Optical coherence tomography

This noninvasive imaging technique is like ultrasound but uses light waves instead of sound waves. Using information contained in the light waves reflected from different depths, OCT reconstructs a depth profile of the structure being analyzed. Relevant to neurology is the analysis of retinal layers in different regions of the eye (eg, macula, optic nerve), which can be interpreted using qualitative and quantitative approaches. Resolution is on the order of 5 to 10 μm.

Clinical aspects

Description. Most ophthalmic OCT devices are tabletop devices with a chin and forehead rest that position the seated patient’s eye in front of a camera. Ophthalmic OCT devices generate 2D and 3D representations of the retina differing by region (eg, optic nerve, macula) and scan protocol (eg, cross-sectional B-scan, volume scan, circle scan). For example, an optic nerve head volume scan can be used to construct a topographical map of the optic nerve head from which optic nerve diameter and cup-to-disc ratio can be calculated. A typical scan protocol takes only a few seconds per eye.

The three main categories of OCT instrumentation are time-domain OCT (TD-OCT), spectral-domain OCT (SD-OCT), and swept-source OCT (SS-OCT). SD-OCT is much faster and has markedly better resolution than TD-OCT and now dominates the market (16). Various manufacturers of OCT instruments differ in their imaging protocols and quantitative analyses. Measurements can not be directly compared between instruments.

Enhanced depth imaging (EDI-OCT) is performed with some SD-OCT instruments. This permits deeper measurements of the optic nerve head down to the lamina cribrosa and is helpful for visualization of pathologies such as optic disc drusen and choroidal changes.

Indications. Optical coherence tomography is useful for evaluating patients with afferent visual pathway disorders, including detection of optic nerve swelling due to elevated intracranial pressure or other causes, optic nerve (ganglion cell) atrophy, and some retinal causes of vision loss (eg, macular degeneration, central serous chorioretinopathy).

Results. Most OCT systems have built-in analytics that segment image layers and provide quantitative measures for total retinal thickness and ganglion cell layer thickness (either ganglion cell complex [inner plexiform layer to inner limiting membrane] or retinal ganglion cell and inner plexiform layer thickness) derived from macula scans. Retinal nerve fiber layer thickness is extracted from a cylindrical (“ring”) scan centered on the optic nerve head and represents the thickness of the ganglion cell axons as they come together to form the optic nerve.

Reduction in the thickness of retinal ganglion cell layers can result from axonal loss caused by retrograde degeneration following ganglion cell injury. Typically, these changes arise from an afferent visual pathway lesion involving the optic nerve, chiasm, or tracts. In the setting of transsynaptic “neuroaxonal” degeneration, postgeniculate lesions in the afferent visual pathway can also cause optic nerve pallor and corresponding retinal nerve fiber layer defects, which can all be readily captured by OCT, allowing evaluation for axonal loss that may not be obvious by fundus examination. Thus, the OCT-derived retinal ganglion cell measurements help assess optic neuropathies that have caused ganglion cell injury. It is important to note that any optic neuropathy, including glaucoma, can lead to decreased ganglion cell layer thickness, so a comprehensive eye and neurologic evaluation are crucial for correct diagnosis.

OCT-measured thinning of the macular ganglion cell layer has been found to have a strong relationship with visual loss across a spectrum of optic neuropathies, including glaucoma, optic neuritis, ischemic optic neuropathy, hereditary optic neuropathy, toxic optic neuropathy, optic nerve glioma, and idiopathic intracranial hypertension.

Thickening of the peripapillary ganglion cell layers around the optic nerve (peripapillary retinal nerve fiber layer) can occur in optic nerve head edema due to swelling of the ganglion cell axons.

