Vision-Related Quality of Life after Transsphenoidal Surgery for Pituitary Adenoma

Abstract

Purpose.: To use the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) to evaluate vision-related quality of life (VR-QOL) in patients with pituitary adenoma who undergo transsphenoidal surgery.

Methods.: The VFQ-25 was self-administered by 74 patients with pituitary adenoma before and 3 months after surgery. Pre- and postoperative clinical data were collected, including age, sex, tumor type and size, logarithm of minimum angle of resolution best corrected visual acuity (logMAR BCVA), critical flicker fusion frequency, static perimetry scores (mean deviation [MD] and corrected pattern SD [CPSD]), duration of ocular symptoms, and number of systemic comorbidities.

Results.: Seventy-four patients with a mean age of 48.2 years were studied. Transsphenoidal surgery for pituitary adenoma significantly improved logMAR BCVA and critical fusion flicker frequency in the worse-seeing eye and MD and CPSD scores in both the better- and worse-seeing eyes (P < 0.001). The VFQ-25 composite score and all subscale scores, except those for the general health and color vision subscales, improved significantly (P < 0.05). A multivariate regression analysis revealed that the preoperative VFQ-25 composite score and the preoperative MD and CPSD scores in the better-seeing eye were related to the postoperative VFQ-25 composite score (P < 0.05).

Conclusions.: This study quantitatively demonstrated that transsphenoidal surgery can dramatically improve VR-QOL in pituitary adenoma and that the preoperative VFQ-25 composite score and visual field disturbance in the better-seeing eye are particularly important predictors associated with the postoperative VR-QOL. The use of VFQ-25 provides a more comprehensive overview of the effectiveness of transsphenoidal surgery.

Visual dysfunction is one of the most common symptoms in patients with pituitary adenoma. The main ocular manifestations of pituitary adenoma include visual field defects, visual disturbance, and oculomotor abnormalities. The frequency of visual field defects associated with pituitary adenoma varies and its occurrence, as reported in the literature, ranges from 9% to 32%. ^1–3 Visual disturbance is reported to be present in 4% to 16% of patients with pituitary adenoma, and oculomotor abnormality is present in 1% to 6% of these patients. ^1–3  

Transsphenoidal surgery, which involves entry into the sphenoid sinus and floor of the sella turcica, is the most frequently used surgical intervention for pituitary adenoma. Currently, this approach is used in more than 95% of cases. ⁴ Vision improves in up to 90% of patients who undergo transsphenoidal surgery. The manifestations begin to improve within a few days after surgery, and the improvement continues through the ensuing weeks. ⁵  

For a quantitative evaluation of the vision-related quality of life (VR-QOL), the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) has been used to track the outcome of many ocular conditions such as cataract, glaucoma, age-related macular degeneration, epiretinal membrane, diabetic retinopathy, keratoconus, and macular hole. ^6–15 Since pituitary adenoma is a systemic disease, previous studies have assessed QOL and well-being in patients who have surgery for pituitary adenoma, by using health-related QOL measures such as the Medical Outcomes Study 36-item Short Form (SF-36). ^16–18 The SF-36 a questionnaire that is widely used to assess global health-related QOL, whereas it is not considered useful for determining the influence of visual disability and visual symptoms, which are the main problems in patients with pituitary adenoma. To the best of our knowledge, the effect of transsphenoidal surgery on VR-QOL in patients with pituitary adenoma has not been studied. The purpose of our study was to evaluate the influence of transsphenoidal surgery for pituitary adenoma on VR-QOL with the VFQ-25 and to investigate the factors relevant to postoperative VR-QOL. 

