Ординатура / Офтальмология / Английские материалы / Medical Contact Lens Practice_Millis_2005

Host response

Inflammation is the response of the host tissues to injury and provides a means to attract cells to the infected site. It consists of cellular and chemical mediators. In vascular tissues the classic signs are redness, swelling, raised temperature and pain, with loss of function, but the cornea reacts differently because it is avascular.

Bacterial ulcers tend to affect the central twothirds of the cornea, and are characterized by edema and a stromal infiltrate of PMNs, around and beneath the ulcer. Epithelial edema, of varying severity, occurs in most cases and causes a loss of transparency, and is due in part to the absorption of hypotonic tears and to endothelial damage.

Polymorphonuclear leukocytes initially enter the site from the tears. The first cells to arrive secrete molecules that attract more cells, resulting in a greater release of attractants and an increased inflammatory reaction.

In most cases of bacterial ulceration there is hyperemia of the limbal vessels as the capillaries dilate. The endothelial cells lining the vessel wall retract, and the tight junctions between them loosen, causing increased capillary permeability and swelling. The blood leukocytes move more slowly and adhere to the endothelium of the vessel wall, through which they squeeze, attracted by chemotactic stimuli from bacteria and the infected tissues. Polymorphonuclear leukocytes migrate into the injured area from the dilated blood vessels within 8–12 hours, and by 48 hours the tear film provides few of the PMNs found in the lesion.

Complement system

The complement system is one of the serum enzyme systems that mediates inflammation and causes membrane damage to pathogens. It consists of nine plasma proteins (C1 to C9) that bind to antigen–antibody complexes in a specific sequence. These proteins interact with one another so that the products of one reaction form the enzymes of the next, resulting in a cascade of reactions.

In the plasma, antibody–antigen complexes bind to the cell surface and activate the classic path, resulting in the attraction of macrophages, capillary dilatation, mast cell degranulation and cell

damage and lysis. Microbial products activate the alternate pathway. The final product of the complement cascade is the Membrane Attack Complex, which is a cylindrical arrangement of molecules that breaches the bacterial cell wall and permits sodium ions and water to enter the cell.

Complement contributes to the immune response by facilitating opsonization, which is the coating of microorganisms with antibody or complement to aid phagocytosis, and the destruction of the organism. Complement fixation is the fixation of complement to the surface of the organism, resulting in opsonization and subsequent lysis of the organism.

Vasoactive mediators

Histamine is formed mainly from mast cells present at the limbus and in the conjunctiva, but not in the cornea itself. Other vasoactive mediators such as prostaglandins and leukotrienes are released from precursors in the plasma.

Changes in epithelial and stromal cells

Epithelial and stromal cells in the area of infection swell and undergo necrosis, and the stromal lamellae become infiltrated with PMNs. Because of the structure of the stroma superficial lesions attract cells from the superficial limbal vessels and deep lesions attract cells from the deep limbal plexus. Either or both may be involved.

Stromal rings, consisting of PMNs, may form due to the action of some endotoxins. They result from centripetally diffusing antibodies meeting with centrifugally diffusing antigen. They are found in cases of Gram-negative infection such as

P. aeruginosa infection, in Acanthamoeba infection, and associated with fungal and viral ulcers.

The anterior stroma demonstrates little opposition to inflammation. Toxins and inflammatory products diffuse in all directions through the stroma and produce a deep area of inflammation and necrosis beneath the ulcer. Descemet’s membrane is an effective barrier against bacteria, but not against toxins, which can diffuse into the aqueous and cause iritis, and may result in a sterile hypopyon. Significant stromal loss (melting) results in corneal thinning, and Descemet’s membrane

may bulge forward, forming a descemetocele, or the cornea may perforate. Perforation can occur within 2 days with P. aeruginosa infection because the organisms spread very rapidly.

Negative cultures may result when organisms have penetrated deep into the stroma, with few remaining in the superficial layers and on the surface. Therefore it is important to take corneal scrapes from the sides and the base of the ulcer, and very rarely corneal biopsy may be necessary to identify the organism.

