Research into Optical Neuroimaging in Multiple Sclerosis

#### **Chapter 4**

## Optical Coherence Tomography (OCT) and Angio-OCT Imaging Techniques in Multiple Sclerosis Patients with or without Optic Neuritis

*Bilyana Mihaylova and Sylvia Cherninkova*

#### **Abstract**

The visual system is typically affected in multiple sclerosis (MS) patients. The most common ocular manifestation during the clinical course of the disease is optic neuritis (ON). Optical coherence tomography (OCT) is well-established tool for biomedical imaging that enables detection of retinal nerve fiber layer and ganglion cell layer thickness reduction – biomarkers of axonal damage and neuronal loss in MS. And OCT angiography (angio-OCT) is another imaging method for assessing retinal and choroidal vessels with no need of contrast dye injection. In our prospective study, we investigate parafoveal and peripapillary microvascular retinal networks in 18 MS patients (35 eyes) through angio-OCT (AngioVue, OptoVue). According to our results, early structural changes in MS patients without previous history of acute ON episode are unable to be detected. As a follow-up imaging technique, OCT is very useful for changes in axonal thickness and defines the progression rate of the disease. Angio-OCT vis-à-vis OCT investigation detects the ocular perfusion reduction before the appearance of structural changes. From all investigated structural and density parameters only those in superficial capillary plexus show significant changes in MS patients without ON. For accurate diagnostic and following-up process, both structural and vascular parameters need to be assessed in MS patients.

**Keywords:** multiple sclerosis, optical coherence tomography, angio-OCT, vessel density, RNFL, GCC

#### **1. Introduction**

Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease of the central nervous system that is accompanied by a parallel process of neurodegeneration (axonal and neuronal), and subsequent atrophy of the brain and spinal cord. The impairment of the visual sensory pathways and more specifically of the optic nerves is a common clinically manifested finding in MS patients at various

stages (at onset or a later stage) of the disease. Optic neuritis (ON), in the majority of MS patients, is characterized by a significant improvement or even complete recovery of the visual functions, however, advanced neuroophthalmological studies, that include automated (computerized) threshold static perimetry, color vision testing, contrast sensitivity examination, etc., demonstrate discrete or more pronounced residual symptoms. Loss of retinal ganglion cells (GCL) and optic nerve atrophy, in combination with signs of inflammation, are established in postmortem studies of eye structures of MS patients [1–3]. Over the last 10–15 years, optical coherence tomography (ОСТ) has been assessed as a highly sensitive and informative technique to follow up the process of neurodegeneration in MS. The method is characterized by high definition and allows for studying individual retinal layers – their morphology and thickness measured in microns (μm).

#### **2. Neuro-ophthalmological manifestations in MS patients**

Neuro-ophthalmological manifestations in MS include visual pathways lesions, oculomotor dysfunctions, pupillary disorders, and other ocular impairments.

As the first (monosymptomatic) disorder in MS, ON is the most frequent ocular manifestation (up to 25% of cases) [4]. During the clinical course of the disease 30–70% of all MS patients develop ON [5, 6]. The following features are observed: decreased visual acuity, visual field defects, color vision disturbances, pupillary disorders, retro-ocular or orbital pain, positive visual phenomena, optic nerve head (ONH) changes, and Uhthoff's sign. In most cases, it occurs as retrobulbar neuritis, but also it could be observed as papillitis (mild or severe edema; local or diffuse edema; with or without ONH or retinal hemorrhages). In the acute ON phase, almost all MS patients have decreased contrast sensitivity using Pelli-Robson's table [7].

In MS patients with established unilateral ON, and no previous history of such, could be observed variations in visual functions of the contralateral eye, which are: mild visual field defects, impairment of contrast sensitivity and color vision, relative afferent pupillary defect (RAPD), and partial atrophy of the optic nerve.

According to the Optic Neuritis Treatment Trial (ONTT), the visual acuity during ON could vary in wide ranges: from 1.0 (Decimal acuity) to counting fingers in front of the eye, hand movement, light perception, or lack of the light perception [8]. ON acute phase is possible to be followed by a period of visual functions deficit: decreased visual acuity (6 months – 1 year); visual field defects (6 months); abnormal color vision (6 months); decreased contrast sensitivity with Pelli-Robson's table (6 months); and RAPD (6 months).