Methods

The study population consisted of a consecutive series of 74 patients (33 men and 41 women) with diagnosed pituitary adenoma, who underwent transsphenoidal surgery between January and September 2006 at the Department of Hypothalamic and Pituitary Surgery at Toranomon Hospital. The mean age of the patients was 48.2 years (range, 20–79). No participant received any medications for pituitary adenoma at the initial interview. All underwent transsphenoidal surgery with the endonasal approach, as described elsewhere. ¹⁹ The exclusion criteria included a history of intraocular surgery, ocular diseases except for mild refractive errors, and systemic disorders other than pituitary adenomas that could affect visual function. The attending physicians explained the nature of the research and the ethical considerations to the participants, who then indicated their understanding by signing an informed consent form. The study was approved by the Institutional Review Board at the Tsukuba University Hospital and complied with the tenets of the Declaration of Helsinki. Surgical indications in patients with pituitary adenoma in this study are as follows: (1) the existence of clinical manifestations due to pressure on adjacent structures in patients with nonfunctioning adenoma; (2) the presence of acromegaly, Cushing's disease, and thyroid-stimulating hormone (TSH)–secreting adenoma; and (3) the presence of prolactin-secreting adenoma not affected by bromocriptine therapy. The control group consisted of 81 healthy individuals who were matched for age and sex. The patients were interviewed to determine the duration of the ocular symptoms associated with the pituitary adenoma, and they underwent ophthalmic examinations. The number of systemic comorbidities and the type and size of the pituitary adenoma were determined from a review of the medical record. 

Logarithm of the minimum angle of resolution best corrected visual acuity (logMAR BCVA), critical flicker fusion frequency (HE-46; Handaya, Tokyo, Japan), and static perimetry (Humphrey Field Analyzer; 30-2 test; Humphrey Instruments, London, UK) were recorded preoperatively and 3 months after surgery. For static perimetry data, reliable visual field test results have been defined as those with less than 20% fixation losses, 33% false-positive errors, and 33% false-negative errors. ²⁰ These percentages are the internal reliability thresholds recommended by the manufacturer. False-positive errors occur when the subject gives a positive response to a nonexistent stimulus, whereas false-negative errors occur when the subject fails to give a positive response to a stimulus that should be visible. To differentiate between the false-negative errors and undetected stimuli in blind positions, we used the following standard catch trial program: Stimuli were uniformly 9 dB brighter than the previously measured threshold value at the same test point location. We obtained two parameters: mean deviation (MD) and corrected pattern standard deviation (CPSD). MD represents the mean difference between the threshold value at each test location and the age-corrected normal value, which is mainly an index of the degree of the visual field defect. CPSD indicates the standard deviation of the mean difference between the threshold value for each test location and the expected normal value, which is an index of localized nonuniformity of the surface of the hill of vision. 

The VFQ-25

The VFQ-25 consists of 25 questions. ^6,7 Each item was assigned to 1 of 12 subscales including general health, general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. Each subscale is concerned with VR-QOL measurement based on the functional vision difficulties faced by the patient (for objective visual functioning and subjective well-being). The scores for each subscale ranged from 0 (worst possible functioning) to 100 (best possible functioning); thus, the higher the score, the better the VR-QOL pertinent to that specific symptom/activity. The composite score was calculated by averaging the scores of all (n = 11) subscales except the general health subscale. ⁶  

The Japanese version of the VFQ-25 was used, which was modified from the original version to conform to Japanese culture and lifestyle. This modified VFQ-25 instrument has been assessed for its reliability and validity and has been shown to appropriately measure the VR-QOL in Japanese individuals. ⁷ The questionnaire was administered before and 3 months after surgery. 

