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Prevalence and Impact of Postoperative Headaches in Nonfunctioning Pituitary Macroadenoma Patients: A Longitudinal Cohort Study
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Please cite this article as: Jang MK, Park CG, Jang S, Kim EH, Prevalence and Impact of Postoperative Headaches in Nonfunctioning Pituitary Macroadenoma Patients: A Longitudinal Cohort Study, World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2019.09.123. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Prevalence and Impact of Postoperative Headaches in Nonfunctioning Pituitary Macroadenoma Patients: A Longitudinal Cohort Study
Min Kyeong Jang1,2, Ph.D., KOAPN, RN, Chang Gi Park2, Ph.D., Seonguk Jang3, BBA, BS, and Eui Hyun Kim4,5,6, Ph.D., M.D. 1
University of Illinois Cancer Center, Chicago, IL, USA; 2University of Illinois at Chicago,
College of Nursing, Chicago, IL, USA; 3University of Minnesota School of Public Health, Minneapolis, MN, USA; 4Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Republic of Korea; 5Pituitary Tumor Center, Severance Hospital, Seoul, Republic of Korea; 6Yonsei Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
Funding: This work was supported by the National Institute of Nursing Research of the National Institutes of Health (K24NR015340); and the Basic Science Research Program through the NRF of Korea (NRF-2018R1C1B5042687) funded by the Korean Ministry of Science, ICT and Future Planning. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Correspondence: Eui Hyun Kim, M.D., Ph.D. Department of Neurosurgery, Yonsei University College of Medicine 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea Tel: +82-2-2228-2155
Fax: +82-2-393-9979
E-mail: [email protected]
Key words: Headache, Pituitary adenoma, Transsphenoidal surgery
Running title: Postoperative Headaches as a Predictor
Postoperative Headaches as a Predictor
1
Prevalence and Impact of Postoperative Headaches in Nonfunctioning
2
Pituitary Macroadenoma Patients: A Longitudinal Cohort Study
3 4
Abstract
5
BACKGROUND: Patients with nonfunctioning pituitary macroadenomas commonly experience
6
headaches before and after surgery, and headaches have been reported to significantly detract
7
from the quality of life. Despite this adverse impact, few studies have examined the prevalence
8
and pattern of headaches on a long-term basis. Thus, this study employed a longitudinal cohort
9
design to identify headache prevalence and severity during a 6-month postoperative period and
10
its predictors.
11
METHODS: Forty patients with nonfunctioning pituitary macroadenomas who underwent
12
transsphenoidal surgery were enrolled as subjects, and Headache Impact Test-6 (HIT-6) was
13
performed at four time points: before and 1, 3, and 6 months after surgery.
14
RESULTS: This study revealed that nonfunctioning pituitary macroadenoma patients suffered
15
from headaches at each of the four time points and that 37.5%, 27.8%, 17.9%, and 12.8% of the
16
patients experienced “substantial and severe impact headaches” before and 1, 3, and 6 months
17
after surgery, respectively. In addition, total HIT-6 scores 1 month after surgery were a
18
significant predictor (B = 0.41, p < 0.001) of headaches 3 and 6 months after surgery. Among the
19
HIT-6 items, pain (B = 0.09, p < 0.001), cognitive function (B = 0.07, p < 0.001), and
20
psychological distress (B = 0.07, p < 0.001) showed the greatest impact on long-term headaches.
21
CONCLUSION: Headaches adversely affected patients even 6 months after surgery.
22
Additionally, headaches 1 month after surgery predicted the prevalence of long-term headaches
23
at 3 and 6 months, demonstrating the importance of timely postsurgical measurement of
24
headaches to anticipate patients’ long-term headache patterns.
1
Postoperative Headaches as a Predictor
25
INTRODUCTION
26
Headaches are one of the most common symptoms experienced by pituitary adenoma patients
27
and have been reported in more than one-third of individuals during the treatment period.1
28
Nonfunctioning pituitary adenoma patients inevitably undergo transsphenoidal surgery as a
29
mainstay of the treatment options,2,3 often resulting in long-term headaches after surgery.4-6 One
30
prospective study reported that almost 50% of pituitary adenoma patients experienced
31
preoperative headaches6, and although headaches decreased after surgery in a significant number
32
of patients, almost 30% of the patients still experienced headaches 6 months post-surgery.
33
Similarly, another longitudinal cohort study reported that 63% of patients experienced headaches
34
before surgery and that 19% showed no improvement in headaches 3 months after surgery.5 Thus,
35
although transsphenoidal surgery results in tumor removal and contributes to headache relief,5-7
36
headaches remain an issue that adversely impacts some patients after surgery.8
37
Previous studies have identified various risk factors for headaches in pituitary adenoma
38
patients. For example, reported risk factors include adenoma size, sinus invasion, hormonal
39
effects, adenoma type, family history of headaches, intrasellar pressure (ISP), and intracranial
40
pain-sensitive structure displacement.1,4,9,10 In addition, one study found that tumor-attributed
41
headaches were associated with a history of headaches, nicotine abuse, taking acute-headache
42
medication, and higher tumor proliferation (reflected by a Ki67-LI >3%).11 Although migraine-
43
like headaches are a common clinical manifestation in patients with nonfunctioning pituitary
44
macroadenomas,10 headache types and locations vary.12 On the whole, the association between
45
pituitary adenoma and headaches is not well understood due to inconsistencies in previous
46
research findings.13 Furthermore, in their recent review article, Donovan and Welch12 noted that
47
the literature on headaches in pituitary adenoma patients was limited to only a few prospective
48
studies that focused on this topic. Although two previous longitudinal studies focused on
49
headache symptoms, these studies addressed many types of pituitary adenomas, and thus the
50
prevalence and pattern of headaches in nonfunctioning pituitary macroadenoma patients were not
51
specifically examined. In the clinical setting, healthcare providers encounter various headache
52
trajectories and require guidance regarding the appropriate times for headache assessment.
53
Considering that headaches adversely affect the quality of life (QOL) and daily life activities of
54
patients,6,14 proper assessment and management of headache symptoms are crucial to streamline 2
Postoperative Headaches as a Predictor
55
the course of treatment. Thus, a longitudinal cohort study is needed to focus on postsurgical
56
measurement of headaches.
57
Although clinics recommend that patients with nonfunctioning pituitary macroadenomas
58
have regular follow-up tests before and after surgery, including magnetic resonance imaging
59
(MRI), Humphrey Visual Field testing, and hormone tests, headache assessments tend to be
60
overlooked as part of routine care. Reflecting this lack of attention to headaches both in the clinic
61
and in research, no guidelines are currently available that specify when and how to assess
62
patients for headache symptoms. To help fill this research gap with respect to headaches in
63
patients with nonfunctioning pituitary macroadenomas and to provide information for such
64
guidelines, this study employed a longitudinal cohort design to identify the pattern and severity
65
of headaches in such patients and determine the best measurement time points for predicting
66
long-term headaches.
67 68
METHODS
69
Study Participants and Data Collection
70
This study was approved by the Institutional Review Board (approval #2013-0494) of
71
the Yonsei University Health System, Severance Hospital, in Republic of Korea. We recruited 40
72
patients diagnosed with nonfunctioning pituitary macroadenoma who were scheduled to undergo
73
transsphenoidal surgery from June 2013 through February 2014. Written informed consent was
74
obtained from all participants.
