Idiopathic intracranial hypertension (IIH), previously known as pseudotumor cerebri or benign intracranial hypertension, is a neurological condition characterized by elevated intracranial pressure (ICP) without identifiable structural or vascular causes [¹]. This disorder mainly affects women of reproductive age and demonstrates a strong association with obesity; despite the current research about IIH, the etiopathogenesis remains not fully understood yet [¹]. The hallmark clinical manifestations of the disease include headache, papilledema, and visual disturbances that may progress to blindness if left untreated with proper management [¹].

The management of IIH follows a systemic approach, beginning with conservative measures such as weight loss and medical therapy, with acetazolamide, topiramate, and diuretics [²,³,⁴]. However, around 25% of patients are developing refractory IIH in which they have limited or poor response to the initial medical interventions, necessitating surgical intervention [⁵]. Among the available surgical options, optic nerve sheath fenestration (ONSF) is considered to be among the surgical interventions for IIH patients to preserve vision in cases of progressive visual deterioration [⁵,⁶]. ONSF involves creating an opening in the optic nerve sheath to reduce localized cerebrospinal fluid (CSF) pressure, which, by role, decreases mechanical compression on the optic nerve [⁷]. While ONSF for IIH has been reported as a successful intervention for IIH in patients with threatened visual loss, previous studies did not have sufficient conclusive evidence about the optimal ONSF approaches and settings regarding its safety and efficacy for IIH patients [⁵,⁸,⁹].

Previous studies have highlighted important considerations in surgical procedures for IIH, but these studies either lacked complete evaluation of visual fields or have become outdated as new surgical techniques and further updated studies have been published [¹,⁵,⁷,⁸,⁹,¹⁰,¹¹,¹²]. The timing of surgical intervention appears critical, with mounting evidence suggesting that delayed intervention may result in irreversible vision loss due to progressive optic nerve damage [¹³]Also, technical aspects of the procedure, such as the size and location of the fenestration, muscle disinsertion requirements, and the use of minimally invasive approaches, may affect its efficacy and complication rates.

Recent advances in surgical techniques, especially the development of endoscopic and minimally invasive approaches, have renewed interest in evaluating the safety and efficacy of ONSF from different prospections, even in the presence of other minimally invasive interventions such as venous sinus stenting where they may not be suitable for some patients due to several factors and considerations [¹⁴]. Additionally, the emergence of large-scale studies with detailed visual outcome data has created an opportunity for a more detailed analysis of factors influencing surgical success with the option of conducting subgroup analysis to explore further more factors affecting ONSF success [¹⁵]. Therefore, we aim to evaluate the safety and efficacy of ONSF in preserving vision in patients with IIH based on the most updated evidence in the most detailed manner, given the currently available data. Our study specifically focuses on three key outcomes: improvement in visual acuity, enhancement of visual fields, and resolution of optic disc swelling, in addition to investigating the reported postoperative complications from ONSF. Our study aims to perform detailed subgroup analyses based on geographical location, study design, surgical approach, and technical variations to identify factors that might influence surgical outcomes. Understanding these variables and factors related to ONSF in IIH patients has important considerations for optimizing patient selection and surgical technique, ultimately improving visual outcomes in this challenging patient population.

Our systematic review and meta-analysis were conducted with adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We conducted a literature search across multiple electronic databases, including PubMed/MEDLINE, Embase, Web of Science, Scopus, Google Scholar, and Cochrane Library, from inception through the 22nd of December 2024. The search strategy incorporated Medical Subject Headings (MeSH) terms and keywords related to "optic nerve sheath fenestration", "ONSF" "idiopathic intracranial hypertension”, “IIH”, “benign intracranial hypertension”, and "pseudotumor cerebri". For methodological clarity, we classified all included studies into two categories: observational and interventional. It is important to note that all studies in both categories involved patients who underwent ONSF; our classification refers to study design rather than treatment allocation. Observational studies (n= 16) included retrospective chart reviews, case series, and cohort studies where the studies analyzed and reported the outcomes after ONSF without a predefined intervention protocol. Interventional studies (three studies) were those with prospective enrollment following a standardized surgical protocol and predefined outcome measures, representing a higher level of methodological confidence and validity.

