Boston type I keratoprosthesis (KPro) in a teenager with a history of Stevens–Johnson syndrome. The device previously consisted of three components: a front plate with an optical stem, a back plate, and a titanium locking ring. The most recent model consists of two components: a front plate and a back plate, which snap together without the locking ring. The front and back plates come together with donor corneal tissue sandwiched in between. The KPro is covered by a bandage contact lens
SJS-TEN is a chronic inflammatory disease that can lead to severe ocular surface scarring, and can be very difficult to treat (Fig. 5.2). In a retrospective review of 41 patients under 18 years old with SJS, 100% experienced long-term complications of their disease and 30% required follow up procedures (Quirke et al. 2015).
Severe keratinization of both the conjunctiva and cornea, symblepharon and ocular surface scarring in a patient with a history of Stevens–Johnson syndrome
Chemical trauma to the ocular surface is another potential cicatrizing condition. Chemical injuries represent 11.5–22.1% of all ocular traumas, and two-thirds of the injuries occur in young male patients. Chemical injuries can be either alkali or acidic in nature. Alkali agents are lipophilic and therefore penetrate tissues more rapidly than acids. They saponify the fatty acids of cell membranes, penetrate the corneal stroma, and destroy proteoglycan ground substance and collagen bundles. These damaged tissues secrete proteolytic enzymes, which can lead to further damage. By contrast, acids tend to penetrate less as they cause denaturing and precipitation of proteins. These coagulated proteins act as a barrier to prevent further penetration (Fish and Davidson 2010). The extent of ocular injury depends on the strength and concentration of the chemical agent, the volume of solution, and the duration of exposure.
The chemicals can damage conjunctival goblet cells and produce limbal ischemia. Destruction of the delicate limbal stem cells can result in permanent corneal opacification. In addition to corneal scarring, patients with severe chemical injury can develop glaucoma, cataract, and lid malposition. Two major classification schemes for corneal burns are the Roper-Hall and the Dua classification (Roper-Hall 1965; Dua et al. 2001). Both are used to predict the outcome of corneal burns. The Roper-Hall classification is based on the degree of corneal involvement and limbal ischemia. The Dua classification is based on an estimate of limbal and conjunctival involvement.
Initial treatment of ocular chemical injury should be directed toward removing all trapped debris and irrigating the eye to return it to a neutral pH. Patients with mild to moderate injury have a good visual prognosis and can often be treated with medical therapy alone. Initial topical medical therapy includes antibiotics, steroids, lubricating eye drops, and a long acting cycloplegic for pain. Steroid drops should be tapered after about a week because the balance of collagen synthesis versus collagen breakdown may tip unfavorably toward collagen breakdown (Donshik et al. 1978). In patients over the age of 9, oral tetracyclines can be employed to reduce the effects of matrix metalloproteinases that can degrade type I collagen. Some authors also advocate for oral or topical vitamin C, which may promote collagen synthesis and reduce corneal ulceration (Pfister et al. 1991).
Amniotic membrane transplantation has also been used in chemical injury for its anti-inflammatory properties (Lo et al. 2013). In one randomized control trial, patients with moderate burns were found to have significantly better final visual acuity with AMT compared to medical therapy alone (Tandon et al. 2011). Similar to SJS-TEN, severe chemical injury can result in a chronic low grade inflammation and keratinization of the ocular surface. Necrotic epithelium should be debrided. If there is significant limbal stem cell loss, limbal stem cell transplant can be attempted (Morgan and Murray 1996). Penetrating keratoplasty or a KPro can be used for corneal scarring, but most authors recommend delaying corneal surgery to minimize inflammation and the incidence of postoperative complications (Kramer 1983). In the pediatric population, consideration must also be made to the risk of amblyopia from corneal opacity, and children may therefore require earlier intervention.
The prognosis of chemical injury is quite variable. Compared to adults, ocular chemical injuries in pediatric patients pose a greater challenge because early diagnosis and intervention may be more difficult. In a retrospective study of 134 pediatric patients in India with ocular burns, the median visual acuity at final follow up was 3/60. Over half of the injuries occurred in patients of preschool age (0–5 years old), and patients required an average of 2.3 surgeries (Vajpayee et al. 2014).
