Multiple Sclerosis and Related Disorders 5 (2016) 66–69
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Clinical trial
Ganglion cell analysis in acute optic neuritis R. Behbehani a,b,n, A. Al-Moosa b, D. Sriraman c, R. Alroughani a,d a
Neurology Clinic, Dasman Institute, Dasman, Kuwait Al-Bahar Ophthalmology Center, Kuwait City, Kuwait Department of Biostatistics, Dasman Institute, Kuwait d Division of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait b c
art ic l e i nf o
a b s t r a c t
Article history: Received 4 May 2015 Received in revised form 16 October 2015 Accepted 21 October 2015
Background: Optic neuritis has a diagnostic and prognostic significance in predicting the development of multiple sclerosis. Optical coherence tomography is being increasingly used to detect and monitor axonal damage in MS by measuring the retinal nerve fiber layer (RNFL). However, RNFL can be affected by edema and inflammation and obscure early axonal damage. Objective: To study the pattern of change in the ganglion cell and inner plexiform layer compared to retinal nerve fibber layer in acute optic neuritis using spectral domain OCT. Methods: Ten patients with acute optic neuritis were followed prospectively for 6 months with spectral domain optical coherence tomography. A group of 40 of eyes of 20 healthy controls was used for baseline comparison. Results: The ganglion cell and inner plexiform layer (GCIPL) was significantly lower (thinner) at onset in patients' affected (p¼ 0.009) eyes. Both RNFL and GCIPL were significantly lower in affected eyes at 6 months (p¼ 0.012 and p¼ 0.007) respectively compared to baseline. Conclusion: The GCIPL is probably more sensitive index of axonal loss than the RNFL in acute optic neuritis and could be a better index to detect neurodegeneration in multiple sclerosis. This can helpful in estimating early axonal loss and can potentially be used in therapeutic trials of neuroprotective drugs. & 2015 Elsevier B.V. All rights reserved.
Keywords: Optic Neuritis Multiple Sclerosis Optical Coherence Tomography Ganglion Cell and Inner Plexiform Layer
1. Introduction Optic neuritis (ON) is a common clinical presentation of multiple sclerosis (MS). It is highly predictive of future development of MS if associated with magnetic resonance imaging (MRI) brain lesions (Miller et al., 2012). Optical coherence tomography (OCT) is a non-invasive tool, which allows quantitative and qualitative assessment of the retinal layers. Measurement of the retinal nerve fiber layer (RNFL) has been used to assess the degree of axonal loss in MS (Trip et al., 2006). Recent algorithms using spectral domain OCT (SDOCT) allow segmentation of retinal layers and measurement of the thickness of ganglion cell layer complex and inner plexiform (GCIPL). RNFL thickness has been studied extensively using time-domain OCT (TDOCT) in patients with clinically isolated syndrome (CIS) or MS (Costello et al., 2006). However, there are few studies on ON using the new spectral domain OCT (SDOCT) that longitudinally examined changes the GCIPL (Garas et al., 2011). Unlike the RNFL, the GCIPLis less affected by axonal swelling due to inflammation and edema in acute optic neuritis. Accurate n
Correspondence to: P.O Box 1180, Dasman 15462, Kuwait. Fax: 965 2249 2406. E-mail address: [email protected] (R. Behbehani).
http://dx.doi.org/10.1016/j.msard.2015.10.008 2211-0348/& 2015 Elsevier B.V. All rights reserved.
assessment of the extent of axonal loss early in the disease can be important from both a diagnostic and therapeutic aspects. We have prospectively evaluated a cohort of patients with acute ON with SDOCT using a segmentation protocol to determine whether GCIPL thinning is seen earlier in patients with CIS with ON at onset and to longitudinally follow the changes of the peripiapillary and macular RNFL, and GCIPL and central macular thickness during a 6-month period.