Our systematic search yielded 597 records, with 19 studies meeting the final inclusion criteria after thorough screening [¹⁸,¹⁹,²⁰,²¹,²²,²³,²⁴,²⁵,²⁶,²⁷,²⁸,²⁹,³⁰,³¹,³²,³³,³⁴,³⁵,³⁶]. The included studies spanned from 1988 to 2021, comprising 16 observational and three interventional studies, with 14 retrospective and five prospective designs (Supplementary Table 1).

In our study, we evaluated the efficacy and safety outcomes of ONSF in IIH patients, focusing on detailed subgroup analyses based on multiple factors. Our findings provide important insights into the factors that may have significant considerations on ONSF outcomes and help identify optimal patient selection criteria.

Our analysis demonstrates that ONSF shows considerable efficacy in improving visual outcomes, with an overall visual acuity improvement rate of 34.5% (95% CI: 31.8-37.3%) and visual field improvement rate of 69.4% (95% CI: 65.9-72.7%). The subgroup analyses revealed several groups for efficacy and treatment success and highlighted several important points that warrant discussion and further investigation. Studies from non-US centers showed significantly higher rates of visual acuity improvement (48.3% vs. 29.8%, p-value<0.001), suggesting potential variations in patient selection criteria or surgical techniques across different geographic regions [³,¹⁶,³⁷,³⁸,³⁹,⁴⁰]. Prospective studies demonstrated markedly better outcomes in visual acuity improvement compared to retrospective designs (80.8% vs 32.7%, p-value<0.001), highlighting the importance of standardized protocols and careful patient monitoring in achieving optimal outcomes, which was previously discussed that we need more optimization and standardization for IIH studies to promote better quality studies and enhance our evidence about the disease [⁴¹]. The surgical approach emerged as a crucial factor, with non-medial transconjunctival approaches showing higher success rates (48.4%) compared to medial transconjunctival approaches (30.6%, p-value<0.001). This finding suggests that surgical technique selection may significantly influence visual outcomes. Sample size analysis revealed interesting patterns, with centers performing more than 30 procedures showing more consistent results compared to those with smaller case volumes. Regarding papilledema resolution, US studies demonstrated significantly better outcomes (97.3% vs. 76.5%, p-value<0.001), as did interventional studies compared to observational ones (98.7% vs. 83.6%, p-value<0.001). Also, the medial transconjunctival approach showed superior results in papilledema resolution (98.8% vs 82.8%, p-value<0.001), which is a complex and contradictory finding, especially since the overall success rates were higher in non-medial transconjunctival approach as we mentioned earlier; and based on that further studies with more focused controls and approach-focused outcomes and complications should be conducted to ensure the results about it.

It is important to mention that we had statistically significant heterogeneity in visual acuity (I²=92.1%) and visual field improvements (I²=73.8%), which warrants careful interpretation. This heterogeneity likely originates from multiple sources identified through additional analyses. First, patient-specific factors varied considerably across studies, with mean age ranging from 26.5 to 40.8 years, mean BMI from 26.8 to 39.6 kg/m², and disease duration before ONSF from 1.3 to 36 weeks. Second, follow-up protocols differed significantly, with some studies reporting outcomes at three months and others at up to two years post-procedure, introducing temporal bias in outcome assessment. Third, there was an inconsistency in measurement techniques, varying from Snellen charts to log MAR for visual acuity and from Goldmann to automated perimetry for visual fields, which created methodological variability that contributed to heterogeneous results. Also, the threshold for defining improvement was inconsistently applied across studies, with some requiring one-line improvement in visual acuity while others demanded two or more lines for positive classification.

