- Email: [email protected]
Preoperative and Postoperative Headache in Patients with Intracranial Tumors
Accepted Manuscript Pre- and postoperative headache in patients with intracranial tumors Bodil Karoline Ravn Munkvold, Medical Student with Research Programme, Lisa Millgård Sagberg, MSc, Asgeir Store Jakola, MD, PhD, Ole Solheim, MD, PhD PII:
S1878-8750(18)30760-5
DOI:
10.1016/j.wneu.2018.04.044
Reference:
WNEU 7880
To appear in:
World Neurosurgery
Received Date: 4 December 2017 Revised Date:
5 April 2018
Accepted Date: 6 April 2018
Please cite this article as: Ravn Munkvold BK, Sagberg LM, Jakola AS, Solheim O, Pre- and postoperative headache in patients with intracranial tumors, World Neurosurgery (2018), doi: 10.1016/ j.wneu.2018.04.044. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
ACCEPTED MANUSCRIPT Munkvold
Pre- and postoperative headache in patients with intracranial tumors
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Authors:
Bodil Karoline Ravn Munkvold (Medical Student with Research Programme) 1
o Postal address: NTNU, Faculty of Medicine and Health Sciences, N-7491
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Lisa Millgård Sagberg (MSc) 2,3,4
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Trondheim, Norway. E-mail: [email protected].
o Postal address: Edvard Griegs gate 8, Nevro øst * 121.03.032. Telephone
-
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number: +47 72575697. E-mail address: [email protected]. Asgeir Store Jakola (MD, PhD) 4,5,6
o Postal address: Blå stråket 5, plan 3, 41345 Göteborg. Telephone number: +46 31-342 27 63. E-mail address: [email protected]. -
Ole Solheim (MD, PhD) 2,3,4
o Postal address: Edvard Griegs gate 8, Nevro øst. Telephone number: +47 73 59
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20 20. E-mail address: [email protected].
1. The Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
2. Norwegian National Advisory Unit for Ultrasound and Image Guided Therapy, St. Olavs
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University Hospital, Trondheim, Norway 3. Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway
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4. Department of Neurosurgery, St. Olav’s University Hospital, Trondheim, Norway
5. Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden
6. Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden
Corresponding author information: Bodil Karoline Ravn Munkvold, Medical research student, Faculty of Medicine, Norwegian University of Science and Technology, Post Box 8905, N-7491 Trondheim, Norway ([email protected]). 1
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Sources of financial and material support: The study was supported by the Norwegian Research Council and the Faculty of Medicine at the
from the Norwegian Cancer Society.
Keywords: Brain neoplasms; Headache; Surgery
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Abbreviations list:
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Norwegian University of Science and Technology (NTNU). Asgeir Jakola has research funding
BTH- Brain tumor related headache
HGG- High-grade glioma
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EORTC- The European Organization for Research and Treatment of Cancer
HUNT- The Nord-Trøndelag Health Study
ICHD- International Classification of Headache Disorders KPS- Karnofsky Performance Status REC- Regional Ethics Committee
Abstract Objective
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WHO- World Health Organization
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We sought to examine prevalence of headache in patients with histopathologically verified intracranial tumors scheduled for surgery, and assess change in headache 1 and 6 months after
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surgical resection. Possible tumor and patient related predictors for preoperative headache and early postoperative symptom relief were also explored.
Methods
The European Organization for Research and Treatment of Cancer (EORTC) has developed a quality of life questionnaire (EORTC QLQ-C30) with a brain cancer specific module, QLQBN20, containing 20 questions rating symptoms the past week on an ordinal scale ranging from 1-4. Analyses are based on question 4 in this questionnaire.
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ACCEPTED MANUSCRIPT Munkvold Results In this prospective population based cohort study of 507 patients we found that headache is a frequent symptom in patients with intracranial neoplasms. 52% reported some degree of preoperative headache, and the prevalence dropped to 43% and 30% 1 and 6 months
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postoperatively. 19% and 9% reported postoperative worsening or new headache 1 and 6 months after surgery. Younger age, female gender and occipital tumor location were significant
predictors for both preoperative headache and early postoperative relief. Additionally, Karnofsky Performance Status (KPS) below 70 was a predictor for headache relief 1 month after surgery.
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No independent risk factors for worsening or new headache after surgery were identified.
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Conclusion
Headache is a common symptom in patients with intracranial tumors, especially in younger and female patients. Many patients experience improvement after surgery, and younger age, female gender, occipital tumor location and functional dependence were identified as factors associated
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with early postoperative headache relief.
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Pre- and postoperative headache in patients with intracranial tumors Introduction
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Headache is a common symptom in patients with intracranial tumors. In case series with
unselected brain tumor patients it is reported that 20 % present with headache as an initial
symptom, 50-60 % experience the symptom during the course of disease1–3 and 36 % suffer from headache at end of life. 4 Headache is the most predominant symptom in about half of the
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patients, 1 and prevalence does not seem to differ between primary and metastatic brain tumor
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patients. 1,5,6
The pathophysiology behind brain tumor related headache (BTH) is poorly understood, and the symptomatic effect of surgical resection is not much studied. Brain parenchyma is insensitive to pain and suggested pathophysiological explanations of BTH include traction of large blood vessels and meninges, and compression of cranial and cervical nerve fibers. 5,7 Histopathology, anatomical location, lesion volume and growth rate are tumor related factors that might explain
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some of the diversity and complexity in BTH. 8–10 Consistent with headache epidemiology in the general population, several patient-related factors are known to be of importance, making it difficult to identify a distinct headache pattern in patients with intracranial neoplasms. 2,10,11
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In this prospective cohort study, we sought to examine preoperative prevalence of self-reported headache in patients scheduled for surgery of intracranial neoplasms and explore the association
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between preoperative headache and tumor and patient related factors. Furthermore, we wanted to assess change in headache after surgical resection and explore factors possibly related to early postoperative relief.
Material and methods Study variables The European Organization for Research and Treatment of Cancer (EORTC) has developed a quality of life questionnaire, EORTC QLQ-C30, with a specific brain cancer module EORTC QLQ-BN20 that assesses disease symptoms, adverse effects of treatment, and some psychosocial 4
ACCEPTED MANUSCRIPT Munkvold aspects of relevance in patients with brain neoplasms. The BN20 module contains 20 questions, among them whether headache is present or not (question no. 4). The symptom burden is rated on an ordinal scale ranging from 1-4, indicating the extent of experienced headache during the past week (1= ‘not at all’, 2= ‘a little bit’, 3= ‘quite a bit’, 4= ‘very much’). Mapping and analysis of
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symptom development was based on this BN20 module. Karnofsky Performance Status (KPS) is a validated ten-level ordinal scale ranging from 100 (normal function) to 0 (death), that was used to rate the patients’ level of functioning. 12
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Data collection
Included patients gave their informed written consent, and filled out the questionnaires 1-3 days
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prior to surgery. The preoperative KPS was scored on admission by a study nurse or the operating surgeon. Follow-up was based on structured telephone interviews performed by a study nurse, approximately 1 month (median 31 days) and 6 months after surgery. Extent of surgical resection was calculated from pre- and early postoperative MRI. The tumor volumes of ellipsoid-shaped lesions were calculated by applying the volume formula ܸ =
ସగభ మ య ଷ
, based on maximal
perpendicular tumor diameters, as done by others. 13 The volumes of cup-shaped residual tumors
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were calculated by subtracting the ellipsoid-shaped resection cavity from the volume of the tumor complex, while more complex tumor configurations were manually segmented. 14 Other study
Included patients
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variables were retrieved from medical records.
712 patients ≥18 years were diagnosed with a histopathologically verified intracranial tumor
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classified according to the 2007 WHO Classification of Tumors of the Central Nervous System15 in the inclusion period from September 2011 to November 2015 at the Department of Neurosurgery at St. Olav’s University Hospital, Trondheim, Norway. Our department serves exclusively a defined geographical catchment region with a population of approximately 720 000, and the study sample is therefore practically an unselected population-based series. The study question regarding headache was filled out at baseline in 507 patients. These served basis for the preoperative prevalence data. To assess the symptomatic effect of surgical tumor resection, 45 patients with biopsy only were excluded. 56 patients did not answer the study question after 1 month, and 105 patients did not answer at 6 months. This left 406 and 357 patients with complete
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ACCEPTED MANUSCRIPT Munkvold pre- and postoperative data for assessment of change in headache 1 and 6 months after surgical resection respectively. The flow chart of the inclusion process is presented in figure 1.