2. Methods We have prospectivley recruited 10 patients with acute ON within 5 weeks of onset of visual symptoms Mean 7SD; 13.7 7 10.7 (range 4–35 days) in the MS clinic at Dasman Institute. All subjects had an neuro-ophthalmologic assessment and spectral domain OCT using the Cirrus HD-OCT 5000 (Cirrhus HDOCT 5000; Carl Zeiss Meditec) was used to obtain perpipapillary and macular data (RNFL, and GCIPL and central macular thickness) using the protocol of optic disc cube scan of 200x200 and macular cube scan of 512x128 centered on the fovea. The built-in algorithm in the ganglion cell analysis measures the combined thickness of the ganglion cell and inner plexiform layer. Because of the similar
R. Behbehani et al. / Multiple Sclerosis and Related Disorders 5 (2016) 66–69
67
Table 1 Summary of the demographics of the studied cohort and control group.
Subjects Age Mean (SD) Gender Male (%) Female (%) Time from symptom onset Mean (SD)
Patients
Control
P value
10 26.8 (1.7)
20 28.6 (4.9)
0.015
4 (40.0) 6 (60.0) 13.7 (10.7) range 4–35 days
5 (55.6) 15 (44.4)
0.403
tissue reflectivity of these two layers, current segmentation algorithms cannot discern the two layers apart and they are measured as one layer (GCIPL). This value has been used as a surrogate to denote ganglion cell layer similar publications. 6 OCT scanning was performed at onset, 3, and 6 months follow up period. We have excluded patients with high refractive errors ( 76 diopters), those with prior history of ON, or patients with other neurological diseases and/or disease of the retina and optic nerve. Furthermore, OCT on 40 eyes of 20 healthy controls was performed for baseline comparison with our cohort. This study was approved by the local ethical committee and was conducted in accordance with the declaration of Helsinki for biomedical research. 2.1. Statistical analysis All statistical analyses were completed using JMPs (SAS Institute Inc., Cary, NC). An Independent t-test was used to determine the difference in RNFL, central macular thickness (CMT) and GCIPL between patients and healthy controls. Paired t-test was used to determine the difference between the onset, 3 months and 6 months follow-up period to evaluate the difference in RNFL, CMT and GCIPL. Data were represented in mean and standard deviation for both the t-tests. Statistical significance was defined as P o0.05.
3. Results The study subjects comprised 6 females and 4 males with the mean age (standard deviation) of 26.8 years (1.7) Six patients had MRI brain lesions consistent with demyelination while 4 had normal brain MRI. Of the six patients who had MRI brain lesions, only 1 satisfied the 2010 McDonald criteria for MS. (Polman et al., 2011) Data of three patients were not available for the 3 month OCT follow up. All patients received IV Methylprednisolone (one gram once daily for 3–5 days) for treatment of acute ON. Patients' affected (n ¼10) and unaffected (n ¼10) eyes were included in final analysis. The clinical characteristics of study subjects are summarized in Table 1. Using the independent t-test at baseline, the mean GCIPL was significantly lower at onset in patient with affected eyes compared to healthy control (p ¼0.009), while RNFLT
Fig. 1. A box-plot showing ganglion cell and inner plexiform layer (GCIPL) thickness in micrometer between control onset and patient onset (p ¼ 0.009).
and CMT were not (Table 2, Fig. 1). Paired t-test was done to compare the difference between onset, 3 months and 6 months follow-up period and both RNFLT (p ¼0.012; Fig. 2A) and GCIPL (p ¼0.007; Fig. 2B) were significantly lower in affected eyes at 6 months compared to onset (Table 3a). There was a trend for GCIPL to be thinner in the patients' unaffected eyes compared to controls (p ¼0.068) but that did not reach statistical significance. Similarly, RNFL and CMT were not significantly thinner at onset in patients' with unaffected eyes compared to healthy controls at onset, 3 months and 6 month follow up (Table 3b).