Statistical Analysis

The paired t-test was used to compare pre- and postoperative visual function (i.e., logMAR BCVA, MD score, CPSD score, and critical flicker fusion frequency) in patients with pituitary adenoma. The mean scores and standard deviations were calculated for each VFQ-25 subscale and for the VFQ-25 composite score. The paired t-test was also used to compare pre- and postoperative VFQ-25 scores in patients with pituitary adenoma. Comparison between the surgery and control groups were tested by Dunnett multiple comparison. The Kruskal-Wallis test was performed to compare the VFQ-25 composite scores in patients with five types of pituitary adenoma. The Mann-Whitney U test was performed to compare the VFQ-25 composite score between the sexes. Multivariate regression analysis was performed to investigate the relationship between clinical variables and the postoperative VFQ-25 score. The covariates tested were preoperative VFQ-25 composite score, preoperative visual function, age, sex, type and size of pituitary adenoma, duration of ocular symptoms, and the number of systemic comorbidities. 

The distributions of eye-specific demographic characteristics were summarized for all eyes and for the better-seeing and worse-seeing eyes of the participant. The eyes were designated as better- and worse-seeing independently, for each demographic characteristic, and thus, the judgment of which eye was better-seeing depended on the characteristic under consideration. 

All tests of association were considered statistically significant when P < 0.05 (StatView, ver. 5.0, for Windows; Abacus Concepts, Berkeley, CA). 

Results

The patients' demographic characteristics are shown in Table 1. The preoperative examination revealed some degree of observational visual dysfunction in all patients, but subjective ocular symptoms were absent in 22 (30%) patients. After surgery, two patients had mild cerebrospinal fluid rhinorrhea that did not require additional surgery. The operation was successful in all patients, and pituitary adenoma did not recur in any of the patients during the study period. 

Table 1.

 

Baseline Characteristics of the Recruited Patients with Pituitary Adenoma

Age, y*	48.2 ± 13.9 (20–79)
Sex, male/female, n	33/41
Tumor type, n
Nonfunctioning adenoma	41
Prolactin-secreting adenoma	2
Acromegaly	19
Cushing's disease	7
TSH-secreting adenoma	5
Tumor size, mm*	24.0 ± 10.1 (8–54)
Duration of ocular symptoms, mo*	3.9 ± 7.1 (0–36)

*  Mean ± SD (range), n = 74.

The pre- and postoperative clinical parameters of visual function are summarized in Table 2. The status of eyes as better- or worse-seeing remained unchanged between pre- and postoperative assessments. Transsphenoidal surgery significantly improved logMAR BCVA and critical fusion flicker frequency in the worse-seeing eye and the MD and CPSD scores in both eyes (P < 0.001). The logMAR BCVA and critical fusion flicker frequency did not improve significantly in the better-seeing eye. 

Table 2.

 

Comparison of the Visual Function before and after Transsphenoidal Surgery for Pituitary Adenoma

	Before Surgery	After Surgery	P
LogMAR BCVA
Better-seeing eye	−0.09 ± 0.17	−0.10 ± 0.08	0.36
Worse-seeing eye	0.11 ± 0.35	−0.001 ± 0.24	<0.001*
Perimetric MD, dB
Better-seeing eye	−4.68 ± 5.02	−2.35 ± 3.18	<0.001*
Worse-seeing eye	−8.87 ± 8.20	−4.83 ± 5.63	<0.001*
Perimetric CPSD, dB
Better-seeing eye	4.96 ± 4.53	3.25 ± 3.21	<0.001*
Worse-seeing eye	7.02 ± 5.13	4.88 ± 4.26	<0.001*
Critical fusion flicker frequency, Hz
Better-seeing eye	35.4 ± 4.1	36.1 ± 3.5	0.19
Worse-seeing eye	31.9 ± 7.2	34.1 ± 5.1	<0.001*

 Data are expressed as the mean ± SD.

*  Statistically significant difference (paired t-test).

Table 3 shows the VFQ-25 composite score and subscale scores before and after surgery in patients with pituitary adenoma and in normal control subjects. When the preoperative scores were compared with the postoperative ones, statistically significant improvement was observed in all VFQ-25 subscales except general health and color vision (P < 0.05, paired t-test). In addition, when the pre- and the postoperative scores were compared with those of normal control subjects by multiple comparison, statistical significance between the postoperative and the normal control scores was not observed on any VFQ-25 subscale except the general health one (P < 0.05, Dunnett test). 