Statistics
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Descriptive analyses were performed to examine prevalence of headache before and after
surgery. The association between headache and categorical factors was explored using the
Pearson Chi-Square or Fishers’ exact test. For continuous variables, normal distribution was assessed using the Shapiro-Wilk test and Q-Q plot. T-test or Mann-Whitney-U test was carried
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out to compare continuous variables depending on whether data was normally distributed or skewed. The Kruskal-Wallis test was used to assess distribution of headache between multiple
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categorical variables. In order to assess possible factors associated with headache, a multivariable logistic regression analysis was performed. Univariables with a statistical trend (p<0.10) were included in the multivariable model. The Hosmer and Lemeshow goodness of fit test was used to determine adequacy of the regression model, and the Nagelkerke R2 value to assess how much variation in the dependent variable could be explained by the model. Statistical significance was
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defined as p<0.05. Analyses were performed using SPSS version 24.
The study was approved by the Regional Committee for Medical and Health Research Ethics as part of a larger project (REC reference 2011/974, “Quality of life in patients with intracranial
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neoplasms”). Informed consent was obtained from all study participants, and the project is
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adherent to the Declaration of Helsinki. 16
Results
Preoperative headache and possibly associated factors As seen in table 1, 264 out of 507 (52%) had experienced some degree of headache during the last week before surgery. 30% rated symptom burden ‘a little bit’, 12% ‘quite a bit’ and 10% ‘very much’ (table 3). As shown in table 1, patients who reported preoperative headache were significantly younger, median age 54.5 years (18-88) vs. 62 years (19-82) (p<0.001). Women reported headache more frequently than men, 62% vs. 44% (p<0.001). Patients with tumor
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cerebellum or brainstem was not associated with statistically significant higher headache
prevalence, 32/51 (63%) vs. 232/456 (51%) (p=0.108). 241/507 (48%) patients had received corticosteroids prior to answering the headache questions at baseline. However, headache
prevalence did not differ between the patient group who had received corticosteroids prior to
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admission and the patient group who had not, 121/241 (50%) vs. 143/266 (54%) respectively (p=0.424).
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Possible predictors for preoperative headache were explored in a multivariable regression analysis (table 2). Intra-axial tumor origin, location in the occipital lobe, age, and gender were tumor factors that exhibited a statistical trend (p<0.1) as univariables, and were therefore included in the multivariable model. Younger age, female gender and occipital tumor location were significantly and positively associated with headache at baseline in the multivariable analysis. The Hosmer and Leweshow test was not significant (p=0.616), implicating that the
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regression model was a good fit. Predictive accuracy (i.e. how good the model is for predicting whether patient has preoperative headache) was 61.7%.
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Change in headache postoperatively
173 of 406 patients (43%) reported some degree of headache 1 month after surgery. 25% experienced ‘a little bit’ headache the past week before filling out the follow-up questionnaire,
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12% ‘quite a bit’, and 6% of patients suffered ‘very much’ from headache during the week before follow-up (table 3). 131/406 patients (32%) patients reported improvement compared to headache at baseline, 199/406 (49%) no change and 76/406 (19%) worsening 1 month postoperatively. A larger proportion of women reported improvement compared to men, 73/186 (39%) vs. 58/220 (26%) (p=0.006). Patients reporting postoperative relief were significantly younger than patients reporting worsened or unchanged headache postoperatively, median 54 years vs. 58 years (p=0.023). 16/31 (52%) of patients with preoperative KPS below 70 reported postoperative relief compared to 110/360 (31%) with KPS ≥ 70 (p=0.016).
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107 of 357 patients (30%) of patients reported some degree of headache 6 months postoperatively; 19% ‘a little bit’, 7% ‘quite a bit’ and 4% ‘very much’. 128/357 (36%) reported
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improvement, 197/357 (55%) no change and 32/357 (9%) worsening 6 months after surgical resection. Women reported improvement more frequently than men, 68/160 (43%) and 60/197 (30%) respectively (p=0.018). The patient group reporting improvement at 6 months was
significantly younger than the group experiencing worsening or unchanged headache, 52 (18-88) years vs. 58 (19-79) years (p=0.002). Median tumor volume was 15.4 ml in patients
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experiencing improvement and 10.6 ml in the group who did not (p=0.022). 59/186 (32%) with
with extra-axial tumors (p=0.089).
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intra-axial tumors experienced headache relief 6 months after surgery compared to 69/171 (40%)
Of patients who reported some degree of headache prior to surgery 60 and 70% reported improvement 1 and 6 months after surgery, while 12% and 6% experienced worsening. As seen in table 4, the risk of postoperative worsening was lower in patients with more preoperative
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symptoms.
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Factors possibly related to early postoperative relief Of factors reported in table 1 only tumor location in the occipital lobe, tumor volume, age, gender and KPS were associated with a statistical trend (p<0.1) for improvement of headache 1 month
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postoperatively as univariables (table 5). These variables were included in the multivariable logistic regression model. Location in the occipital lobe, female gender, younger age and KPS <70 were significant positive predictors for postoperative relief 1 month after surgery in the multivariable model. Larger tumor volume did not reach statistical significance in the
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multivariable model, OR=1.01 per 1 ml increase in tumor volume (p=0.059). The Hosmer and Leweshow test was not significant (p=0.179), implicating that the regression model was a good fit. Predictive accuracy (i.e. how good the model is for predicting whether headache was
worsened/ unchanged headache).
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improved or worsened/unchanged) was 69% (95% correct prediction in the group experiencing
Possible predictors for worsening 1 month after surgery were also explored. However, a multivariable model was not developed because non-frontal tumor location was the only variable showing a statistical trend with regard to prediction of worsening. The risk of symptomatic
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worsening or new headache was 18/130 (14%) in patients with tumors in the frontal lobe compared to 58/276 (21%) in other tumor locations.
Discussion
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In this prospective population based cohort study we found that headache is a frequent symptom in patients with intracranial neoplasms. More than one half of the patients reported some degree
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of headache prior to surgery. The prevalence dropped gradually to one third at 6 months after surgery. Younger age, female gender and occipital tumor location were the only independent factors that were associated with higher headache prevalence at baseline in the multivariable analysis. Among patients with headache prior to surgical resection, 60% and 70% reported improvement 1 and 6 months postoperatively, while 12% and 6% reported worsening of headache or new headache complaints. Occipital tumor location, younger age, female gender, and KPS <70 were identified as independent predictors for improvement 1 month after surgery. We could not identify independent risk factors for worsening or new headache after surgery.
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ACCEPTED MANUSCRIPT Munkvold The high prevalence of headache at baseline is comparable to findings from other studies in patients with intracranial tumors. 2,10 However, many patients received corticosteroid treatment before inclusion and may therefore have experienced symptom relief before answering the questionnaires at baseline. Some patients also received chemotherapy and/ or radiotherapy after
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surgery, possibly interfering with symptom evaluation postoperatively. A substantial proportion of patients experienced improvement of headache after surgery. Postoperative relief may be directly attributed to the surgical treatment, but it is perhaps not unlikely that surgery also
provides some placebo effect or regression to the mean like for example seen after surgery for
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arachnoid cysts. 17,18 To be noted, 19% and 9% of patients reported worsening or new headache 1 and 6 months after surgery but risk factors could not be identified. As the follow-up
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questionnaires were filled out, some patients with high-grade gliomas (HGG) had experienced disease progression but we did not evaluate the potential effect of tumor progression on headache symptoms in the present study. Still, worsening was not associated with histopathology. At 1 month after surgery some patients may still be suffering from postcraniotomy headache, which is a known complication following surgery, although resolving in with time in most cases. 19 The risk of postoperative worsening was lower in patients with more preoperative symptoms,
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probably reflecting a ceiling effect. It is difficult to know for certain whether there is direct causality between postoperative headache relief and the surgical intervention. Similarly, postoperative symptom worsening is not necessarily surgery-related either. Even so, the potential risk of headache worsening following surgery should nevertheless be taken into consideration,
for surgery.