4. Discussion We have found that GCIPL was significantly thinner at onset of optic neuritis in the involved with a trend to significance in the non-involved eye when compared to healthy controls. Peripapillary RNFL and CMT were not significantly different at onset in either the affected eyes or unaffected eyes compared to healthy controls.This suggests that GCIPL is a more sensitive index for early axonal loss in acute optic neuritis . Both GCIPL and RNFL were significantly thinner at 6 months compared to baseline. Although we cannot determine the exact time at which GCIPL thinning starts because of the variable points in the time window in which SDOCT was obtained, we speculate that most of the thinning of GCIPL takes place between onset and 3 months while RNFLT thinning progressed over the follow-up period. (Fig. 2A and B) Previous studies have shown that RNFL thinning progresses up to 6 months. (Costello et al., 2006, 2011). While GCIPL thinning starts around 3 months in other studies, we have found that in some
Table 2 Independent t-test shows the measurements of the RNFLT, CMT and GCIPL in the affected and unaffected eyes between studied control and patients. Affected eyes
RNFLT (μm) CMT (μm) GCIPL (μm)
Unaffected eyes
Control Onset Mean 7 SD
Patient Onset Mean 7 SD
P value
Control Onset Mean 7 SD
Patient Onset Mean 7 SD
P value
94.9 7 6.0 244.37 20.0 84.17 3.5
90.9 7 13.5 241.5 7 19.4 75.17 8.6
0.385 0.686 0.009
94.9 7 6.0 244.37 20.0 84.17 3.5
89.6 7 15.0 242.47 14.9 77.0 7 10.8
0.302 0.735 0.068
SD ¼ Standard deviation; RNFLT ¼Peripapillary Retinal Nerve Fiber Layer Thickness; CMT ¼ Central Macular Thickness; GCIPL ¼ Ganglion cell and Inner Plexiform Layer; μm¼ micrometer.
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R. Behbehani et al. / Multiple Sclerosis and Related Disorders 5 (2016) 66–69
Fig. 2. A: A graph showing Retinal Nerve Fiber Layer (RNFL) thickness in patient with affected eyes at onset and 6 months follow-up (p ¼0.012). B: graph showing ganglion cell and inner plexiform layer (GCIPL) thickness in patient with affected eyes at onset and 6 months follow-up (p ¼0.007). Table 3a Paired t-test shows the measurements of the RNFLT, CMT and GCIPL in the affected eyes over the onset, 3 months (3M) and 6 months (6M) follow-up period Onset to 3 Months (3M)
RNFLT (μm) CMT (μm) GCIPL (μm)
3M to 6 Months (6M)
Onset to 6M
Onset
3M
P value
3M
6M
P value
Onset
6M
P value
90.9 7 13.5 238.9 7 23.1 74.0 7 9.6
83.4 7 11.1 239.1 716.3 70.67 7.9
0.119 0.937 0.267
83.4 711.1 239.17 16.3 70.6 7 7.9
82.0 7 14.1 239.1 714.8 67.8 7 9.6
0.405 0.357 0.120
90.9 713.5 238.9 723.1 74.0 7 9.6
82.0 7 14.1 239.17 14.8 67.8 7 9.6
0.012 0.278 0.007
Table 3b Paired t-test shows the measurements of the RNFLT, CMT and GCIPL in the unaffected eyes over the onset, 3 months (3M) and 6 months (6M) follow-up period Onset to 3 Months (3M)
RNFLT (μm) CMT (μm) GCIPL (μm)
3M to 6 Months (6M)
Onset to 6M
Onset
3M
P value
3M
6M
P value
Onset
6M
P value
89.6 715.0 242.47 14.9 77.0 710.8
83.1 712.4 238.7 7 19.6 75.4 7 11.3
0.022 0.383 0.839
83.1 712.4 238.7 7 19.6 75.4 7 11.3
89.0 7 16.2 244.07 15.3 76.7 7 10.9
0.458 0.714 0.231
89.6 7 15.0 242.47 14.9 77.0 7 10.8
89.0 7 16.2 244.07 15.3 76.7 7 10.9
0.197 0.721 0.419
SD ¼ Standard deviation; RNFLT ¼Peripapillary Retinal Nerve Fiber Layer Thickness; CMT¼ Central Macular Thickness; GCIPL ¼ Ganglion cell and Inner Plexiform Layer; μm¼ micrometer.
Fig. 3. (A) (Top) shows RNFL pattern deviation map (left) and RNFLT quadrants and (B) (Bottom) shows ganglion cell deviation map (left) and thickness sectors (right) , at onset and 6 months. Areas highlighted represent o 1% of distributixon of normal values of same age and sex and indicate thinning. There is increased thickness in the RNFLT quadrants at onset (axonal swelling) while (B) there is already ganglion cell layer thinning seen in the deviation map and thickness sectors. The ganglion cell thickness remains stable while the RNFL swelling subsides at 6 months and is still within normal.
