The stromal layer makes up to 90% of the corneal thickness, it is composed of regularly orientated collagen type I and V fibrils layers whose space is maintained by proteoglycan ground substance (chondroitin and keratan sulphate) with interspread modified fibroblast cells (keratocytes). The superficial portion of the stroma is called the Bowman membrane that constitutes an acellular portion of the stroma. It is, in part, the congruent and precise distri‐ bution of the collagen fibers of the stromal layer that permits the structure of the cornea to be transparent, letting the spectrum of visible light to pass through into the inner structures of the eye to finally allowing us to see.

The endothelial layer consists of a single layer of hexagonal cells that sits on a fine basal membrane made of a latticework of collagen fibers named the Descemet membrane. This layer and its indemnity is also crucial in keeping the transparency of the cornea by reducing the amount of water in the corneal stroma through an active membrane channels mechanism that allows the movement of water from the stroma into the anterior chamber of the eye. The endothelial cells cannot regenerate as they are arrested in the G1 phase of the cell cycle; the normal adult cell density is about 2500 cells/mm2 , this amount of cells decreases at a rate of 0.6% per year. When the cell density falls to about 500 cells/mm2 , corneal edema develops and then corneal transparency is reduced.

In 2013, the Dua's layer was described for the first time. In a paper published by Dua et al., experimental and electron microscopy studies revealed the existence of a thin layer (15 microns) of corneal collagen between the corneal stroma and the Descemet membrane. This layer has physical properties that are different to the stromal layer and the Descemet mem‐ brane, having the highest resistance to pressure among the corneal layers. Its discovery has implications in corneal surgical procedures.

Macrophages and dendritic antigen presenting cells are present mainly in the epithelium and the anterior stroma. Small numbers of macrophages are also present in the posterior stroma.

The sensory innervation of the cornea derives from the trigeminal nerve (V1) and it is mainly distributed in the sub-epithelial region and anterior stroma as sub-epithelial plexus, it is therefore at this level that we can find most nerves in the corneal structure.

### **3. Keratitis: Clinical history**

**Figure 1.** Corneal layers

208 Ophthalmology - Current Clinical and Research Updates

to the clear cornea.

the eye to finally allowing us to see.

The epithelial layer is formed by a stratified, squamous and non-keratinized epithelium that comprises a single layer of basal columnar cells attached by hemi-desmosomes to the under‐ lying basement membrane followed by two to three rows of epithelial wing cells and two external layers of squamous surface cells which surface area is increased by microplicae and microvilli that facilitates the attachment of the mucin layer of the tear film. After a lifespan of approximately twenty-four hours the superficial cells are often shed into the tear film. The epithelial stem cells are located in the limbal region (this is the area between the cornea and the sclera), within the palisades of Vogt mainly located in the superior and inferior limbus. The indemnity of the corneal stem cells is essential for the maintenance of a healthy corneal epithelium and they also act as a barrier, preventing conjunctival epithelium from growing on

The stromal layer makes up to 90% of the corneal thickness, it is composed of regularly orientated collagen type I and V fibrils layers whose space is maintained by proteoglycan ground substance (chondroitin and keratan sulphate) with interspread modified fibroblast cells (keratocytes). The superficial portion of the stroma is called the Bowman membrane that constitutes an acellular portion of the stroma. It is, in part, the congruent and precise distri‐ bution of the collagen fibers of the stromal layer that permits the structure of the cornea to be transparent, letting the spectrum of visible light to pass through into the inner structures of

The endothelial layer consists of a single layer of hexagonal cells that sits on a fine basal membrane made of a latticework of collagen fibers named the Descemet membrane. This layer and its indemnity is also crucial in keeping the transparency of the cornea by reducing the amount of water in the corneal stroma through an active membrane channels mechanism that A detailed clinical history is crucial in the diagnosis keratitis. Demographic aspects like age, sex, ethnicity and occupation are always needed and can orientate to certain specific associated pathologies or risk factors. The use of contact lenses is important to note in detail including the type of lenses, length of use, cleaning systems used and daily routines (i.e. tap water washing, swimming, etc). History of any recent injury to the eye or systemic disease that might relate to corneal compromise is also needed. History of recent infec‐ tions, cold sores or flu can be helpful in orientating a diagnosis. The use of topical eye drops or any other medication needs to be recorded as the use of topical steroids, anesthet‐ ics, etc can be significant as a risk factor for infections and anatomical/ functional changes of the corneal surface.

### **4. Keratitis: Anatomical classification**

Keratitis can be classified on the portion of the cornea affected. It is important to note that perhaps most of the cases have more than one layer involved and in some cases all three are compromised, however this classification can help the diagnosis of more pure forms of keratitis.

Epithelial: when the most superficial layer of the cornea is affected, a characteristic epithelial defect or epithelial cellular infiltrate can be seen, fluorescein staining can help in the

diagnosis, there are multiple sizes and possible shapes for both the defect and/or the infiltration. Some of the epithelial defects are pathognomonic as it is the dendriform seen in herpes simplex virus keratitis, it is therefore important to note the size, shape and depth of the defect in any epithelial form, as it will certainly help not only in the diagnosis but also in the assessment of the progression or recovery of the affected patient. In the case of the infiltrate, it is important to note the size, color and quality of the borders that can be of help in diagnosis and follow up. Any satellite lesions need also to be assessed as well as the upper and lower tarsal plates in search for any foreign bodies or other associated lesions like calcareous concretions, meibomian gland cysts, papillae or follicles. The epithelial form of keratitis is extremely painful and at times enlarged or infiltrated corneal nerves can be seen. Usually the anterior stroma is also affected with an inflammatory cellular infiltrate surrounding the epithelial lesions, it has in general poorly defined borders. Corneal pannus can be seen as a result of previous episodes of epithelial keratitis in some cases. Examples include herpetic epithelial keratitis, adenoviral keratoconjunctivitis, microbial corneal ulcers and contact lens related keratitis.

**5.1. Infectious keratitis**

*5.1.1. Viral*

correct clinical diagnosis.

as it is frequently seen with the herpes virus family.

**Figure 2.** Herpes simplex virus epithelial keratitis as typical dendrite.

As an important component of the anatomical anterior wall of the eye, the cornea is a structure highly exposed and vulnerable to external pathogens. The use of contact lenses constitutes an accumulative risk for developing infectious keratitis, as it is also any history of chronic corneal disease or the use of topical steroids. Any corneal epithelial disruption as seen sometimes in dry eye syndrome, severe blepharitis and injuries are able to cause disruptions of the epithelial barrier as seen in corneal abrasions, post-surgical procedures or corneal foreign bodies that can predispose to corneal infections. Sometimes it is the result of highly pathogenic microor‐ ganisms with high affinity to the epithelial cells the ones that can cause a direct involvement

Keratitis — A Clinical Approach http://dx.doi.org/10.5772/58411 211

By far the most frequent cause of viral keratitis is the one caused by herpes viruses type 1 and 2, also varicella-zoster virus can sometimes be responsible in the context of herpes zoster ophthalmicus. The typical form of viral keratitis is epithelial, with a characteristic dendritiform epithelial defect and secondary infiltrate very easy to diagnose with fluorescein staining (Fig 2). The epithelial defect seen in herpes zoster infection is classically described as geographic rather than dendritiform. In less than 10% of the cases the compromise can be primarily stromal or endothelial that typically is associated with elevated intraocular pressure (Fig 3). A PCR for virology in a swab of the epithelial lesion usually confirms diagnosis. Recent history of herpes zoster or recurrent cold sores can also orientate the clinician. If PCR is not available, another way of confirming diagnosis is by performing antibodies serology (IgG / IgM) for HSV and VZV at the time of presentation, an elevated IgM would confirm the diagnosis of recent infection and an elevated IgG a recurrence. This form of keratitis leaves behind sometimes significant corneal scarring with pannus, this clinical finding, in the context of an atypical recurrent hypertensive stromal or endothelial keratouveitis, can help sometimes achieve the

Stromal: this is the keratitis that has primarily a compromise of the corneal stroma. An associated epithelial defect may be or not detected at initial presentation. The main finding in this type of keratitis is an infiltration of the collagen layers in the stroma by inflammato‐ ry cells, this can be seen at any depth, it can be unifocal or multifocal, with many differ‐ ent shapes and sizes, but usually has a very well defined and regular edge. There is in general some degree of anterior chamber cell reaction and at times keratic precipitates can be seen. Thickening of the cornea is another way to appreciate the cellular infiltration seen in these cases. Examples are herpetic stromal keratitis, sclero-keratitis and fungal/atypical microorganisms' related keratitis.

Endothelial: the main structure affected in these cases is the endothelial layer. Characteristic features include keratic precipitates, descemet folds and almost invariably a significant anterior chamber cells reaction. Secondary diffuse corneal thickening at later stages can be seen as a result of impaired endothelial function. Examples include corneal graft rejection, herpetic endothelial keratitis, any form of kerato-uveitis, and post-traumatic/post-surgical endothelial damage.

### **5. Keratitis: Causes**

The cornea is sometimes the target of one direct pathophysiological condition, others, the compromise is secondary to an external indirect event in the complex functional anatomical triad between the lids, the cornea and the tear film.

There are multiple different causes of keratitis; these can be grouped in three major groups including infectious, autoimmune/inflammatory, neoplastic and traumatic causes.

### **5.1. Infectious keratitis**

diagnosis, there are multiple sizes and possible shapes for both the defect and/or the infiltration. Some of the epithelial defects are pathognomonic as it is the dendriform seen in herpes simplex virus keratitis, it is therefore important to note the size, shape and depth of the defect in any epithelial form, as it will certainly help not only in the diagnosis but also in the assessment of the progression or recovery of the affected patient. In the case of the infiltrate, it is important to note the size, color and quality of the borders that can be of help in diagnosis and follow up. Any satellite lesions need also to be assessed as well as the upper and lower tarsal plates in search for any foreign bodies or other associated lesions like calcareous concretions, meibomian gland cysts, papillae or follicles. The epithelial form of keratitis is extremely painful and at times enlarged or infiltrated corneal nerves can be seen. Usually the anterior stroma is also affected with an inflammatory cellular infiltrate surrounding the epithelial lesions, it has in general poorly defined borders. Corneal pannus can be seen as a result of previous episodes of epithelial keratitis in some cases. Examples include herpetic epithelial keratitis, adenoviral keratoconjunctivitis, microbial

Stromal: this is the keratitis that has primarily a compromise of the corneal stroma. An associated epithelial defect may be or not detected at initial presentation. The main finding in this type of keratitis is an infiltration of the collagen layers in the stroma by inflammato‐ ry cells, this can be seen at any depth, it can be unifocal or multifocal, with many differ‐ ent shapes and sizes, but usually has a very well defined and regular edge. There is in general some degree of anterior chamber cell reaction and at times keratic precipitates can be seen. Thickening of the cornea is another way to appreciate the cellular infiltration seen in these cases. Examples are herpetic stromal keratitis, sclero-keratitis and fungal/atypical

Endothelial: the main structure affected in these cases is the endothelial layer. Characteristic features include keratic precipitates, descemet folds and almost invariably a significant anterior chamber cells reaction. Secondary diffuse corneal thickening at later stages can be seen as a result of impaired endothelial function. Examples include corneal graft rejection, herpetic endothelial keratitis, any form of kerato-uveitis, and post-traumatic/post-surgical endothelial

The cornea is sometimes the target of one direct pathophysiological condition, others, the compromise is secondary to an external indirect event in the complex functional anatomical

There are multiple different causes of keratitis; these can be grouped in three major groups

including infectious, autoimmune/inflammatory, neoplastic and traumatic causes.

corneal ulcers and contact lens related keratitis.

210 Ophthalmology - Current Clinical and Research Updates

microorganisms' related keratitis.

damage.

**5. Keratitis: Causes**

triad between the lids, the cornea and the tear film.

As an important component of the anatomical anterior wall of the eye, the cornea is a structure highly exposed and vulnerable to external pathogens. The use of contact lenses constitutes an accumulative risk for developing infectious keratitis, as it is also any history of chronic corneal disease or the use of topical steroids. Any corneal epithelial disruption as seen sometimes in dry eye syndrome, severe blepharitis and injuries are able to cause disruptions of the epithelial barrier as seen in corneal abrasions, post-surgical procedures or corneal foreign bodies that can predispose to corneal infections. Sometimes it is the result of highly pathogenic microor‐ ganisms with high affinity to the epithelial cells the ones that can cause a direct involvement as it is frequently seen with the herpes virus family.

### *5.1.1. Viral*

By far the most frequent cause of viral keratitis is the one caused by herpes viruses type 1 and 2, also varicella-zoster virus can sometimes be responsible in the context of herpes zoster ophthalmicus. The typical form of viral keratitis is epithelial, with a characteristic dendritiform epithelial defect and secondary infiltrate very easy to diagnose with fluorescein staining (Fig 2). The epithelial defect seen in herpes zoster infection is classically described as geographic rather than dendritiform. In less than 10% of the cases the compromise can be primarily stromal or endothelial that typically is associated with elevated intraocular pressure (Fig 3). A PCR for virology in a swab of the epithelial lesion usually confirms diagnosis. Recent history of herpes zoster or recurrent cold sores can also orientate the clinician. If PCR is not available, another way of confirming diagnosis is by performing antibodies serology (IgG / IgM) for HSV and VZV at the time of presentation, an elevated IgM would confirm the diagnosis of recent infection and an elevated IgG a recurrence. This form of keratitis leaves behind sometimes significant corneal scarring with pannus, this clinical finding, in the context of an atypical recurrent hypertensive stromal or endothelial keratouveitis, can help sometimes achieve the correct clinical diagnosis.

