AIOS – S. D Athawale Award
Dr. Goyal J L, G03947, Dr. Vikas Veerwal, Dr. Ritu Arora, Dr. Pooja Jain, Dr. Vikas Veerwal MS, Dr Ritu Arora MD, Dr Pooja Jain MS
ABSTRACT
Purpose: To evaluate changes in Pattern electroretinogram (PERG), Retinal nerve fiber layer (RNFL) and Ganglion Cell Complex (GCC) over 6 months in acute unilateral optic neuritis.
Methods: 16 patients of unilateral optic neuritis treated with methylprednisolone were evaluated using Optical Coherence Tomography(OCT) and PERG over 6 months.
Results: Mean logMAR BCVA improved from 1.43±0.56 to 0.06±0.14 over 6 months. PERG showed significantly reduced mean N95 amplitude (11.06 to 6.48μV) in affected eyes at 6 months while mean P50 latency and amplitude along with mean N95 latency showed no significant change.
At 6 months, OCT RNFL (123μm to 80 μm) and GCC thickness (95 μm to 75 μm) had statistically significant thinning. Significant correlation between GCC thickness and mean N95 amplitude was seen confirming significant loss of ganglion cells.
Conclusion: Significant residual abnormalities in anatomical (GCC and RNFL) and electrophysiological (PERG) parameters are seen in optic neuritis
1.Introduction
Acute Optic Neuritis (ON) is an inflammatory disorder of the optic nerve primarily affecting young adults resulting in a rapid progressive loss of vision1,2. ON is often idiopathic but may be associated with a variety of autoimmune or infectious etiologies2-5. Typical demyelinating ON is a presenting feature of multiple sclerosis (MS) and is known to occur in 30-70% patients of MS during the course of their illness2,5. Recovery of high contrast visual acuity (VA) in ON is usually complete, regardless of treatment but despite normal VA, poor quality of vision is often reported by patients due to persistent residual deficits in contrast sensitivity, colour vision and visual fields (VF)1,6,7.
Many of the clinical characteristics of ON have particularly strong correlations with underlying pathologic and pathophysiologic changes. Inflammatory demyelination of the optic nerve with axonal injury and atrophy are the primary cause of neurological deficits in ON and MS8-10.
Pattern Electroretinogram (PERG) has been used to determine possible ganglion cell layer damage. PERG is the response of the retinal ganglion cell function to an iso-luminant stimulus. It helps in differentiating between optic nerve and macular pathology11,12. The N95 component of the PERG is thought to be of ganglion cell origin12. Previous studies have primarily performed a cross-sectional evaluation of PERG in ON and found conflicting results in these cases13,14.
Axonal loss is an important contributor to the pathophysiology of persistent visual deficits seen in cases of ON14. The retinal nerve fiber layer (RNFL) is devoid of myelin and contains the axons of retinal ganglion cells15 and therefore reduction in its thickness gives a much better insight into the loss of optic nerve axons. Being a non-invasive technique, an in-vivo assessment of RNFL thickness by optical coherence tomography (OCT) has been used to assess axonal loss seen in ON14,16.
The lesions of acute ON may cause atrophy of the RNFL by acute transaction of axons and consequently by retrograde degeneration lead to neuronal (Retinal Ganglion Cell) loss in the macula causing a decrease in the macular volume and Retinal Ganglion Cell Layer (RGCL) thickness10,14. Optical Coherence Tomography (OCT) is a non-invasive, reproducible imaging technique that has been used to quantify Retinal Ganglion Cell (RGC) loss. The potential utility of assessment of Ganglion Cell Complex (GCC) and macular volume to monitor neuroprotective effects of novel agents in therapeutic trials in cases of MS and ON has been hypothesized17.
Longitudinal assessment of GCC in cases of acute unilateral ON has rarely been done and there are no studies correlating changes in PERG with GCC loss in these cases. In this study, we aimed to comprehensively and prospectively evaluate cases presenting with first episode of acute unilateral ON and find out changes that occur in visual functions, GCC thickness, Electrophysiology and RNFL thickness over a 6 month follow-up period.
2.Materials and Methods
2.1. Study Design: This was a prospective cohort study conducted from October 2012 to March 2014 at a tertiary care centre. Patients were recruited from Out-patient Department and Neuro-Ophthalmology Clinic of the institute. The study protocol was approved by the institutional ethics committee and written informed consent from all subjects was taken after explaining the nature of the study. The study was in accordance with the tenets of the Declaration of Helsinki.
