The Role of Fibrin Sealants in Endoscopic Repair of Cerebrospinal Fluid Rhinorrhea: A Comprehensive Review of Recurrence Rates

I. Executive Summary

This report provides a comprehensive analysis of the use of fibrin sealants, such as Beriplast, in the surgical management of cerebrospinal fluid (CSF) rhinorrhea, with a specific focus on postoperative recurrence rates. A critical evaluation of the available clinical evidence, from observational studies to high-level systematic reviews and meta-analyses, indicates that while fibrin sealants are widely employed as a surgical adjunct, their use does not confer a statistically significant reduction in the long-term rate of CSF leak recurrence following endoscopic repair.

The primary determinants of a durable, successful repair are twofold. First is the meticulous surgical technique centered on a robust, multilayered structural reconstruction of the skull base defect. The choice of repair material—ranging from autologous free grafts for small defects to vascularized pedicled flaps for larger, more complex scenarios—is the foundational element of the procedure's success. Second, and of equal importance, is the identification and aggressive management of the underlying etiology, particularly elevated intracranial pressure (ICP), which is a principal driver of failure in spontaneous CSF leaks.

The role of fibrin sealants is best understood as that of a temporary bio-adhesive. They facilitate the initial placement and stabilization of grafts, particularly avascular free grafts, against CSF pulsations during the critical early healing phase. However, they do not contribute to the long-term biomechanical strength of the repair. Therefore, clinical focus and strategy should be directed toward optimizing the structural integrity of the reconstruction and mitigating the physiological forces that challenge it, rather than on the adjunctive use of a sealant.

II. Cerebrospinal Fluid Rhinorrhea: A Clinical Overview

Pathophysiology of CSF Leaks

Cerebrospinal fluid rhinorrhea is a pathological condition defined by the leakage of CSF into the nasal and paranasal sinus cavities.1 It results from an anomalous communication between the subarachnoid space and the external aerodigestive tract, which occurs following a breach of the multiple layers separating the intracranial environment from the sinonasal mucosa: the dura mater, arachnoid membrane, and the bone of the skull base.2 CSF, produced primarily by the choroid plexus in the cerebral ventricles, circulates through the subarachnoid space before being reabsorbed into the venous system. A dural and osseous defect creates a pressure gradient that allows this fluid to escape, manifesting as clear nasal discharge.1

Etiological Classification and Clinical Significance

The causes of CSF rhinorrhea are broadly classified as traumatic and non-traumatic. Historically, trauma is the leading overall cause, responsible for 80% to 90% of all cases.1 Traumatic leaks are further subdivided into accidental (e.g., craniofacial fractures) and iatrogenic, with functional endoscopic sinus surgery (FESS) being a prominent iatrogenic cause. The lateral lamella of the cribriform plate is a site of particular vulnerability during FESS due to its thinness.1

However, a critical distinction exists between the epidemiology of all CSF leaks and the etiology of leaks presenting for surgical repair. While trauma is the most common cause overall, a significant proportion of these leaks—approximately 70%—resolve spontaneously with conservative management, such as bed rest and observation.5 In contrast, non-traumatic or spontaneous leaks, which are often associated with underlying pathologies like idiopathic intracranial hypertension (IIH) or congenital skull base defects, are far less likely to resolve on their own and almost invariably require surgical intervention.7 This phenomenon creates a "surgical filter," whereby patient cohorts in surgical studies are disproportionately composed of spontaneous leaks and traumatic leaks that have failed conservative measures. This explains why large surgical series frequently report spontaneous leaks as the most common etiology, with one major study finding them to account for 54.32% of surgically treated cases.3

The Imperative for Surgical Intervention: Preventing Meningitis

The primary and most compelling reason for the surgical repair of a persistent CSF leak is the prevention of life-threatening ascending bacterial meningitis.1 The direct communication between the non-sterile sinonasal cavity and the subarachnoid space creates a pathway for infection, with the reported risk of developing meningitis varying widely in untreated patients, from 5.6% to as high as 60%.3

The protective benefit of surgical intervention is profound and has been quantified by high-level evidence. A systematic review and meta-analysis of spontaneous lateral skull base CSF leaks calculated the pooled preoperative risk of meningitis to be 0.16 (a 16% incidence).9 Following surgical repair, the postoperative pooled risk fell dramatically to 0.01 (a 1% incidence). This represents a relative risk of 0.02, signifying a 98% reduction in the likelihood of developing meningitis after successful surgery.9 This stark contrast underscores the high stakes of the procedure. A failed repair, or recurrence, re-exposes the patient to this significant risk, making the long-term durability of the closure a matter of paramount clinical importance.

