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A Window to Beyond the Orbit: the value of optical coherence tomography
in non-ocular disease
James R. Cameron 1
Andrew J. Tatham 2
1
Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK
2
Princess Alexandra Eye Pavilion, Edinburgh, UK
Corresponding Author:
Dr. James R Cameron MSc FRCOphth
Anne Rowling Regenerative Neurology Clinic
University of Edinburgh
Chancellor’s Building
49 Little France Crescent
Edinburgh
EH16 4SB
UK
Tel: +44 (0)131 465 9500
Email: [email protected]
Abstract:
Optical coherence tomography (OCT) imaging of the eye has become an essential tool for the
ophthalmologist, aiding diagnosis and assisting with treatment decisions, in many ocular
diseases. However, there is an evolving role for OCT in informing on non-ocular diseases,
which ophthalmologists should be aware of. The purpose of this review is to examine recent
evidence for the role of ocular OCT imaging to evaluate disease beyond the orbit and to
discuss possible opportunities and challenges arising from this, from the perspective of the
ophthalmologist.
Keywords:
optical coherence tomography - retinal imaging - systemic disease – neurodegeneration –
biomarker – glaucoma
1
Introduction
Since first used to image the eye in 1991, optical coherence tomography (OCT) has become
an integral tool for the diagnosis and management of a diverse range of ocular diseases, with
the versatility of OCT providing the means to obtain quantitative information about the optic
nerve head, macula and anterior segment. (Huang et al. 1991) The original technology of
time domain OCT (TD-OCT) has been surpassed by newer generation spectral domain OCT
(SD-OCT), which benefits from enhanced image quality due to improved spatial resolution
and averaging of multiple images within each scan, made possible by a much faster scan
speed. Increasingly sophisticated SD-OCT segmentation software has also become available
that produces more accurate automated segmentation of inner retinal layers. (Mwanza et al.
2012)
Although ophthalmologists are familiar with the many uses of OCT in ophthalmic disease,
not all may be aware that OCT imaging of the eye is increasingly explored as a possible tool
for identifying ocular biological markers of predominantly non-ophthalmic diseases, ranging
from multiple sclerosis to cardiovascular disease. The purpose of this review is to examine
recent evidence for the role of ocular OCT imaging to evaluate disease beyond the orbit and
to discuss possible opportunities and challenges arising from this from the perspective of the
ophthalmologist.
2
Methods
A PubMed and Medline database search was performed on 20 September 2015 using the
following search terms: ((((((((((“optical coherence tomography”[Title/Abstract]) NOT ("Eye
Diseases"[Mesh])) AND English[Language]) NOT Review[Publication Type]) NOT
Comment[Publication Type]) NOT animals[MeSH Terms]) NOT mice[MeSH Terms]))))
AND ((eye OR retina OR macula OR "retinal nerve fiber layer")).
This search yielded 2,059 results. Although searching with Medical Subject headings (MeSH
terms) may exclude newer citations and articles that do not yet include MeSH subject terms,
we avoided this problem by excluding rather than including articles based on MeSH terms.
Therefore a manuscript describing an animal study without a MeSH term for animal would
not have been excluded at this stage.
Article titles were then manually reviewed and those relating primarily to ocular diseases
(such as glaucoma or age-related macular degeneration) or studies in healthy subjects were
excluded. Studies relating to use of OCT for non-ocular imaging or anterior segment imaging
were also excluded. We also purposefully excluded animal studies, letters, comments, review
articles and articles not published in English. We also excluded articles describing OCT in
systemic diseases with well know ocular manifestations such as hypertension, diabetes and
albinism.
References of the articles retrieved from the above search were also manually scanned to
identify additional studies. Details of the studies remaining after the search are summarised in
Table 1.
3
Table 1. Summary of papers reporting OCT studies in non-ocular diseases from initial Pubmed search.