Our safety analysis revealed an overall complication rate of 9% (95% CI: 5-16%, I²=48%), which is lower than previously reported in some studies from previous literature. The subgroup analyses of complications provided important significant considerations and factors to highlight risks and possible preventive strategies.

Geographic variation was significant, with non-US centers reporting higher complication rates (13.9% vs 7.4%, p=0.007). This difference might reflect variations in surgical expertise, patient selection, guidelines, or reporting practices between the US and other countries [¹⁷,³⁸]. The surgical approach significantly affected complication rates, with the medial transconjunctival technique showing lower complications (7.7% vs 13.2%, p=0.023), suggesting it might be the safer approach, although the surgical technique findings warrant further verification as they are contradictory within our analysis findings between different variables. Sample size-based subgroup analysis demonstrated that centers in which they performed more than 30 procedures reported in their research paper had significantly lower complication rates (6.6%) compared to those with fewer cases (15.2% for <30 cases, p<0.001), highlighting the importance of surgical experience and center volume, and may also be considered that there is a possible effect from the influence of sample size power on overall results. Specific complications showed varying patterns, with diplopia being the most common (3%, I²=24%), followed by anisocoria (4%, I²=0%).

Our findings both support and extend the conclusions of the previous meta-analyses. Unlike Kalyvas et al.’s study [⁸], which focused broadly on various surgical interventions for IIH; our analysis provides a detailed focus on ONSF outcomes only. Compared to Friso et al.’s [⁴²] pediatric-focused review, our study offers a comprehensive analysis across all age groups. When compared to Santos et al. study [⁴³], they included only ten studies, with limited outcomes assessment compared to our defined methodology and results. Also, in comparison with the recent Prokop et al. meta-analysis [⁴⁴], they had several limitations in their study, which we worked to overcome in our analysis, including more comprehensive subgroup analysis, analysis of postoperative complications in which they did not perform, handling of publication bias using multiple statistical techniques, correction of bias through trim-and-fill technique, performing more detailed risk of bias assessment, in addition to the introduction of a GRADE framework approach to our analysis in which they did not perform.

Despite the strengths and novel points of our analysis compared to previous studies, our study has several limitations that warrant acknowledgment. First, the retrospective nature of most included studies introduces selection and reporting biases. Second, the heterogeneity in outcome reporting and surgical techniques across studies may affect the generalizability of our findings. Third, the lack of standardized visual outcome measurements across studies made some comparisons challenging. Future studies should focus on prospective data collection with standardized outcome measures and longer follow-up periods. Multicenter randomized controlled trials comparing different surgical approaches would be valuable in definitively establishing the optimal technique. Additionally, studies investigating the role of modern surgical adjuncts and their impact on outcomes would be beneficial.

ONSF demonstrated significant efficacy in improving visual outcomes, with promising results in visual field improvement (69.4%) and papilledema resolution (90.9%). The procedure’s effectiveness varied between different settings and approaches, with prospective studies and non-medial transconjunctival approaches showing superior visual acuity improvement rates. Centers performing more than 30 procedures demonstrated better outcomes and lower complication rates, suggesting a volume-outcome relationship in ONSF procedures. The overall safety profile was favorable, with a 9% complication rate, mostly including manageable complications such as diplopia (3%) and anisocoria (4%). The medial transconjunctival approach emerged as the safer technique with significantly lower complication rates (7.7% vs 13.2%), despite the fact that non-medial transconjunctival approaches demonstrated better efficacy outcomes earlier. Geographic variations in both efficacy and safety outcomes address the importance of standardizing surgical techniques and patient selection criteria. US centers showed better papilledema resolution rates and better safety profiles compared to non-US centers, suggesting possible differences in practice patterns that warrant further investigation. These findings support ONSF as a viable surgical option for IIH patients, especially when performed in experienced centers using appropriate surgical techniques. Future studies should focus on prospective studies with standardized outcome measures and surgical protocols to further optimize patient outcomes. Also, developing formal training programs and surgical guidelines could help reduce the observed outcome variations across different centers and regions.