Optical Coherence Tomography in Neurological and Vessel Diseases: History
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Aurelian Mihai Ghita
,
Daniela Adriana Iliescu
,
Ana Cristina Ghita
,
Larisa Adriana Ilie
,
Alexandru Otobic

For glaucoma evaluation, several studies have suggested that in the early stages, ganglion cell complex (GCC) analysis, especially the thickness of the infero and that of the inferotemporal GCC layers, is a more sensitive examination than circumpapillary retinal nerve fiber layer (pRNFL). In the moderate stages of glaucoma, inferior pRNFL thinning is better correlated with the disease than in advanced cases. Another strategy for glaucoma detection is to find any asymmetry of the ganglion cell–inner plexiform layers (GCIPL) between the two macular hemifields, because this finding is a valuable indicator for preperimetric glaucoma, better than the retinal nerve fiber layer (RNFL) thickness or the absolute thickness parameters of GCIPL. In preperimetric and suspected glaucoma, GCC and pRNFL have better specificity and are superior to the visual field. In advanced stages, pRNFL and later, GCC reach the floor effect. 

  • ganglion cell complex
  • retinal nerve fiber layer
  • optical coherence tomography

1. Introduction

The analysis of ganglion cell complex (GCC) parameters according to different possible situations, with a focus on glaucomatous eyes, is reported. The optical coherence tomography (OCT) is a noninvasive imaging method that has been widely used for the evaluation of structural abnormalities that are affecting the optic nerve head, retinal nerve fiber layer (RNFL) of the peripapillary region and the macular area including the GCC [1][2][3]. The circumpapillary RNFL (pRNFL) has long been used as an OCT parameter for the evaluation of glaucoma and other ocular diseases affecting the optic nerve. Nevertheless, by analyzing only the axons of the retinal ganglion cells, impairments on the ganglion cell layers (GCL) and the inner plexiform layers (IPL) are missed [4][5][6]. In addition, in the central retina, the thickness of the GCL is significantly larger than that of the nerve fiber layer, with the ganglion cell body rows having a 10-fold increased thickness compared to the axons layer [7]. The evaluation of the macular GCC is now available by using automatized segmentation of the retinal layers with the introduction of newer OCT technology [8]. While the time-domain OCT devices were able to analyze only the total macular thickness, which is not correlated with a good accuracy in diagnosing glaucoma patients, the recent spectral-domain OCT (SD-OCT) devices allow the measurement of all three layers that form the macular GCC: macular retinal nerve fiber layer (mRNFL), GCL and IPL [9]. GCC is one of the parameters used for the early-stage diagnosis of the glaucomatous disease, the evaluation of the disease progression and monitoring the advanced stages [4][10][11]. Given the fact that the first segment affected regarding the ganglion cells is the IPL (synapses at this level are initially damaged), followed by the GCL, GCC may prove to be a better diagnostic tool for the early glaucomatous lesions. The process of mitochondrial splitting is one of the initial changes observed that demonstrates the damage on the dendritic layer of the ganglion cells (IPL) [12]. In addition, it has been found that GCC is a superior parameter in cases of ocular hypertension that were associated with structural changes like tilted disc or atrophy surrounding the optic nerve, in which the pRNFL could not be properly determined on the OCT [13]. On the other hand, the changes of GCC are nonspecific, like the pRNFL, and can be altered in other ocular diseases such as multiple sclerosis, ocular ischemia, diabetes mellitus and toxic syndrome [14][15][16].