III. The Modern Surgical Paradigm: Endoscopic Endonasal Repair

Evolution from Open Craniotomy

The surgical management of CSF rhinorrhea has undergone a significant transformation over the past several decades. The traditional approach involved an open transcranial craniotomy, a major neurosurgical procedure requiring a large incision and retraction of the brain to access the skull base defect.1 While effective in many cases, this approach was associated with considerable morbidity, including the risk of anosmia (loss of smell), brain edema and contusion from retraction, hematoma, and seizures.10

The Endoscopic Approach as the Standard of Care

The advent of the rigid endoscope has revolutionized the treatment of CSF rhinorrhea, establishing the endoscopic endonasal approach (EEA) as the current standard of care for the vast majority of leaks.5 This minimally invasive technique, performed entirely through the nostrils, avoids external incisions and brain retraction, leading to lower morbidity and faster recovery times.3 The efficacy of the EEA is well-established, with consistently high success rates reported across the literature. A large systematic review encompassing 1,778 fistula repairs found an overall success rate of 90% for primary repairs, rising to 97% for secondary (revision) repairs.15 Numerous other series corroborate these findings, with success rates routinely exceeding 90%.5

Core Principles of the Endoscopic Technique

The high success rate of the EEA is not merely a function of its less invasive nature. Rather, the technology of the endoscope enhances the surgeon's ability to apply fundamental surgical principles with greater precision.

• Precise Localization: Accurate identification of the defect is the first critical step. This is achieved through a combination of preoperative high-resolution imaging, such as CT scans or CT/MR cisternography, and intraoperative visualization.6 The use of intrathecal fluorescein, a dye injected into the CSF via a lumbar puncture, is a key technique. Under the endoscope's blue light filter, the fluorescein-tinged CSF glows a brilliant green-yellow, allowing for the direct and unambiguous localization of even very small or intermittent leaks.4

• Defect Preparation: Once identified, the mucosa surrounding the bony edges of the defect is carefully removed. This creates a raw, bleeding surface that promotes the integration and healing of the graft material that will be used for the repair.5

The endoscope's core advantages—superior illumination, high-magnification view, and the ability to use angled lenses to see around corners—directly facilitate these critical steps.3 This enhanced visualization allows for more accurate localization, more complete preparation of the recipient site, and more precise placement of the reconstructive materials, which are the ultimate drivers of the high success rates associated with the modern endoscopic approach.

IV. A Multi-faceted Approach to Skull Base Reconstruction

The cornerstone of a durable CSF leak repair is the structural reconstruction of the skull base defect. Modern surgical practice employs a graduated approach, tailoring the reconstructive technique to the specific characteristics of the leak, primarily its size and flow rate.

The Foundational Role of Structural Grafts and Flaps

The primary component of any repair is the biological material used to physically bridge the defect.

• Autologous Free Grafts: For small- to moderate-sized defects with low CSF flow, avascular free grafts harvested from the patient are commonly used. These include fascia lata (a thick, fibrous tissue from the thigh), adipose tissue (fat), and cartilage.20 These grafts rely on the blood supply from the prepared edges of the defect for their survival and integration.