75
In this longitudinal study, each participant met the following inclusion criteria: each
76
patient had to (1) be more than 20 years of age, (2) have been diagnosed by MRI with a
77
macroadenoma with a diameter greater than 2 cm, (3) not have been indicated for medical
78
treatment (for endocrine-inactive pituitary adenomas), (4) be scheduled to undergo
79
transsphenoidal surgery, and (5) be able to understand and respond to the study survey. The
80
number of subjects for this study was estimated to be 40 for a generalized estimating equation
81
(GEE) analysis with an assumption of effect size of 0.23, power of 0.8, and alpha as 0.05.
82
For data collection, the Headache Impact Test-6 (HIT-6) was administered to the
83
participants in an outpatient setting at four time points: preoperatively (40 participants) and
84
postoperatively at 1 (36), 3 (39), and 6 months (39). In addition, the participants’ charts were 3
Postoperative Headaches as a Predictor
85
reviewed to identify their general and clinical characteristics.
86
All patients underwent preoperative dynamic MRI of the sellar region using a 3.0-Tesla
87
system (Achieva; Philips, Best, The Netherlands). Tumor size was measured as a maximal
88
diameter on a coronal plane. Immediate postoperative 3-Tesla diagnostic MRI was performed
89
within 48 h after the surgery and the extent of tumor removal was determined. The
90
endocrinological assessment with combined pituitary function test (CPFT) was fully described in
91
our previous report.15 The CPFT was performed to evaluate anterior pituitary function before
92
surgery and 6 months after surgery, and the results were confirmed by two endocrinologists.
93
Patient visual field was evaluated by standard automated perimetry using a Humphrey Visual
94
Field Analyzer (Carl Zeiss Meditec Inc., Germany). Olfactory function was measured by the
95
Korean version of Sniffin’ Sticks (KVSS).
96 97
Measure
98
The HIT-6 developed by Kosinski et al (2003)16 and translated by Chu et al. (2008)17
99
was used to measure the impact of headaches on the participants. The scale employs six items to
100
assess headache complexity by addressing pain, social function, role function, cognitive function,
101
psychological distress, and vitality. Each item is scored from 6 to 13, and total scores range from
102
36 to 78. Total scores fall into four categories: little to no impact headaches (36-49), some impact
103
headaches (50-55), substantial impact headaches (56-59), and severe impact headaches (60-78).
104
The total score indicates the effect that the headaches have on normal daily life and the ability to
105
function.
106 107
Statistical Analysis
108
Both general and clinical participant characteristics as well as the prevalence and
109
severity of the participants’ headaches were analyzed using a descriptive statistical method. To
110
enrich unbiased estimation of population-averaged regression coefficients, GEEs were used to
111
analyze the longitudinal headache data. During the study, a small number of participants failed to
112
contribute data during various postsurgical time points. However, the quantity of missing data
113
was below 5%, so a missing data approach was not employed. All statistical analyses were
114
performed using SPSS version 24.0 (SPSS Inc., Chicago, IL, USA). All statistical tests were two4
Postoperative Headaches as a Predictor
115
tailed, and p < 0.05 was considered to indicate a significant result.
116
RESULTS
117
General and Clinical Characteristics
118
Participant demographics and clinical characteristics are summarized in Table 1 and
119
Table 2, respectively. The 40 nonfunctioning pituitary macroadenoma patients consisted of 19
120
males (47.5%) and 21 females (52.5%) with a mean age of 52 years; ages ranged from 22 to 77
121
years. The mean tumor size was 3.2 cm (range, 2.0–6.4 cm). Of the participants, 29 (72.5%)
122
underwent total resection of the tumors, and 11 (27.5%) underwent subtotal resection.
123
Furthermore, 17 (42.5%) of the participants required hormone replacement therapy after surgery
124
and eventually during the follow-up period. Anterior pituitary function was assessed in 29
125
patients in whom comparisons between their preoperative and 6-month postoperative CPFT data
126
were available. At least one axis of anterior pituitary hormones showed preoperative or
127
postoperative hypopituitarism in 27 (67.5%) and 23 (57.5%) of the participants, respectively.
128
Anterior pituitary function worsened in 8 (27.6%), improved in 11 (37.9%), and did not change
129
in 10 of the patients (34.5%).
130 131
Headache Prevalence and Severity
132
With respect to total HIT-6 scores, headaches 1 month after surgery showed the highest
133
score (47.19 ± 9.16), with scores ranging from 36 to 74. Whereas headaches 6 months after
134
surgery showed the lowest score (40.95 ± 7.55), with scores ranging from 36 to 64. Before
135
surgery, the mean headache score was 46.85 ± 8.98, and scores ranged from 36 to 65; whereas 3
136
months after surgery, the mean headache score was 43.44 ± 6.77, and scores ranged from 36 to
137
58. Among the HIT-6 items, “pain” had the highest score at all time points over the 6 month
138
duration. “Vitality” had the lowest scores before surgery and 3 months after surgery; whereas
139
“cognitive function” had the lowest scores 1 and 6 months after surgery. The total HIT-6 scores
140
of all the participants across all time points fell into the “little to no impact headache” category.
141
However, in the HIT-6 impact categories (Fig. 1), 15 (37.5%), 10 (27.8%), 7 (17.9%), and 5
142
(12.8%) of the participants reported moderate, substantial, or severe impact headaches before
143
surgery and 1, 3, and 6 months after surgery, respectively.
144
Table 3 shows the change in headache patterns between before surgery and 1 month after 5
Postoperative Headaches as a Predictor
145
surgery and between the 1 month after surgery and 6 months after surgery. These comparisons
146
were based on the responses for patients who had no missing data in the three follow-up
147
timepoint tests. Among 35 total participants, the level of headaches in 10 participants (28.6%)
148
decreased 1 month after surgery compared to before surgery. Among 10 participants, 9
149
participants (90%) did not require hormonal replacement after surgery and 6 participants (60%)
150
had no comorbidities. On the contrary, the level of headaches in 7 participants (20.0%) increased
151
1 month after surgery compared to before surgery. Among these 7 participants, 6 participants
152
reported to have “little to no impact headache” in the preoperative period, thus these cases were
153
regarded as new headaches. Furthermore, 5 of these 7 participants (71.4%) underwent subtotal
154
resection surgery, and 4 (57.1%) required hormone replacement therapy. For these 35
155
participants, the size of the tumor, presence of cavernous sinus invasion, extent of tumor
156
resection, changes in visual field, presence of postoperative hyposmia, presence of preoperative
157
hypopituitarism, and outcome of pituitary hormonal function were not associated with HIT-6
158
scores or its changes during the first 6 months.
159 160
Longitudinal Headache Prediction Model
161
Table 4 summarizes the GEE analysis results. Controlling for general and clinical
162
participant characteristics, the total HIT-6 score at 1 month after surgery was a significant
163
predictor of headaches 3 and 6 months after surgery (B = 0.41, p < 0.001). In addition, each HIT-
164
6 item score was found to significantly predict long-term headaches. Specifically, the strongest
165
predictors of long-term headaches were “pain” (B = 0.09, p < 0.001), “cognitive function” (B =
166
0.07, p < 0.001), and “psychological distress” (B = 0.07, p < 0.001), whereas “social function”
167
(B = 0.07, p < 0.01) was the weakest predictor. The total HIT-6 score 1 month after surgery
168
remained a significant predictor of long-term headaches (p < 0.05) when we did not control for
169
participant characteristics, but the p-value indicated less significance than when we adjusted for
170
these characteristics.