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especially if the indication for treatment is relative. Headache alone is a controversial indication
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Globally, the prevalence of active headache disorders is 46% for headache in general in the adult population, 11% for migraine, 42% for tension-type headache and 3% for chronic daily headache. 20
Although questionnaires are not necessarily comparable, these numbers are perhaps not very
different from the prevalence reported in our brain tumor cohort after surgery. We failed to identify any tumor related factors that were independently associated with headache at baseline, but found that prevalence of headache was higher in young and female patients both at baseline and after surgery. 21 However, younger age and female gender are well-known risk factors for headache also in the general population. 11 A large Norwegian population health study, HUNT-3,
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ACCEPTED MANUSCRIPT Munkvold included 39,690 individuals22 over the age of 20, and found that the overall age- adjusted 1-year headache prevalence was 43% in women and 30% in men. 23 The correlation between headache and age in the general population varies somewhat with phenotype of headache, but a declination in symptom burden is expected with age. 11,24 Since headache may be associated with intracranial
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hypertension1,6,10 it may be speculated that age related brain atrophy might counteract intracranial hypertension caused by expansive intracranial lesions and explain the lower prevalence of headache among the elderly. 25
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The International Classification of Headache Disorders (ICHD-3) chapter 7.4.1 defines headache as secondary to an intracranial neoplasm if there is a clear temporal relation between tumor
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diagnosis and onset of symptoms, and if symptom burden worsens significantly with progression of disease or improves significantly after receiving effective treatment (surgical removal or administration of corticosteroids). Higher pain intensity in the morning and aggravation by coughing/ Valsalva maneuver are other criteria included in the ICHD-3 definition of “classic” brain tumor headache (BTH). Headache was not formally classified or subclassified according to the ICHD-3 criteria in this study. However, the clinical manifestations of BTH according to the
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ICHD-classification are inconsistent in literature. A review article from 2014 reports that headache rarely satisfies the ICHD-3 criteria, but often resembles benign primary headaches (tension-type, migraine-like or unspecified), and are generally described as diffuse, non-specific, and of moderate intensity, lasting a few hours and respondent to common analgesics. 10,26 The
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syndrome referred to as the “brain tumor triad” consisting of early morning occurrence, nausea and/ or vomiting and severe pain, has also lost some topical actuality, because it only occurs in a minority of patients. 1 The symptomatic effect of surgery on BTH is not much studied, despite
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being part of the definition according to the ICHD classification system. However, both patients and clinicians may be misled by the fact that headache is a common cause for ordering diagnostic imaging that leads to the tumor diagnose, suggestive of a temporal relationship also in incidental cases. To be noted, the one-year prevalence of headache is 37% in the general population22 and it is not unlikely that headache and intracranial neoplasms may coexist without causality. Thus, headache in patients with intracranial tumors is not always tumor related. In a recent study in patients with pituitary adenoma, we found that headache prevalence was low compared to the
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ACCEPTED MANUSCRIPT Munkvold general population, and that no clinical or radiological variables were associated with headache or relief. 27
The association between different tumor-related factors (such as tumor location, tumor volume,
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histopathology and growth rate) and headache differs substantially across studies. Tumor
location in the posterior fossa (cerebellum/ brain stem) seems to cause headache more often than supratentorial tumors, with a prevalence ranging from 60 to 83% in literature. 5,6,28 Furthermore, headache caused by posterior fossa tumors often occurs at an earlier stage compared to headache
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in patients with other tumor locations, possibly explained by obstruction of cerebrospinal fluid drainage causing hydrocephalus and increased intracranial pressure. We found a somewhat larger
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proportion reporting preoperative headache and postoperative relief among patients with tumor location in the cerebellum or brainstem, but statistical significance was not shown. Tumor location in the occipital lobe was a significant predictor for headache at baseline, and for early postoperative relief of headache. Visual disturbances of various causes are known to be associated with headache. 17,29–32 It is further known that various cerebral lesions, including primary and metastatic tumors, 33arteriovenous malformations34 and cerebral vascular disease35
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can trigger migraine attacks with visual symptoms. There are case reports indicating that tumors located in the occipital lobe may present with migraine with a typical visual aura, followed by throbbing hemicranial headache accompanied by photo- and phonophobia and nausea. 36 However, only 11 patients in our study had strict occipital lesions. Multiple significance testing
II statistical errors.
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in small subgroups and the mentioned ceiling effect also imply a potential for false positive type
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The relationship between tumor size and headache is inconsistent in literature. Forsyth and Posner reported that tumor size was related to headache, 1 while other studies have not found a similar correlation. 2,3,9,10 In the present study we found no correlation between tumor volumes and preoperative headache, but larger tumor volume was found to be positively associated with early postoperative relief. However, tumor volume was not significant in the multivariable analysis. Tumor volume was associated with relief at 6 months. To be noted, there is a likely dependence between some tested variables in the regression models, such as or example KPS and tumor volume, which could conceal positive findings.
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It has been speculated that the tumor growth rate increases the likelihood of headache, and some studies report higher prevalence in glioblastomas and metastases compared to tumor entities with a slower growth, such as meningiomas and low-grade gliomas. Valentinis et al. found that
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probability of developing BTH was higher in glioblastomas and secreting adenomas compared to anaplastic gliomas in a multivariate logistic regression analysis. Even so, the proportion of patients reporting headache and not did not differ significantly across histopathological
diagnoses. 10 Also in or study, headache prevalence did not differ across histological entities at
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baseline, and we did not find a correlation between histopathology and postoperative relief or worsening. As mentioned, the routine use of corticosteroids in HGG patients and patients with
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metastases might have influenced our findings.
Our study has several strengths, including being an unselected population based cohort with a large sample size. Data is collected prospectively, and assessment of symptom burden is standardized using the validated EORTC QLQ-BN20 questionnaire both at baseline and at follow-up. There are still limitations that must be taken into consideration when interpreting the
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results. As mentioned, many patients had received corticosteroid treatment preoperatively, possibly improving symptoms before inclusion in the study and answering the questionnaire at baseline, leading to under-reporting of headache. Also tumor progression was not assessed at follow-up, and some patients had also received adjuvant treatment following surgery. New,
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relapsing or worsening of headache could therefore possibly be explained either by relapsing tumor or side effects of adjuvant chemo- or radiotherapy. The headache questions exhibit a ceiling effect, and may influence analyses of change over time. Dependence between some of the
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tested variables may have influenced results in the regression analyses.
Conclusions
In conclusion, headache is common in patients with intracranial neoplasms and the majority report postoperative relief. Consistent with headache epidemiology in general, younger age and female gender were identified as risk factors for headache at baseline. Occipital tumor location was the only tumor related factor associated with headache preoperatively. Younger age, female
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ACCEPTED MANUSCRIPT Munkvold gender, low KPS and tumor location in the occipital lobe were predictors for experiencing early relief of headache following surgical tumor resection.
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Disclosure The study was supported by the Norwegian Research Council and the Faculty of Medicine at the Norwegian University of Science and Technology (NTNU). Asgeir Jakola has research funding from the Norwegian Cancer Society. The authors report no conflicts of interest concerning the
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materials or methods used in this study or the findings specified in this paper.
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A Longitudinal Cohort Study. Neurosurgery. 2016;78(3):316-323.
22.
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doi:10.1227/neu.0000000000001067.
Linde M, Stovner LJ, Zwart J-A, Hagen K. Time trends in the prevalence of headache disorders. The Nord-Trøndelag Health Studies (HUNT 2 and HUNT 3). Cephalalgia. 2011;31(5):585-596. doi:10.1177/0333102410391488.
23.
Hagen K, Zwart J-A, Vatten L, Stovner L, Bovim G. Prevalence of Migraine and NonMigrainous Headache—Head-HUNT, A Large Population-Based Study. Cephalalgia.
24.
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2000;20(10):900-906. doi:10.1046/j.1468-2982.2000.00145.x. Bigal ME, Liberman JN, Lipton RB. Age-dependent prevalence and clinical features of migraine. Neurology. 2006;67(2):246-251. doi:10.1212/01.wnl.0000225186.76323.69. 25.
Lowry JK, Snyder JJ, Lowry PW. Brain tumors in the elderly: recent trends in a Minnesota
26.