2.2. Subjects:
A total of 16 patients aged between 18 to 50 years who presented with first episode of unilateral optic neuritis within 14 days of symptom onset were included in the study. The diagnosis of ON was based on clinical findings, including presence of decreased visual acuity, painful eye movements, color vision loss, relative afferent pupillary defect, and fundus examination. We excluded all patients who had a history of a previous attack of ON, who were unable to cooperate for OCT or VEP testing, who had other causes of vision loss in the clinically affected eye (including amblyopia, any retinal pathology or glaucoma), and who had contraindications for systemic steroid use like diabetes mellitus, severe hypertension, miliary tuberculosis and other systemic infections, etc. Each patient was evaluated at presentation and treated with IV methylprednisolone sodium succinate (MPSS) 500 mg BD in 500 ml of 5% dextrose for three days followed by 11 days of oral prednisolone 1 mg/kg body weight and the dose was tapered over 2 weeks according to the recommendations of the ONTT9. Thirty two eyes of 16 age and gender matched control subjects were selected and tested on the same parameters as the cases. None of the control subjects had any ophthalmological or systemic disease. All patients as well as control subjects were ethnically Indian in origin.
2.3. Clinical Assessment: At presentation, after relevant history was taken, each patient underwent a comprehensive systemic and ophthalmological examination including complete general physical examination, visual acuity using Snellen’s chart (converted to logMAR values for ease of statistical analysis); fundus examination (direct and indirect); color vision testing using Ishihara color plates; contrast sensitivity testing at low (1.5 cycles per degree) and high (18 cycles per degree) spatial frequency using Functional Acuity Contrast Test (FACT) chart recorded as A and E, respectively; Pattern ERG (on Medelec Synergy System using the guidelines of International Society for Clinical Electrophysiology of Vision); Spectral domain OCT (Optovue, Heidelberg Engineering, Heidelberg, Germany RT 100 version 5.1). Patients underwent periodic evaluations at presentation, at 1 month, 3 months and 6 months after presentation.
2.4. Statistical Analysis: The data was analyzed using Statistical Package for the Social Sciences (SPSS) version 17.0. Pre-treatment, post-treatment and follow-up parameters for affected eyes were compared using the Paired ‘t’ test, or non-parametric Wilcoxon signed- rank test (in case distribution was not normal). Parameters between affected and fellow eyes of the patients as well as those of control subjects were compared using unpaired ‘t‘ test, or non- parametric Mann Whitney test (in case distribution was not normal). For qualitative data chi-square test/ Fisher’s exact test was used. P value <0.05 was considered as statistically significant. Correlation between PERG and OCT parameters were evaluated at 6 months.
3.RESULTS:
3.1 Demographic profile and clinical characteristics: Thirty two eyes of 16 patients with first episode of acute unilateral optic neuritis were included in the study. Thirty-two eyes of 16 age and sex matched control subjects were also evaluated. The demographic and clinical profile of the subjects has been given in Table 1.
Table 1. Demographics and clinical characteristics
| No. of Cases (n)
Controls (c) |
16
16 |
| Mean age in years – Cases
Controls |
28+6.89 (range 18 to 45 years)
27+6.19 (range 20 to 42 years) |
| Male:Female – Cases
Controls |
4:12
4:12 |
| Mean duration of presentation (in days) | 7+2.51 (range 3 to 12 days) |
| Diagnosis: Papillitis
Retrobulbar Neuritis |
6 cases (37.50%)
10 cases (62.50%) |
| Cases with decreased vision at presentation | 16 (100%) |
| RAPD | 16 (100%) |
| Ocular discomfort | 14 (87.50%) |
| Pain on ocular movements | 12 (75%) |
Visual acuity was evaluated using Snellen’s visual acuity chart and the values converted to get logMAR visual acuity values. Mean BCVA in the affected eyes at presentation was logMAR 1.43+0.56 which improved to logMAR 0.45+0.37 by 1 week and to logMAR 0.11+0.23 by 2 weeks post treatment. By 1 month mean BCVA improved to logMAR 0.06+0.14 and no further improvement was seen at 6 months (p<0.0005). At 6 months BCVA ranged from 6/18 to 6/6 on Snellen’s chart (logMAR 0.477 to 0). Two out of 16 patients (12.5%) did not have complete recovery of visual acuity. All other patients regained 6/6 (logMAR 0) vision in the affected eye. All patients had BCVA of 6/6 on Snellen’s visual acuity chart (logMAR 0) in the unaffected eyes which remained the same over the follow up period.