Multiple sclerosis and other neuro-inflammatory disorders. Reductions in peripapillary retinal nerve fiber layer thickness have been reported in different multiple sclerosis-related subtypes from clinically isolated syndromes to secondary progressive multiple sclerosis. Several studies have also confirmed atrophy of the ganglion cell-inner plexiform layer in multiple sclerosis. Associations between OCT-derived retinal thickness, contrast acuity and sensitivity, cerebral atrophy quantified by MRI, treatment, and disease severity have also been reported, leading to the proposed use of OCT as a biomarker of multiple sclerosis disease progression in the clinic (15; 11; 13). However, the nonspecific nature of these changes and magnitude within the range of test-retest variability limit their clinical application.

Acute optic neuritis is associated with optic nerve swelling in about one third of patients, and this can be detected with OCT. In the months following recovery from optic neuritis, disc swelling (if present) resolves, and ganglion cell layer thinning develops. This is not a new injury; rather, it reflects the time for the injured cells to atrophy (14). Peripapillary retinal nerve fiber layer thickness decreases by approximately 10 to 40 µm in 3 to 6 months after the acute episode, and stabilization is observed at 7 to 12 months (10; 02). This thinning is more pronounced after neuromyelitis optica-associated optic neuritis.

Nonarteritic ischemic optic neuropathy. OCT can be used to monitor the disease course with the assessment of optic nerve head edema that defines this condition in the acute setting, and optic atrophy that develops later. However, nonarteritic anterior ischemic optic neuropathy remains a clinical diagnosis. Acute findings include increased peripapillary retinal thickness associated with optic disc edema, and some cases have subretinal fluid visible. Chronically, the macular ganglion cell inner plexiform layer thinning pattern often matches the chronic visual field defect. Ganglion cell layer and internal plexiform layer thinning has shown to be better than retinal nerve fiber thinning in indicating early structural loss in nonarteritic ischemic optic neuropathy, both because it occurs faster and because optic nerve swelling precludes detection of thinning of the retinal nerve fiber layer.

Papilledema, pseudopapilledema. Similar to optic neuritis and nonarteritic ischemic optic neuropathy, OCT measurements can demonstrate optic nerve head elevation characteristic of papilledema due to elevated intracranial pressure. This can be used to quantify and monitor pre- and post-treatment responses. In cases that have ganglion cell injury, macular ganglion cell thickness measurements can detect this.

The ability to differentiate papilledema due to raised intracranial pressure from other forms of optic disc edema or from pseudopapilledema can be clinically challenging, particularly when the degree of edema is not severe. OCT can be used to detect optic disc drusen, one cause of pseudopapilledema, using enhanced depth imaging (EDI-OCT). One can see optic disc drusen as hyporeflective structures with a hyper-reflective margin and no shadowing.

Compressive optic neuropathies. Compression of the optic nerve or chiasm usually leads to optic atrophy over time, which, due to retrograde degeneration, can be visualized on OCT. Subtle optic nerve damage from compressive optic neuropathy can be appreciated on OCT before it can be seen on ophthalmoscopy. This is especially true for the macular ganglion cell layer analysis because macular ganglion cell thinning precedes peripapillary retinal nerve fiber layer loss, and, occasionally, ganglion cell thinning can be observed even before appreciable changes are detectable on visual field testing.

OCT measures can indicate visual prognosis following treatment for compressive optic neuropathy, with minimal retinal nerve fiber layer loss indicating a better prognosis for recovery of a visual deficit (12; 09; 03; 07).

The pattern of macular ganglion cell loss helps localize compressive optic neuropathies involving the chiasm or optic tract because the pattern matches the characteristic pattern of visual field loss. In chiasmal injury, binasal macular thinning occurs because the crossing nasal fibers are damaged with chiasm compression. Homonymous hemi-macular ganglion cell loss suggests injury to the optic tract or lateral geniculate nucleus from various etiologies (eg, tumor, stroke, or demyelination) (05).

Adverse effects. OCT may require pupillary dilation in some patients with very small pupils, which carries a small risk. Patients with poor mobility or orthopedic restraints may experience difficulty with head positioning or fatigue, but overall, this is a well-tolerated procedure.