Nutritional deficiencies can also lead to tear film instability and severe ocular surface disease. Until the late twentieth century, vitamin A deficiency was the leading cause of childhood blindness in developing countries (Humphrey et al. 1992). A series of studies in the 1980s revealed that not only is vitamin A critical for retinal function and ocular surface integrity, but lack of vitamin A can lead to significant morbidity and mortality (Sommer et al. 1983). In India, for example, mortality among preschool-age children was lowered by 54% upon distribution of small, weekly doses of vitamin A (Rahmathullah et al. 1990). Vitamin A distribution programs are now credited with saving the sight and lives of nearly half a million children every year (Sommer 2014). However, vitamin A deficiency still remains a problem in some developing countries. Vitamin A deficiency can also be seen in developed countries in the setting of anorexia/bulimia, vegetarian or vegan diet, cystic fibrosis, short bowel syndrome, liver disease, or other malabsorption syndromes (Braunstein et al. 2010).
Vitamin A is a fat soluble vitamin that is critical in the homeostasis of the visual pigment of photoreceptors. Deficiency can thus lead to nyctalopia (night blindness). Deficiency can also cause a keratinizing metaplasia of the mucosal surfaces throughout the body, including the lungs and intestine. The conjunctival epithelium can change from a normal columnar to a stratified squamous type. There is subsequent loss of goblet cells and conjunctival “xerosis” or dryness. On exam, patients may show the pathognomonic Bitot spots, which are tangles of keratin admixed with saprophytic bacteria on the conjunctiva. Vitamin A deficiency has also been shown to reduce aqueous tear production (Sommer and Emran 1982). In more advanced disease, the cornea can become keratinized and ulcerate, producing permanent vision loss.
Once vitamin A deficiency is recognized, patients should have prompt treatment given the high rates of morbidity and mortality. In children over 12 months of age and all women of childbearing age, vitamin A supplementation can be given orally as 110 mg of retinal palmitate or 66 mg retinal acetate for two days in a row and then again two weeks later to boost liver reserves. Children 6–12 months should be given 1/2 the dose, and children less than 6 months should be given one quarter of the dose (Krachmer et al. 2011). In the absence of significant scarring, vitamin A supplementation can lead to swift healing and good visual recovery.
Pediatric allergic eye disease is quite common and can be associated with ocular surface disease. Patients have chronic inflammation of the conjunctiva and cornea, which can lead to a loss of goblet cells, limbal stem cell deficiency, and corneal scarring (Vichyanond et al. 2014). Schirmer values are significantly lower in patients with childhood onset atopic keratoconjunctivitis compared to adult onset atopic keratoconjunctivitis and controls (Onguchi et al. 2006). Similarly, children with vernal keratoconjunctivitis have been found to have reduced tear break up time and ocular surface remodeling from persistent inflammation (Vichyanond et al. 2014; Villani et al. 2015). For a review of pediatric allergic eye disease, please see Chap. 4.
The cornea is the most densely innervated tissue in our body. This innervation is necessary to regulate corneal epithelial integrity, proliferation, and wound healing. In humans, the first branch (ophthalmic branch) of the trigeminal nerve provides innervation to the cornea, and damage to the trigeminal nerve leads to decrease or absent corneal sensation and the development of neurotrophic keratitis. The reduction in corneal sensitivity ultimately leads to corneal epithelial changes, corneal ulceration, stromal scarring, and neovascularization (Ramaesh et al. 2007). The ophthalmic branch of the trigeminal nerve has two reflex arcs: a motor arc that regulates eye movement (blinking) and an autonomic arc that regulates the secretion of goblet cells, lacrimal and meibomian glands (Mantelli et al. 2015). Taken together, these two arcs maintain the stability of the pre-ocular tear film. While many of the changes seen in the neurotrophic cornea are a result of epithelial breakdown, there is increasing evidence that alteration of corneal sensitivity may also affect all corneal structures, including corneal endothelial morphology (Lambiase et al. 2013).
The trigeminal nerve also supplies trophic factors to the cornea, playing a key role in maintaining anatomic integrity and function of the ocular surface. It influences the release of cytokines, neuropeptides, and neuromediators. Impairment of the nerve causes metabolic epithelial disturbances and persistent epithelial defects (Fig. 5.3) (Bonini et al. 2003). Management of neurotrophic keratitis should be based on clinical severity and aimed at promoting corneal wound healing and halting progression of the disease, which if unchecked can lead to corneal melting and perforation (Sacchetti and Lambiase 2014).