Case Report
Case-control /
Cohort-study
Random allocation
Meta-analysis
Multiple sclerosis
6
132
0
0
Neuromyelitis Optica
3
18
0
0
Dementia
0
12
0
3
Parkinson’s Disease
2
27
0
1
Multiple System Atrophy
0
5
0
0
Motor Neurone Disease
0
2
0
0
Autism
0
1
0
0
Traumatic brain injury
1
3
0
0
Chiasmal compression
2
6
0
0
Optic pathway glioma
0
2
0
0
Schizophrenia
0
2
0
0
Neurosarcoid
0
1
0
0
Stroke
0
3
0
0
Migraine
0
6
0
1
Cluster headache
0
1
0
0
Systemic lupus erythematosus
0
1
0
0
A selection process was used to determine which articles were suitable for inclusion in the
review. Abstracts were retrieved for all studies collected in Table 1.
Abstracts were reviewed for the quality of study design using the levels of evidence hierarchy
described by the Oxford Centre for Evidence Based Medicine (OCEBM Levels of Evidence
Working Group*. “The Oxford Levels of Evidence 2”. Oxford Centre for Evidence-Based
Medicine. http://www.cebm.net/index.aspx?o=5653). Only the studies with the highest level
of evidence for each disease category were retained. These were then compared for
representative studies, across appropriate comparisons and correlations, to give the reader a
fair consensus opinion of the current state of knowledge in this rapidly evolving subject area.
For example, priority was given to papers utilising newer generation spectral-domain OCT,
over previous generations.
4
Although retinal nerve fibre layer (RNFL) thickness is typically measured in the
circumpapillary region, with the exact location dependant on the OCT device, more recently
segmentation of the RNFL in the macula is possible. For simplicity throughout this article,
when referring to RNFL thickness we refer to the circumpapillary RNFL.
Review of Diseases
It is in the field of neurodegenerative diseases that the use of OCT is seeing rapid uptake, as
the technology has arrived at a time when there is a great unmet need for reliable and
sensitive biomarkers of disease status. Not only do several of these conditions feature anterior
visual pathway involvement - thus making OCT of the neuroretina a logical investigation but there is an increasing belief that many diseases of the brain will reflect their pathology in
the eye, thus making it a unique entry point to directly visualise the central nervous system,
both neural and vascular tissue.
The concept of the retina being an anatomical and functional surrogate of the central brain is
increasingly recognised. (MacGillivray et al. 2014) Therefore it is not only the
neurodegenerative diseases of the central nervous system (CNS) that are under investigation,
but diseases where either a retinopathy is described, or where there is a plausible hypothesis
for retinal metrics to provide surrogate measures of CNS status.
Multiple Sclerosis
Multiple Sclerosis (MS) is a common neurological disease, characterised by recurrent
inflammatory episodes within the CNS, causing demyelination with associated relapse
symptoms, and ultimately neuronal loss and permanent functional disability. Existing
radiological and clinical markers of disease assist in phenotypic diagnosis and disease course
to a degree. However, the wide heterogeneity in the disease group necessitates a search for
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better biomarkers of individuals, to more precisely track the gradient of disease, and provide
an important metric of impact of disease-modifying treatments.
With 138 publications, MS was by far the leading disease identified in our literature search.
The first paper to investigate OCT as a potentially useful biomarker in the assessment of MS,
alongside functional measures of vision, was published in 2006. (Fisher et al. 2006) This
study reported reduced RNFL thickness in patient with MS - with and without a history of
optic neuritis (ON) - with RNFL thickness correlated to visual acuity and contrast sensitivity.