R. Behbehani et al. / Multiple Sclerosis and Related Disorders 5 (2016) 66–69
cases it starts as early as the first 1–2 weeks and the thinning continues to around 3 months and changes less after that compared to RNFLT (Syc et al., 2012) (Fig. 3). Recently , Rebolleda et al. reported four cases with acute anterior optic neuritis in whom (GCIPL) thinning was detected weeks before RNFL loss and concluded that GCIPL analysis may provide more accurate information than RNFLT about neuronal loss (Rebolleda et al., 2015) . While other studies have demonstrated that GCIPL was thinner in ON patients with and without a history of ON when compared with healthy controls, they have included in their cohorts a significant proportion of patients with existing MS, which may have confounded their findings (Syc et al., 2012; Davies et al., 2011). Our cohort though included 1 patient who had met the revised 2010 McDonald diagnostic criteria for MS, is composed predominantly of CIS patients (Davies et al., 2011). We found that there was a trend for GCIPL to be thinner in the unaffected eye compared to healthy controls (p o0.068). Previous studies using time-domain OCT (TDOCT) did not find evidence of peripapillary RNFL or macular thickness thinning in the non-affected eyes of patients with CIS optic neuritis when compared to healthy controls (Outteryck et al., 2009). A recent cross sectional study using SDOCT and retinal segmentation also detected thinning of the GCIPL in CIS eyes without clinical history of optic neuritis (Oberwahrenbrock et al., 2013). This can be explained by early neurodegenerative activity in CIS patients. An alternative explanation would be bilateral asymmetric optic neuritis or tran-synapatic degeneration arising from occult lesions and inflammation in the brain involving the posterior visual pathways rather than a direct, immune-mediated mechasnim (Sriram et al., 2012). We could not find a difference in the RNFLT between the affected (90.9 microns) and unaffected (89.6 microns) eyes at onset of ON. Previous studies reported thicker RNFLT at onset in the affected compared to the unaffected eyes. Our cohort did not demonstrate marked early RNFL thickening. (Syc et al., 2012). However, we cannot rule out the possibility of missing the early axonal edema and RNFL thickening since the timing of the first OCT was not standardized and this varied from 4 to 35 days. Our pilot study has several limitations including small sample size, and relatively short follow up duration. Our control group was slightly older than
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other cohorts but the difference was minor and that probably adds more strength to the findings. ON is the best studied CIS and it can serve as a good model for studying neurodegeneration and the effects potential neuroprotective drugs. This pilot study along with other prior studies suggest that measuring the GCIPL can provide early assessment of neurodegenration (Garas et al., 2011). Future prospective studies are needed to assess the change of GCIPL and the effects of neuroprotective agents in patients with ON.
