Figure 3-6 Printout from a Humphrey 30-2 automated static perimetry program, with explanations of statistical analysis,

grayscale, and probability plots (red type). (Courtesy of Anthony C. Arnold, MD.)

The long duration and repetitiveness of the original full-threshold perimetry test fatigued patients and thus reduced the accuracy of the test results. A shorter version, FASTPAC, reduces testing time but at a cost of accuracy. Use of the Swedish interactive threshold algorithm (SITA) shortens the time needed to complete the full-threshold test by half but maintains the accuracy necessary for reliability. (See BCSC Section 10, Glaucoma.)

The reliability of perimetry test results is assessed by identifying the following patient response characteristics:

False-positive response rate: how frequently the patient signals when no light is displayed (The acceptable rate is typically <25% on threshold testing and <15% on SITA testing.) False-negative response rate: how often the patient fails to signal when a target brighter than the previously determined threshold for that spot is displayed (The acceptable rate is typically <25%, but the incidence increases in regions of true visual field loss, as the patient is unable to accurately reproduce responses.)

Fixation losses: how often the patient identifies the stimulus in the previously plotted physiologic blind spot location (ie, a response not expected), indicating that the eye is not aligned with the fixation target

Short-term fluctuation measurement: how consistent the patient responses are at specific points at which repeat testing is performed to evaluate consistency (ie, double determinations)

Global indices are calculated to help determine changes in sensitivity over time. Such indices include a center-weighted mean of all point sensitivity depressions from normal (ie, mean deviation) and various means of addressing localized defects (eg, pattern standard deviation, corrected pattern deviation, loss variance).

Barton JJS, Benatar M. Field of Vision: A Manual and Atlas of Perimetry. Totowa, NJ: Humana Press; 2003.

Newman SA. Automated perimetry in neuro-ophthalmology. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 1995, module 6.

Adjunctive Testing

Contrast sensitivity testing

Whereas visual acuity testing uses targets that vary in size but have a single high level of contrast, contrast sensitivity testing uses targets with varying contrast levels. Two types of contrast sensitivity tests exist: grating tests and letter tests. Grating tests display rows of sine wave grating patches, each row reflecting a different spatial frequency. The minimum contrast the patient can detect at each spatial frequency level (the contrast threshold) is plotted, and the resulting graph of threshold versus frequency—the contrast sensitivity function (CSF)—represents the sensitivity of the central retinal region over a range of contrast levels rather than only the contrast level demonstrated with standard visual acuity testing. Grating tests, although arguably superior to letter tests, are difficult to administer and to reproduce reliably. A simpler contrast sensitivity test using a single-size optotype with a

gradually diminishing contrast level is more commonly used. Another such test uses low-contrast letters of decreasing size.

Contrast sensitivity testing can detect and quantify vision loss in the presence of normal visual acuity. Such testing, however, is not specific for optic nerve dysfunction; media irregularities and macular lesions may also yield abnormal results. Interpreting contrast sensitivity test data is more complicated than interpreting visual acuity data, particularly with regard to differentiating subtle abnormalities from normal. Contrast sensitivity testing has not gained widespread acceptance in clinical practice.

Contrast sensitivity testing is discussed further in BCSC Section 3, Clinical Optics, and Section 12, Retina and Vitreous.

Owsley C. Contrast sensitivity. Ophthalmol Clin North Am. 2003;16(2):171–177.

Photostress recovery test

The photostress recovery test may help differentiate vision loss caused by a macular lesion or ocular ischemia from that caused by optic neuropathy. Best-corrected visual acuity is measured (a visual acuity of 20/80 or better is required). Testing monocularly, the patient gazes directly for 10 seconds into a strong light held 2–3 cm from the eye. After the light is removed, the patient attempts to read the next larger Snellen visual acuity line above that for BCVA (eg, 20/25 vs 20/20) as soon as possible. Normal photostress recovery time is less than 30 seconds, but patients with maculopathy or severe carotid artery stenosis show prolonged recovery times, frequently 90–180 seconds or more. Patients with optic neuropathy maintain normal recovery times from photostress.

Glaser JS, Savino PJ, Sumers KD, McDonald SA, Knighton RW. The photostress recovery test in the clinical assessment of visual function. Am J Ophthalmol. 1977;83(2):255–260.

Potential acuity meter

Potential acuity meter (PAM) testing can help determine if media irregularities or opacities are the cause of decreased vision. Optotypes are projected onto the retina through a dilated pupil, providing an estimate of best potential visual acuity. Thus, for a patient with 20/200 visual acuity and a potential visual acuity determined to be 20/60, the ophthalmologist should search for a cause other than media opacities, such as optic neuropathy or maculopathy. Conversely, a patient with 20/100 visual acuity who improves to 20/20 on PAM testing probably does not require further testing. (See BCSC Section 3, Clinical Optics, for more information.)

Reid O, Maberley DA, Hollands H. Comparison of the potential acuity meter and the visometer in cataract patients. Eye. 2007;21(2):195–199. Epub 2005 Nov 4.

