Therapeutic Keratoplasty

Anatomy and Physiology

Anatomy

The corneal tissue is composed of cellular and acellular components. The cellular components comprise epithelial cells, keratocytes, and endothelial cells. The acellular component is composed of collagenous protein and glycosaminoglycans.[14] The epithelial cells originate from the epidermal ectoderm, and the keratocyte and endothelial cells are derived from the neural crest. The cornea comprises five layers epithelium, bowman's, stroma, Descemet, and endothelium.[15]

Recently sixth layer has also been defined as Dua's layer, which is also labeled as the pre-descematic layer. In anterior lamellar keratoplasty, the area of focus is the anterior stroma, and in cases with posterior lamellar keratoplasty, the area of focus is Descemet and endothelium. Penetrating keratoplasty is a technique where the full thickness of the host cornea is trephine and replaced by a full-thickness donor button. All the cornea layers are transplanted. In cases with lamellar patch graft, the corneal tissue up to the anterior stroma is dissected, and the partial thickness donor button is sutured to the host rim.[16]

Physiology

Ocular Immune Privilege

Active

There is an increased expression of inhibitory cell surface molecules- FAS ligands, decay accelerating factor, CD46, and CD59. The presence of an immunosuppressive microenvironment also leads to the expression of transforming growth beta (TGF-B), Alpha melanocytic stimulating hormone (a- MSH), Vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), migration inhibitory factor (MIF) and free cortisol.[17]

Passive

Passive immunity contributes to the blood tissue barrier, deficient efferent lymphatics, and reduced MHC complex I and II expression.[18]

Indications

Infectious Keratitis

Fungal Keratitis

• Not improving (refractory) after maximal medical therapy; usually, the window period is 2 weeks. However, early keratoplasty is usually indicated in specific scenarios after 7 to 10 days.
• Corneal perforation
• Scleral involvement[19]
• Rapid corneal melt
• Non-compliance with medications or failed medical therapy
• Descemetocele[20]

Bacterial Keratitis

• Not improving (refractory) after maximal medical therapy; usually, the window period is 2 weeks. However, in specific scenarios, such as pseudomonas keratitis, early keratoplasty is indicated usually after 7-10 days.[21]
• Descemetocele
• Corneal perforation
• Limbus to limbus corneal involvement
• Corneoscleral abscess
• Non-compliance to medications
• Resistant to conventional therapy
• Mycobacterial keratitis
• Infectious crystalline keratopathy

Pythium Keratitis

• Descemetocele[22]
• Corneal perforation
• Early limbal spread
• Peripheral guttering
• Corneal melt[23]
• Not improving (refractory) after maximal medical therapy. The widow period is usually less than 7 to 10 days.[24]
• Graft reinfection[25]
• Nonresolving endoexudates[26]

Acanthamoeba Keratitis

• Descemetocele
• Corneal perforation
• Severe scleral involvement
• Non-resolving keratitis with maximal medical therapy[27]

Viral Keratitis

• Herpes simplex keratitis
• Herpes zoster keratitis
• Secondary bacterial infiltrate with corneal melt
• Corneal perforation[28]

Others

• Neurotrophic keratitis[29]
• Corneal melt due to thermal injury
• Corneal perforation secondary to keratoconjunctivitis sicca
• Neuroparalytic keratitis[30]
• Exposure keratopathy with corneal perforation
• Persistent epithelial defect leading to perforation

Equipment

• Side port 15-degree blade or MVR blade
• Screw speculum
• Corneoscleral fixation- Flieringa ring
• Ophthalmic Viscosurgical Device
• Normal saline or balanced salt solution
• Conjunctival forceps
• Conjunctival scissors
• Vannas scissors
• Trephine
• Lim's forceps
• Rhexis forceps
• 26 G needle cystitome
• Bimanual irrigation and aspiration Simcoe cannula
• Graft punch
• Cornisol solution
• Topical betadine
• Injection moxifloxacin
• Injection voriconazole
• Automated anterior vitrectomy
• Suture holding forceps
• McPherson forceps
• Suture-tying plane forceps
• 10-0 nylon monofilament suture
• 9-0 nylon monofilament suture
• Cotton bud
• Cotton swab
• Fluorescein dye

Personnel

The ophthalmic surgeon performs the preoperative medical management, surgical planning, keratoplasty, and postoperative management of these patients—the nursing staff in the outpatient department. The nursing staff in the operation theatre, counselor, and pharmacist play crucial roles in patient management.[31]

Preparation

Preoperative patient preparation is extremely critical while planning and attempting keratoplasty.