References Miller, D.H., Chard, D.T., Ciccarelli, O., 2012. Clinically isolated syndromes. Lancet Neurol. 11, 157–169. Trip, S.A., Schlottmann, P.G., Jones, S.J., et al., 2006. Optic nerve atrophy and retinal nerve fibre layer thinning following optic neuritis: evidence that axonal loss is a substrate of MRI-detected atrophy. NeuroImage 31, 286–293. Costello, F., Coupland, S., Hodge, W., et al., 2006. Quantifying axonal loss after optic neuritis with optical coherence tomography. Ann. Neurol. 59, 963–969. Garas, A., Simo, M., Hollo, G., 2011. Nerve fiber layer and macular thinning measured with different imaging methods during the course of acute optic neuritis. Eur. J. Ophthalmol. 21, 473–483. Costello, F., 2011. Evaluating the use of optical coherence tomography in optic neuritis. Mult. Scler. Int. 2011, 148394. Syc, S.B., Saidha, S., Newsome, S.D., et al., 2012. Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis. Brain: J. Neurol. 135, 521–533. Rebolleda, G., de Dompablo, E., Munoz-Negrete, F.J., 2015. Ganglion cell layer analysis unmasks axonal loss in anterior optic neuritis. J. Neuro-Ophthalmol. 35, 165–167. Davies, E.C., Galetta, K.M., Sackel, D.J., et al., 2011. Retinal ganglion cell layer volumetric assessment by spectral-domain optical coherence tomography in multiple sclerosis: application of a high-precision manual estimation technique. J. Neuro-Ophthalmol.: Off. J. N. Am. Neuro-Ophthalmol. Soc. 31, 260–264. Polman, C.H., Reingold, S.C., Banwell, B., et al., 2011. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol. 69, 292–302. Outteryck, O., Zephir, H., Defoort, S., et al., 2009. Optical coherence tomography in clinically isolated syndrome: no evidence of subclinical retinal axonal loss. Arch. Neurol. 66, 1373–1377. Oberwahrenbrock, T., Ringelstein, M., Jentschke, S., et al., 2013. Retinal ganglion cell and inner plexiform layer thinning in clinically isolated syndrome. Mult. Scler. 19, 1887–1895. Sriram, P., Graham, S.L., Wang, C., Yiannikas, C., Garrick, R., Klistorner, A., 2012. Transsynaptic retinal degeneration in optic neuropathies: optical coherence tomography study. Investig. Ophthalmol. Vis. Sci. 53, 1271–1275.
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Clinical trial
Ganglion cell analysis in acute optic neuritis R. Behbehani a,b,n, A. Al-Moosa b, D. Sriraman c, R. Alroughani a,d a
Neurology Clinic, Dasman Institute, Dasman, Kuwait Al-Bahar Ophthalmology Center, Kuwait City, Kuwait Department of Biostatistics, Dasman Institute, Kuwait d Division of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait b c
art ic l e i nf o
a b s t r a c t
Article history: Received 4 May 2015 Received in revised form 16 October 2015 Accepted 21 October 2015
Background: Optic neuritis has a diagnostic and prognostic significance in predicting the development of multiple sclerosis. Optical coherence tomography is being increasingly used to detect and monitor axonal damage in MS by measuring the retinal nerve fiber layer (RNFL). However, RNFL can be affected by edema and inflammation and obscure early axonal damage. Objective: To study the pattern of change in the ganglion cell and inner plexiform layer compared to retinal nerve fibber layer in acute optic neuritis using spectral domain OCT. Methods: Ten patients with acute optic neuritis were followed prospectively for 6 months with spectral domain optical coherence tomography. A group of 40 of eyes of 20 healthy controls was used for baseline comparison. Results: The ganglion cell and inner plexiform layer (GCIPL) was significantly lower (thinner) at onset in patients' affected (p¼ 0.009) eyes. Both RNFL and GCIPL were significantly lower in affected eyes at 6 months (p¼ 0.012 and p¼ 0.007) respectively compared to baseline. Conclusion: The GCIPL is probably more sensitive index of axonal loss than the RNFL in acute optic neuritis and could be a better index to detect neurodegeneration in multiple sclerosis. This can helpful in estimating early axonal loss and can potentially be used in therapeutic trials of neuroprotective drugs. & 2015 Elsevier B.V. All rights reserved.
Keywords: Optic Neuritis Multiple Sclerosis Optical Coherence Tomography Ganglion Cell and Inner Plexiform Layer
1. Introduction Optic neuritis (ON) is a common clinical presentation of multiple sclerosis (MS). It is highly predictive of future development of MS if associated with magnetic resonance imaging (MRI) brain lesions (Miller et al., 2012). Optical coherence tomography (OCT) is a non-invasive tool, which allows quantitative and qualitative assessment of the retinal layers. Measurement of the retinal nerve fiber layer (RNFL) has been used to assess the degree of axonal loss in MS (Trip et al., 2006). Recent algorithms using spectral domain OCT (SDOCT) allow segmentation of retinal layers and measurement of the thickness of ganglion cell layer complex and inner plexiform (GCIPL). RNFL thickness has been studied extensively using time-domain OCT (TDOCT) in patients with clinically isolated syndrome (CIS) or MS (Costello et al., 2006). However, there are few studies on ON using the new spectral domain OCT (SDOCT) that longitudinally examined changes the GCIPL (Garas et al., 2011). Unlike the RNFL, the GCIPLis less affected by axonal swelling due to inflammation and edema in acute optic neuritis. Accurate n
Correspondence to: P.O Box 1180, Dasman 15462, Kuwait. Fax: 965 2249 2406. E-mail address: [email protected] (R. Behbehani).
