Dr. MOUSUMI BANERJEE

Dr. SWATI PHULJHELE

Semi Finals

Abstract

PURPOSE :To quantify the relationship between ONH

tomography with visual acuity (VA),contrast and perimetric sensitivity,VER in early and established

cases of papilledema in IIH at their presentation and at 6

months follow up .

METHODS: 27 patients with variable degrees of

recently diagnosed papilledema in IIH were evaluated.

RESULTS: At presentation, VA did not show any correlation

with any structural parameters. A negative correlation

between mean deviation with disc height (r=-0.46; p =

0.0005) and RNFL(r=-0.45;p=0.0007) and positive

correlation with RGCL(r=0.4;p=0.002) were

noted.

At 6 months, functional parameters had moderate correlation with baseline disc height and

RGCL thickness.

CONCLUSION: Structural parameters did not correlate with presenting visual

acuity. Mean deviation and contrast sensitivity could be better

functional parameters than visual acuity to prognosticate IIH.

RGCL and optic disc height may be better

predictors of functional outcome than RNFL.

Full Text

AIM : To determine the correlation between functional parameters and OCT features in patients of idiopathic intracranial hypertension (IIH).

METHODS : A prospective observational study in early and established cases of papilledema in IIH presenting from December 2017 to February 2019. The inclusion criteria were age>= 18yrs, diagnosed cases of IIH based on modified Dandy criteria^.. Functional parameters (visual acuity, contrast sensitivity , mean deviation, VER, MfERG) and structural parameters (RNFL,GCL-IPL AND optic disc height) were measured at baseline and at every 6 weeks for 6 months. . Patients were advised treatment in the form of weight loss, acetazolamide ranging from 750/day to 1.5mg/day as per response, and topiramate as advised by the neurologist.

RESULTS At baseline, average RNFL values had a moderate negative correlation with mean deviation (r=-0.45,p=0.0007) . RNFL and logMAR visual acuity had a positive co-relation (r=0.18; p=0.17), on the contrary baseline GCL and logMAR  visual acuity had a negative co-relation (r= -0.4, p=0.02). Optic disc height (ODH) had a negative correlation with mean deviation (r= -.046; p=0.0005) .

At six months, ODH values had a positive correlation with visual acuity in logMAR (r=0.43; p=0.001).GCL-IPL complex had a positive moderate correlation with contrast sensitivity (r=0.56; p <0.001) and mean deviation ( r-= 0.52; p <0.001).However, RNFL values did not show any significant correlation with any of the functional parameters.

Baseline GCL-IPL  and optic disc height values  had a moderate and significant correlation with final functional parameters. However, RNFL did not show any correlation.

Correlation between 6 weeks GCL-IPL and final functional parameters were stronger than that of baseline GCL values.

CONCLUSION: In the setting of severe papilledema, RNFL can misguide the prognosis. Despite the limitation, the GCL-IPL thickness can be a valuable tool for an objective evaluation of the integrity of the optic nerve in patients with IIH and ODH may be used as an alternative or in combination with GCL-IPL in these cases.

 Introduction

Optical coherence tomography (OCT) is a non-invasive, noncontact trans-pupillary imaging technology providing high resolution, cross-sectional images of ocular and biological structures to visualize and measure anatomic layers of the retina. It is a useful investigation to diagnose and monitor the cases of papilledema.[1,2]

Serial monitoring of peripapillary Retinal Nerve Fibre Layer (RNFL) thickness may provide a quantitative, objective, and sensitive measurement of changes in the papilledema [3] especially when the patient is seen by different care providers. A reduction in peripapillary RNFL thickness can be a result of the improvement of papilledema or worsening axonal loss from disease progression. Combining the macular ganglion cell layer-inner plexiform layer thickness (GCL-IPL) with the peripapillary RNFL thickness allows one to evaluate for optic neuropathy in the presence of papilledema.[4] Successful treatment with the protection of neuroaxonal structure will cause a reduction in the peripapillary RNFL thickness with a preserved macular GCIP thickness. However, a concordant reduction in the RNFL thickness and macular GCIP thickness indicates worsening optic neuropathy and could be an indication of treatment failure.[5]

Materials and Methods

The study was a prospective observational study done in a tertiary eye care center undertaken in early and established cases of papilledema in IIH recruited from the outpatient department and neuro-Ophthalmology clinic and neurology OPD of a tertiary care center presenting from December 2017 to February 2019.