The same group have been leaders in this field, with a series of publications since. Important
findings have included demonstration of a relationship between thinner RNFL and reduced
magnetic resonance imaging (MRI)-measured brain parenchymal fraction (BPF) (GordonLipkin et al. 2007). Patients with MS have also been shown in longitudinal studies to
experience progressive thinning of the RNFL with or without a prior history of ON, although
patients with visual deterioration during follow-up seem to have greater loss of RNFL than
those with stable vision. (Talman et al. 2010)
Correlations with spinal cord MRI (Oh et al. 2015), and visual evoked potentials (VEPs)
(Sriram et al. 2014) have further validated the importance of measuring RNFL thickness in
these patients, and a recent review of vision-related outcome measures from a key author in
the field has cemented the importance of OCT structural measures as a surrogate outcome in
MS trials. (Balcer et al. 2015)
The evolution of OCT technology has led to a surge of studies in MS over recent years, with
more confidence and statistical certainty, thanks to the improved resolution and segmentation
software. The ability to also measure the retinal ganglion cell layer has provided new insights
into the temporal relationship of damage following ON. (Syc et al. 2012; Costello et al. 2015)
In addition, longitudinal studies are confirming that progressive neuronal loss continues
despite no clinically evident inflammation. (Narayanan et al. 2014) This is an excellent
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example of clinical research now informing on the pathophysiology of disease, assisting in
understanding the disease and suggesting new areas for basic research.
Neuromyelitis Optica
The second condition identified by our search was Neuromyelitis Optica (NMO), a clinical
variant of MS, which has long been observed to frequently cause a more damaging insult to
the optic nerve than the typical demyelinating optic neuritis seen in relapsing-remitting MS.
(Ratchford et al. 2009; Monteiro et al. 2012) OCT has rapidly gained importance as a tool to
quantify optic nerve damage in this condition, to the extent that it has been recommended by
expert consensus, along with MRI of the brain and spinal cord, as an essential imaging
modality. (Trebst et al. 2014)
Dementia
We identified 12 case-control/cohort studies and 3 meta-analyses examining the use of OCT
in dementia. The dementias have a complex heterogeneous aetiology and are the focus of
intense international research attention, with ocular imaging of particular interest.
A recent meta-analysis on the utility of OCT in dementia concluded that measurement of
RNFL thickness has potential utility in the diagnosis and discrimination of dementia types.
(Thomson et al. 2015) To this end, there have been studies of OCT in Alzheimer’s Disease
(Marziani et al. 2013; Polo et al. 2014) and Mild Cognitive Impairment (Shen et al. 2014),
generally demonstrating retinal thinning, and in particular RNFL thinning associated with the
disease. However, as has been learnt from glaucoma research, it is important to differentiate
observed RNFL changes over time associated with disease from normal age-related decline.
Of particular importance, a recent study has suggested that retinal changes may be visible
before memory becomes affected, raising the possibility that OCT might be used to identify
7
patients that may benefit from early use of future neuroprotective treatments. (Garcia-Martin
et al. 2014)
Parkinson’s Disease
Parkinson’s disease (PD) was the second most common condition identified by our literature
search. However, evidence to support the use of OCT in PD is scanty. The earliest studies of
OCT in PD reported no difference in RNFL thickness between cases and controls, but
patients with PD were found to have thinner maculas, predominantly thought to be due to
thinning of the outer retinal layers. (Aaker et al. 2010)
Subsequent studies provided somewhat contradictory results with some reporting macular but
not RNFL thinning (Mailankody et al. 2015) and others also finding thinner RNFL. (Satue et
al. 2013; Satue et al. 2014) To complicate matters, a large case-control study which included
108 patients and 165 controls found no difference in RNFL or macula volume. (Bittersohl et
al. 2015)
Nevertheless, a recent meta-analysis concluded that OCT might be useful for monitoring PD
progression. (Yu et al. 2014) Interestingly, one study has suggested that OCT might be useful
for differentiating the atypical Parkinsonian syndromes, with 96% sensitivity and 70%
specificity for differentiating between PD and progressive supranuclear palsy (PSP).
(Albrecht et al. 2012)
8
The remaining conditions had relatively few published studies, with less than 10 articles
identified for each.
Multiple System Atrophy
A recent paper described a case-control study of 24 patients with MSA and 35 controls.