http://dx.doi.org/10.1016/j.msard.2015.10.008 2211-0348/& 2015 Elsevier B.V. All rights reserved.
assessment of the extent of axonal loss early in the disease can be important from both a diagnostic and therapeutic aspects. We have prospectively evaluated a cohort of patients with acute ON with SDOCT using a segmentation protocol to determine whether GCIPL thinning is seen earlier in patients with CIS with ON at onset and to longitudinally follow the changes of the peripiapillary and macular RNFL, and GCIPL and central macular thickness during a 6-month period.
2. Methods We have prospectivley recruited 10 patients with acute ON within 5 weeks of onset of visual symptoms Mean 7SD; 13.7 7 10.7 (range 4–35 days) in the MS clinic at Dasman Institute. All subjects had an neuro-ophthalmologic assessment and spectral domain OCT using the Cirrus HD-OCT 5000 (Cirrhus HDOCT 5000; Carl Zeiss Meditec) was used to obtain perpipapillary and macular data (RNFL, and GCIPL and central macular thickness) using the protocol of optic disc cube scan of 200x200 and macular cube scan of 512x128 centered on the fovea. The built-in algorithm in the ganglion cell analysis measures the combined thickness of the ganglion cell and inner plexiform layer. Because of the similar
R. Behbehani et al. / Multiple Sclerosis and Related Disorders 5 (2016) 66–69
67
Table 1 Summary of the demographics of the studied cohort and control group.
Subjects Age Mean (SD) Gender Male (%) Female (%) Time from symptom onset Mean (SD)
Patients
Control
P value
10 26.8 (1.7)
20 28.6 (4.9)
0.015
4 (40.0) 6 (60.0) 13.7 (10.7) range 4–35 days
5 (55.6) 15 (44.4)
0.403
tissue reflectivity of these two layers, current segmentation algorithms cannot discern the two layers apart and they are measured as one layer (GCIPL). This value has been used as a surrogate to denote ganglion cell layer similar publications. 6 OCT scanning was performed at onset, 3, and 6 months follow up period. We have excluded patients with high refractive errors ( 76 diopters), those with prior history of ON, or patients with other neurological diseases and/or disease of the retina and optic nerve. Furthermore, OCT on 40 eyes of 20 healthy controls was performed for baseline comparison with our cohort. This study was approved by the local ethical committee and was conducted in accordance with the declaration of Helsinki for biomedical research. 2.1. Statistical analysis All statistical analyses were completed using JMPs (SAS Institute Inc., Cary, NC). An Independent t-test was used to determine the difference in RNFL, central macular thickness (CMT) and GCIPL between patients and healthy controls. Paired t-test was used to determine the difference between the onset, 3 months and 6 months follow-up period to evaluate the difference in RNFL, CMT and GCIPL. Data were represented in mean and standard deviation for both the t-tests. Statistical significance was defined as P o0.05.
3. Results The study subjects comprised 6 females and 4 males with the mean age (standard deviation) of 26.8 years (1.7) Six patients had MRI brain lesions consistent with demyelination while 4 had normal brain MRI. Of the six patients who had MRI brain lesions, only 1 satisfied the 2010 McDonald criteria for MS. (Polman et al., 2011) Data of three patients were not available for the 3 month OCT follow up. All patients received IV Methylprednisolone (one gram once daily for 3–5 days) for treatment of acute ON. Patients' affected (n ¼10) and unaffected (n ¼10) eyes were included in final analysis. The clinical characteristics of study subjects are summarized in Table 1. Using the independent t-test at baseline, the mean GCIPL was significantly lower at onset in patient with affected eyes compared to healthy control (p ¼0.009), while RNFLT
Fig. 1. A box-plot showing ganglion cell and inner plexiform layer (GCIPL) thickness in micrometer between control onset and patient onset (p ¼ 0.009).