On evaluation of color vision using Ishihara plates, mean value of color vision improved from 3.25+2.14 plates read correctly at presentation to 15.13+2.39 plates read correctly at 6 months in the affected eyes (p<0.005). However, statistically significant deficit in mean color vision in the affected eyes as compared to the unaffected eyes was noted at 6 months (p=0.002). 5 out of 16 (31.25%) patients had abnormal color vision at 6 months. All patients had significantly reduced contrast sensitivity on FACT chart at low (1.5 cycles per degree- cpd), medium (6 cpd) and high (18 cpd) spatial frequencies in affected eyes at presentation. There was a statistically significant improvement in contrast sensitivity to 1.37+0.10 at 1.5 cpd and 0.75+0.22 at 18 cpd, at 6 months in affected eyes (p<0.005 and p<0.005, respectively). Even after significant improvement, residual deficit in contrast sensitivity was seen in affected eyes compared to unaffected/control eyes at 6 months (p<0.0005). No abnormality in color vision or contrast sensitivity was seen in the unaffected eyes of patients over the study period.
Visual field (VF) evaluation revealed mean value for Mean Deviation (MD) in the affected eyes as -18.75+7.46 at presentation as compared to -2.58+1.93 in the unaffected eyes (p<0.0005). Mean MD improved significantly from -18.75+7.46 to -5.61+3.12 at 6 months (p<0.005). The difference in mean MD in the affected eyes as compared to the unaffected eyes at 6 months was statistically significant (p<0.0005). At 6 months, VF was ONL (ONL) in 75% patients in affected eyes while 18.75% patients had VF ONL in their unaffected eyes.
3.2 Pattern Electroretinogram:
P50 latency and amplitude- Mean P50 latency was 50.88+4.53 ms at presentation and51.97+2.45 ms at 6 months in the affected eyes as compared to 50.64+3.45 ms in the unaffected eyes and 51.57+3.49 ms in control subjects in our study. The difference was statistically not significant (p=0.4).Mean P50 amplitude was 4.78+1.96 µV at presentation and 4.78+1.65 at 6 months in the affected eyes as compared to 4.95+2.59 in the unaffected eyes and 4.79+1.25µV in control subjects. The difference was statistically not significant (p=0.4).
N95 latency and amplitude- Mean N95 latency was 101.10+6.98 ms at presentation and 100.89+4.33 ms at 6 months in the affected eyes as compared to 99.96+3.29 ms in the unaffected eyes. The difference was statistically not significant (p=0.2). The change in mean N95 latency in the affected eyes over 6 months was also statistically not significant (p=0.46). However, the mean N95 latency was 97.33+3.11 ms in control subjects and the difference between mean N95 latency in the affected eyes of patients at presentation and at 6 months when compared to that of controls was statistically significant (p=0.006 and p=0.001, respectively).
Mean N95 amplitude, at presentation, was 11.06+3.24 µV in the affected eyes as compared to 12.57+5.68 µV in the unaffected eyes and 10.11+2.07 µV in control subjects. The difference was statistically not significant (p=0.181 and p=0.331, respectively). At 6 months, mean N95 amplitude had reduced significantly to 6.48+3.20 µV in the affected eyes (p<0.005). The difference between affected as compared to unaffected as well as control eyes at 6 months was statistically significant (p<0.0005 and p<0.0005, respectively). The results of PERG have been presented in TABLE 2.
Table 2. PERG findings on longitudinal evaluation in patients with acute unilateral ON.