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cohort study. Arch Neurol. 1998;55(7):922-928. Nelson S, Taylor LP. Headaches in brain tumor patients: primary or secondary? Headache. 2014;54(4):776-785. doi:10.1111/head.12326. Gravdahl GB, Tronvik EA, Fougner SL, Solheim O. Pituitary Adenoma and Non-acute
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27.
Headache: Is There an Association, and Does Treatment Help? World Neurosurg. 2016;92:284-291. doi:10.1016/j.wneu.2016.04.071. 28.
Lyons MK, Kelly PJ. Posterior fossa ependymomas: report of 30 cases and review of the literature. Neurosurgery. 1991;28(5):655-659.
29.
Hadjikhani N, Sanchez del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci. 2001;98(8):4687-4692. doi:10.1073/pnas.071582498.
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Moriyama H, Hesaka H, Tachibana T, Honda Y. Mucoceles of ethmoid and sphenoid sinus with visual disturbance. Arch Otolaryngol Neck Surg. 1992;118(2):142-146. doi:10.1001/archotol.1992.01880020034012.
31.
Panayiotopoulos CP. Visual phenomena and headache in occipital epilepsy: a review, a
http://europepmc.org/abstract/MED/10937155. 32.
Thacker AK, Prasad G, Verma RB, Srivastava PK. Headache and visual disturbance. Postgrad Med J. 1996;72(843):61-63.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2398309/. 33.
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systematic study and differentiation from migraine. Epileptic Disord. 1999;1(4):205-216.
Pepin EP. Cerebral metastasis presenting as migraine with aura. Lancet.
34.
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1990;336(8707):127-128. doi:https://doi.org/10.1016/0140-6736(90)91653-R. Lees F. THE MIGRAINOUS SYMPTOMS OF CEREBRAL ANGIOMATA. J Neurol Neurosurg & Psychiatry. 1962;25(1):45-50. doi:10.1136/jnnp.25.1.45. 35.
Kawamura J, Meyer JS. Headaches due to cerebrovascular disease. Med Clin North Am. 1991;75(3):617-630.
36.
Verma A, Rosenfeld V, Forteza A ro, Sharma KR. Occipital Lobe Tumor Presenting as
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Migraine With Typical Aura. Headache J Head Face Pain. 1996;36(1):49-52. doi:10.1046/j.1526-4610.1996.3601049.x. 37.
Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro Oncol.
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2015;17(suppl_4):iv1-iv62.
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Figure legends
Figure 1. Flowchart showing included patients. Table 1. Baseline characteristics, preoperative headache prevalence and possibly associated factors.
Table 2. Possible predictors for headache at baseline were explored in a multivariable logistic regression analysis. Table 3. Prevalence of headache reported preoperatively and 1 and 6 months after surgery. Table 4. Change in headache 1 and 6 months after surgery, relative to symptom burden reported prior to surgery.
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Table 5. Possible predictors for postoperative relief 1 month after surgical resection.
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ACCEPTED MANUSCRIPT Table 1. Baseline characteristics, preoperative headache prevalence and possibly associated factors. Patient and tumor characteristics
Headache, n/N (%)
No headache, n/N (%)
p- value
Male
123/278 (44)
155/278 (56)
<0.001
Female
141/229 (62)
88/229 (38)
Age, median (range)
54.5 (18-88)
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Gender
Intra-axial
155/316 (49)
Extra-axial
109/191 (57)
Histopathology 73/162 (45)
Low grade glioma Meningioma Metastasis Pituitary adenoma
89/162 (55) 29/65 (45)
68/115 (59)
47/115 (41)
36/69 (52)
33/69 (48)
33/64 (52)
31/64 (48)
4/6 (67)
2/6 (33)
0.388
14/26 (54)
12/26 (46)
72/154 (47)
82/154 (53)
34/56 (61)
22/56 (39)
11/24 (46)
13/24 (54)
9/11 (82)
2/11 (18)
Cerebellum/brain stem
32/51 (63)
19/51 (37)
Basal ganglia*/intraventricular
5/18 (28)
13/18 (72)
Pituitary
32/62 (52)
30/62 (48)
Multilobar
69/131 (53)
62/131 (47)
15.31 (0.01-321.54)
12.29 (0.01-161.73)
0.246
1 (0-60)
3 (0-80)
0.139
Location Frontal Temporal Parietal
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Occipital
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Other
0.080
36/65 (55)
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Lymphoma
161/316 (51) 82/191 (43)
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High grade glioma
<0.001
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Tumor origin
62 (19-82)
Tumor volume (ml), median (range)
0.046
Distance to meninges (mm) median (range) Max peritumoral edema (mm),
ACCEPTED MANUSCRIPT median (range)
8 (0-82)
9 (0-65)
0.869
1-2
195/368 (53)
173/368 (47)
0.501
3-4
69/139 (50)
70/139 (50)
< 70
33/58 (57)
25/58 (43)
≥ 70
220/429 (51)
ASA score
Yes
121/241 (50)
No
143/266 (54)
120/321 (50)
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*Basal ganglia/thalamus/corpus callosum/insula
0.422
209/429 (49)
123/266 (46)
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Corticosteroids on admission
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Karnofsky performance status
0.424
ACCEPTED MANUSCRIPT Table 2. Possible predictors for headache at baseline were explored in a multivariable logistic regression analysis. Univariable
95% CI
p-value
Multi-
odds ratio
variable
(OR)
odds ratio
95% CI
p-value
Intra-axial tumor (extra-
0.72
0.51-1.04
0.080
4.25
0.91-19.88
0.066
Age (continuous)
0.97
0.96-0.99
<0.001
Female (male reference)
2.02
1.41-2.88
<0.001
Occipital tumor location
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(other location reference)
0.83
0.57-1.22
0.340
4.85
1.02-23.14
0.048
0.97
0.96-0.99
<0.001
1.93
1.34-2.80
<0.001
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axial reference)
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(OR)
ACCEPTED MANUSCRIPT Table 3. Prevalence of headache reported preoperatively and 1 and 6 months after surgery. Headache reported from the
Preoperatively
1 month
6 months
n/N (%)
postoperatively
postoperatively
n/N (%)
n/N (%)
BN20 module
243/507 (48)
233/406 (57)
250/357 (70)
2= a little bit
153/507 (30)
100/406 (25)
67/357 (19)
3= quite a bit
61/507 (12)
47/406 (12)
26/357 (7)
4= very much
50/507 (10)
26/406 (6)
14/357 (4)
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1= not at all
ACCEPTED MANUSCRIPT Table 4. Change in headache 1 and 6 months after surgery, relative to symptom burden reported prior to surgery. Change in
Change in headache
headache reported
headache 1 month
6 months
from the BN20
postoperatively n/N
postoperatively n/N
(%)
(%)
module
2= a little bit
No change
138/188 (73)
153/173 (88)
Worsening
50/188 (27)
20/173 (12)
Improvement
70/127 (55)
67/107 (63)
No change
36/127 (28)
30/107 (28)
Worsening
21/127 (17)
10/107 (9)
Improvement
28/48 (58)
33/40 (83)
No change
15/48 (31)
5/40 (12)
Worsening
5/48 (11)
2/40 (5)
Improvement
33/43 (77)
28/37 (76)
No change
10/43 (23)
9/37 (24)
Worsening
-
-
76/406 (19)
32/357 (9)
Improvement
131/218 (60)
128/184 (70)
No change
61/218 (28)
44/184 (24)
Worsening
26/218 (12)
12/184 (6)
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4= very much
Sum 1-4
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3= quite a bit
Improvement
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1= not at all
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Preoperative
Any worsening or new
-
Sum 2-4 (patients with preoperative
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headache)
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headache
ACCEPTED MANUSCRIPT Table 5. Possible predictors for postoperative relief 1 month after surgical resection. Univariable
95% CI
p-value
odds ratio
ble odds
(OR)
ratio (OR) 0.90-11.73
0.072
1.01
1.00-1.02
0.064
Age (continuous)
0.99
0.97-1.00
0.044
Female gender (male
1.80
1.19-2.75
0.006
2.42
1.16-5.08
0.019
(other location reference) Tumor volume (ml)
Karnofsky performance
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reference)
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status <70 (≥70 reference)
p-value
1.32-23.32
0.019
1.01
1.00-1.02
0.059
0.98
0.97-1.00
0.018
1.92
1.23-3.01
0.004
2.26
1.02-5.02
0.044
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(continuous)
5.55
95% CI
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3.25
Occipital tumor location
Multivaria
Figure 1: Flowchart showing included ACCEPTED patients. MANUSCRIPT 712 histologically confirmed brain tumors operated in the study period
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187 without consent Administrative failure, n=53 Unwillingness to participate, n=72 Severe illness, n=23 (informed consent impossible) Aphasia/ dysphasia, n=8 Cognitive failure, n=14 Did not understand the Norwegian language, n=5 Emergency surgery, n= 10 Abscess, not tumor suspected, n= 2
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525 with informed consent
18 EORTC QLQ-BN20 study question 4 not filled out at baseline
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507 EORTC QLQ-BN20 study question 4 filled out at baseline.