Institutional ethics committee approval was obtained from the Institutional Review Board/Ethics Committee. The research was conducted adhering to the tenets of the Declaration of Helsinki and informed consent was taken from the patients and healthy controls. The inclusion criteria were age>= 18yrs, diagnosed cases of IIH based on modified Dandy criteria^.,[6]early and established cases.

Patients with evidence of hydrocephalus, space-occupying lesion, structural/vascular lesion, venous sinus thrombosis on MRV, pre-existing optic neuropathies including glaucoma and glaucoma suspects, dense media opacification (e.g. cataract) precluding precise ocular and OCT examinations, patients with chronic and atrophic papilledema and patients not willing giving consent were excluded from the study.

Details regarding the onset, progression and duration of symptoms, and presence of pre-existing co-morbidities were recorded. Patients were advised treatment in the form of weight loss, acetazolamide ranging from 750/day to 1.5mg/day as per response, and topiramate as advised by the neurologist.

Best-corrected visual acuity was recorded with the ETDRS chart (Early Treatment Diabetic Retinopathy Study).Slit-lamp anterior segment examination and posterior segment examination was performed by 90D slit lamp bio-microscopy. Magnetic resonance Imaging with contrast was performed to rule out any space-occupying lesion. Optic nerve function tests were performed which included color vision (Ishihara pseudo isochromatic plates1997 version; Kanehara & Co., Ltd., Tokyo, Japan), contrast sensitivity (Pelli-Robson chart), and visual field charting (30-2 SITA Standard, Humphrey, San Leandro, CA).Pattern-reversal Visual Evoked Response(VER) and multifocal electroretinogram (Metrovision Monpack, Pierenchies, France) were also performed.

Spectral-domain OCT (Cirrus HD-OCT Model 4000;Carl Zeiss Meditec Inc., Dublin, CA) was performed in all cases and controls. Retinal nerve fiber layer thickness was measured with the RNFL scan centered on the optic disc (optic disc cube 200 x 200 volume scans ), average RNFL values were used for final correlation. Macular Ganglion Cell Layer-Inner Plexiform Layer . thickness was evaluated with the help of the automated algorithm of  Cirrus HD-OCT Model 4000 (Carl Zeiss Meditec Inc., Dublin, CA) centered on the fovea (512 x 128 volume scans ). For optic disc height (ODH) 5 line raster scan with 5 horizontally oriented line of length 9 mm, separated by 0.5 mm spread across the entire surface of the optic disc was used and was measured by manually placing a vertical line from a line connecting the RPE layer, temporal and nasal neural canal borders to the top of ONH. The average value of the 5 lines was considered to be the mean optic disc height.[7] All scans had a signal strength of a minimum of 6 and scans were repeated if any motion artefact was noted.(Figure 1)

The ocular parameters were measured at baseline and every 6 weeks for 6 months.

Analysis

The data was collected in a predesigned proforma and spread on Microsoft Excel Worksheet and statistical analysis of the study was done using SPSS IBM Statistical Package software version 21.0. Descriptive statistics; mean, median, range were used to summarize the various variables at baseline and 6 months. Mann Whitney test and student t-test were used for comparing non-parameteric and parametric data. Multiple linear regression was done to analyze the changes in various parameters for 6 months. Correlation between two variables was analyzed with Spearman correlation and Pearson correlation for non-parametric and parametric data respectively. The p-values of<=0.05 were considered to be significant.

Results

The mean age of patients in our study was 31±7.53 years, our study included 21 females and 6 males. The mean duration of symptoms in our cases was 4.5 months. Headache constituted the most common symptom which was present in 90.7% of our cases followed by transient visual obscuration (TVO) in 40.7%. Other symptoms were diminution of vision in 29% and diplopia in 20.3%.

There was a significant difference in OCT and functional parameters between cases and control at baseline (table 1).  A  reduction in RNFL thickness and disc height was noted over 6 months.