| Parameters | At Presentation | 1 month | 3 months | 6 months |
| Mean P50 Latency (ms)+SD | ||||
| Affected Eye | 50.88+4.53 | 50.58+3.22 | 50.96+2.81 | 51.97+2.45 |
| Unaffected Eye | 50.64+3.45 | 50.87+2.54 | 50.46+2.39 | 51.78+3.15 |
| P-value (v/s Unaffected) | P=0.433 | P=0.390 | P=0.298 | P=0.424 |
| P-value (v/s Controls) | P=0.282 | P=0.173 | P=0.273 | P=0.088 |
| Mean P50 Amplitude (µV)+SD | ||||
| Affected Eye | 4.78+1.96 | 4.99+1.83 | 4.45+1.08 | 4.78+1.65 |
| Unaffected Eye | 4.95+2.59 | 4.81+1.76 | 5.44+1.76 | 5.25+1.96 |
| P-value (v/s Unaffected eye) | P=0.417 | P=0.388 | P=0.032 | P=0.234 |
| P-value (v/s Controls) | P=0.484 | P=0.328 | P=0.179 | P=0.284 |
| Mean N95 Latency (ms)+SD | ||||
| Affected Eye | 101.10+6.98 | 99.13+3.37 | 99.33+3.00 | 100.89+4.33 |
| Unaffected Eye | 99.96+3.29 | 99.41+5.05 | 99.28+3.81 | 101.94+5.78 |
| P-value (v/s Unaffected eye) | P=0.279 | P=0.429 | P=0.482 | P=0.283 |
| P-value (v/s Controls) | P=0.006 | P=0.036 | P=0.019 | P=0.001 |
| Mean N95 Amplitude (µV)+SD | ||||
| Affected Eye | 11.06+3.24 | 9.82+4.21 | 8.22+3.02 | 6.48+3.20 |
| Unaffected Eye | 12.57+5.68 | 11.51+4.06 | 11.43+3.77 | 12.34+3.34 |
| P-value (v/s Unaffected eye) | P=0.181 | P=0.128 | P=0.006 | P<0.0005 |
| P-value (v/s Controls) | P=0.331 | P=0.374 | P=0.014 | P<0.0005 |
PERG- Pattern Electroretinogram; ON- Optic Neuritis
3.3 OCT RNFL: Due to disc edema, affected eyes showed an increased mean RNFL thickness (µm) of 123.50+29.30 (range 101 to 195 µm) at presentation. It reduced significantly to 80.38+8.77 µm (range 65 to 99 µm) over 6 months (p<0.005). No thinning was noted in fellow eyes. Statistically significant thinning in RNFL thickness in affected eyes compared to fellow eyes was first seen at 3 months post treatment (p<0.0005). Control subjects had a mean RNFL thickness of 107.56+6.58 µm (range 96 to 118 µm). Affected eyes of patients showed statistically significant thinning in mean RNFL when compared to fellow eyes as well as control subjects at 6 months post follow up (p<0.0005 and p<0.0005, respectively).
3.4 OCT GCC thickness: On OCT evaluation for ganglion cell complex thickness, mean GCC thickness in affected eyes reduced significantly from 95.01+6.70 µm at presentation to 75.74+8.32 µm at 6 months (p<0.005). Reduction in mean GCC thickness in fellow eyes from 94.35+7.01 µm at presentation to 92.19+6.11 µm at 6 months was also noted (p=0.03). Mean GCC thickness was 93.89+3.61 µm in control subjects. Thinning in GCC in affected eyes when compared to fellow and control eyes was statistically highly significant over 6 months follow up period (p<0.0005 and p<0.0005, respectively).
Correlation between PERG and OCT:
On evaluation of correlations between various parameters at 6 months, there was no significant correlation between P50 wave latency and amplitude with OCT GCC thickness or. While N95 latency also showed similar results, however N95 wave amplitude revealed statistically significant correlation with GCC thickness at 6 months (Pearson’s coefficient=0.517, p=0.040). There was a statistically significant correlation between N95 amplitude when compared with GCC thickness (Adjusted R2=0.726, P value<0.0005). On regression analysis, 5.23µm decrease in GCC thickness resulted in 1µv decrease in N95 amplitude.
4.Discussion:
The clinical and demographic profile of the patients in our study was similar to that reported in the Optic Neuritis Treatment Trial (ONTT) but was significantly different from study on Asian population by Wang et al. 20011,18. Retrobulbar neuritis was more common presentation than papillitis. Rapid visual recovery was noted in all patients with only two patients (12.5%) having incomplete visual recovery. Various studies have previously reported residual abnormalities in contrast sensitivity, colour vision and VF in cases ON and MS even after complete recovery of high contrast VA1,19,20,21. We found similar results in our study.
Multiple studies in patients of MS and those with ON have given conflicting results on evaluation of PERG. Most of these studies have been cross-sectional.
PERG has been previously studied in cases of MS and known optic nerve demyelination showing 40% PERG abnormality, with 85% of these abnormalities affecting the N95 component12.
Our study revealed results conflicting with some of the previous studies13,14. Unlike previous cross-sectional studies, our study was a longitudinal study in patients of acute unilateral ON. Our study confirmed the hypothesis of retrograde degeneration of retinal ganglion cells in cases of optic nerve injury due to ON by showing a progressive significant decrease in N95 amplitude over 6 months follow up. We found no significant changes in P50 wave in the affected eyes indicating that P50 wave is principally affected by retinal and macular dysfunction and might not be affected by retinal ganglion cell loss.