171 172
DISCUSSION
173
This study identified the importance of measuring headaches 1 month after surgery as a
174
predictor for long-term headaches and a basis for quality care. In our study findings, the total 6
Postoperative Headaches as a Predictor
175
HIT-6 score did not impact “substantial and severe impact headaches” at each time point because
176
each of the mean values of the total HIT-6 score tended to belong to the “little impact or no
177
impact headaches” range of scores. However, in Figure 1, “substantial and severe impact
178
headache” scores were 37.5%, 27.8%, 17.9%, and 12.8%, before surgery and 1, 3, and 6 months
179
after surgery, respectively. In other words, headaches are the common symptom of
180
nonfunctioning pituitary macroadenoma during the treatment process, and transsphenoidal
181
surgery did not guarantee total resolution of the headache symptoms. Similar to our findings,
182
other longitudinal studies have also reported that 20–30% of pituitary adenoma patients still
183
suffer from headaches, and therefore headaches remain an essential issue.5,6 Headaches are a
184
significant symptom for pituitary adenoma patients before surgery (p < 0.001), and chronic
185
headaches are more prevalent for these patients when compared to the general population (p =
186
0.001).2 Therefore, healthcare providers recognize that headaches associated with pituitary
187
adenoma are a common long-term issue, and the prevalence and severity of the headaches are
188
still an important consideration during the treatment process.
189
Postoperative headaches are simply regarded as a surgical procedure-related symptom;
190
however, headache mechanisms derived from the pituitary adenoma are complicated and not
191
well understood. Indeed, it has been reported that transsphenoidal surgery is not guaranteed to
192
positively influence headache symptoms for a certain period of time after surgery.1,18 In our
193
findings, 7 participants (20%) experienced an increased level of headaches 1 month after surgery
194
compared to the preoperative period. Among these participants, 5 (71.4%) underwent subtotal
195
resection surgery and 4 (57.1%) experienced hormonal deficiency after surgery. In contrast, for
196
other 10 participants who experienced decreased headache symptoms after surgery, 5 (50%)
197
underwent total resection surgery, and 9 (90%) had no hormonal deficiency after surgery. Based
198
on these findings, both hormonal sufficiency or deficiency and extent of tumor resection may be
199
predictors of headache relief or severity after surgery. Pathophysiology of headache in pituitary
200
adenoma includes various mechanical, biochemical, vascular, and biopsychosocial mechanisms.
201
In addition, tumor size is known as an important pathophysiological cause of headaches.1 In
202
other words, pituitary tumor size, or the “mass effect,” can lead to increased ISP. A previous
203
study reported that patients with headaches were more likely to have higher ISP levels compared
204
to patients without headaches, and those symptoms were related to intratumoral hemorrhage and 7
Postoperative Headaches as a Predictor
205
compromised dural integrity at the sella.18 In cases of postsurgical pituitary tumors and
206
headaches, residual tumors in the cavernous sinus and endocrine imbalances may increase the
207
headache symptoms, so optimal management strategies are consistently required after surgery.13
208
Therefore, future studies need to comprehensively investigate the risk factors and epidemiology
209
of headaches, including comparison of headache patterns before and after surgery.
210
Furthermore, this study contributed to the understanding that the presence of headaches
211
1 month after surgery was a significant predictive factor for headaches 3 and 6 months after
212
surgery when controlling for all general and clinical patient characteristics. This phenomenon
213
shows the importance of screening for headaches 1 month after surgery as an indicator for long-
214
term headaches. Also, there was substantial variation in headache scores, which ranged from 36
215
to 74 1 month after surgery. The prevalence of postoperative headaches suggests that measures
216
should be taken to successfully address and manage headaches 1 month after surgery in an
217
outpatient setting. Considering that headaches are a signature factor affecting QOL, health
218
providers cannot overlook the importance when patients return to their general lives. In addition,
219
although the main symptoms reported by patients with nonfunctioning primary adenoma are
220
headaches, visual deterioration, and hypopituitarism, inpatient and outpatients assessments
221
regularly include MRI, Humphrey visual field, and hormonal tests; headache assessments are
222
noticeably absent. Because headaches are a subjective symptom, they are neglected because of
223
the difficulty to objectively measure and complex causality. However, regular assessment and
224
management of headaches 1 month after surgery should be considered using pharmacological
225
and nonpharmacological approaches. Our findings suggest that timely, appropriate assessment
226
and efficient management may help treat headache symptoms and improve patient QOL.
227
Although preoperative headaches are a common symptom of pituitary adenomas and one of the
228
surgical indications, patients should be informed that they may experience headaches for a
229
certain period of time after surgery and should consult a physician for appropriate management.
230
If patient headaches persist 1 month after surgery, proper professional medical intervention with
231
regular monitoring should be provided because they have a higher chance of long-term
232
headaches. Whether medical intervention can decrease the probability of long-term headaches
233
should be further investigated.
234
In our research phase, we realized that a disease-specific headaches as an instrument for 8
Postoperative Headaches as a Predictor
235
pituitary adenoma patients should be developed by incorporating systematic review of headache
236
risk factors. Although HIT-6 is a validated instrument used to assess headaches and the impact on
237
daily function for patients with primary adenoma, items on the HIT-6 cover broader concepts to
238
assess headache impact rather than an in-depth assessment of headaches for pituitary adenoma.
239
Specifically, known risk factors for headaches in patients with pituitary adenoma are tumor size,
240
sinus invasion, hormone unbalance, and headache history; however, these risk factors are not
241
assessed as part of the HIT-6 instrument. Thus, it would be beneficial for future studies and
242
clinical assessments to develop a new evidence-based and disease-specific instrument that
243
includes more objective risk factors for pituitary adenoma. The new headache assessment could
244
be an essential instrument for assessing symptoms for patients with pituitary adenoma to
245
efficiently improve quality of care in a neurosurgical clinical setting.
246
Future studies should include broader pituitary adenoma patients and use a disease-
247
specific instrument for headaches. Many healthcare providers tend to overlook headache
248
symptoms due to noticeable neurological symptoms, including visual deterioration and hormonal
249
effects. However, considering that headaches significantly impact QOL, a longitudinal
250
prospective cohort study will be needed to conduct regular and more accurate assessments and to
251
identify effective treatments in the management of headaches. Although the pattern and risk
252
factors for headaches are still unclear and an area of active study in pituitary adenoma, screening
253
for headaches 1 month after surgery should be conducted to prevent chronic headaches and their
254
impact on quality of care in a neurosurgical clinical setting.
255 256
CONCLUSION
257
Although transsphenoidal surgery is the best way to treat and cure nonfunctioning
258
pituitary adenoma, patients still reported headaches as a common symptom after surgery. Our
259
findings indicated that headaches 1 month after surgery could be a predictor for long-term,
260
chronic headaches, and therefore assessment and management of headaches should be regularly
261
applied. This study further suggests that an evidence-based and disease-specific instrument for
262
headache assessment in pituitary adenoma should be systematically developed.
263
9
Postoperative Headaches as a Predictor
264
Figure Legends
265
FIGURE 1. Prevalence and severity of headaches. Headaches worsened after surgery as
266
shown by the highest Headache Impact Test-6 (HIT-6) score 1 month after surgery. Headaches
267
gradually decreased, and HIT-6 scores were lower 6 months after surgery than before surgery.
268
Overall, 37.5%, 27.8%, 17.9%, and 12.8% of the participants reported moderate, substantial, or
269
severe impact headaches before surgery and 1, 3, and 6 months after surgery, respectively.