and CMT were not (Table 2, Fig. 1). Paired t-test was done to compare the difference between onset, 3 months and 6 months follow-up period and both RNFLT (p ¼0.012; Fig. 2A) and GCIPL (p ¼0.007; Fig. 2B) were significantly lower in affected eyes at 6 months compared to onset (Table 3a). There was a trend for GCIPL to be thinner in the patients' unaffected eyes compared to controls (p ¼0.068) but that did not reach statistical significance. Similarly, RNFL and CMT were not significantly thinner at onset in patients' with unaffected eyes compared to healthy controls at onset, 3 months and 6 month follow up (Table 3b).
4. Discussion We have found that GCIPL was significantly thinner at onset of optic neuritis in the involved with a trend to significance in the non-involved eye when compared to healthy controls. Peripapillary RNFL and CMT were not significantly different at onset in either the affected eyes or unaffected eyes compared to healthy controls.This suggests that GCIPL is a more sensitive index for early axonal loss in acute optic neuritis . Both GCIPL and RNFL were significantly thinner at 6 months compared to baseline. Although we cannot determine the exact time at which GCIPL thinning starts because of the variable points in the time window in which SDOCT was obtained, we speculate that most of the thinning of GCIPL takes place between onset and 3 months while RNFLT thinning progressed over the follow-up period. (Fig. 2A and B) Previous studies have shown that RNFL thinning progresses up to 6 months. (Costello et al., 2006, 2011). While GCIPL thinning starts around 3 months in other studies, we have found that in some
Table 2 Independent t-test shows the measurements of the RNFLT, CMT and GCIPL in the affected and unaffected eyes between studied control and patients. Affected eyes
RNFLT (μm) CMT (μm) GCIPL (μm)
Unaffected eyes
Control Onset Mean 7 SD
Patient Onset Mean 7 SD
P value
Control Onset Mean 7 SD
Patient Onset Mean 7 SD
P value
94.9 7 6.0 244.37 20.0 84.17 3.5
90.9 7 13.5 241.5 7 19.4 75.17 8.6
0.385 0.686 0.009
94.9 7 6.0 244.37 20.0 84.17 3.5
89.6 7 15.0 242.47 14.9 77.0 7 10.8
0.302 0.735 0.068
SD ¼ Standard deviation; RNFLT ¼Peripapillary Retinal Nerve Fiber Layer Thickness; CMT ¼ Central Macular Thickness; GCIPL ¼ Ganglion cell and Inner Plexiform Layer; μm¼ micrometer.
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R. Behbehani et al. / Multiple Sclerosis and Related Disorders 5 (2016) 66–69
Fig. 2. A: A graph showing Retinal Nerve Fiber Layer (RNFL) thickness in patient with affected eyes at onset and 6 months follow-up (p ¼0.012). B: graph showing ganglion cell and inner plexiform layer (GCIPL) thickness in patient with affected eyes at onset and 6 months follow-up (p ¼0.007). Table 3a Paired t-test shows the measurements of the RNFLT, CMT and GCIPL in the affected eyes over the onset, 3 months (3M) and 6 months (6M) follow-up period Onset to 3 Months (3M)
RNFLT (μm) CMT (μm) GCIPL (μm)
3M to 6 Months (6M)
Onset to 6M
Onset
3M
P value
3M
6M
P value
Onset
6M
P value
90.9 7 13.5 238.9 7 23.1 74.0 7 9.6
83.4 7 11.1 239.1 716.3 70.67 7.9
0.119 0.937 0.267
83.4 711.1 239.17 16.3 70.6 7 7.9
82.0 7 14.1 239.1 714.8 67.8 7 9.6
0.405 0.357 0.120
90.9 713.5 238.9 723.1 74.0 7 9.6
82.0 7 14.1 239.17 14.8 67.8 7 9.6
0.012 0.278 0.007
Table 3b Paired t-test shows the measurements of the RNFLT, CMT and GCIPL in the unaffected eyes over the onset, 3 months (3M) and 6 months (6M) follow-up period Onset to 3 Months (3M)
RNFLT (μm) CMT (μm) GCIPL (μm)
3M to 6 Months (6M)
Onset to 6M
Onset
3M
P value
3M
6M
P value
Onset
6M
P value
89.6 715.0 242.47 14.9 77.0 710.8
83.1 712.4 238.7 7 19.6 75.4 7 11.3
0.022 0.383 0.839
83.1 712.4 238.7 7 19.6 75.4 7 11.3
89.0 7 16.2 244.07 15.3 76.7 7 10.9
0.458 0.714 0.231
89.6 7 15.0 242.47 14.9 77.0 7 10.8
89.0 7 16.2 244.07 15.3 76.7 7 10.9
0.197 0.721 0.419
SD ¼ Standard deviation; RNFLT ¼Peripapillary Retinal Nerve Fiber Layer Thickness; CMT¼ Central Macular Thickness; GCIPL ¼ Ganglion cell and Inner Plexiform Layer; μm¼ micrometer.