Prevalence of preoperative headache was assessed in these 507 patients.
45 biopsy only
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462 underwent tumor resection.
56 EORTC QLQ-BN20 study question 4 not filled out 1 month postoperatively. 105 study question not filled out 6 months postoperatively.
406 filled out EORTC QLQ-BN20 study question 4 preoperatively and 1 month postoperatively.
357 filled out study question 6 months postoperatively.
Change in headache 1 month after surgical resection was assessed in these 406 patients.
Change in headache 6 months after surgical resection was assessed in these 357 patients.
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Highlights -
Headache is a common symptom in patients with intracranial tumors, especially in younger and female patients. Occipital tumor location was identified as a tumor related predictor for headache at baseline. Among patients with headache prior to surgical tumor resection, 60% and 70% reported improvement 1 and 6 months postoperatively.
Occipital tumor location, younger age, female gender, and KPS <70 were identified as
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independent predictors for improvement 1 month after surgery.
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S1878-8750(18)30760-5
DOI:
10.1016/j.wneu.2018.04.044
Reference:
WNEU 7880
To appear in:
World Neurosurgery
Received Date: 4 December 2017 Revised Date:
5 April 2018
Accepted Date: 6 April 2018
Please cite this article as: Ravn Munkvold BK, Sagberg LM, Jakola AS, Solheim O, Pre- and postoperative headache in patients with intracranial tumors, World Neurosurgery (2018), doi: 10.1016/ j.wneu.2018.04.044. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
ACCEPTED MANUSCRIPT Munkvold
Pre- and postoperative headache in patients with intracranial tumors
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Authors:
Bodil Karoline Ravn Munkvold (Medical Student with Research Programme) 1
o Postal address: NTNU, Faculty of Medicine and Health Sciences, N-7491
-
Lisa Millgård Sagberg (MSc) 2,3,4
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Trondheim, Norway. E-mail: [email protected].
o Postal address: Edvard Griegs gate 8, Nevro øst * 121.03.032. Telephone
-
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number: +47 72575697. E-mail address: [email protected]. Asgeir Store Jakola (MD, PhD) 4,5,6
o Postal address: Blå stråket 5, plan 3, 41345 Göteborg. Telephone number: +46 31-342 27 63. E-mail address: [email protected]. -
Ole Solheim (MD, PhD) 2,3,4
o Postal address: Edvard Griegs gate 8, Nevro øst. Telephone number: +47 73 59
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20 20. E-mail address: [email protected].
1. The Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
2. Norwegian National Advisory Unit for Ultrasound and Image Guided Therapy, St. Olavs
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University Hospital, Trondheim, Norway 3. Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway
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4. Department of Neurosurgery, St. Olav’s University Hospital, Trondheim, Norway
5. Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden
6. Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden
Corresponding author information: Bodil Karoline Ravn Munkvold, Medical research student, Faculty of Medicine, Norwegian University of Science and Technology, Post Box 8905, N-7491 Trondheim, Norway ([email protected]). 1
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Sources of financial and material support: The study was supported by the Norwegian Research Council and the Faculty of Medicine at the
from the Norwegian Cancer Society.
Keywords: Brain neoplasms; Headache; Surgery
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Abbreviations list:
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Norwegian University of Science and Technology (NTNU). Asgeir Jakola has research funding
BTH- Brain tumor related headache
HGG- High-grade glioma
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EORTC- The European Organization for Research and Treatment of Cancer
HUNT- The Nord-Trøndelag Health Study
ICHD- International Classification of Headache Disorders KPS- Karnofsky Performance Status REC- Regional Ethics Committee
Abstract Objective
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WHO- World Health Organization
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We sought to examine prevalence of headache in patients with histopathologically verified intracranial tumors scheduled for surgery, and assess change in headache 1 and 6 months after
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surgical resection. Possible tumor and patient related predictors for preoperative headache and early postoperative symptom relief were also explored.
Methods
The European Organization for Research and Treatment of Cancer (EORTC) has developed a quality of life questionnaire (EORTC QLQ-C30) with a brain cancer specific module, QLQBN20, containing 20 questions rating symptoms the past week on an ordinal scale ranging from 1-4. Analyses are based on question 4 in this questionnaire.
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ACCEPTED MANUSCRIPT Munkvold Results In this prospective population based cohort study of 507 patients we found that headache is a frequent symptom in patients with intracranial neoplasms. 52% reported some degree of preoperative headache, and the prevalence dropped to 43% and 30% 1 and 6 months
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postoperatively. 19% and 9% reported postoperative worsening or new headache 1 and 6 months after surgery. Younger age, female gender and occipital tumor location were significant
predictors for both preoperative headache and early postoperative relief. Additionally, Karnofsky Performance Status (KPS) below 70 was a predictor for headache relief 1 month after surgery.
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No independent risk factors for worsening or new headache after surgery were identified.
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Conclusion
Headache is a common symptom in patients with intracranial tumors, especially in younger and female patients. Many patients experience improvement after surgery, and younger age, female gender, occipital tumor location and functional dependence were identified as factors associated
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with early postoperative headache relief.
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Pre- and postoperative headache in patients with intracranial tumors Introduction
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Headache is a common symptom in patients with intracranial tumors. In case series with
unselected brain tumor patients it is reported that 20 % present with headache as an initial
symptom, 50-60 % experience the symptom during the course of disease1–3 and 36 % suffer from headache at end of life. 4 Headache is the most predominant symptom in about half of the
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patients, 1 and prevalence does not seem to differ between primary and metastatic brain tumor
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patients. 1,5,6
The pathophysiology behind brain tumor related headache (BTH) is poorly understood, and the symptomatic effect of surgical resection is not much studied. Brain parenchyma is insensitive to pain and suggested pathophysiological explanations of BTH include traction of large blood vessels and meninges, and compression of cranial and cervical nerve fibers. 5,7 Histopathology, anatomical location, lesion volume and growth rate are tumor related factors that might explain
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some of the diversity and complexity in BTH. 8–10 Consistent with headache epidemiology in the general population, several patient-related factors are known to be of importance, making it difficult to identify a distinct headache pattern in patients with intracranial neoplasms. 2,10,11
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In this prospective cohort study, we sought to examine preoperative prevalence of self-reported headache in patients scheduled for surgery of intracranial neoplasms and explore the association
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between preoperative headache and tumor and patient related factors. Furthermore, we wanted to assess change in headache after surgical resection and explore factors possibly related to early postoperative relief.
Material and methods Study variables The European Organization for Research and Treatment of Cancer (EORTC) has developed a quality of life questionnaire, EORTC QLQ-C30, with a specific brain cancer module EORTC QLQ-BN20 that assesses disease symptoms, adverse effects of treatment, and some psychosocial 4
ACCEPTED MANUSCRIPT Munkvold aspects of relevance in patients with brain neoplasms. The BN20 module contains 20 questions, among them whether headache is present or not (question no. 4). The symptom burden is rated on an ordinal scale ranging from 1-4, indicating the extent of experienced headache during the past week (1= ‘not at all’, 2= ‘a little bit’, 3= ‘quite a bit’, 4= ‘very much’). Mapping and analysis of
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symptom development was based on this BN20 module. Karnofsky Performance Status (KPS) is a validated ten-level ordinal scale ranging from 100 (normal function) to 0 (death), that was used to rate the patients’ level of functioning. 12
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Data collection
Included patients gave their informed written consent, and filled out the questionnaires 1-3 days
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prior to surgery. The preoperative KPS was scored on admission by a study nurse or the operating surgeon. Follow-up was based on structured telephone interviews performed by a study nurse, approximately 1 month (median 31 days) and 6 months after surgery. Extent of surgical resection was calculated from pre- and early postoperative MRI. The tumor volumes of ellipsoid-shaped lesions were calculated by applying the volume formula ܸ =
ସగభ మ య ଷ
, based on maximal
perpendicular tumor diameters, as done by others. 13 The volumes of cup-shaped residual tumors
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were calculated by subtracting the ellipsoid-shaped resection cavity from the volume of the tumor complex, while more complex tumor configurations were manually segmented. 14 Other study
Included patients
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variables were retrieved from medical records.
