Headache in Patients with Sellar Disease: Clinicomorphological Predictors of Headache and the Outcome of Endoscopic Transsphenoidal Surgery

• Abstract
• Introduction
• Materials and Methods
• Population
• Tumor Characteristics
• Radiology
• Histopathology
• Endocrine
• Headache Outcomes
• Presence
• Phenotype
• Severity
• Statistical Analysis
• Results
• Participant Demographics and Baseline Lesion Characteristics
• Baseline Headache
• Demographic Predictors of Headache
• Radiological Predictors of Headache
• Histological Predictors
• Endocrine Predictors of Headache
• Surgery and Headache
• Discussion
• Conclusion
• References

Abstract

Objectives Sellar pathologies are frequently found on imaging performed to investigate headache. However, both headache and incidental sellar lesions are common. Hence, this study prospectively examined headache prevalence, phenotype, and severity in patients with sellar pathologies and the impact of transsphenoidal surgery on headache.

Methods Patients undergoing transsphenoidal resection of sellar lesions were consecutively recruited. At baseline, participants were defined as having headache or not and headache phenotype was characterized using validated questionnaires. Headache severity was assessed at baseline and 6 months postoperatively using the Headache Impact Test-6 (HIT-6) and Migraine Disability Assessment Score (MIDAS). Tumor characteristics were defined using radiological, histological, and endocrine factors. Primary outcomes included baseline headache prevalence and severity and headache severity change at 6 months postoperatively. Correlation between headache and radiological, histological, and endocrine characteristics was also of interest.

Results Sixty participants (62% female, 47.1 ± 18.6 years) were recruited. Sixty-three percent possessed baseline headache. HIT-6 scores were higher in patients with primary headache risk factors, including younger age (R²  = −0.417, p = 0.010), smoking history (63.31 ± 7.93 vs 54.44 ± 9.21, p = 0.0060), and family headache history (68.13 ± 7.01 vs 54.94 ± 9.11, p = 0.0030). Headaches were more common in patients with dural invasion (55.70 ± 12.14 vs 47.18 ± 10.15, p = 0.027) and sphenoid sinus invasion (58.87 ± 8.97 vs 51.29 ± 10.97, p = 0.007). Postoperative severity scores improved more with higher baseline headache severity (HIT-6: R² = −0.682, p < 0.001, MIDAS: R² = −0.880, p < 0.0010) and dural invasion (MIDAS: −53.00 ± 18.68 vs 12.00 ± 17.54, p = 0.0030).

Conclusion Headaches in sellar disease are likely primary disorders triggered or exacerbated by sellar pathology. These may respond to surgery, particularly in patients with severe headache and dural invasion.

Introduction

Headache is common to the presentation of patients with sellar disease, with a reported prevalence of 33 to 72%.[1] However, headaches themselves are exceedingly prevalent and nonspecific.[2] Moreover, the discovery of incidental cranial pathologies has increased alongside the accessibility of sophisticated neuroimaging modalities.[3] [4] [5] Clinicians face a difficult diagnostic challenge in determining whether headaches are secondary manifestations of sellar disease or unrelated primary disorders. This distinction is paramount in dictating subsequent therapeutic decision-making, particularly regarding invasive surgical intervention.

At present, the International Classification of Headache Disorders (ICHD) defines secondary headache as occurring “in close temporal proximity to an illness, which can probably cause headache.”[6] However, given the long natural history of sellar pathologies, assessing temporal correlation is difficult. Diagnosis is further complicated by the variability of headache phenotypes in patients with pituitary tumors, including migraine, tension-type headache (TTH), and the various trigeminal autonomic cephalalgias.[7] [8] [9]

Historically, seminal studies of intracranial space-occupying lesions proposed that lesion growth produces dural stretch, thereby stimulating pain-sensitive intracranial meningeal arteries and afferent trigeminal fibers.[10] [11] Invasion of the adjacent cavernous sinus is also a possible contributing factor, given lesions may irritate the nociceptive afferents of the intracavernous carotid artery and trigeminal nerve.[12] [13] However, most studies fail to validate these mechanical hypotheses in sellar tumors.[1] [8] [9] [14] [15] [16] [17] [18] [19] More recent investigations have alternatively suggested that the growth rate of sellar lesions may be more critical than absolute size, as evidenced by a positive association reported between headache prevalence and K_i-67 index.[8] [20]

Nevertheless, such mechanical etiologies do little to explain the headaches encountered in patients with small intrasellar lesions, particularly in the case of prolactin- and growth hormone–secreting tumors.[1] [7] Additional predictors may include the hormonal secretory status of tumors or clinical measures of raised intrasellar pressure, including hyperprolactinemia secondary to a pituitary stalk effect.[16] [21] [22] Correlations between headache and histopathological features including dural invasion and intratumoral hemorrhage are also needed areas of further research.

