Delhi Journal of Ophthalmology

Update on Surgical Interventions In Management of Dry Eyes

V Anitha1, R Meenakshi1, M Vanathi2
1Department of Ophthalmology, The Institution Aravind Eye Hospital, Tirunelveli, India
2Department of Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, New Delhi, India

Corresponding Author:

Venugopal Anitha 
DNB, FAICO (CORNEA), FICO 
Senior Consultant, Cornea and Refractive Services 
Aravind Eye Hospitals & Postgraduate Institute Tirunelveli, Tamil Nadu, India
Email: aniths22@ymail.com.

Received: 10-JUN-2020

Accepted: 10-SEP-2020

Published Online: 09-JUL-2021

DOI:http://dx.doi.org/10.7869/djo.650

Abstract
Dry eye disease (DED) is an inflammatory disease with tear film instability and  hyperosmolarity. It is also a common symptom encountered in a general ophthalmology practice. The DED symptoms range from mild, moderate to severe. The Rapid Diagnosis with non-invasive techniques are possible in the out-patient clinic itself. The management includes medical and surgical, which depends on the patients' objective symptoms, subjective complaints, and the severity of the disease. Medical treatment includes preservative-free tear substitutes, oral secretagogues, topical, and systemic anti-inflammatory therapy. The surgical modalities are the treatment options in very severe disease. The severity of the disease at the time of presentation, lifestyle modifications, compliance with the treatment is associated with a better prognosis. This review provides an update with a practical approach to surgical interventions of DED with emphasis on treatment for specific disease subtype and severity of the condition.

Keywords :Dry Eyes, Surgery For Dry Eyes, Tarsorrhaphy, Punctal Plugs

Introduction
Dry eye disease (DED) is one of the common symptoms of presentation to ophthalmologist’s office. It is a growing public health concern, causing ocular discomfort, irritation, visual disturbance and fatigue, interfering with the quality of life. The prevalence of DED varies from 3.4 – 48%1 predominantly in postmenopausal women2 and is more prevalent in Asian compared to western countries.3 In 2017, the International Dry eye workshop (DEWS II)4 report revised the definition of dry eye as “It is a multifactorial disease of the ocular surface Characterized by a loss of homeostasis of the tear film and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage and neurosensory abnormality play etiological roles”. The understanding of the vicious cycle of tear film instability, hyperosmolarity and ocular surface inflammation aids in treatment for DED. The first-line therapy is medical treatment but for chronic and severe DED, surgical options play a pivotal role in management. This article reviews the advances and interventions in the surgical management of DED.

Etiopathogenesis
The appropriate understandings of the pathophysiology, risk factors and aetiology of DED have led to better treatment strategies in the last decade. Dry eye is divided into two groups, 1) aqueous production deficient dry eyes 2) evaporative dry eyes. Insufficient or unstable tear film causes hyperosmolarity, key factor for release of inflammatory mediators, causes damage to DNA repair system, reduces epithelial cell volume, increases apoptosis and oxidative stress5. The inflammatory event involves release of numerous mediators such as, Matrix metalloproteinases (MMP) – MMP-9, MMP-13 and MMP-14, TNF-a, Mitogen- activated protein kinase, over expression of interleukins(IL)-1 ß, IL-6, IL-17, IL-22, INF-gamma, chemokines (C-Cmotif) ligand 2 (CCL2). They are responsible for the cascade of events, leading to further ocular surface damage and lacrimal unit dysfunction (figure 1).5,6 Management is complex due to multiple risk factors and the overlapping of etiological factors associated with DED. The risk factors for DED6 are as follows:


Figure 1: Pathogenesis of DED

1. Older age
2. Female sex
3. Sex hormones dysregulation- reduce tear secretions, causes meibomian gland (MG) dysfunction and reduce goblet cell density
4. Long term contact lens wears
5. Refractive surgeries and cataract surgery
6. Smoking
7. Diet low in omega-3 EFA and high ratio of omega 6:3 EFA 
8. Low humidity conditions – office environment, air-conditioned cars, airplane cabins, extreme hot or cold weather
9. Alcohol consumption 
10. Systemic drugs –Antihistamines, beta-blockers, oral Contraceptive pills
11. Chronic use of topical drops with preservatives- Antiglaucoma, anti-inflammatory etc
12. Following allogenic hematopoetic stem cell transplantation – ocular Graft versus Host Disease (oGVHD)
13. Extended visual tasking like prolonged reading, computer and television use.
14. Associated with anxiety disorders, sleep disorders and depression

