Optical Coherence Tomography in Neuro-Ophthalmology

INTRODUCTION: Optical coherence tomography (OCT) is a potential tool for diagnosis and follow-up in diseases of the anterior visual pathway in that it provides a reproducible and reliable quantification of retinal nerve fiber layer (RNFL) thickness. A review of the literature was conducted to define the utility of OCT in neuro-ophthalmology. MATERIALS AND METHODS: The clinical applications of RNFL thickness measurement by OCT time domain were analyzed. The PubMed search engine enabled us to select the relevant publications, using the following keywords: "optic neuropathy", "retinal nerve fiber layer thickness", and "optical coherence tomography". Publications concerning glaucoma were excluded from this review. RESULTS: The course of RNFL thickness depends on the underlying disease: (I) progressive reduction toward atrophy (e.g., optic neuritis, chiasmal compression) or (II) initial increase in RNFL thickness followed by a reduction toward (IIa) normalization (papilledema) or (IIb) atrophy (anterior ischemic optic neuropathy, Leber hereditary optic neuropathy). DISCUSSION: Depending on the type of anterior visual pathway impairment, OCT provides RNFL data relevant for diagnosis, follow-up, and prognosis. As in macular disease, OCT has become an important clinical tool for routine disease assessment in neuro-ophthalmology.


Introduction
In optic nerve disease excluding glaucoma, mainly three ophthalmoscopic presentations of the optic disc can be encountered: an apparently normal optic disc, an atrophic or an edematous optic disc. Many documentation methods in optic neuropathy (ON) have been used: drawings; color, monochromatic and angiographic photographs.
The optical coherence tomography (OCT), based on interferometry analysis, is a major achievement particularly for documentation of quantitative changes in the optic nerve head: it allows a measure of the retinal nerve fiber layer thickness (RNFL). This retinal layer is composed of non myelinated axons (myelination is generally posterior to the cribriform lamina). OCT can quantify a decrease in thickness due to the atrophy by axonal loss or increase in thickness related to edema. This review aims to illustrate the usefulness of this RNFL quantification in the exploration of optic nerve and anterior visual pathway diseases.

Materials and methods
An extensive review of the literature on applications of OCT in optic neuropathy was performed. The PubMed search engine was applied to the keywords "optic neuropathy", "optical coherence tomography" and "retinal nerve fiber layer". Studies exploring the various diseases of the optic nerve were classified according to the OCT results obtained at the initial visit. Glaucomatous neuropathy was excluded from this review. Characteristic diseases are illustrated by clinical case reports.

Results
The average RNFL thickness is the most common parameter encountered in all publications. It represents the average of all measured thickness values in a predefined annular zone adjacent to the optic disc. In some publications, the macular volume has also been evaluated.
The change over time of the average RNFL thickness could be characterized by two different patterns: • a normal RNFL thickness at the initial visit, followed by a gradual decrease: progressive RNFL decrease • an increased RNFL thickness at the initial visit.

Inflammatory diseases: Multiple sclerosis (case reports 1 et 2)
Multiple sclerosis (MS) is the most common cause of optic neuropathy, therefore the evaluation of RNFL thickness in MS was the subject of numerous publications [1,2] At the initial stage of optic neuritis, RNFL thickness is within normal limits, after 2 months it decreases and stabilizes between 6 and 12 months [3,4] as highlighted in case report 1.

Case report 1:
A 35 year-old man was admitted for subacute left monocular impairment. Left orbital pain increased by ocular movements was reported. Visual acuity was 1.0 on the right eye and 0.4 in the left eye. Ophthalmoscopy noted normal appearance of the right optic disc and slight left optic disc hyperhemia (figure 1). Acute optic neuritis was suspected. On the OCT, there is a slight RNFL swelling in its nasal superior part, however the mean thickness remains within normal limits (figure 2). The left visual field was abnormal with a nasal inferior defect, the right visual field was normal (figure 3). After stabilization of the affected eye following an episode of optic neuritis, average RNFL thickness is between 59.75 and 85.00 μm. In the contralateral eye, this parameter is between 82.73 and 99.80 μm (normal range: 102.90 -111.10 μm) [5]. Thus, axonal loss is often present in both eyes even if symptomatic optic neuritis affects one eye only.