Fluorescein angiography

Fluorescein angiography may help differentiate macular from optic nerve–related vision loss. Although most cases of maculopathy show an obvious retinal abnormality, the following disorders may demonstrate only subtle clinical signs:

retinal capillary dropout mild cystoid macular edema

minor collections of submacular fluid (eg, central serous retinopathy) toxic maculopathies (eg, chloroquine)

early cone dystrophies

Subtle abnormalities may become more evident on angiography as avascular zones, dye leakage, or irregularities of the retinal pigment epithelium (RPE). Angiographic leakage can differentiate a truly swollen optic nerve from pseudoedema of the disc, which does not leak. Pseudoedema is characteristic of Leber hereditary optic neuropathy.

Angiography may also demonstrate delayed or absent choroidal filling, either with or without disc edema. This finding may explain vision loss due to choroidal ischemia, which may strongly suggest a diagnosis of giant cell arteritis (Fig 3-7). Indocyanine green (ICG) angiography may better assess choroidal blood flow and deep inflammatory lesions; it may be useful as a supplement to fluorescein angiography in selected cases.

For further discussion of fluorescein angiography, see BCSC Section 12, Retina and Vitreous.

Figure 3-7 Fluorescein angiography image of a retina exhibiting signs of giant cell arteritis. Normally, the choroid fills completely within 3–5 seconds and before the retinal arteries do. The fluorescein dye appears dark in this negative image. The retinal arteries and veins are filled, and the temporal choroid has a large perfusion defect consistent with choroidal

ischemia from giant cell arteritis. (Reprinted with permission from Lee AG, Brazis PW. Giant cell arteritis. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2005; module 6. Cover image.)

Arnold AC, Hepler RS. Fluorescein angiography in acute nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol. 1994;117(2):222–230.

Galor A, Lee MS. Slowly progressive vision loss in giant cell arteritis. Arch Ophthalmol. 2006;124(3):416–418.

Lee AG, Brazis PW. Giant cell arteritis. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2005, module 6:1–15.

Optical coherence tomography

Optical coherence tomography (OCT) provides noninvasive, high-resolution, in situ visualization of the retinal layers and optic disc acquired rapidly and in real time. In this technique, near-infrared light waves reflected from the retina and optic discs are measured and used to construct 2- and 3- dimensional tomographic images. OCT has become instrumental in evaluating and managing a variety of retinal diseases, intraocular tumors, glaucoma, and neuro-ophthalmic conditions. (See BCSC Section 10, Glaucoma, and Section 12, Retina and Vitreous, for more information.)

With OCT, the peripapillary retinal nerve fiber layer (RNFL) thickness can be measured and compared with measurements in an age-matched, normative database. An abnormally thickened RNFL does not reliably distinguish between cases of true optic disc edema and pseudoedema of the disc. However, repeat OCT measurements may reveal an increase in RNFL thickening over time that would not occur in pseudoedema of the disc. As in glaucoma, the RNFL thickness can be monitored over time to quantify axonal loss in chronic neuro-ophthalmic conditions such as optic atrophy in multiple sclerosis and compressive optic neuropathy.

Mendoza-Santiesteban CE, Gonzalez-Garcia A, Hedges TR III, et al. Optical coherence tomography for neuro-ophthalmologic diagnoses. Semin Ophthalmol. 2010;25(4):144–154.

Electrophysiologic testing

With central or peripheral vision loss but no obvious fundus abnormality, ancillary electrophysiologic testing may help confirm or rule out occult abnormalities of the optic nerve or retinal function. Electrophysiologic testing is discussed at length in BCSC Section 12, Retina and Vitreous.

Visual evoked potential The visual evoked potential (VEP), or visual evoked response (VER), measures electrical signals produced in response to a visual stimulus; the signals are recorded at the scalp overlying the occipital cortex. Damage anywhere along the afferent visual pathway can reduce the amplitude or speed of the signal. Because the central visual field predominates in the occipital cortex, isolated peripheral vision loss may yield normal VEP results.

The most common stimulus used for VEP testing is a checkerboard target with a pattern that reverses every half second. The pattern size may also be varied, with smaller pattern sizes allowing detection of smaller changes in function. If patients with poor vision cannot easily see a pattern stimulus, a flash stimulus may be used instead. The response from the checkerboard pattern, however, provides a more quantifiable and reliable VEP waveform.

The most commonly studied VEP waveform typically contains an initial negative peak (N1), followed by a positive peak (P1, also known as P100 for its usual location at 100 ms); second negative (N2) and positive (P2) peaks follow. The P100 latency and, to a lesser degree, the amplitude are the most useful features analyzed. Peak latencies are relatively consistent, and accurate normative data exist; amplitude data are less consistent between subjects but relatively symmetric between the eyes of an individual subject. Waveform abnormalities result from impairment occurring anywhere along the visual pathways, but unilateral abnormalities may reflect optic neuropathy and thus may help reveal lesions in the absence of clear-cut fundus abnormalities. Demyelination of the optic nerve results in increased latency of the P100 waveform without significant effect on amplitude, whereas ischemic, compressive, and toxic damage reduce amplitude primarily, with less effect on

latency.