The diagnosis of DED can be done in outpatient clinic. The evaluation of severity is done by the following tests:
Tear film break-up time (TFBUT) - a measure of Tear film stability. 
Conjunctival and Corneal Staining with either rose Bengal, lissamine green or and fluorescein stains for assessment of ocular surface dessication. 
Measuring tear volume – Schirmer’s test and Tear film meniscus height. 
Quality of tears is assessed by measuring osmolarity 5.

The diagnosis of DED is confirmed by the presence of subjective symptoms with OSDI score of >13 and objective DED signs in worse eye with TFBUT < 10sec, Schirmer’s test < 5 mm and corneal staining grade >1. 7

The common laboratory tests are, mucus ferning test, conjunctival impression cytology, tear film interferometry, tear film osmolarity, tear lysozyme, lactoferrin levels, tear protein electrophoresis, tear glycoprotein and immunoglobulins.7-10

Management
DED treatment requires multipronged approach including life style modifications, tear conservation, tear replacement, anti -inflammatory drugs and surgical approaches. The Dry eye society of Japan, proposed etiology oriented protocol known as “Tear Film – Oriented Therapy” (TFOT), which recommends replacement of deficient tears with the artificial tears accordingly (Table 1), this concept of TFOT was discussed and accepted in the meetings held by ADES (Asian Dry Eye Society) and TFOS ( Tear Film and Ocular surface Society).11 



The ultimate aim of treatment12,13 (Flowchart 1)14,15 are to:
1. Restore homeostasis of the ocular surface 
2. Break the vicious cycle of inflammation 
3. Ensure long term ocular surface stability


Flowchart 1: Aim of current treatment approaches

Although medical therapy is the mainstay of treatment, to reduce the inflammation and ocular surface damage but the chronicity, progressive nature of the disease and overlap of symptoms of different DED types, necessitates surgical options in certain scenarios.16 The major disadvantages of medical therapy are chronic use of drugs; preservatives induced ocular surface toxicity, compliance to treatment, the economic burden due to frequent follow-up visits, medical costs involved, eye drop contamination and ocular surface infections.
The recommendations for management of DED17 are elaborated in (Table 2). The indications for surgical interventions in DED management are severe dry eyes associated with systemic diseases, autoimmune disorders, and DED refractory to medical therapy, corneal epithelial defects, ulcerations, delayed epithelial healing, lacrimal gland diseases, chronic end-stage inflammation and scarring conditions of ocular surface and dry eyes following severe chemical burns.



The various surgical approaches of DED can be considered primarily in Four groups 
1) Procedures to avoid rapid loss of natural tears 
2) Procedures which provides lacrimal substitutes 
3) Neural stimulation of lacrimal tears 
4) Miscellaneous

The various intervention procedures involved in these are detailed in the following section.18 

1. The procedures to avoid rapid loss of natural tears include: 
a) Occlusion of upper lacrimal pathways 
Occlusion of upper lacrimal pathways which retains the lacrimal pool can be done by: Dacryocystectomy, Canalicular excision, Canalicular strangulation, Canalicular glavanocauterisation, Diathermy, Chemical caustication, Punctal/Canalicular plugs, Punctal patching, Punctal suturing, “Dome” Cisternoplasty.
b) Lid procedures
Tear Evaporation is delayed by Blepharoptosis, Tarsorrhaphy and AMG

2. Procedures for providing lacrimal substitutes: 
Minor and Major salivary gland transplantations
Parotid duct transplant
Dacryoreservoirs
Lubricating inserts
Valved aqueous tube shunts

3. Lacrimal tear stimulation treatments: 
True tears (Newer modality)
Tear Implants
Corneal Neurotisation
4. Miscellaneous: Conjunctivochalasis (CCH) excision 

PUNCTAL / CANALICULAR OCCLUSION
Enhanced retention of tears on the ocular surface can be achieved by blocking the pathway for tear clearance and drainage. This is indicated in patients refractory to medical therapy, Schirmer’s test < 5 mm at 5 min and positive ocular surface staining. Temporary and permanent methods are available (Table 3) and the choice depends on the severity of the disease.



