Quantitative Assessment of Optic Disc Elevation in Idiopathic Intracranial Hypertension

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1 Med. J. Cairo Univ., Vol. 81, No. 1, September: , Quantitative Assessment of Optic Disc Elevation in Idiopathic Intracranial Hypertension AHMAD M.M. SHALABY, M.D.*; MOHAMMAD A. NASR, M.D.**; NEVIN M. SHALABY, M.D.***; ASMAA M. EBRAHEIM, M.D.*** and REHAM SHAMLOUL, M.D.*** The Departments of Ophthalmology*, Ophthalmic Diagnostic & Laser Unit (DL U)**, Kasr Al Aini Teaching Hospital and Neurology***, Faculty of Medicine, Cairo University Abstract Introduction: Quantification of optic disc elevation in papilledema may predict CSF opening pressure. Objective: To correlate height of papilledema in idiopathic intracranial hypertension (IIH) to cerebrospinal fluid (CSF) opening pressure and visual function and monitor its rate of resolution. Design: Cross-sectional ecological study. Patients and Methods: Twenty female patients with IIH with a mean age of 29.8±5.8 years and mean body mass index (BMI) of 37.3±5.5Kg/m 2 underwent general and neuroophthalmological assessment, brain CT/MRI and magnetic resonance venography (MRV), visual field testing, lumbar puncture (LP) with measuring of CSF opening pressure, and optical coherence tomography (OCT) to measure degree of optic disc elevation at presentation, 3 and 7 days post LP and after 3 and 6 weeks, with clinical follow-up. Results: Mean optic disc elevation from retinal surface to summit pre-lp was 469±216.5tim and mean CSF opening pressure was ±93.85mmH 2 0; they did not correlate with each other. Visual field losses and visual acuity (VA) did not correlate with optic disc height, but correlated positively with CSF opening pressure. The mean optic disc elevation was significantly lower 3 days post-lp and after 6 weeks from treatment compared to pre-lp. Repeated therapeutic LP showed a higher rate of resolution relative to acetazolamide alone. Conclusion: The height of papilledema in IIH is not indicative of CSF opening pressure or visual function. OCT is a beneficial tool for monitoring resolution of papilledema and hence therapeutic efficacy through measuring disc height. Resolution of papilledema is attained within 6 weeks with proper therapeutic measures. Key Words: Optic disc elevation Idiopathic intracranial hypertension. Correspondence to: Dr. Ahmad M.M. Shalaby, The Department of Ophthalmology, Faculty of Medicine, Cairo University Introduction A HALLMARK of idiopathic intracranial hypertension (IIH), is papilledema which is nearly always bilateral, although may be asymmetrical ill. Unfortunately, identification of papilledema in the neurological clinic requires experienced ophthalmoscopic examination. Evaluation is qualitative and subjective and up to 6% of IIH patients do not present with clinical papilledema [2]. Monitoring of IIH using visual field testing provides functional information concerning the degree of optic nerve damage and the change of papilledema over time, therefore provides a useful structural measure of the clinical course and effect of treatment [3]. Optical coherence tomography (OCT) is a promising objective examination modality for optic disc evaluation in IIH with superior sensitivity compared to direct ophthalmoscopy, and fundus photography. Moreover, it improves the identification of subtle disc swellings and measures changes over time [4]. The technique of OCT has been developed for noninvasive cross-sectional imaging in biological systems. OCT produces a two-dimensional image of optical scattering from internal tissue microstructures in a way similar to ultrasonic pulse-echo imaging. OCT has longitudinal and lateral spatial resolutions of a few micrometers [5] (Fig. 1). The rational of this study was based on two main themes; the first is that lumbar puncture may be painful, technically difficult to perform, and may cause a low-pressure headache ill. So, trying to find a means to predict the CSF opening pressure indirectly warrants investigation. Another point is about the frequently raised question: When papilledema is expected to resolve? This study aims at correlating the height of papilledema in IIH patients 643