**Figure 2.** Herpes simplex virus epithelial keratitis as typical dendrite.

**Figure 4.** A patient with pseudomonas sp keratitis.

media that is more specific for fungal growth.

**Figure 5.** Fungal keratitis pre / post treatment.

It is a rare cause of keratitis in temperate climates but common cause of keratitis in tropical countries. It is difficult to treat. Usually occurs following trauma to the cornea especially the one caused by vegetable matter. Also contact lens wearing is emerging as a significant risk factor. The course is indolent sub-acute, it takes weeks for the patient to seek help as it does not cause significant discomfort in the early stages as fungi are slow in replicate. The clinical presentation is that of a stromal form of keratitis, an epithelial defect can or not be present, but usually is small compared to the amount of stromal infiltrate associated. The stromal infiltrate is always irregular in the borders and poorly defined, it has a 'fluffy' aspect and very white (Fig 5). In very advanced cases the infiltration of the stroma can be full thickness with associated anterior chamber whitish solid hypopyon. The diagnosis is often confirmed by a corneal scrape or a corneal biopsy sent for microbiological studies; the gram stain can be very useful in identifying hyphae, filaments or microorganisms very quickly, for the culture it is important to repeat the cultures described for bacteria (in case of mixed infection) and also a Sabouraud's

Keratitis — A Clinical Approach http://dx.doi.org/10.5772/58411 213

*5.1.3. Fungal*

**Figure 3.** Herpes simplex virus stromal keratitis.

#### *5.1.2. Bacterial*

For bacteria to act as a pathogen in the cornea, it is necessary a disruption in the epithe‐ lial barrier like the ones seen in injuries (corneal foreign bodies and corneal abrasions) or a significant risk factor like contact lens wear or use of topical steroids. Almost any bacterium is able to cause keratitis, the most frequently involved are the ones that are the gram positive microorganisms found in the eyelids margin and skin (staphylococcus sp, streptococcus sp), sometimes gram negative bacteria like pseudomonas sp can be isolat‐ ed. The typical keratitis caused by bacteria is epithelial and the presentation is acute; it usually has a well-defined epithelial defect surrounded by a stromal grayish infiltrate, which has a depth and extension proportional to the time of onset to presentation. Often a level of hypopyon and anterior chamber reaction are seen. The speed and extension of the compromise also depends on the pathogenicity of the bacteria involved, often being worse in the case of gram-negative microorganisms (Fig 4). Slow growth bacteria like streptococ‐ cus viridans can give the aspect of crystalline keratitis, as the invasion of the corneal stroma is very slow following the branching of the collagen layers. The diagnosis is usually confirmed by a corneal scrape of the lesion that can be sent for microbiological studies; in any ophthalmic setting it is crucial to perform a gram stain, blood agar, brain heart infusion (BHI) and cooked meat broth (CMB) cultures to be able to isolate the pathogen and determine the sensitivities to antibiotic therapy. The gram stain can give immediate initial information of the type of microorganism excluding other causes of keratitis. In contact lens wearers is important also to send for culture the contact lenses container and the last pair of lenses used.

**Figure 4.** A patient with pseudomonas sp keratitis.

#### *5.1.3. Fungal*

**Figure 3.** Herpes simplex virus stromal keratitis.

212 Ophthalmology - Current Clinical and Research Updates

For bacteria to act as a pathogen in the cornea, it is necessary a disruption in the epithe‐ lial barrier like the ones seen in injuries (corneal foreign bodies and corneal abrasions) or a significant risk factor like contact lens wear or use of topical steroids. Almost any bacterium is able to cause keratitis, the most frequently involved are the ones that are the gram positive microorganisms found in the eyelids margin and skin (staphylococcus sp, streptococcus sp), sometimes gram negative bacteria like pseudomonas sp can be isolat‐ ed. The typical keratitis caused by bacteria is epithelial and the presentation is acute; it usually has a well-defined epithelial defect surrounded by a stromal grayish infiltrate, which has a depth and extension proportional to the time of onset to presentation. Often a level of hypopyon and anterior chamber reaction are seen. The speed and extension of the compromise also depends on the pathogenicity of the bacteria involved, often being worse in the case of gram-negative microorganisms (Fig 4). Slow growth bacteria like streptococ‐ cus viridans can give the aspect of crystalline keratitis, as the invasion of the corneal stroma is very slow following the branching of the collagen layers. The diagnosis is usually confirmed by a corneal scrape of the lesion that can be sent for microbiological studies; in any ophthalmic setting it is crucial to perform a gram stain, blood agar, brain heart infusion (BHI) and cooked meat broth (CMB) cultures to be able to isolate the pathogen and determine the sensitivities to antibiotic therapy. The gram stain can give immediate initial information of the type of microorganism excluding other causes of keratitis. In contact lens wearers is important also to send for culture the contact lenses container and the last pair

*5.1.2. Bacterial*

of lenses used.

It is a rare cause of keratitis in temperate climates but common cause of keratitis in tropical countries. It is difficult to treat. Usually occurs following trauma to the cornea especially the one caused by vegetable matter. Also contact lens wearing is emerging as a significant risk factor. The course is indolent sub-acute, it takes weeks for the patient to seek help as it does not cause significant discomfort in the early stages as fungi are slow in replicate. The clinical presentation is that of a stromal form of keratitis, an epithelial defect can or not be present, but usually is small compared to the amount of stromal infiltrate associated. The stromal infiltrate is always irregular in the borders and poorly defined, it has a 'fluffy' aspect and very white (Fig 5). In very advanced cases the infiltration of the stroma can be full thickness with associated anterior chamber whitish solid hypopyon. The diagnosis is often confirmed by a corneal scrape or a corneal biopsy sent for microbiological studies; the gram stain can be very useful in identifying hyphae, filaments or microorganisms very quickly, for the culture it is important to repeat the cultures described for bacteria (in case of mixed infection) and also a Sabouraud's media that is more specific for fungal growth.

**Figure 5.** Fungal keratitis pre / post treatment.

### *5.1.4. Acanthamoeba*

It is a rare cause of keratitis caused by one of the most common protozoa found in soil and water. In 90% of the cases a history of contact lens wear is found. Clinically this form of keratitis is combined with an epithelial and stromal component. The epithelial component is charac‐ teristically a large epithelial defect with abundant sub-epithelial infiltrate and enlargement of the corneal nerves that have been described as invaded by the pathogen at some stages of the disease, causing intense pain; this is perhaps the most painful form of keratitis, and this is regarded as a significant clinical finding at the time of diagnosing contact lens related keratitis. The stromal infiltrate is grey-whitish with irregular, multiple or single lesions, sometimes satellite areas can be seen (Fig 6 a & b). The diagnosis is confirmed by scrape or corneal epithelial biopsy sent for microbiological studies, it is important to repeat the gram and all the previously described medias (blood, BHI, CMB, Sabouraud's) and add the E. coli enriched non-nutrient agar media where this pathogen can be detected easily.

of postoperative, traumatic or previous corneal pathology situations. The course is always chronic, unresponsive to multiple previous treatments and the clinical picture varies between an epithelial and stromal form of keratitis with atypical features (Fig 7). Perhaps the most important aspect is the invariable presence of a significant risk factor like previous surgery, as this pathogen needs a significant break in the epithelial barrier to be able to invade and cause the condition due to its relative large size. The isolation of mycobacterium to confirm diagnosis depends on a high level of suspicion and the scrape or corneal biopsy culture that needs all the previously described media plus a Zhiel-Neelsen gram stain for identification of acid-fast

Keratitis — A Clinical Approach http://dx.doi.org/10.5772/58411 215

bacteria and Lowenstein-Jensen agar for culture growth.

**Figure 7.** Atypical keratitis caused by mycobacterium abscessus after LASIK pre / post treatment.

**5.2. Inflammatory — Autoimmune keratitis (Non suppurative keratitis)**

corneal stromal melting associated to inflammation (Fig 9 a & b).

*5.2.1. Autoimmune*

Any condition that can induce an inflammatory response of the cornea can be classified in this group of causes of keratitis. There are autoimmune and no autoimmune related diseases.

Like in any other autoimmune condition where the main target is the collagen in the body, the so-called autoimmune collagen or connective tissue diseases can be responsible for various forms of inflammatory keratitis, due to the high content of collagen seen in the corneal and scleral tissue. In some patients the cornea is the initial manifestation of the autoimmune process sometimes well in advance before the systemic condition manifests. The collagen diseases related to peripheral corneo-scleral ulceration or sclero-keratitis, include systemic lupus erythematosus, rheumatoid arthritis, Wegener's granullomatosis and polyarteritis nodosa. The form of keratitis seen in theses cases is epithelial with a significant stromal component mainly in the form of subtle infiltrate with severe stromal melting and associated episcleral or scleral vasculitis (Fig 8). In other circumstances the cornea is the only affected structure as it is seen in Mooren's or peripheral ulcerative keratitis, the characteristic clinical finding is

**Figure 6.** a) Epithelial infiltrate with perineuritis in a patient with acanthamoeba keratitis. b) Diffuse stromal infiltrate in early acanthamoeba keratitis.

#### *5.1.5. Atypical*

This term is used to describe an infectious keratitis caused by atypical microorganisms like mycobacterium. The pattern of keratitis can be very confusing as it occurs usually in the context of postoperative, traumatic or previous corneal pathology situations. The course is always chronic, unresponsive to multiple previous treatments and the clinical picture varies between an epithelial and stromal form of keratitis with atypical features (Fig 7). Perhaps the most important aspect is the invariable presence of a significant risk factor like previous surgery, as this pathogen needs a significant break in the epithelial barrier to be able to invade and cause the condition due to its relative large size. The isolation of mycobacterium to confirm diagnosis depends on a high level of suspicion and the scrape or corneal biopsy culture that needs all the previously described media plus a Zhiel-Neelsen gram stain for identification of acid-fast bacteria and Lowenstein-Jensen agar for culture growth.

**Figure 7.** Atypical keratitis caused by mycobacterium abscessus after LASIK pre / post treatment.

#### **5.2. Inflammatory — Autoimmune keratitis (Non suppurative keratitis)**

Any condition that can induce an inflammatory response of the cornea can be classified in this group of causes of keratitis. There are autoimmune and no autoimmune related diseases.

#### *5.2.1. Autoimmune*

*5.1.4. Acanthamoeba*

214 Ophthalmology - Current Clinical and Research Updates

in early acanthamoeba keratitis.

*5.1.5. Atypical*

It is a rare cause of keratitis caused by one of the most common protozoa found in soil and water. In 90% of the cases a history of contact lens wear is found. Clinically this form of keratitis is combined with an epithelial and stromal component. The epithelial component is charac‐ teristically a large epithelial defect with abundant sub-epithelial infiltrate and enlargement of the corneal nerves that have been described as invaded by the pathogen at some stages of the disease, causing intense pain; this is perhaps the most painful form of keratitis, and this is regarded as a significant clinical finding at the time of diagnosing contact lens related keratitis. The stromal infiltrate is grey-whitish with irregular, multiple or single lesions, sometimes satellite areas can be seen (Fig 6 a & b). The diagnosis is confirmed by scrape or corneal epithelial biopsy sent for microbiological studies, it is important to repeat the gram and all the previously described medias (blood, BHI, CMB, Sabouraud's) and add the E. coli enriched

**Figure 6.** a) Epithelial infiltrate with perineuritis in a patient with acanthamoeba keratitis. b) Diffuse stromal infiltrate

This term is used to describe an infectious keratitis caused by atypical microorganisms like mycobacterium. The pattern of keratitis can be very confusing as it occurs usually in the context

non-nutrient agar media where this pathogen can be detected easily.

Like in any other autoimmune condition where the main target is the collagen in the body, the so-called autoimmune collagen or connective tissue diseases can be responsible for various forms of inflammatory keratitis, due to the high content of collagen seen in the corneal and scleral tissue. In some patients the cornea is the initial manifestation of the autoimmune process sometimes well in advance before the systemic condition manifests. The collagen diseases related to peripheral corneo-scleral ulceration or sclero-keratitis, include systemic lupus erythematosus, rheumatoid arthritis, Wegener's granullomatosis and polyarteritis nodosa. The form of keratitis seen in theses cases is epithelial with a significant stromal component mainly in the form of subtle infiltrate with severe stromal melting and associated episcleral or scleral vasculitis (Fig 8). In other circumstances the cornea is the only affected structure as it is seen in Mooren's or peripheral ulcerative keratitis, the characteristic clinical finding is corneal stromal melting associated to inflammation (Fig 9 a & b).

*5.2.2. Non autoimmune*

(Fig 12).