Unfortunately, the VEP is of limited clinical usefulness. It is subject to influence by numerous factors that may produce abnormal waveforms despite normal visual pathways, including uncorrected refractive error, media opacities, amblyopia, fatigue, and inattention (intentional or unintentional). The VEP, however, remains clinically useful in 2 situations: (1) evaluation of the visual pathway in the inarticulate patient, and (2) confirmation of intact visual pathways in the patient with suspected nonorganic disease. A consistently abnormal flash response in the infant or inarticulate adult reflects gross impairment. An abnormal pattern response may indicate damage or may be a false-negative result for the reasons just cited. Normal responses confirm intact visual pathways.

A new technique being developed is the multifocal VEP (mfVEP), which is designed to detect small abnormalities in optic nerve transmission and provide topographic correlation along the visual pathway. Limited studies to date of the anterior visual pathways correlate visual field abnormalities to the abnormalities confirmed by mfVEP.

Fishman GA, Birch DG, Holder GE, Brigell MG. Electrophysiologic Testing in Disorders of the Retina, Optic Nerve, and Visual Pathway. 2nd ed. Ophthalmology Monograph 2. San Francisco: American Academy of Ophthalmology; 2001.

Hood DC, Odel JC, Winn BJ. The multifocal visual evoked potential. J Neuroophthalmol. 2003;23(4):279–289.

Electroretinogram The electroretinogram (ERG) measures the electrical activity of the retina in response to various light stimuli under different states of light adaptation. Electrical activity is measured at the corneal surface by electrodes embedded in a corneal contact lens worn for testing.

The full-field electroretinogram response is generated by stimulating the entire retina with a light source under varying conditions of retinal adaptation. Major components of the electrical waveform generated and measured include the a-wave, primarily derived from the photoreceptor layer; the b- wave, derived from the inner retina, probably Müller and ON-bipolar cells; and the c-wave, derived from the RPE and photoreceptors. Rod and cone photoreceptor responses can be separated by varying the stimuli and the state of retinal adaptation during testing.

Electroretinogram testing is useful in detecting diffuse retinal disease in cases of generalized or peripheral vision loss. Disorders such as retinitis pigmentosa (including the forms without pigmentation), cone–rod dystrophy, toxic retinopathies, and the retinal paraneoplastic syndromes— cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR)—may present with variably severe vision loss and minimal visible ocular abnormality. Invariably, the ERG pattern is severely depressed by the time substantial vision loss has occurred, and thus testing is extremely useful. The full-field test, however, measures only a mass response of the entire retina; minor or localized retinal disease, particularly maculopathy—even with severe visual acuity loss—may not produce an abnormal response.

The ERG response generated by a pattern-reversal stimulus similar to VEP testing has been studied and is termed the pattern ERG, or PERG. Ganglion cell activity is thought to be reflected in the N95 component of the waveform, and thus the technique may detect subtle optic neuropathies. Reports have suggested the usefulness of PERG in distinguishing between ischemic and demyelinating optic neuropathy: the N95 component remains relatively normal (if not atrophic) in demyelination and appears abnormal in ischemia. The test has not gained wide clinical use.

A newer technique termed multifocal ERG simultaneously records and topographically maps ERG signals from up to 250 focal retinal locations within the central 30° (Fig 3-8). Because it does not rely on a massed retinal response, as does a full-field ERG, multifocal ERG has demonstrated great value in detecting occult focal retinal abnormalities within the macula or more peripherally. The

technique is useful in distinguishing between optic nerve and macular disease in occult central vision loss, as the signal generally remains normal in optic nerve disease. Also, it may detect regions of focal retinal dysfunction too small to be measured by the full-field technique.

Figure 3-8 Multifocal electroretinogram response of a patient with maculopathy. The pattern from the affected eye (A) shows flattening of the foveal waveforms compared with that of the normal eye (B). (Courtesy of Anthony C. Arnold, MD.)

Fishman GA, Birch DG, Holder GE, Brigell MG. Electrophysiologic Testing in Disorders of the Retina, Optic Nerve, and Visual Pathway. 2nd ed. Ophthalmology Monograph 2. San Francisco: American Academy of Ophthalmology; 2001.

Holder GE. Pattern electroretinography (PERG) and an integrated approach to visual pathway diagnosis. Prog Retin Eye Res. 2001;20(4):531–561.

Hood DC, Bach M, Brigell M, et al. ISCEV guidelines for clinical multifocal electroretinography (2007 edition). Doc Ophthalmol. 2008;116(1):1–11. Epub 2007 Oct 31.

Hood DC, Odel JG, Chen CS, Winn BJ. The multifocal electroretinogram. J Neuroophthalmol. 2003;23(3):225–235.