Case report 2
A 54-year-old woman suffered from multiple sclerosis and had already a left demyelinating optic neuritis a few years ago. Flair-weighted axial magnetic resonance image shows periventricular plaques (figure 4).  On ophthalmoscopy, a left temporal disc pallor indicative of previous optic neuritis was noted ( figure 6).   However, the importance of RNFL loss depends on the severity of MS in which optic neuritis occurs.
In the eye affected by inaugural optic neuritis, the RNFL thickness stabilizes at 58.10 microns, and at 101.20 microns in the contralateral eye.
If optic neuritis occurs in patients presenting with a relapsing form of MS, RNFL loss is greater in the affected eye, stabilizing at an average thickness of 48.20 μm whereas the contralateral eye remains unaffected, the thickness remains at a high average level of 103.70 μm.
In secondary progressive forms, characterized by a continuous evolution toward a severe neurological disability, axonal loss is even greater in the affected eye of optic neuritis (39.50 μm on average), but also affects the contralateral eye (83.40 μm on average) [6]. This RNFL loss predominates in the temporal quadrant [3] [7], a clinical model demonstrating the coexistence of axonal loss and demyelinating lesions in MS.
Other parameters have been evaluated with OCT in MS, especially a decrease in macular volume which is correlated with axonal loss [8] [9]. The relationship between central and peripheral macular thickness is an indicator of the evolution of the disease [10]. In addition, in MS, RNFL loss is considered to be a fairly accurate indicator of overall axonal loss, both ocular and extraocular. In the early course of the disease, there is a correlation between the decrease in RNFL thickness and neurological disability assessed by the Expanded Disability Status Scale (EDSS) [11] which represents the global axonal loss in MS. There is a relationship between RNFL loss and brain atrophy [12]. Thus RNFL thickness also appears as a reliable marker of disease severity.
Finally, some correlations between OCT parameters and morphological and functional data have been reported.
At the initial stage of optic neuritis: when RNFL thickness is often normal, visual evoked potentials (VEP) (and MRI when it is rapidly accessible) is more efficient to objectify the optic nerve lesions (eliminating a pithiatism when there is a doubt). Thus, at the early stages of MS, OCT is less sensitive than VEP for detecting clinical and subclinical optic neuropathy [13].
At distance of the initial attack of optic neuritis • there is no correlation between RNFL thickness (a marker of axonal loss) and P100 latency (a marker of demyelination) [14]. In optic neuritis, the increase of cup/disc ratio is inversely proportional to the decrease in visual acuity and the decrease in RNFL thickness [15]; • there is a correlation between RNFL thickness (morphological marker of axonal loss) and visual acuity (a loss of one line of visual acuity corresponds to an average decrease of 5,40 μm in thickness) [16], pattern electroretinogram or pupillary reflex (functional markers of axonal loss) [17,18].

Degenerative diseases: Neuromyelitis Optica (NMO) or Devic's disease (case report 3)
In Devic's syndrome, unlike MS, optic neuropathy is severe and is associated with spinal cord lesions without brain damage (figure 10). In OCT, the significant decrease in the thickness of the layer of ganglion fibers reflects an atrophy more severe and diffuse than that observed in MS, mainly in the upper and lower quadrants [19,20]. As in MS, there is a correlation between the retinal nerve fiber layer thickness and the overall neurological disability assessed by the EDSS [21]. OCT can thus provide morphological arguments in the differential diagnosis of Devic's syndrome and MS. In a comparative study, the average thickness was 63.60 μm in Devic's syndrome, whereas it is 88.30 μm in MS (102.00 μm in the group of MS patients in an eye with no history of optic neuropathy) [22]. The average RNFL loss is 15 μm in a patient suffering from MS, whereas it is 39.00 μm in the case of Devic's syndrome [22].

Case 3
A 35-year-old woman had bilateral optic neuritis. Left visual acuity was 1.0. Despite antiinflammatory treatment, right visual acuity had not recovered and remained very low (0.02).  Transverse myelitis was found on the MRI scan ( Figure 10) as part of Devic's disease.

Compressive disease (case 4)
Compression of visual pathways caused by a pituitary adenoma induces axonal loss responsible for RNFL loss on time domain OCT. The importance of this axonal loss predicts visual acuity changes and visual field recovery after surgery for pituitary adenoma [23]. The postoperative recovery is significantly better if the preoperative thickness is greater than 85.00 μm [24].

Case 4
A 75 year-old man complained of chronic headache. Visual acuity was 0.8 on the right eye and 0.4 in the left one. Visual fields showed temporal defects in particular in the left field ( Figure 11). Magnetic resonance imaging discovered a large pituitary tumor with chiasm compression ( figure 12).
Preoperative average RNFL thickness attests of significant axonal loss in the temporal area.

Dominant Optic Atrophy (DOA) or Kjer's disease (Case 5)
In dominant optic atrophy (DOA), there is bilateral symmetric optic nerve pallor (Case 5) related to retinal ganglion cell death. The decrease in the RNFL thickness in OCT is dominant in the temporal part [25].

Case 5
A seven year old girl is referred for poor visual acuity (RE 20/40, LE 20/50) associated with bilateral optic disc atrophy ( Figure 14). On color vision testing there is a blue-yellow confusion axis ( Figure 15). On the time domain OCT, a major bilateral RNFL loss is noted ( Figure 16).  There is no compressive process on the brain MRI which only displays atrophic optic nerves ( figure 17).

Other hereditary optic neuropathies
In the authors' clinical experience, OCT is also useful in the morphological evaluation of optic neuropathies encountered in other hereditary diseases such as recessive optic neuropathy and Wolfram's disease. However no reports on this subject could be found.