Ocular Examination

Torch Light Examination

Detailed torch light and slit lamp evaluation are mandatory in each case. Torchlight examination helps grossly assess ocular motility, the presence of any strabismus, and adnexal pathology.[32]

Anterior Segment Assessment

A detailed anterior segment examination is mandatory to assess the extent and depth of infiltrate, extent of corneal involvement, limbal involvement, anterior chamber depth, presence and absence of exudates, iris, pupil, and lens status if visible.[33] The corneal involvement should be documented photographically with dimensions of the corneal infiltrate, which help plan the trephination size intraoperatively. The corneal should be examined meticulously to assess any site of corneal perforation and iris prolapse. In doubtful cases, Seidel's test with topical fluorescein can also be performed on the slit lamp.[34] The anterior segment should also be assessed for anterior chamber inflammation, cells, flare, and exudates. It is also essential to rule out secondary glaucoma, scleral abscess, scleritis, endophthalmitis, and dry eyes.

Posterior Segment Assessment

Usually, the posterior segment assessment is masked by the corneal infiltrate, but a dilated fundus assessment can still be attempted.[35] Regarding B scan evaluation, there are two schools of thought. One is A and B scan should be done to rule out endophthalmitis when the fundus is not visualized in these cases.

Another school of thought is that B scan should be avoided preoperatively to avoid cross-transmission of infection and instruments becoming unsterilized. Postoperatively when the patient has undergone TPK, the retina will be better visualized, and a B scan can be attempted to assess the status of the retina. If retinal intervention is needed can be done as a staged procedure post-TPK. Endophthalmitis risk is higher in long-standing chronic infection, aphakia, and corneal perforation patients who have undergone cataract extraction previously.[36]

Preoperative Antimicrobial Therapy

All patients should be treated with preoperatively topical and systemic antimicrobial therapy in required cases. Targeted antimicrobial therapy is warranted when the etiology is known to reduce the virulence of microorganisms and the microbial load.[37]

Broad-spectrum antimicrobial therapy should be given in cases where etiology is doubtful and not labeled. Donnenfeld et al. proposed that topical ofloxacin (0.3%) should be used hourly for patients prepared for TPK to prevent the risk of secondary bacterial infection irrespective of the etiology. They also proposed that a tablet of ofloxacin 400 mg should be used 12 hours before admission, and intravenous vancomycin and tobramycin should be given after admission. As per significant studies, topical steroids should be avoided because it worsens the infectious process.[38]

In contrast, one of the studies recommended the use of topical and systemic steroids in cases with fungal keratitis. Besides antibiotics, antifungals such as natamycin, Itraconazole, and voriconazole are used in patients with established fungal etiology. The other adjuvant drugs needed are topical timolol and homatropine.[39]

Corneal Scraping

Gentle corneal scraping should be done in all cases when the patient first presents to the clinical outpatient setting. This helps in knowing the etiology and prescribing targeted antimicrobial therapy. Smear and culture analysis should be performed wherever possible. The culture report can be assessed after 48 to 72 hours. Preoperative culture reports give an idea regarding postoperative antimicrobial regimen and deciding on when to start steroids.[40]

Preoperative Intravenous Mannitol

Preoperative intravenous mannitol 50-100 ml should be given as a routine in all cases undergoing TPK to decompress the vitreous and reduce positive vitreous thrust while performing surgery.[41] The contraindications for intravenous mannitol, such as anuria, kidney disease, pulmonary congestion, pulmonary congestion, severe dehydration, active intracranial bleeding, progressive heart failure, and mannitol hypersensitivity, should be ruled out before injecting the drug. In cases where mannitol injection is not possible, oral glycerol of 20 to 30 ml can be given to the patient.[42]