712 patients ≥18 years were diagnosed with a histopathologically verified intracranial tumor
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classified according to the 2007 WHO Classification of Tumors of the Central Nervous System15 in the inclusion period from September 2011 to November 2015 at the Department of Neurosurgery at St. Olav’s University Hospital, Trondheim, Norway. Our department serves exclusively a defined geographical catchment region with a population of approximately 720 000, and the study sample is therefore practically an unselected population-based series. The study question regarding headache was filled out at baseline in 507 patients. These served basis for the preoperative prevalence data. To assess the symptomatic effect of surgical tumor resection, 45 patients with biopsy only were excluded. 56 patients did not answer the study question after 1 month, and 105 patients did not answer at 6 months. This left 406 and 357 patients with complete
5
ACCEPTED MANUSCRIPT Munkvold pre- and postoperative data for assessment of change in headache 1 and 6 months after surgical resection respectively. The flow chart of the inclusion process is presented in figure 1.
Statistics
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Descriptive analyses were performed to examine prevalence of headache before and after
surgery. The association between headache and categorical factors was explored using the
Pearson Chi-Square or Fishers’ exact test. For continuous variables, normal distribution was assessed using the Shapiro-Wilk test and Q-Q plot. T-test or Mann-Whitney-U test was carried
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out to compare continuous variables depending on whether data was normally distributed or skewed. The Kruskal-Wallis test was used to assess distribution of headache between multiple
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categorical variables. In order to assess possible factors associated with headache, a multivariable logistic regression analysis was performed. Univariables with a statistical trend (p<0.10) were included in the multivariable model. The Hosmer and Lemeshow goodness of fit test was used to determine adequacy of the regression model, and the Nagelkerke R2 value to assess how much variation in the dependent variable could be explained by the model. Statistical significance was
Ethics
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defined as p<0.05. Analyses were performed using SPSS version 24.
The study was approved by the Regional Committee for Medical and Health Research Ethics as part of a larger project (REC reference 2011/974, “Quality of life in patients with intracranial
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neoplasms”). Informed consent was obtained from all study participants, and the project is
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adherent to the Declaration of Helsinki. 16
Results
Preoperative headache and possibly associated factors As seen in table 1, 264 out of 507 (52%) had experienced some degree of headache during the last week before surgery. 30% rated symptom burden ‘a little bit’, 12% ‘quite a bit’ and 10% ‘very much’ (table 3). As shown in table 1, patients who reported preoperative headache were significantly younger, median age 54.5 years (18-88) vs. 62 years (19-82) (p<0.001). Women reported headache more frequently than men, 62% vs. 44% (p<0.001). Patients with tumor
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cerebellum or brainstem was not associated with statistically significant higher headache
prevalence, 32/51 (63%) vs. 232/456 (51%) (p=0.108). 241/507 (48%) patients had received corticosteroids prior to answering the headache questions at baseline. However, headache
prevalence did not differ between the patient group who had received corticosteroids prior to
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admission and the patient group who had not, 121/241 (50%) vs. 143/266 (54%) respectively (p=0.424).
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Possible predictors for preoperative headache were explored in a multivariable regression analysis (table 2). Intra-axial tumor origin, location in the occipital lobe, age, and gender were tumor factors that exhibited a statistical trend (p<0.1) as univariables, and were therefore included in the multivariable model. Younger age, female gender and occipital tumor location were significantly and positively associated with headache at baseline in the multivariable analysis. The Hosmer and Leweshow test was not significant (p=0.616), implicating that the
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regression model was a good fit. Predictive accuracy (i.e. how good the model is for predicting whether patient has preoperative headache) was 61.7%.
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Change in headache postoperatively
173 of 406 patients (43%) reported some degree of headache 1 month after surgery. 25% experienced ‘a little bit’ headache the past week before filling out the follow-up questionnaire,
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12% ‘quite a bit’, and 6% of patients suffered ‘very much’ from headache during the week before follow-up (table 3). 131/406 patients (32%) patients reported improvement compared to headache at baseline, 199/406 (49%) no change and 76/406 (19%) worsening 1 month postoperatively. A larger proportion of women reported improvement compared to men, 73/186 (39%) vs. 58/220 (26%) (p=0.006). Patients reporting postoperative relief were significantly younger than patients reporting worsened or unchanged headache postoperatively, median 54 years vs. 58 years (p=0.023). 16/31 (52%) of patients with preoperative KPS below 70 reported postoperative relief compared to 110/360 (31%) with KPS ≥ 70 (p=0.016).
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107 of 357 patients (30%) of patients reported some degree of headache 6 months postoperatively; 19% ‘a little bit’, 7% ‘quite a bit’ and 4% ‘very much’. 128/357 (36%) reported
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improvement, 197/357 (55%) no change and 32/357 (9%) worsening 6 months after surgical resection. Women reported improvement more frequently than men, 68/160 (43%) and 60/197 (30%) respectively (p=0.018). The patient group reporting improvement at 6 months was
significantly younger than the group experiencing worsening or unchanged headache, 52 (18-88) years vs. 58 (19-79) years (p=0.002). Median tumor volume was 15.4 ml in patients
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experiencing improvement and 10.6 ml in the group who did not (p=0.022). 59/186 (32%) with
with extra-axial tumors (p=0.089).
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intra-axial tumors experienced headache relief 6 months after surgery compared to 69/171 (40%)
Of patients who reported some degree of headache prior to surgery 60 and 70% reported improvement 1 and 6 months after surgery, while 12% and 6% experienced worsening. As seen in table 4, the risk of postoperative worsening was lower in patients with more preoperative
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Factors possibly related to early postoperative relief Of factors reported in table 1 only tumor location in the occipital lobe, tumor volume, age, gender and KPS were associated with a statistical trend (p<0.1) for improvement of headache 1 month
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postoperatively as univariables (table 5). These variables were included in the multivariable logistic regression model. Location in the occipital lobe, female gender, younger age and KPS <70 were significant positive predictors for postoperative relief 1 month after surgery in the multivariable model. Larger tumor volume did not reach statistical significance in the
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multivariable model, OR=1.01 per 1 ml increase in tumor volume (p=0.059). The Hosmer and Leweshow test was not significant (p=0.179), implicating that the regression model was a good fit. Predictive accuracy (i.e. how good the model is for predicting whether headache was
worsened/ unchanged headache).
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improved or worsened/unchanged) was 69% (95% correct prediction in the group experiencing
Possible predictors for worsening 1 month after surgery were also explored. However, a multivariable model was not developed because non-frontal tumor location was the only variable showing a statistical trend with regard to prediction of worsening. The risk of symptomatic
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worsening or new headache was 18/130 (14%) in patients with tumors in the frontal lobe compared to 58/276 (21%) in other tumor locations.
Discussion
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In this prospective population based cohort study we found that headache is a frequent symptom in patients with intracranial neoplasms. More than one half of the patients reported some degree
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of headache prior to surgery. The prevalence dropped gradually to one third at 6 months after surgery. Younger age, female gender and occipital tumor location were the only independent factors that were associated with higher headache prevalence at baseline in the multivariable analysis. Among patients with headache prior to surgical resection, 60% and 70% reported improvement 1 and 6 months postoperatively, while 12% and 6% reported worsening of headache or new headache complaints. Occipital tumor location, younger age, female gender, and KPS <70 were identified as independent predictors for improvement 1 month after surgery. We could not identify independent risk factors for worsening or new headache after surgery.