Visual field defects include the following options: central and cecocentral scotomas, arcuate and altitudinal defects, diffuse loss of retinal light sensitivity in central 30°, chiasmal defects, retrochiasmal defects, and other visual field defects [7].

Oculomotor disorders in MS are results of demyelinating lesions in infranuclear, nuclear, supranuclear, and internuclear structures. In 15% of MS patients, ocular disorders are clinical onset debut of the disease and could precede months or years of the appearance of other neurological features. The most common infranuclear lesion is those of n. abducens (CN VI), less common is those of n. oculomotorius (CN III), and least common is those of n. trochlearis (CN IV) [9]. Internuclear ophthalmoparesis (INO) is a result of fasciculus longitudinalis medialis demyelinating lesions between nuclei of n. oculomotorius and n. abducens. The nerve impulse transmission along a neuron pathway is impaired, and clinically it is manifested as a lack of or partially

*Optical Coherence Tomography (OCT) and Angio-OCT Imaging Techniques in Multiple… DOI: http://dx.doi.org/10.5772/intechopen.106585*

limited adduction in the ipsilateral eye [10]. In the literature, there is a rule: the most common reason for bilateral INO in young adults and adults is MS [6]. Combinations of oculomotor lesions such as one-and-a-half syndrome describe horizontal eye movement disorder – ipsilateral conjugate horizontal gaze palsy (one) and ipsilateral INO (a half).

Pupillary abnormalities are not uncommon in MS [11]. According to different authors, they seem to be underestimated independently of the presence of ON [12]. The following disturbances in pupillary reactions have been reported: 1. RAPD during the acute ON phase. It could be seen even after full visual functions recovery; 2. Ophthalmoparesis oculomotoria interna a rare pathological pupillary manifestation, which is caused by n. oculomotorius infranuclear lesions and concomitant parasympathetic nerve fibers damage; 3. Argyll-Robertson's syndrome rarely has been evaluated in MS; 4. Horner's syndrome; and 5. Pupillary hippus.

Other ocular manifestations in MS, which could be observed are 1. Peripheral retinal periphlebitis – a vasculitis that affects approximately 10% of patients with MS and is associated with higher disease activity in relapses [13]; 2. Microcystic macular edema in 0.5–5% of patients with MS and is associated probably with MS activity or previous ON [13]; and 3. Uveitis – it is an intraocular inflammation of the uvea, retina, or vitreous body and appears rarely in MS. The association of MS with uveitis is unclear. The most common type of uveitis seems to be intermediate uveitis, which primarily involves vitreous, peripheral retina, and pars plana of the ciliary body. Another type that could be observed in MS is granulomatous anterior uveitis [14].

#### **2.1 Optical coherence tomography as an imaging method in ophthalmology**

OCT is a relatively new noninvasive imaging technology that uses near-infrared light to generate high-resolution, cross-sectional, or three-dimensional images of the eye [15]. It was demonstrated in 1991 by David Huang. Then he established for the first time the applicability of the low-coherence interferometry in the quantitative assessment of biological systems. The technique was initially applied for imaging in the eye. Up to now, OCT has had the largest clinical impact in ophthalmology. OCT has revolutionized the clinical practice of ophthalmology and become a standard of clinical care for diagnosis, treatment, and monitoring of many posterior segment diseases [15]. With a longitudinal resolution of 5–7 μm OCT provides images comparable and close to an in-vivo "optical biopsy" of the retina.

OCT uses the light from a broadband light source, which is divided into a reference and a sample beam. The sample beam backscatters from the retina and interferes with the reference beam. This interference pattern is used to measure the light echoes versus the depth profile of the tissue in vivo [16, 17].

OCT is used extensively for analyzing the morphology and quantitative changes of retinal layer volume and thickness of the posterior segment structures such as macula, GCL, ONH, retinal nerve fiber layer (RNFL), and choroidea. Anterior segment-OCT (AS-OCT) is used basically for visualizing cornea and corneal thickness, anterior chamber angle, iris, irido-corneal apposition, etc. [18].