**Figure 10.** Typical marginal keratitis associated to rosacea.

**Figure 11.** Superficial epithelial defects in dry eye syndrome.

In this group, we find conditions that can compromise the delicate functional triad between the cornea, the tear film and the lids. If any of these is affected it will indirectly affect the anatomy and function of the other, potentially causing an inflammatory keratitis. Lids conditions like blepharitis, rosacea, lagophthalmos, entropion, ectropion, tarsal calcareous concretions or tear film dysfunctions like the ones seen in Sjogren's or severe dry eye syndrome can directly or indirectly cause keratitis in the form of marginal keratitis (Fig 10), phlyctenular keratoconjunctivitis and sometimes diffuse punctate keratitis as seen in Thygeson's keratitis. Usually the clinical pattern in this form of keratitis is epithelial with isolated or multiple epithelial defects and sub-epithelial superficial mild infiltrates (Fig 11), filaments can also sometimes be seen. When chronically affected a peripheral corneal pannus can often be seen

Keratitis — A Clinical Approach http://dx.doi.org/10.5772/58411 217

**Figure 8.** Sclerokeratitis in a patient with Wegener's granullomatosis.

**Figure 9.** a) Peripheral ulcerative keratitis with associated scleritis and corneal stromal corneal infiltrate. b) Typical case of Mooren's keratitis.

### *5.2.2. Non autoimmune*

**Figure 8.** Sclerokeratitis in a patient with Wegener's granullomatosis.

216 Ophthalmology - Current Clinical and Research Updates

**Figure 9.** a) Peripheral ulcerative keratitis with associated scleritis and corneal stromal corneal infiltrate. b) Typical case

of Mooren's keratitis.

In this group, we find conditions that can compromise the delicate functional triad between the cornea, the tear film and the lids. If any of these is affected it will indirectly affect the anatomy and function of the other, potentially causing an inflammatory keratitis. Lids conditions like blepharitis, rosacea, lagophthalmos, entropion, ectropion, tarsal calcareous concretions or tear film dysfunctions like the ones seen in Sjogren's or severe dry eye syndrome can directly or indirectly cause keratitis in the form of marginal keratitis (Fig 10), phlyctenular keratoconjunctivitis and sometimes diffuse punctate keratitis as seen in Thygeson's keratitis. Usually the clinical pattern in this form of keratitis is epithelial with isolated or multiple epithelial defects and sub-epithelial superficial mild infiltrates (Fig 11), filaments can also sometimes be seen. When chronically affected a peripheral corneal pannus can often be seen (Fig 12).

**Figure 10.** Typical marginal keratitis associated to rosacea.

**Figure 11.** Superficial epithelial defects in dry eye syndrome.

**Figure 12.** Peripheral pannus in chronic dry eye syndrome.

#### **5.3. Neoplasia associated inflammatory corneal involvement**

Any neoplastic process in the limbal region and surrounding conjunctiva can indirectly extend to the cornea and cause an inflammatory reaction, this is generally not considered in the differential diagnosis of keratitis and is perhaps the most rare and less suspected cause of corneal and limbal inflammation, however it is important to consider it in order to achieve an early diagnosis, as this type of conditions untreated can extend quickly with some mortality rate.

**Figure 14.** Conjunctival intraepithelial neoplasia (CIN) grade 3 treated with topical mytomicin C.

They are rare but lethal. They can be very polymorphic with multiple types of different clinical presentation, pigmented (melanotic) or not pigmented (amelanotic), they are of rapid growth and can invade distant organs especially lungs and liver. The most likely origin is at the conjunctival epithelial cells when some pigmentation is associated. Isolated or multiple

Keratitis — A Clinical Approach http://dx.doi.org/10.5772/58411 219

**Figure 15.** Four different conjunctival melanomas with corneal involvement, notice the polymorphism in clinical pre‐

In this group we can consider trauma by direct blunt injury with secondary corneal abrasion and corneal edema, or a surgical injury that damages the endothelial layer causing secondary corneal edema and endothelial failure with concurrent bullous keratopathy. The type of keratitis seen in these situations is mainly endothelial and stromal with multiple descemet folds, stromal collagen fibers disorganization, keratic precipitates and often associated anterior chamber reaction. At later stages if the endothelial layer does not recover from the insult, a severe corneal edema may lead to epithelial bullous formation and consequent epithelial keratitis. A clear history of trauma might not be obvious and the clinicians are encouraged to obtain it from the clinical history remembering that sometimes the traumatic event can precede

the clinical manifestation for many years (i.e. previous cataract surgery, etc)

*5.3.2. Conjunctival / limbal melanomas*

sentation.

**5.4.  Conjunctival intraepithelial neoplasia and squamous carcinoma*

Neoplasia of the conjunctival epithelial cells is more commonly seen in the elderly. There are different grades of penetration in the underlying tissue and the amount of cellular atypical cells defines also the degree of malignancy ranging from grade 1 to a carcinoma in situ. The more invasive the type of neoplasia, the more likely this will extend to the adjacent corneal tissue and regional lymphonodes; the corneal involvement always remains superficial (Fig 13, 14).

**Figure 13.** Conjunctival intraepithelial neoplasia (CIN) grade 3 with and without fluorescein staining.

**Figure 14.** Conjunctival intraepithelial neoplasia (CIN) grade 3 treated with topical mytomicin C.

### *5.3.2. Conjunctival / limbal melanomas*

**Figure 12.** Peripheral pannus in chronic dry eye syndrome.

218 Ophthalmology - Current Clinical and Research Updates

rate.

13, 14).

**5.3. Neoplasia associated inflammatory corneal involvement**

*5.3.1. Conjunctival intraepithelial neoplasia and squamous carcinoma*

Any neoplastic process in the limbal region and surrounding conjunctiva can indirectly extend to the cornea and cause an inflammatory reaction, this is generally not considered in the differential diagnosis of keratitis and is perhaps the most rare and less suspected cause of corneal and limbal inflammation, however it is important to consider it in order to achieve an early diagnosis, as this type of conditions untreated can extend quickly with some mortality

Neoplasia of the conjunctival epithelial cells is more commonly seen in the elderly. There are different grades of penetration in the underlying tissue and the amount of cellular atypical cells defines also the degree of malignancy ranging from grade 1 to a carcinoma in situ. The more invasive the type of neoplasia, the more likely this will extend to the adjacent corneal tissue and regional lymphonodes; the corneal involvement always remains superficial (Fig

**Figure 13.** Conjunctival intraepithelial neoplasia (CIN) grade 3 with and without fluorescein staining.

They are rare but lethal. They can be very polymorphic with multiple types of different clinical presentation, pigmented (melanotic) or not pigmented (amelanotic), they are of rapid growth and can invade distant organs especially lungs and liver. The most likely origin is at the conjunctival epithelial cells when some pigmentation is associated. Isolated or multiple sentinel vessels are a pathognomonic feature (Fig. 15).

**Figure 15.** Four different conjunctival melanomas with corneal involvement, notice the polymorphism in clinical pre‐ sentation.

#### **5.4. Traumatic keratitis**

In this group we can consider trauma by direct blunt injury with secondary corneal abrasion and corneal edema, or a surgical injury that damages the endothelial layer causing secondary corneal edema and endothelial failure with concurrent bullous keratopathy. The type of keratitis seen in these situations is mainly endothelial and stromal with multiple descemet folds, stromal collagen fibers disorganization, keratic precipitates and often associated anterior chamber reaction. At later stages if the endothelial layer does not recover from the insult, a severe corneal edema may lead to epithelial bullous formation and consequent epithelial keratitis. A clear history of trauma might not be obvious and the clinicians are encouraged to obtain it from the clinical history remembering that sometimes the traumatic event can precede the clinical manifestation for many years (i.e. previous cataract surgery, etc)

### **6. Keratitis: Treatment**

The treatment of keratitis will depend on the direct cause; it is for this reason that an appro‐ priate diagnosis is crucial at the moment of deciding the initial treatment.

of any suspicious lesion ideally has to have a margin of two centimeters of healthy tissue to prevent recurrences. In CIN cases concomitant cryotherapy is useful as well as topical mytomicin C or 5 – fluorouracil at different concentrations. In melanomas a systemic workup including chest CT scan and liver function tests at regular intervals to detect metastasis is important, concomitant local radiotherapy has been advocated as well at the time of removal

Keratitis — A Clinical Approach http://dx.doi.org/10.5772/58411 221

In cases of corneal abrasion the treatment of choice is to use topical antibiotic ointments to prevent infections and to pad the eye for 24 hours to allow epithelisation of the cornea, the use of preservative free cycloplegic drops initially to relief pain is recommended before padding. In blunt injuries the use of topical anti-inflammatory or steroid drops is useful depending on the severity of the inflammation. In cases of bullose keratopathy, endothelial corneal trans‐ plantation is highly successful, the use of highly osmotic drops like NACL 5% or bandage contact lenses can sometimes clear the corneal stroma and relief pain while waiting for a

A clear and simple approach to the differential diagnosis of keratitis has been presented. The methodological clinical diagnostic remains the cornerstone of medicine at anytime, the clinical history, examination of the patient and auxiliary diagnostic methods to confirm a suspected diagnosis are all crucial in achieving a clinical improvement of the clinical condition known

The simple classification based on clinical findings will help ophthalmologists, general practitioners to assess patients with this condition and start an adequate initial investigation

Keratitis remains one of the most frequent diagnoses in ophthalmology and a comprehensive

review like the one here presented is useful for any levels of clinical practice.

of the lesion.

**6.4. Traumatic**

corneal donor.

**7. Conclusion**

as keratitis.

and treatment

**Author details**

Patricio A. Pacheco1,2

1 Moorfields Eye Hospital, London, UK

2 West Hertfordshire Hospitals, NHS trust, UK

### **6.1. Infectious causes**

In viral herpetic keratitis cases, the drug of choice is acyclovir in topical or oral form depending on the extension of the keratitis within the corneal layers. A typical dose is ointment acyclovir 3% five times daily for one week or 400 mg orally five times a day for the same period. In severe cases both forms can be used to maximize effect. In children and the elderly the oral formula‐ tion is recommended due to difficulties in the application of the ointment. In resistant cases the alternative treatment will be topical trifluorthymidine 1% (F3T) or vidarabine 3% (Vira-Atm). If high intraocular pressure (IOP) is detected this also need to be treated with lowering IOP agents. Other antiviral agents like topical ganciclovir 0.15% (Zirgantm) have started to be used more widely in recent years.

In bacterial suspected infections the initial treatment of choice is topical ciprofloxacin 0.3%, Ofloxacin 0.3% or levofloxacin 0.3% hourly, when significant anterior chamber reaction is found a cycloplegic/dilating drop to minimize pain and reduce the formation of posterior synechias is recommended and depending on the bacterial sensitivities results the treatment should be adjusted accordingly.

In acanthamoeba the treatment requires a combination of poly-hexyl-methyl-biguanide 0.02% (PHMB) and propamide isethionate 0.1% (Brolenetm), alternatively preparations of chlorhexi‐ dine 0.02% can be used as well.

In atypical keratitis one can start treatment based on the suspicious on the most likely clinically apparent etyiological cause and adequate it based on the findings from the sampling.

### **6.2. Inflammatory / autoimmune**

For autoimmune keratitis usually systemic therapy is needed, the important approach in the treatment is to identify corneal limbal ischemia and/or corneal melting as these are reasons not to use topical steroids due to the high risk of perforation. Severe cases will need high dose of oral steroids and immunosuppressant agents. No autoimmune cases, presenting with inflammatory features due to blepharitis and/or dry eyes with marginal infiltrates do benefit from topical steroids, however is also very important to treat the initial cause of corneal inflammation as this is usually secondary, i.e. removal of concretions and ectopic eyelashes, repair lagophthalmos or other lids malpositions, treat dry eyes with topical lubricants, etc.

### **6.3. Neoplasia associated**

Surgical removal and biopsy is important as it is based on the histological diagnosis that further interventions like cryotherapy or radiotherapy might be indicated and planned. The excision of any suspicious lesion ideally has to have a margin of two centimeters of healthy tissue to prevent recurrences. In CIN cases concomitant cryotherapy is useful as well as topical mytomicin C or 5 – fluorouracil at different concentrations. In melanomas a systemic workup including chest CT scan and liver function tests at regular intervals to detect metastasis is important, concomitant local radiotherapy has been advocated as well at the time of removal of the lesion.

### **6.4. Traumatic**

**6. Keratitis: Treatment**

220 Ophthalmology - Current Clinical and Research Updates

used more widely in recent years.

should be adjusted accordingly.

dine 0.02% can be used as well.

**6.2. Inflammatory / autoimmune**

topical lubricants, etc.