16-year-old patient with a neurotrophic cornea in the setting of a meningioma affecting her trigeminal nucleus (a). Note the heaped and irregular epithelium (b). The epithelium improved dramatically following regular PROSE use (c)
When neurotrophic disease is suspected, corneal sensitivity should be measured before the application of fluorescein. It can be measured by testing sensitivity with the tip of a cotton swab, or it can be quantified with esthesiometers like the Cochet-Bonnet esthesiometer (Luneau Ophthalmologie). Practitioners should also look for the presence of other cranial nerve involvement. If there is concomitant dysfunction of the third, fourth, or sixth cranial nerve, cavernous sinus pathology should be considered (Newman 2007). Concomitant dysfunction of the seventh or eighth cranial nerve can be seen with acoustic neuromas or in the setting of surgical damage. The iris should be carefully inspected, as sector iris atrophy can be seen with herpetic disease. The tear film can be analyzed by Schirmer testing, tear break up time, and tear osmolarity. Confocal imaging can be used to evaluate corneal nerve pathology.
Neurotrophic corneal disease can result from damage to the trigeminal nucleus, root, ganglion, or any segment of the ophthalmic branch of the cranial nerve. Infectious disease, most notably the herpetic diseases: herpes simplex virus (HSV) and varicella zoster virus (VZV) can also lead to neurotrophic keratopathy. Other etiologies include congenital neurotrophic cornea, iatrogenic injury (surgery damaging the trigeminal nerve, refractive surgery leading to reduced sensation), topical medications (beta blockers, NSAIDs, trifluridine), and chemical injuries. In adults, long standing diabetes and advanced age are associated with reduced corneal sensation, but this is less of a problem in the pediatric population. Neurotrophic keratitis is thought to affect 5/10,000 individuals (Sacchetti and Lambiase 2014).
Ocular infections from HSV are quite common in the pediatric population and are often initially misdiagnosed. HSV can present as either a blepharoconjunctivitis or a keratitis, and the latter is associated with reduced corneal sensation in 64% of children. Recurrence of HSV keratitis is more common in children than adults, seen in upwards of 50% of children, necessitating long-term antiviral prophylaxis (Liu et al. 2012). By contrast, herpes zoster ophthalmicus (HZO) from VZV is quite rare in children, but is more commonly associated with neurotrophic corneal disease in adults (Ghaznawi et al. 2011).
Congenital corneal anesthesia is a rare condition that usually presents bilaterally, before the age of three, with associated painless corneal opacities and sterile ulceration (Ramaesh et al. 2007). Rosenberg divided congenital corneal anesthesia in three distinct groups: group 1 is an isolated trigeminal anesthesia due to primary hypoplasia of the hindbrain, group 2 is associated with mesenchymal anomalies, and includes Mobius syndrome and Riley–Day syndrome/Familial Dysautonomia, and group 3 is associated with focal brainstem signs without evidence of mesenchymal dysplasia. The etiology is thought to be due to prenatal injury (Rosenberg 1984).
Familial Dysautonomia (FD, also known as Riley–Day syndrome) is an autosomal recessive disease characterized by extensive central and peripheral autonomic disturbances as well as small fiber sensory dysfunction. Patients have decreased pain perception along the trigeminal nerve, diminished corneal reflexes, and decreased taste perception. Consistent with neurotrophic disease, patients have insensitivity to corneal trauma, decreased blinking, and alacrima (Alves et al. 2008). Autonomic dysfunction includes postural hypotension and oropharyngeal incoordination. There is progressive neuronal degeneration throughout life, and patients have a shortened lifespan, frequently dying from infection (Shohat and Weisz Hubshman 1993). The genetic defect has been mapped to the DYS gene on chromosome 9q31-33. It is principally seen in patients of Ashkenazi Jewish descent, where the carrier frequency is 1 in 32. The overall presence of FD is 1 in 1,000,000 (Blumenfeld et al. 1993).
Mobius syndrome is a rare developmental anomaly of the hindbrain that leads to a nonprogressive congenital paralysis of the facial and abducens nerve. In a minority of cases, the trigeminal nerve can also be involved. Corneal damage from neurotrophic keratopathy can be compounded with exposure keratopathy from seventh nerve paralysis (MacKinnon et al. 2014).
The trigeminal nerve can be damaged in the setting of surgical procedures for tumors and maxillary fractures, and ablative procedures in trigeminal neuralgia. Lambiase et al. conducted a retrospective review of patients aged 1–19 who experienced unilateral neurotrophic keratitis after neurosurgery (Lambiase et al. 2013). Indications for neurosurgery included acoustic neuroma, meningioma and chondroma. All patients showed superficial punctate keratitis and dry eye as evidenced by tear film function tests. On in vivo confocal imaging, patients had reduced epithelial and endothelial keratocyte densities.