A number of studies have shown RNFL loss on OCT in patients with ON. Previous studies have reported that in MS associated ON, loss of RNFL thickness is in the range of 5–40 μm, averaging at 10–20 μm12,13,20,22. Most of these have been cross-sectional studies. It has been shown that axonal loss continues in the affected eyes for at least 12 months after acute ON, but most thinning in RNFL occurs by 6 months (Costello et al. 2006)23.
Our study also had similar results having significant thinning in mean RNFL thickness in affected eyes at 6 months in spite of visual recovery seen in these patients. This confirmed the reports of previous studies10,12,20-22. Even though, we evaluated patients of acute isolated unilateral ON not associated with MS, RNFL thinning seen in our study was similar to previous studies conducted in isolated as well as MS associated ON.
SD-OCT is an effective non-invasive tool that produces high resolution images of the ocular internal tissue microstructures. Few previous studies have reported decrease in GCC thickness in eyes affected with ON with most of these studies being cross-sectional10,24,25. Garas et al. reported that ganglion cell thickness decreased in affected eyes of ON patients on OCT24.Davies et al. reported significantly lower GCL volumes in MS patient eyes as compared to control eyes. GCL volumes were significantly lower in MS eyes with a prior history ON as compared to MS eyes without a prior history of ON25. Syc B et al. reported a significant thinning of the ganglion cell layer (GCL) plus the inner plexiform layer (IPL), in eyes affected by ON at 3 months and 6 months follow up in comparison to the unaffected eyes10. Using GCC protocol in Spectral Domain-OCT RTVue, we found a significant reduction in mean GCC average thickness in affected eyes as compared to fellow eyes at 6 months which corroborates with the previous studies10,24. This signified ganglion cell loss in cases of ON.
Contrary to the study by Syc B et al. we found a small but significant reduction in mean GCC average thickness in the fellow eyes as well10. This could signify subclinical inflammation and neuronal loss in the fellow eyes of patients with unilateral ON. Thus, GCC average thickness can be an effective tool for analysing the RGC loss in cases of ON and can help greatly in understanding the pathophysiology of this disease.
This is the first study to prospectively evaluate PERG and Retinal Ganglion Cell Layer thickness in cases of acute optic neuritis. On correlating PERG parameters with Ganglion Cell Complex assessment on OCT, we found statistically significant correlation of N95 amplitude with GCC thickness (Pearson’s coefficient=0.517, p=0.040), while no significant correlation was found between other PERG parameters and GCC thickness. The study revealed that 72.6% of the change in N95 wave in these cases was attributable to ganglion cell loss (Adjusted R2=0.726). This not only confirmed the pathophysiological basis of abnormalities seen in these cases on progressive evaluation of PERG in our study but also suggested that GCC thickness or loss of ganglion cells is an excellent predictor of changes seen in N95 wave of PERG in cases of ON.
Despite few limitations (small sample size, short follow up of 6 months), our study was able to clearly define and delineate longitudinal changes occurring in PERG and ganglion cell complex on OCT in cases of acute ON. This is the first study to prospectively evaluate PERG and GCC thickness and to find the correlation between the two in cases of ON. The statistically significant reduction in N95 amplitude and GCC thickness validated and confirmed the neuronal loss that occurs in cases of ON and MS. Absence of swelling in the ganglion cell complex in the acute stages of ON is particularly advantageous to get true baseline values for longitudinal evaluation that are not confounded by the oedema that usually affects the RNFL layer leading to abnormally high baseline values before showing thinning on prospective evaluation. Thus, longitudinal evaluation of PERG, and quantifying neuronal loss by OCT GCC thickness can probably provide better outcome measures in neuroprotection trials evaluating effectiveness of neuroprotective agents in cases of ON and MS. Therefore, we recommend that PERG and OCT RNFL and GCC thickness assessment should become an integral part of a comprehensive workup of every patient with ON and MS.
5.REFERENCES
1.The clinical profile of optic neuritis. Experience of the Optic Neuritis Treatment Trial. Optic Neuritis Study Group. Arch Ophthalmol. 1991 Dec;109(12):1673-8.
2.Toosy AT, Mason DF, Miller DH. Optic neuritis. Lancet Neurol. 2014 Jan;13(1):83-99.
3.Menon V, Saxena R, Misra R, Phuljhele S. Management of optic neuritis. Indian J Ophthalmol. 2011 Mar-Apr;59(2):117-22.
4.Pau D, Al Zubidi N, Yalamanchili S, Plant GT, Lee AG. Optic neuritis. Eye (Lond). 2011 Jul;25(7):833-42.