**6.3. Neoplasia associated**

**6.1. Infectious causes**

The treatment of keratitis will depend on the direct cause; it is for this reason that an appro‐

In viral herpetic keratitis cases, the drug of choice is acyclovir in topical or oral form depending on the extension of the keratitis within the corneal layers. A typical dose is ointment acyclovir 3% five times daily for one week or 400 mg orally five times a day for the same period. In severe cases both forms can be used to maximize effect. In children and the elderly the oral formula‐ tion is recommended due to difficulties in the application of the ointment. In resistant cases the alternative treatment will be topical trifluorthymidine 1% (F3T) or vidarabine 3% (Vira-Atm). If high intraocular pressure (IOP) is detected this also need to be treated with lowering IOP agents. Other antiviral agents like topical ganciclovir 0.15% (Zirgantm) have started to be

In bacterial suspected infections the initial treatment of choice is topical ciprofloxacin 0.3%, Ofloxacin 0.3% or levofloxacin 0.3% hourly, when significant anterior chamber reaction is found a cycloplegic/dilating drop to minimize pain and reduce the formation of posterior synechias is recommended and depending on the bacterial sensitivities results the treatment

In acanthamoeba the treatment requires a combination of poly-hexyl-methyl-biguanide 0.02% (PHMB) and propamide isethionate 0.1% (Brolenetm), alternatively preparations of chlorhexi‐

In atypical keratitis one can start treatment based on the suspicious on the most likely clinically

For autoimmune keratitis usually systemic therapy is needed, the important approach in the treatment is to identify corneal limbal ischemia and/or corneal melting as these are reasons not to use topical steroids due to the high risk of perforation. Severe cases will need high dose of oral steroids and immunosuppressant agents. No autoimmune cases, presenting with inflammatory features due to blepharitis and/or dry eyes with marginal infiltrates do benefit from topical steroids, however is also very important to treat the initial cause of corneal inflammation as this is usually secondary, i.e. removal of concretions and ectopic eyelashes, repair lagophthalmos or other lids malpositions, treat dry eyes with

Surgical removal and biopsy is important as it is based on the histological diagnosis that further interventions like cryotherapy or radiotherapy might be indicated and planned. The excision

apparent etyiological cause and adequate it based on the findings from the sampling.

priate diagnosis is crucial at the moment of deciding the initial treatment.

In cases of corneal abrasion the treatment of choice is to use topical antibiotic ointments to prevent infections and to pad the eye for 24 hours to allow epithelisation of the cornea, the use of preservative free cycloplegic drops initially to relief pain is recommended before padding. In blunt injuries the use of topical anti-inflammatory or steroid drops is useful depending on the severity of the inflammation. In cases of bullose keratopathy, endothelial corneal trans‐ plantation is highly successful, the use of highly osmotic drops like NACL 5% or bandage contact lenses can sometimes clear the corneal stroma and relief pain while waiting for a corneal donor.

### **7. Conclusion**

A clear and simple approach to the differential diagnosis of keratitis has been presented. The methodological clinical diagnostic remains the cornerstone of medicine at anytime, the clinical history, examination of the patient and auxiliary diagnostic methods to confirm a suspected diagnosis are all crucial in achieving a clinical improvement of the clinical condition known as keratitis.

The simple classification based on clinical findings will help ophthalmologists, general practitioners to assess patients with this condition and start an adequate initial investigation and treatment

Keratitis remains one of the most frequent diagnoses in ophthalmology and a comprehensive review like the one here presented is useful for any levels of clinical practice.

### **Author details**

Patricio A. Pacheco1,2

1 Moorfields Eye Hospital, London, UK

2 West Hertfordshire Hospitals, NHS trust, UK

### **References**

[1] Chow, C.Y.; Foster, C.S. (1996). Mooren's ulcer. *International Ophthalmology clinics*, Vol. 36, (Winter 1996), pp. 1-13

**Section 3**

**Updates in Posterior Segment Diseases**

**Updates in Posterior Segment Diseases**

**References**

Vol. 36, (Winter 1996), pp. 1-13

222 Ophthalmology - Current Clinical and Research Updates

tember 2013), pp. 1778-1785

Vol. 86, (May 2002), pp. 536-542

409-416

*Cornea*, Vol. 18, (March 1999), pp. 144-154

ISBN 0-323-03737, 1st edition, Philadelphia, USA

*ogy*, Vol. 44, (March-April 2000), pp. 146-150

*vey Ophthalmology*, Vol. 32, (January 1987), pp. 94-110

[1] Chow, C.Y.; Foster, C.S. (1996). Mooren's ulcer. *International Ophthalmology clinics*,

[2] Donzis, P.B.; Mondino, B.J. (1987). Management of non infectious corneal ulcers. *Sur‐*

[3] Dua, H.S.; Faraj, L.A.; Said, D.G.; Gray, T.; Lowe, J. *Ophthalmology*, Vol. 120 (9), (Sep‐

[4] Holland, E.J.; Schwartz, G.S. (1999). Classification of herpes simplex virus keratitis,

[5] Kanski, J.; Pavesio C. & Tuft S. (2006). Ocular Inflammatory Disease, Mosby-Elsevier,

[6] Ladas, J.G.; Mondino, B.J. (2000). Systemic disorders associated with peripheral cor‐ neal ulcération. *Current opinion Ophthalmology*, Vol. 11, (December 2000), pp. 468-471

[7] Radford, C.F.; Minassian, D.C. & Dart, J.K. (2002). Acanthamoeba keratitis in Eng‐ land and Wales: incidence, outcomes and risk factors. *British Journal Ophthalmology*,

[8] Rohatgi, J.; Dhaliwal, U. (2000). Phlyctenular eye disease. *Japanese Journal Ophthalmol‐*

[9] Suchecki, J.K. ; Donshik, P. & Ehlers W.H. (2003). Contact lens complications. *Oph‐*

[10] Solomon, A.; Karp, C.L. & Miller, D. (2001). Mycobacterium interface keratitis after laser in situ keratomileusis. *Ophthalmology*, Vol. 108, (December 2001), pp. 2201-2208

[11] Stern, M.; Gao, J & Siemasko, K. F. (2004). The rôle of the lacrimal functional unit in the pathophysiology of dry eye. *Experimental Eye Research*, Vol. 78, (March 2004), pp.

*thalmology Clinics North America*, Vol. 16, (March 2003), pp. 471-484

**Chapter 10**

**Structure and Function Relationship in Glaucoma-**

Physicians, by nature, seem to strive for more precise means to diagnose, quantify and manage chronic disease. It seems intuitive that doing so will help us diagnose earlier, have an increased understanding for the relative severity of disease in individual patients and, ultimately, through more timely diagnosis, mitigate morbidities associated with that disease. In the example of diabetes, we can now look at glycosylated hemoglobin levels (HbA1c) and derive a reasonable understanding of risk level and relative treatment success for individual patients. While the HbA1c value is not flawless as a metric, it has become an extremely robust and accepted tool in diabetes management. Our efforts to coalesce ocular physical measurements with functional values seem to point to our desire to define glaucoma in one simple value. While the effort itself has already shed great benefits to our understanding of this complex disease, it ultimately seems unlikely that we will ever be able to adequately define glaucoma

During the past century, the metrics used to diagnose and manage glaucoma have varied and evolved. In the 1950's, using Schiotz tonometry, Leydecker showed that approximately 2.5% of the population had intraocular pressures greater than 21mm Hg. It was also determined that a similar number of people in that study had glaucoma. From that point forward, 21mm Hg became the empirical metric for determining who was at risk. More than fifty years has passed since the publication of Leydecker's study and a cornucopia of compelling scientific literature has been presented which has shed light on the diversity and complexity of glaucoma and clearly diminishes its relevance as a stand-alone diagnostic feature. Ironically, the vast body of evidence which clearly discourages reliance of the old 21 mm red flag in glaucoma diagnosis seems not to have been sufficient to clear it from the minds and hearts of too many

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Historical Perspective to a Practical Approach**

Additional information is available at the end of the chapter

Elliot M. Kirstein

**1. Introduction**

http://dx.doi.org/10.5772/57601

in terms of a singular value.

## **Structure and Function Relationship in Glaucoma-Historical Perspective to a Practical Approach**

Elliot M. Kirstein

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57601

### **1. Introduction**

Physicians, by nature, seem to strive for more precise means to diagnose, quantify and manage chronic disease. It seems intuitive that doing so will help us diagnose earlier, have an increased understanding for the relative severity of disease in individual patients and, ultimately, through more timely diagnosis, mitigate morbidities associated with that disease. In the example of diabetes, we can now look at glycosylated hemoglobin levels (HbA1c) and derive a reasonable understanding of risk level and relative treatment success for individual patients. While the HbA1c value is not flawless as a metric, it has become an extremely robust and accepted tool in diabetes management. Our efforts to coalesce ocular physical measurements with functional values seem to point to our desire to define glaucoma in one simple value. While the effort itself has already shed great benefits to our understanding of this complex disease, it ultimately seems unlikely that we will ever be able to adequately define glaucoma in terms of a singular value.

During the past century, the metrics used to diagnose and manage glaucoma have varied and evolved. In the 1950's, using Schiotz tonometry, Leydecker showed that approximately 2.5% of the population had intraocular pressures greater than 21mm Hg. It was also determined that a similar number of people in that study had glaucoma. From that point forward, 21mm Hg became the empirical metric for determining who was at risk. More than fifty years has passed since the publication of Leydecker's study and a cornucopia of compelling scientific literature has been presented which has shed light on the diversity and complexity of glaucoma and clearly diminishes its relevance as a stand-alone diagnostic feature. Ironically, the vast body of evidence which clearly discourages reliance of the old 21 mm red flag in glaucoma diagnosis seems not to have been sufficient to clear it from the minds and hearts of too many

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

eye doctors in this century. It would appear that we have an inner need to strive for and adhere to simple answers to even the most complex problems.

**Figure 2.** Early Welsh Allyn ophthalmoscope

**3. Disc documentation**

of the disc remained the clinical standard.

which were rendered by professional medical artists.

**3.1. Drawings**

In 1915, Francis A. Welch and William Noah Allyn invented the world's first hand-held direct illuminating ophthalmoscope, precursor to the device now used by clinicians around the world. This refinement and updating of von Helmholtz's invention enabled ophthalmoscopy to become one of the most ubiquitous medical screening techniques in the world today. The

Structure and Function Relationship in Glaucoma-Historical Perspective to a Practical Approach

http://dx.doi.org/10.5772/57601

227

The need for stereopsis arose soon after the discovery of the ophthalmoscope. Given the limitations of a two dimensional view, the glaucomatous cup was, at first, mistaken for a swelling. At that time, Brewster's popular stereoscope was introduced, and its theory and method were then applied to ophthalmoscopy by Giraud-Teulon. His was the first binocular instrument, subsequently much improved by Zachariah Laurence. Binocular indirect oph‐ thalmoscopy was abandoned toward the end of the 19th century in favor of direct monocular ophthalmoscopy, until it was revived in the 1950s by Schepens. More recently, hand held biomicroscopic lenses, which were popularized in the late 1980's by Volk Optical, Inc., are now a clinical standard for indirect three dimensional observations and evaluation of the nerve. [3]

Having the ability to view the nerve in vivo, proper scientific method deemed it necessary to document of these observations. For the better part of the twentieth century, manual drawing

While disc drawing and careful direct observation of the nerve still have significant benefits, our scientific curiosity and our frank understanding of the likelihood of human variability and error with manual drawings, has driven us to develop methods of observation and recording which yield information down to the cellular level and render documentation which is relatively free of the obvious variability in individual observer skill and methodology.

Before the mid 1970's, eye doctors, in training, could not yet see photographs of the live human retina. Ophthalmic texts traditionally included drawings of normal and pathological eyes,

company started as a result of this invention is Welch Allyn. [2]

**Figure 1.** CURRENT SIGNIFICANCE OF 21 mmHg: The distribution of IOP in the general population as studied by Ley‐ decker (normal IOP was statistically defined two standard deviations above and below mean, as 11-21 mmHg) is not Gaussian, but is slightly skewed towards higher IOP's [1]

Beyond the early observation that glaucomatous vision loss is generally accompanied with high intraocular pressure, scientists began to observe the physical changes within the eye that seemed to occur in concert with that loss. In 1885, Priestley Smith elegantly defined glaucoma, stating that "The excavation of the disc in glaucoma is not a purely mechanical result of exalted pressure; it is, in part at least, an atrophic condition which, though primarily due to pressure, includes vascular changes and impaired nutrition of the substance of the optic disc… which may possibly progress even though all excessive pressure be removed". Given this under‐ standing, eye doctors started to look for tools to study the eye and its function in greater detail.

Today, eye doctors are challenged with a new puzzle. In current clinical practive we can obtain physical and psychometric data that was previously unimaginable. We are still attempting to determine which of the vast data has the greatest utility and specificity in regard to the diagnosis, quantification and management of glaucoma.

### **2. Observation and measurement of structure**

### **2.1. Ophthalmoscopy**

Understandably, long before doctors could document the eye's interior contents with imaging techniques, observation and evaluation of the nerve was performed by ophthalmoscopy. Observations were recorded with drawings. Though others produced earlier versions of the ophthalmoscope, in 1851, Hermann von Helmholtz reported its usefulness and, therein, revolutionized ophthalmology.

**Figure 2.** Early Welsh Allyn ophthalmoscope

eye doctors in this century. It would appear that we have an inner need to strive for and adhere

**Figure 1.** CURRENT SIGNIFICANCE OF 21 mmHg: The distribution of IOP in the general population as studied by Ley‐ decker (normal IOP was statistically defined two standard deviations above and below mean, as 11-21 mmHg) is not

Beyond the early observation that glaucomatous vision loss is generally accompanied with high intraocular pressure, scientists began to observe the physical changes within the eye that seemed to occur in concert with that loss. In 1885, Priestley Smith elegantly defined glaucoma, stating that "The excavation of the disc in glaucoma is not a purely mechanical result of exalted pressure; it is, in part at least, an atrophic condition which, though primarily due to pressure, includes vascular changes and impaired nutrition of the substance of the optic disc… which may possibly progress even though all excessive pressure be removed". Given this under‐ standing, eye doctors started to look for tools to study the eye and its function in greater detail.

