|Year : 2013 | Volume
| Issue : 3 | Page : 137-142
Retinal nerve fibre layer thickness by OCT3 provides direct assessment of axonal loss in optic neuritis and may help in the early diagnosis and progression analysis of multiple sclerosis
Subhrangshu Sengupta1, Partha Biswas2, Chandrima Paul1, Ajoy Paul2
1 Regional Institute of Ophthalmology, Kolkata, India
2 B B Eye Foundation, Sukhsagar, Kolkata, India
|Date of Submission||13-Mar-2013|
|Date of Acceptance||20-May-2013|
|Date of Web Publication||23-Aug-2013|
3R-1/12, Ananya, 25C, RMDG Lane, Beliaghata, Kolkata - 700 010
Source of Support: None, Conflict of Interest: None
Context: Retinal nerve fibre layer (RNFL) being unmyelinated, RNFL thickness (RNFLT) provides direct evidence of axonal loss in optic neuritis (ON) and may prove to be a valuable diagnostic and prognostic tool in the development of multiple sclerosis (MS). Aims: Assessment of RNFLT by OCT3 in patients with recent onset retrobulbar ON, comparison of obtained values based on presence or absence of the periventricular white matter lesion (PVWML) on magnetic resonance imaging (MRI), comparison with the RNFLT of a control group, and analysis of the obtained results. Settings and Design: Cross-sectional study. Materials and Methods: Eighteen patients with <=3 weeks onset clinically diagnosed retrobulbar ON between 19 and 55 years were included. RNFLT was assessed on presentation by OCT3 for both the eyes. MRI of brain and spinal cord with gadolinium enhancement was also performed in all patients, after adequate medical clearance. Patients were divided into: group A (10 patients) with no MRI-proven PVWML and group B (8 patients) with one or more PVWML, operationally deemed to have MS. RNFLT analysis was also done in 18 age-matched controls who were assigned to group C. Statistical Analysis Used: ANOVA and Student's t test. Results: ON eyes in group B had thinnest RNFLT (average temporal = 39.75 μ), followed by group A (average temporal = 44.3 μ), and finally by group C (average temporal-OU = 80.78 μ). Conclusions: Our study shows that patients with ON, irrespective of detection of PVWML on MRI, have thinner RNFL compared to age-matched controls (P < 0.001). The average RNFLT values are lowest in patients with PVWML. The aspect of RNFL thinning in non-ON eyes should be further studied as a possible subclinical indicator of MS.
Keywords: Magnetic resonance imaging, mulitple sclerosis, optic neuritis, optical coherence tomography, retinal nerve fibre layer thickness
|How to cite this article:|
Sengupta S, Biswas P, Paul C, Paul A. Retinal nerve fibre layer thickness by OCT3 provides direct assessment of axonal loss in optic neuritis and may help in the early diagnosis and progression analysis of multiple sclerosis. J Clin Ophthalmol Res 2013;1:137-42
|How to cite this URL:|
Sengupta S, Biswas P, Paul C, Paul A. Retinal nerve fibre layer thickness by OCT3 provides direct assessment of axonal loss in optic neuritis and may help in the early diagnosis and progression analysis of multiple sclerosis. J Clin Ophthalmol Res [serial online] 2013 [cited 2020 Dec 2];1:137-42. Available from: https://www.jcor.in/text.asp?2013/1/3/137/116842
Optic neuritis (ON) is frequently the first manifestation of multiple sclerosis (MS), , characterized by acute onset of visual acuity (VA) loss often accompanied by visual field loss, color desaturation, and pain with eye movement.  Approximately 15%-20% of MS cases present as ON, and from 38% to 50% of MS cases develop it at some point.  Although MS is a primary demyelinating disease affecting the central nervous system (CNS), axonal injury and loss (mainly by Wallerian degeneration More Details) that occurs in the anterior visual pathway, as well as in rest of the CNS, appear to be the major cause of chronic disability in MS. 
