of tear secretion
DATS was performed for the objective imaging of tear secretion. The palpebral lobe of the lacrimal gland was exposed by pulling the upper eyelid in the superotemporal direction while the patient was asked to look in the inferonasal direction. The anophthalmic side was examined with the prosthesis in place as this helped to displace the lacrimal gland anteriorly. One drop of dye, fluorescein sodium (Minims fluorescein sodium 2%, Bausch and Lomb, Surrey, UK), was then applied to the surface of the exposed gland while filming the area under illumination with blue light (wavelength 465 nm), using the fluorescein illumination mode of the OCULUS Keratograph 5M (Oculus GmbH, Wetzlar, Germany), in order to monitor the washout of dye by the tear fluid from the orifices of the excretory ducts. The area of exposed gland was recorded as a baseline measurement. Tear flow was determined by measuring the area of dye washout at 1, 2, 3, 4 and 5 s after applying fluorescein. Subsequently, the percentage of washout area was calculated by comparing these measurements with the baseline area of the exposed gland. The temperature in the examination room was kept constant at 23°C and the illumination was the same for all examinations.
DEQ-5 questionnaire to assess dry eye symptoms
The DEQ-5 questionnaire was used to assess symptoms of dry eye. This questionnaire is a validated screening tool for dry eye disease, recommended for use in scientific studies by the Tear Film and Ocular Surface Society.22 The items include questions regarding perceived eye discomfort, dryness and tearing. A total score≥6 is considered indicative of dry eye disease.21 22
Meibography
Meibography was performed using the OCULUS Keratograph 5M. Infrared photographs (wavelength 840 nm) were taken of the everted upper and lower eyelids, except in the patients where the upper eyelids could not be everted. Only the lower eyelids were examined in those patients. The area occupied by the meibomian glands was determined from the photographs and expressed as arbitrary area units (calculated as the number of pixels divided by 1000). The areas were determined separately for the upper and lower eyelids. The values obtained from the anophthalmic side were then compared with those on the contralateral side, with the normal eye serving as a control.
Statistics
Data are presented as median values and range. The Wilcoxon matched-pairs signed-rank test was used to compare the DATS and meibography results obtained from the anophthalmic socket and the contralateral eye. Significance was defined as p≤0.05. Statistical analyses were conducted using GraphPad Prism 10 (GraphPad Software, San Diego, California, USA).
Results
External ophthalmological examination
On ophthalmological examination, two patients were found to have post-enucleation socket syndrome. Blepharitis was found in one patient, on both sides. One patient had lagophthalmos and three patients had giant papillary conjunctivitis in the anophthalmic socket, but not in the contralateral eye. One of the patients with giant papillary conjunctivitis had had a recent acute onset of discharge in the anophthalmic socket which was resolved by treatment with topical steroids and mast cell stabilisers.
Tear secretion measured by DATS
No statistically significant difference was found between the amount of tear secretion in the anophthalmic socket and the contralateral eye, with or without the use of a topical anaesthetic (p=0.28 and p=0.23, 1 s after fluorescein application, figure 1).
Scatter plots of the amount of tear secretion from the lacrimal gland in the contralateral eye (blue) and the anophthalmic socket (red). Measurements of DATS were performed and quantified as a percentage 1, 2, 3, 4 and 5 s after applying the fluorescein dye, with (A) and without (B) a topical anaesthetic. The horizontal black lines indicate the median values. Statistical analysis was performed using the Wilcoxon matched-pairs signed-rank test, p>0.05 was defined as not significant (n.s.). DATS, direct assessment of tear secretion.
Meibography
The area occupied by meibomian glands in the tarsal plates was smaller on the side of the anophthalmic socket than in the contralateral eye, in both the upper and lower eyelids (p=0.027 and p=0.005, respectively, (figure 2)). A representative photograph of meibomian glands in a prosthetic eye wearer is shown in figure 3.
Scatter plots of the area occupied by meibomian glands as a fraction of the area of the tarsal plate: On the anophthalmic side (red) and the contralateral side (blue) which served as control. Statistical analysis was performed using the Wilcoxon matched-pairs signed-rank test. Significance was defined as p<0.05 (*), p<0.01 (**), and p>0.05 (not significant, n.s.).
Photographs of the everted upper (top panels) and lower (bottom panels) eyelids in a patient who had had a prosthetic eye on the left side for 23 years. Note the dropout of meibomian glands on the side with the prosthetic eye.
Dry eye symptoms assessed with the DEQ-5 questionnaire
Seven patients had a total score≥6 on the anophthalmic side in the DEQ-5 questionnaire indicating dry eye disease. Two of the seven patients had symptoms of dry eye also in the contralateral eye.
Discussion
In this study, the tear secretion has been measured in anophthalmic sockets by direct imaging of the lacrimal gland. These measurements are thus not affected by the pooling of tears behind the prosthesis as may be the case in previous measurements using the Schirmer test.2–4 13 14 18 19 The results of the present study show no difference in tear secretion between the anophthalmic socket and the contralateral eye. Interestingly, the area occupied by the meibomian glands was significantly smaller on the anophthalmic side than on the contralateral side which is in line with previous studies.8 13 Taken together, these findings suggest that meibomian gland dysfunction, but not aqueous tear deficiency, contributes to the frequent symptoms of dry eye in anophthalmic sockets.