• Vascularized Pedicled Flaps: For large defects, high-flow leaks, or in revision surgery where the local tissue bed may be compromised, a vascularized flap is often the preferred choice. The pedicled nasoseptal flap (Hadad-Bassagasteguy flap) has become the workhorse for endoscopic skull base reconstruction.16 This flap consists of mucosa and periosteum from the nasal septum, kept alive by its own dedicated blood supply from the posterior septal artery. This intrinsic vascularity makes it exceptionally robust and has been shown to improve success rates in challenging repairs.5 However, its reach can be limited, particularly for defects located high in the frontal sinus.5

The Principle of Multilayered Closure

Regardless of the primary material used, modern reconstruction almost universally employs a multilayered technique to enhance the strength and seal of the repair.10 This often involves a "sandwich" or "inlay-overlay" technique, where one layer of graft material (the inlay) is placed extradurally, between the dura and the bone, and a second layer (the overlay) is placed on the sinonasal side of the defect.22 Evidence suggests that the number of layers correlates with success. One study found a statistically significant lower recurrence rate with 3- or 4-layered repairs compared to 2-layered repairs (8% and 25% vs. 50%, respectively; ).23

The choice of reconstructive material is the primary strategic decision in CSF leak surgery, as summarized in Table 1.

Table 1: Comparison of Reconstruction Materials for CSF Rhinorrhea Repair

Material/Technique	Primary Indications	Advantages	Disadvantages/Limitations	Key References
Free Graft (e.g., Fascia Lata, Fat, Mucosa)	Small defects ( cm), low-flow leaks, primary repairs	Readily available, low donor site morbidity, versatile	Avascular, relies on surrounding tissue for healing, may be insufficient for high-pressure leaks	3
Vascularized Flap (e.g., Nasoseptal Flap)	Large defects ( cm), high-flow leaks, revision cases, post-radiation	Robust vascular supply promotes healing, high success rate for complex defects	Requires more extensive dissection, limited reach to certain areas (e.g., far-lateral frontal sinus), potential donor site morbidity	5
Rigid Reconstruction (e.g., Bone, Cartilage)	Defects requiring structural support, prevention of encephalocele formation, often used in combination with other grafts	Provides a solid barrier, prevents herniation of brain tissue	Can be more complex to place, potential for resorption over time	24

V. Fibrin Sealants in Neurosurgery: Mechanism and Application

Biochemical Composition and Action

Fibrin sealants, sold under brand names such as Beriplast and Tissucol, are two-component biological adhesives used widely in surgery.25 The system is designed to mimic the final step of the physiological coagulation cascade.26 The first component contains a concentrated solution of fibrinogen and Factor XIII, often with aprotinin to inhibit premature clot breakdown. The second component contains thrombin and calcium chloride. When mixed at the time of application, the thrombin rapidly converts the fibrinogen into fibrin monomers, which then polymerize and are cross-linked by Factor XIII to form a stable, solid fibrin clot within seconds.26

Intended Role as an Adjunctive Agent

In the context of skull base surgery, fibrin sealants are intended to serve three main functions: as a topical hemostatic agent to control minor bleeding, as a tissue adhesive to help secure grafts, and as a sealant to provide an immediate watertight closure.27

The biochemical nature and clinical application of these products define their role as a temporary adjunct to the healing process, not as a permanent component of the repair itself. The fibrin clot formed is a biological material that is eventually resorbed by the body's natural fibrinolytic processes. Its function is to act as a "primary seal (scab) until the biological implant [the graft] has the opportunity to mature and be integrated into a permanent scar that will serve as a long term seal".27 This means its primary purpose is to provide immediate, temporary adhesion, holding the main structural graft in position against the pulsatile forces of CSF and gravity during the critical initial days of healing. It is not designed to, nor can it, provide the long-term mechanical strength required to resist chronic physiological forces, a distinction fundamental to understanding its impact—or lack thereof—on long-term recurrence rates.28

VI. Evidence-Based Analysis of Recurrence Rates: Fibrin Sealant vs. No Sealant

A hierarchical review of the clinical evidence is necessary to directly address the question of whether the use of fibrin sealants like Beriplast reduces the rate of CSF leak recurrence.

Highest-Level Evidence: Systematic Reviews and Meta-Analyses

The most robust evidence comes from comprehensive reviews that aggregate data from multiple studies.