Today, eye doctors are challenged with a new puzzle. In current clinical practive we can obtain physical and psychometric data that was previously unimaginable. We are still attempting to determine which of the vast data has the greatest utility and specificity in regard to the

Understandably, long before doctors could document the eye's interior contents with imaging techniques, observation and evaluation of the nerve was performed by ophthalmoscopy. Observations were recorded with drawings. Though others produced earlier versions of the ophthalmoscope, in 1851, Hermann von Helmholtz reported its usefulness and, therein,

to simple answers to even the most complex problems.

226 Ophthalmology - Current Clinical and Research Updates

Gaussian, but is slightly skewed towards higher IOP's [1]

diagnosis, quantification and management of glaucoma.

**2. Observation and measurement of structure**

**2.1. Ophthalmoscopy**

revolutionized ophthalmology.

In 1915, Francis A. Welch and William Noah Allyn invented the world's first hand-held direct illuminating ophthalmoscope, precursor to the device now used by clinicians around the world. This refinement and updating of von Helmholtz's invention enabled ophthalmoscopy to become one of the most ubiquitous medical screening techniques in the world today. The company started as a result of this invention is Welch Allyn. [2]

The need for stereopsis arose soon after the discovery of the ophthalmoscope. Given the limitations of a two dimensional view, the glaucomatous cup was, at first, mistaken for a swelling. At that time, Brewster's popular stereoscope was introduced, and its theory and method were then applied to ophthalmoscopy by Giraud-Teulon. His was the first binocular instrument, subsequently much improved by Zachariah Laurence. Binocular indirect oph‐ thalmoscopy was abandoned toward the end of the 19th century in favor of direct monocular ophthalmoscopy, until it was revived in the 1950s by Schepens. More recently, hand held biomicroscopic lenses, which were popularized in the late 1980's by Volk Optical, Inc., are now a clinical standard for indirect three dimensional observations and evaluation of the nerve. [3]

### **3. Disc documentation**

### **3.1. Drawings**

Having the ability to view the nerve in vivo, proper scientific method deemed it necessary to document of these observations. For the better part of the twentieth century, manual drawing of the disc remained the clinical standard.

While disc drawing and careful direct observation of the nerve still have significant benefits, our scientific curiosity and our frank understanding of the likelihood of human variability and error with manual drawings, has driven us to develop methods of observation and recording which yield information down to the cellular level and render documentation which is relatively free of the obvious variability in individual observer skill and methodology.

Before the mid 1970's, eye doctors, in training, could not yet see photographs of the live human retina. Ophthalmic texts traditionally included drawings of normal and pathological eyes, which were rendered by professional medical artists.

**Figure 5.** Optic nerve photograph

**3.3. Beyond photography**

**Figure 6.** Simultaneous digital stereo disc photograph captured using the Nidek 3-DX system

While photography had given us robust methodology for documentation of the appearance of the optic nerve head, it seemed natural to look for ways to numerically quantify various nerve attributes. An early attempt called the Glaucomascope, cast a series of infrared bars across the surface of the nerve. The variation in line contours signaled the instrument to make calculations regarding cup dimensions and, hopefully, track topographical change in con‐ cordance with glaucoma progression. The next generation of devices including the GDX (Carl Ziess) and the Heidelberg Retinal Tomograph (HRT) (Heidelberg Engineering), provided a

Structure and Function Relationship in Glaucoma-Historical Perspective to a Practical Approach

http://dx.doi.org/10.5772/57601

229

**Figure 3.** Typical clinician's disc drawing

**Figure 4.** Medical artist's disc drawing of glaucomatous optic nerve

#### **3.2. Photography**

With fundus photography becoming commonplace by the early 1980's, stereo disc photogra‐ phy became possible and earned its place as the clinical gold standard in optic nerve docu‐ mentation for the remainder of the twentieth century.

Recently, digital two and three dimensional photography have quickly outpaced conventional film photography of the nerve because of its obvious advantages in efficiency, economy and portability.

**Figure 5.** Optic nerve photograph

**Figure 3.** Typical clinician's disc drawing

228 Ophthalmology - Current Clinical and Research Updates

**Figure 4.** Medical artist's disc drawing of glaucomatous optic nerve

mentation for the remainder of the twentieth century.

With fundus photography becoming commonplace by the early 1980's, stereo disc photogra‐ phy became possible and earned its place as the clinical gold standard in optic nerve docu‐

Recently, digital two and three dimensional photography have quickly outpaced conventional film photography of the nerve because of its obvious advantages in efficiency, economy and

**3.2. Photography**

portability.

**Figure 6.** Simultaneous digital stereo disc photograph captured using the Nidek 3-DX system

#### **3.3. Beyond photography**

While photography had given us robust methodology for documentation of the appearance of the optic nerve head, it seemed natural to look for ways to numerically quantify various nerve attributes. An early attempt called the Glaucomascope, cast a series of infrared bars across the surface of the nerve. The variation in line contours signaled the instrument to make calculations regarding cup dimensions and, hopefully, track topographical change in con‐ cordance with glaucoma progression. The next generation of devices including the GDX (Carl Ziess) and the Heidelberg Retinal Tomograph (HRT) (Heidelberg Engineering), provided a more comprehensive perspective of nerve attributes and, with GDX, added new measure‐ ments of the nerve fiber layer surrounding the papilla. The HRT was the first to incorporate nerve progression analysis.

**Figure 7.** HRT 3-D image of the optic nerve and retinal nerve fiber layer (RNFL)

The Heidelberg Retina Tomograph (HRT) is a confocal scanning laser ophthalmoscope. A laser light scans the retina in 24 millisecond sequential scans, starting above the retinal surface, then capturing parallel images at increasing depths. The stacks of images can be combined to create a three-dimensional (3-D) topographic image of the retina. Images are aligned and compared using TruTrack™ software for both individual examinations and for detecting change between examinations.

A Dutch study found that while there is a correlation between standard automated perimetry and GDx, variable corneal compensation (VCC) measurements in patients with glaucoma, suggesting that GDx VCC measurements relate well with functional loss in glaucoma. In healthy subjects, they found virtually no correlation between perimetry and GDx VCC measurements. This would cast doubt on its predictive value and suggests false positives. [4]

Structure and Function Relationship in Glaucoma-Historical Perspective to a Practical Approach

http://dx.doi.org/10.5772/57601

231

Optical coherence tomography (OCT) has advanced considerably since it was first applied to the eye. It is an extension of a technique called low-coherence interferometry, which was initially applied to ophthalmology for in vivo measurements of eye axial length. OCT cross sections are used to evaluate the optic disc and retinal layers such as the retinal nerve fiber layer (RNFL). Scan patterns that enabled reproducible measurements were developed, and these eventually became incorporated into commercial systems. In 2000 Zangwill et al published a study comparing OCT nerve fiber thickness values against stereo photography and threshold visual field results showing that the OCT shows promise for providing quan‐

With these improvements in speed and sensitivity as seen in spectral domain OCT, it is now feasible to collect volumetric (three-dimensional; 3D) scans of tissue, whereas in the past, the amount of time required to do this would have been prohibitive. Broadband volumetric retinal imaging with SD-OCT have demonstrated speeds of up to 312,500. To date, most clinical systems operate at an acquisition rate of ∼27,000 A-scans/s and an axial resolution of 5 to 6 µm. The unprecedented speed and versatility of current forms of OCT have given us a new and vast data set, allowing us to seek out specific retinal measurements that are most highly specific for the diagnosis and observation of glaucomatous progression. Having the capacity to observe tissue at a cellular level, we now can more aptly compare between individuals and with specific

**4. Ocular Coherence Tomography (OCT) – the new gold standard**

**Figure 8.** GDX ONH image

titative measures of RNFL thickness for diagnosing and monitoring glaucoma. [5]

When applying the technology to glaucoma, the HRT takes data from a 3-D stack of tomo‐ graphic images of the optic nerve and retinal nerve fiber layer (RNFL), aligns the images and computes a 3-D topographic map of the surface of the retina. This 3-D topographic map is analyzed for signs of glaucomatous damage and the results are displayed on either a single eye examination report or on an OU examination report.

The GDx nerve fiber analyzers measures the retinal nerve fiber layer (RNFL) thickness with a scanning laser polarimeter based on the birefringent properties of the RNFL. Measurement is obtained from a band 1.75 disc diameters concentric to the disc.

The GDx projects a polarized beam of a light into the eye. As this light passes through the NFL tissue, it changes in speed. The detectors measure the change and convert it into thickness units that are graphically displayed. The GDx measures modulation around an ellipse just outside the optics disc and ratios of the thickest points either superiorly or inferiorly to the temporal or nasal regions.

The state of polarization of the light is change (retardation) as it passes through birefringent tissue (cornea and RNFL). Corneal birefringence is eliminated (in part) by a propriety 'corneal compensator'. The amount of retardation of light reflected from the fundus is converted to RNFL thickness.

**Figure 8.** GDX ONH image

more comprehensive perspective of nerve attributes and, with GDX, added new measure‐ ments of the nerve fiber layer surrounding the papilla. The HRT was the first to incorporate

The Heidelberg Retina Tomograph (HRT) is a confocal scanning laser ophthalmoscope. A laser light scans the retina in 24 millisecond sequential scans, starting above the retinal surface, then capturing parallel images at increasing depths. The stacks of images can be combined to create a three-dimensional (3-D) topographic image of the retina. Images are aligned and compared using TruTrack™ software for both individual examinations and for detecting change between

When applying the technology to glaucoma, the HRT takes data from a 3-D stack of tomo‐ graphic images of the optic nerve and retinal nerve fiber layer (RNFL), aligns the images and computes a 3-D topographic map of the surface of the retina. This 3-D topographic map is analyzed for signs of glaucomatous damage and the results are displayed on either a single

The GDx nerve fiber analyzers measures the retinal nerve fiber layer (RNFL) thickness with a scanning laser polarimeter based on the birefringent properties of the RNFL. Measurement is

The GDx projects a polarized beam of a light into the eye. As this light passes through the NFL tissue, it changes in speed. The detectors measure the change and convert it into thickness units that are graphically displayed. The GDx measures modulation around an ellipse just outside the optics disc and ratios of the thickest points either superiorly or inferiorly to the temporal

The state of polarization of the light is change (retardation) as it passes through birefringent tissue (cornea and RNFL). Corneal birefringence is eliminated (in part) by a propriety 'corneal compensator'. The amount of retardation of light reflected from the fundus is converted to

**Figure 7.** HRT 3-D image of the optic nerve and retinal nerve fiber layer (RNFL)

eye examination report or on an OU examination report.

obtained from a band 1.75 disc diameters concentric to the disc.

nerve progression analysis.

230 Ophthalmology - Current Clinical and Research Updates

examinations.

or nasal regions.

RNFL thickness.

A Dutch study found that while there is a correlation between standard automated perimetry and GDx, variable corneal compensation (VCC) measurements in patients with glaucoma, suggesting that GDx VCC measurements relate well with functional loss in glaucoma. In healthy subjects, they found virtually no correlation between perimetry and GDx VCC measurements. This would cast doubt on its predictive value and suggests false positives. [4]

### **4. Ocular Coherence Tomography (OCT) – the new gold standard**

Optical coherence tomography (OCT) has advanced considerably since it was first applied to the eye. It is an extension of a technique called low-coherence interferometry, which was initially applied to ophthalmology for in vivo measurements of eye axial length. OCT cross sections are used to evaluate the optic disc and retinal layers such as the retinal nerve fiber layer (RNFL). Scan patterns that enabled reproducible measurements were developed, and these eventually became incorporated into commercial systems. In 2000 Zangwill et al published a study comparing OCT nerve fiber thickness values against stereo photography and threshold visual field results showing that the OCT shows promise for providing quan‐ titative measures of RNFL thickness for diagnosing and monitoring glaucoma. [5]

With these improvements in speed and sensitivity as seen in spectral domain OCT, it is now feasible to collect volumetric (three-dimensional; 3D) scans of tissue, whereas in the past, the amount of time required to do this would have been prohibitive. Broadband volumetric retinal imaging with SD-OCT have demonstrated speeds of up to 312,500. To date, most clinical systems operate at an acquisition rate of ∼27,000 A-scans/s and an axial resolution of 5 to 6 µm.