Early treatment for neurotrophic keratitis is aimed at maintaining a healthy ocular surface through the use of artificial tears, N-acetylcysteine, and systemic tetracycline if the child is old enough. For persistent epithelial defects, a bandage contact lens can be used short term or specialized scleral lenses like the PROSE lens can be used long term (Fig. 5.3c). For moderate-to-severe disease, amniotic membranes, tarsorrhaphies, or conjunctival flaps can be used. In the pediatric population, amblyopia must always be considered with these occlusive therapies. Newer treatments like nerve growth factor hold some promise to accelerate epithelial healing (Lambiase et al. 2013; Bonini et al. 2000).
Exposure Keratitis and Eyelid Disorders
The eyelids provide a moveable mucosal lining that can cover the entire ocular surface, preventing dehydration and trauma to the underlying globe. Eyelid movement is critical to tear film dynamics (pumping and distribution). A complete blink also leads to meibomian gland secretion of lipid, which decreases tear film evaporation. Poor eyelid functioning can result in exposure keratopathy, tear film abnormalities, and ocular surface scarring.
During sleep, the lipid layer of the tear film coupled with good eyelid closure prevents the evaporation of tears, maintaining moisture of the cornea. The Bell’s phenomenon, where there is upward rotation of the eyeball during eyelid closure, further protects the cornea. Lagophthalmos is the inability of the eyelids to fully close, and results in increased tear evaporation, corneal drying, and ocular surface breakdown. In early exposure keratopathy, there are superficial punctate micro epithelial erosions in the inferior one-third of the cornea (in the area of exposure). These can eventually coalesce to marco epithelial defects and ulceration (Pereira and Gloria 2010).
Lagophthalmos can be seen following surgical repair for congenital ptosis. Children with congenital ptosis often have poor levator function and undergo a frontalis suspension procedure, where the frontalis muscle is linked to the tarsus of the upper lid. Children have varying degrees of lagophthalmos following this procedure (Kim et al. 2012). An intact Bell’s phenomenon has been found to be protective, leading to less tear film and ocular surface instability. In fact, some authors have recommended that children with poor Bell’s phenomenon undergo less surgical correction for congenital ptosis than patients with an intact Bell’s phenomenon (Yoon et al. 2008).
Lagophthalmos can also be seen in facial nerve palsies. In a review of children with Mobius syndrome, for example, lagophthalmos was present in 83% of cases (Carta et al. 2011). It can also be associated with Grave’s disease. Children comprise only 5.8% of patients with Grave’s disease and tend to have less severe ophthalmic pathology then adults (Durairaj et al. 2006). Lagophthalmos was seen in 37.1% of pediatric patients with Grave’s disease. In the setting of Grave’s disease, exposure keratopathy can also result from eyelid retraction and exophthalmos, which were seen in 82.9 and 74.3% respectively in pediatric patients.
During sleep, there is a tonic muscular activity in the orbicularis oculi muscle with concomitant inhibition of tonus of levator palpebral superioris. This delicate coordination between muscles can be compromised in the intensive care unit (ICU) setting as a result of metabolic derangements, mechanical ventilation, and decreased level of consciousness. Sedatives in the ICU setting inhibit active contraction of the orbicularis oculi muscle, resulting in lagophthalmos. Exposure keratopathy can be seen in 3.6–60% of ICU patients (Grixti et al. 2012). Sedated patients are unable to protect their eyes, blink, or complain about ophthalmic symptoms. Moreover, the medical staff is often concerned about restoring hemodynamic stability, and ophthalmic disease may go unnoticed. Critically ill patients are at risk of developing microbial keratitis secondary to exposure, immune suppression, and positive pressure ventilation. In a study of pediatric ICU patients, the ocular infection rate was 7% (Milliken et al. 1988). ICU practitioners should pay particular attention to exposure keratopathy and treat with lubrication and temporary eyelid closure (taping, polyethylene films, tarsorrhaphy) when necessary.
Eyelid malpositioning can also lead to increased exposure and lagophthalmos. Ectropion, or a turning out of the lids away from the globe, can be seen congenitally, following trauma or infection, or in the setting of scarring from oculocutaneous conditions like ichthyosis or xerodermal pigmentosa.