Ulcer formation and subsequent repair and scar formation

Within 24 hours macrophages from the limbus appear at the site of infection and ingest organisms, dying PMNs and dead necrotic corneal tissue. Progressive tissue necrosis with sloughing of the epithelium and stroma forms a sharply demarcated ulcer surrounded by PMNs.

The ulcer may increase in size due to phagocytosis of organisms and debris, but the infiltrate at the base and edges disappears, and a demarcation line forms between the normal and infected cornea.

Superficial corneal abrasions heal by regeneration of the corneal epithelium, and the new cornea cannot be distinguished from the old. However, most ulcers with stromal loss heal by repair, and result in scar formation.

In small lesions, epithelial cells in the vicinity of the lesion slide to cover the defect, but in larger ulcers the epithelium is resurfaced by migration of new epithelial cells formed from multipotential stem cells at the limbus.

Healing takes place in an orderly fashion, with repair of the edge of the ulcer occurring first, and only then does the center heal, a process known as centripetal migration.28

In the stroma keratocytes transform into fibroblast-like cells, which migrate to the injured site and form scar tissue. The defect may be filled in to the level of normal cornea, but the stroma is usually thinned over the ulcer site and a concavity persists, which is filled to a greater or lesser extent by epithelial hyperplasia. Small vessels are obliterated and larger ones empty of blood, but may remain as ghost vessels. There may be differentiation and calcification of the scar.

Anatomic features of the site of infection

The cornea is avascular and this results in slow response to infection, which means that th cornea is not as resistant to infection as othe tissues.

CLINICAL FEATURES OF BACTERIAL KERATITIS

Bacterial keratitis causes diminished vision, pho tophobia, tearing and pain. The conjunctiva show severe injection and there is a staining cornea epithelial defect, which tends to be situate centrally. The ulcer is surrounded by stromal infil trate and there are cells in the anterior chamber. I severe cases there is stromal melting and necrosi and a hypopyon may form. There may be muco purulent material at the base of the ulcer.

Pseudomonas aeruginosa infection causes larg diffuse ulcers with ragged edges surrounded by dense stromal infiltrate and epithelial edema (Fig 6.1 and 6.2). Staphylococcal ulcers tend to b more discrete and may be sited more peripherall with less dense stromal infiltration (Fig. 6.3) Streptococcal ulcers tend to have feathery margin (previously called crystalline keratopathy), les stromal necrosis, and there may be satellite lesions

It is important to differentiate the findings from sterile infiltrates, which are generally less tha 1 mm in diameter, do not stain, are usually site 1–2 mm from the limbus, and are not associate with anterior chamber activity (Fig. 6.4). There i

Figure 6.1 Pseudomonas keratitis in a soft lens wearer.

Figure 6.2 Contact lens-related microbial keratitis that had remained untreated for 5 days.

immediate relief on removal of the lens, and the lesion heals rapidly without complications, but may leave a scar. Sterile ulcers, sometimes called contact lens peripheral ulcers (CLPUs) may be single or multiple and may coalesce to form an arcuate lesion. They are believed to be due to a hypersensitivity reaction in which staphylococcal exotoxin results in the formation of antibody– antigen precipitates or adherent organisms may act as antigens.

It has been suggested29 that most CLRMK ulcers are in fact of the sterile kind, but this has been refuted.30 As the incidence of CLRMK is low, only practices with a very large patient base are likely to see a case. It is therefore vital that the clinician is aware of the possible diagnosis of an infected corneal ulcer because it is essential to start treatment rapidly. If there is doubt about whether or not the ulcer is infected it should be treated as infected until bacteriology results confirm or refute the diagnosis. In all cases of suspected CLRMK early referral to an ophthalmologist is vital.

wearers. All types of contact lenses have been implicated, as have the use of homemade saline using distilled water and salt tablets, chlorinebased disinfection systems, contaminated lens solutions, swimming in pools or the sea and tap water. Since the reduction in the use of chlorinebased systems there has been a definite fall in the number of infections,31 but it is too soon to be complacent. There is often an increase in cases in the summer and autumn.

