More than two thirds of our cohort with RCC were affected by headaches pre-operatively. Endoscopic drainage of RCC provided headache relief at 6 and 12 months with a mean decrease by 7 and 6 points in HIT-6 score respectively. In total, 63% of patients with pre-operative headache had reduction in HIT-6 score within 12 months. Previous studies were largely retrospective, had poor reporting of time point and method of assessing headache outcome, or where known, used subjective measure at a single timepoint post-operatively. Our study utilized a prospectively collected database to assess longitudinal change in headache at the individual level over several timepoints post-operatively, and employed a validated, quantifiable assessment tool; it is the largest such study in the literature.

Headache is the most common presenting complaint in RCC patients, found in 58.7% in a retrospective study of 46 patients [1]. Headaches tend to be non-pulsating, usually bilateral and frontal, similar to headaches in patients with pituitary adenoma. In pituitary adenoma, it is thought that stretching of diaphragma sellae and surrounding structures cause headaches [9, 10]. The pathophysiological basis for headaches in RCC is less studied, but may be additionally due to the secretion of cyst contents into the subarachnoid space causing an inflammatory reaction, given the potent stimulating effect of mucous cystic content [1]. In the study by Nishioka and colleagues [1], headaches did not correlate with cyst size (maximum diameter ranged 10–38 mm), but correlated with chronic inflammation in cyst wall on histopathology, and with high- and isointensity on T1 weighted- MRI. The later reflected high protein content compared to RCCs with low T1 intensity which contained CSF-like low viscous fluid. A recent study correlating histopathological characteristics and clinical presentation of RCCs further demonstrated that the prevalence of headache increases with severity of inflammation, and was associated with adjacent adenohypophyseal inflammation [11]. We did not find a significant association between MRI signal or histopathology characteristics with headache relief. In another retrospective study of 62 RCC patients undergoing surgery [12], 71% had headaches on presentation, most of whom had chronic headaches, but 16% developed sudden onset severe headaches possibly due to hemorrhage into cyst contents or secretion of inflammatory cyst contents.

While there is strong evidence for improvement in vision after surgery in up to 83–98% of RCC patients [12,13,14], and endocrinopathy to a much lesser extent [14, 15], the role of surgery in relieving headache in RCC patients is less well studied. In the absence of symptoms beyond headache, a surveillance approach is traditionally favored. Whether headache alone can be an indication for surgery in RCC requires assessment of its efficacy in providing durable headache relief, balanced against risks of surgery. A previous meta-analysis found a pooled headache resolution prevalence of 71.7% across 10 studies among patients who underwent RCC resection [3]. Interestingly, studies with longer follow-up times showed higher rates of headache reduction, suggesting the effect is durable. However, all except one study used self-reported headache outcomes rather than a validated scale for standardised assessment.

Several comparable studies are summarized in Table 2 [1, 12, 15,16,17,18,19,20]. Only two studies used a prospectively collected database [15, 18].Two used validated headache assessment metric with sample size of 10 and 13 [18, 19].No study collected data at multiple prespecified timepoints of follow-up as undertaken in our current study. In the retrospective case series by Nishioka et al. [1], headache improvement was seen in 17 of 21 patients (81%) who underwent transsphenoidal surgery for partial resection of the cyst wall. However, they did not describe the time point at which headache was assessed, and did not report rates of post-operative complications. Meanwhile, Wait et al. [15] reported resolution of headache in 68% of patients and improvement in 21% of patients who underwent surgery, but the surgical technique was a mixture of sublabial and transnasal approach, with a complete resection of cyst wall undertaken in 18 of 73 patients. In this study, 20% of patients developed new postoperative anterior pituitary deficits, 34% had diabetes insipidus and a high rate of CSF leak was observed (45% intraoperative and 8% persistent). In our study, cysts were commonly drained by puncturing the cyst wall with cyst biopsy. Only one case involved resection of cyst which resulted in post-operative CSF leak and development of diabetes insipidus. Meanwhile, Truong et al. [16] undertook a retrospective observational study comparing 39 RCC patients conservatively managed and 18 surgically treated patients and observed a similar rate of headache resolution in both groups. The interpretation of the results is however limited by significantly larger RCC with more frequent suprasellar extension in the surgical group (70.6% ≥ 10 mm diameter) compared to conservative group (40.5% ≥ 10 mm), and the lack of reporting of time point at which outcomes were assessed.