The unprecedented speed and versatility of current forms of OCT have given us a new and vast data set, allowing us to seek out specific retinal measurements that are most highly specific for the diagnosis and observation of glaucomatous progression. Having the capacity to observe tissue at a cellular level, we now can more aptly compare between individuals and with specific individuals over time. The additional information at hand also allows us to emerge from cup/ disc ratio, the age old and weather beaten descriptive of the nerve in the context of glaucoma. It is now possible to look far deeper into retinal and nerve attributes and across a wider diameter of retina, to look for structural changes that are most highly pathognomonic of glaucoma and its progression. [6]

**5. Measuring the nerve**

In quantifying glaucoma risk and severity, the C/D ratio of the optic nerve has been the standard bearer during the past one hundred years. An eye with a low ratio was considered less apt to be glaucomatous and, if glaucoma was diagnosed, was known to be less advanced. High ratios implied high risk and or advanced disease. Some investigators noted that that the significance of a specific C/D value would vary widely depending on the diameter of the nerve itself. Investigators also began to note that nerve attributes such as rim thickness can be quite meaningful. For example, given two nerves with C/D=.50, one may have a well centered cup and no glaucomatous visual field loss, while another,.50 nerve, with loss if the inferior margin may show a severe superior nasal field defect. To further confuse the notion of C/D, more recent attention has been given to disc diameter and its implications on the significance of C/D in individual patients. Our current understanding is that nerve diameter plays a large role in the relative value of C/D. A C/D of.60 with a relatively small nerve is likely to have far greater

Structure and Function Relationship in Glaucoma-Historical Perspective to a Practical Approach

http://dx.doi.org/10.5772/57601

233

Given the additional perspective of the influence of cup position and nerve diameter, it should be easy to understand the now diminished value of C/D as a singular descriptive value of the state of disease. Reminiscent of the loss of relevance of the age old "21 mm Hg" standard, our current understanding of the scope of changes that occur within the nerve, surrounding the nerve and, more recently, those changes in the axonal bed and the peri papillary ganglion cell layer, further disenfranchises C/D and the meaningful descriptive of structural change in

Technologies such as GDX and, more recently, OCT provide nerve fiber measurements outside of the boundaries of the disc and it has become evident that axonal changes in the area surrounding the nerve are important in understanding the nature and severity of

In a study performed by Bowd et al, clearly revealed that OCT revealed statistically significant quantitative differences in RNFL thickness between OHT and normal eyes within their study

Additional studies such as those performed by Garas (2009), Sehi (2009) and Savini (2009) (table 1) have helped develop greater confidence in our ability to clinically determine RNFL thickness and to evaluate those findings in comparison to a reasonable field of normative

Similar investigations in the following years helped give confidence that there was finally a method of determining RNFL thickness that was reliable enough so that meaningful compar‐ isons could be made between normal and glaucomatous subjects. Beyond that general comparison, investigators could search for specific nerve and other retinal attributes which are more specific to the diagnosis and management of glaucoma. In 2010, Mansoori et al

implications with regard to glaucoma than the same C/D in a large nerve.

**5.1. Cup Disc Ratio (C/D)**

glaucoma.

glaucoma. [7, 8]

population. [9]

data. [10-12]

**5.2. Retinal nerve fiber layer**

**Figure 9.** OCT crossectional view of the optic nerve

**Figure 10.** OCT three dimensional optic nerve scan

### **5. Measuring the nerve**

### **5.1. Cup Disc Ratio (C/D)**

individuals over time. The additional information at hand also allows us to emerge from cup/ disc ratio, the age old and weather beaten descriptive of the nerve in the context of glaucoma. It is now possible to look far deeper into retinal and nerve attributes and across a wider diameter of retina, to look for structural changes that are most highly pathognomonic of

glaucoma and its progression. [6]

232 Ophthalmology - Current Clinical and Research Updates

**Figure 9.** OCT crossectional view of the optic nerve

**Figure 10.** OCT three dimensional optic nerve scan

In quantifying glaucoma risk and severity, the C/D ratio of the optic nerve has been the standard bearer during the past one hundred years. An eye with a low ratio was considered less apt to be glaucomatous and, if glaucoma was diagnosed, was known to be less advanced. High ratios implied high risk and or advanced disease. Some investigators noted that that the significance of a specific C/D value would vary widely depending on the diameter of the nerve itself. Investigators also began to note that nerve attributes such as rim thickness can be quite meaningful. For example, given two nerves with C/D=.50, one may have a well centered cup and no glaucomatous visual field loss, while another,.50 nerve, with loss if the inferior margin may show a severe superior nasal field defect. To further confuse the notion of C/D, more recent attention has been given to disc diameter and its implications on the significance of C/D in individual patients. Our current understanding is that nerve diameter plays a large role in the relative value of C/D. A C/D of.60 with a relatively small nerve is likely to have far greater implications with regard to glaucoma than the same C/D in a large nerve.

Given the additional perspective of the influence of cup position and nerve diameter, it should be easy to understand the now diminished value of C/D as a singular descriptive value of the state of disease. Reminiscent of the loss of relevance of the age old "21 mm Hg" standard, our current understanding of the scope of changes that occur within the nerve, surrounding the nerve and, more recently, those changes in the axonal bed and the peri papillary ganglion cell layer, further disenfranchises C/D and the meaningful descriptive of structural change in glaucoma.

### **5.2. Retinal nerve fiber layer**

Technologies such as GDX and, more recently, OCT provide nerve fiber measurements outside of the boundaries of the disc and it has become evident that axonal changes in the area surrounding the nerve are important in understanding the nature and severity of glaucoma. [7, 8]

In a study performed by Bowd et al, clearly revealed that OCT revealed statistically significant quantitative differences in RNFL thickness between OHT and normal eyes within their study population. [9]

Additional studies such as those performed by Garas (2009), Sehi (2009) and Savini (2009) (table 1) have helped develop greater confidence in our ability to clinically determine RNFL thickness and to evaluate those findings in comparison to a reasonable field of normative data. [10-12]

Similar investigations in the following years helped give confidence that there was finally a method of determining RNFL thickness that was reliable enough so that meaningful compar‐ isons could be made between normal and glaucomatous subjects. Beyond that general comparison, investigators could search for specific nerve and other retinal attributes which are more specific to the diagnosis and management of glaucoma. In 2010, Mansoori et al showed that SD-OCT identified differences in most parameters between eyes with glaucoma and normal eyes and also between eyes with glaucoma and OHT. It was important to note that they also observed that there was overlap of RNFL thickness between normal and OHT eyes, which somewhat limits the ability of this instrument to differentiate between normal and OHT subjects.[13]

**Table 1.** Retinal nerve fiber layer thickness averages in normal patients. Garas et al 2009 (14 normals), Sehi et al (20 normals) and Savini et al (23 normals)

**Figure 11.** The RTVue scanning zones for assessment of the peripapillary retinal nerve fiber layer (RNFL) and the gan‐

Structure and Function Relationship in Glaucoma-Historical Perspective to a Practical Approach

http://dx.doi.org/10.5772/57601

235

**Figure 12.** Optovue OCT report showing RNFL and GCC thickness. Colors green, yellow and red indicate normal, bor‐

glion cell complex (GCC)

derline and abnormal (low) findings.

#### **5.3. Ganglion cell layer**

Most recently, the new abundant source of data rendered via spectral domain OCT measure‐ ments, allow us to document structural changes in the axonal bed as well as other retinal layers which were thought to, possibly, have close association with some types of glaucomatous progression. It seems intuitive that failing nerves might show changes at their endpoints before doing so in their mid-sections. Additionally, it seemed likely that axonal ganglia might show changes in concert with various types of axonal demise. Studies such as those conducted Desatnik et al and Ziemer et al in the 1990's helped point us to our new appreciation of the value of perimacular measurements. [14, 15]

Determining the extent of retinal ganglion cell loss may prove to be a superior method for identifying glaucomatous progression. The loss of these cells leads to functional deficits and structural changes in the retinal nerve fiber layer (RNFL). In their efforts to correlate structural and functional loss in glaucoma, Harwerth and associates showed that the number of retinal ganglion cells can be reliably estimated from either visual field sensitivity data or from OCT RNFL analysis. [16]

### **6. Functional measurement**

### **6.1. Subjective testing**

The first record of a visual field defect is found in Hippocrates description of a hemianopia from the late fifth century B.C. Ptolemy (150 B.C.) first attempted to quantify the visual field Structure and Function Relationship in Glaucoma-Historical Perspective to a Practical Approach http://dx.doi.org/10.5772/57601 235

showed that SD-OCT identified differences in most parameters between eyes with glaucoma and normal eyes and also between eyes with glaucoma and OHT. It was important to note that they also observed that there was overlap of RNFL thickness between normal and OHT eyes, which somewhat limits the ability of this instrument to differentiate between normal and OHT

 **Garas Sehi Savini**

**Average** 106.7 7.5 91.7 to 103.3 12.6 78.1 to 105.8 14.9 76.7 to **RNFL** 121.7 128.5 135.6 **Superior** 128.8 12.8 103.2 to 134.5 18.6 97.3 to 128.44 24.48 83.48 to

**Inferior** 136.6 12.7 111.2 to 129.7 16.9 95.9 to 137.15 21.99 93.17 to

**Table 1.** Retinal nerve fiber layer thickness averages in normal patients. Garas et al 2009 (14 normals), Sehi et al (20

Most recently, the new abundant source of data rendered via spectral domain OCT measure‐ ments, allow us to document structural changes in the axonal bed as well as other retinal layers which were thought to, possibly, have close association with some types of glaucomatous progression. It seems intuitive that failing nerves might show changes at their endpoints before doing so in their mid-sections. Additionally, it seemed likely that axonal ganglia might show changes in concert with various types of axonal demise. Studies such as those conducted Desatnik et al and Ziemer et al in the 1990's helped point us to our new appreciation of the

Determining the extent of retinal ganglion cell loss may prove to be a superior method for identifying glaucomatous progression. The loss of these cells leads to functional deficits and structural changes in the retinal nerve fiber layer (RNFL). In their efforts to correlate structural and functional loss in glaucoma, Harwerth and associates showed that the number of retinal ganglion cells can be reliably estimated from either visual field sensitivity data or from OCT

The first record of a visual field defect is found in Hippocrates description of a hemianopia from the late fifth century B.C. Ptolemy (150 B.C.) first attempted to quantify the visual field

**S/I** 0.943 1.037 0.936

**Mean Std. 95% Mean Std. 95% Mean Std. 95%**

**Dev. Normal Normal Dev. Normal Range Range Range**

154.4 171.1 173.4

162 163.5 181.13

subjects.[13]

234 Ophthalmology - Current Clinical and Research Updates

**Ratio**

normals) and Savini et al (23 normals)

value of perimacular measurements. [14, 15]

**5.3. Ganglion cell layer**

RNFL analysis. [16]

**6.1. Subjective testing**

**6. Functional measurement**

**Figure 11.** The RTVue scanning zones for assessment of the peripapillary retinal nerve fiber layer (RNFL) and the gan‐ glion cell complex (GCC)

**Figure 12.** Optovue OCT report showing RNFL and GCC thickness. Colors green, yellow and red indicate normal, bor‐ derline and abnormal (low) findings.

and noted its circular form. According to Lloyd, Galen was the first physician "to record a recognition of Extramacular fields." He suggests the first illustration of the visual field was published in an article by Ulmus of Padua in 1602.

which perimetry can be performed by bypassing the problem of local retinal adaptation, which

Structure and Function Relationship in Glaucoma-Historical Perspective to a Practical Approach

http://dx.doi.org/10.5772/57601

237

**Figure 15.** The normal island of vision. The hill is highest at fixation, where visual sensitivity is greatest. The height of

the hill of vision declines toward the periphery as visual sensitivity diminishes.

requires a 2-second interval between stimuli if adjacent locations are tested.

**Figure 14.** Albrecht von Graefe

Early in the sixteenth century (about 1510) Leonardo da Vinci recognized that temporally the visual field reaches around more than 90 degrees from fixation. He said (Manuscript D. folio 8 verso), "the eye sees those objects behind it that are placed in lateral areas." He suggested that the cornea and the aqueous served to bend the light rays into the eye.

**Figure 13.** DaVinci's Illustration of rays approaching the cornea from different directions

Von Graefe (below) is credited with introducing perimetry into clinical medicine. In 1855, at the age of 28, he published "Examination of the Visual Functions in Amblyopic Affections." Von Graefe built on the work of Helmholtz. Helmholtz had recommended that, in order to keep one's bearing during the examination of the ocular fundus, a numbered grid be placed in front of the patient to direct the patient's eye into certain known directions of gaze. It was a piece of blackboard marked in this way that von Graefe used as a tangent screen. He worked at a distance of 18 inches and used as a test object a piece of white chalk, about 1 cm across, held in a wire. He made use of various symbols and dots as a fixation point so that the patient could recognize his deficits more easily. [17]

It was not until the late 1980's, when automated perimetry became widely available, that manual methods of visual field assessment were finally outpaced as the clinical standard. With the newfound ability to determine the relative depth of defect of a given point, clinicians had the ability to appreciate a three dimensional plot of one's visual status.

The introduction of computers and automation heralded a new era in perimetric testing. Static testing can be performed in an objective and standardized fashion with minimal perimetrist bias. A quantitative representation of the visual field can be obtained more rapidly than with manual testing. The computer allows stimuli to be presented in a pseudorandom, unpredict‐ able fashion. Patients do not know where the next stimulus will appear, so fixation is improved, thereby increasing the reliability of the test. Random presentations also increase the speed with which perimetry can be performed by bypassing the problem of local retinal adaptation, which requires a 2-second interval between stimuli if adjacent locations are tested.