Punctal Plugs
The indications for punctal plug insertion in DED include dry eye syndrome19,20, filamentary keratitis,21 contact-lens related dry eyes,22 chronic SJS,23 severe trachoma,24 neurotrophic keratopathy,25 post penetrating epithelial defects, photorefractive procedures - PRK/LASIK. 
The use of punctual plugs is beneficial in DED as they help to prevent the drainage of aqueous tears, and topical medications via the nasolacrimal drainage system, thereby beneficial in increasing effect of the medications. This is a relatively safe, out-patient procedure, and can be easily inserted, with minimal side effects and few complications.
Punctal plugs can be categorized into absorbable plugs and non-absorbable plugs.
1. Absorbable plugs are made of catgut, gelatin, hydroxyl propyl cellulose and collagen plugs, being absorbed within a short period, are effective for short term use (3 days to few weeks).
2. Non- absorbable plugs are intended for long term occlusion, with the insertion being slightly difficult. They are made of silicone, teflon, hydroxyl ethyl methacrylate (HEMA), polyethylene and PMMA. Some of the commonly used plugs include Freeman style plug, Herrick lacrimal plug and Smart plug.

The method of removal is different; both smart plugs and Herrick lacrimal plugs26 (Figure 2 & 3) can be flushed into the lacrimal passage, Freeman style plugs can be removed with the special forceps as they lie on the surface of the puncta.27 Comparative study of punctual plug with artificial tears in trachoma patients showed improvement in signs and symptoms with the use of plugs. There are few concerns associated with non- absorbable plugs.28 Epiphora and ocular surface irritation are common with Freeman style plugs. Epiphora necessitated removal of 5.4% of plugs among 203 eyes19. Extrusion and internal migration of Freeman style plug has been reported to be high, as they are located in the surface (extrusion rate 29-50.7 %). Internal migration is rare, and it may occasionally migrate into the canaliculus, 44% of the patients have been reported to be positive for staphyloccous species with punctal plugs.29 Bacterial colonisation can occur in the plugs with increased duration. Other uncommon complications include acute conjunctivitis, canaliculitis and dacryocystitis, pyogenic granuloma, canalicular stenosis and punctual scarring.30-34 Decrease in tear film osmolarity has also been reported.35 Improvement in goblet cell density with use of punctal plugs seems to be controversial.36,37 Other permanent methods of punctual occlusions include punctal cautery, laser, diathermy and incisional surgery.





Different surgical techniques described to occlude tear drainage include canalicular ligation, canalicular off-set, canalicular excision, punctual tarsorrhaphy, Punctal patching with autologous conjunctiva, AMG, or Tenon’s patch38 and canaliculectomy.39 Canalicular off-set40 comprises of applying galvanocautery to the canalicular openings after dissection into the freeborder of the lid medial to punta, lid sutures applied to reappose the wound with an offset of the two openings of the lacerated canaliculus. Canalicular excision41 involves excision of the canaliculi through the cutaneous incision over the lid 2 mm medial to the punctum, after introducing the lacrimal probe as a guide, wound sutured. Puntum closed with diathermy. Canalicular ligature is an effective and permanent method of occlusion of lacrimal pathways. The surgical steps involved in canalicular ligation are shown in (Figure 4a-4c).42 






The canalicular surgeries are effective than the cautery due to its high (50%) failure rates and laser (86%). It is necessary to destroy the deeper part of lacrimal punctum and canaliculus for better and long term results. In patients with recurrent plugs extrusion, Yaguchi et al used high temperature disposable cautery device for punctual cauterization and observed it to be safe and effective without complication of recanalization.