The efficacy of surgery in providing headache relief is perhaps better examined in two studies of sub-centimeter RCCs where patients were offered surgery solely for intractable headaches, unlike previous studies where patients underwent surgery for varying indications such as visual deficit or mass effect. Fukui and colleagues [19] examined 13 patients with chief complaint of severe headaches with a mean size of cysts 7.0 ± 1.8 mm undergoing endoscopic transsphenoidal drainage. All patients had relief within 1 week of surgery, with significantly lower mean HIT-6 score of 37.2 at 3 months post-operatively. In this cohort, most of cyst contents were T1 hyperintense with pathologic inflammation observed at cyst wall. Similarly, in a retrospective study by Mathios et al. [18],10 patients with RCC ≤ 1 cm who had seen a specialist for their headache and had at least 3 months of medical treatment for it underwent RCC fenestration. They found that the average intensity of headache reduced from 8.7 to 2.9 at 1 month and 0.9 at 1 year in 8 patients with available data. However, the study was limited by significant recall bias with response received at average of 38.8 months after surgery and lack of formal statistical analysis. It is unclear at present whether the efficacy of surgery for headache relief differs for small and large RCCs. These preliminary studies suggest that RCCs can cause headaches even if volume is small, possibly through release of inflammatory cystic contents. In fact, Hayes et al. [11] demonstrated a correlation between inflammatory infiltrate and prevalence of headache, but not for pituitary dysfunction or visual impairment. The site of inflammation and concentration of inflammatory cells influenced the prevalence of headache, but cyst volume was not different in patients with and without headache, nor associated with presence of inflammation. This provides further evidence for the potential mechanism by which subcentimeter RCCs can also cause intractable headaches.

Our group previously showed that RCC patients had transiently worsened overall QoL which normalized by 6 weeks in addition to worsening of sinonasal QoL which resolved within 3 weeks post-operatively [13]. Here, in the group of RCC patients affected by headache, overall quality of life returned to baseline at 6 weeks with a trend for improvement at 6- and 12- months, although this was not statistically significant. Greater headache severity at 12 months however was associated with reduced overall QoL.

In this study, we showed that durable and clinically meaningful headache improvement can be achieved safely from endoscopic endonasal drainage of RCCs. While ongoing prospective data for patients with RCCs with mass effect is being collected, our findings lend support to considering surgery in patients with intractable headaches as primary indication. The two aforementioned studies showed dramatic improvement in headache after drainage of subcentimeter RCCs, albeit with study limitations. This is worthy of further investigation in a clinical trial, ensuring patients have other potential causes of headache excluded following specialist consultation, and medical management trialled. In this setting, there would also be greater equipoise for including a control group of subcentimeter RCCs managed conservatively. Alternate means to address potential mechanism of inflammatory infiltrate, such as steroids could also be considered [11, 21].

This study aimed to assess the change in headache outcome after endoscopic endonasal drainage of Rathke’s cleft cyst using the validated HIT-6 questionnaire assessed longitudinally during the first postoperative year. Limitations include small sample size and surgeon selection bias for large RCCs that caused visual deficits, pituitary dysfunction or demonstrated concerning radiological features. Self-selection bias is possible, where loss to follow-up may have been due to those experiencing worse headache outcome, thereby leading to an overestimation in headache relief post-operatively. Equally, the study may attract follow-up from those who experience ongoing symptoms, with those experiencing relief not completing surveys. The subtle distinction between headache as the initial presenting complaint and headache at time of presentation was not captured in our data, nor in previous studies. Potential confounding factors such as other headache syndrome not related to RCC or concurrent illness that affected their headache could be present. Specific features and duration of headache pre-operatively were not available to allow further characterization. Future studies should incorporate larger sample size and consider inclusion of a comparison group of patients conservatively managed. Longer follow-up period is required to assess potential improvement in overall QoL not detected in this study.