Technique or Treatment

TPK is one of the most difficult ophthalmic surgeries as surgery is performed in an inflamed and open globe. TPK should be attempted by an experienced surgeon with good exposure to performing keratoplasties.[43] The surgery is usually performed with local anesthesia; general anesthesia is also required in selective cases. If the block is inadequate, it invites intraoperative complications. Depolarizing agents should be avoided as they can increase intraocular pressure in an open globe.[44]

Before the surgery, the donor tissue should be available, and the count and storage condition should be checked. The tissue is made available from the eye bank. The corneoscleral rim from the donor's eye should be stored in 4 C McCarey-Kaufman, Cornisol, or chondroitin sulfate-containing media having gentamicin.[45]

The criteria for TPK storage are not as strict as for a graft with optical penetrating keratoplasty quality. In case of tissue shortage, the cryopreserved or glycerin-preserved cornea and sclera have been suggested. A good quality donor tissue in TPK also helps in visual rehabilitation in TPK. The integrity of healthy corneal tissue has inherent advantages, such as the epithelium remaining intact and the risk of infection is minimized. A clear graft also helps to assess the anterior chamber reaction during the postoperative period.[46]

Lid Speculum or Sutures

A good self-retaining speculum of the lid or lid sutures helps prevent pressure on the globe.[47]

Scleral Fixation Ring

Scleral fixation rings like the Flieringa ring provide structural support and make the surgery easier. Killingsworth suggested that the scleral fixation ring should be avoided as it makes suturing difficult when the globe is hypotonus. The use Flieringa ring is variable and varies from surgeon to surgeon and center to center.[48]

Conjunctival Peritomy

In cases with large or eccentric grafts, conjunctival peritomy is recommended to avoid passing the suture through the conjunctiva. In my cases, practitioners rarely attempt a peritomy because if taken care of and the needle direction is kept right, the suture passes through the sclera. Peritomy becomes mandatory in cases with the scleral extension of the infectious foci to avoid cheeses wiring of the scleral tissue. Cautery can be done in cases where there is excess bleeding.[49]

Paracentesis

A small initial paracentesis in the accessible area is recommended. It has a few advantages. First, it reduces the intraocular pressure in cases with secondary glaucoma, second anterior chamber exudates can be drained through the paracentesis, and third viscoelastic can be put which helps push the iris lens diaphragm backward and helps in good trephination, which prevents injury to the iris.[50]

Host Trephination

Before trephination, the size of the infiltrate is measured with the help of calipers, and subsequently, the infiltrate with a 0.5 mm free margin of the cornea is marked with the use of ink. A central dot over the central portion of the cornea, followed by eight subsequent markings, is done in the peripheral cornea. Next, the sharp edge of the trephine is ink marked, and after aligning the trephine with the markings over the cornea, the recipient bed is trephined partial thickness.[51]

Care should be taken to avoid excess pressure over the recipient bed as it can damage the iris lens diaphragm and may lead to the extrusion of intraocular contents.[52] Trephination becomes problematic in cases with more extensive perforation as it is hypotony due to zero IOP, and pressure cannot be applied with the trephine over the recipient bed. In such scenarios, free hand dissection is attempted, or vacuum trephine is used. One of the previous studies suggested that in cases with central and peripheral larger corneal perforations, Hessberg Baron and Hanna suction trephines are easier to use than Franceschetti-type free blade trephines.[53]

The advantage of suction trephines is that lower incidence of shallowing of the anterior chamber and iris prolapse compared to free blade trephines. Suction trephines help to provide peripheral support and counter traction with the advancing blade, whereas the free blade trephines depend totally on the stability of the cornea, which is minimal in cases with perforation. As per the literature, the Hanna trephine is comparatively easier to use than the Hessberg Baron trephine as it provides a wide ring of peripheral suction, resulting in less central corneal distortion and holding the cornea in a more natural configuration. The trephines can be disposable as well as reusable. The disposable ones are readily available. Rao et al. suggested using cyanoacrylate glue or a patch graft in perforated eyes. They also suggested freehand dissection in cases with extensive perforation or entire corneal involvement.[54]

Graft Size

Graft size depends on the size of the infiltrate. Usually, the donor corneal button size is kept 0.5-1mm larger than the recipient trephined bed. Small grafts, eccentric grafts, and patch grafts have inherent disadvantages, such as sutures obscuring the visual axis and causing crowding of the anterior segment. Large grafts are more prone to graft rejection, failure, and post-keratoplasty glaucoma (peripheral anterior synechiae formation and synechial angle closure).