10
References 1. Kreitschmann Andermahr I, Siegel S, Weber Carneiro R, Maubach J, Harbeck B, Brabant G. Headache and pituitary disease: A systematic review. Clin Endocrinol(Oxf). 2013;79(6):760-769. 2. Gravdahl GB, Tronvik EA, Fougner SL, Solheim O. Pituitary adenoma and non-acute headache: Is there an association, and does treatment help? World Neurosurg. 2016;92:284-291. 3. Murad MH, Fernández Balsells M, Barwise A, et al. Outcomes of surgical treatment for nonfunctioning pituitary adenomas: A systematic review and meta analysis. Clin Endocrinol (Oxf). 2010;73(6):777-791. 4. Suri H, Dougherty C. Clinical presentation and management of headache in pituitary tumors. Curr Pain Headache Rep. 2018;22(8):55. 5. Rizzoli P, Iuliano S, Weizenbaum E, Laws E. Headache in patients with pituitary lesions: A longitudinal cohort study. Neurosurgery. 2015;78(3):316-323. 6. Wolf A, Goncalves S, Salehi F, et al. Quantitative evaluation of headache severity before and after endoscopic transsphenoidal surgery for pituitary adenoma. J Neurosurg. 2016;124(6):1627-1633. 7. Hayashi Y, Kita D, Iwato M, et al. Significant improvement of intractable headache after transsphenoidal surgery in patients with pituitary adenomas; preoperative neuroradiological evaluation and intraoperative intrasellar pressure measurement. Pituitary. 2016;19(2):175-182. 8. Siegel S, Carneiro RW, Buchfelder M, et al. Presence of headache and headache types in patients with tumors of the sellar region—can surgery solve the problem? results of a prospective single center study. Endocrine. 2017;56(2):325-335. 9. Gondim JA, Almeida JP, de Albuquerque, Lucas Alverne F, Gomes E, Schops M, Ferraz T. Pure endoscopic transsphenoidal surgery for treatment of acromegaly: Results of 67 cases treated in a pituitary center. Neurosurgical focus. 2010;29(4):E7. 10. Yu B, Ji N, Ma Y, Yang B, Kang P, Luo F. Clinical characteristics and risk factors for headache associated with non-functioning pituitary adenomas. Cephalalgia. 2017;37(4):348-355. 11. Schankin CJ, Reifferscheid AK, Krumbholz M, et al. Headache in patients with pituitary adenoma: Clinical and paraclinical findings. Cephalalgia. 2012;32(16):1198-1207. 12. Donovan LE, Welch MR. Headaches in patients with pituitary tumors: A clinical conundrum. Curr Pain Headache Rep. 2018;22(8):57. 13. Levy MJ. The association of pituitary tumors and headache. Curr Neurol Neurosci Rep. 2011;11(2):164-170. 14. Pereira-Neto A, Borba AM, Mello PAd, Naves LA, Araújo Jr, Antônio Santos de, Casulari LA. Mean intrasellar pressure, visual field, headache intensity and quality of life of
patients with pituitary adenoma. Arq Neuropsiquiatr. 2010;68(3):350-354. 15. Lee EJ, Ahn JY, Noh T, Kim SH, Kim TS, Kim SH. Tumor tissue identification in the pseudocapsule of pituitary adenoma: Should the pseudocapsule be removed for total resection of pituitary adenoma? Oper Neurosurg. 2009;64(suppl_1):ONS62-ONS70. 16. Kosinski M, Bayliss M, Bjorner J, et al. A six-item short-form survey for measuring headache impact: The HIT-6™. Qual Life Res. 2003;12(8):963-974. 17. Chu M, Im H, Ju Y, Yu K, Ma H, Lee B. Validity and reliability assessment of Korean headache impact test-6 (HIT-6). J Korean Neurol Assoc. 2008;27(1):1-6. 18. Hayashi Y, Sasagawa Y, Oishi M, et al. Contribution of intrasellar pressure elevation to headache manifestation in pituitary adenoma evaluated with intraoperative pressure measurement. Neurosurgery. 2018;84(3):599-606.
Table 1. Demographic and Clinical Characteristics
(N=40)
Category Age (years)
Sex
Marital status
Religion
Economic burden
Mean ± SD 51.95 ± 15.10 (range, 22-77)
20-29
3(7.5)
30-39
6(15.0)
40-49
9(22.5)
50-59
7(17.5)
60-69
9(22.5)
70-79
6(15.0)
Male
19(47.5)
Female
21(52.5)
Single
9(22.5)
Married
31(77.5)
None
13(32.5)
Christian
15(37.5)
Buddhist
9(22.5)
Catholic
3(7.5)
Never
23(57.5)
A little
13(32.5)
Very Education
Occupation
Comorbidity
n (%)
4(10.0)
Middle school
12(30.0)
High school
12(30.0)
≥College
16(40.0)
None
13(32.5)
Yes
27(67.5)
None
21(52.5)
Diabetes
2(5.0)
Hypertension
4(10.0)
Others
13(32.5)
SD—Standard Deviation
1
Table 2. General clinical outcomes of 40 patients with nunfunctioning pituitary adenomas Category Extent of resection
Visual field
Subtotal
11 (27.5)
Total
29 (72.5)
Improved (>5dB)
27 (67.5)
Unchanged
13 (32.5)
Worsened (>5dB) Olfaction (n=32) *
Preoperative hypocortisolemia
Anterior pituitary function (n=29) **
Postoperative hormonal replacement
n (%)
0 (0)
Hyposmia
7 (21.9)
Normal
25 (78.1)
Yes
14 (35.0)
No
26 (65.0)
Normal to normal
2 (6.8)
Improved
11 (38.0)
Persisted
8 (27.6)
Aggravated
8 (27.6)
Yes
17 (42.5)
No
23 (57.5)
*Total number of patients in whom Korean version of Sniffin’s Sticks was performed after surgery ** Total number of patients in whom comparison between preoperative and postoperative combined pituitary function test was available
1
Table 3. Postoperative headache during the first 6 months in the patients who underwent transsphenoidal surgery for nonfunctioning pituitary macroadenomas (n=35) Headache
Before surgery
Headache
1 month after surgery
Change
Versus
Change
Versus
1 month after surgery n
Increased
Decreased
No change or no headache
7
10
18
6 month after surgery
%
20.0
28.6
51.4
n
%
Increased
0
0
Decreased
7
20.0
No change
0
0
Increased
1
2.9
Decreased
0
0
No change
9
25.7
Increased
1
2.9
Decreased
1
2.9
No change
16
45.7
Table 4. Estimated effect of postoperative 1 month headache on the following headaches Headache
Headache Impact Test (postoperative 1 month) B
SE
95% CI
Wald X2
p value
.41
.10
.21 to .61
15.72
<.001***
Pain
.09
.02
.05 to .12
19.98
<.001***
Social Functioning
.07
.03
.02 to .12
6.71
.01*
Role Functioning
.06
.02
.02 to .10
8.31
.004**
Cognitive Functioning
.07
.02
.03 to .11
13.90
<.001***
Psychological Distress
.07
.02
.04 to .10
17.35
<.001***
Validity
.06
.02
.02 to .10
9.97
Total HIT-6
CI—Confidence interval; HIT-6—Headache Impact Test-6; SE—Standard Error *p<0.05, **p<0.01, ***p<0.001
1
.002**
Abbreviations List CPFT: Combined Pituitary Function Test GEE: Generalized Estimating Equation HIT-6: Headache Impact Test-6 ISP: IntraSellar Pressure MRI: Magnetic Resonance Imaging
S1878-8750(19)32565-3
DOI:
https://doi.org/10.1016/j.wneu.2019.09.123
Reference:
WNEU 13423
To appear in:
World Neurosurgery
Received Date: 26 July 2019 Revised Date:
21 September 2019
Accepted Date: 23 September 2019
Please cite this article as: Jang MK, Park CG, Jang S, Kim EH, Prevalence and Impact of Postoperative Headaches in Nonfunctioning Pituitary Macroadenoma Patients: A Longitudinal Cohort Study, World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2019.09.123. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Prevalence and Impact of Postoperative Headaches in Nonfunctioning Pituitary Macroadenoma Patients: A Longitudinal Cohort Study
Min Kyeong Jang1,2, Ph.D., KOAPN, RN, Chang Gi Park2, Ph.D., Seonguk Jang3, BBA, BS, and Eui Hyun Kim4,5,6, Ph.D., M.D. 1
University of Illinois Cancer Center, Chicago, IL, USA; 2University of Illinois at Chicago,
