Ординатура / Офтальмология / Английские материалы / Atlas of Glaucoma, Second Edition_Choplin, Lundy_2007

The optic nerve in glaucoma 67

Differential diagnosis

Disturbances in one or more components of axo-

Careful evaluation of the ONH characteristics and

plasmic flow at the level of the lamina cribrosa can

result in axonal injury and subsequent cell death as

associated clinical findings will in most cases allow

a result of increased IOP. The precise mechanisms

one to differentiate GON from non-glaucomatous

by which this occurs are not known, but it is thought

optic neuropathy. Nonetheless, a number of clinical

that backward bowing of the lamina from elevated

conditions may mimic GON and must be considered

IOP causes ‘kinking’ of the axons within the pores,

and excluded (see Figures 6.16a–e). These include:

resulting in a disruption of axoplasmic flow. Left

A physiological or congenitally large optic cup

untreated, the nerve fiber eventually dies. Another

(Figure 6.8c). Examination of close relatives

proposed mechanism is the obstruction of the retro-

may reveal a similar configuration and will help

grade axoplasmic flow, which may alter the normal

in the differential diagnosis. A large disc with a

delivery of neurotrophic factors at the lamina cribrosa,

normal number of nerve fibers is likely to have a

resulting in ganglion cell death.

large cup.

Congenital anomalies of the optic nerve, such

Vascular

as congenital pits, colobomas (Figure 6.16a), the

This theory proposes that the basic pathogenic

morning glory syndrome, and the tilted disc

mechanism responsible for the death of ganglion

syndrome can occasionally mimic the appearance

cells in glaucoma is an insufficient blood supply to

of a glaucomatous nerve.

the ONH. Despite extensive investigation, the precise

Pale, cupped nerves can sometimes result from

level at which this abnormality occurs is at this

other entities. Arteritic ischemic optic neuropathy

time unknown. It is therefore not clear at what location

can result in an enlarged cup, but in this case

an ischemic injury must occur to produce the charac-

peripapillary atrophy is lacking. Demyelinating

teristic findings of GON. This mechanism has been

disease, central retinal artery occlusion, toxic

postulated as being responsible for the optic neu-

optic neuropathy, traumatic optic atrophy and

ropathy seen in many patients with GON and normal

compressive lesions can also result in glaucoma-

IOP (normal-tension glaucoma). Several non-invasive

like cupping. Age-related macular degeneration

methods to measure the circulation of the posterior

has been shown to produce enlarged cups. A

pole of the eye and the orbit have recently been deve-

thorough history and physical examination will

loped. For example, color Doppler ultrasonographic

often guide the clinician in the appropriate

analysis has allowed estimates of blood supply through

direction and reveal the underlying condition.

the ophthalmic artery, nasal and temporal short

Tilted normal nerves in myopic patients (Figure

posterior ciliary arteries and central retinal artery.

6.16b) can simulate glaucomatous cupping and

Posterior ciliary, retinal and choroidal circulation

require careful differentiation. Examination of

differences between normals and glaucoma patients

the visual fields and rNFL can be very useful in

have been reported, but the precise significance of these

these cases.

findings is at this time of uncertain clinical signifi-

Theories of etiology of glaucomatous optic

cance. It is difficult to estimate the degree to which

these or other mechanisms play a role in a particu-

neuropathy

lar patient, since these theories are not exclusive.

Glaucomatous optic neuropathy probably repre-

Decreased circulation and a tendency to an elevated

sents the final common pathway for various mecha-

IOP are two known occurrences in elderly indivi-

nisms of injury. It is generally appreciated that IOP

duals in the Western world. There is evidence that

alone cannot explain the occurrence of GON in

significant nocturnal systemic arterial hypotension

every patient. As understanding of the pathophysi-

can occur in some individuals, theoretically compro-

ology of GON expands, so too will diagnostic and

mising the blood supply to the optic nerves. In

therapeutic approaches to these diseases. Outlined

addition, some data suggest that, in some elderly

briefly below are several of the current theories

patients with glaucoma, the damage to the optic

regarding the mechanisms of damage in GON.

nerve may result from a chronic vascular occlusive

process, at least partly independent of the level of

Mechanical

IOP. It is therefore difficult to separate the mechani-

cal and vascular mechanisms as isolated causes of

This theory supports the opinion that elevated IOP

GON in a given patient.

is the primary mechanism responsible for the dam-

age to neural cells through biomechanical or struc-

Biochemical

tural factors. It is commonly recognized that IOP is

probably the single most important identifiable risk

Multiple alterations have been found at the cellular

factor in the development of GON and the only one

and molecular levels in optic nerves with glau-

currently treatable. Levels of IOP appear to corre-

coma. These include abnormal astrocyte deposition

late with degrees of ONH damage in many patients.

of collagen IV in the lamina cribrosa and changes

The optic nerve in glaucoma 69

in the composition of the extracellular matrix.

control mechanisms, possibly genetic in origin.