Currently available are different OCT technologies, namely time domain (TD-OCT), spectral domain (SD-OCT), swept-source (SS-OCT) technology, and others that are in development [19, 20]. The measurements with different OCT devices show significant differences from one instrument to another, therefore, the providing values are noninterchangeable in healthy eyes and in MS patients, even when the comparisons are between SD-OCT and TD-OCT devices or only between two different SD-OCT devices [21–23].

The next two figures (**Figures 1** and **2**) represent the most important structural information in the retina obtained with OCT concerning MS patients. In **Figure 1** is shown *ONH/GCC* (ganglion cell complex) *OU* (oculus uterque – Latin for both eyes) *Report* image obtained with angio-OCT (AngioVue, OptoVue) in a healthy woman. *GCC NBD* (Normative Database) *Reference* and *GCC Analysis* give a summary of

#### **Figure 1.**

*ONH/GCC OU Report (AngioVue, OptoVue) in a healthy woman.*

#### **Figure 2.**

*Retina map report of right eye in a healthy woman.*

*Optical Coherence Tomography (OCT) and Angio-OCT Imaging Techniques in Multiple… DOI: http://dx.doi.org/10.5772/intechopen.106585*

inner retinal layers thickness in macular area (bodies + dendrites + axons of ganglion cells). *Optic Nerve Head Map*, *RNFL Analysis*, and *ONH Analysis* provide information about ONH parameters (vertical and horizontal cup/disc area ratio, disc/rim area, and cup volume) and RNFL thickness around ONH (Average/Superior Half/Inferior Half /and combinations). Through color codes, the protocol also provides quantitative data, with which retinal layer thickness could be interpreted. Green color means normal thickness compared to NDB, yellow color is borderline thickness, and red color is significantly reduced thickness. TSNIT NDB Reference shows RNFL thickness curve in fourth peripapillary quadrants according to the ISNT rule – the RNFL thickness decreases as follows – inferior quadrant (I) → superior quadrant (S) → nasal quadrant (N) → temporal quadrant (T). The part *TSNIT Symmetry Plot* shows RNFL thickness symmetry between both eyes.

In **Figure 2** could be seen *Retina Map Report* obtained with angio-OCT (AngioVue, OptoVue) in a healthy woman. Except infrared image of the eye fundus, OCT B-scan in macular zone central through the fovea, the protocol gives information about retinal thickness in macular area. The examiner has the possibilities to choose what thickness to analyze – full retinal/inner retinal/outer retinal or all of them if needed. In the same way as pervious protocol, the information about retinal thickness could be interpreted by colors and values compared with reference data.

#### **2.2 Optical coherence tomography as a window to the MS brain**

Over the last 10–15 years, ОСТ has been assessed as a highly sensitive and informative technique to investigate retinal neuro-axonal loss and follow up on the process of neurodegeneration in MS [24]. Using ОСТ, we can directly examine a structure in the central nervous system (CNS), such as the retina, which consists of isolated axons, because as part of the RNFL they are not myelinated. The assessment of the GCL thickness, which consists of the three innermost layers of the retina (axons + bodies + dendrites of the ganglion cells) in the macular area, provides information on the neuro-axonal loss. Also, the reduction in peripapillary RNFL (pRNFL) thickness has been reported in different MS-related subtypes as an expression of the axonal loss. Multiple studies show a significant decrease in RNFL thickness in MS patients who have had ON, in comparison to a healthy control group or fellow eye that is not affected by ON [25–32]. A more manifest thinning of RNFL is seen in the temporal axons of the retina, due to the predilection impairment of the papillomacular bundle by the inflammatory process. Studies using OCT method in MS patients with no history of optic neuritis and completely normal visual functions also demonstrate a reduction in RNFL thickness, but to a lower extent compared to the eyes affected by optic neuritis [25, 28, 33–35]. This difference is a result of the more severe axonal loss in the retina in eyes with history of ON. Even in the absence of previous ON episodes, RNFL reduction may occur as a biomarker of disease progression [36].

In 2017 a meta-analysis proposes OCT scans in two different ocular regions – ONH and macular area to be routinely included in MS clinical practice because OCT could have the role of a predictive biomarker in disease duration and clinical assessment [32].