Hence, the aims of this prospective study were threefold. First, a cross-sectional arm aimed to determine the prevalence, phenotype, and burden of headache in patients with sellar disease. Second, it aimed to also identify the patient and disease factors predicting headache presentations in these patients. Third, a longitudinal case–control study assessed the impact of endoscopic transsphenoidal surgery (TSS) on headache burden at 6 months postoperatively.

Materials and Methods

A prospective study was conducted by recruiting consecutive patients who underwent endoscopic TSS to resect radiologically confirmed sellar lesions between September 2016 and September 2017. Patients were managed by the St. Vincent's Hospital's pituitary multidisciplinary team. Ethics approval was granted by the St. Vincent's Hospital Human Research Ethics Committee. All participants provided written consent for the release of medical data and tissue under the Rhinology Tissue Bank Program (HREC/10/SVH/117) and the Garvan Institute of Medical Research Pituitary Biobank (HREC/12/SVH/33).

Population

All participants were >18 years and indication(s) for surgery had been determined prior to inclusion. These included ophthalmologic (chiasmic compression with existing/imminent visual deficits or ophthalmoplegias), neuroradiological (invasion or rapid tumor growth), and/or hormonal hypersecretion. Headache was not a primary surgical indication.

All participants completed a brief preoperative health survey of demographic and select baseline factors including age, gender, and smoking status. Furthermore, participants received a dedicated preoperative pituitary magnetic resonance imaging (MRI) study, including coronal, sagittal, and transverse T1 (pre- and postcontrast), T2, and dynamic sequences.

TSS was conducted by a single otolaryngologist/skull base surgeon (R. J. H.), who partnered with one of three neurosurgeons (B. P. J., M. J. W., A. S. D.). Anatomical samples of tumor were collected intraoperatively for histopathological analysis. A dural specimen was also collected from the anterior pituitary fossa, following removal of the seller floor and prior to exploration of the sella turcica, as described by Meij et al.[23]

Tumor Characteristics

Radiology

The maximal diameter (mm) of lesions in the anteroposterior, transverse, and craniocaudal planes was recorded and used to dichotomize participants with microadenoma (<10 mm) or macroadenoma (≥10 mm). Lesion volume was calculated using orthogonal tumor diameters (a, b, c) as follows[1]:

Volume = [4/3 π (a/2 × b/2 × c/2)

Cavernous sinus invasion was graded with coronal T1, T2, and dynamic series according to the Knosp classification (0–4) ([Fig. 1]): grade 0, tumor does not approach medial cavernous wall (preinvasive); grade 1, tumor abuts medial intercarotid line but does not cross it (preinvasive); grade 2, tumor crosses medial intercarotid line but not median intercarotid line (preinvasive); grade 3, tumor crosses median intercarotid line but not lateral intercarotid line (invasive); grade 4, tumor encases intracavernous carotid (invasive).[24]

Suprasellar extension was assessed dichotomously (present/absent) and defined as sagittal extension, above the tuberculum sellae, or coronal extension above the diaphragma sellae ([Fig. 2]). Sphenoidal sinus invasion was graded dichotomously (present/absent) and defined as tumor erosion and extension below the sella floor on sagittal and coronal imaging. MRI variables were graded by a single observer (M. J.) and 10 test MRIs were also assessed by a second observer (R. A.) for validation.

Histopathology

Adenoma samples were assessed for their K_i-67 labeling index by using the avidin-biotin-peroxidase method and incubating with the anti–K_i-67 antibody (Ventana Medical Systems, CONFIRM anti–K_i-67 (30–9), Arizona, United States) and expressed a percentage of positive tumor cells in a representative field of at least 500 cells. Intratumoral hemorrhage was assessed microscopically by the identification of hemosiderin deposits, primarily on hematoxylin and eosin–stained sections, with the addition of Perls staining when required.

Dural samples were analyzed microscopically on hematoxylin and eosin–stained sections. Microscopic dural invasion was diagnosed when individual cell invasion or dissection of the dural collagen planes by clusters of tumor cells was evident. A smooth well-defined interface between dura and adenoma was not classified as dural invasion.