Table 1 : Structural and functional parameters between cases and controls at baseline

and at 6 months

STRUCTURAL PARAMETERS	CASES at baseline (N=54EYES)	CONTROLS  at baseline (N=80EYES)	P VALUE	CASES  at 6 months	CONTROLS at 6 months	P value
RNFL (µm)	269.97 ±91.09	88.11 ±2.17	<0.001	93.35±27.58	88.11±2.17	0.16
RGCL-IPL complex ( µm)	63.35 ±23.58	79.85 ±3.31	<0.001	73.96±11.11	79.85±3.3	0.0003
Optic disc height(µm)	1053.18 ±207.03	0	<0.001	444.44±218.66 (median :448)	0 ±0	<0.0001
FUNCTIONAL PARAMETERS
BCVA (logMAR)	0.13± 0.16	0±0	<0.001	0.02±0.06 (median :0)	0±0	0.01
Contrast sensitivity	1.466±0.028	1.66±0.005	<0.001	1.59±0.10	1.66±0.03	<0.0001
Colour Vision	Normal-75.93% Abnormal -24.07%	Normal-100%	–	Normal- 92% Abnormal-8%	Normal-100%	–
Mean deviation	-9.92±6.82	-1.90 ± 0.441	<0.001	-4.60±5.5 (median :              -2.95)	-1.90±0.44	0.0045
Pattern standard deviation	6.21±0.45	1.85±0.45	<0.001	3.51± 0.51	1.85±0.45	<0.001
VER amp P100(µV)	7.13±3.14	14.70±1.03	<0.001	11.33±3.75	14.70 ±1.03	<0.0001
VER latency P100(ms)	121.10±10.82	100.53±2.12	<0.001	107.59±8.95	100.53±2.12	<0.0001
mfERG P1amp(NV)	895.16±53	1669.85±284.19	<0.001	1303.88±565.72	1669.85±284.19	<0.0001
MfERG P1 IT(ms)	48.035±3.959	42.466±0.917	<0.001	44.17±1.84	42.46±0.917	<0.0001

Correlation At baseline

At baseline, average RNFL values had a moderate negative correlation with mean deviation (r=-0.45,p=0.0007) and a moderate positive correlation with VER P100 latency ( r=0.35;p=0.008). At baseline RNFL and logMAR visual acuity had a positive co-relation (r=0.18; p=0.17), on the contrary baseline GCL and logMAR  visual acuity had a negative co-relation (r= -0.4, p=0.02). Baseline GCL-IPL thickness values had  moderate positive correlation with contrast sensitivity (r=0.34;p=0.01) and mean deviation (r=0.4;p=0.002) and a negative moderate correlation with mfERG implicit time(IT) of P1 wave (r=-0.41;p=0.0019). Optic disc height at baseline had a negative correlation with mean deviation (r= -.046; p=0.0005) and a positive moderate correlation with VER P100 latency (r=0.55;p<0.001). (Table 2) 

Correlation At 6 months

At six months, optic disc height values had a positive correlation with visual acuity in logMAR (r=0.43; p=0.001).GCL-IPL complex at six months had a positive moderate correlation with contrast sensitivity (r=0.56; p <0.001) and mean deviation ( r-= 0.52; p <0.001).However, RNFL values did not show any significant correlation with any of the functional parameters at six  months.(Table2)

Table 2: Correlation between structural and functional parameters at  baseline and at 6  

 Months

AT BASELINE

Structural parameters	Visual acuity	Contrast sensitivity	Mean deviation	VER P100 amp	VER P100 latency	mfERG P1 amp	mfERG P1 implicit time
1.RNFL	r =0.18; p=0.17	r=-0.12; p=0.36	r=-0.49; p=0.0007	r=0.06; p=0.6	r=0.35; p=0.008	r=-0.13; p=0.34	r=0.16; p=0.24
2.GCL-IPL	r=-0.4; p=0.02	r=0.34; p=0.01	r=0.4; p=0.002	r=0.12 ; p=0.4	r=-0.25; p=0.07	r=0.02 ; p=0.85	r=-0.4; p=0.001
3.OD height	r=0.16; p=0.23	r=-0.22;  p=0.1	r=-0.5; p = 0.0005	r=-0.21; p=0.1	r=0.55; p=<0.0001	r=-0.28;     p = 0.03	r=0.27;       p = 0.04