**Figures 3** and **4** are examples of the same protocols as the previous two pictures but provide information about structural retinal changes in young MS patients (25 years) investigated 6 months after an acute ON episode of the right eye. The significantly reduced RNFL, GCC thickness, and total retinal thickness in the affected eye are obvious. What makes an impression is also the affected retinal structures (total retinal thickness, blue color code) of the fellow (left) eye with no history of acute ON episode.

#### **Figure 3.**

*ONH/GCC OU Report of a young male patient (25 years) after an acute episode of MS associated ON in right eye.*

**Figure 4.**

*Retina Map OD/OS Report of a young male patient (25 years) after an acute episode of MS associated ON in right eye.*

#### **2.3 OCT-angiography in MS patients**

Frequent association between neuronal changes in MS and vascular diseases is mentioned in different publications, although past reports show controversial results. These vascular changes can possibly contribute to neuronal or degenerative dysfunction in patients with MS [37].

The entry into the clinic of OCT-angiography (angio-OCT) gives new expectations for better knowledge and understanding of retinal and neurodegenerative diseases [38]. Angio-OCT is an imaging method for assessing retinal and choroidal vessels with no need of contrast dye injection. It images blood flow due to red blood cells movement and changes in reflectivity signals after a series of A-scans at one particular point [39]. The areas in ocular fundus, which are constant and no movement is detected there, show no change in reflectivity signals, but those once with moving

#### *Optical Coherence Tomography (OCT) and Angio-OCT Imaging Techniques in Multiple… DOI: http://dx.doi.org/10.5772/intechopen.106585*

objects show large deviations in reflectivity signals. In the retina, there are no changeable areas giving differences in reflectivity signals with the exception of blood vessels. And while with the fluorescein angiography imaging method only superficial retinal vessels are visualized, with angio-OCT all retinal capillary networks are visualized, including the choroidal capillary layer [40].

This new imaging method assesses retinal vessel density parameters in both areas – macula and ONH. Some recent reports present convincing and detailed data that significant vascular abnormalities are involved in MS pathology. A vessel density reduction in eyes of MS patients is available when compared to controls [38]. Some papers reporting the above-mentioned statements suggest that angio-OCT could be a good marker of disease and disability in MS [41].

In **Figure 5a** is shown the very informative *Angio Retina QuickVue Report* of the right eye (macular area) in a healthy woman. The four angio images at the top of the picture represent from left to right, respectively, superficial capillary plexus (from inner limiting membrane – ILM to inner plexiform layer – IPL), deep capillary plexus

**Figure 5.**

*a. Angio Retina QuickVue Report of the right eye (macular area) in a healthy woman. b. Part of Angio Retina Report in healthy woman showing differences in angio images and color codes of superficial (both left images) and deep capillary plexus density.*

(from IPL to outer plexiform layer – OPL), outer retina (from OPL to Bruch's membrane – BRM), and choriocapillaris (from BRM + 30 μm). Quantitative values are also represented for superficial vessel density and inner and full retinal thickness. 5B part shows differences in angio images and color codes of superficial (both left images) and deep capillary plexus density.

**Figure 6** best illustrates vessel density of the peripapillary capillary plexus through *Angio Disc QuickVue Vessel Report*. In addition to data about peripapillary vessel density parameters, the report also provides such about pRNFL thickness, ONH parameters, and angio images in different levels of the peripapillary area.

**Figure 7** is an example of *Angio Retina QuickVue Report* of a young male patient (25 years) after acute episode of MS associated ON in right eye. Easily can be observed the difference in superficial vessel density between the healthy subject (**Figure 5a** and **b** in superficial capillary plexus) and the patient with history of ON – diffuse and local vessel density reduction are observed in this example.

**Figure 7** is an example of *Angio Disc QuickVue Report* in an MS patient (46 years, male) who demonstrated significantly reduced vessel density of peripapillary capillary plexus after two ON episodes of the left eye. The difference in reduced vessel density (local and diffuse) can be easily observed when **Figures 6** and **7** are compared not only by reduced density values but also by color codes (blue for reduced density) and angio RPC images (RPC – radial peripapillary capillary).