**Figure 14.** Albrecht von Graefe

and noted its circular form. According to Lloyd, Galen was the first physician "to record a recognition of Extramacular fields." He suggests the first illustration of the visual field was

Early in the sixteenth century (about 1510) Leonardo da Vinci recognized that temporally the visual field reaches around more than 90 degrees from fixation. He said (Manuscript D. folio 8 verso), "the eye sees those objects behind it that are placed in lateral areas." He suggested

Von Graefe (below) is credited with introducing perimetry into clinical medicine. In 1855, at the age of 28, he published "Examination of the Visual Functions in Amblyopic Affections." Von Graefe built on the work of Helmholtz. Helmholtz had recommended that, in order to keep one's bearing during the examination of the ocular fundus, a numbered grid be placed in front of the patient to direct the patient's eye into certain known directions of gaze. It was a piece of blackboard marked in this way that von Graefe used as a tangent screen. He worked at a distance of 18 inches and used as a test object a piece of white chalk, about 1 cm across, held in a wire. He made use of various symbols and dots as a fixation point so that the patient

It was not until the late 1980's, when automated perimetry became widely available, that manual methods of visual field assessment were finally outpaced as the clinical standard. With the newfound ability to determine the relative depth of defect of a given point, clinicians had

The introduction of computers and automation heralded a new era in perimetric testing. Static testing can be performed in an objective and standardized fashion with minimal perimetrist bias. A quantitative representation of the visual field can be obtained more rapidly than with manual testing. The computer allows stimuli to be presented in a pseudorandom, unpredict‐ able fashion. Patients do not know where the next stimulus will appear, so fixation is improved, thereby increasing the reliability of the test. Random presentations also increase the speed with

that the cornea and the aqueous served to bend the light rays into the eye.

**Figure 13.** DaVinci's Illustration of rays approaching the cornea from different directions

the ability to appreciate a three dimensional plot of one's visual status.

could recognize his deficits more easily. [17]

published in an article by Ulmus of Padua in 1602.

236 Ophthalmology - Current Clinical and Research Updates

**Figure 15.** The normal island of vision. The hill is highest at fixation, where visual sensitivity is greatest. The height of the hill of vision declines toward the periphery as visual sensitivity diminishes.

Any clinically or statistically significant deviation from the normal shape of the hill of vision can be considered a visual field defect. In glaucoma, these defects are either diffuse depressions of the visual field or localized defects that conform to nerve fiber bundle patterns. [18]

### **6.2. Current choices in subjective functional testing**

The addition of computerization to assessment of the eyes functional performance led the way to the development of several testing alternatives. Early white on white threshold testing strategies were followed with faster and more efficient programs such as Humphries Swedish Interactive Testing Algorithm (SITA) and the Haag-Streit Tendency Oriented Perimetry (TOP), Along with unenhanced test specificity, both strategies significantly reduce testing times by over 70%. The TOP strategy requires less than three minutes per eye per test.

A daunting point of frustration with the limits of threshold analysis came from the under‐ standing that significant axonal loss had to have occurred before a repeatable threshold could be demonstrated. In 1982, Quigley reported that as much as 40% of optic nerve fibers may be lost before significant threshold visual field loss. [19]

**Figure 16.** Visual Evoked Potential (VEP), pattern electroretinography (pERG) (Diopsys, Inc.)

Structure and Function Relationship in Glaucoma-Historical Perspective to a Practical Approach

http://dx.doi.org/10.5772/57601

239

**Figure 17.** RAPDx (Konan, USA) measures Relative Afferent Pupillary Defect

Alternatives more recent methods in subjective field analysis, such as short wavelength (blue – yellow) and flicker strategies, were developed with the goal of reliably eliciting subject glaucomatous defects at an earlier point the progression of the disease. It is now shown that the flicker type tests such as Frequency Doubling Technology will have a role to play as a glaucoma screening tests, where as the the blue-yellow tests may not be as predictive as once throught. 20 Recently, there has been increased inteest in 10 degree white on white threshold fields because of its greater test point density and its apparent structure relationship to new OCT ganglion cell complex (GCC) imaging analyses. 14, 15

### **6.3. Objective testing**

Objective methods such as Visual Evoked Potential (VEP), pattern electroretinography (pERG) (Diopsys, Inc.), and Relative Afferent Pupillary Defect (RAPDx) (Konan, USA) offer the potential of earlier and more specific functional testing but here continues to be a need to more reliably access functional loss at an earlier point in glaucomagenesis. While VEP and pERG measure the relative integrity of the electrical signal that passes through the nerve during the visual process,

RAPDx expands on the notion of diminished afferent pupillary reflex that may occur as nerve integrity is lost and glaucoma progresses.

With newer imaging methods such as OCT, we have made significant strides in earlier detection of structural loss, while our ability to detect functional loss earlier than what we achieve via white on white threshold field analysis remains a challenge. Given early evidence that VEP, pERG and RAPDx may offer some reliable evidence of early functional change, one can only hope that robust scientific evidence paired with more technical advancement of these types of tools may help us get a bit closer. [21-23]

Structure and Function Relationship in Glaucoma-Historical Perspective to a Practical Approach http://dx.doi.org/10.5772/57601 239

**Figure 16.** Visual Evoked Potential (VEP), pattern electroretinography (pERG) (Diopsys, Inc.)

Any clinically or statistically significant deviation from the normal shape of the hill of vision can be considered a visual field defect. In glaucoma, these defects are either diffuse depressions of the visual field or localized defects that conform to nerve fiber bundle patterns. [18]

The addition of computerization to assessment of the eyes functional performance led the way to the development of several testing alternatives. Early white on white threshold testing strategies were followed with faster and more efficient programs such as Humphries Swedish Interactive Testing Algorithm (SITA) and the Haag-Streit Tendency Oriented Perimetry (TOP), Along with unenhanced test specificity, both strategies significantly reduce testing times by

A daunting point of frustration with the limits of threshold analysis came from the under‐ standing that significant axonal loss had to have occurred before a repeatable threshold could be demonstrated. In 1982, Quigley reported that as much as 40% of optic nerve fibers may be

Alternatives more recent methods in subjective field analysis, such as short wavelength (blue – yellow) and flicker strategies, were developed with the goal of reliably eliciting subject glaucomatous defects at an earlier point the progression of the disease. It is now shown that the flicker type tests such as Frequency Doubling Technology will have a role to play as a glaucoma screening tests, where as the the blue-yellow tests may not be as predictive as once throught. 20 Recently, there has been increased inteest in 10 degree white on white threshold fields because of its greater test point density and its apparent structure relationship to new

Objective methods such as Visual Evoked Potential (VEP), pattern electroretinography (pERG) (Diopsys, Inc.), and Relative Afferent Pupillary Defect (RAPDx) (Konan, USA) offer the potential of earlier and more specific functional testing but here continues to be a need to more reliably access functional loss at an earlier point in glaucomagenesis. While VEP and pERG measure the relative integrity of the electrical signal that passes through the nerve during the

RAPDx expands on the notion of diminished afferent pupillary reflex that may occur as nerve

With newer imaging methods such as OCT, we have made significant strides in earlier detection of structural loss, while our ability to detect functional loss earlier than what we achieve via white on white threshold field analysis remains a challenge. Given early evidence that VEP, pERG and RAPDx may offer some reliable evidence of early functional change, one can only hope that robust scientific evidence paired with more technical advancement of these

over 70%. The TOP strategy requires less than three minutes per eye per test.

**6.2. Current choices in subjective functional testing**

238 Ophthalmology - Current Clinical and Research Updates

lost before significant threshold visual field loss. [19]

OCT ganglion cell complex (GCC) imaging analyses. 14, 15

**6.3. Objective testing**

visual process,

integrity is lost and glaucoma progresses.

types of tools may help us get a bit closer. [21-23]

**Figure 17.** RAPDx (Konan, USA) measures Relative Afferent Pupillary Defect

## **7. Combining structural and functional data to optimize specificity in diagnosis**

Tomograph ONH images were divided into 36 sectors; and the sector rim areas normalized to account for changes in the total rim area. These were then correlated with SAP thresholds. For each visual field location, a map was produced indicating the strength of correlation between the normalized sector rim areas and thresholds. Their efforts resulted in a map relating regions of the ONH to SAP test locations. This map may be useful in elucidating the structure-function

Structure and Function Relationship in Glaucoma-Historical Perspective to a Practical Approach

http://dx.doi.org/10.5772/57601

241

Their results also indicate that narrowing of the neuroretinal rim in some areas appeared to be more significant than in others, in terms of predicting functional loss; in particular in the polar areas of the ONH. This may account for some of the limitations of predictive power that

In 2010, Harwerth et al attempted to build a model of these linking propositions using data from investigations of the relationships between losses of visual sensitivity and thinning of retinal nerve fiber layer over progressive stages of glaucoma severity. A foundation for the model was laid through the pointwise relationships between visual sensitivities (behavioral perimetry in monkeys with experimental glaucoma) and histological analyses of retinal ganglion cell densities in corresponding retinal locations. The subsequent blocks of the model were constructed from clinical studies of aging in normal human subjects and of clinical glaucoma in patients to provide a direct comparison of the results from standard clinical perimetry and optical coherence tomography. The final formulation is a nonlinear structurefunction model that was evaluated by the accuracy and precision of translating visual sensitivities in a region of the visual field to produce a predicted thickness of the retinal nerve fiber layer in the peripapillary sector that corresponded to the region of reduced visual sensitivity. The model was tested on two independent patient populations, with results that confirmed the predictive relationship between the retinal nerve fiber layer thickness and visual sensitivities from clinical perimetry. Thus, the proposed model for linking structure and function in glaucoma has provided information that is important in understanding the results of standard clinical testing and the neuronal losses caused by glaucoma, which may have clinical application for inter-test comparisons of the stage of disease. The model was tested on two independent patient populations, with results that confirmed the predictive relationship between the retinal nerve fiber layer thickness and visual sensitivities from clinical perimetry. Thus, the proposed model for linking structure and function in glaucoma has provided information that is important in understanding the results of standard clinical testing and the neuronal losses caused by glaucoma, which may have clinical application for inter-test

In 2012, Medeiros et al confirmed that an index combining structure and function performed better than isolated structural and functional measures for detection of perimetric and preperimetric glaucoma as well as for discriminating different stages of the disease. Observa‐ tional study included 333 glaucomatous eyes (295 with perimetric glaucoma and 38 with preperimetric glaucoma) and 330 eyes of healthy subjects. All the eyes were tested with standard automated perimetry and spectral domain optical coherence tomography within 6 months. Estimates of the number of retinal ganglion cells (RGCs) were obtained from standard automated perimetry and spectral domain optical coherence tomography and a weighted

relationship, particularly for cases of localized glaucomatous loss.

has been shown of global HRT indices. [31]

comparisons of the stage of disease. [16]

Along with our better understanding of the various limitations of either structural or functional analysis as a singular metric for glaucoma management, the obvious question has become can we, somehow, fortuitously coalesce both data sets? By combining the two, can we apprehend glaucoma earlier in its progression and develop better methods of dividing glaucoma into more meaningful subtypes? Will doing so allow us to treat more promptly, effectively and more specifically? Finally, is there a way to combine structural tests with functional tests to give us some type of unified glaucoma value?

Several investigators pioneered early structure function studies with the goal of establishing a better understanding of the relationships between various structural and functional values. In 1976, Stephen Drance described optic disc changes as they correlated to visual field defects in chronic open-angle glaucoma. Drance's studies were followed by Hoskins et al and Hitchings et al who also observed the nature of optic changes which occurred in concert with glaucomatous visual field changes (ref's). [24-26] These investigations were conducted with the goal of pairing specific anatomical changes commonly associated with glaucoma with associated functional (visual field) changes. Others tried to find a common more useful value in combining structural and functional data in different ways. [24-26]

Perhaps, the most renowned investigations which have established the foundations of our current understanding of the structure function relationship were performed by Quigley et al during the 1980's. Glaucomatous eyes were studied posthumously to determine how the number and distribution of human optic nerve axons compared with clinical measurements available the same eyes, including visual acuity, disc appearance, and visual field studies. Quigley reported that definite loss of axons occurs prior to reproducible visual field defects in some patients suspected of having glaucoma. In glaucoma, the superior and inferior poles of the nerve lose nerve fibers at a selectively greater rate, leading to an hourglass-shaped atrophy. He also reported that the pattern of atrophy in examples of toxic amblyopia, ischemic optic neuropathy and chronic papilledema differ from that of glaucoma, suggesting different mechanisms of damage in these conditions.

In later investigations, Harwerth et al described relationships between field loss and retinal ganglion cells. The data were analyzed by a model that predicted ganglion cell densities from standard clinical perimetry, which were then compared to histologic cell counts. Their work became part of the foundation for our current interest and understanding of function‐ al loss in the context of retinal tissue changes beyond the losses previously described in retinal axons. [27-30]

In 2005, Gardiner et al produced a topographical map to demonstrate how sectors of the optic nerve head (ONH) are related to locations in the visual field, using empiric cross-sectional patient data. They observed one hundred nine subjects with healthy eyes and 166 subjects with diagnosed or suspected glaucoma (one test per patient) were evaluated using a Heidelberg Retina tomograph (HRT) and white-on-white standard automated perimetry (SAP). The Tomograph ONH images were divided into 36 sectors; and the sector rim areas normalized to account for changes in the total rim area. These were then correlated with SAP thresholds. For each visual field location, a map was produced indicating the strength of correlation between the normalized sector rim areas and thresholds. Their efforts resulted in a map relating regions of the ONH to SAP test locations. This map may be useful in elucidating the structure-function relationship, particularly for cases of localized glaucomatous loss.