AT 6 MONTHS

Structural parameters	Visual acuity	Contrast sensitivity	Mean deviation	VER P100 amp	VER P100 latency	mfERG P1 amp	mfERG P1 implicit time
RNFL	r=0.03; p=0.78	r=0.2; p=0.1	r=0.17; p=0.2	r=-0.17;  p=0.2	r=-0.33; p=0.01	r=-0.35; p=007	r=-0.2; p=0.14
GCL-IPL	r=-0.28; p= 0.03	r=0.54; p<0.0001	r=0.52; p<0.0001	r=-0.17; p=0.2	r=-0.27; p=0.04	r=0.02; p=0.88	r=0.01; p=0.9
OD height	r=0.4;   p= 0.001	r=-0.01; p=0.9	r=-0.12; p=0.34	r=-0.19; p=0.16	r=-0.18; p=0.18	r=-0.13; p=0.32	r=0.1; p=0.4

Baseline structural parameters vs final outcome correlation

Baseline GCL-IPL  and optic disc height values  had a moderate and significant correlation with final  mean deviation (r=0.354;p=0.006 and r=-0.44; p =0.0007 respectively),contrast sensitivity (r=0.33;p=0.01 and r=-0.35; p=0.01 respectively),visual acuity ( r=-0.37;p=0.005 and r=0.41;p=0.002 respectively) whereas RNFL did not show any correlation with final functional parameters in our study. The co-relation between structural and functional parameters at different time points have been summarized in Figure 3. In addition to correlation with baseline GCL-IPL we correlated the visual function with GCL-IPL at 6 weeks. The correlation coefficient and p value for visual acuity, mean deviation and contrast sensitivity was r = -0.34, p=0.01; r = 0.44, p<0.001 and r = 0.45, p<0.001 respectively.

Discussion

The emerging popularity of the use of OCT in neuro-ophthalmic disorders is due to its ability for excellent imaging of each layer of the retina and optic disc. The present study was conducted to observe the changes in OCT parameters and their relationship with the functional parameters.

RNFL thickness is a commonly used parameter for the detection and monitoring of papilledema. RNFL thickness is increased in patients with IIH due to the axoplasmic flow stasis [8] and in both short and long term follow up, RNFL thickness has been noted to normalize [9]. In the present study, the RNFL thickness was significantly higher than control at the baseline and progressively decreased over 6 months suggestive of resolution of papilledema.

Unfortunately, the OCT-derived RNFL thickness alone sometimes does not differentiate treatment response from the development of optic atrophy.[10]Ganglion cell layer–inner plexiform layer(GCL-IPL) specifically helps to evaluate the integrity of the optic nerve in the setting of disc edema.[5] Thinning of the GCL-IPL complex in presence of normal RNFL may be suggestive of optic atrophy.[1]In our study, we found that mean GCL-IPL thickness was significantly low as compared to controls at baseline as well as at 6 months follow-up, while the RNFL thickness at 6 months was not significantly different from the control group.59.25% of patients had GCL within 2SD of the control group, 40.74% had lower value at 6-month follow up. A similar observation has been made by Bianchi et al and Dalia et al where they have reported that  10% and 13% of their patients respectively  in various stages of papilledema had thinner GCL-IPL even when the RNFL was still elevated.[11,12] Athappilly G also reported a similar observation in their 18 patients where they found  GCL-IPL was significantly thinner than the control group at all time points, while RNFL was significantly thicker at initial stages.[13] Interestingly, on the linear analysis, we found that GCL-IPL thickness showed  statistically significant improvement from baseline value  to  that of six weeks follow up, followed by  an improving trend over the six months though the difference was not significant after six weeks.

Both RNFL and GCL-IPL layers showed a significant correlation with mean deviation at baseline. GCL-IPL also showed a moderate correlation with visual acuity and contrast sensitivity at baseline. At 6 months RNFL did not show a significant correlation with any of the visual functional parameters. At six months GCL-IPL layer showed moderate correlation with mean deviation and contrast sensitivity , thus the role of GCL IPL thickness as a structural  parameter for  indirect assessment of functional parameters cannot be ruled out.