College of Nursing, Chicago, IL, USA; 3University of Minnesota School of Public Health, Minneapolis, MN, USA; 4Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Republic of Korea; 5Pituitary Tumor Center, Severance Hospital, Seoul, Republic of Korea; 6Yonsei Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
Funding: This work was supported by the National Institute of Nursing Research of the National Institutes of Health (K24NR015340); and the Basic Science Research Program through the NRF of Korea (NRF-2018R1C1B5042687) funded by the Korean Ministry of Science, ICT and Future Planning. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Correspondence: Eui Hyun Kim, M.D., Ph.D. Department of Neurosurgery, Yonsei University College of Medicine 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea Tel: +82-2-2228-2155
Fax: +82-2-393-9979
E-mail: [email protected]
Key words: Headache, Pituitary adenoma, Transsphenoidal surgery
Running title: Postoperative Headaches as a Predictor
Postoperative Headaches as a Predictor
1
Prevalence and Impact of Postoperative Headaches in Nonfunctioning
2
Pituitary Macroadenoma Patients: A Longitudinal Cohort Study
3 4
Abstract
5
BACKGROUND: Patients with nonfunctioning pituitary macroadenomas commonly experience
6
headaches before and after surgery, and headaches have been reported to significantly detract
7
from the quality of life. Despite this adverse impact, few studies have examined the prevalence
8
and pattern of headaches on a long-term basis. Thus, this study employed a longitudinal cohort
9
design to identify headache prevalence and severity during a 6-month postoperative period and
10
its predictors.
11
METHODS: Forty patients with nonfunctioning pituitary macroadenomas who underwent
12
transsphenoidal surgery were enrolled as subjects, and Headache Impact Test-6 (HIT-6) was
13
performed at four time points: before and 1, 3, and 6 months after surgery.
14
RESULTS: This study revealed that nonfunctioning pituitary macroadenoma patients suffered
15
from headaches at each of the four time points and that 37.5%, 27.8%, 17.9%, and 12.8% of the
16
patients experienced “substantial and severe impact headaches” before and 1, 3, and 6 months
17
after surgery, respectively. In addition, total HIT-6 scores 1 month after surgery were a
18
significant predictor (B = 0.41, p < 0.001) of headaches 3 and 6 months after surgery. Among the
19
HIT-6 items, pain (B = 0.09, p < 0.001), cognitive function (B = 0.07, p < 0.001), and
20
psychological distress (B = 0.07, p < 0.001) showed the greatest impact on long-term headaches.
21
CONCLUSION: Headaches adversely affected patients even 6 months after surgery.
22
Additionally, headaches 1 month after surgery predicted the prevalence of long-term headaches
23
at 3 and 6 months, demonstrating the importance of timely postsurgical measurement of
24
headaches to anticipate patients’ long-term headache patterns.
1
Postoperative Headaches as a Predictor
25
INTRODUCTION
26
Headaches are one of the most common symptoms experienced by pituitary adenoma patients
27
and have been reported in more than one-third of individuals during the treatment period.1
28
Nonfunctioning pituitary adenoma patients inevitably undergo transsphenoidal surgery as a
29
mainstay of the treatment options,2,3 often resulting in long-term headaches after surgery.4-6 One
30
prospective study reported that almost 50% of pituitary adenoma patients experienced
31
preoperative headaches6, and although headaches decreased after surgery in a significant number
32
of patients, almost 30% of the patients still experienced headaches 6 months post-surgery.
33
Similarly, another longitudinal cohort study reported that 63% of patients experienced headaches
34
before surgery and that 19% showed no improvement in headaches 3 months after surgery.5 Thus,
35
although transsphenoidal surgery results in tumor removal and contributes to headache relief,5-7
36
headaches remain an issue that adversely impacts some patients after surgery.8
37
Previous studies have identified various risk factors for headaches in pituitary adenoma
38
patients. For example, reported risk factors include adenoma size, sinus invasion, hormonal
39
effects, adenoma type, family history of headaches, intrasellar pressure (ISP), and intracranial
40
pain-sensitive structure displacement.1,4,9,10 In addition, one study found that tumor-attributed
41
headaches were associated with a history of headaches, nicotine abuse, taking acute-headache
42
medication, and higher tumor proliferation (reflected by a Ki67-LI >3%).11 Although migraine-
43
like headaches are a common clinical manifestation in patients with nonfunctioning pituitary
44
macroadenomas,10 headache types and locations vary.12 On the whole, the association between
45
pituitary adenoma and headaches is not well understood due to inconsistencies in previous
46
research findings.13 Furthermore, in their recent review article, Donovan and Welch12 noted that
47
the literature on headaches in pituitary adenoma patients was limited to only a few prospective
48
studies that focused on this topic. Although two previous longitudinal studies focused on
49
headache symptoms, these studies addressed many types of pituitary adenomas, and thus the
50
prevalence and pattern of headaches in nonfunctioning pituitary macroadenoma patients were not
51
specifically examined. In the clinical setting, healthcare providers encounter various headache
52
trajectories and require guidance regarding the appropriate times for headache assessment.
53
Considering that headaches adversely affect the quality of life (QOL) and daily life activities of
54
patients,6,14 proper assessment and management of headache symptoms are crucial to streamline 2
Postoperative Headaches as a Predictor
55
the course of treatment. Thus, a longitudinal cohort study is needed to focus on postsurgical
56
measurement of headaches.
57
Although clinics recommend that patients with nonfunctioning pituitary macroadenomas
58
have regular follow-up tests before and after surgery, including magnetic resonance imaging
59
(MRI), Humphrey Visual Field testing, and hormone tests, headache assessments tend to be
60
overlooked as part of routine care. Reflecting this lack of attention to headaches both in the clinic
61
and in research, no guidelines are currently available that specify when and how to assess
62
patients for headache symptoms. To help fill this research gap with respect to headaches in
63
patients with nonfunctioning pituitary macroadenomas and to provide information for such
64
guidelines, this study employed a longitudinal cohort design to identify the pattern and severity
65
of headaches in such patients and determine the best measurement time points for predicting
66
long-term headaches.
67 68
METHODS
69
Study Participants and Data Collection
70
This study was approved by the Institutional Review Board (approval #2013-0494) of
71
the Yonsei University Health System, Severance Hospital, in Republic of Korea. We recruited 40
72
patients diagnosed with nonfunctioning pituitary macroadenoma who were scheduled to undergo
73
transsphenoidal surgery from June 2013 through February 2014. Written informed consent was
74
obtained from all participants.