Brain magnetic resonance imaging (MRI) is useful for assessing the probability of whether a patient presenting with ON will develop additional neurologic problems and be diagnosed to have clinically definite MS. ,
Optic atrophy and thinning of the peripapillary retinal nerve fiber layer (RNFL) are typical findings on ophthalmoscopic examination of patients with MS and a history of ON.  Optical coherence tomography (OCT) has enabled measurement of peripapillary RNFL loss with micron-level resolution and excellent reproducibility. , OCT employs low-coherence interferometry to generate noninvasive, in vivo, high-resolution (<10 μm), cross-sectional images of the RNFL by measuring backscatter of infrared light. ,,
Our study aim was to assess retinal nerve fibre layer thickness (RNFLT) by OCT3 in patients with recent onset retrobulbar ON, compare the obtained values based on presence or absence of periventricular white matter lesion (PVWML) on MRI study, and also compare with the RNFLT of a control group and analyze the results obtained.
| Materials and Methods|| |
Institutional ethical committee clearance was obtained for conducting this cross-sectional study. Eighteen patients presenting to our tertiary eye care centre with the first episode of recent onset (symptoms for less than or equal to three weeks) retrobulbar ON between 19 and 55 years of age were included in the study. Diagnosis of retrobulbar ON in the study eye was based on a combination of various observations which included a history of sudden onset decrease in VA and painful ocular movements within the last three weeks, decreased VA on presentation, presence of relative affarent pupillary defect (RAPD), defective color vision (by Ishihara Plates), suggestive field defects on peripheral 60-4 Threshold Test (SITA Standard) by Humphrey Field Analyser (Carl Zeiss, USA) and characteristic visual evoked potential changes, and normal fundus picture on indirect ophthalmoscopy. None of the subjects had any comorbid ocular conditions unrelated to ON or MS (as ascertained by a detailed history and examination). All patients had no significant systemic or drug history and were treatment naive for the presenting problem. Eighteen age-matched disease-free control participants were included from among staff and family members of patients and had no history of any ocular or neurologic disease.
All 18 patients and controls underwent complete ophthalmological examination at presentation. They were then tested for RNFLT using the time domain OCT3 (Carl Zeiss, USA) using the fast RNFL thickness software protocol. The RNFLT of both the eyes was tested. The fast RNFLT protocol computes the average of three circumferential scans 360° around the optic disc, 256 axial scans, 3.4 mm in diameter. Good scans were defined according to specifications in the OCT-3 users' manual: well-centered scans with signal strength of >= 7 (maximum, 10) and uniform brightness across the scan circumference.  Scans meeting the above criteria only were selected. The RNFLT scans, along with other relevant ophthalmological examinations, were repeated in the subsequent visits. The results of the subsequent visits have not been discussed in the current study, as they are beyond the purview of the defined aims and objectives of this study. Average overall RNFL thickness at presentation (averaged for peripapillary retina 360° around the optic disc) and thickness values for each of the four quadrants (temporal, superior, nasal, and inferior) were recorded from the OCT printouts:
The most valuable predictor for the development of subsequent clinically definite MS (CDMS) in atients with ON, according Beck et al., is the presence of white matter abnormalities (demyelinating lesions) on brain MRIs. A substantial percentage (27% in the ON treatment trial (ONTT), up to 70% in other studies) of patients with isolated ON demonstrate initially abnormal MRI scans, as evidenced by two or more white matter lesions 3 mm in size on T2 images.  In our study, MRI of brain and spinal cord with gadolinium enhancement was performed in all the 18 patients of the study group at presentation. Patients were divided into two groups based on MRI report:
- for eyes with ON (ON eyes);
- fellow eyes of ON patients (non-ON eyes);
- Disease-free controls (average of both eyes).
Group A: (10 patients) no MRI-proven PVWML;
Group B: (8 patients) one or more MRI-proven PVWML.