• A 2016 systematic review analyzed 32 studies on the use of fibrin sealants in dura sealing.29 It included one randomized controlled trial (RCT), the highest level of evidence. This RCT found that while fibrin sealant significantly improved the rate of achieving an intraoperative watertight closure compared to sutures alone (92.1% vs. 38.0%), it was associated with a higher, though not statistically significant, rate of postoperative CSF leakage (6.7% in the sealant group vs. 2.0% in the control group).29

• A more recent systematic review and meta-analysis from 2020 provides the most definitive conclusion to date.30 This study pooled data to directly compare outcomes. The analysis found that "Reconstruction with a tissue sealant did not significantly reduce postoperative CSF leak risk compared with reconstruction without sealant (Risk Difference [95% CI] = 0.02 [−0.01, 0.05])".30 Further sub-analyses of specific dural sealants and fibrin glues yielded similarly unremarkable results, showing no statistically significant benefit.

Observational Data and Older Studies

Lower-level evidence from individual cohort studies and case series provides additional context.

• A notable retrospective study from 1990 evaluated the use of Beriplast in 126 transsphenoidal surgeries.25 It reported a low postoperative rhinorrhea rate of 1.6%. The authors compared this to historical literature rates for repairs using autologous tissue alone (which ranged from 1.5% to 9.6%) and concluded that using fibrin glue "does not raise the incidence of postoperative rhinorrhea." This finding supports the safety (non-inferiority) of the sealant but does not demonstrate its superiority in preventing leaks.

• A very small 2012 case series from a developing country reported on five patients, four of whom had their repairs sealed with Beriplast.20 All five cases were successful. While encouraging, such a small, uncontrolled series cannot be used to draw generalizable conclusions about efficacy.

The apparent paradox from the RCT—that sealants can achieve a better immediate intraoperative seal yet fail to improve long-term postoperative outcomes—is resolved by understanding the different failure mechanisms. The immediate seal is a simple mechanical challenge that a rapid-acting glue can solve. However, postoperative recurrence is a failure of biological healing and the repair's ability to withstand chronic physiological stress. This failure can be due to graft migration, necrosis, or, most critically, mechanical disruption from persistent, unmanaged forces like elevated ICP. As the sealant is resorbed over days to weeks, it plays no role in the final biological integration of the graft or in buttressing the repair against these chronic forces. Therefore, the findings of the high-level reviews are not contradictory but are biologically and mechanically logical. The sealant solves a short-term problem (graft placement) but does not address the long-term challenges that are the true drivers of recurrence.

Table 2: Summary of Key Clinical Studies on Fibrin Sealant Efficacy and Recurrence Rates

Study (Identifier)	Study Design	Population/Intervention	Key Finding on Recurrence	Reported Recurrence Rates (Sealant vs. Control)
Ramakrishnan et al. 2020 30	Systematic Review & Meta-Analysis	Endoscopic skull base surgery	No significant difference in postoperative CSF leak risk with sealant use.	Risk Difference 0.02 (95% CI: -0.01 to 0.05)
Psaltis et al. 2016 29	Systematic Review (incl. 1 RCT)	Dura sealing in neurosurgery	Higher (non-significant) postoperative leak rate with sealant in the single RCT.	6.7% vs. 2.0% () in the RCT
Shaffrey et al. 1990 25	Retrospective Cohort	Transsphenoidal surgery	Sealant use does not increase the leak rate compared to historical rates with autografts alone (non-inferiority).	1.6% vs. 1.5%-9.6% (historical control)

VII. Critical Determinants of Surgical Success Beyond Sealant Use

The evidence strongly suggests that focusing on the use of an adjunctive sealant is a distraction from the factors that truly dictate long-term surgical outcomes. CSF leak recurrence is best understood as a failure of a biomechanical system, where success depends on achieving a state where the structural resistance of the repair exceeds the physiological load placed upon it.