75
In this longitudinal study, each participant met the following inclusion criteria: each
76
patient had to (1) be more than 20 years of age, (2) have been diagnosed by MRI with a
77
macroadenoma with a diameter greater than 2 cm, (3) not have been indicated for medical
78
treatment (for endocrine-inactive pituitary adenomas), (4) be scheduled to undergo
79
transsphenoidal surgery, and (5) be able to understand and respond to the study survey. The
80
number of subjects for this study was estimated to be 40 for a generalized estimating equation
81
(GEE) analysis with an assumption of effect size of 0.23, power of 0.8, and alpha as 0.05.
82
For data collection, the Headache Impact Test-6 (HIT-6) was administered to the
83
participants in an outpatient setting at four time points: preoperatively (40 participants) and
84
postoperatively at 1 (36), 3 (39), and 6 months (39). In addition, the participants’ charts were 3
Postoperative Headaches as a Predictor
85
reviewed to identify their general and clinical characteristics.
86
All patients underwent preoperative dynamic MRI of the sellar region using a 3.0-Tesla
87
system (Achieva; Philips, Best, The Netherlands). Tumor size was measured as a maximal
88
diameter on a coronal plane. Immediate postoperative 3-Tesla diagnostic MRI was performed
89
within 48 h after the surgery and the extent of tumor removal was determined. The
90
endocrinological assessment with combined pituitary function test (CPFT) was fully described in
91
our previous report.15 The CPFT was performed to evaluate anterior pituitary function before
92
surgery and 6 months after surgery, and the results were confirmed by two endocrinologists.
93
Patient visual field was evaluated by standard automated perimetry using a Humphrey Visual
94
Field Analyzer (Carl Zeiss Meditec Inc., Germany). Olfactory function was measured by the
95
Korean version of Sniffin’ Sticks (KVSS).
96 97
Measure
98
The HIT-6 developed by Kosinski et al (2003)16 and translated by Chu et al. (2008)17
99
was used to measure the impact of headaches on the participants. The scale employs six items to
100
assess headache complexity by addressing pain, social function, role function, cognitive function,
101
psychological distress, and vitality. Each item is scored from 6 to 13, and total scores range from
102
36 to 78. Total scores fall into four categories: little to no impact headaches (36-49), some impact
103
headaches (50-55), substantial impact headaches (56-59), and severe impact headaches (60-78).
104
The total score indicates the effect that the headaches have on normal daily life and the ability to
105
function.
106 107
Statistical Analysis
108
Both general and clinical participant characteristics as well as the prevalence and
109
severity of the participants’ headaches were analyzed using a descriptive statistical method. To
110
enrich unbiased estimation of population-averaged regression coefficients, GEEs were used to
111
analyze the longitudinal headache data. During the study, a small number of participants failed to
112
contribute data during various postsurgical time points. However, the quantity of missing data
113
was below 5%, so a missing data approach was not employed. All statistical analyses were
114
performed using SPSS version 24.0 (SPSS Inc., Chicago, IL, USA). All statistical tests were two4
Postoperative Headaches as a Predictor
115
tailed, and p < 0.05 was considered to indicate a significant result.
116
RESULTS
117
General and Clinical Characteristics
118
Participant demographics and clinical characteristics are summarized in Table 1 and
119
Table 2, respectively. The 40 nonfunctioning pituitary macroadenoma patients consisted of 19
120
males (47.5%) and 21 females (52.5%) with a mean age of 52 years; ages ranged from 22 to 77
121
years. The mean tumor size was 3.2 cm (range, 2.0–6.4 cm). Of the participants, 29 (72.5%)
122
underwent total resection of the tumors, and 11 (27.5%) underwent subtotal resection.
123
Furthermore, 17 (42.5%) of the participants required hormone replacement therapy after surgery
124
and eventually during the follow-up period. Anterior pituitary function was assessed in 29
125
patients in whom comparisons between their preoperative and 6-month postoperative CPFT data
126
were available. At least one axis of anterior pituitary hormones showed preoperative or
127
postoperative hypopituitarism in 27 (67.5%) and 23 (57.5%) of the participants, respectively.
128
Anterior pituitary function worsened in 8 (27.6%), improved in 11 (37.9%), and did not change
129
in 10 of the patients (34.5%).
130 131
Headache Prevalence and Severity
132
With respect to total HIT-6 scores, headaches 1 month after surgery showed the highest
133
score (47.19 ± 9.16), with scores ranging from 36 to 74. Whereas headaches 6 months after
134
surgery showed the lowest score (40.95 ± 7.55), with scores ranging from 36 to 64. Before
135
surgery, the mean headache score was 46.85 ± 8.98, and scores ranged from 36 to 65; whereas 3
136
months after surgery, the mean headache score was 43.44 ± 6.77, and scores ranged from 36 to
137
58. Among the HIT-6 items, “pain” had the highest score at all time points over the 6 month
138
duration. “Vitality” had the lowest scores before surgery and 3 months after surgery; whereas
139
“cognitive function” had the lowest scores 1 and 6 months after surgery. The total HIT-6 scores
140
of all the participants across all time points fell into the “little to no impact headache” category.
141
However, in the HIT-6 impact categories (Fig. 1), 15 (37.5%), 10 (27.8%), 7 (17.9%), and 5
142
(12.8%) of the participants reported moderate, substantial, or severe impact headaches before
143
surgery and 1, 3, and 6 months after surgery, respectively.
144
Table 3 shows the change in headache patterns between before surgery and 1 month after 5
Postoperative Headaches as a Predictor
145
surgery and between the 1 month after surgery and 6 months after surgery. These comparisons
146
were based on the responses for patients who had no missing data in the three follow-up
147
timepoint tests. Among 35 total participants, the level of headaches in 10 participants (28.6%)
148
decreased 1 month after surgery compared to before surgery. Among 10 participants, 9
149
participants (90%) did not require hormonal replacement after surgery and 6 participants (60%)
150
had no comorbidities. On the contrary, the level of headaches in 7 participants (20.0%) increased
151
1 month after surgery compared to before surgery. Among these 7 participants, 6 participants
152
reported to have “little to no impact headache” in the preoperative period, thus these cases were
153
regarded as new headaches. Furthermore, 5 of these 7 participants (71.4%) underwent subtotal
154
resection surgery, and 4 (57.1%) required hormone replacement therapy. For these 35
155
participants, the size of the tumor, presence of cavernous sinus invasion, extent of tumor
156
resection, changes in visual field, presence of postoperative hyposmia, presence of preoperative
157
hypopituitarism, and outcome of pituitary hormonal function were not associated with HIT-6
158
scores or its changes during the first 6 months.
159 160
Longitudinal Headache Prediction Model
161
Table 4 summarizes the GEE analysis results. Controlling for general and clinical
162
participant characteristics, the total HIT-6 score at 1 month after surgery was a significant
163
predictor of headaches 3 and 6 months after surgery (B = 0.41, p < 0.001). In addition, each HIT-
164
6 item score was found to significantly predict long-term headaches. Specifically, the strongest
165
predictors of long-term headaches were “pain” (B = 0.09, p < 0.001), “cognitive function” (B =
166
0.07, p < 0.001), and “psychological distress” (B = 0.07, p < 0.001), whereas “social function”
167
(B = 0.07, p < 0.01) was the weakest predictor. The total HIT-6 score 1 month after surgery
168
remained a significant predictor of long-term headaches (p < 0.05) when we did not control for
169
participant characteristics, but the p-value indicated less significance than when we adjusted for
170
these characteristics.