2 644 Quantitative Assessment of Optic Disc Elevation to CSF opening pressure and visual function, and monitoring the rate of resolution of papilledema utilizing OCT. Subjects and Methods The study included 40 papilledemic eyes of 20 female patients with IIH, according to modified Dandy criteria [2], who were recruited from Kasr Al-Aini Neurology outpatient clinic during Their age ranged from years with a mean of 29.8±5.8 years. Patients were excluded if they had ventricular enlargement or mass lesion on brain imaging, evidence of venous sinus thrombosis on MRV or abnormal CSF chemistry. Patients were compared according to certain characteristics including history of intake of hormonal contraception (estro-progestinic drugs), and disease duration, where they were divided into two groups of <1 year and >1 year duration. The study was performed following all the guidelines for experimental investigations required by the Ethics Committee of Faculty of Medicine, Cairo University. All patients underwent: Clinical assessment including history taking and general medical examination including measuring blood pressure as well as weight and height to calculate BMI in Kg/m 2. Proper neurological examination was done to exclude deficits that may indicate focal brain lesions. Thorough neuro-ophthalmological examination was carried out for 40 eyes which were evaluated for best corrected visual acuity using Snellen chart, ocular motility, pupillary reactions, intraocular pressure and degree of papilledema using indirect ophthalmoscopy. Papilledema was graded into grades I, II, III, IV, and V according to Frisen [6]. Visual field testing was done using the Humphrey automated perimetry where the full threshold test 24-2 test strategy was used. It evaluates the mean deviation and pattern standard deviation (PSD) of retinal sensitivity (MD) in each eye, and the size of the blind spot. The PSD was used to evaluate the deterioration; the higher the PSD the more is the visual field deterioration ill. OCT to measure the degree of optic disc elevation (papilledema height) was carried out in the Ophthalmic Diagnostic and Laser Unit, Kasr Al-Aini Hospital using OCT/SLO (OTI, Toronto, Ontario) device. OCT was performed at initial presentation before performing lumbar puncture, 3days and 7 days after lumbar puncture and then by the end of the 3rd and 6th weeks. Disc elevation was measured from the retinal surface to summit in the superior, inferior, nasal and temporal quadrants, and then the mean disc elevation in the four quadrants was calculated. Brain Imaging by CT/MRI and MRV was done for all patients. Spinal tap was carried out for all patients. The procedure was explained to the patient. LP was done under complete aseptic conditions, the area was carefully prepared. The location of the needle was identified between the two spinous processes of L4 and L5 levels. A 20- gauge needle was used, CSF opening pressure was measured in the left lateral decubitus using a manometer, and CSF samples were obtained. Frequency of lumbar puncture and amount of CSF withdrawn was determined for each patient individually. Clinical follow-up for symptomatic improvement and fundus picture was done after 1 week, 3, 6 and 8 weeks. Treatment modality was reported and the dose of medical treatment and amount of CSF withdrawn were recorded. Statistical analysis: Descriptive analyses were conducted to examine frequencies; mean was used as measure of central tendency with standard deviation as measure of dispersion. Pearson correlation was used to study the relation between qualitative variables. To test the significance of difference between quantitative and qualitative variable t-test was used. Paired t- test was used to compare pre and post variables of the same patient. Results Patients and headache characteristics: The mean BMI for the patients was 37.3±5.5 Kg/m 2. The mean duration of the syndrome was 23.7±32.7 months, where 12 patients (24 eyes, 60%) reported <1 year duration and 8 patients (16 eyes, 40%) reported >1 year duration (one of them had a duration of 9 years). Eight patients only (16 eyes, 40%) received estro-progestinic drugs for hormonal contraception at a certain time in their lives for periods ranging from 4-24 months, but none of them was using it at time of presentation. History of menstrual irregularities was given by 10 patients (20 eyes, 50%), hormonal assay for whom was not done, being outside the scope of our study. Grade I papilledema was observed in 15 eyes (37.5%), grade II in 24 eyes (60%) and grade V in 1 eye (2.5%). Corrected visual acuity was 6/6 in 13 eyes (32.5%), 6/9 in 13 eyes (32.5%), 6/18 in 8 eyes (20%), 6/24 in 3 eyes (7.5%), 6/36 in 2 eyes (5%) and counting fingers at 50cm in 1 eye (2.5%) which had post papilledemic optic atrophy. The pattern standard deviation (PSD) of visual field testing of both eyes ranged from DB with a mean of 3.79±2.1 DB.