**7. Combining structural and functional data to optimize specificity in**

Along with our better understanding of the various limitations of either structural or functional analysis as a singular metric for glaucoma management, the obvious question has become can we, somehow, fortuitously coalesce both data sets? By combining the two, can we apprehend glaucoma earlier in its progression and develop better methods of dividing glaucoma into more meaningful subtypes? Will doing so allow us to treat more promptly, effectively and more specifically? Finally, is there a way to combine structural tests with functional tests to

Several investigators pioneered early structure function studies with the goal of establishing a better understanding of the relationships between various structural and functional values. In 1976, Stephen Drance described optic disc changes as they correlated to visual field defects in chronic open-angle glaucoma. Drance's studies were followed by Hoskins et al and Hitchings et al who also observed the nature of optic changes which occurred in concert with glaucomatous visual field changes (ref's). [24-26] These investigations were conducted with the goal of pairing specific anatomical changes commonly associated with glaucoma with associated functional (visual field) changes. Others tried to find a common more useful value

Perhaps, the most renowned investigations which have established the foundations of our current understanding of the structure function relationship were performed by Quigley et al during the 1980's. Glaucomatous eyes were studied posthumously to determine how the number and distribution of human optic nerve axons compared with clinical measurements available the same eyes, including visual acuity, disc appearance, and visual field studies. Quigley reported that definite loss of axons occurs prior to reproducible visual field defects in some patients suspected of having glaucoma. In glaucoma, the superior and inferior poles of the nerve lose nerve fibers at a selectively greater rate, leading to an hourglass-shaped atrophy. He also reported that the pattern of atrophy in examples of toxic amblyopia, ischemic optic neuropathy and chronic papilledema differ from that of glaucoma, suggesting different

In later investigations, Harwerth et al described relationships between field loss and retinal ganglion cells. The data were analyzed by a model that predicted ganglion cell densities from standard clinical perimetry, which were then compared to histologic cell counts. Their work became part of the foundation for our current interest and understanding of function‐ al loss in the context of retinal tissue changes beyond the losses previously described in

In 2005, Gardiner et al produced a topographical map to demonstrate how sectors of the optic nerve head (ONH) are related to locations in the visual field, using empiric cross-sectional patient data. They observed one hundred nine subjects with healthy eyes and 166 subjects with diagnosed or suspected glaucoma (one test per patient) were evaluated using a Heidelberg Retina tomograph (HRT) and white-on-white standard automated perimetry (SAP). The

in combining structural and functional data in different ways. [24-26]

**diagnosis**

give us some type of unified glaucoma value?

240 Ophthalmology - Current Clinical and Research Updates

mechanisms of damage in these conditions.

retinal axons. [27-30]

Their results also indicate that narrowing of the neuroretinal rim in some areas appeared to be more significant than in others, in terms of predicting functional loss; in particular in the polar areas of the ONH. This may account for some of the limitations of predictive power that has been shown of global HRT indices. [31]

In 2010, Harwerth et al attempted to build a model of these linking propositions using data from investigations of the relationships between losses of visual sensitivity and thinning of retinal nerve fiber layer over progressive stages of glaucoma severity. A foundation for the model was laid through the pointwise relationships between visual sensitivities (behavioral perimetry in monkeys with experimental glaucoma) and histological analyses of retinal ganglion cell densities in corresponding retinal locations. The subsequent blocks of the model were constructed from clinical studies of aging in normal human subjects and of clinical glaucoma in patients to provide a direct comparison of the results from standard clinical perimetry and optical coherence tomography. The final formulation is a nonlinear structurefunction model that was evaluated by the accuracy and precision of translating visual sensitivities in a region of the visual field to produce a predicted thickness of the retinal nerve fiber layer in the peripapillary sector that corresponded to the region of reduced visual sensitivity. The model was tested on two independent patient populations, with results that confirmed the predictive relationship between the retinal nerve fiber layer thickness and visual sensitivities from clinical perimetry. Thus, the proposed model for linking structure and function in glaucoma has provided information that is important in understanding the results of standard clinical testing and the neuronal losses caused by glaucoma, which may have clinical application for inter-test comparisons of the stage of disease. The model was tested on two independent patient populations, with results that confirmed the predictive relationship between the retinal nerve fiber layer thickness and visual sensitivities from clinical perimetry. Thus, the proposed model for linking structure and function in glaucoma has provided information that is important in understanding the results of standard clinical testing and the neuronal losses caused by glaucoma, which may have clinical application for inter-test comparisons of the stage of disease. [16]

In 2012, Medeiros et al confirmed that an index combining structure and function performed better than isolated structural and functional measures for detection of perimetric and preperimetric glaucoma as well as for discriminating different stages of the disease. Observa‐ tional study included 333 glaucomatous eyes (295 with perimetric glaucoma and 38 with preperimetric glaucoma) and 330 eyes of healthy subjects. All the eyes were tested with standard automated perimetry and spectral domain optical coherence tomography within 6 months. Estimates of the number of retinal ganglion cells (RGCs) were obtained from standard automated perimetry and spectral domain optical coherence tomography and a weighted averaging scheme was used to obtain a final estimate of the number of RGCs for each eye. The CSFI was calculated as the percent loss of RGCs obtained by subtracting estimated from expected RGC numbers. The performance of the CSFI for discriminating glaucoma from normal eyes and the different stages of disease was evaluated by receiver operating charac‐ teristic curves. [32, 33]

findings suggest that using these different data sources together may improve our under‐ standing of glaucomatous damage and aid in the management of patients with glaucoma. [35]

Structure and Function Relationship in Glaucoma-Historical Perspective to a Practical Approach

http://dx.doi.org/10.5772/57601

243

In 2013, Hye-Young Shin et al Two hundred and thirteen eyes of 213 patients with glaucoma were observed to explore and compare the relationships between the visual field (VF) sensitivities assessed by standard automated perimetry (SAP) and the ganglion cell inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thicknesses as measured by Cirrus high-definition optical coherence tomography (HD-OCT) in glaucoma‐

The average and sectorial GCIPL thicknesses determined by Cirrus HD-OCT were signifi‐ cantly associated with global and regional VF sensitivity in patients with glaucoma. They concluded that the macular GCIPL thickness values may provide more valuable information than temporal profile thickness values for understanding the structure–function relationships

In 2013, Marín-Franch et al reported their comparison structural and functional damage from glaucoma often using statistical methods such as linear regression, which was agreed to have limitations that can lead to inadequate clinical recommendations. These limitations were analyzed, using examples from the literature. Inferences from linear regression are model dependent. They concluded that tests of linear relations between structure and function in glaucoma may be improved by the use of Deming regression, although its application requires

It has been said that in Einstein's Grand Quest for a Unified Theory "He failed, of course, but he didn't exactly waste his time." Similarly, our search for a simplified common denominator to describe glaucoma in a simple way is likely to fail. Our methods of documenting the optic nerve and various ocular structures related to the genesis of glaucoma have evolved from direct observation paired with hand drawings to ocular corherance tomographic devices, which render elegant cross sectional views with as little as 5 microns of resolution. Quantifi‐ cation of the visual field has also evolved to sophisticated threshold subjective analyses and promising new objective strategies. In spite of this impressive technical evolution, we have yet to agree upon a practical combination of structural and functional data that can provide a

Perhaps, the solution to this conundrum can be derived from our acceptance that glaucoma does not appear to be one simple disease, but rather one that is the result of a litany of risk factors that commonly result in the untimely deterioration of the optic nerve. As investigators have and continue to examine the many structural and functional changes that may occur in the process of glaucoma, the field of clinical variables ironically seems to expand rather than contract. Physical changes may be observed at the neural retinal rim first, while in other patients changes in the peri macular ganglion cell layer may be the first signal of glaucomatous

single metric for risk of glaucoma and the level of its progression.

knowledge about test-retest variability of measures of glaucomatous damage. [37, 38]

tous eyes.

of the macular region. [35]

**8. Summary**

**Figure 18.** Polar analysis of a threshold visual field showing severity of the defect in concert with nerve anatomy. While traditional graphical reports of field analysis show projected (inverted) findings, the polar analysis is anatomical‐ ly correct.

In 2013, Meira-Freitas et al demonstrated that baseline and longitudinal estimates of retinal ganglion cell counts based on combined structure and function tests may be helpful in predicting progression, and performed significantly better than conventional approaches for risk stratification of glaucoma suspects. The study included 288 glaucoma suspect eyes of 288 patients followed for an average of 3.8 ± 1.0 years. Estimates of RGC counts were obtained by combining data from SAP and OCT according to previously described method. Joint longitu‐ dinal survival models were used to evaluate the ability of baseline and rates of change in estimated RGC counts for predicting progression over time, adjusting for confounding variables. [34]

Also, in 2013, Le et al implemented fourier-domain optical coherence tomography (FD-OCT) system to map the macula and peripapillary regions of the retina in 56 eyes of 38 patients with perimetric glaucoma. The macular GCC and peripapillary NFL thicknesses were mapped and standard automated perimetry (SAP) was performed. Loss of GCC and NFL were correlated with the VF map on both a point-by-point and regional basis, showing that there are significant point-specific and regional correlations between GCC loss, NFL loss, and deficits on SAP. Their findings suggest that using these different data sources together may improve our under‐ standing of glaucomatous damage and aid in the management of patients with glaucoma. [35]

In 2013, Hye-Young Shin et al Two hundred and thirteen eyes of 213 patients with glaucoma were observed to explore and compare the relationships between the visual field (VF) sensitivities assessed by standard automated perimetry (SAP) and the ganglion cell inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thicknesses as measured by Cirrus high-definition optical coherence tomography (HD-OCT) in glaucoma‐ tous eyes.

The average and sectorial GCIPL thicknesses determined by Cirrus HD-OCT were signifi‐ cantly associated with global and regional VF sensitivity in patients with glaucoma. They concluded that the macular GCIPL thickness values may provide more valuable information than temporal profile thickness values for understanding the structure–function relationships of the macular region. [35]

In 2013, Marín-Franch et al reported their comparison structural and functional damage from glaucoma often using statistical methods such as linear regression, which was agreed to have limitations that can lead to inadequate clinical recommendations. These limitations were analyzed, using examples from the literature. Inferences from linear regression are model dependent. They concluded that tests of linear relations between structure and function in glaucoma may be improved by the use of Deming regression, although its application requires knowledge about test-retest variability of measures of glaucomatous damage. [37, 38]

### **8. Summary**

averaging scheme was used to obtain a final estimate of the number of RGCs for each eye. The CSFI was calculated as the percent loss of RGCs obtained by subtracting estimated from expected RGC numbers. The performance of the CSFI for discriminating glaucoma from normal eyes and the different stages of disease was evaluated by receiver operating charac‐

**Figure 18.** Polar analysis of a threshold visual field showing severity of the defect in concert with nerve anatomy. While traditional graphical reports of field analysis show projected (inverted) findings, the polar analysis is anatomical‐

In 2013, Meira-Freitas et al demonstrated that baseline and longitudinal estimates of retinal ganglion cell counts based on combined structure and function tests may be helpful in predicting progression, and performed significantly better than conventional approaches for risk stratification of glaucoma suspects. The study included 288 glaucoma suspect eyes of 288 patients followed for an average of 3.8 ± 1.0 years. Estimates of RGC counts were obtained by combining data from SAP and OCT according to previously described method. Joint longitu‐ dinal survival models were used to evaluate the ability of baseline and rates of change in estimated RGC counts for predicting progression over time, adjusting for confounding

Also, in 2013, Le et al implemented fourier-domain optical coherence tomography (FD-OCT) system to map the macula and peripapillary regions of the retina in 56 eyes of 38 patients with perimetric glaucoma. The macular GCC and peripapillary NFL thicknesses were mapped and standard automated perimetry (SAP) was performed. Loss of GCC and NFL were correlated with the VF map on both a point-by-point and regional basis, showing that there are significant point-specific and regional correlations between GCC loss, NFL loss, and deficits on SAP. Their

teristic curves. [32, 33]

242 Ophthalmology - Current Clinical and Research Updates

ly correct.

variables. [34]

It has been said that in Einstein's Grand Quest for a Unified Theory "He failed, of course, but he didn't exactly waste his time." Similarly, our search for a simplified common denominator to describe glaucoma in a simple way is likely to fail. Our methods of documenting the optic nerve and various ocular structures related to the genesis of glaucoma have evolved from direct observation paired with hand drawings to ocular corherance tomographic devices, which render elegant cross sectional views with as little as 5 microns of resolution. Quantifi‐ cation of the visual field has also evolved to sophisticated threshold subjective analyses and promising new objective strategies. In spite of this impressive technical evolution, we have yet to agree upon a practical combination of structural and functional data that can provide a single metric for risk of glaucoma and the level of its progression.