The size of the trephine usually varies from 7.00 mm to 12.00 mm. The important goal is removing the diseased host rim even if the graft size is larger. After trephination, the recipient should be divided into two parts and sent for microbiological and histopathological analysis. The material can be inoculated in blood agar, chocolate agar Sabouraud's dextrose agar, brain heart infusion broth, and non-nutrient agar with E.coli.[44]

Anterior Chamber Entry and Management

After marking the recipient bed with a trephine, anterior chamber entry is done with the help of a side port blade; subsequently, a 360-degree host cornea is excised. Once the diseased corneal portion is removed, the anterior chamber exudates, and purulent and fibrous membranes are removed with the help of forceps or can also be irrigated slowly. The iris is cleared of membranes, and occasionally the iris can bleed. Efforts should be made to minimize bleeding from the iris surface. Various authors have suggested using intracameral antifungals and antibiotics to irrigate the iris surface and reduce the infective foci.[55]

Peripheral Iridectomy 

This is followed by peripheral iridectomy. Some authors perform one; some perform two iridectomies to prevent pupillary block glaucoma postoperatively. Care should be taken to avoid damage to the anterior lens capsule and the lens. There can be torrential bleeding sometimes after performing an iridectomy. The bleed can be controlled with gentle irrigation or minimal adrenaline.[8]

Lens Management

The recommendation is to preserve the lens in most cases as it acts as a barrier against migration of infection to the posterior segment and vitreous. Donnenfeld recommended 2% pilocarpine over the iris surface in phakic and pseudophakic patients to preserve the iris lens diaphragm and prevent spontaneous lens expulsion.[1]

The following case scenarios are based on the author's recommendations for lens management. 

• In an elderly patient with a hard cataract and no retro iris exudates, lens removal can be attempted, and the posterior capsule should be preserved. This helps push the iris lens diaphragm backward, opens up the angle, and helps prevent synechial angle closure glaucoma postoperatively.
• In another case scenario, if there are retroiris exudates and the lens is cataract, lens removal should be performed to prevent the recurrence of infection, and it also helps in anterior chamber formation.[56]
• In cases with lens abscess, the lens should be removed.
• In pseudophakic patients with endophthalmitis, the IOL should be explanted. The lens should be preserved in patients younger than 50 with early cataracts and no retroiris exudates.[57] The lens acts as a barrier, and the accommodation and visual function is retained.[58]

Open Sky Vitrectomy

Automated anterior vitrectomy is recommended in cases with spontaneous lens expulsion and posterior capsular breach to remove the prolapsed vitreous. Intravitreal antimicrobials should be injected in these cases. The vitrectomy should be prompt and meticulous to prevent the risk of expulsive choroidal hemorrhage. A vitreous tap is also recommended in these cases for culture and sensitivity. If the microorganisms are unknown, intravitreal injection of vancomycin (1 mg in 0.1 mL) and ceftazidime (2.5 mg in 0.1 mL) should be given in aphakic patients and patients complicated by lens expulsion.[59]

Donor Button Preparation

Here again, there are two schools of thought. The question is whether to perform donor button excision before the host trephination or after host trephination.[60] Some surgeons perform donor button excision before trephination to prevent the risk of expulsive choroidal hemorrhage, as vitreous prolapse can occur, and the surgeon may not get adequate time to perform an anterior vitrectomy. Some believe that the excision of the donor button should always be performed after the host trephination as necrosed wound architecture may require additional trimming and may change the size of the graft. The donor button is punched endothelial side up and is kept 0.5 to 1 mm more than the host trephination size.[46]