As an operational definition for this study, patients with one or more MRI-proven PVWML were considered to have MS and those without any PVWML on MRI were considered to be free from MS. The 18 age- and sex-matched controls were assigned to group C. The RNFLT values of the various groups were analyzed with ANOVA (analysis f variance) using Microsoft Excel (United States) and statistical package for the social sciences (SPSS, IBM, USA) softwares.
All the patients in the study group were referred to neurology department of a tertiary hospital for detailed neurological check up and further investigations and management. After clearance from physician and testing of adequate blood parameters, the patients were administered intravenous methylprednisolone (250 mg every 6 h for 3 days), followed by oral prednisone (1 mg per kilogram of body weight per day [rounded to the nearest 10 mg]) for 11 days under the care of the neurologists. The treatment period was followed by a short period during which the oral dose was tapered, to 20 mg on day 15 and to 10 mg on days 16 and 18. Oral treatment was given in a single morning dose with adequate proton-pump inhibitor coverage. This treatment regime is based on the recommendations of the ON study group. 
The ONTT reported increased rates of visual recovery during the first 15 days after vision loss using this treatment regime. At successive follow-up examinations, however, this effect diminished; by 6 months, there was minimal difference between treated and placebo groups, and by 1 year and thereafter, there was no significant long-term benefit for visual function.  However, VA remained stable in most patients over 15 years.  The VA results in our study group have not been discussed as this is beyond the scope of the current study design.
Further investigations and management, including use of immunomodulation agents (IMAs) in selected cases was carried out at the neurology department itself, with regular ophthalmological checkups at our eye hospital.
| Results|| |
The average age at presentation of the 18 patients with recent onset retrobulbar ON was 41 years and 12 patients were females. The best-corrected visual acuity (BCVA) at presentation in the affected eye (ON eye) ranged from 20/120 to finger counting at 1 meter. The BCVA in unaffected eyes (non-ON eye) ranged from 20/20 to 20/40. The average age of the eighteen controls was also 41 years at presentation with BCVA ranging from 20/20 to -20/40. The sex ratio was the same as that of the study group.
[Table 1] and [Table 2] demonstrate the age, sex, BCVA, and RNFLT distribution of eyes affected with ON eyes and the fellow eyes (non-ON eyes), respectively, in patients belonging to group A (no MRI-proven PVWML) at presentation. Group A ON eyes have an average RNFLT of 72.95 μ, whereas group A non-ON eyes have an average RNFLT of 90.31 μ. The difference between the two values are statistically significant (F = 129.87; p < 0.001, ANOVA). It is also observed that ON eyes have a thinner RNFLT for all quadrants compared to non-ON eyes in group A.
|Table 1: Age, sex, BCVA, and RNFLT distribution of eyes affected with optic neuritis (ON eyes) in patients belonging to group A (no MRI-proven periventricular white matter lesion)|
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|Table 2: Age, sex, BCVA, and RNFLT distribution of unaffected eyes (non-ON eyes) in patients belonging to group A (no MRI-proven periventricular white matter lesion)|
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[Table 3] and [Table 4] demonstrate the age, sex, BCVA, and RNFLT distribution of eyes affected with ON eyes and the fellow eyes (non-ON eyes), respectively, in patients belonging to group B (one or more MRI-proven PVWML) at presentation. Group B ON eyes have an average RNFLT of 62.95 μ, whereas group B non-ON eyes have an average RNFLT of 85.86 μ. The differences between the two values are statistically significant as well (F = 152.62; p < 0.001, ANOVA). It is also observed that ON eyes have a thinner RNFLT for all quadrants as well, when compared to non-ON eyes in both groups A and B.