Dome Cisternoplasty
Dome cisternoplasty is an easy technique to enlarge the natural lacrimal cistern.44 This procedure does not increase the production of tears but enhances the retention and distribution of artificial tear drops thereby increasing the time interval between two instillations of artificial tears. The volume of a normal lacrimal basin is 7µl. A drop of artificial tears is 30µl and overcharges the lacrimal pool, five minutes after instilling the drop, the lacrimal pool returns to 7 ul. The Cisternoplasty procedure quadruplicates the content of the lacrimal basin and the time of retention. The surgical procedure is illustrated in the (Figure 5a-5e).



Tarsorrhaphy
Tarsorrhaphy (Figure 6) promotes healing of corneal surface in persistent epithelial defects (PED) secondary to exposure keratitis, neurotropic keratitis and DED. Tarsorrhaphy and AMT seem to have equal efficacy in management of PEDs but faster healing time has been reported with tarsorrhaphy, with a success rate of 80-100% for ocular surface healing.45 Tarsorrhaphy decreases the evaporation rate of tears by decreasing the palpebral fissure width. The exposed cornea is in close contact with accessory lacrimal glands facilitating redistribution of tears, reducing the traumatic effect of the moving lids on the healing epithelium, promoting oxygenation and allowing instillation of eye drops with added advantage of retention of partial eye sight and examination of cornea.46-49 Complications of tarsorrhaphy, include localised trichiasis, lid margin deficiency, suture granulomas, focal cellulitis, premature separation of tarsorrhaphy, cheese wiring of suture, distichiasis and skin breakdown. 



Amniotic membrane grafts
The uncontrolled inflammation in dry eyes leads to delayed ocular surface healing, progressive tissue damage and vision threatening complications such as scarring and haze. The amniotic membrane grafting (AMG), controls inflammation and rehabilitates the ocular surface. AMG acts as a therapeutic bandage & keeps eye moist, controlling ocular surface inflammation by inducing apoptosis of neutrophils, monocytes and macrophages and promotes epithelial healing by retention of tears and regeneration of corneal nerves.50

There are two types of AMG 50, 51 
1. Cryopreserved AMG (CAM): PROKERA (Slim, Bio-tissue, Miami, FL, USA) and 
2. Dehydrated AMG: Amnio Disk (Katena), BioDoptix (Integra life science).

The efficacy of PROKERA for DED and neurotropic keratitis has been widely explored.50-54 Common indications for AMG include epithelial nonhealing/persistent defects, filamentary keratitis, exposure keratitis and neurotropic keratitis. CAM was shown to effect improvement in 88 % cases in 5.4 ± 2.8 days without adverse events, with only 10% requiring repeat procedures. It was also observed to significantly increase corneal nerve density and reduce dry symptoms for 3 months 51 CAM has also been noted to be efficacious in immune mediated DED with symptomatic and visual acuity improvement.55 

Dacryo reservoirs
Dacryo reservoir, first suggested by Murube et al,56 is a mechanical device designed to deliver artificial tears to ocular surface through interpalpebral fissure, subcutaneous tunnels in the temple and anterior abdominal wall (Figure 7), that ensures continued lubrication of ocular surface. It is useful for patients with severe dry eyes, requiring frequent instillation of eye drops every 5-10 minutes. Previously these reservoirs were attached to spectacles or placed in the pockets of patients clothes and were not in popular use, due to the associated discomfort during physical activities and frequent infections. Later these devices were placed in the subcutaneous tunnels created in the temple. Murube’s abdominal pump dacryo reservoir57 gained importance due to its increased comfort. The titanium box containing the artificial tears is fixed to the abdominal wall and delivers tears through a silicone catheter that ascends subcutaneously along the chest, neck and temple. It exteriorizes into lacrimal basin in upper conjunctival cul-de-sac and thus avoids skin penetration. Complications that can occur include skin ulceration, infections and loosening of titanium box.



Double tube Valved shunts for aqueous diversion
In chronic, end-stage inflammatory and scarring conditions of the ocular surface such as OCP, SJS, GVHD and severe chemical burns, with totally dry keratinised corneas, specially designed double–tubed valve shunt [New World Medical, Inc (Rancho Cucamongo, CA)] have been implanted to divert aqueous humour to the inferior fornix, thereby wetting the eye.58 

Salivary gland transplantation
The composition of saliva and tears are similar in its complexity and in several specific parameters. The albumin, immunoglobulin’s, growth factors, mucins and lipids in saliva, are present in tears too. The amylase in saliva is not found to cause deleterious effect to ocular surface. The actively fluid secreting tissues such as mucosa and glands (both minor and major salivary glands) are the viable option to provide sufficient volume of substitute for lubrication. The major salivary glands are submandibular and parotid.59,60 The minor salivary glands are labial, buccal and palatal glands.