Table 3.

 

Summary Statistics for the National Eye Institute 25-item Visual Function Questionnaire (VFQ-25) and Comparison between Preoperative and Postoperative Scores in Patients with Pituitary Adenoma and Normal Controls

	Pituitary Adenoma Patients			Normal Controls	ANOVA P	Dunnett test P < 0.05
	Preoperative Patients	Postoperative Patients	Paired t-test P
General health	42.4 ± 19.9	46.3 ± 18.4	0.300	55.9 ± 20.0	<0.001†	‡,§
General vision	61.0 ± 22.2	75.0 ± 13.5	<0.001*	70.0 ± 15.9	<0.001†	‡
Ocular pain	75.0 ± 17.5	83.6 ± 16.5	<0.001*	79.5 ± 16.4	0.032†
Near activities	69.5 ± 18.5	80.9 ± 15.7	<0.001*	82.1 ± 14.5	<0.001†	‡
Distance activities	69.7 ± 17.0	80.1 ± 14.9	<0.001*	82.1 ± 13.9	<0.001†	‡
Social functioning	83.0 ± 14.8	88.7 ± 14.2	0.013*	90.3 ± 11.5	0.017†	‡
Mental health	68.0 ± 21.8	82.4 ± 17.2	<0.001*	85.0 ± 13.9	<0.001†	‡
Role difficulties	75.3 ± 20.2	87.2 ± 16.5	<0.001*	85.0 ± 17.2	0.014†
Dependency	83.9 ± 20.3	92.6 ± 13.3	<0.001*	95.2 ± 10.7	<0.001†	‡
Driving	75.5 ± 19.4	83.0 ± 17.4	<0.001*	83.9 ± 12.6	0.193
Color vision	91.0 ± 12.7	92.9 ± 11.3	0.290	93.1 ± 11.2	0.553
Peripheral vision	65.4 ± 19.5	77.7 ± 17.8	<0.001*	81.9 ± 19.1	<0.001†	‡
Composite score	74.1 ± 13.6	84.2 ± 10.8	<0.001*	84.5 ± 9.8	<0.001†	‡

 Data are expressed as the mean ± SD.

*  Statistically significant difference between preoperative and postoperative scores.

†  Statistically significant difference among three groups.

‡  Statistically significant difference between preoperative and normal control scores.

§  Statistically significant difference between postoperative and normal control scores.

The mean preoperative VFQ composite score of patients in each of the five groups classified according to pituitary adenoma: nonfunctioning adenoma, 73.1 ± 14.0 (range, 48.0–97.0); acromegaly, 80.6 ± 9.9 (range, 58.4–95.1); prolactin-secreting adenoma, 85.0 ± 17.7 (range, 72.5–97.5); Cushing's disease, 74.6 ± 17.1 (range, 40.0–93.6); and TSH-secreting adenoma, 70.8 ± 20.2 (range, 46.3–91.6). There were no significant differences between any of the five pituitary adenoma groups (P = 0.43, Kruskal-Wallis test) or between the sexes (P = 0.65, Mann-Whitney U test). 

Table 4 shows the results of multivariate regression analysis on the relation between the postoperative VFQ-25 composite score and clinical variables. Among all the variables, the postoperative VFQ-25 composite score correlated significantly with the preoperative VFQ-25 composite score (P < 0.001, Fig. 1), the preoperative MD score in the better-seeing eye (P = 0.044, Fig. 2), and the preoperative CPSD score in the better-seeing eye (P = 0.045, Fig. 3), whereas other variables showed no relationship with the postoperative VFQ-25 composite score. The significant relationship between the pre- and the postoperative VFQ-25 composite score could be statistically understood as one of excluding the effect of other clinical variables. 

Table 4.