Acanthamoeba feeds on bacteria and other organisms and can attach to and penetrate the cornea in the absence of a corneal lesion. The characteristic feature of the infection is pain, which is out of proportion to the severity of the signs, and may necessitate using topical anesthetic drops to be able to examine the eye. There is conjunctival injection and photophobia, which are less severe than in cases of bacterial keratitis, and the course of the disease is longer.

Acanthamoeba keratitis may initially show corneal changes similar to those of herpes simplex infection, with superficial punctate keratitis and sometimes pseudodendrites and microcystic edema (Figs 6.6 and 6.7). These features may delay the diagnosis unless the possibility of amebic infection is kept in mind. Later a radial neurokeratitis (Fig. 6.8) appears along the corneal nerves, with perineural infiltrates, which have been found to contain trophozoites, extending from the central cornea towards the periphery; it is presumably this neural involvement that is responsible for the severe pain. Stromal ring infiltrates develop late in the disease and there may be a progressive loss of stroma with corneal thinning. Limbitis may occur early and late in the disease and sensation is sometimes reduced.

It is important that patients understand the need for handwashing, and the use of a contact lens surfactant with a rub and rinse step. They should perform careful disinfection with regular cleaning and replacement of the lens case if lenses are not 1-day disposables. Tap water and swimming with lenses should be avoided.

Most care systems are not tested for their effectiveness against Acanthamoeba. It is believed that killing other bacteria, which are their food source, will eliminate amebae, but this is rare in practice because current systems disinfect and do

not sterilize. Hydrogen peroxide is the only sys tem that has been shown to be effective agains bacteria in biofilm, and against Acanthamoeb cysts, if used for 4 hours. One-step systems ar

Figure 6.6 Acanthamoeba keratitis.

Figure 6.7 Acanthamoeba keratitis.

Figure 6.8 Radial neurokeratitis in a case of

Acanthamoeba sp. infection

inadequate for this purpose. Multipurpose solutions are active against trophozoites, but require a longer soaking period to achieve the same level of activity.

MANAGEMENT OF CLRMK

In all cases of corneal ulceration details of the size, shape and site of the ulcer should be recorded at the initial visit. The preferred method is photography or image capture, but if these techniques are not available a careful drawing should be made, annotated with the dimensions of the epithelial defect and infiltrate in two meridia at 90° to one another, an estimate of the amount of anterior chamber activity, and the depth of the ulcer. It is helpful if these details are supplied in the referral letter to the hospital.

Investigations

All cases of suspected CLRMK should be referred urgently for an ophthalmologist’s opinion; and so that the ulcer can be scraped and the scrapings cultured to identify the infecting organism for the appropriate treatment. The patient’s contact lenses, solutions and cases should also be cultured.

Treatment

In cases of bacterial keratitis, treatment should commence immediately without waiting for culture and sensitivity results. Hourly broad-spectrum topical antibiotics are started with a review of treatment after 48 hours, when it can be altered in the light of the bacteriology report. If more frequent administration of drops is thought necessary, particularly throughout the night, or the patient is likely to be noncompliant, it may be preferable to admit the patient to hospital, otherwise the patient may be treated as an outpatient.

Treatment is commenced with ofloxacin eye drops 0.3%, with ceftazidime eye drops added if pseudomonas infection is suspected. It is preferable to treat patients with preservative-free drops if they need to instill them more than four times a

day. This minimizes the risk to the epithelium of a toxic reaction, which can delay healing.

Progress of the disease should have ceased after 48 hours of treatment, and under these circumstances the existing regimen should be continued. If progression continues the patient should be admitted to hospital and, providing there is no evidence to the contrary, the initial regimen is continued hourly day and night for 2 days and during the day only thereafter. The patient should be reviewed after 1 week and if resolution is proceeding the drops may be reduced to a maintenance dose.31–34 Once the ulcer is improving and the epithelium is healing (about 5 days), low-dose topical steroids can be introduced to reduce inflammation.