2. Acquisition Technique of GCC

The macular GCC quantifies the thickness between the internal limiting membrane and the outer border of IPL. GCC analysis evaluates the inner layers of the retina and includes GCL, IPL and facultative mRNFL (depending on the OCT machine). There are different acquisition settings available for the evaluation of GCC using the SD-OCT. They have distinct methods for the analysis of the GCC layers. Even though there are more than 10 SD-OCT devices available, a general presentation of the OCT machines that can analyze GCC includes Cirrus HD-OCT (Carl-Zeiss Meditec, Dublin, CA, USA), Spectralis (Heidelberg Engineering, Heidelberg, Germany), RTVue-100 (Optovue Inc., Fremont, CA, USA), RS-3000 SD OCT (Nidek, San Jose, CA, USA) and 3D OCT (Topcon, Livermore, CA, USA).
The characteristics of the GCC examination are speed of acquisition, examined area (dimension and centered or not on the fovea) and number of layers considered in the examination [4]. All these perform GCC scans from the center of the macula to an area that varies between a 6 × 6 mm2 grid (Cirrus HD-OCT, Carl Zeiss) to a 9 × 9 mm2 grid (RS-3000 SD-OCT, Nidek). Approximately half of the total number of retinal ganglion cells are centered in 5 mm of the foveal zone. The topographic distribution analysis of the ganglion cells has shown a much higher density in the central macular area compared to the more peripheral retina [17]. Depending on the manufacturer, the acquisition rate can vary between 26,000 A-scans per second (for the RTVue-100, Optovue) to 85,000 scans per second for the Spectralis OCT2 module (Heidelberg Engeneering) [18]. Such a high scan rate provides data for the 3D imaging of the interest area. The progression analysis software is another useful tool that enables the comparison of the data available at the baseline and the follow-up value to observe a progressive decrease of the GCC thickness. The mean values of the GCC thickness are around 100 µm, conditioned by the OCT type. Although the available OCTs scan the macular region for the measurement of GCC, the segmentation protocol is different between manufacturers.
The Cirrus HD-OCT (Carl-Zeiss Meditec) scans at a rate of 27,000 A scans/sec and analyzes both the IPL and the GCL. The algorithm of Cirrus OCT segments and identifies the outer boundary of the IPL and the external limit of the nerve fiber layer. The data are collected from an area of 14.13 mm2 with the center at the level of the fovea. The results are presented as 6 sectorial thickness maps that show the absolute values and probability colored maps, resulted through comparison with a normative database. The green, yellow, or red of the probability maps show the normal (p = 5–95%), borderline (p = 1–5%) and, respectively, abnormal values (p ˂ 1%) [4][19][20].
Spectralis (Heidelberg Engineering) OCT is able to segment and quantify each of the three layers composing the GCC. The data are acquired from a perifoveolar volume scan (30 × 25°), consisting of 61 B scans. The retinal thickness maps are analyzed from 9 macular areas centered on the fovea. The areas are divided into rings that contain the superior, inferior, nasal and temporal zones. The retinal maps with colorimetric scale are displayed. The posterior pole asymmetry protocol of Spectralis OCT can present asymmetric patterns between the macular regions of the eyes [21].
The RTVue-100 (Optovue Inc.) system maps an area of 7 × 7 mm2, centered 0.75 mm temporal to the fovea. The software measures the GCC thickness formed from the combination of mRNFL, GCL and IPL [9]. The acquisition rate is of 26,000 A scans/sec. The results are presented as a colorimetric scale map of the GCC thicknesses, a deviations map that shows the percentage of the GCC loss compared to the OCT’s normative database and a significance map. The GCC scanning protocol utilizes a 7 mm horizontal scan line, together with 15 vertical 7 mm lines. Two parameters also result from the acquired data: the focal loss volume (FLV) and the global loss volume (GLV), which appear to be more accurate in the diagnosis than the average GCC loss [4][22].
The RS-3000 SD OCT (Nidek) has a depth resolution of 7 µm and of 20 µm in the transverse section of the tissue. The GCC is scanned from an area of 9 × 9 mm2 centered on the fovea. From this, the central 1.5 mm diameter circle is excluded from the analysis. The scanning density consists of a horizontal line scan of 512 A-scans and a vertical line of 128 B-scans. The collected data are displayed as superior and inferior thickness values [23].
The 3D OCT from Topcon has a scanning rate of 50,000 scans/sec and consists of 512 horizontal A scan lines and 128 vertical A scan lines. It has a depth resolution of 6 µm and a lateral resolution of 20 µm. The scanned macular area is 6 × 6 mm2 and provides fundus imaging. The software can analyze the mRNFL, GCL together with the IPL and GCC. The results are compared to the normative data and presented as color-coded maps [4][24].

3. OCT in Neurological and Vessel Diseases

GCC and RNFL have been extensively studied in recent decades. Many neurological and ophthalmological diseases involve the optic nerve and affect GCC and pRNFL. For this reason, GCC changes are not specific only for glaucoma. All the modern OCT machines measure the pRNFL and the GCC quantitatively and compare the results with the normative data. Advanced analysis software will even compare the superior and inferior parts of the median raphe to detect the early changes in patients with optic nerve diseases.
GCC is similar to pRNFL regarding glaucoma detection and can be a useful tool in monitoring progression. Donaldson et al. compiled an exhaustive study of neuro-ophthalmology diseases and their OCT results [25]. As long as there is no coexisting macular damage or edema, the GCL measurements can be used as a tool to monitor the optic nerve insult in cases of papillary edema, because the increase of pRNFL will mask any axonal loss. In addition, GCC is useful in cases in which the pRNFL measurements are unreliable (high myopia, small or tilted optic nerve head) [25].
In some cases of branch retinal artery occlusion, the altitudinal visual field (VF) defects can be similar to those found in non-arteritic anterior ischemic optic neuropathy (NAION). The inner nuclear layer (retinal ganglion cell body) atrophy is always expected after a retinal arterial occlusion, but not after NAION, thus easing the diagnosis [26].
At onset, optic neuritis is associated with a mild pRNFL thickness increase, while the GCL and IPL remain normal. An episode of optic neuritis is followed by thinning of the pRNFL and ganglion cell—inner plexiform layer (GCIPL), which is more pronounced than pRNFL and starts approximately 2 weeks after the onset of symptoms. Even though the retrobulbar portion of the optic nerve is the main location of the optic neuritis damage, retrograde axonal degeneration appears quickly, being the highest in the first month and leading to the GCIPL thinning. The normal GCIPL with no asymmetry between eyes at 4–6 weeks after the onset of the symptoms usually makes the optic neuritis diagnosis improbable [25].
Studies have shown that there is a correspondence between the neurologic disease location and the pRNFL and GCC loss. The lesions that are closer to the globe and before the lateral geniculate nucleus tend to develop a fast and severe pRNFL and GCC loss, whereas the diseases that involve the optic radiations and the occipital cortex will cause a mild, unspecific RGC loss that is not proportional to the injury [25].
The optic chiasm lesions will usually result in the damage of the decussating nasal fibers, followed by the retrograde degeneration of the ganglion cell axons and the binasal thinning of the GCIPL in about 4 weeks. It has been noted that in cases of suspicion of chiasmal lesions, 50% of patients will have normal VF, but GCIPL thinning. This suggests that the decrease of GCC is prior to VF changes and may be a good indicator of the need for surgical treatment [27]. In addition, the loss of normal nasal–temporal asymmetry (the nasal GCIPL is thicker than the temporal GCIPL) can be an early structural change in parasellar lesions. The absence of GCIPL thinning in patients with chiasmal lesions is a good prognostic factor for the postoperative improvement of VF [28].
Similarly, optic tract lesions will cause homonymous GCIPL thinning respecting the vertical midline [29].
The lesions involving the optic radiations and the occipital lobes will be followed by trans-synaptic degeneration with varying rates of RNFL and GCIPL thinning, which seems to be the highest in the first 2 years after the insult [30].

This entry is adapted from the peer-reviewed paper 10.3390/diagnostics13020266

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