#### **2.4 Our experience**

In our prospective randomized study, 38 participants were included – 18 patients with confirmed MS (35 eyes) and 20 healthy volunteers (20 eyes). The research was conducted over a year (2020–2021) at two different hospitals – 1) Clinic of Nervous Diseases at University Hospital "Alexandrovska" in Sofia, Bulgaria where the MS diagnostic tests and

#### **Figure 6.**

*Angio Disc QuickVue Report showing vessel density of the peripapillary capillary plexus in a healthy woman.*

*Optical Coherence Tomography (OCT) and Angio-OCT Imaging Techniques in Multiple… DOI: http://dx.doi.org/10.5772/intechopen.106585*

**Figure 7.**

*Angio Retina QuickVue Report of a young male patient (25 years) after acute episode of MS associated ON in right eye.*

neurologic following-up are performed and 2) Eye Hospital "Vision" in Sofia, Bulgaria where complete eye examination, specialized ophthalmology tests, and imaging methods (OCT and angio-OCT) are performed. All subjects included in this work gave their consent for inclusion before they participated. The work was conducted in accordance with the Declaration of Helsinki. The authors have no relevant financial or nonfinancial conflicts of interest to declare. The purpose of our work is to investigate parafoveal and peripapillary microvascular retinal networks through angio-OCT (AngioVue, OptoVue).

The MS patients were divided into two groups: 1. MS with previous episodes of ON (19 eyes) and 2. MS without previous episodes of ON (16 eyes). All subjects underwent the standard set of neuro-ophthalmologic examination. In addition, angio-OCT was performed – structural (pRNFL and GCC) and vessel density (Superficial / Deep in macular area and RPC) parameters were achieved for each single (see theoretical part and methodology – Sections 2.1; 2.2; and 2.3 for used AngioVue protocols).

The statistical analysis includes descriptive statistics – results are represented as a mean and standard deviation (Mean±SD); one-sample Kolmogorov-Smirnov test – to check the normality of distribution; Kruskal Wallis Test – nonparametric test used to determine if there are statistically significant differences between two or more independent groups in distribution different from normal; Mann-Whitney test – again nonparametric test, but it is used to determine if there is statistically significant difference between two independent groups in distribution different from normal.

According to our results the investigation of the retinal structural parameters (GCC and pRNFL) showed:

Average pRNFL decreases in the following order: Controls (100.35 ± 8.37 μm) → MS without ON (96.44 ± 8.76 μm) → MS with ON (74.79 ± 13.28 μm). The significant difference was found between Controls and MS with ON (p < 0.001), and between MS with and without MS (p < 0.001), but such a difference was not found between Controls and MS without ON (0.265).

Average GCC decreases in the following order: Controls (96.80 ± 7.32 μm) → MS without ON (92.19 ± 5.74 μm) → MS with ON (72.89 ± 7.87 μm). The same significant differences as those in Average pRNFL were observed: between Controls and MS with ON (p < 0.001), and between MS with and without MS (p < 0.001), absence of such significance between Controls and MS without ON (0.175).

In **Table 1** is shown density (%) of the superficial capillary plexus in macular area (**Figures 5a, b** and **7**). We investigated 5 density parameters: 1. Whole (Ring diameter – 3 mm) 2. Superior-Hemi (superior half of the ring) 3. Inferior-Hemi (inferior half of the ring) 4. Fovea and 5. Parafovea (Ring diameter – 1 mm). We applied a nonparametric Kruskal-Wallis statistical test for more than two independent groups. The results show that values for all 5 density parameters decrease in following order: Controls → MS without ON episode → MS with ON episode. This comparative analysis demonstrated a statistically significant difference for all 5 parameters. Therefore, another nonparametric intergroup comparative analysis was applied – Mann-Whitney test to compare two independent groups (**Table 2**). The results show a significant difference between Controls and MS with ON for all 5 density parameters. Four out of the five parameters show a significant difference between Controls and MS without ON (exception Parafovea), between the two MS groups (exception Fovea). The same statistical tests were applied to investigate the density of the deep capillary plexus (**Tables 3** and **4**).

The mean deep density values in the three groups are very close and statistical significant difference was not found with exception of one of them – Fovea. Only for this parameter additional intergroup statistical analysis was applied.