Major salivary gland transplantation: When tear deficiency in cicatrizing ocular surface disorders such as SJS, OCP is absolute, the only beneficial option is transplantation of salivary glands. An autologous submandibular transplantation (SMGT) can be done in the temporal fossa and anastomosed to the superficial temporal artery and vein, and the excretory duct is implanted into upper conjunctival fornix  (Figure 8). This enables continuous and sero-mucinous fluid lubrication which is similar to the tears. Long term (5 years) results of SMGT, shown improvement of discomfort, tear film parameters (Schirmers test), ocular surface parameters (Corneal & Conjunctival staining patterns) and decreased the need for tear substitutes.61 The limitations include long duration of surgery, need for general anesthesia, 20% failure rates, infections, stenosis of the duct, microcystic corneal edema sometimes overproduction of tears requiring Botox injections.



The minor salivary gland transplantation (MSGT) also provides sufficient quantity of tears and for long duration and was first conceived by  Murube J et al.62 MSGT is a less cumbersome procedure which comprises of transplantation of about 12- 15 minor salivary glands from the lower labial mucosa or buccal mucosa to the upper and lower forniceal region. This enables increase in surface lubrication, moderate to significant reduction in dry eye symptoms 62 with reported graft survival rate of 90 - 97% over a follow-up ranging from 3 to 4.5 years.63 The secretion is more viscous than tears with seromucinous consistency, rich in IgA, growth factors. The reported complications include ptosis and infections.65

Lubricating inserts 
The hydroxypropyl cellulose inserts are well known devices used as once a day insert in the inferior cul-de-sac. These are sterile, preservative free, water soluble and slow-release lubricants, indicated in moderate to severe dry eyes and in patients not willing or cannot use artificial tears at frequent basis.66 They afford good improvement with once a day dosage without any severe side effect of blurred vision14. 

Corneal Neurotisation
Normal corneal sensation is essential for the maintenance of structure and function of corneal epithelium, for the normal blink reflex, for maintenance of lacrimal neural reflex for tear secretion and for wound healing ( Flow chart 2).67 



Corneal neurotisation is a revolutionary technique showing promising results for neurotrophic corneas, as almost 1.5% of the fibres exiting the trigeminal ganglion supply the cornea making it the most sensitive organ in the body.68 The corneal sensation recovers after six months of procedure. In this procedure healthy donor nerve graft is transferred to corneo-limbal area, which re-establishes the sub-basal plexus regeneration and reverses the neurotrophic disease.69,70 In 2009, Terzis et al reintroduced this technique with the treatment of unilateral facial nerve palsy, in which 5 out of 6 patients had improved corneal sensation after 6 months of procedure as confirmed with esthesiometry.71 Jacinto et al in 2016 used ipsilateral supraorbital nerve for his patient with neurotic cornea following ocular surgery and photocoagulation.72 Leyngold et al had first attempted endoscopic contralateral nerve transfer of frontal nerves, which saved the surgical time and healing time with favourable outcomes in Herpes zoster patient in 3 months duration.73 Later, Jowett et al harvested the great auricular nerve using endoscopy.74 The great auricular nerve was used as an interposition graft (indirect nerve transfer) as end to end anastomosis to ipsilateral supratrochlear nerve. Elbaz et al used the sural nerve to the contralateral supratrochlear or supraorbital nerve.75 Allevi et al had used contralateral supratrochlear and supraorbital nerves for anesthetic corneas.76 

Corneal neurotisation procedures can be considered under two headings:
1. Direct nerve transfer. 
2. Indirect nerve transfer. 

This procedure is gaining importance in treatment of neurotrophic corneas due to various causes such as congenital causes, herpes zoster, cerebello-pontine angle tumors, severe dry eye disease needing keratoplasty or keratoprosthesis in future.77,78 This procedure needs a multidisciplinary approach and longer surgical time, and is a budding revolutionary technique, showing promising results for end-stage disease.