Rebolleda et al in their study found a significant correlation between baseline RNFL and  final mean deviation at one year. They reported that the mean RNFL at 1 year had normalized in 90% of eyes with a statistically significant inverse correlation with baseline mean deviation.[14]Skau et al also reported a similar correlation between change in RNFL over 3 months with change in mean deviation.[15] Both of these studies were done on the stratus model of OCT in which  GCL-IPL evaluation was not available. To understand the predictive value of baseline OCT parameters, a correlation between the baseline structural parameters  with the final visual functions were sought. Baseline GCL-IPL values showed a significant correlation with the final visual acuity, mean deviation, and contrast sensitivity. However, baseline RNFL thickness did not show a statistically significant correlation with any of the final visual functional parameters. Since there was a significant improvement in the GCL-IPL layer between baseline and 6 weeks follow up, we correlated the final functional parameters with GCL-IPL at 6 weeks and interestingly the relationship was stronger at this time point (visual acuity r = -0.34, p=0.01; Mean deviation r = 0.44, p<0.001 and  contrast sensitivity r = 0.45, p<0.001). Athappilly G et al in their retrospective study also found that baseline RNFL did not correlate with the final mean deviation (r=0.012; p=0.95). Nonetheless, they also observed that the GCL-IPL layer thickness at the second visit significantly correlated with final mean deviation albeit at one year (r=0.47;p=0.007).[13]Chen et al in their retrospective study of 31 patients with visual acuity of less than 25/20, also observed a similar relationship between the mean deviation and GCL-IPL measured by Iowa protocol. Interestingly they also found that GCL-IPL at 2-3 weeks correlated better with the final visual outcome.[5]

Even though all these studies including the present study have heterogeneity in their methodology, the results indicate that GCL-IPL may be used as a marker to predict the final visual outcome in patients of IIH. Contrary to these results, IIHTT has reported no significant correlation between OCT parameters and visual function. The study included patients with only mild visual field defects (PMD of −2.00 dB to −7.00 dB) which might explain the dissimilar results.

The Iowa 3D segmentation protocol to measure RNFL and GCL-IPL requires superior technical skills and is time-consuming to be replicated in a busy outpatient department. However, optic disc height (ODH) evaluated by IIHTT using 5 line raster scan seemed to be a faster and simpler method of assessment of optic disc edema. The optic disc height was measured manually for each line and an average of 5 lines was considered for final evaluation. The study reported a strong correlation of ODH with peripapillary RNFL thickness and total retinal thickness.[7]. In our study, we followed the same method and found a strong and significant correlation of ODH with RNFL and GCL-IPL layer[0.622 (<0.001) and -0.604 (<0.001)]. ODH gradually decreased over 6 months and showed a good correlation with visual functional parameters. At baseline it had a significant negative correlation with mean deviation (r= -.046; p=0.0005) and a positive moderate correlation with VER P100 latency (r=0.55;p<0.001). At six months, it had a positive correlation with visual acuity in logMAR (r=0.43; p=0.001). The baseline ODH showed moderate and significant correlation with mean deviation (r=-0.44; p =0.0007), contrast sensitivity (r=-0.35; p=0.01),visual acuity (r=0.41;p=0.002) which was equal (or marginally more) to that of GCL-IPL layer in strength. These results suggest that till a more robust segmentation algorithm for measurement of RNFL and GCL layer becomes available, ODH may be used as a tool to monitor and prognosticate patients of IIH.

Limitations of our study include relatively small sample size and use of the commercial algorithm for measurement of RNFL and GCL layer.

Conclusion

It is a matter of time before the commercially available algorithms become more reliable because of the increased resolution of OCT and improved segmentation algorithms. For the time being, it is important to be able to identify artifacts in the GCL-IPL measurements, particularly in presence of disc edema. In the setting of severe papilledema, RNFL can misguide the prognosis. Despite the limitation, the GCL-IPL thickness can be a valuable tool for an objective evaluation of the integrity of the optic nerve in patients with IIH and ODH may be used as an alternative or in combination with GCL-IPL in these cases.

References

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