3 Ahmad M.M. Shalaby, et al. 645 Headache was the presenting symptom in all patients (100%), the main visual symptoms were blurring of vision in 18 patients (36 eyes, 90%) and transient visual obscurations in 10 patients (20 eyes, 50%), diplopia was reported by 2 patients (4 eyes, 10%), but no limitation of ocular motility was observed by time of examination, and diminution of VA was reported by one patient (2 eyes, 5%). Other associated symptoms included intracranial noises (10 patients; 50%); nausea (8 patients; 40%); phonophobia (3 patients; 15%); fatigue (4 patients; 20%); dizziness (3 patients; 15%) and photophobia (1 patient, 5%). The treatment modalities used were acetazolamide which was received by all patients (100%) at a mean dose of 1475±543mg, repeated therapeutic LP, carried out for 8 patients (40%) after the primary LP done with OCT, where the mean amount of CSF withdrawn was 140.8±40.7mm and lumboperitoneal shunt was done for 1 patient (5%). Corticosteroids were reserved to those who complained of diminution of VA, and in our series the only patient who had this complaint was diabetic. Pre-LP findings: Regarding the findings of OCT, the mean optic disc diameter of both eyes was 1.68±0.16mm, of the right eye 1.67±0.11mm, and of the left eye was 1.68±0.21mm with no significant difference between both eyes (p=0.9). The mean optic disc elevation from retinal surface to summit pre-lp was 469±216.5gm. It ranged from p,m in clinically diagnosed grade I papilledema and from gm in grade II. The right optic disc diameter showed inverse correlation with degree of disc elevation but this was far from statistical significance (r=-0.17, p=0.63) and no correlation was observed between optic disc diameter of both eyes and mean degree of disc elevation (r=0.24, 0.27). Pattern standard deviation (PSD) of retinal sensitivity did not correlate with either mean degree of disc elevation (r=-0.13, p=0.58) or optic disc diameter (r=0.26, p=0.25). No correlation was found between degree of disc elevation and VA (r=0.14, p=0.5), age (r=-0.27, p=0.21), BMI (r=-0.21, p=0.35). Mean optic disc elevation did not differ between patients with and without menstrual irregularities (p=0.63). However, patients who received hormonal contraception had higher mean disc elevation compared to those who did not receive (p=0.04). Regarding results of visual field testing in relation to patients and disease characteristics, PSD of retinal sensitivity correlated positively with BMI (r=0.46, p=0.04), and age of the patients but this latter relation did not reach statistical significance (x=0.43, p=0.05). No correlation was found between visual field deterioration and VA (r=0.36, p=0.11) or disease duration (r=-0.25, p=0.28). Post-LP findings: The CSF opening pressure ranged from mmH 2 0 with a mean of mmH 2 0; 10 patients had a CSF opening pressure of mmH20. No statistically significant correlation was found between mean degree of disc elevation and CSF opening pressure neither in the whole patient group (r=0.09, p=0.69) nor in the recently diagnosed ones alone (<1 year duration) (r=0.04, p=0.78). Also, the height of each disc sector individually (upper, lower, nasal and temporal) did not correlate with CSF opening pressure (p>0.05). CSF opening pressure did not correlate with optic disc diameter (r=0.28, p=0.20), however, it correlated positively with PSD of retinal sensitivity on visual field testing (r=0.49,p=0.02) and negatively with VA (r=-0.43, p=0.03). Mean CSF opening pressure did not differ between patients who received hormonal contraception compared to those who did not (p=0.7). A statistically significant correlation was found between CSF opening pressure and age of the patients (r=0.7, p=0.0001). CSF opening pressure tended to correlate positively with BMI but it hardly reached statistical significance (x=0.40, p=0.05). No correlation was found between opening pressure and disease duration (r=-0.06, p=0.79). The mean amount of CSF withdrawn on initial LP was 130.3±50.3mm. Disc elevation correlated inversely with amount of CSF withdrawn, however, this relation did not reach statistical significance (r=-0.21, p=0.42). The mean optic disc elevation was significantly lower 3 days after the initial LP (p0.01) (Fig. 