Acanthamoeba keratitis progresses more slowly than that due to pseudomonas infection, and initial treatment is commenced with a broad-spectrum antibiotic until bacteriology reports show Acanthamoeba to be the pathogen, when treatment should be changed to propamidine isetionate (Brolene®) and chlorhexidine or neomycin drops. If this regimen proves inadequate the drops should be changed to polyhexamethylene biguanide. Treatment needs to be intensive for a couple of weeks and continued for several months to ensure eradication.

Restarting lens wear

Contact lens wear in patients with a history of CLRMK may be safe and may be the best way to obtain good vision, particularly when there are residual scars. The patient must understand that extended wear must cease if this is how they have been wearing the lens. It may be preferable to refit with a gas-permeable lens or a soft daily disposable lens. A care regimen that provides maximal disinfection should be selected if soft or rigid lenses other than 1-day disposable lenses are chosen. We always prefer to use a regimen that consists of a separate cleaner and disinfectant, and to emphasize the necessity for cleaning and a rub and rinse step and to use a hydrogen peroxide system. Care should be taken to rebuild the wearing time slowly and the patient should be monitored carefully until successful all-day wear has been resumed.

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CHAPTER CONTENTS

Hypersensitivity 75

IgE-mediated or type I hypersensitivity (including anaphylaxis) 76

Ocular allergy 77 References 81

The prevalence of systemic allergic disease i increasing and is accompanied by an increase i ocular allergy. The eye encounters many potentia antigens (allergens) in the environment, in cos metics, and in topical medication, as well as i pathogens and systemic medications. Allergic reac tions cause itchy, watery, burning, red eyes tha may, or may not, be related to contact lens wear. I is important to decide whether lens wear is a fac tor before deciding to change the lens or solution.

The normal immune response is a protectiv reaction aimed at overcoming microorganisms an foreign substances that may cause damage an disease, but sometimes the reaction is excessive o unsuitable, and causes damage to its own tissues This is called hypersensitivity and is seen in number of conditions affecting the eyelids and th ocular surface

HYPERSENSITIVITY

There are four types of hypersensitivity reactio (Table 7.1) and elements of all or any may be pre sent, but one type usually predominates in an particular condition (Table 7.2).

Hypersensitivity is mediated by:

●IgE from B cells in seasonal allergic conjunctiviti (SAC) and perennial allergic conjunctivitis (PAC

●cell-mediated immunity and T cells in atopi keratoconjunctivitis (AKC) and vernal conjunc tivitis (VKC).

Macrophages, polymorphonuclear leukocyte (PMNs) and eosinophils occur in all types o

Table 7.1 Classification of hypersensitivity reactions

Table 7.2 Ocular disease and hypersensitivity reactions

hypersensitivity, but in differing proportions. The most important cells are the mast cells, which are increased in all types of allergic disease.

Contact lens patients are mainly affected by types I and IV hypersensitivity.

IgE-MEDIATED OR TYPE I

HYPERSENSITIVITY (INCLUDING

ANAPHYLAXIS)

When individuals come into contact with the particular antigen (allergen) to which they have been sensitized there is an immediate acute immune response. The reaction can be triggered by a number of factors including pollen, animal protein such as horse dander, or house dust. There is often a family history of atopic disease, such as asthma, hay fever

or eczema, and the relevant IgE can be found in the tears and in the serum.

In type I reactions mast cells bind IgE. When two of these IgE molecules are bridged by antigen, mast cells are stimulated to degranulate and release chemical inflammatory mediators, including histamine, into the tears, and attract leukocytes into the conjunctiva. The rapid release of the mediators is responsible for the immediate symptoms and signs of this type of allergic eye disease.

