DOI: https://doi.org/10.21203/rs.2.9467/v1
Visual field defects observed in patients with pituitary adenoma are thought to result from compression of the optic chiasm, the displacement of which is evidenced on magnetic resonance imaging (MRI). 1 It has been demonstrated that chiasm compression from below generates significantly elevated tissue pressure in the central portion of the chiasm, where the nasal halves of the left and right optic nerve fibers cross to the contralateral optic tracts. 2 The crossing nerve fibers corresponding to the temporal hemifield of vision in the left and right eyes are dominantly damaged.
While bitemporal visual field defects are characteristic in pituitary adenoma cases, it is rare to have complete bitemporal hemianopsia that is symmetrical in both eyes and has absolute scotoma throughout both temporal hemifields. 3 It has been reported that an asymmetric tumor location that affects the optic pathway in the coronal section on MRI could predict left-right asymmetry in visual field defects. 4 Unequal visual field defects in left and right eyes have also been described in the literature as well as several textbooks. 5-8
Not only is inter-eye asymmetry present between left and right eyes, but intra-eye or upper-lower asymmetry may also be present. Visual field defects tend to show an upper-to-lower progression in the temporal hemifield and lower-to-upper progression in the nasal hemifield. 9 Prior damage in the lower part of the nasal hemifield related to uncrossed fibers in the optic chiasm may be caused by ischemia in the upper part of the temporal chiasm, which is stretched due to upward displacement of the optic chiasm. 9Another possible mechanism of the lower-dominant visual field defects in the nasal hemifield may be compression of the prechiasmal optic nerve against the falciform ligament, which has recently been suggested in the neurosurgical literature of visual field defects.10-12
While several researches have investigated asymmetric visual field defects in patients with pituitary adenoma,4, 6, 13 no precise investigation with statistical analysis regarding the inter-eye and intra-eye symmetry of visual field defects has yet been reported. In this study, we conducted quantitative analysis to explore the asymmetric properties of visual field defects in pituitary adenoma patients.
Preoperative Humphrey 30-2 perimetry results were reviewed retrospectively using charts of pituitary adenoma patients who subsequently underwent surgery at the Department of Neurosurgery of the University of Yamanashi Hospital between June 2004 and July 2016. Patients had undergone a preoperative routine ophthalmic examination including visual acuity testing, slit-lamp examination, measurement of intraocular pressure, and funduscopic examination. Patients with glaucoma, retinal diseases, or optic nerve diseases causing visual field defects were excluded.
The perimetry results consisted of light sensitivity measurements at test points 6 degrees apart from each other in the central visual field (30-degree radius). Results were obtained using a Humphrey Field Analyzer (Zeiss-Humphrey Systems, Dublin, CA, USA) with either the Swedish Interactive Thresholding Algorithm (SITA)-standard, SITA-fast, or Fastpac protocol. Unreliable results with fixation loss greater than 20%, false positive error greater than 33%, or false negative error greater than 33% were not included in the analysis. 14 Eligible data were obtained from 28 patients (15 men and 13 women aged 28 to 78 years, median age = 58 years).
We evaluated light sensitivity values shown in the numeric display of Humphrey perimetry results at 74 locations in the visual field, excluding two points at 15 degrees temporal and 3 degrees superior or inferior, corresponding to Marriott’s blind spot. To investigate left-right asymmetry, we compared inter-eye light sensitivity at 36 test points in the temporal and at 38 test points in the nasal hemifields. We defined left-right asymmetry in the temporal or nasal hemifield as cases where light sensitivity in the left eye differed significantly from that in the corresponding hemifield of the right eye with a P-value < 0.05 (Mann-Whitney U test).
Upper-lower asymmetry was investigated in each patient’s worse eye, which had lower average light sensitivity at the 74 test points. In normal eyes light sensitivity differs in the upper and lower halves of the Humphrey 30-2 perimetry results,15 so we studied upper-lower asymmetry by comparing differences in the frequency of severe scotoma (light sensitivity of 5 dB or lower).
Statistical analyses were conducted using StatFlex (Version 6.0; Artec, Osaka, Japan).