 

Results of Multivariate Regression Analysis on the Postoperative VFQ-25 Composite Score and Covariates

Covariates	Estimate	SE	P
Intercept	64.27	15.27	<0.001
Preoperative VFQ-25 composite score	0.463	0.105	<0.001*
LogMAR BCVA in the better-seeing eye	15.482	7.842	0.053
LogMAR BCVA in the worse-seeing eye	−4.821	5.021	0.341
Perimetric MD in the better-seeing eye	0.982	0.476	0.044*
Perimetric MD in the worse-seeing eye	0.214	0.332	0.522
Perimetric CPSD in the better-seeing eye	0.839	0.409	0.045*
Perimetric CPSD in the worse-seeing eye	0.231	0.321	0.474
Critical fusion flicker frequency in the better-seeing eye	0.465	0.413	0.265
Critical fusion flicker frequency in the worse-seeing eye	−0.798	0.413	0.059
Age	−0.095	0.079	0.235
Sex	2.948	2.344	0.214
Tumor type	0.006	0.807	0.994
Tumor size	0.049	0.109	0.655
Duration of ocular symptoms	−0.195	0.175	0.272
Number of comorbidities	−0.467	1.279	0.717

*  Statistically significant difference (ANCOVA).

Figure 1.

 

Pre- and postoperative and VFQ-25 composite scores (P < 0.001).

Figure 2.

 

Postoperative VFQ-25 composite score and preoperative perimetric MD in the better-seeing eye (P = 0.044).

Figure 3.

 

Postoperative VFQ-25 composite score and preoperative perimetric CPSD in the better-seeing eye (P = 0.045).

Discussion

Surgery, radiotherapy, and pharmacotherapy constitute the present therapeutic armamentarium for the management of pituitary adenoma. Surgery, which includes transfrontal craniotomy and transsphenoidal surgery, allows removal of the adenoma or reduction of the tumoral mass and is considered the first-line therapy for nonfunctioning adenoma and acromegaly. Several studies have reported recovery of visual function after transsphenoidal surgery. ^19,21–23 The present study for the first time revealed that transsphenoidal surgery for pituitary adenoma can improve not only visual dysfunction but also deteriorated VR-QOL (Tables 2, 3). Thus far, the improvement in VR-QOL after surgical interventions for macular hole, epiretinal membrane, and age-related macular degeneration has been evaluated. ^8,12–14,24 Compared with that reported in these previous studies, the VR-QOL in the patients in this study improved to a greater degree after transsphenoidal surgery for pituitary adenoma. Because most pituitary tumors are benign and rarely infiltrate the optic nerve or chiasm, transsphenoidal surgery usually enables the removal of the pituitary tumors without wounding the optic nerve or chiasm. ²⁵ Therefore, visual dysfunction of pituitary tumors, which is caused, not by infiltration but by mass effects, may be easily improved by transsphenoidal surgery. 

When the VFQ-25 scores at 3 months after surgery were compared with those of normal controls, a statistically significant difference was not observed in the VFQ-25 composite score and scores of all subscales except the general health subscales (Table 3). This result indicated that transsphenoidal surgery for pituitary adenoma restores the VR-QOL to nearly the normal level by 3 months after surgery. However, on the general health subscale, a significant difference was observed, not between the pre- and postoperative scores, but between the postoperative scores and those of normal control subjects. This finding indicates that the effect of surgery on the general health subscale was limited. This subscale partially reflects the health-related QOL, and it is influenced by various factors that are absent in the cases of microprolactinomas, such as mass effects of pituitary macroadenomas, hypopituitarism, and the effects of surgery and/or radiotherapy. Indeed, in previous studies, health-related QOL did not recover in patients after treatment for acromegaly, Cushing's disease, or nonfunctioning adenoma. ^17,26–31 Exposure to excessive amounts of endogenous growth hormone and glucocorticoids in acromegaly and Cushing's disease, respectively, can cause irreversible signs and symptoms, that persist despite long-term treatment for the disease. ^26,27 Moreover, in patients reported to have nonfunctioning adenomas, the presence of multiple pituitary deficiencies is a predominant postoperative predictor of decreased health-related QOL. ²⁸ Thus, health-related QOL, which is indicated by the general health subscale, is affected by various factors, and surgical intervention alone may not improve it significantly. 