Limitations. Several factors can affect image quality, including pupil size, ophthalmic media opacity (eg, cataract or corneal dryness), and ability of the patient to fixate. The automatic segmentation algorithms that generate quantitative measurements are more likely to have errors when image quality is poor. Structural distortions of the eye due to axial length or ophthalmic pathology can also lead to algorithmic errors. To evaluate for these effects, the interpreting provider should review the cross-sectional images on the report, including the segmentation lines. Classification of quantitative measurements should be interpreted in the context of the normative group used, which is often comprised of Caucasian subjects grouped by age, with normative data typically not available for children.

Table 1. Imaging Modalities in Optic Nerve Abnormalities

B- and A-scan ophthalmic ultrasonography

Ophthalmic ultrasound provides quick, noninvasive, and cost-effective evaluations of the eye and the orbit. It allows clinicians to view structures not visible with routine ophthalmic equipment and below the resolution of neuroimaging techniques. It provides diagnostic information in various ophthalmic conditions, such as papilledema or pseudopapilledema, thyroid eye disease, and scleritis as well as retinal detachment or presence and type of an ocular malignancy or foreign body.

Clinical aspects

Description. Ophthalmic ultrasound uses reflected sound waves to produce an image from tissue. The probe records relative density and reflectivity of the tissue and generates either a plot of depth (A scan) or intensity (B scan). A-scan can be used to measure the ocular axial length, among other things, but ultimately is beyond the scope of this article.

Indications. B-scan ultrasound can be used to evaluate the anterior optic nerve as well as retrobulbar structures in the orbit, such as the optic nerve sheath and extraocular muscles.

Results.

Optic disc drusen. B-scan ultrasound can be utilized to evaluate for optic disc drusen or buried optic nerve drusen, which are visible as punctate hyper-reflective regions in the optic nerve head. However, it is not likely to be as sensitive as enhanced depth imaging and relies more on the operator (06).

Optic nerve sheath. Optic nerve sheath ultrasound measures the optic nerve sheath diameter in the setting of trauma or nonacute settings to assess for increased intracranial pressure (01; 04; 17; 08).

Thyroid eye disease. Ultrasound can measure extraocular muscle reflectivity and thickness. Color Doppler can assess blood flow before and after thyroid ophthalmopathy treatment to measure response.

Posterior scleritis. Posterior scleritis causes intense boring eye pain with a clinically unremarkable screening ophthalmic examination. Ultrasound can demonstrate thickening of the posterior sclera, which is visible as a “T sign” on the ultrasound.

Carotid-cavernous fistula. Ultrasound findings include thickened or congested choroid and dilated superior ophthalmic vein.

Adverse effects. Globe rupture can be worsened by ocular ultrasonography and should be avoided.

Limitations. Ultrasonography is operator-dependent and subject to user training and experience.

Fluorescein angiography

Fluorescein angiography is used to examine blood flow in the retina and detect breakdown in vascular integrity supplying the retina, choroid, and optic nerve. A skilled ophthalmic photographer is needed to capture the images.

Clinical aspects

Description. When using fluorescein angiography, the patient is given intravenous fluorescein, and retinal photography is performed to examine vascular filling patterns and defects in the retinal, choroidal, and optic nerve head veins and arteries.

Approximately 10 seconds after injection of contrast, the dye enters the short posterior ciliary arteries and appears in the optic nerve and choroid. Ten to 15 seconds after injection, the retinal circulation appears. Photos are taken every 1 to 2 seconds in the earlier phase. Peak fluorescence takes place at around 30 seconds, with recirculation following. Around 10 minutes after injection, the fluorescein is no longer visualized in the retinal vessels; however, the sclera, Bruch’s membrane, and optic nerve will continue to fluoresce. Contrast is excreted in the urine in the next 24 to 36 hours.