2) and after 6 weeks from treatment (whether medical alone or accompanied with repeated LPs) (p0.02) compared to pre-lp measurement (Fig. 3). The disc elevation was also lower after 7 days and 3 weeks than pre-lp, yet the difference was not statistically significant (p0.06 and 0.71 respectively). Table (1) and Fig. (4) show the mean optic disc height pre-lp and serially after therapy. Patients who underwent repeated therapeutic LPs (n=8) showed a higher rate of papilledema resolution (percent of change of disc height) compared to those who underwent single diagnostic LP (received medical treatment only), however the difference did not reach statistical significance (p=0.07) (Fig. 5).

4 646 Quantitative Assessment of Optic Disc Elevation Fig. (1): An OCT tomogram of a normal retina NFL: Nerve fiber layer, RPE: Retinal pigmentary epithelium. Fig. (2): OCT 3 days post-lp. Fig. (3): Retinal OCT Pre-LP " 50 0 Pre-LP 3 days Post-LP Mean Disc Thickness) 7 7 days 3 weeks 6 weeks Post-LP Fig. (4): Serial mean optic disc height (um) by OCT during the follow-up period Single LP Repeated LP Fig. (5): Percentage of resolution of papilledema in patients who underwent single diagnostic LP compared to those who underwent repeated therapeutic LPs. Table (1): Mean optic disc height by OCT on serial measurements. Timing Mean (SD) Gm) p-value (In relation to Pre-LP measurement) Pre-LP 469 (216.5) 3 Days after initial LP 326 (190.5) 0.01 * 7 Days after initial LP (202) weeks after initial LP 440 (224.9) weeks after initial LP 340 (172.6) 0.02* * Statistically significant. Discussion This study was directed to investigate the relation of CSF opening pressure to optic disc height in papilledema of IIH patients as well as to followup the rate of resolution of papilledema. The CSF opening pressure did not correlate with the mean degree of optic disc elevation even in the recently diagnosed patients (<1 year; to avoid possibility of gliosis of optic nerve head with long standing papilledema) [7]. This lack of significant correlation was also observed clinically; some patients with early papilledema had high CSF opening pressure

5 Ahmad M.M. Shalaby, et al. 647 and conversely others with evident mushrooming of optic disc exhibited modest pressure elevations. This agrees with what has been mentioned in literature that IIH could occur without papilledema; in a previous study 10% of 62 patients with headache had elevated CSF opening pressure but none of the patients had papilledema [8], implying that high CSF pressure does not necessarily have to be fully transmitted to the optic nerve head. This can be explained on the basis of anatomic and histological considerations; the lamina cribrosa is related to the direct transmission of elevated CSF pressure, a more posterior lamina cribrosa position is related to greater ophthalmoscopically non apparent edema [7]. Also, the prelaminar region of the optic nerve contains bundles of axons within astrocytic channels the processes of which form loose supportive glial tissue which does not bind the axon bundles tightly together, therefore fibers are easily separated and the disc swells easily in papilledema [9]. Radius and Gonzales [10] have confirmed a regional variation in the distribution of supportive glial and connective tissue between nerves of different individuals. These anatomic considerations can also contribute to asymmetrical bilateral papilledema. One study 1111 utilizing a comparable technique, which is laser scanning tomography (LST), could find significant linear correlation of the papilla height with the CSF opening pressure. This difference can be largely attributed to the use of various techniques. Though LST allows a 2.5-dimensional assessment of the papilla and its volume, yet OCT utilized in this study, has a superior axial resolution [12]. Another possible factor was that none of the patients in the other study had a CSF opening pressure higher than 400mm water, while in our study 10 patients had a CSF opening pressure of mm water. A further concern might be a potential ceiling effect, despite an increasing CSF opening pressure over 400mm water, the papilla volume and height would not be expected to reveal infinite linear correlation, but would instead