Alterations in elastin, tropoelastine, fibronectin,

Further research will define the possible role of this

glial fibrillary acidic protein and hyaluronic acid have

mechanism in the pathogenesis of glaucoma.

been demonstrated. It must be noted that some of

these biochemical changes have been found in normal,

CLINICAL EXAMINATION TECHNIQUES

aging optic nerves without evidence of glaucoma.

Neurochemical

Optic nerve damage and rNFL damage are the hall-

marks of glaucoma. Careful clinical examination is

It is well known that typical glaucomatous ONH

the key to detection of glaucoma. While obvious GON

changes occur in eyes without documented elevated

is not difficult to identify, the subtle early changes

IOP or demonstrable circulatory (‘vascular’) insuf-

may escape detection unless the clinician is systematic

ficiency. A third proposed mechanism of neuronal

about optic nerve examination. Each examination

injury is one of a neurochemical nature. A number

of the optic nerve should include evaluation of the

of substances have been shown to have a damaging

optic nerve size, neuroretinal rim (ISNT rule), region

effect on neural cells and deserve mention.

of peripapillary atrophy, retinal nerve fiber layer,

The excitotoxins (excitatory neurotransmitters)

and disc hemorrhage documentation. Systematic

are found in normal neural tissue and, in high con-

examination will allow detection of the early

centrations, have been shown to be toxic to neurons.

changes of GON.

One of these compounds, glutamate, was found in

Glaucomatous optic neuropathy is at this time

high amounts in glaucomatous eyes. Later studies

considered an irreversible process. Its detection at the

have failed to confirm this finding.

earliest stages becomes of the utmost importance in

An uncontrolled accumulation of intracellular

order to prevent or ameliorate functional loss. Several

calcium can cause neuronal damage and subsequent

subjective, qualitative methods of examination have

cell death. Calcium channel blockers have shown not

traditionally been used to evaluate glaucomatous

only a vasodilating action in cases of normal tension

damage. Newer objective methods have been devel-

glaucoma attributed to vasospasm, but also a decrease

oped to evaluate the ONH and rNFL. Comparisons

in the intracellular concentration of calcium.

between these methods have been conducted, show-

Astrocytes have been shown to increase the expres-

ing that at present no single method is clearly the best

sion of certain molecules (e.g. nitric oxide synthase)

in detecting early glaucomatous damage. Like any

under hyperbaric conditions. Nitric oxide can act as

diagnostic process in most areas of medicine, these

a neurotransmitter and has vasodilating effects. It

techniques appear to complement each other. Evidence

has also shown toxic effects (probably glutamate-

has suggested that up to 40% of the nerve fibers may

mediated) on neurons. A group of substances pro-

have been destroyed before a diagnostic visual field

duced by the vascular endothelium called endothelins

defect is shown by standard automated perimetry.

have shown a marked vasoconstrictive effect on the

Therefore, some clinical techniques have detected the

ONH, and their role in the pathogenesis of GON is

presence of ONH and NFL abnormalities prior to the

being investigated. An increase in oxygen free radicals

occurrence of typical glaucomatous visual field defects.

has been found in certain neurological diseases,

Still, careful examination by an experienced observer

and a role in ganglion cell damage appears possible.

remains one of the best tools to detect glaucomatous

The future importance of these alternative mech-

damage.

anisms in the pathogenesis of glaucoma lies in the

Although a careful observer can obtain excellent

possibility of pharmacological intervention. This may

reproducibility, the variability between observers

allow us to ‘protect’ the cells and in some cases halt

using subjective techniques and the lack of standard-

or even reverse the alleged chemically mediated

ized terminology to describe various clinical obser-

neuronal damage.

vations have created the need for more objective

Apoptosis

techniques to record the appearance of the ONH.

Examination techniques currently in use by clinicians

It has been shown that ganglion cell loss occurs in

in the assessment of the ONH include the following.

the optic nerves of normal individuals throughout life

at a fairly steady rate. Much attention has been given

Direct ophthalmoscopy

recently to a specific and distinct process of cellular

death called apoptosis that occurs in many cells,

Direct ophthalmoscopy has been used for many years

including neurons. Each cell carries a predetermined

to examine the posterior pole of the eye. A direct oph-

(‘programmed’) intrinsic self-destruction mechanism

thalmoscope yields a virtual, upright image with a 15

that ultimately results in its death. There is evidence

magnification, with good illumination but a limited

that apoptosis occurs in eyes with experimental

field of view. The major drawback of this monocular

glaucoma. Glaucoma could theoretically result from

technique is the lack of a three-dimensional view.