Endocrine

Serum hormonal assays (prolactin, thyroid-stimulating hormone, adrenocorticotrophic hormone, and insulin-like growth factor-1) were collected on all patients within the 6 months preceding TSS.

Headache Outcomes

Headache presence, phenotype, and severity were assessed in all participants, irrespective of baseline headache status.

Presence

In this study, the presence of headache was defined at baseline as a moderate impact as assessed by the Headache Impact Test-6 (HIT-6) and/or mild disability as assessed by the Migraine Disability Assessment Score (MIDAS).

Phenotype

Phenotype was assessed at baseline (preoperatively) via an 18-item questionnaire, derived from two internationally validated diagnostic questionnaires (EUROLIGHT, HARDSHIP).[25] [26] These assessed the frequency of episodes (days/month) and their onset (sudden/abrupt), duration (hours), rhythmicity (episodic/continuous), laterality (bilateral/unilateral side-locked/unilateral side-switching), severity (not bad/bad/very bad), and associated symptoms (photophobia, phonophobia, nausea, and vomiting). These questions were utilized to algorithmically phenotype headaches as migraine, TTH, probable migraine, probable TTH, or other.

Severity

All participants also completed two self-assessment questionnaires to assess headache severity, both at baseline and 6 months postoperatively. These included the HIT-6 and MIDAS.[27] [28] HIT-6 is a 6-item questionnaire providing a global measure of adverse headache impact. Scores range from 36 to 78, and responders are also graded on an ordinal impact scale (little/moderate/substantial/severe). MIDAS is a 5-item questionnaire that scores how many of the preceding 90 days responders have experienced headache-related activity limitation. Scores range from 0 to 450, and responders are graded on an ordinal disability scale (little/mild/moderate/severe).

Statistical Analysis

Statistical analysis was conducted using SPSS version 24 (IBM 2018), adopting an α-level of p < 0.05. All interval-scaled data were expressed as mean ± standard deviation and proportional data as percentages. The association between baseline headache (present/absent) and continuous data was assessed via t-test, nominal data via chi-square, and ordinal data via Kendall's tau-b. The association between baseline and postoperative headache severity and continuous data was assessed via Pearson correlation, dichotomous data via t-test, nominal data via regression analysis, and ordinal data via Spearman correlation. McNemar's test was used to determine headache proportions before and after surgery.

Results

Participant Demographics and Baseline Lesion Characteristics

Sixty participants (62% female, 47.66 ± 18.10 years of age) with radiologically confirmed sellar lesions were assessed ([Table 1]). On histopathological diagnosis, pituitary adenoma (PA) was present in 83%, Rathke's cleft cyst (RCC) in 12%, and other lesions in 5% (meningioma, germinoma, and Langerhans histiocytosis). Surgery was conducted in 80% of participants for surgically naïve tumors and the remainder for residual/recurrent disease.

Lesions ≥ 10 mm were present in 75% of participants. Cavernous sinus invasion (Knosp grade ≥ 3) was present in 26%, suprasellar extension in 48%, and sphenoid sinus invasion in 14%. Mean K_i-67 index (%) was 2.45 ± 3.20. Dural invasion by tumor cells was present in 20% and intratumoral hemorrhage in 18%.

Baseline Headache

Baseline headache was present in 63% of participants. The ICHD phenotype was TTH (44%), undefined (39%), and migraine (17%).

Specific headache characteristics were heterogeneous. Most headaches were episodic (56%), while 44% experienced constant pain. Reported duration of headache episodes was 16.1 ± 36.1 hours (range, 0.03–168 hours). Onset was gradual in most (80%). Headache quality was pulsatile in 45% and pressure or tension-like in 55%. Pain was bilateral in 60% of participants, unilateral and consistently on the same side in 28%, and unilateral but intermittently switching sides in 12%. Associated symptoms included photophobia (52%), phonophobia (38%), and nausea and/or vomiting (28%).

Baseline HIT-6 score was 51.3 ± 11.7 (moderate impact) and mean MIDAS score 27.6 ± 67.4 (severe disability).

Demographic Predictors of Headache

Participants with baseline headache were significantly younger than those without (43.2 ± 17.1 vs 55.1 ± 17.6, p = 0.013). No other demographic predictors were significant (data not shown).

Headache phenotype was not significantly affected by demographic predictors (data not shown).

HIT-6 severity scores were significantly higher in participants who were younger (R² = −0.417, p = 0.010), smokers (63.31 ± 7.93 vs 54.44 ± 9.21, p = 0.0060), and those with a family headache history (68.14 ± 7.01 vs 54.94 ± 9.11, p = 0.003). Headache severity was not significantly associated with other demographic predictors (data not shown).