Using the SF-36, Johnson et al. demonstrated that there were differences in health-related QOL among patients with different types of pituitary adenomas; patients with Cushing's disease were the most severely affected. ¹⁶ In contrast, there were no significant differences in the preoperative VFQ-25 composite score among patients who had one of five types of pituitary adenoma in the present study. The nonsignificance of differences among the types of adenoma may indicate that VR-QOL is not affected by psychiatric changes that accompany changes in various endocrine hormone, but that it is affected more by mass effects. 

Considering the predictive factors of therapeutic effectiveness is very important for neurosurgeons and ophthalmologists when discussing the risks and benefits of a surgical intervention with patients. Investigators in other studies have reported several predictive factors: shorter duration of symptoms, younger age, less damage of preoperative visual acuity, and a smaller deficit in preoperative visual fields. However, these assessments were qualitative or semiquantitative and thus were not highly precise. Our results quantitatively revealed that the preoperative VFQ-25 composite score and the preoperative MD and CPSD in the better-seeing eye were the most relevant factors for predicting VR-QOL status after transsphenoidal surgery and thus should be carefully considered (Fig. 1, 2, 3). For example, pituitary adenoma patients with low preoperative visual field status (low MD and CPSD scores) in the better-seeing eye should not expect significant improvements in VR-QOL with transsphenoidal surgery. In an earlier study, we found that the degree of visual field defect in the better-seeing eye was significantly related to the decline in VR-QOL before surgery in patients with pituitary adenoma. ³² Therefore, the present results reveal that visual field status in the better-seeing eye affects not only preoperative but also postoperative VR-QOL. 

We quantitatively examined the recovery of visual field defects in patients with pituitary adenoma with static retinal perimetry (Humphrey Field Analyzer; Humphrey Instruments). The perimeter not only provides a complete quantitative assessment of the visual field, but also incorporates tests for patient reliability and adjustments for changes in the visual field caused by increasing age, the presence of cataracts, and small pupils. In addition, the system is automated and thus is less prone to examiner bias than other nonautomated methods used for assessing the visual field. ^20,33  

One of the limitations of our present study is that the patients were examined at 3 months after surgery. Although a previous study has reported that the recovery of visual field progresses over several years and that most of the recovery (>50%) occurs in the first 3 to 6 months after surgery, the time course of visual function recovery after transsphenoidal surgery for pituitary adenomas is unclear. ¹⁶ As expected from the results of previous reports, examination at a later stage may lead to a better outcome of VR-QOL. Another potential limitation of our study is that we evaluated visual field defects on the basis of the visual field of each eye separately and used static perimetry (Humphrey Field Analyzer; Humphrey Instruments). The visual field of each eye may not always provide an accurate description of the binocular visual field. We assessed the static visual field and not the kinetic visual field with emphasis on quantitative evaluation, because no standardized method is available for the quantitative assessment of kinetic perimetry. However, static perimetry (30-2 test) does not assess the complete visual field including the periphery. 

In conclusion, the VR-QOL as well as visual function in patients with pituitary adenoma dramatically improved after transsphenoidal surgery. Indeed, the levels achieved were nearly equal to those in normal control subjects. The preoperative VFQ-25 composite score and extent of visual field defects (as assessed by CPSD and MD scores) in the better-seeing eye are particularly important predictors of VR-QOL after transsphenoidal surgery. 

Footnotes

 Disclosure: Y. Okamoto, None; F. Okamoto, None; S. Yamada, None; M. Honda, None; T. Hiraoka, None; T. Oshika, None