accelerated or premature apoptosis due to defective

Subtle yet important topographic changes in the

ONH may be overlooked. A rough idea of the topo-

magnification makes this an effective technique

graphy of the optic nerve can be obtained by direct

(‘biomicroscope indirect ophthalmoscopy’). A real,

ophthalmoscopy. It can be quite useful for detecting

inverted image is created between the examiner and

optic nerve hemorrhages and for estimating disc

the lens. Lenses of 78 D and 90 D of power are most

size but it remains a suboptimal method for thor-

commonly used today although a wide range of

ough evaluation of the optic nerve. It is nonetheless

powers are available. As a non-contact technique,

a useful tool for non-ophthalmologist physicians, for

it is comfortable for the patient and does not interfere

screening purposes, and whenever a small pupil

with further eye examination since no coupling

precludes other types of ophthalmoscopy.

material is needed. Good illumination and magnifi-

cation can be obtained from the slit lamp. The 78 D

Standard binocular indirect ophthalmoscopy

lens gives better magnification while the 90 D lens

allows examination through smaller pupils. There

In this technique peripheral light rays from the

are 54 D and 60 D lenses available that give image

patient’s retina are ‘captured’ by aspheric condensing

magnification close to 1 . With increasing power, a

lenses and projected into the examiner’s retina allow-

reduced depth perception results from the inherent

ing a much wider field of view. A real and inverted

optics of these lenses, which can result in an under-

image is formed between the lens and the exam-

estimation of cupping and other topographic changes.

iner. The power of the lenses used for indirect oph-

A lower power lens should be used for better depth

thalmoscopy varies from 15 to 30 diopters, yielding a

perception.

lateral magnification that ranges from 2 to 4 .

Although a stereoscopic view is obtained, these levels

Nerve fiber layer examination

of magnification are inadequate for the evaluation of

fine details. Under these conditions the assessment of

The fundamental pathological process occurring in

subtle variations in ONH color and surface is difficult

the glaucomatous optic nerve is a loss of retinal gang-

to make. An increase in axial magnification adds to

lion cells and their axons. This loss of nerve fibers

this inconvenience. It is not recommended that one

follows the pattern of their structural arrangement

rely on standard indirect ophthalmoscopy when

in the retina and defines the sequence of the natural

examining glaucoma patients.

course of the disease. A normal NFL has a striated

appearance radiating from the optic disc and is more

Slit lamp biomicroscopy

prominent in the superior and inferior poles of the

nerve, where the nerve bundles have a larger dia-

The excellent illumination, high magnification and

meter. Temporal and nasal fibers are thinner and

stereoscopic view obtainable through a slit lamp

tightly arranged, giving the peripapillary retina a

biomicroscope with a supplemental lens makes this

more uniform appearance. Thus, focal NFL loss will

type of examination highly desirable for the clinical

show a radiating wedge-shaped defect of variable

evaluation of the ONH.

width on the surface of the retina. Diffuse NFL loss

The Hruby lens (adapted to the slit lamp) is a

will show a uniform decrease in the NFL pattern,

plano-concave lens of –55 D of power. It provides an

being more difficult to identify in its early stages or

upright virtual image with good magnification.

when both types of defect coexist.

Unfortunately, the small field of view makes this

technique challenging and may preclude good stere-

Biomicroscopy

opsis. It is a non-contact technique that has largely

Even though large NFL defects can often be seen

been replaced by more convenient lenses.

with white light, more subtle defects require spe-

The Goldmann fundus contact lens, like the

cial variations in technique and instrumentation. A

Hruby lens, creates an upright virtual image. Its use

better view is obtained at the slit lamp after pupil-

requires a coupling material between the lens and the

lary dilatation using a red-free (green) filter and

cornea. This allows some control of the globe during

good illumination. As this is a subjective examina-

the examination. Adequate magnification can be

tion, the potential for interobserver variability is

obtained from the optical system of the slit lamp

always present.

(up to 16 and higher), since the lens itself provides

little magnification. With a fully dilated pupil and

Photography

good illumination, this technique provides the best

view available for the clinical assessment of the

Different photographic techniques have been

ONH. Unfortunately, the use of coupling material

described and attempts have been made to enhance

can affect the view during subsequent examination

visibility of the NFL. It appears that the use of blue

or fundus photography.

or green filters with proper focusing gives the best

Condensing bi-convex aspheric lenses of high

results. A high-contrast, fine-grain black-and-white

power allows the use of the slit lamp for binocular

film is currently recommended. Even though NFL

indirect ophthalmoscopy. The availability of high

photographic analysis has been greatly improved,