(Mendoza-Santiesteban et al. 2015) RNFL and GCL thicknesses were reduced in MSA
compared to controls, particularly in the inferior quadrant, where the mean difference was
around 10 microns.
The same paper also included patients with PD, and found no significant difference between
MSA and PD on OCT, except in the macula where the GCL thickness tended to be more
reduced in PD than in MSA.
Motor Neurone Disease
Motor neurone disease (also known as amyotrophic lateral sclerosis) is traditionally
understood to spare the anterior visual pathways, although non-motor neurone manifestations
of the disease, such as cognitive change, are increasingly recognised. At present, there is no
clear evidence for the utility of OCT in motor neurone disease, with two studies revealing
contrasting results about whether or not there is any detectable retinal thinning associated
with the disease. (Roth et al. 2013; Ringelstein et al. 2014) Although interestingly, the two
studies used different OCT machines, and had slightly different criteria for selecting their
patients.
Autism
Autism is a complex area of study, but one where there is again need for biomarkers of
structural abnormality. A single paper (Emberti Gialloreti et al. 2014) looked at subjects with
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high functioning autism (HFA) or Asperger Syndrome (AS), and found reduced global RNFL
thickness in HFA compared with both AS subjects and controls. In addition, they found that
the cognitive assessments of Verbal-IQ/performance-IQ discrepancy correlated with RNFL
thickness.
Traumatic brain injury
Shaken Baby Syndrome (SBS) is well known to be associated with multi-layered retinal
haemorrhages, but recently OCT studies have also revealed findings of vitreoretinal traction
and macular hole. (Sturm et al. 2008; Scott et al. 2009) Hand-held OCT shows potential in
being a useful clinical tool in this group, and may reveal more specific findings in the future.
(Avery et al. 2014)
Chiasmal compression
Traditionally, pathologies causing compression of the chiasm (for example, pituitary
adenoma, craniopharyngioma, suprasellar meningioma) have been monitored via radiological
imaging and visual field testing. Recent work has suggested that RNFL and retinal ganglion
cell (RGC) layer thinning assessed with SD-OCT correlate with the visual field (VF) loss.
(Monteiro et al. 2014) OCT may therefore provide a more objective measure of disease
status.
In addition, it has been proposed that measuring RNFL thickness pre-operatively could be
used to assess the prognosis of visual field recovery post-operatively, with a better visual
prognosis for patients with a closer to normal RNFL thickness. (Garcia et al. 2014; DaneshMeyer et al. 2015; Park et al. 2015)
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Optic pathway gliomas
Whilst the natural history of OCT changes in optic pathway glioma has not been described,
one report has suggested that RNFL analysis assessment using SD-OCT is superior to visual
function assessment and optic disc evaluation as a clinical screening tool for optic pathway
gliomas, in paediatric patients with neurofibromatosis-1. (Parrozzani et al. 2013)
This was followed by a more recent paper supporting this view, reporting that children
experiencing vision loss from optic pathway gliomas frequently demonstrated a ≥10%
decline of RNFL thickness in 1 or more anatomic sectors. (Avery et al. 2015)
Schizophrenia
Psychiatric brain diseases have not been traditionally viewed as neurodegenerative in nature,
but with MRI investigations now reporting some degree of gray and white matter atrophy in
conditions like schizophrenia, a few groups have investigated OCT measures, as a surrogate
measure of this.
The first group looked at macula volume and RNFL thickness comparing schizophrenia and
healthy controls. They found no overall difference between the groups, but within the patient
group, there was an association between ‘positive symptom’ severity and reduced macular
volume. (Chu et al. 2012)
Another group, which recruited similar subjects, did find reduced RNFL thickness in
schizophrenia, particularly in those with a longer duration of illness. (Lee et al. 2013)
Neurosarcoid
Ophthalmologists will be familiar with using OCT in the clinical assessment of ocular
sarcoid, to visualise granulomas and markers of inflammation in the retina and choroid.