Ichthyosis is a general term used to describe a diverse group of skin disorders, characterized by excessively dry skin and accumulation of scale. Ichthyosis vulgaris is the most common, affecting 1 in 250–300 people. Lamellar ichthyosis and congenital ichthyosiform erythroderma are much rarer variants, but cicatricial ectropion is commonly seen and may require surgical correction. Lamellar ichthyosis is present at birth. The entire skin surface is encased in a colloidan like membrane, which sloughs over the first few weeks of life (Oestreicher and Nelson 1990). Infants subsequently have large plate-like scales and scarring across their entire skin surface. Children with keratitis ichthyosis deafness (KID) syndrome have thickened keratinized lids as well as corneal stromal vascularization and deafness. The corneal disease is secondary to a generalized ectodermal disturbance and limbal stem cell deficiency (Messmer et al. 2005). It is caused by mutations in the GJB2 gene, coding for connexin 26, a component in gap junctions in epithelial cells. Connexin 26 may act as a tumor suppressor, and these patients are at an increased risk of squamous cell cancer (Kone-Paut et al. 1998).
Xeroderma Pigmentosa is a rare autosomal recessive disorder that is the result of an enzymatic defect in the ability to repair DNA damage by shortwave length light (Goyal et al. 1994). Infants can show freckling in the first year of life. The eyelids often atrophy and may have madarosis, ectropion, and malignant degeneration. Patients are at high risk of malignant skin neoplasms. Squamous cell carcinoma of the limbus, for example, can be seen in 20% of patients.
Eyelid anatomy can also be compromised by infectious etiologies. Trachoma is the leading cause of infectious blindness in the world, and has caused corneal scarring and blindness in 4.9 million living people. Another 10 million people are suffering from trachoma and at risk of blindness (Mabey et al. 2003). Its hallmark is a chronic keratoconjunctivitis, caused by the bacteria Chlamydia trachomatis. The infection usually takes place early in childhood and it is nearly always bilateral. It begins in the upper tarsal conjunctiva and leads to severe inflammation, which in turn produces tissue destruction and scarring. Follicles appear at the limbus during the acute infection, and when healed produce Herbert’s pits, characteristic scars at the limbus. This can be followed by further corneal scarring and vascularization. Recurrent inflammation can also lead to scarring of the palpebral conjunctiva. A characteristic linear scar can be present in the sulcus subtarsalis, called Arlt’s line. Entropion, or turning in of the lid against the globe, and trichiasis can produce further ocular surface damage.
Trachoma is primarily a disease of overcrowding and poor hygiene. Risk factors for children to develop trachoma include poor facial cleanliness, living more than two hours away from a water source, and familial cattle ownership (Hsieh et al. 2000). Trachoma can be treated with topical tetracycline for a minimum of 6 weeks. A single dose of oral azithromycin 1 g also shows great promise, and has been used to eradicate trachoma in several countries (Sommer et al. 2014).
Limbal Stem Cell Deficiency (LCSD)
In the healthy eye, there is a subpopulation of stem cells that reside at the corneoscleral limbus that serve to repopulate the corneal epithelium. These limbal stem cells are found in the basal layer of the limbal epithelium, arranged in the palisades of Vogt configuration. The corneal epithelium undergoes a constant process of cell renewal and regeneration. Damage to the limbal stem cells can result in epithelial breakdown with chronic inflammation. Ultimately, there may be ingrowth of conjunctiva, vascularization and corneal scarring (Hatch and Dana 2009). LCSD can be seen in a number of congenital conditions including aniridia and ectodermal dysplasia. As discussed above, it can also be seen following trauma (chemical burns) and Stevens–Johnson syndrome. Severe contact lens over wear, multiple ocular surgeries (especially with the use of mitomycin c), and medication toxicity can also lead to LCSD.
Congenital aniridia is characterized by hypoplasia of the iris. It occurs at a frequency of 1/64,000–1/96,000 births and is autosomal dominantly inherited in two-thirds of patients, and sporadic in the remaining one-third (Lee and Colby 2013). Patients with sporadic inheritance have an increased risk of developing Wilms’ tumor and require genetic testing or frequent screening (Gronskov et al. 2001). Aniridia is associated with other ophthalmic pathology including foveal and optic nerve hypoplasia, glaucoma, and cataracts. We have learned, through impression cytology, that there is a reduction of limbal stem cells in aniridia. Over time, this leads to aniridic keratopathy (Fig. 5.4). Characteristically, patients develop an irregular and thickened epithelium during childhood, which progresses to superficial and then deep neovascularization. Confocal microscopy has shown disruption of the Vogt palisades at the limbus and, in severe cases, conjunctivalization of the ocular surface (Le et al. 2013). Patients with aniridia are also more likely to have abnormal tear film stability and meibomian gland dysfunction (Jastaneiah and Al-Rajhi 2005).