converge to a limiting value of papilla volume and papilla height which seems logical for anatomic reasons [9]. On the other hand, Skau et al. [4], using OCT, reported that increased peripapillary retinal thickness measurements is closely associated with increased CSF opening pressure in newly diagnosed IIH patients. However, in patients with long-term IIH, OCT is of limited value in predicting intracranial pressure. The patient sample in that study was double the sample we studied. Also the OCT utilized, though a time domain one as the OCT we used; is a faster and more advanced machine and the authors used different measurement technique. We also investigated the effect of optic disc diameter as well as body mass index on degree of optic disc elevation, and we observed an inverse correlation between right disc diameter and disc height, but this was far from statistical significance. BMI had no influence on disc height though it tended to correlate positively with CSF opening pressure (p=0.05). This goes in accordance with Whiteley et al. [13] who stated that body mass index had a small but clinically insignificant influence on CSF opening pressure. No correlation was found between visual field losses and height of papilledema in the current work. Studies evaluating the correlation between degree of papilledema and visual field loss have reported different and, at least inpart, conflicting results. Although a qualitative correlation between high-grade papilledema and perimetric loss has been found by some investigators [14], Gael et al. [is], in accordance with our results did not find any quantitative correlation between Heidelberg retina tomograph measurements of disc swelling and automated field sensitivity. Mulholland et al. [16] reported that, in individual patients with IIH, changes in disc volume were qualitatively correlated with corresponding perimetric sensitivity changes in the short term. However, no quantitative correlations were reported, either in cross-sectional or longitudinal measurements. In this work, the VA did not correlate with degree of disc elevation. There is no evidence of whether functional damage is related mostly to the ophthalmoscopically apparent or non-apparent edema [7]. However, in another study vision tended to be worse in the eye with the high-grade papilledema [17]. Both visual field losses and visual acuity were worse with higher CSF pressure (p.02 and 0.03 respectively). Previous CT and MRI studies in patients with chronically high CSF pressure have postulated that the true edema has only a contributing role in disc elevation, indicating a bulging of the terminal optic sheath subarachnoid space into the posterior aspect of the globe at the optic nerve head as a major factor [18], thus another factor, in addition to edema, contributes to further compression of optic nerve axons in cases of high CSF pressure and hence worsening of visual function. In this work, more visual field losses were observed in patients with higher BMI who tended to have higher CSF opening pressure. An interesting finding was that patients who received hormonal contraception had statistically significant higher mean disc elevation compared to those who did not (p=0.04), however, they did not differ in CSF opening pressure. Yanoff and

6 648 Quantitative Assessment of Optic Disc Elevation Fine7 mentioned that in addition to blockade of the optic nerve axoplasmic flow at the level of lamina choroidalis and lamina scleralis through increased intracranial pressure, hormonal contraception induces local phenomenon at the lamina cribrosa, but they did not specify such phenomenon. A theoretically attractive concept, to explain this, can be the increasing incorporation of progesterone into estrogen contraceptive pills [19], it is known that high levels of estrogen and progesterone cause increased connective tissue laxity, as during pregnancy [20], this increased laxity may involve the optic nerve supportive tissue inducing more looseness of axon bundles and allowing easier separation and more swelling in cases of papilledema. However, all the patients in the current study were not on hormonal contraception at time of presentation or shortly before, and investigating such relation