(Wong et al. 2009; Gungor et al. 2014) However, even in the absence of ocular signs or
11
symptoms, RNFL and macula thinning has been reported in patients with neurosarcoid.
(Eckstein et al. 2012)
Stroke
Much has been written about retinal manifestations of cerebrovascular disease, with recent
work including findings of localised RNFL defects in patients with previous or acute stroke
(Wang et al. 2014) and RNFL thinning after internal carotid artery (ICA) occlusion and
middle cerebral artery (MCA) infarction. (Gunes et al. 2014)
In addition, reduced macula ganglion cell complex layer thickness has been described in
patients with homonymous hemianopia following PCA infarction. (Yamashita et al. 2012)
Migraine
Migraine has long been recognised as a risk factor for normal tension glaucoma. A recent
study has examined the RNFL in patients with migraine without a diagnosis of glaucoma, and
found some patients have a significant degree of RNFL thinning in the superior quadrant,
compared with normal. (Gipponi et al. 2013) This is thought to be due to recurrent
vasoconstriction in the supply to this area of the retina, causing permanent structural change.
A meta-analysis of six case-control studies found a significant reduction in global RNFL
thickness in migraine patients. (Feng et al. 2015)
Cluster Headache
We identified a single study examining OCT and cluster headache (CH), which included 107
patients with CH and 65 controls. Patients with CH were found to have significantly thinner
temporal RNFL (mean difference 6 µm). (Ewering et al. 2015) The authors suggested that
this observation might be due to the temporal RGC axons being more vulnerable to hypoxia,
12
as they are thinner - thus giving rise to this pattern of temporal loss, also seen in
mitochondrial optic neuropathies.
Systemic Lupus Erythematosus
A single small study compared RNFL thickness in patients with systemic lupus
erythematosus (SLE) (with and without neuropsychiatric symptoms) to healthy controls.
Although there was no difference in RNFL between the SLE groups, both showed retinal
thinning (full thickness and RNFL) compared to controls. (Liu et al. 2015) Patients with SLE
had an average macular volume 0.30 mm3 less than controls, with an average 8µm thinner
global RNFL thickness. The authors did not offer any hypothesis suggested for this
observation.
Discussion
Our literature search and review has demonstrated a plethora of studies examining the
possible application of OCT in neurological and systemic disease.
RNFL thinning is a recurring theme, but few clear phenotypic patterns have emerged thus far.
Most evidence exists for MS, with almost 140 studies identified. These have consistently
shown temporal thinning, which has emerged as a sensitive biomarker of disease status, and
now being used as an endpoint in trials of new treatments. It should however be emphasised
that high quality studies are largely lacking, particularly given the multiple confounders
known to influence quantitative measurements of retinal layers such as axial length, age and
scan quality amongst others. Despite the limitations of current studies, interest in imaging the
13
eye, as a window to beyond the orbit, is likely to grow, with important implications for the
ophthalmologist.
Many ophthalmologists may have already had requests from neurologists for OCT in patients
with MS and other conditions. As demonstrated by the wide range of diseases identified in
this review, future requests may be forthcoming from other specialties. However, as the
evidence-base for OCT grows, neurologists are increasingly seeking greater access to OCT,
with some units purchasing their own device. With imaging training provided to nonophthalmologists by device manufacturers, there will be less dependence on ophthalmology
departments for access to OCT. However, the use of OCT by non-ophthalmic trained
individuals is likely to lead to an increase in referrals to ophthalmic services for investigation
of incidental findings, a phenomenon already encountered with increasing use of OCT in the
community by optometrists. There is however enormous potential for collaborative work
between neurologists and ophthalmologists, with ophthalmologists already experienced in
using OCT for diagnosis and monitoring progression in a good position to knowledge share.