Fig. 3. (A) (Top) shows RNFL pattern deviation map (left) and RNFLT quadrants and (B) (Bottom) shows ganglion cell deviation map (left) and thickness sectors (right) , at onset and 6 months. Areas highlighted represent o 1% of distributixon of normal values of same age and sex and indicate thinning. There is increased thickness in the RNFLT quadrants at onset (axonal swelling) while (B) there is already ganglion cell layer thinning seen in the deviation map and thickness sectors. The ganglion cell thickness remains stable while the RNFL swelling subsides at 6 months and is still within normal.
R. Behbehani et al. / Multiple Sclerosis and Related Disorders 5 (2016) 66–69
cases it starts as early as the first 1–2 weeks and the thinning continues to around 3 months and changes less after that compared to RNFLT (Syc et al., 2012) (Fig. 3). Recently , Rebolleda et al. reported four cases with acute anterior optic neuritis in whom (GCIPL) thinning was detected weeks before RNFL loss and concluded that GCIPL analysis may provide more accurate information than RNFLT about neuronal loss (Rebolleda et al., 2015) . While other studies have demonstrated that GCIPL was thinner in ON patients with and without a history of ON when compared with healthy controls, they have included in their cohorts a significant proportion of patients with existing MS, which may have confounded their findings (Syc et al., 2012; Davies et al., 2011). Our cohort though included 1 patient who had met the revised 2010 McDonald diagnostic criteria for MS, is composed predominantly of CIS patients (Davies et al., 2011). We found that there was a trend for GCIPL to be thinner in the unaffected eye compared to healthy controls (p o0.068). Previous studies using time-domain OCT (TDOCT) did not find evidence of peripapillary RNFL or macular thickness thinning in the non-affected eyes of patients with CIS optic neuritis when compared to healthy controls (Outteryck et al., 2009). A recent cross sectional study using SDOCT and retinal segmentation also detected thinning of the GCIPL in CIS eyes without clinical history of optic neuritis (Oberwahrenbrock et al., 2013). This can be explained by early neurodegenerative activity in CIS patients. An alternative explanation would be bilateral asymmetric optic neuritis or tran-synapatic degeneration arising from occult lesions and inflammation in the brain involving the posterior visual pathways rather than a direct, immune-mediated mechasnim (Sriram et al., 2012). We could not find a difference in the RNFLT between the affected (90.9 microns) and unaffected (89.6 microns) eyes at onset of ON. Previous studies reported thicker RNFLT at onset in the affected compared to the unaffected eyes. Our cohort did not demonstrate marked early RNFL thickening. (Syc et al., 2012). However, we cannot rule out the possibility of missing the early axonal edema and RNFL thickening since the timing of the first OCT was not standardized and this varied from 4 to 35 days. Our pilot study has several limitations including small sample size, and relatively short follow up duration. Our control group was slightly older than
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other cohorts but the difference was minor and that probably adds more strength to the findings. ON is the best studied CIS and it can serve as a good model for studying neurodegeneration and the effects potential neuroprotective drugs. This pilot study along with other prior studies suggest that measuring the GCIPL can provide early assessment of neurodegenration (Garas et al., 2011). Future prospective studies are needed to assess the change of GCIPL and the effects of neuroprotective agents in patients with ON.
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