|Table 3: Age, sex, BCVA, and RNFLT distribution of eyes affected with optic neuritis (ON eyes) in patients belonging to group B (MRI-proven periventricular white matter lesion)|
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|Table 4: Age, sex, BCVA, and RNFLT distribution of unaffected eyes (non-ON eyes) in patients belonging to group B (MRIproven periventricular white matter lesion)|
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[Table 5] enumerates the average RNFLT values (in microns) in the various groups. It is observed that the temporal quadrants have the thinnest RNFL in all groups. Overall RNFL values are the lowest in group B ON eyes and highest in the group C eyes. Student's two-tailed t-test was performed amongst the RNFLT of the various groups and a value of p < 0.001 was considered to be statistically significant. The eyes with ON in both groups A and B had thinner RNFL when compared to group C and the differences were statistically significant (P < 0.001) across individual quadrants as well as the overall values. However, it is interesting to note that non-ON eyes of groups A and B also have thinner RNFL compared to group C eyes and the differences were significant between these groups as well (P < 0.001). It is also seen that group B ON eyes have thinner RNFL than group A ON eyes and the difference is statistically significant for superior quadrant, inferior quadrant, and overall average RNFLT (P < 0.001, ANOVA), was statistically significant for temporal quadrant (F = 5.76; P < 0.05, i.e., P = 0.0289, ANOVA), and was not statistically significant for the nasal quadrant only (F = 2.95; P = 0.105, ANOVA).
|Table 5: Average retinal nerve fi bre layer thickness values of various groups|
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| Discussion|| |
MRI is considered to be the technique of choice for assessing overall disease burden and atrophy in MS, with emphasis on inflammation and demyelination.  However, the capacity for MRI techniques to quantify precisely axonal and neuronal loss within the brain has been limited to novel and costly methods such as diffusion tensor imaging and magnetic resonance spectroscopy. Furthermore, MRI provides essentially no information regarding chronic disease in the anterior visual pathways.
In our study, 44% of the patients presenting with first episode of ON had one or more PVWML on MRI, which is quite similar to that reported by Beck et al., who also found approximately 50% of patients in their study to have MRI changes consistent with areas of subclinical demyelination in the brain at the time of a first episode of ON. 
OCT is a highly reliable technique for measuring RNFL thickness with statistically proven high levels of reproducibility for the third generation of commercial OCT (OCT-3, Carl Zeiss Meditec, Inc., Dublin, CA) in eyes of normal subjects.  RNFLT measurement by OCT is relatively inexpensive, reproducible, and fast. RNFLT is considered to be a promising surrogate marker for optic nerve damage in glaucoma, a disorder that is, in part, defined by the presence of axonal loss. 
In a pilot study, Parisi et al.  used OCT to compare RNFLT values between fourteen MS patients and normal control subjects. The study reported reductions in overall average RNFL thickness in eyes with a history of acute ON and in contralateral eyes without an acute ON history. When compared with control eyes, RNFLT was found to be 46% worse in eyes affected with acute ON and 28% worse when compared to the unaffected eyes of the same patient (P < 0.01). In our study, the average RNFLT of ON eyes was 67.95 microns, 34% worse than normal eyes in group C (102.59 microns), and 23% worse than fellow/unaffected eyes of group A and B subjects (88.09 microns).
A second study by Trip et al.,  compared RNFL measures to tests of visual function among 25 patients with incomplete recovery after ON and reported reduced RNFL values, which correlated with diminished VA, color vision, and visual field function among patients. The present study design does not correlate RNFLT with visual functions, which is a limitation.
Fisher et al.,  reported the results of OCT testing in a heterogenous MS cohort, which included 90 MS patients (with and without a history of ON) and 36 disease free controls. Because the MS disease process affects multiple regions of the CNS, they explored the relation of RNFL thickness to measures of overall neurologic impairment. They found the average RNFL thickness was significantly reduced in all MS eyes as compared to normal subjects, with the lowest RNFL values noted in MS patients with a prior clinical history of ON. In our study as well, we observe that all patients in group B (deemed to have a diagnosis of MS based on our operational definition) had significantly thinner RNFL (P < 0.001 for all quadrants in both ON and non-ON eyes) compared to the subjects in group C (age- and sex-matched controls).
