• Neuro-Ophthalmology/Orbit

    Introduction

    Optical coherence tomography (OCT) is a noninvasive, high-resolution technique that uses near-infrared light to measure the thickness of intraocular structures, such as retinal nerve fiber layer (rNFL). Ophthalmic applications have included accurate assessment of macular thickening in diabetic and cystoid macular edema, and capturing retinal ganglion cell and axonal loss in glaucoma. There is recent evidence that OCT may have a potential role as a biomarker for axonal loss in multiple sclerosis (MS).

    Background

    MS is a chronic immune-mediated disease of the central nervous system (CNS), with inflammatory and degenerative components. The visual system, both afferent and efferent, is frequently involved, and many patients initially present with visual loss from optic neuritis.1 Although traditional definitions of the disease emphasized primary demyelination of the CNS, it has become clear through multiple avenues of research that progressive axonal loss is a critical feature of MS and correlates with ultimate disability.2 OCT is therefore an appealing candidate as a biomarker for early axonal loss in MS for several reasons:

    • The results are highly reproducible.
    • The images are easily acquired through noninvasive methods.
    • The study is relatively inexpensive.
    • The peripapillary retinal nerve fiber layer consists of unmyelinated axons, allowing direct, quantitative assessment of axonal loss.

    Early observational studies using ophthalmoscopy have demonstrated loss of retinal nerve fiber layer in MS patients, and it occurs in those with and without a history of optic neuritis or subjective visual loss.3 These observations were  limited because they relied on ophthalmoscopy alone and highly depended on operator technique and interpretation.  More recent research has identified subclinical visual loss in many MS patients that can be detected using low-contrast visual-acuity testing and contrast-sensitivity measurements.4 It has become evident that MS patients, even those with normal high-contrast Snellen visual acuity and no overt visual attacks, have measurable visual function loss that may not be adequately captured on standardized MS disability scales.

    OCT and Optic Neuritis

    Although the loss of retinal nerve fiber layer in progressive optic neuropathies such as glaucoma has been well-documented, the application of OCT to optic neuritis and other optic neuropathies is relatively recent. Trip et al5 demonstrated loss of rNFL in the eyes of patients with optic neuritis compared with matched controls. Costello et al6 performed a study evaluating the timing and extent of rNFL loss in patients presenting with isolated optic neuritis. They found that rNFL thinning (presumably representing axonal loss) occurred in most patients, even those with full clinical recovery. Loss of rNFL began at approximately 3 months after onset of optic neuritis for most patients, and continued for up to 6 months. Other studies have confirmed these initial findings.7

    OCT and MS

    The quantitative assessment of brain axonal transection and axonal loss is cumbersome and technically challenging. Available imaging techniques include magnetic resonance spectroscopy, magnetization transfer imaging, volumetric analysis, and diffusion tensor imaging. Although all these methods have been used in practice and in clinical trials, they are time-consuming and expensive and often require the use of high-strength magnets (4.0 Tesla or higher). Further, the results often reflect a combination of demyelination, reactive gliosis, and axonal loss, increasing the background "noise," making pure axonal loss harder to assess.7

    The advantages of OCT are ease of use and the ability to directly assess unmyelinated axons. Fisher et al8 assessed a cohort of patients with clinically definite MS, including those with and without a history of optic neuritis. OCT measurements were performed in all patients after a complete neuro-ophthalmic examination, and results were compared with matched controls. The results showed as expected that eyes in patients with MS and a history of optic neuritis had significantly lower rNFL compared with eyes in patients without a history of optic neuritis and in control eyes. However, eyes in patients with MS, even those without a history of optic neuritis, also had significantly lower rNFL than controls. Macular volume was also similarly decreased, suggesting loss of retinal ganglion cell bodies as well.

    These findings support subclinical axonal loss in asymptomatic eyes in patients with MS. The rNFL thickness was inversely proportional to Extended Disability Score Statusscale, suggesting that axonal loss within the anterior visual pathway paralleled, to at least some extent, axonal loss in the brain. Other studies have shown similar results,7 and indeed, current MS clinical trials are including rNFL as an outcome marker.

    It is worth emphasizing that OCT has not yet been validated as a specific biomarker for MS or any other neurological disorder. As with any paraclinical test, the data from OCT should not be used in the absence of a comprehensive ophthalmologic examination because many ophthalmic diseases may cause reduced rNFL (most commonly glaucoma, but also high myopia, macular degeneration, and congenital optic nerve anomalies). The normative database for OCT was developed from a relatively small sample size, so it is possible that the range of normal may be larger than anticipated. The most valuable for OCT in MS may be longitudinal rather than cross-sectional data.

    Summary and Future Directions

    Peripapillary retinal nerve fiber layer thickness assessed using OCT may prove to be a candidate biomarker for axonal loss in MS. Future work may involve the use of OCT in other demyelinating diseases including neuromyelitis optica, a condition that preferentially involves the optic nerve and spinal cord. Others have already investigated OCT in other neurological diseases, such as Alzheimer's disease.9

    References

    1. Sorenson TL, Frederiksen JL, Bronnum-Hansen H, Petersen HC. Optic neuritis as onset manifestation of multiple sclerosis: a nationwide, long term survey. Neurology. 1999;53(3):473-478.
    2. Trapp BD, Peterson J, Ranshoff RM, Rudick R et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338(5):278-285.
    3. Frisen L, Hoyt WF. Insidious atrophy of retinal nerve fibers in multiple sclerosis. Fundoscopic identification in patients with and without visual complaints. Arch Ophthalmol. 1974 1974;92(2):91-97.
    4. Balcer LJ, Baier ML, Cohen JA, Kooijmans MF et al. Contrast letter acuity as a visual component for the Multiple Sclerosis Functional Composite. Neurology. 2003;61(10):1367-1373.
    5. Trip SA, Schlottman PG, Jones SJ, Altmann DR et al. Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol. 2005;58(3):383-391.
    6. Costello F, Coupland S, Hodge W, Lorello GR et al. Quantifying axonal loss after optic neuritis with optical coherence tomography. Ann Neurol. 2006;59(6):963-969.
    7. Sergott RC, Frohman E, Glanzman R, Al-Sabbagh A, OCT in MS Expert Panel. The role of optical coherence tomography in multiple sclerosis: expert panel consensus. J Neurol Sci. 2007;263(1-2):3-14.
    8. Fisher JB, Jacobs DA, Markowitz CE, Galetta SL et al. Relation of visual function to nerve fiber layer thickness in multiple sclerosis. Ophthalmology. 2006;113(2):324-332.
    9. Iseri PK, Altinas O, Tokay T, Yuksel N. Relationship between cognitive impairment and retinal morphological and visual functional abnormalities in Alzheimer disease. J Neuroophthalmol. 2006;26(1):18-24.

    Author Disclosure

    Dr. Van Stavern states that he has no financial relationship with the manufacturer or provider of any product or service discussed in this article or with the manufacturer or provider of any competing product or service.