Radiological Predictors of Headache

Prevalence of headache at baseline was not significantly associated with radiological parameters ([Table 2]). Headache phenotype was not significantly related to radiological variables (data not shown).

MIDAS severity scores were lower in those with cavernous sinus invasion (Knosp grade ≥ 3) (8.71 ± 17.04 vs 35.54 ± 78.43, p = 0.045). HIT-6 scores were higher in participants with sphenoid sinus invasion (58.87 ± 8.97 vs 51.29 ± 10.97, p = 0.0070). Severity was not associated with other radiological parameters ([Table 2]).

Histological Predictors

Prevalence of headache at baseline was not significantly associated with histological predictors ([Table 3]). Continuous versus episodic headache was more prevalent in those with dural invasion (100.0% vs 30.8%, p = 0.029). No other phenotypic features were otherwise associated with histopathological variables analyzed (data not shown). HIT-6 severity scores were significantly increased in RCC compared with PA (59.83 ± 13.39 vs 47.68 ± 9.91, p = 0.010) and with microscopic dural invasion (55.70 ± 12.14 vs 47.18 ± 10.15, p = 0.027). Severity scores were not significantly associated with K_i-67 index nor intratumoral hemorrhage (data not shown).

Endocrine Predictors of Headache

Baseline headache presence, phenotype, and severity were not significantly associated with serum hormone levels (prolactin, thyroid-stimulating hormone, insulin-like growth factor-1, and adrenocorticotrophic hormone) (data not shown).

Surgery and Headache

Forty-five (75%) participants completed a follow-up assessment of headache severity at 6 months postoperatively. Longitudinal data beyond 6 months were not collected.

No overall difference was observed between the proportion of participants reporting headache at baseline and those still reporting headache at 6 months post operatively (57 vs 48%, p = 0.73 [McNemar's test]). Of patients without baseline headache, a new headache impact was observed in 16% and a new headache disability in 10% at 6 months postoperatively.

Of patients with baseline headache, HIT-6 impact status (little/moderate/substantial/severe) was improved or completely resolved in 78% and unchanged in 22%. MIDAS disability status (little/mild/moderate/severe) was improved or completely resolved in 64% and unchanged in 36%.

Absolute postoperative HIT-6 scores decreased significantly more as baseline HIT-6 scores increased (R² = −0.682, p < 0.0010). Postoperative MIDAS scores also decreased significantly more as baseline MIDAS scores increased (R² = −0.880, p < 0.0010). Moreover, complete headache resolution or improvement was more common when participants had a substantial or severe baseline HIT-6 impact grade compared with little or moderate impact grade (78 vs 11%, p < 0.0010). Complete headache resolution or improvement was also more common in participants with a moderate or severe baseline MIDAS disability grade compared with a little or mild baseline disability grade (67 vs 33%, p = 0.013).

Postoperative MIDAS scores reduced more in participants with dural invasion (−53.00 ± 18.68 vs 12.00 ± 17.54, p = 0.003). Postoperative change in headache severity scores was otherwise not significantly associated with demographic, histological, or radiological predictors (data not shown).

Discussion

In this prospective study of patients with sellar tumors, headaches were both more prevalent and severe in those with risk factors for primary headache, including younger age, family headache history, and smoking. Headaches also presented with greater severity in those with radiological sphenoid sinus invasion and histopathological dural invasion. Headache severity was also higher in RCC compared with PA. Overall, TSS significantly improved headache in 64 to 78% of participants, but a new headache disability was observed in 10% and new headache impact in 16% of participants at 6 months postoperatively. Postoperatively, headaches improved significantly in participants with dural invasion and highest baseline headache severity.

Cited estimates of headache prevalence in patients with sellar tumors are heterogeneous and likely relate to variable methods used to define headache. Nevertheless, prevalence spans between 33 and 72%.[1] Overall, the headache prevalence in this study population (63%) conforms with previous literature. This study also observed higher headache severity in RCC than in PA. This provides further validation to literature describing a comparatively higher headache burden in RCC than PA.[29] [30] Hence, an intrinsic difference(s) in the biochemical and/or mechanical behavior of RCC may lend to more aggressive headache initiation.