Suturing the Donor Button

The donor button is sutured to the host rim with interrupted 10-0 monofilament nylon sutures. In cases with the cornea to limbal sutures, 9-0 monofilament nylon should be used. In cases of emergency when a particular suture type is unavailable, 10-0 or 9-0 can be used interchangeably.[61]

The suture depth should be 90% on the donor and host sides. The literature review also suggests 75% depth, but most surgeons attempt 90%. Complete thickness sutures should be avoided, as they form a suture tract from where aqueous can lead, and it also acts as a nidus for infection to pass from the cornea to the anterior chamber. Most surgeons prefer a 1:1 ratio of suture bites on the host and donor sides.[9]

However, some prefer larger bites on the host side to prevent cheese wiring of the host tissue through a potentially necrotic zone. All suture knots should be buried on the host side. Additional sutures can be attempted to prevent any subtle leak, and wound closure should be done meticulously. Pressure should be avoided over the globe throughout the surgery. Intracameral moxifloxacin should be given, and anterior chamber formation should be done.[62]

Check for Leakage

Before closing the case, fluorescein dye can be spread over the graft host junction and looked for any leaks. A cotton bud or a swab can also be used to look for leaks. In case of any suspected leakage, additional sutures should be placed.[63]

Pad and Bandage

After completion of the surgery, a pad and bandage are applied, preferably under a topical antibiotic or ointment cover. The pad and bandage can be opened after 4 to 6 hours, and appropriate postoperative drugs should be given.[64]

Postoperative Management

Postoperatively the patient should be started on antimicrobials for a brief initial period. Antibiotics should be started 6 to 8 times daily, along with adjuvant therapy in cases with bacterial keratitis as the etiology. Similarly, in patients with fungal etiology, antifungals should be started. The duration of antimicrobial therapy is governed by the severity of infection, microorganism load and virulence, and the pre-operative and postoperative culture results.[43]

After 3 or 4 weeks, the patient should be started on topical steroids if there are no signs of infection. The concept I follow is if the pre-operative and postoperative culture reports are negative and there are no clinical signs of infections, steroids can be started after two weeks post keratoplasty. If either of the culture reports is positive, it is better to wait three weeks before starting steroids; if both are positive, it is better to wait at least 4 weeks before starting steroids.

Fungal and Acanthamoeba keratitis cases usually require long-term postoperative antimicrobial therapy for several months. Cycloplegics are needed to relieve ciliary spasms, reduced uveitis, pain, pupillary block, posterior synechiae, and PAS formation. Antiglaucoma drugs are required to reduce the raised intraocular pressure in cases with trabeculitis, PAS, and uveitis after TPK.

Topical steroids should be started after a brief interval, as explained above. Topical steroids reduce inflammation and improve visual outcomes. Initiation of steroids should be under antimicrobial cover for approximately two weeks, and later patient can be given steroids alone. Topical steroids can be given from day 1 in viral keratitis cases under antiviral cover. Lubricating eye drops helps in reepithelization. In patients with neuroparalytic keratitis, dry eyes, and recurrent graft infection, lateral tarsorrhaphy with conjunctival flap should be considered.[65]

Postoperative Drug Regimes

Bacterial Keratitis

• Topical moxifloxacin or gatifloxacin or tobramycin, or amikacin 6-8 times per day to reduce the bacterial load (based on the etiology)
• Topical timolol or other adjuvant antiglaucoma medications two times per day. Miotics and prostaglandins should be avoided in an inflamed eye.
• Topical homatropine or atropine two times per day
• Topical lubricating hydroxypropyl methylcellulose or carboxymethylcellulose eye drops to regularize and smoothen the ocular surface. It also promotes re-epithelialization.
• Oral anti-inflammatory drugs such as diclofenac or paracetamol reduce pain and periorbital edema.[21]

Fungal Keratitis

Topical natamycin, voriconazole, or itraconazole 6-8 times daily to reduce the fungal load (based on the etiology). Rest adjuvant drugs remain the same. Oral ketoconazole may be required in cases with scleritis and endophthalmitis.[66]

Acanthamoeba Keratitis

Topical chlorhexidine or poly hexamethylene biguanides or neomycin, along with adjuvant drugs.[67]