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ACCEPTED MANUSCRIPT Munkvold The high prevalence of headache at baseline is comparable to findings from other studies in patients with intracranial tumors. 2,10 However, many patients received corticosteroid treatment before inclusion and may therefore have experienced symptom relief before answering the questionnaires at baseline. Some patients also received chemotherapy and/ or radiotherapy after
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surgery, possibly interfering with symptom evaluation postoperatively. A substantial proportion of patients experienced improvement of headache after surgery. Postoperative relief may be directly attributed to the surgical treatment, but it is perhaps not unlikely that surgery also
provides some placebo effect or regression to the mean like for example seen after surgery for
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arachnoid cysts. 17,18 To be noted, 19% and 9% of patients reported worsening or new headache 1 and 6 months after surgery but risk factors could not be identified. As the follow-up
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questionnaires were filled out, some patients with high-grade gliomas (HGG) had experienced disease progression but we did not evaluate the potential effect of tumor progression on headache symptoms in the present study. Still, worsening was not associated with histopathology. At 1 month after surgery some patients may still be suffering from postcraniotomy headache, which is a known complication following surgery, although resolving in with time in most cases. 19 The risk of postoperative worsening was lower in patients with more preoperative symptoms,
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probably reflecting a ceiling effect. It is difficult to know for certain whether there is direct causality between postoperative headache relief and the surgical intervention. Similarly, postoperative symptom worsening is not necessarily surgery-related either. Even so, the potential risk of headache worsening following surgery should nevertheless be taken into consideration,
for surgery.
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especially if the indication for treatment is relative. Headache alone is a controversial indication
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Globally, the prevalence of active headache disorders is 46% for headache in general in the adult population, 11% for migraine, 42% for tension-type headache and 3% for chronic daily headache. 20
Although questionnaires are not necessarily comparable, these numbers are perhaps not very
different from the prevalence reported in our brain tumor cohort after surgery. We failed to identify any tumor related factors that were independently associated with headache at baseline, but found that prevalence of headache was higher in young and female patients both at baseline and after surgery. 21 However, younger age and female gender are well-known risk factors for headache also in the general population. 11 A large Norwegian population health study, HUNT-3,
10
ACCEPTED MANUSCRIPT Munkvold included 39,690 individuals22 over the age of 20, and found that the overall age- adjusted 1-year headache prevalence was 43% in women and 30% in men. 23 The correlation between headache and age in the general population varies somewhat with phenotype of headache, but a declination in symptom burden is expected with age. 11,24 Since headache may be associated with intracranial
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hypertension1,6,10 it may be speculated that age related brain atrophy might counteract intracranial hypertension caused by expansive intracranial lesions and explain the lower prevalence of headache among the elderly. 25
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The International Classification of Headache Disorders (ICHD-3) chapter 7.4.1 defines headache as secondary to an intracranial neoplasm if there is a clear temporal relation between tumor
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diagnosis and onset of symptoms, and if symptom burden worsens significantly with progression of disease or improves significantly after receiving effective treatment (surgical removal or administration of corticosteroids). Higher pain intensity in the morning and aggravation by coughing/ Valsalva maneuver are other criteria included in the ICHD-3 definition of “classic” brain tumor headache (BTH). Headache was not formally classified or subclassified according to the ICHD-3 criteria in this study. However, the clinical manifestations of BTH according to the
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ICHD-classification are inconsistent in literature. A review article from 2014 reports that headache rarely satisfies the ICHD-3 criteria, but often resembles benign primary headaches (tension-type, migraine-like or unspecified), and are generally described as diffuse, non-specific, and of moderate intensity, lasting a few hours and respondent to common analgesics. 10,26 The
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syndrome referred to as the “brain tumor triad” consisting of early morning occurrence, nausea and/ or vomiting and severe pain, has also lost some topical actuality, because it only occurs in a minority of patients. 1 The symptomatic effect of surgery on BTH is not much studied, despite
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being part of the definition according to the ICHD classification system. However, both patients and clinicians may be misled by the fact that headache is a common cause for ordering diagnostic imaging that leads to the tumor diagnose, suggestive of a temporal relationship also in incidental cases. To be noted, the one-year prevalence of headache is 37% in the general population22 and it is not unlikely that headache and intracranial neoplasms may coexist without causality. Thus, headache in patients with intracranial tumors is not always tumor related. In a recent study in patients with pituitary adenoma, we found that headache prevalence was low compared to the
11
ACCEPTED MANUSCRIPT Munkvold general population, and that no clinical or radiological variables were associated with headache or relief. 27
The association between different tumor-related factors (such as tumor location, tumor volume,
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histopathology and growth rate) and headache differs substantially across studies. Tumor
location in the posterior fossa (cerebellum/ brain stem) seems to cause headache more often than supratentorial tumors, with a prevalence ranging from 60 to 83% in literature. 5,6,28 Furthermore, headache caused by posterior fossa tumors often occurs at an earlier stage compared to headache
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in patients with other tumor locations, possibly explained by obstruction of cerebrospinal fluid drainage causing hydrocephalus and increased intracranial pressure. We found a somewhat larger
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proportion reporting preoperative headache and postoperative relief among patients with tumor location in the cerebellum or brainstem, but statistical significance was not shown. Tumor location in the occipital lobe was a significant predictor for headache at baseline, and for early postoperative relief of headache. Visual disturbances of various causes are known to be associated with headache. 17,29–32 It is further known that various cerebral lesions, including primary and metastatic tumors, 33arteriovenous malformations34 and cerebral vascular disease35
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can trigger migraine attacks with visual symptoms. There are case reports indicating that tumors located in the occipital lobe may present with migraine with a typical visual aura, followed by throbbing hemicranial headache accompanied by photo- and phonophobia and nausea. 36 However, only 11 patients in our study had strict occipital lesions. Multiple significance testing
II statistical errors.
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in small subgroups and the mentioned ceiling effect also imply a potential for false positive type
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The relationship between tumor size and headache is inconsistent in literature. Forsyth and Posner reported that tumor size was related to headache, 1 while other studies have not found a similar correlation. 2,3,9,10 In the present study we found no correlation between tumor volumes and preoperative headache, but larger tumor volume was found to be positively associated with early postoperative relief. However, tumor volume was not significant in the multivariable analysis. Tumor volume was associated with relief at 6 months. To be noted, there is a likely dependence between some tested variables in the regression models, such as or example KPS and tumor volume, which could conceal positive findings.
12
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It has been speculated that the tumor growth rate increases the likelihood of headache, and some studies report higher prevalence in glioblastomas and metastases compared to tumor entities with a slower growth, such as meningiomas and low-grade gliomas. Valentinis et al. found that
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probability of developing BTH was higher in glioblastomas and secreting adenomas compared to anaplastic gliomas in a multivariate logistic regression analysis. Even so, the proportion of patients reporting headache and not did not differ significantly across histopathological
diagnoses. 10 Also in or study, headache prevalence did not differ across histological entities at
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baseline, and we did not find a correlation between histopathology and postoperative relief or worsening. As mentioned, the routine use of corticosteroids in HGG patients and patients with
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metastases might have influenced our findings.
Our study has several strengths, including being an unselected population based cohort with a large sample size. Data is collected prospectively, and assessment of symptom burden is standardized using the validated EORTC QLQ-BN20 questionnaire both at baseline and at follow-up. There are still limitations that must be taken into consideration when interpreting the
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results. As mentioned, many patients had received corticosteroid treatment preoperatively, possibly improving symptoms before inclusion in the study and answering the questionnaire at baseline, leading to under-reporting of headache. Also tumor progression was not assessed at follow-up, and some patients had also received adjuvant treatment following surgery. New,
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relapsing or worsening of headache could therefore possibly be explained either by relapsing tumor or side effects of adjuvant chemo- or radiotherapy. The headache questions exhibit a ceiling effect, and may influence analyses of change over time. Dependence between some of the
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tested variables may have influenced results in the regression analyses.
Conclusions
In conclusion, headache is common in patients with intracranial neoplasms and the majority report postoperative relief. Consistent with headache epidemiology in general, younger age and female gender were identified as risk factors for headache at baseline. Occipital tumor location was the only tumor related factor associated with headache preoperatively. Younger age, female
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ACCEPTED MANUSCRIPT Munkvold gender, low KPS and tumor location in the occipital lobe were predictors for experiencing early relief of headache following surgical tumor resection.
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Disclosure The study was supported by the Norwegian Research Council and the Faculty of Medicine at the Norwegian University of Science and Technology (NTNU). Asgeir Jakola has research funding from the Norwegian Cancer Society. The authors report no conflicts of interest concerning the
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materials or methods used in this study or the findings specified in this paper.