The majority of headaches in this study population resembled the two most prevalent primary phenotypes: TTH and migraine. Moreover, the prevalence and severity of headaches were significantly higher in participants with known primary headache risk factors.[31] [32] [33] This supplements existing evidence that the majority of headache disorders in patients with sellar lesions are likely to be either unrelated or exacerbated primary headaches.[1] In migraine, for example, headache is thought to be initiated by irritation of nociceptive afferent trigeminal plexuses encasing cerebral and pial vessels, venous sinuses, and dura mater.[31] Sellar lesions may induce similar dural and cavernous irritation in patients with a pre-existing predisposition to primary headache, thereby producing comparable pain phenotypes. Overall, however, this study reinforces that there is no pathognomonic headache phenotype in patients with sellar-related headache.

No association between baseline headache and lesion diameter or volume was observed. This supplements mounting evidence that large lesions are not prerequisites for headache.[1] [8] [9] [14] [15] [16] [17] [19] [20] [21] Similarly, for cavernous sinus invasion, like most studies, this investigation found that neither frank invasion nor increasing degrees of carotid ensheathment predicted headache.[1] [8] [9] [14] [15] [16] [18] [19] [20] In fact, headache severity was paradoxically lower with cavernous invasion, echoing a recent cross-sectional investigation.[9] Perhaps, then, cavernous invasion may provide lateral sella decompression and headache relief.

However, we found a significant association between headache severity and sphenoid sinus invasion. Sphenoid sinus invasion involves distortion of dura, bone, and underlying mucosa. These structures may each present a headache focus; the dura through mechanisms discussed, the bone through irritation of periosteal afferents,[34] and the paranasal mucosa through reflex activation of mucosal trigeminal afferents in a mechanism comparable to rhinogenic headache.[35] This novel finding presents a possible morphological predictor of secondary headache assessable on preoperative MRI, requiring further validation.

This study also found a significant association between headache severity and microscopic dural invasion. Given the causal relationship between primary headache and dural irritation aforementioned, this finding further suggests that sella lesions may mimic primary headaches via comparable irritation of the dural stroma and trigeminal afferents.[31]

Although neuroendocrine disturbances are proposed as a biochemical basis for headache, this is overwhelmingly unsubstantiated in sellar disease. Two studies have reported no headache difference between functional and nonfunctional lesions,[17] [36] while others also report equivocal headache prevalence when stratifying by secretory subtype.[8] [9] [12] [14] [15] [17] [20] [37] The nonsignificant findings of this study further suggest that hormonal status cannot reliably predict secondary headache.

Most studies have historically reported significant headache alleviation following neurosurgical intervention.[14] [15] [16] [24] [26] [29] [38] [39] [40] [41] [42] [43] Our study offered a similar optimistic impression of headache alleviation following TSS, with 64 to 78% of participants experiencing measurable postoperative headache relief. However, more recent longitudinal investigations have also cautioned a worsening headache in 9.0 to 29.7% of participants postoperatively.[9] [22] Likewise, the current study found new headache impact in 10% and disability in 16% of participants. Hence, TSS does carry potential headache morbidity, perhaps from anatomical manipulation and surgical trauma. It is uncertain whether these new headaches persist beyond the study's longitudinal 6-month postoperative follow-up interval.

This investigation found significantly greater headache improvement in participants who showed the highest baseline headache severity. This holds substantial clinical significance by proposing that validated headache severity metrics, including HIT-6 and MIDAS questionnaires, may be incorporated into clinical practice to guide the likelihood of postoperative headache correction. The results of this study would suggest a proposed HIT-6 threshold of ≥56 (≥substantial impact) or MIDAS threshold of ≥21 (≥severe disability). Furthermore, headache improvement was greater in participants with dural invasion. This reinforces an active nociceptive dural process that is amenable to resection.

Overall, this study underscores that headaches occurring in patients with sellar pathology present commonly as primary headache disorders particularly in those with pre-existing risk factors for headaches. It is likely the headache disorder is triggered or exacerbated by the presence of sellar pathology. Nevertheless, it appears possible to predict headaches that are amenable to surgical resection by the presence of sphenoid and dural invasion and high baseline headache severity. Hence, formal preoperative severity assessment may inform clinicians regarding the likelihood of postoperative symptom correction. Furthermore, as the first study examining sphenoid and dural invasion, these findings warrant validation in larger populations.

The data presented in this study are prospective and employ validated headache assessment tools, thereby mitigating recall and misclassification biases inherent to most retrospective studies in this area. Furthermore, all radiological variables were graded by a single observer to eliminate interobserver variability. Finally, the study employed standardized longitudinal headache assessment at 6 months postoperatively, which improves upon most investigations to date that employ retrospective review and variable time to follow-up.

