ReviewOptical coherence tomography in multiple sclerosis: a systematic review and meta-analysis
Introduction
Optical coherence tomography (OCT) is a non-invasive technique1 that enables a so-called optical biopsy of accessible tissues such as the retina (figure 1). During the past decade, OCT has matured into an interesting and highly sensitive method for imaging of neurodegeneration in multiple sclerosis (MS);2, 3 because the retina is the only place where a tissue layer made up of axons can be imaged directly, quantification of the retinal nerve fibre layer (RNFL) has the potential to open a diagnostic window for monitoring of neurodegeneration. Loss of visual function is a frequent presenting sign in MS and can be caused by optic neuritis (MSON). Most patients with MSON have good recovery of visual function, but demyelination, ion-channel redistribution, and axonal loss cause remaining subtle signs and symptoms. Visual function is affected in most patients with longstanding MS, and loss of vision is the second most important deficit causing reduced quality of life. Because axonal loss, by contrast with demyelination, is not reversible and is therefore an important cause of sustained disability, a validated tool for monitoring of axonal loss is needed.
We present a systematic review of studies investigating OCT in patients with MS. Special care is taken to distinguish axonal damage caused by clinically evident MSON from more subtle retinal axonal damage in unaffected eyes of patients with MS. We review the anatomical and functional correlations, focusing first on the visual system and second on more global measures of disability in MS. The relation between OCT data and established electrophysiological techniques and imaging modalities is also discussed. Finally, we provide a glimpse into future research areas of advanced OCT imaging that might affect assessment of axonal damage relevant to a patient's disease activity and response to treatment.
Section snippets
Search strategy and selection criteria
We searched Dutch, English, French, German, Italian, and Spanish literature for all studies using OCT in patients with MS from the first description of the method by Huang1 in 1991, to May, 2010, including reports published online ahead of print. We searched PubMed, Embase, Medline, Web of Science, and the Cochrane Register of Diagnostic Test Accuracy Studies using the search terms: “multiple sclerosis”, “MS”, “optic neuritis”, “ON”, “optical coherence tomography”, “OCT”, “retinal nerve fibre
Axonal loss in the retina
With the invention of the ophthalmoscope by von Helmholtz in 1851, in-vivo detection of optic-disc atrophy became technically possible. For example, in 1879, Gowers38 described sectoral RNFL loss in a woman with syphilis. In this case, the remaining nerve fibres were more visible than normal because of swelling.38 A later case of sectoral RNFL loss in which sequential in-vivo images allowed identification of ascending axonal degeneration (now known as Wallerian degeneration) was facilitated by
Timecourse of RNFL loss in MS
As a rule of thumb, RNFL loss becomes readily detectable with OCT about 3 months after acute optic neuritis. Early reduction in RNFL thickness caused by axonal atrophy is clinically difficult to distinguish from a reduction due to resolution of axonal swelling, which is common in acute optic neuritis. Costello and colleagues7 presented longitudinal data for RNFL thickness during the first 12 months after optic neuritis (figure 7). These data show continuing axonal loss in the affected eye for
OCT and disability in MS
There are well characterised limitations to the clinical disability scales currently used in MS research,61 not least of which is that they do not fully capture the range of disability seen in the disease, especially if they are not in the domain of patient mobility and motor function. Useful surrogate markers are challenging to validate. The driving force of disability in MS, axonal loss, seems to be associated with changes in the RNFL that are statistically related to changes in clinical
OCT and electrophysiology in MS
OCT allows structural properties of the retina to be studied, thus complementing the many electrophysiological techniques aimed at functional assessment. Researchers have examined possible associations between the two domains. Recalling the simplified sketch from figure 6, one can formulate two key hypotheses to be tested. First, is there a relation between RNFL loss and VEP/pattern electroretinogram (ERG) amplitude reduction (figure 6B, D)? Second, does VEP evidence for demyelination in the
OCT and imaging in MS
The association between structural changes within the visual pathways as assessed by brain imaging techniques and OCT data was investigated in several studies included in our systematic review.11, 12, 22, 23, 75, 81, 82 These investigators focused on optic-nerve imaging11, 81, 82 and whole-brain imaging techniques.11, 12, 22, 23, 45, 75 The published data suggest correlations between RNFL thickness and measures of brain atrophy on MRI,12, 23, 75 but a consensus has yet to emerge with respect to
OCT and the macula in MS
Changes in macular volume, as well as inner and outer macular segments, consistently show volume loss caused by loss of RGCs.12, 14, 18, 19, 20, 21, 24, 30, 35, 37, 74, 84, 85 All reported the macular volume was reduced in patients with MS compared with controls. Loss of macular volume was correlated with loss of RNFL in four studies.14, 24, 37, 81 Of note, retinal thickness in the macula is made up of many RGCs (cones in the macula have a 1:1 correlation with RGCs, whereas in the periphery
Conclusions
There is much excitement about OCT in MS research, and as one of the first neurologists to make extensive use of the ophthalmoscope, Hughlings Jackson (1835–1911), said: “It is not too much to say that, without an extensive knowledge of ophthalmology, a methodological investigation of diseases of the nervous system is not merely difficult, but impossible.”109 OCT is a new and promising technique that has potential for monitoring of treatment effects in trials of neuroprotective strategies in
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