The "load" on the repair is primarily determined by the patient's intracranial pressure. This load is highest and most relentless in patients with untreated IIH, which is why spontaneous leaks are associated with the highest recurrence rates.7 The "resistance" of the repair is determined by the quality of the structural reconstruction—the type of graft used (vascularized flaps are more robust), the number of layers applied (more layers are stronger), and the size of the defect it must span (larger defects are inherently weaker and are a predictor of recurrence).23

Recurrence occurs when the load exceeds the resistance. A fibrin sealant is a negligible factor in this equation; it does not materially increase the long-term resistance of the repair, nor does it decrease the physiological load. Therefore, a successful, evidence-based surgical strategy must focus on maximizing resistance and minimizing load. This involves:

• Tailoring the Repair: Using a robust, multilayered repair with a vascularized flap for large, high-flow defects, and an appropriate free graft for smaller defects.3

• Managing ICP: Aggressively diagnosing and treating elevated ICP in patients with spontaneous leaks through measures like weight loss, diuretics (e.g., acetazolamide), or, in refractory cases, CSF shunting procedures.1

• Considering Adjunctive Measures: The use of perioperative lumbar drains is a common but controversial adjunct. While they can temporarily reduce the load on a repair, evidence suggests they significantly increase the length of hospital stay without necessarily reducing recurrence rates.17 Their use is typically reserved for specific high-flow situations or to help manage ICP postoperatively.13

VIII. Expert Consensus and Clinical Practice Guidelines

Professional societies, such as the American Rhinologic Society (ARS), provide guidance on best practices. The ARS has developed an expert practice statement (EPS) specifically on skull base reconstruction following endoscopic surgery, which explicitly addresses the roles of various materials, including dural sealants.32 While the abstracts of these guidelines do not detail the final specific recommendations, the focus of the documents and the broader consensus in the literature point away from sealants as a critical component.33

General patient information provided by the ARS emphasizes that the specifics of the repair, such as using a single layer versus multiple layers, depend on the size and location of the defect—a key determinant of success.13 The document makes no mention of sealants as an essential element for a successful outcome. The lack of a strong, definitive recommendation for the routine use of fibrin sealants in major clinical guidelines, when combined with the high-level evidence showing no significant benefit, is itself a powerful indicator of their non-essential role in preventing recurrence. The consensus is that the focus should remain on the impactful variables: appropriate structural reconstruction and management of underlying pathology.

IX. Conclusion and Clinical Recommendations

Definitive Synthesis of Evidence

Based on a critical appraisal of the available literature, with the greatest weight given to high-level systematic reviews and meta-analyses, the adjunctive use of Beriplast or other fibrin sealants does not result in a statistically significant reduction in the long-term recurrence rate of CSF rhinorrhea following endoscopic repair. While these agents may offer an intraoperative advantage in temporarily securing a graft, this benefit does not translate to improved long-term durability of the skull base closure.

Evidence-Based Clinical Recommendations

1. Prioritize Structural Reconstruction: The foundation of a durable repair is a meticulous, multilayered closure using appropriate structural materials. The choice between an avascular free graft and a vascularized pedicled flap must be dictated by a careful assessment of the defect's size, location, CSF flow characteristics, and the patient's surgical history.

2. Identify and Manage Underlying Etiology: In all cases of spontaneous CSF rhinorrhea, a high index of suspicion for elevated ICP must be maintained and investigated. Failure to diagnose and effectively manage underlying conditions like IIH is a primary and preventable cause of surgical failure, irrespective of the reconstructive technique employed.

3. Contextualize the Role of Fibrin Sealants: Fibrin sealants should be viewed as an optional surgical adjunct, not an essential component for preventing recurrence. Their primary utility is as a temporary bio-adhesive to aid in the initial placement and stabilization of avascular free grafts. Their use remains a matter of surgeon preference and should not be relied upon to ensure the long-term success of the repair.

4. Future Research: While current evidence is compelling, there remains a need for large, well-designed prospective randomized controlled trials to definitively confirm these findings and to explore whether sealants may have a niche role in specific, narrowly defined patient subgroups. However, based on the existing body of evidence, it is unlikely that such studies will alter the primary conclusion that structural integrity and pressure management are the true cornerstones of successful CSF rhinorrhea repair.

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