Costello et al.,  found in a prospective study of 54 patients with ON, significant RNFL thinning occurring in the majority (74%) of clinically affected eyes, often within 3-6 months of the acute event. They also established a threshold value of 75 μ by time domain OCT, below which there was a corresponding decline in visual function by computerized static perimetry visual field mean deviation. In our study, the reported RNFLT values are those obtained on the visit at presentation, which according to our inclusion criteria is within three weeks of first onset of symptoms of ON. Even at such an early spectrum of the disease, we are able to pick up significant RNFLT thinning by OCT in the ON patients, which substantiates the promise of this relatively inexpensive diagnostic modality as a surrogate biomarker for axonal loss in MS at an early stage.
Previous studies have shown significant peripapillary RNFL dropout even in MS non-ON eyes.  Walter et al., also noted significant thinning of the macular RNFL in MS non-ON eyes versus controls, attributing this pattern of injury to subclinical episodes of ON.  In our study as well, non-ON eyes of groups A and B patients have thinner RNFL compared to group C eyes (P < 0.001).
In another study, Costello et al.,  concluded that RNFLT is likely to represent structural changes that are related to MS subtypes. Our current study can be further extended with the help of our neurologist colleagues to look into RNFLT changes in various MS subtypes. A longitudinal study will also help to monitor response to various treatment modalities.
With the advent of spectral domain OCT (SD-OCT) segmentation of the retinal layers has been made possible. In a pilot study, Davies et al., showed the eyes of patients with MS (n = 16) had significantly lower ganglion cell layer (GCL) volume as compared with controls (P < 0.001). , These studies provide us avenues for further research using SD-OCT. Moreover, a longitudinal study using GCL-IPL complex thickness by SD OCT in ON patients can be applied to establish a spatial and temporal relationship between axonal injury and ganglion cell loss.
The salient conclusions of the present study can be summed as:
Our study therefore shows that patients with ON, irrespective of detection of PVWML on MRI, have thinner RNFL compared to age matched controls. However, the average RNFLT values are lowest in patients with PVWML.
- RNFLT is the least in group B ON eyes for all quadrants as well as for average value.
- RNFLT in group A and group B eyes (both ON and non-ON eyes) is lesser than group C eyes. (Results significant at P < 0.001.)
- Strongest statistical significance is obtained for group B eyes when compared to group C eyes.
OCT is a relatively inexpensive, non-invasive, fast, reliable, and reproducible diagnostic modality and RNFL being unmyelinated, RNFLT provides direct evidence of axonal loss in ON patients and may prove to be a valuable diagnostic and prognostic tool in development of MS. Further, the finding of retinal nerve fibre layer thinning in non-ON eyes could be the foundation stone for further studies of RNFLT analysis as a possible subclinical indicator of MS.
Further, the concept that axonal loss is an early feature in demyelinating lesions, as is substantiated in our study by significant RNFL thinning in otherwise normal patients with first episode of less than three weeks' onset ON, and that subclinical permanent damage occurs early, gradually accumulating enough injury to result in clinical manifestations, forces us to rethink therapy. If early demyelinating episodes were not associated with axonal injury, early and aggressive therapy was only justified to reduce symptomatology during the flare-up, whereas the finding of early axonal damage suggests that we do everything possible to reduce the number and severity of attacks, beginning with the first evidence of disease. 
MS being a disease continuum, diagnosing the disease at a pre clinical state using an inexpensive, reproducible, and non-invasive tool like OCT may pave the way for a paradigm shift in the early diagnosis of MS and its subsequent management. In other words, MRI and further costlier investigations may be taken up in ON patients with lower RNFLT values, while those with a near normal RNFLT may be clinically followed up periodically by both ophthalmologists and neurologists. This cost-effective approach is of paramount importance in the Indian Scenario, where medical insurance coverage is not available to all sections of the society. Further, serial RNFLT measurement using OCT can be used to determine the efficacy of various treatment modalities of MS including neuroprotection and neurorepair and to follow disease progression.
| Acknowledgement|| |
The West Bengal University of Health Sciences, DD Block, Salt Lake City, Kolkata - 700064. West Bengal
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]