Cytokines (e.g. interleukins) are messenger proteins that are stored and released by mast cells. Interleukin-4 (IL-4) causes B cells to produce IgE instead of IgM and is an important mediator in allergic eye disease. It is believed that some IL-4 is contained in the granules of the mast cell during inactive SAC, and a different form is found within the cell membrane during attacks.1

Eosinophils are able to release toxic proteins (e.g. major basic protein), which can damage the corneal epithelium. There are increased numbers of eosinophils in the conjunctival epithelium and the tears in AKC and VKC, and greater numbers are found during the active phase of SAC than during the inactive phase. They are present in all allergic reactions in varying amounts depending on the disease.

Many allergic diseases occur in atopic patients. The term “atopy” means an increased response to protein antigens. In this condition, a tendency for which can be inherited, the antibody, IgE or skin sensitivity antibody is present in the cutaneous tissues. Atopic patients have any combination of asthma, eczema or hay fever. Atopic diseases manifest type I hypersensitivity.

Anaphylaxis related to ocular stimuli is rare, but has occurred with topical anesthetics and antibiotics. Anaphylaxis causes acute bronchospasm, circulatory collapse, shock and even death. Urgent medical treatment is required: the airway must be restored, the patient laid flat and the feet raised to maintain the circulation, and intramuscular epinephrine (adrenaline) administered.

T cell-mediated (type IV) hypersensitivity

T cell-mediated (type IV) hypersensitivity results in a delayed response and occurs in more chronic disorders and those associated with viruses, fungi

and protozoa. It is characterized by the presence of T cells. Antibodies are not involved. It takes time for the T cells to react, and there is usually a delay of about 12 hours. Antigen-sensitized CD4 T cells attract macrophages and activate them at the site.

Contact hypersensitivity is an example of a type IV reaction. Normal levels of T cells are found in SAC and PAC, but CD4 T cell levels are raised in AKC, VKC and giant papillary conjunctivitis (GPC), but there is no increase in CD8 T cells in these conditions (see Ch. 6).

OCULAR ALLERGY

In the eye conjunctival mast cell degranulation causes conjunctival redness, chemosis, mucous discharge and itching. The cornea does not contain mast cells or blood vessels, but because of the limbal vessels it can take part in immune reactions. Immune rings, which are rings of immune precipitates containing PMNs and complement, may form in the cornea in some reactions.

Allergic conjunctivitis

Seasonal allergic conjunctivitis (hay fever)

Seasonal allergic conjunctivitis causes inflammation of the conjunctiva (Fig. 7.1), which is often associated with nasal inflammation (rhinitis) and asthma. It is a type I response triggered by airborne allergens such as pollen, dust and animal dander.2 Because these are more prevalent at certain times of the year, the disease is seasonal, depending on the specific allergen. In the UK the hay fever season extends from March to August. Hay fever due to plane trees tends to occur in April, and fungal spores may be the cause later in the season. There is often a history of atopic disease such as asthma, hay fever or eczema.

The disease is bilateral, but one eye may be more affected than the other. The patient suffers itching, burning, tearing and a milky or stringy mucous discharge, with papillae on the upper tarsal conjunctiva. Papillae are most easily seen on the tarsal conjunctiva where fibrous septa tie the conjunctiva to the tarsus. They are characterized by a central fibrovascular core, which is surrounded by edema and mixed inflammatory cells (Fig. 7.2). The

Figure 7.1 Seasonal allergic conjunctivitis.

Conjunctival epithelium

Edema and mixed inflammatory cells

Fibrovascular core

(a)

Conjunctival epithelium

Lymphocytes, plasma cells and mast cells

Blood vessel

(b)

Figure 7.2 A: Diagram to show structure of a papilla. B: Diagram to show structure of a follicle.

papillae are raised and result in a smooth, velvety appearance in mild cases, and the central blood vessel can be seen by the slit lamp as a small red dot in the center of the lesion. They should be dif ferentiated from follicles, which are collections o lymphocytes surrounded by plasma cells and mast cells. In follicles blood vessels surround th follicle, but are not seen within the follicle.

Perennial allergic conjunctivitis

The symptoms and signs of PAC are similar t those in SAC, but are less severe and are presen