171 172
DISCUSSION
173
This study identified the importance of measuring headaches 1 month after surgery as a
174
predictor for long-term headaches and a basis for quality care. In our study findings, the total 6
Postoperative Headaches as a Predictor
175
HIT-6 score did not impact “substantial and severe impact headaches” at each time point because
176
each of the mean values of the total HIT-6 score tended to belong to the “little impact or no
177
impact headaches” range of scores. However, in Figure 1, “substantial and severe impact
178
headache” scores were 37.5%, 27.8%, 17.9%, and 12.8%, before surgery and 1, 3, and 6 months
179
after surgery, respectively. In other words, headaches are the common symptom of
180
nonfunctioning pituitary macroadenoma during the treatment process, and transsphenoidal
181
surgery did not guarantee total resolution of the headache symptoms. Similar to our findings,
182
other longitudinal studies have also reported that 20–30% of pituitary adenoma patients still
183
suffer from headaches, and therefore headaches remain an essential issue.5,6 Headaches are a
184
significant symptom for pituitary adenoma patients before surgery (p < 0.001), and chronic
185
headaches are more prevalent for these patients when compared to the general population (p =
186
0.001).2 Therefore, healthcare providers recognize that headaches associated with pituitary
187
adenoma are a common long-term issue, and the prevalence and severity of the headaches are
188
still an important consideration during the treatment process.
189
Postoperative headaches are simply regarded as a surgical procedure-related symptom;
190
however, headache mechanisms derived from the pituitary adenoma are complicated and not
191
well understood. Indeed, it has been reported that transsphenoidal surgery is not guaranteed to
192
positively influence headache symptoms for a certain period of time after surgery.1,18 In our
193
findings, 7 participants (20%) experienced an increased level of headaches 1 month after surgery
194
compared to the preoperative period. Among these participants, 5 (71.4%) underwent subtotal
195
resection surgery and 4 (57.1%) experienced hormonal deficiency after surgery. In contrast, for
196
other 10 participants who experienced decreased headache symptoms after surgery, 5 (50%)
197
underwent total resection surgery, and 9 (90%) had no hormonal deficiency after surgery. Based
198
on these findings, both hormonal sufficiency or deficiency and extent of tumor resection may be
199
predictors of headache relief or severity after surgery. Pathophysiology of headache in pituitary
200
adenoma includes various mechanical, biochemical, vascular, and biopsychosocial mechanisms.
201
In addition, tumor size is known as an important pathophysiological cause of headaches.1 In
202
other words, pituitary tumor size, or the “mass effect,” can lead to increased ISP. A previous
203
study reported that patients with headaches were more likely to have higher ISP levels compared
204
to patients without headaches, and those symptoms were related to intratumoral hemorrhage and 7
Postoperative Headaches as a Predictor
205
compromised dural integrity at the sella.18 In cases of postsurgical pituitary tumors and
206
headaches, residual tumors in the cavernous sinus and endocrine imbalances may increase the
207
headache symptoms, so optimal management strategies are consistently required after surgery.13
208
Therefore, future studies need to comprehensively investigate the risk factors and epidemiology
209
of headaches, including comparison of headache patterns before and after surgery.
210
Furthermore, this study contributed to the understanding that the presence of headaches
211
1 month after surgery was a significant predictive factor for headaches 3 and 6 months after
212
surgery when controlling for all general and clinical patient characteristics. This phenomenon
213
shows the importance of screening for headaches 1 month after surgery as an indicator for long-
214
term headaches. Also, there was substantial variation in headache scores, which ranged from 36
215
to 74 1 month after surgery. The prevalence of postoperative headaches suggests that measures
216
should be taken to successfully address and manage headaches 1 month after surgery in an
217
outpatient setting. Considering that headaches are a signature factor affecting QOL, health
218
providers cannot overlook the importance when patients return to their general lives. In addition,
219
although the main symptoms reported by patients with nonfunctioning primary adenoma are
220
headaches, visual deterioration, and hypopituitarism, inpatient and outpatients assessments
221
regularly include MRI, Humphrey visual field, and hormonal tests; headache assessments are
222
noticeably absent. Because headaches are a subjective symptom, they are neglected because of
223
the difficulty to objectively measure and complex causality. However, regular assessment and
224
management of headaches 1 month after surgery should be considered using pharmacological
225
and nonpharmacological approaches. Our findings suggest that timely, appropriate assessment
226
and efficient management may help treat headache symptoms and improve patient QOL.
227
Although preoperative headaches are a common symptom of pituitary adenomas and one of the
228
surgical indications, patients should be informed that they may experience headaches for a
229
certain period of time after surgery and should consult a physician for appropriate management.
230
If patient headaches persist 1 month after surgery, proper professional medical intervention with
231
regular monitoring should be provided because they have a higher chance of long-term
232
headaches. Whether medical intervention can decrease the probability of long-term headaches
233
should be further investigated.
234
In our research phase, we realized that a disease-specific headaches as an instrument for 8
Postoperative Headaches as a Predictor
235
pituitary adenoma patients should be developed by incorporating systematic review of headache
236
risk factors. Although HIT-6 is a validated instrument used to assess headaches and the impact on
237
daily function for patients with primary adenoma, items on the HIT-6 cover broader concepts to
238
assess headache impact rather than an in-depth assessment of headaches for pituitary adenoma.
239
Specifically, known risk factors for headaches in patients with pituitary adenoma are tumor size,
240
sinus invasion, hormone unbalance, and headache history; however, these risk factors are not
241
assessed as part of the HIT-6 instrument. Thus, it would be beneficial for future studies and
242
clinical assessments to develop a new evidence-based and disease-specific instrument that
243
includes more objective risk factors for pituitary adenoma. The new headache assessment could
244
be an essential instrument for assessing symptoms for patients with pituitary adenoma to
245
efficiently improve quality of care in a neurosurgical clinical setting.
246
Future studies should include broader pituitary adenoma patients and use a disease-
247
specific instrument for headaches. Many healthcare providers tend to overlook headache
248
symptoms due to noticeable neurological symptoms, including visual deterioration and hormonal
249
effects. However, considering that headaches significantly impact QOL, a longitudinal
250
prospective cohort study will be needed to conduct regular and more accurate assessments and to
251
identify effective treatments in the management of headaches. Although the pattern and risk
252
factors for headaches are still unclear and an area of active study in pituitary adenoma, screening
253
for headaches 1 month after surgery should be conducted to prevent chronic headaches and their
254
impact on quality of care in a neurosurgical clinical setting.
255 256
CONCLUSION
257
Although transsphenoidal surgery is the best way to treat and cure nonfunctioning
258
pituitary adenoma, patients still reported headaches as a common symptom after surgery. Our
259
findings indicated that headaches 1 month after surgery could be a predictor for long-term,
260
chronic headaches, and therefore assessment and management of headaches should be regularly
261
applied. This study further suggests that an evidence-based and disease-specific instrument for
262
headache assessment in pituitary adenoma should be systematically developed.
263
9
Postoperative Headaches as a Predictor
264
Figure Legends
265
FIGURE 1. Prevalence and severity of headaches. Headaches worsened after surgery as
266
shown by the highest Headache Impact Test-6 (HIT-6) score 1 month after surgery. Headaches
267
gradually decreased, and HIT-6 scores were lower 6 months after surgery than before surgery.
268
Overall, 37.5%, 27.8%, 17.9%, and 12.8% of the participants reported moderate, substantial, or
269
severe impact headaches before surgery and 1, 3, and 6 months after surgery, respectively.