5.Balcer LJ. Clinical practice.Optic neuritis. N Engl J Med. 2006 Mar;354(12):1273-80.
6.Frederiksen JL, Sørensen TL, Sellebjerg FT. Residual symptoms and signs after untreated acute optic neuritis.A one-year follow-up. ActaOphthalmol Scand.1997 Oct;75(5):544-7.
7.Beck RW. Optic Neuritis Study Group: The optic neuritis treatment trial. Arch Ophthalmol 1998 Aug; 106(88):1051–3.
8.Trapp BD, Ransohoff R, Rudick R. Axonal pathology in multiple sclerosis: relationship to neurologic disability. CurrOpin Neurol. 1999 Jun;12(3):295-302.
9.Trapp BD, Bö L, Mörk S, Chang A. Pathogenesis of tissue injury in MS lesions. J Neuroimmunol. 1999 Jul;98(1):49-56.
10.Syc SB, Saidha S, Newsome SD, Ratchford JN, Levy M, Ford E et al. Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis.Brain. 2012 Feb;135(Pt 2):521-33
11.Holder GE. The incidence of abnormal pattern electroretinography in optic nerve demyelination.ElectroencephalogrClinNeurophysiol. 1991 Jan;78(1):18-26.
12.Holder GE. Pattern electroretinography (PERG) and an integrated approach to visual pathway diagnosis.ProgRetin Eye Res. 2001 Jul;20(4):531-61.
13.Atilla H, Tekeli O, Ornek K, Batioglu F, Elhan AH, Eryilmaz T. Pattern electroretinography and visual evoked potentials in optic nerve diseases. J ClinNeurosci. 2006 Jan;13(1):55-9.
14.Trip SA, Schlottmann PG, Jones SJ, Altmann DR, Garway-Heath DF, Thompson AJet al. Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol 2005; 58:383–91.
15. Ogden TE. Nerve fiber layer of the primate retina: thickness and glial content. Vision Res. 1983;23(6):581-7.
16. Costello F, Hodge W, Pan YI, Eggenberger E, Coupland S, Kardon RH. Tracking retinal nerve fiber layer loss after optic neuritis: a prospective study using optical coherence tomography. Mult Scler 2008;14:893-905.
17.Burkholder BM, Osborne B, Loguidice MJ, Bisker E, Frohman TC, Conger A, et al. Macular volume determined by optical coherence tomography as a measure of neuronal loss in multiple sclerosis. Arch Neurol. 2009 Nov;66(11):1366-72.
18.Wang JC, Tow S, Aung T, Lim SA, Cullen JF. The presentation, aetiology, management and outcome of optic neuritis in an Asian population.Clin Experiment Ophthalmol.2001;29:312-5.
19.Keltner JL, Johnson CA, Cello KE, Dontchev M, Gal RL, Beck RW, et al. Visual field profile of optic neuritis: a final follow-up report from the optic neuritis treatment trial from baseline through 15 years. Arch Ophthalmol. 2010 Mar;128(3):330-7.
20.Henderson APD, Altmann RD, Trip SA, Kallis C, Jones JS, Schlottmann GP et al. A serial study of retinal changes following optic neuritis with sample size estimates for acute neuroprotection trials. Brain. 2010 Sep;133(9):2592-602.
21.Henderson APD, Altmann DR, Trip SA, Miszkiel KA, Schlottmann PG, Jones SJet al. Early factors associated with axonal loss after optic neuritis. Ann Neurol. 2011 Dec;70(6):955-63.
22.Petzold A, de Boer JF, Schippling S, Vermersch P, Kardon R, Green A, et al. Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol. 2010 Sep;9(9):921-32.
23.Costello F, Coupland S, Hodge W, Lorello GR, Koroluk J, Pan YI, et al. Quantifying axonal loss after optic neuritis with optical coherence tomography. Ann Neurol. 2006 Jun;59(6):963-9.
24.Garas A, Simó M, Holló G. Nerve fiber layer and macular thinning measured with different imaging methods during the course of acute optic neuritis. Eur J Ophthalmol. 2011 Jul-Aug;21(4):473-83.
25.Davies EC, Galetta KM, Sackel DJ, Talman LS, Frohman EM, Calabresi PA, et al. Retinal ganglion cell layer volumetric assessment by spectral-domain optical coherence tomography in multiple sclerosis: application of a high-precision manual estimation technique. J Neuroophthalmol. 2011 Sep;31(3):260-4.