warrants further research as it is beyond the scope of this study. Another interesting finding was the presence of a statistically significant correlation between CSF opening pressure and age of the patients (r=0.7, p=0.0001). Although absorption of cerebrospinal fluid (CSF) occurs through arachnoid granulations and extracranial lymphatics, outflow resistance is increased in IIH; therefore, intracranial pressure must increase for CSF to be absorbed [21]. An MRI imaging-based study [22] showed that there was increased CSF production in aged subjects as compared with production in young subjects. Hence our result could be expected. The second objective in our study was to assess quantitatively the rate of resolution of papilledema following the primary LP and medical treatment. To serve this aim, patients were followed with OCT 3 days and 1 week after spinal tap and after 3 and 6 weeks. Disc elevation correlated inversely with amount of CSF withdrawn; however, this correlation did not reach statistical significance. Generally, the disc height showed fluctuation in the follow-up period (in comparison to pre-lp findings) to be at the lowest level 3 days post-lp (p=0.01); then a slight rise occurred after 7 days (p=0.06); a further significant rise occurred by 3 weeks which almost approached the pre-lp level (p=0.7), which can be attributed to: The reluctance of patients in receiving their medications due to improvement of symptoms and/or appearance of acral paresthesia caused by acetazolamide; under dosage of medical treatment; variable rate of reformation of CSF and the need for repeated lumbar punctures. At this point, strict instructions were given to patients to receive their medication regularly, potassium supplements were added, doses were readjusted, and repeated therapeutic LPs were done for selected patients, so by 6th week another remarkable decline in disc height was observed (p=0.02). The 8 patients who underwent repeated LP showed better resolution of papilledema than those who only performed the initial LP. This implies that OCT can serve in assessment of the efficacy of line of treatment used, thus can contribute to modification of dosage of medical treatment or recommends another line of treatment, this in agreement with Mulholland et al. [16] who used a comparable technique (confocal scanning laser tomography) to confirm therapeutic failure by detecting stable or increasing disc volume. Confocal scanning laser tomography can quantify the magnitude and monitor the resolution of papilledema in IIH. Studies of optic nerve head topography may provide further insight into optic nerve compliance with elevated intracranial pressure [4]. Patients were followed-up to 6 weeks. Papilledema showed evident resolution by the 6th week with our treatment policy. One patient presented with post-papilledemic optic atrophy and a VA of counting fingers at 50cm in right eye and deterioration of VA and grade II papilledema in the left eye underwent lumboperitoneal shunt, though the papilla height was comparable in both eyes, yet no improvement of VA in the right eye, while the left eye VA improved to 6/6 and fundus picture was almost normal after 1 month. This implies that disc height does not predict prognosis. Conclusion: The height of optic disc in papilledema of IIH patients does not necessarily reflect the CSF opening pressure or visual function; however, serial measurement of this height by OCT can be a useful tool for monitoring the therapeutic efficacy via observing the degree of decline or rise and accordingly helps adjusting treatment plan. Repeated therapeutic LPs result in a more rapid resolution of papilledema than acetazolamide alone. With proper plan of therapy the resolution of papilledema can be attained over 6 (provided the course is not malignant). OCT cannot replace the fundamental role of visual field testing. References 1- KANSKI J.J.: Clinical Ophthalmology, A systematic Approach. 5th ed. Butterworth Heinemann, Elsevier Science Limited, DIGRE K.B., NAKAMOTO B.K., WORNER J.E.A., LANGERBERG W.J., BAGGALEY S.K. and KATZ B.J.: A comparison of idiopathic intracranial hypertension with and without papilledema. Headache, 49: , 2009.

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