Toxic optic neuropathy
OCT can be useful for the follow-up of visual loss in patients with toxic optic neuropathy due to smoking, alcohol consumption or treatment for tuberculosis. In the early stages of toxic optic neuropathy, RNFL edema may be detected in some patients before permanent visual loss occurs. RNFL decrease consecutive to the withdrawal of the toxic agent can be monitored with OCT.

Case 6
A 48-year-old woman complained of progressive and painless visual loss. She had alcohol and tobacco addiction. She was deficient in B vitamins. Visual acuity was 0.3 in the right eye and 0.4 in the left eye. Color fundus photos showed pale optic discs without hemorrhage. Miliary drusens were also observed on macular areas ( Figure 19). OCT confirmed optic nerve atrophy demonstrating a global RNFL loss.
Optical Coherence Tomography

Gradual RNFL reduction following initial increase of RNFL thickness
In optic disc swelling, an increase in the RNFL thickness can be quantified by OCT.
Depending on the underlying disease, the condition will either resolve with normalization or shift to optic atrophy with axonal loss. This evolution can be monitored with OCT.

Papilledema (case 7)
Optic disc swelling due to idiopathic intracranial hypertension is referred to as papilledema [26]. It may be responsible for the deterioration of visual function and progression to optic atrophy. Visual field and VEP are prognostic indicators for visual outcome [27]. This is not the case for RNFL thickness changes which only enable to monitor the progression of the disease.

Case 7
A 28-year-old woman suffered from headache and vomiting. On ophthalmologic examination, visual acuity was 0.9 on the right eye and 1.0 on the left eye without oculomotor paralysis. This condition was due to intracranial hypertension. A bilateral papilloedema, venous engorgement, white exudates and superficial retinal folds was found ( Figure 22).  After spinal puncture and acetazolamide medication, she recovered normal visual acuity. OCT follow-up enabled to monitor the improvement with treatment ( Figure 24).

Anterior Ischemic Optic Neuropathy (AION)
At the initial stage of an anterior ischemic optic neuropathy, there is most often a progressive optic disc swelling. Then, axonal loss is responsible for a gradual reduction of RNFL leading to a variable stage of optic atrophy stabilizing at six months of onset [28].

Case 8
An 11-year-old girl with no family history of Leber's disease suddenly presented with severe painless central vision loss in the right eye. Dilated capillaries in the retina adjacent to the optic nerve head were found in both eyes. Two months after onset, visual acuity in the left eye also decreased. Average RNFL thickness was increased in both eyes on the initial examination and it then slowly decreased as optic atrophy developed.

Secondary intracranial hypertension
Many different diseases can be responsible for increased intracranial pressure such as infectious meningitis (case 9). As in other diseases with initial optic disc swelling, OCT enables to monitor RNFL thickness reduction after causal treatment.

Case 9
A 47-year-old man was admitted for visual field disorders with papulosquamous eruption of the palms and soles within two weeks following a previous asymptomatic general skin eruption. Visual acuity was 0.8 in both eyes. Bilateral optic nerve head swelling was observed ( figure 28). Serological tests on blood and cerebrospinal fluid confirmed a syphilitic infection. After initial intravenous penicillin G, the patient was discharged with ceftriaxone injections (1 g/day) for three weeks. On the OCT scans, the decrease of optic nerve head swelling was replaced with superior optic atrophy (figure 30).

Limitations
Although OCT provides very useful quantitative information on RNFL thickness, there are several limitation inherent to the device which should be highlighted.

Age
In the OCT database, normal values apply only to patients over 18 years. Evaluation of RNFL thickness is based on the assumption that there are no significant changes in normals from birth to the age of 18.

Morphological variations
RNFL thickness evaluation by OCT is not a reliable method in case of major morphologic changes of the optic nerve head such peripapillary atrophy in high myopia, staphyloma or optic pits.

Refractive media disorders
Ultra-red light has to pass through the transparent media of the eye to reach the retina. In case of corneal dystrophy, cataract, vitreous opacity, there is a signal decrease and RNFL thickness measurements become less reliable.

Discussion
As in macular disease, OCT has become a precious tool that contributes to improve management of optic nerve disease. This review illustrates the many indications in neuro-ophthalmology, although there are limitations to its use. OCT measures RNFL thickness to assess axonal loss [31]. Axonal loss may be masked in cases with optic nerve head swelling due to the inhibition of orthograde axoplasmic transport at the initial stage of the disease.
Despite the high utility of OCT in neuro-ophthalmology, exclusive RNFL thickness analysis is not sufficient for assessing optic nerve disease. OCT results should always be interpreted in the light of clinical ophthalmoloscopy and visual function (visual acuity, perimetry, visual evoked potentials).

Declaration of interest
The authors hereby declare that they have no conflict of interest related to this article.