10
References 1. Kreitschmann Andermahr I, Siegel S, Weber Carneiro R, Maubach J, Harbeck B, Brabant G. Headache and pituitary disease: A systematic review. Clin Endocrinol(Oxf). 2013;79(6):760-769. 2. Gravdahl GB, Tronvik EA, Fougner SL, Solheim O. Pituitary adenoma and non-acute headache: Is there an association, and does treatment help? World Neurosurg. 2016;92:284-291. 3. Murad MH, Fernández Balsells M, Barwise A, et al. Outcomes of surgical treatment for nonfunctioning pituitary adenomas: A systematic review and meta analysis. Clin Endocrinol (Oxf). 2010;73(6):777-791. 4. Suri H, Dougherty C. Clinical presentation and management of headache in pituitary tumors. Curr Pain Headache Rep. 2018;22(8):55. 5. Rizzoli P, Iuliano S, Weizenbaum E, Laws E. Headache in patients with pituitary lesions: A longitudinal cohort study. Neurosurgery. 2015;78(3):316-323. 6. Wolf A, Goncalves S, Salehi F, et al. Quantitative evaluation of headache severity before and after endoscopic transsphenoidal surgery for pituitary adenoma. J Neurosurg. 2016;124(6):1627-1633. 7. Hayashi Y, Kita D, Iwato M, et al. Significant improvement of intractable headache after transsphenoidal surgery in patients with pituitary adenomas; preoperative neuroradiological evaluation and intraoperative intrasellar pressure measurement. Pituitary. 2016;19(2):175-182. 8. Siegel S, Carneiro RW, Buchfelder M, et al. Presence of headache and headache types in patients with tumors of the sellar region—can surgery solve the problem? results of a prospective single center study. Endocrine. 2017;56(2):325-335. 9. Gondim JA, Almeida JP, de Albuquerque, Lucas Alverne F, Gomes E, Schops M, Ferraz T. Pure endoscopic transsphenoidal surgery for treatment of acromegaly: Results of 67 cases treated in a pituitary center. Neurosurgical focus. 2010;29(4):E7. 10. Yu B, Ji N, Ma Y, Yang B, Kang P, Luo F. Clinical characteristics and risk factors for headache associated with non-functioning pituitary adenomas. Cephalalgia. 2017;37(4):348-355. 11. Schankin CJ, Reifferscheid AK, Krumbholz M, et al. Headache in patients with pituitary adenoma: Clinical and paraclinical findings. Cephalalgia. 2012;32(16):1198-1207. 12. Donovan LE, Welch MR. Headaches in patients with pituitary tumors: A clinical conundrum. Curr Pain Headache Rep. 2018;22(8):57. 13. Levy MJ. The association of pituitary tumors and headache. Curr Neurol Neurosci Rep. 2011;11(2):164-170. 14. Pereira-Neto A, Borba AM, Mello PAd, Naves LA, Araújo Jr, Antônio Santos de, Casulari LA. Mean intrasellar pressure, visual field, headache intensity and quality of life of
patients with pituitary adenoma. Arq Neuropsiquiatr. 2010;68(3):350-354. 15. Lee EJ, Ahn JY, Noh T, Kim SH, Kim TS, Kim SH. Tumor tissue identification in the pseudocapsule of pituitary adenoma: Should the pseudocapsule be removed for total resection of pituitary adenoma? Oper Neurosurg. 2009;64(suppl_1):ONS62-ONS70. 16. Kosinski M, Bayliss M, Bjorner J, et al. A six-item short-form survey for measuring headache impact: The HIT-6™. Qual Life Res. 2003;12(8):963-974. 17. Chu M, Im H, Ju Y, Yu K, Ma H, Lee B. Validity and reliability assessment of Korean headache impact test-6 (HIT-6). J Korean Neurol Assoc. 2008;27(1):1-6. 18. Hayashi Y, Sasagawa Y, Oishi M, et al. Contribution of intrasellar pressure elevation to headache manifestation in pituitary adenoma evaluated with intraoperative pressure measurement. Neurosurgery. 2018;84(3):599-606.
Table 1. Demographic and Clinical Characteristics
(N=40)
Category Age (years)
Sex
Marital status
Religion
Economic burden
Mean ± SD 51.95 ± 15.10 (range, 22-77)
20-29
3(7.5)
30-39
6(15.0)
40-49
9(22.5)
50-59
7(17.5)
60-69
9(22.5)
70-79
6(15.0)
Male
19(47.5)
Female
21(52.5)
Single
9(22.5)
Married
31(77.5)
None
13(32.5)
Christian
15(37.5)
Buddhist
9(22.5)
Catholic
3(7.5)
Never
23(57.5)
A little
13(32.5)
Very Education
Occupation
Comorbidity
n (%)
4(10.0)
Middle school
12(30.0)
High school
12(30.0)
≥College
16(40.0)
None
13(32.5)
Yes
27(67.5)
None
21(52.5)
Diabetes
2(5.0)
Hypertension
4(10.0)
Others
13(32.5)
SD—Standard Deviation
1
Table 2. General clinical outcomes of 40 patients with nunfunctioning pituitary adenomas Category Extent of resection
Visual field
Subtotal
11 (27.5)
Total
29 (72.5)
Improved (>5dB)
27 (67.5)
Unchanged
13 (32.5)
Worsened (>5dB) Olfaction (n=32) *
Preoperative hypocortisolemia
Anterior pituitary function (n=29) **
Postoperative hormonal replacement
n (%)
0 (0)
Hyposmia
7 (21.9)
Normal
25 (78.1)
Yes
14 (35.0)
No
26 (65.0)
Normal to normal
2 (6.8)
Improved
11 (38.0)
Persisted
8 (27.6)
Aggravated
8 (27.6)
Yes
17 (42.5)
No
23 (57.5)
*Total number of patients in whom Korean version of Sniffin’s Sticks was performed after surgery ** Total number of patients in whom comparison between preoperative and postoperative combined pituitary function test was available
1
Table 3. Postoperative headache during the first 6 months in the patients who underwent transsphenoidal surgery for nonfunctioning pituitary macroadenomas (n=35) Headache
Before surgery
Headache
1 month after surgery
Change
Versus
Change
Versus
1 month after surgery n
Increased
Decreased
No change or no headache
7
10
18
6 month after surgery
%
20.0
28.6
51.4
n
%
Increased
0
0
Decreased
7
20.0
No change
0
0
Increased
1
2.9
Decreased
0
0
No change
9
25.7
Increased
1
2.9
Decreased
1
2.9
No change
16
45.7
Table 4. Estimated effect of postoperative 1 month headache on the following headaches Headache
Headache Impact Test (postoperative 1 month) B
SE
95% CI
Wald X2
p value
.41
.10
.21 to .61
15.72
<.001***
Pain
.09
.02
.05 to .12
19.98
<.001***
Social Functioning
.07
.03
.02 to .12
6.71
.01*
Role Functioning
.06
.02
.02 to .10
8.31
.004**
Cognitive Functioning
.07
.02
.03 to .11
13.90
<.001***
Psychological Distress
.07
.02
.04 to .10
17.35
<.001***
Validity
.06
.02
.02 to .10
9.97
Total HIT-6
CI—Confidence interval; HIT-6—Headache Impact Test-6; SE—Standard Error *p<0.05, **p<0.01, ***p<0.001
1
.002**
Abbreviations List CPFT: Combined Pituitary Function Test GEE: Generalized Estimating Equation HIT-6: Headache Impact Test-6 ISP: IntraSellar Pressure MRI: Magnetic Resonance Imaging