Newer treatments for stimulation of tears
The future developments in the treatment of DED aim at stimulation of lacrimal tears through neural mechanism.79 “Onions” are known to cause reflex lacrimal tear secretions. Few devices are being made to stimulate the nasal mucosa for reflex lacrimal tear secretion. True tear is one such device, which is a hand held stimulator inserted into the nose to stimulate nerves which produces tears. US FDA has approved this device since 2017. Another device is the “Implantable Neurostimulator” devised by Michael Ackermann. A tiny wireless implant developed by Oculeve Company, sends micro-electrical pulses to lacrimal gland when implanted under the skin above the upper eyelids. It can also be placed in the nasal mucosa. This device is under clinical trial.80

Miscellaneous
Conjunctivochalasis (CCH) is the redundant , loose, non-edematous bulbar conjunctiva interposed between globe and eyelid. It is often bilateral, unrecognised condition, occurring in inferior bulbar conjunctiva. The prevalence rate is 44.8% in those over 60 years of age.81 It is considered as the most important differential diagnosis and also a cause for of dry eyes. It causes tear film instability and mechanical occlusion of lower punctum by excess conjunctiva as well as delayed clearance of tears, thereby causing symptoms of dry eyes. About 50% of patients with CCH have been reported to have  dry eye symptoms with reduced Schirmer’s test and TBUT values  It is important to diagnose and differentiate CCH from DED (Table 4). Inflammation is the common etiological factor in both these conditions 83with elevated pro MMP-9 levels been documented in CCH 84. The association of cytokines with CCH and dry eye symptoms has been widely reported.82-88 The treatment options for CCH are elaborated in (Table 5). 





Role of Nerve growth factors in dry eyes 
The Concept of Nerve growth factor (NGF) was introduced by Samii in 1972.89 It stimulates CNS to secrete acetyl choline and PS to produce substance-P, which activate tropomyosin receptor kinase A and p 75 neurotrophin receptors expressed on the corneal epithelial cells and sensory neurons. They stimulate goblet cell differentiation and mucin release. NGF/ Cenegermin,90 is a polypeptide discovered in the early 1950 s by Levi-Montalcini. It is a naturally occurring protein responsible for the development, maintenance and survival of nerve cells. NGF originally developed for neurotrophic keratitis, also has a promising role in treatment of dry eyes. It promotes: 

1. corneal epithelial healing, 
2. restores sensitivity 
3. increases tear production 
4. increases goblet cell density 
5. promotes nerve regeneration after injury 91.

Oxervate is a recombinant version of NGF, discovered by Dr Rita levi-Montalchini of Italy. It is available at 20µg/ml and 4µg/ml concentration.91 Both the doses have been found to be safe and effective in improvement of signs and symptoms of dry eyes in the phase IIa trials conducted in Austria.92 Several other newer biological agents are also under trial for treatment of neurotic corneas and DED. These include epidermal growth factor, IGF-1, substance-P derived pepetide-amide, vascular endothelial growth factor, Semaphorins, Neurotrophins 3&4, Growth associated protein-43, Matrix therapy agent (RGTA).93,94,95 Pergolide, a dopamine receptor agonist, has been evaluated for its function in promoting NGF expression, corneal wound healing and corneal nerve regeneration in cornea scratch mouse model.96

Conclusion
Dry eye is a multifactorial disease of tears and ocular surface. The complex pathophysiology and overlapping symptoms of DED, makes the choice of treatment difficult, although a variety of treatment modalities are available. The selection of treatment depends on the patient’s subjective complaints, objective symptoms, history of systemic diseases and thorough clinical evaluation of the patient. The medical management is usually chosen for mild-moderate DED. The patient with severe symptoms and extreme ocular surface damage necessitates multiple approaches, combining both medical therapy and surgical treatment.  In recent times, surgical treatment for dry eyes has improved the quality of life in many patients. The newer developments like corneal neurotisation have revolutionised the field of ophthalmology. Customised treatment for dry eyes in every patient has shown resolution of symptoms.

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