Conclusion

In patients with tumors of the sella region, headaches are likely to be primary disorders, possibly exacerbated by concomitant sellar disease. There is no reproducible pathognomonic headache phenotype and few robust clinicomorphological predictors for headache. Neurosurgical resection can alleviate headache to a significant degree in many patients, but not absolute prevalence of headache. However, the greatest postoperative headache correction can be predicted in those patients with invasion of the contiguous dura or sphenoid sinus and high preoperative headache severity.

Conflict of Interest

R. J. H. is consultant with Medtronic, Stryker, Novartis, Meda, and NeilMed pharmaceuticals. Research grant funding received from Glaxo-Smith-Kline and Stallergenes. He has been on the speakers' bureau for Glaxo-Smith-Kline, Meda Pharmaceuticals, and Seqirus. A. M. has received speaker fees and research grants from Novartis Pharmaceuticals, Ipsen, and Pfizer. B. P. J. has received speaker fees from Integra LifeSciences Corporation. L. H. K. is on the speakers' bureau for Care Pharmaceuticals and Mylan Pharmaceuticals. R. S. is a consultant for Medtronic and is in the speaker bureau for Meda Pharmaceuticals. All other authors have no financial disclosures or conflicts of interest.

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• 38 Benveniste RJ, King WA, Walsh J, Lee JS, Naidich TP, Post KD. Surgery for Rathke cleft cysts: technical considerations and outcomes. J Neurosurg 2004; 101 (04) 577-584
  CrossrefPubMedGoogle Scholar
• 39 Fan M-C, Wang QL, Wang JF. et al. Surgical treatment of symptomatic Rathke's cleft cysts: clinical features, therapy considerations and outcomes. Chin Med J (Engl) 2012; 125 (16) 2919-2924
  PubMedGoogle Scholar
• 40 Fleseriu M, Yedinak C, Campbell C, Delashaw JB. Significant headache improvement after transsphenoidal surgery in patients with small sellar lesions. J Neurosurg 2009; 110 (02) 354-358
  CrossrefPubMedGoogle Scholar
• 41 Kim E. Symptomatic Rathke cleft cyst: clinical features and surgical outcomes. World Neurosurg 2012; 78 (05) 527-534
  CrossrefPubMedGoogle Scholar
• 42 Potts MB, Jahangiri A, Lamborn KR, Blevins LS, Kunwar S, Aghi MK. Suprasellar Rathke cleft cysts: clinical presentation and treatment outcomes. Neurosurgery 2011; 69 (05) 1058-1068 , discussion 1068–7
  CrossrefPubMedGoogle Scholar
• 43 Rizzoli P, Iuliano S, Weizenbaum E, Laws E. Headache in patients with pituitary lesions: a longitudinal cohort study. Neurosurgery 2016; 78 (03) 316-323
  CrossrefPubMedGoogle Scholar

Address for correspondence

Publication History

Received: 17 July 2022

Accepted: 09 February 2023

Accepted Manuscript online:
15 February 2023

Article published online:
20 March 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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  CrossrefPubMedGoogle Scholar
• 38 Benveniste RJ, King WA, Walsh J, Lee JS, Naidich TP, Post KD. Surgery for Rathke cleft cysts: technical considerations and outcomes. J Neurosurg 2004; 101 (04) 577-584
  CrossrefPubMedGoogle Scholar
• 39 Fan M-C, Wang QL, Wang JF. et al. Surgical treatment of symptomatic Rathke's cleft cysts: clinical features, therapy considerations and outcomes. Chin Med J (Engl) 2012; 125 (16) 2919-2924
  PubMedGoogle Scholar
• 40 Fleseriu M, Yedinak C, Campbell C, Delashaw JB. Significant headache improvement after transsphenoidal surgery in patients with small sellar lesions. J Neurosurg 2009; 110 (02) 354-358
  CrossrefPubMedGoogle Scholar
• 41 Kim E. Symptomatic Rathke cleft cyst: clinical features and surgical outcomes. World Neurosurg 2012; 78 (05) 527-534
  CrossrefPubMedGoogle Scholar
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  CrossrefPubMedGoogle Scholar
• 43 Rizzoli P, Iuliano S, Weizenbaum E, Laws E. Headache in patients with pituitary lesions: a longitudinal cohort study. Neurosurgery 2016; 78 (03) 316-323
  CrossrefPubMedGoogle Scholar