In healthy tissue, the blood-retina barrier prevents fluorescein from diffusing into retinal tissue, and the images show the dye as it passes from arterial to venous structures. Leakage of dye outside the vessels can show in areas with new vessel growth or in regions with blood-ocular barrier defects induced by inflammation or ischemia. There are some neuro-ophthalmic conditions for which fluorescein angiography can help make a diagnosis.

Indications. Fluorescein angiography is commonly utilized to evaluate perfusion abnormalities resulting from retinal vascular occlusions and to detect vessel leakage, for example, due to neovascularization, vasculitis, or optic disc edema.

Results.

Retinal vascular occlusions. These are visible as retinal filling delay or asymmetry in retinal vascular filling. This can help confirm branch and central retinal artery occlusions as a cause of vision loss or detect asymptomatic events, for example, as in Susac syndrome.

Optic nerve head edema. Leakage on the optic nerve surface and staining occur in cases of pathological optic nerve head edema, which can help to distinguish it from pseudopapillema.

Giant cell arteritis. Affected patients can have patchy or delayed choroidal filling indicative of choroidal vascular supply involvement.

Adverse effects. The procedure requires dilation of the pupils and intravenous administration of fluorescein dye. Although generally well tolerated, there can be nausea, vomiting, and vasovagal responses. The procedure is relatively contraindicated in pregnancy. Urine will be bright yellow after the procedure.

Limitations. Interpretation of images is subjective rather than quantitative. It requires a trained photographer and specialized equipment, including invasive intravenous access. It is otherwise somewhat time-consuming and those with media opacities might not produce quality images.

Fundus autofluorescence

Fundus autofluorescence is an imaging technique used to visualize changes or injury to the retina and retinal pigment epithelium that would otherwise not be well visualized on retinoscopy. Fundus autofluorescence is not invasive and does not require dye or contrast.

Description. Fundus autofluorescence detects fluorophores, including lipofuscin. These are in the outer segment of the photoreceptors, at the level of the retinal pigment epithelium. This technique provides insight into the metabolic status of the retinal pigmentary epithelium by revealing the distribution and accumulation of lipofuscin. Different ocular structures display varying degrees of autofluorescence and can be termed as being hyperautofluorescent if there is a brighter appearance or higher intensities than the background level (the homogenous level of autofluorescence generated in the posterior pole fundus of a healthy eye) and hypofluorescent if there is a darker appearance or lower intensities than the background level.

Indications. Fundus autofluorescence is used to evaluating patients with suspected optic nerve head drusen, maculopathies, or outer retinopathies.

Results. In a normal eye, the optic nerve head is hypo-autofluorescent, as there is no retinal pigmentary epithelium layer. Retinal pathologies can cause dysfunction of retinal pigment epithelium and lipofuscin accumulation; this results in abnormal autofluorescence patterns.

Optic disc drusen. Optic disc drusen are typically hyperautofluorescent and visualized when they are near the surface of the optic disc. This is useful as an adjunct to enhanced-depth imaging OCT.

Acute idiopathic blind spot enlargement. Patients typically complain of positive visual phenomena and an enlarged blind spot. A fundus examination can demonstrate mild disc elevation. Fundus autofluorescence can show peripapillary fundus hyperfluorescence.

Multiple evanescent white dot syndrome. This presents with acute painless unilateral vision loss with scotomas. These patients also show multiple white lesions that appear as hypofluorescent at the level of the retinal pigment epithelium. On color photos of the retina, these appear as hypopigmented lesions thought to be due to disruption of the outer retina.

Adverse effects. Like OCT, this imaging may require pupillary dilation in some patients with very small pupils, and this carries a small risk. Although generally well tolerated, those with mobility or physical impairments may experience fatigue or soreness based on positioning.

Limitations. Interpretation is qualitative rather than objective. Some patients might require dilation before photography. This imaging is susceptible to artifact, including media opacities in the vitreous or anterior segment. In patients with these types of pathology, this imaging might be of limited utility. Imaging might be limited in patients with mobility or physical impairment, depending on positioning.