The growing number of studies providing evidence of abnormal retinal structural
measurements in diseases viewed as predominantly non-ocular also has important
implications for the management of ophthalmic disease. For example, RNFL thinning due to
systemic or neurological diseases may complicate the management of glaucoma in which
measurement of change in RNFL thickness over time is commonly used to detect
progression. Particularly in the elderly population where comorbidity is common, a condition
such as dementia, which has been reported to be associated with RNFL thinning, may
introduce a potentially confounding factor to the assessment of glaucoma progression. On the
other hand, the observation that diseases such as glaucoma and dementia have shared features
raises the possibility that neuroprotective treatments effective for one disease may be utilised
14
for another. For example, neuroprotective and neuroregenerative treatments that aim to
protect existing and regenerate damaged cells respectively may be effective for a range of
diseases with heterogeneous mechanisms from Alzheimer’s disease to glaucoma. (Gupta &
Yucel 2007; Johnson et al. 2011; Chang & Goldberg 2012)
The ability to identify ocular biomarkers of systemic disease is an attractive prospect as the
optical properties of the eye permit visualisation of vascular and neural tissues that is not
possible in any other part of the body. The identification of ocular biomarkers of systemic
and predominantly non-ocular disease is not a new concept and it is clear that many ocular
diseases, such as diabetic retinopathy and arteritic ischemic optic neuropathy are a direct
consequence of systemic pathology. In fact the diabetic retinopathy grading system is an
excellent example of the use of ocular biomarkers for monitoring a systemic disease, with
other useful diabetes biomarkers including HbA1c and blood pressure. The introduction of
OCT has however, led to the realisation that an increasing number of conditions can have
ocular manifestations, and it is possible to quantify these changes using imaging devices.
There is therefore the possibility that OCT imaging might reduce the need for more invasive,
time consuming or costly tests, for example reducing the need for MRI imaging of the brain
to monitor for disease progression in multiple sclerosis. Measurements from OCT may be
used for diagnoses, assessing disease progression, for predicting clinical outcomes, or for
providing more acceptable and cost-effective ways to assess the effect of new treatments. In
clinical trials, appropriately used biomarkers have the potential to replace or supplement
conventional endpoints with something that can be measured earlier, more easily and more
frequently. (Medeiros 2014)
We should though exercise caution when considering introducing new biological markers,
particularly if considering them for inclusion as endpoints in clinical trials or to base
15
decision-making regarding effectiveness of treatment. Few biomarkers fully capture the full
effect of treatment, and this is particularly likely to be true for ocular biomarkers of systemic
diseases. (Lesko & Atkinson 2001) Nevertheless, there is great hope that quantification of
retinal parameters using OCT may be a useful surrogate for the assessment of a wide range of
predominantly non-ocular dieases.
Limitations of optical coherence tomography
It is important to appreciate the limitations of OCT, which despite improvements in
technology is still subject to poor scan quality, artefact and segmentation errors. Without
appropriate training, non-ophthalmic specialists may refer patients to ophthalmologists based
on anomalous OCT findings alone. For example, failures in accurate segmentation of retinal
layers may lead to the erroneous conclusion that a patient has an ocular abnormality.
However, this situation is the same for any imaging device or investigational procedure, any
of which can lead to false positive referrals. Incidental abnormalities may also be identified in
asymptomatic individuals.
To aid diagnosis, imaging device software is often used to categorize patients as within
normal limits, borderline, or outside normal limits. However, there are limitations of applying
the built in normative databases to heterogeneous populations with complex systemic disease.
The normative databases used to determine whether a patient is outside normal limits are
comprised of relatively small numbers of patients and often specifically excludes those with
other diseases. The databases also differ in size, eligibility criteria and ethnic makeup
between manufacturers. (Realini et al. 2014) Normative databases are improving, however
many consist primarily of Caucasian subjects, within a narrow age range and with limited
refractive error.
16
Conclusion
The growing interest among non-ophthalmic clinicians in ocular biomarkers derived from
OCT has potential implications for ophthalmologists. There are exciting opportunities for
collaborative work in this evolving arena, provided the limitations are understood.
17
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