**Table 4** best visualized the results after Mann-Whitney test was applied for deep density parameter – Fovea. Significantly statistical differences were detected between


#### **Table 1.**

*Density (%) of the superficial capillary plexus. Kruskal-Wallis statistical test.*

*Optical Coherence Tomography (OCT) and Angio-OCT Imaging Techniques in Multiple… DOI: http://dx.doi.org/10.5772/intechopen.106585*


#### **Table 2.**

*Density (%) of the superficial capillary plexus. Mann-Whitney statistical test.*


#### **Table 3.**

*Density (%) of the deep capillary plexus. Kruskal-Wallis statistical test.*

Controls and MS with ON/MS without ON, but that difference was not found between the two MS groups.

**Table 5** illustrates the results of statistical analysis of the RPC parameters. We used represented above *Angio Disc QuickVue Report* (**Figures 6** and **8**) to provide a scanning area of 4.5×4.5 mm. The three global parameters are 1. Whole 2. Inside disc 3. Peripapillary. Mean values of 2 out of the three parameters have significant differences – Whole and Peripapillary (Kruskal-Wallis test). These two parameters were investigated additionally with Mann-Whitney test (**Table 6**). Significant differences were found between Controls and MS with ON, and between MS with and without ON.


#### **Table 4.**

*Density (%) of the deep capillary plexus. Mann-Whitney statistical test.*


#### **Table 5.**

*Density (%) of the RPC plexus. Kruskal-Wallis test.*

#### **Figure 8.**

*Angio Disc QuickVue Report showing RPC vessel density in the patient (46 years, male) after two ON episodes of MS associated ON in left eye.*

*Optical Coherence Tomography (OCT) and Angio-OCT Imaging Techniques in Multiple… DOI: http://dx.doi.org/10.5772/intechopen.106585*


#### **Table 6.**

*Density (%) of the RPC plexus. Mann-Whitney test.*

The results show that the significant difference in Whole parameter is mainly due to density changes in peripapillary capillary vessels.

#### **3. Conclusions**

Our results could be summarized as follows: OCT (AngioVue) investigation is unable to detect significant early structural changes in global retinal thickness parameters such as Average GCC and pRNFL in MS patients without previous history of acute ON episodes. As a follow-up imaging technique, it is very useful to detect changes in the structural axonal loss. Therefore, it is especially helpful also in assessment of the disease progression rate.

The peripapillary vessel density changes, but not the whole scanned area or inside disc area, underline the significant decreases of the RPC vessel density in MS patients only with ON. Again early changes in MS without ON are not detectable in RPC.

As a whole, deep retinal microvascular network remains significantly nonaffected in MS with exception of the central macular zone (Fovea parameter), where significant decreases in vessel density could be seen independently of the disease stage (this statement is valid for both superficial and deep vessel networks). From all investigated vessel parameters, Fovea is the only one that changes significantly in both retinal networks – superficial and deep. From superficial vessel density significantly decreases as follows: Controls → MS without ON → MS with ON.

From all investigated structural and density parameters only those in superficial capillary plexus show significant changes in MS patients without ON. This particular result is of big importance in our research because it shows that vessel changes in superficial plexus precede structural changes in MS patients without ON.

In conclusion, we could summarize that angio-OCT is an important and useful imaging technique for MS patients because of its possibilities for noninvasive quantitative and qualitative evaluation of the microvascular retinal network. It is especially useful in MS patients with no previous history of acute ON episodes when significant changes in retinal microvascular network are able to be detected in the absence of significant structural changes. For accurate diagnostic and following-up process, both structural and vascular parameters need to be assessed in MS patients.

#### **Author details**

Bilyana Mihaylova1 \* and Sylvia Cherninkova<sup>2</sup>

1 Eye Hospital "Vision", Sofia, Bulgaria

2 University Hospital "Alexandrovska", Clinic of Neurology, Sofia, Bulgaria

\*Address all correspondence to: b51@abv.bg

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Optical Coherence Tomography (OCT) and Angio-OCT Imaging Techniques in Multiple… DOI: http://dx.doi.org/10.5772/intechopen.106585*

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Section 4