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Gee JR, Ishaq Y, Vijayan N. Postcraniotomy headache. Headache. 2003;43(3):276-278. http://onlinelibrary.wiley.com/store/10.1046/j.1526-4610.2003.03053.x/asset/j.15264610.2003.03053.x.pdf?v=1&t=j8ztpcpv&s=96176572157d01c223992a5a3ffa0468de0320
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Pepin EP. Cerebral metastasis presenting as migraine with aura. Lancet.
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Kawamura J, Meyer JS. Headaches due to cerebrovascular disease. Med Clin North Am. 1991;75(3):617-630.
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Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro Oncol.
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Figure legends
Figure 1. Flowchart showing included patients. Table 1. Baseline characteristics, preoperative headache prevalence and possibly associated factors.
Table 2. Possible predictors for headache at baseline were explored in a multivariable logistic regression analysis. Table 3. Prevalence of headache reported preoperatively and 1 and 6 months after surgery. Table 4. Change in headache 1 and 6 months after surgery, relative to symptom burden reported prior to surgery.
17
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Table 5. Possible predictors for postoperative relief 1 month after surgical resection.
18
ACCEPTED MANUSCRIPT Table 1. Baseline characteristics, preoperative headache prevalence and possibly associated factors. Patient and tumor characteristics
Headache, n/N (%)
No headache, n/N (%)
p- value
Male
123/278 (44)
155/278 (56)
<0.001
Female
141/229 (62)
88/229 (38)
Age, median (range)
54.5 (18-88)
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Gender
Intra-axial
155/316 (49)
Extra-axial
109/191 (57)
Histopathology 73/162 (45)
Low grade glioma Meningioma Metastasis Pituitary adenoma
89/162 (55) 29/65 (45)
68/115 (59)
47/115 (41)
36/69 (52)
33/69 (48)
33/64 (52)
31/64 (48)
4/6 (67)
2/6 (33)
0.388
14/26 (54)
12/26 (46)
72/154 (47)
82/154 (53)
34/56 (61)
22/56 (39)
11/24 (46)
13/24 (54)
9/11 (82)
2/11 (18)
Cerebellum/brain stem
32/51 (63)
19/51 (37)
Basal ganglia*/intraventricular
5/18 (28)
13/18 (72)
Pituitary
32/62 (52)
30/62 (48)
Multilobar
69/131 (53)
62/131 (47)
15.31 (0.01-321.54)
12.29 (0.01-161.73)
0.246
1 (0-60)
3 (0-80)
0.139
Location Frontal Temporal Parietal
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Occipital
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Other
0.080
36/65 (55)
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Lymphoma
161/316 (51) 82/191 (43)
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High grade glioma
<0.001
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Tumor origin
62 (19-82)
Tumor volume (ml), median (range)
0.046
Distance to meninges (mm) median (range) Max peritumoral edema (mm),
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8 (0-82)
9 (0-65)
0.869
1-2
195/368 (53)
173/368 (47)
0.501
3-4
69/139 (50)
70/139 (50)
< 70
33/58 (57)
25/58 (43)
≥ 70
220/429 (51)
ASA score
Yes
121/241 (50)
No
143/266 (54)
120/321 (50)
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*Basal ganglia/thalamus/corpus callosum/insula
0.422
209/429 (49)
123/266 (46)
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Corticosteroids on admission
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Karnofsky performance status
0.424
ACCEPTED MANUSCRIPT Table 2. Possible predictors for headache at baseline were explored in a multivariable logistic regression analysis. Univariable
95% CI
p-value
Multi-
odds ratio
variable
(OR)
odds ratio
95% CI
p-value
Intra-axial tumor (extra-
0.72
0.51-1.04
0.080
4.25
0.91-19.88
0.066
Age (continuous)
0.97
0.96-0.99
<0.001
Female (male reference)
2.02
1.41-2.88
<0.001
Occipital tumor location
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(other location reference)
0.83
0.57-1.22
0.340
4.85
1.02-23.14
0.048
0.97
0.96-0.99
<0.001
1.93
1.34-2.80
<0.001
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axial reference)
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(OR)
ACCEPTED MANUSCRIPT Table 3. Prevalence of headache reported preoperatively and 1 and 6 months after surgery. Headache reported from the
Preoperatively
1 month
6 months
n/N (%)
postoperatively
postoperatively
n/N (%)
n/N (%)
BN20 module
243/507 (48)
233/406 (57)
250/357 (70)
2= a little bit
153/507 (30)
100/406 (25)
67/357 (19)
3= quite a bit
61/507 (12)
47/406 (12)
26/357 (7)
4= very much
50/507 (10)
26/406 (6)
14/357 (4)
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1= not at all
ACCEPTED MANUSCRIPT Table 4. Change in headache 1 and 6 months after surgery, relative to symptom burden reported prior to surgery. Change in
Change in headache
headache reported
headache 1 month
6 months
from the BN20
postoperatively n/N
postoperatively n/N
(%)
(%)
module
2= a little bit
No change
138/188 (73)
153/173 (88)
Worsening
50/188 (27)
20/173 (12)
Improvement
70/127 (55)
67/107 (63)
No change
36/127 (28)
30/107 (28)
Worsening
21/127 (17)
10/107 (9)
Improvement
28/48 (58)
33/40 (83)
No change
15/48 (31)
5/40 (12)
Worsening
5/48 (11)
2/40 (5)
Improvement
33/43 (77)
28/37 (76)
No change
10/43 (23)
9/37 (24)
Worsening
-
-
76/406 (19)
32/357 (9)
Improvement
131/218 (60)
128/184 (70)
No change
61/218 (28)
44/184 (24)
Worsening
26/218 (12)
12/184 (6)
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4= very much
Sum 1-4
-
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3= quite a bit
Improvement
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1= not at all
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Preoperative
Any worsening or new
-
Sum 2-4 (patients with preoperative
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headache)
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headache
ACCEPTED MANUSCRIPT Table 5. Possible predictors for postoperative relief 1 month after surgical resection. Univariable
95% CI
p-value
odds ratio
ble odds
(OR)
ratio (OR) 0.90-11.73
0.072
1.01
1.00-1.02
0.064
Age (continuous)
0.99
0.97-1.00
0.044
Female gender (male
1.80
1.19-2.75
0.006
2.42
1.16-5.08
0.019
(other location reference) Tumor volume (ml)
Karnofsky performance
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reference)
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EP
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status <70 (≥70 reference)
p-value
1.32-23.32
0.019
1.01
1.00-1.02
0.059
0.98
0.97-1.00
0.018
1.92
1.23-3.01
0.004
2.26
1.02-5.02
0.044
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(continuous)
5.55
95% CI
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3.25
Occipital tumor location
Multivaria
Figure 1: Flowchart showing included ACCEPTED patients. MANUSCRIPT 712 histologically confirmed brain tumors operated in the study period
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187 without consent Administrative failure, n=53 Unwillingness to participate, n=72 Severe illness, n=23 (informed consent impossible) Aphasia/ dysphasia, n=8 Cognitive failure, n=14 Did not understand the Norwegian language, n=5 Emergency surgery, n= 10 Abscess, not tumor suspected, n= 2
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525 with informed consent
18 EORTC QLQ-BN20 study question 4 not filled out at baseline
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507 EORTC QLQ-BN20 study question 4 filled out at baseline.
Prevalence of preoperative headache was assessed in these 507 patients.
45 biopsy only
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462 underwent tumor resection.
56 EORTC QLQ-BN20 study question 4 not filled out 1 month postoperatively. 105 study question not filled out 6 months postoperatively.
406 filled out EORTC QLQ-BN20 study question 4 preoperatively and 1 month postoperatively.
357 filled out study question 6 months postoperatively.
Change in headache 1 month after surgical resection was assessed in these 406 patients.
Change in headache 6 months after surgical resection was assessed in these 357 patients.
ACCEPTED MANUSCRIPT
Highlights -
Headache is a common symptom in patients with intracranial tumors, especially in younger and female patients. Occipital tumor location was identified as a tumor related predictor for headache at baseline. Among patients with headache prior to surgical tumor resection, 60% and 70% reported improvement 1 and 6 months postoperatively.
Occipital tumor location, younger age, female gender, and KPS <70 were identified as
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independent predictors for improvement 1 month after surgery.
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