Data were analyzed using the Mann-Whitney U test because the data did not appear to follow a normal distribution.
Left-right asymmetry
A representative case displaying left-right asymmetry is shown in Fig. 1a. Each light sensitivity value in the temporal hemifield of the left and right eyes (Fig. 1a, red boxes) is plotted in Fig. 1b, which indicates significantly lower sensitivity in the right eye (Mann-Whitney U test, P < 0.0001). The left-right differences in the nasal hemifields (Fig. 1a, blue boxes) shown in Fig. 1c were also significant (P = 0.0001), although less prominent.
Left-right asymmetry was observed in 17 cases (61%) in the temporal hemifield and in 16 cases (57%) in the nasal hemifield. Only six cases (21%) showed no left-right asymmetry in either the temporal or nasal hemifield. We therefore classified the 28 cases into four categories: asymmetric in both temporal and nasal hemifields (11 cases, 39%) (Fig. 2a); asymmetric only in the temporal hemifield (6 cases, 21%) (Fig. 2b); asymmetric only in the nasal hemifield (5 cases, 18%) (Fig. 2c); and not asymmetric in either hemifield (6 cases, 21%) (Fig. 2d).
Upper-lower asymmetry
The test points for severe scotoma, defined as a light sensitivity less than or equal to 5 dB, are shown as red circles in the numeric display of Humphrey 30-2 perimetry results in the representative case in Fig. 3. Average light sensitivity in the right eye (4.2 dB) was lower than in the left eye (12.0 dB), so in this case data from the right eye were analyzed to study upper-lower asymmetry.
The frequency of severe scotoma test points in the 28 cases is shown in Fig. 4. The value at each test point shows the percentage of patients with less than or equal to 5 dB light sensitivity at the corresponding test point in their worse eye.
Test points that show severe scotoma at frequencies of 50% or higher are observed in ten out of 18 (56%) points in the superotemporal quadrant but only three out of 18 (17%) points in the inferotemporal quadrant. The frequency of severe scotoma at the 18 test points in the superotemporal quadrant was thus significantly higher than in the inferotemporal quadrant (P = 0.00029, Mann-Whitney U-test; Fig. 5 left).
Although upper-lower asymmetry was less prominent in the nasal hemifield, the upper-lower relationship in the nasal hemifield was the inverse of the relationship in the temporal hemifield, with the frequency of severe scotoma being higher in the inferonasal quadrant compared to the superonasal quadrant (P = 0.00268, Mann-Whitney U-test, Fig. 5 right).
Clinical studies using Humphrey 30-2 perimetry in patients with pituitary adenoma have been reported by several researchers, including Lee et al 4 and Boland et al. 13 The former analyzed the Humphrey results qualitatively, classifying them as normal, unreliable, bitemporal, mixed (bitemporal and additional defects), monocular, homonymous, nonspecific, or other. The latter did not analyze light sensitivity itself using Humphrey 30-2 perimetry but rather the sum of the total or temporal scores of the neurologic hemifield test (NHT), which was assessed by the original ranking scales for probability of pattern deviation obtained from Humphrey 30-2 perimetry.
Total deviation, which is the reduction in dB below the expected age matched level, may be preferable to study light sensitivity at different test points in the visual field in many subjects of different age 16 because it eliminates age and eccentricity effects. In the current study we analyzed light sensitivity values instead of the total deviation because the objective of the study is inter-eye comparison of light sensitivity at corresponding test points in the same subjects. The results demonstrate that visual field defects were asymmetric between left and right eyes in about 80% of cases in the temporal or nasal hemifield or both.
Left-right visual field defect asymmetry may be caused by asymmetric enlargement of pituitary tumors, which is sometimes evidenced in the coronal section on MRI (Fig. 6). Lee et al 4 suggested that asymmetric compression of the chiasm by the tumor on MRI could predict visual field asymmetry with a sensitivity of 44% and with a specificity of 80%. Although statistical significance was not achieved (P = 0.06), Boland et al. 13 reported a possible relationship between tumor asymmetry on MRI and asymmetric visual field defects in the two eyes.