The regulation of lacrimal gland secretion is complex. Tear secretion is stimulated by the activation of polymodal nociceptors, and, to a lesser extent, mechanoreceptors and cold receptors, in the cornea.23 24 Stimulation of conjunctival receptors does not seem to contribute to the stimulation of the lacrimal gland.23 The sensory input is modulated in the lacrimal nucleus of the brain and combined with, for example, neural signals from stimulation of other parts of the trigeminal nerve (for example, the nasal mucosa or the periocular skin/muscles), activation of the retina (photo-lacrimal reflex) and emotional input to generate graded stimulation of the lacrimal gland.25 26 Low levels of stimulation produce a sufficient amount of tears to cover the ocular surface (ie, basal tear production) while more intense stimulation increases tear production (ie, reflex tearing).25 27
Murube has shown that stimulation of one eye produces hypersecretion in the lacrimal glands of both eyes.26 It may be that the sensory input from the cornea of the contralateral eye is sufficient to stimulate normal tear production bilaterally, thus explaining why the absence of neural input from the cornea and retina in an anophthalmic socket does not influence tear secretion. It appears that corneal sensitivity must be reduced bilaterally to affect tear production, for example, in patients with diabetic neuropathy or those who have undergone bilateral LASIK surgery.16 28 In addition, the periocular skin and muscles around the anophthalmic socket are often intact and sensory input from these may contribute to lacrimal gland stimulation.
The symptoms of DASS may be caused by reduced tear quality, conjunctival inflammation or suboptimal tear distribution4 13 rather than a deficiency in tear secretion, as indicated by the results of the present study. Indeed, a significant loss of meibomian glands was seen in the eyelids overlying the prosthetic eye, compared with the contralateral eyelids, which is in line with the findings of previous studies.8 13 The meibomian glands produce the outer lipid layer of the tear film, enabling the formation of a thin, stable tear film, providing lubrication for blinking and eye movements, preventing evaporation of tears and sealing the lid margins to prevent drying during prolonged eye closure.29 A significant reduction in meibomian glands in eyelids overlying prosthetic eyes may lead to increased evaporation of tears and reduce the lubricating properties of tears. Two mechanisms that may contribute to the destruction of meibomian glands have been proposed. The first is that the mechanical rubbing of the eyelid margin over the prosthesis induces hyperkeratinisation and inflammation leading to meibomian gland dropout.8 The other is that the weakened eyelid blinking associated with prosthetic eyes leads to a reduction in meibum secretion and subsequently obstruction of the meibomian gland orifices.8 Redlich et al found markedly reduced electrical potentials in anophthalmic socket eyelids which lends support to the latter theory.30 In addition, weakened eyelid blinking together with pooling of tears behind the prosthesis may lead to suboptimal tear distribution, further aggravating the symptoms of dry eye.
In 2020, Rokohl et al reported that 63% of patients suffered from anophthalmic socket dryness.4 This is consistent with the findings of the present study where 7 out of 11 patients reported symptoms indicative of dry eye disease in the anophthalmic socket compared with only 2 in the contralateral eye. All patients with a total score on the DEQ-5 questionnaire of≥6 in the anophthalmic socket had pronounced meibomian gland dropout and therefore fulfilled the criteria for DASS.
The manipulation of the eyelids in order to prolapse the preseptal portion of the lacrimal gland to perform DATS likely increased sensory stimulation of the lacrimal nucleus. However, the investigation was performed in an identical manner on both sides and an equal number of prosthetic eyes were examined as the first and second eye. In addition, there was no difference in tear secretion when measured with and without topical anaesthesia. Sockets that had undergone irradiation therapy where the eye was lost due to chemical injury and patients with mucous membrane disease or Sjögren’s syndrome were not included in the present study and in these situations there may be a reduced tear secretion from the lacrimal gland.
Conclusions
Tear secretion by the lacrimal gland is not affected in anophthalmic sockets. However, there is a significant loss of meibomian glands in the eyelids overlying an eye prosthesis which may contribute to the frequently perceived symptoms of dryness. This should be considered in future treatment strategies for dry anophthalmic socket syndrome to successfully alleviate this troublesome problem.
Data availability statement
All data relevant to the study are included in the article.
Ethics statements
Patient consent for publication
Ethics approval
The study was evaluated and approved by the Swedish Ethical Review Authority (ref. no. 2022-05003-01). Participants gave informed consent to participate in the study before taking part.
References
Footnotes
Presented at ESOPRS full member meeting in Zell am See 2024 This study was presented at the ESOPRS full member meeting in Zell am See 2024.
Funding This study was supported by the Swedish Government Grant for Clinical Research (ALF), Skåne University Hospital (SUS) Research Grants, Lund University grant for Research Infrastructure, Skåne County Council Research Grants, Crown Princess Margaret’s Foundation (KMA), Carmen and Bertil Regnér’s Foundation, the Karolinska Institutet Grant for Eye Research, the Foundation for the Visually Impaired in the County of Malmöhus, the Swedish Eye Foundation and the Edvin Giström Foundation.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.