Pythium Keratitis

Topical linezolid or azithromycin along with adjuvant drugs. Oral azithromycin may be required in cases with scleritis and endophthalmitis.[20]

Viral Keratitis

Topical antibiotics and steroids, along with adjuvant drugs.[28]

Steroid Regimen

Initially, steroids are started 3 or 4 times for the first seven days under antimicrobial cover as steroid initiation may invite infection. Once there are no signs of infection, I prefer to continue the steroid regimen 4/3/2/1 for 3 months each and later once for lifelong and antiglaucoma coverage. The patient should be regularly followed up to look for any signs of infection and loose suture removal intermittently, if any. All suture removal can be done in 12 months. If the graft in TPK fails after a period of time, then optical penetrating keratoplasty (OPK) can be attempted 12 months postoperatively once suture removal has been done. OPK can also be attempted in one-eyed patients at 6 to 8 months.[68]

Complications

The complications of therapeutic teratoplasty can be listed as follows:

Intraoperative

• Inadequate analgesia
• Inadequate akinesia
• Eccentric host trephination
• Irregular host rim
• Post irregular ledge at the host rim
• Iridodialysis
• Lens expulsion
• Posterior capsular rent
• Vitreous prolapse
• Expulsive choroidal hemorrhage
• Hyphema[44]

Postoperative

Early

• Wound gape
• Loose sutures
• Suture infiltrate
• Shallow or flat anterior chamber
• Anterior chamber leak
• Iris prolapse through graft host junction[69]
• Graft infiltrate
• Epithelial defect
• Anterior uveitis
• Peripheral anterior synechiae
• Secondary glaucoma

Late

• Choroidal effusion
• Peripheral anterior synechiae
• Hypotony
• Choroidal detachment
• Retinal detachment
• Cataract
• Graft failure
• Graft ectasia
• Secondary glaucoma

Secondary Glaucoma

There are various causes for secondary glaucoma

• Retained viscoelastic
• Pupillary block glaucoma
• Synechial angle closure
• Large graft occluding the angle
• Smaller graft with crowded anterior chamber angle
• Steroid-induced glaucoma as a late sequelae
• Malignant glaucoma

Clinical Significance

The clinical significance of TPK lies in eliminating the infection and providing good anatomical and functional outcomes to the patient. TPK is a boon for patients suffering from severe microbial keratitis and changes the quality of life of the patients. It is an essential surgical procedure in the surgeon's armamentarium for patients' ocular rehabilitation, especially in the developing world.

TPK plays a crucial role when globe integrity is compromised, and preoperative and postoperative antimicrobial therapy is crucial in these cases. A large-sized graft is mandatory in cases where the infiltrate size is larger. TPK with a suitable donor graft can restore visual function and may also obviate the need for second-stage optical keratoplasty.[7]

Enhancing Healthcare Team Outcomes

Managing a patient with a corneal ulcer is always a challenge. The decision of when to take the patient for TPK rest with the surgeon is based on his expertise and experience. The good outcome of TPK depends on the combined and coordinated effort of the nursing staff, mid-level ophthalmic personnel, Ophthalmic surgeons, assisting staff in the operating room, optometrist, technicians, pharmacist, and counselor. The surgeon's responsibility is good decision-making, counseling regarding regular use of medications, meticulous surgery, and regular follow-up of patients, which governs the good outcome of TPK.[70]

Nursing, Allied Health, and Interprofessional Team Interventions

The nursing and the allied health staff help take the patient to the operating room, arrange the equipment and instrument trolley, drape the patients, and assist in surgical intervention. They also help in patient examination preoperatively as well as postoperatively. Also, assist in regular monitoring, counseling, and follow-up of these patients. The mid-level ophthalmic personnel helps in patient recruitment, assistance in the outpatient department, corneal scraping, and explaining the procedure and time needed for the scraping results to arrive.[71]

Nursing, Allied Health, and Interprofessional Team Monitoring

The nursing, allied health professionals, and the rest of the interprofessional team help regularly monitor the patients, visual acuity, intraocular pressure, regular follow-up, application of topical drugs, intake of oral medications, and patient's ocular improvement.[72]