Apart from detailing temporal hemifield defects, the present study revealed that visual field defects extend into the nasal hemifield, which also demonstrates left-right asymmetry in many cases. Advanced bitemporal visual field defects seen in pituitary adenoma patients is likely to be followed by visual field loss in the nasal hemifield. 9 This could be attributed to damaged uncrossed nerve fibers, either because the growing pituitary tumor may successively damage directly the uncrossed fibers or because the growing tumor compresses the uncrossed fibers in the lateral part of the optic chiasm against the surrounding structures.
In terms of upper-lower asymmetry, it has been reported that the mean of the total deviation of Humphrey 30-2 perimetry results tends to be greater in the superotemporal quadrant compared to the inferotemporal quadrant, although statistical analysis failed to reveal significant differences. 17 In the present study, by investigating the frequency of severe scotoma instead of total deviation, we were successfully able to demonstrate statistically significant upper-lower asymmetry with upper-dominant deterioration in the temporal hemifield and lower-dominant deterioration in the nasal hemifield. While the upper-lower asymmetry was demonstrated with the definition of severe scotoma as light sensitivity of 5 dB or lower in the present study, the statistical results were the same when the threshold of zero dB or 10 dB was adopted as the definition of severe scotoma.
The pattern of asymmetry showing upper-dominant deterioration in the temporal hemifield and lower-dominant deterioration in the nasal hemifield may conform to Hedges’ report, 9 in which visual field damage in the inferonasal quadrant precedes damage in the superonasal quadrant. The mechanism for higher frequencies of severe scotoma in the inferonasal compared to the superonasal quadrant of the visual field may implicate compression of the prechiasmal optic nerve against the falciform ligament, which has been reported recently in neurosurgical literature. 10-12, 18
The optic nerve is roofed by the falciform ligament, which forms the sharp edge of a dural fold where it enters the optic canal anterior to the chiasm. It has been reported that compression of the optic nerve against the falciform ligament caused by the ectatic internal carotid artery may result in visual field defects, which could be resolved with microvascular decompression surgery. 11, 12, 18 Meningiomas that elevate the optic nerve from below and cause compression against the falciform ligament have also been reported to cause inferior altitudinal hemianopsia. 10 When the optic chiasm is elevated by an inferiorly-placed pituitary tumor, the superotemporal portion of the optic nerve fibers might become more damaged by the compression against the falciform ligament, leading to visual field damage in the inferonasal quadrant.
The limitations of the present study include its retrospective nature and relatively small amount of patient data. The data in the study were obtained using three different types of Humphrey algorithms. However we do not think that it would affect the comparison between right and left eyes, which were tested using the same algorithm. The order of perimetric examination of right to left or left to right was not controlled. The leaning effect in Humphrey perimetry might have influenced the results of inter-eye asymmetry. We were unable to use MRI data to assess horizontal tumor deviation and thereby investigate the relationship with left-right visual field defect asymmetry. Future large-scale prospective studies undertaken with the cooperation of neuroradiologists may be expected to lead to a more precise understanding of visual field defect pathophysiology in patients with pituitary adenoma.
Visual field defects observed in pituitary adenoma patients frequently exhibits inter-eye asymmetry in both temporal and nasal hemifields. Upper-lower asymmetry is also present, in which the upper quadrant in the temporal hemifield and the lower quadrant in the nasal hemifield are more severely damaged.
magnetic resonance imaging (MRI)
Swedish Interactive Thresholding Algorithm (SITA)
neurologic hemifield test (NHT)
Ethics approval and consent to participate
This study was approved by the University of Yamanashi Hospital ethics committee (registration number: 1600).
Consent for publication
An opt-out consent option was provided for all patients.
Availability of data and material
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests
None.
Funding
Any funding bodies had no role in the design of the study, the collection, analysis, and interpretation of data, or the writing of the manuscript.
Authors’ contributions
YK conceived the study, collected and analyzed data, and helped prepare the manuscript. MK collected and analyzed data and revised the manuscript for important intellectual content. MO and HK analyzed data and revised the manuscript for important intellectual content. HI supervised the study design, conducted statistical analysis, and drafted the manuscript. All authors have read and approved the final manuscript.
Acknowledgements
Not applicable.